HK1227038B - Anti-cd3 antibodies and methods of use - Google Patents

Description

Anti-CD3 antibodies and methods of use

Field of the Invention

The present invention relates to anti-cluster of differentiation 3 (CD3) antibodies and methods of using the same.

background

Cell proliferative disorders, such as cancer, are characterized by the uncontrolled growth of a subpopulation of cells. They are the leading cause of death in the developed world and the second leading cause of death in the developing world, with more than 12 million new cancer cases diagnosed and 7 million cancer deaths each year. The U.S. National Cancer Institute estimates that more than 500,000 Americans will die from cancer in 2013, accounting for nearly a quarter of the nation's deaths. As the elderly population grows, the incidence of cancer is also rising, as the chance of developing cancer is more than doubled after the age of 70. Cancer care therefore represents a significant and growing burden on society.

Long-term approaches for cancer treatment include chemotherapy, radiotherapy, and surgery to remove solid tumors. Recently, immunotherapies based on bispecific antibodies have been developed. Such bispecific antibodies are able to simultaneously bind to cell surface antigens on cytotoxic cells and tumor cells, with the intention that the bound cytotoxic cells destroy the bound tumor cells. Existing bispecific antibodies currently in clinical trials for cancer treatment are limited by their short half-life and/or uncertain efficacy. Thus, the need for developing effective bispecific antibodies for cancer treatment remains unmet in the art.

Summary of the Invention

The present invention relates to anti-cluster of differentiation 3 (CD3) antibodies and methods of using the same.

In one aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6. In some embodiments, the binding domain comprises (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 184; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 185; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 184. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 185. In some embodiments, the binding domain comprises (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 186; (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 187; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 186. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 187.

In one aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence _of X1 _{X2 YSX3 X4 X5} FDY, wherein _X1 is selected from the group consisting of D, T, and S; _X2 is selected from the group consisting of G, A, and S; _X3 is R or N; _X4 is Y or A; and _X5 is Y or A (SEQ ID NO: 181); (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of _{X1 X2 SX3 X4} LRT, wherein X In some embodiments, the binding domain comprises the following six HVRs: _(a ) HVR- _H1 comprising the amino acid _sequence of SEQ ID NO: 7; (b) HVR- _H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 188; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 189; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 188. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 189.

In other embodiments, the binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 190; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 191; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 190. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 191.

In other embodiments, the binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 192; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 193; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 192. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 193.

In other embodiments, the binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 194; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 195; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 194. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 195.

In other embodiments, the binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 196; (b) a VL domain comprising an amino acid sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 197; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 196. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 197.

In other embodiments, the binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 198; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 199; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 198. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 199.

In other embodiments, the binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 200; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 201; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 200. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 201.

In other embodiments, the binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 202; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 203; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 202. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 203.

In other embodiments, the binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 204; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 205; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 204. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 205.

In other embodiments, the binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 206; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 207; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 206. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 207.

In some aspects, the invention features an anti-CD3 antibody comprising a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 188 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 189; (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 190 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 191; (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 192 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 193; (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 194 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 195; (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 196 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 197; (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 198 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: NO: 199; (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 200 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 201; (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 202 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 203; (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 204 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 205; or (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 206 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 207.

In some aspects, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding _domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino _acid sequence _{of LINPYKGVX1TYX2X3X4X5KX6} , wherein _X1 is S or T; _X2 is N _or A; _X3 is Q or D; _X4 is K or S; _X5 is F or V; _{and X6} is D or G (SEQ ID NO: 183); (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28. In some embodiments, the binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 208; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 209; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 208. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 209.

In other embodiments, the binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 210; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 211; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 210. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 211.

In other embodiments, the binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 212; (b) a VL domain comprising an amino acid sequence that has at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 213; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 212. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 213.

In some aspects, the invention features an anti-CD3 antibody comprising a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 208 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 209; (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 210 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 211; or (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 212 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 213.

In some aspects, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:36. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 214; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 215; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 214. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 215. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 216; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 217; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 216. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO:217.

In some aspects, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 214 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 215; or (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 216 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 217.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:42. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 218; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 219; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 218. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 219. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 220; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 221; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 220. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO:221.

In some aspects, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 218 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 219; or (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 220 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 221.

In some aspects, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:48. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 222; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 223; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 222. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 223. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 224; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO: 225; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 224. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 225. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 226; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 227; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 226. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 227.

In some aspects, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 222 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 223; (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 224 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 225; (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 226 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 227.

In some aspects, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:54. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 228; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 229; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 228. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 229. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 230; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 231; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 230. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO:231.

In some aspects, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 228 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 229; or (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 230 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 231.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:60. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 232; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 233; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 232. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 233.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 232 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 233.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:66. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 234; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 235; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 234. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 235.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 234 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 235.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 236; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 237; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 236. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 237.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 236 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 237.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:78. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 238; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 239; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 238. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 239.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 238 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 239.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:84. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 240; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 241; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 240. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 241.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 240 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 241.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:90. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 242; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 243; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 242. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 243.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 242 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 243.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:96. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 244; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 245; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 244. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 245.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 244 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 245.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:102. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 246; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 247; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 246. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 247.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 246 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 247.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 248; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 249; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 248. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 249.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 248 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 249.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 250; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 251; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 250. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 251.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 250 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 251.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 252; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 253; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 252. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 253.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 252 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 253.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 254; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 255; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 254. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 255.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 254 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 255.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 256; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 257; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 256. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 257.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 256 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 257.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 258; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 259; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 258. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 259.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 258 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 259.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 260; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 261; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 260. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 261.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 260 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 261.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 262; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 263; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 262. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 263.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 262 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 263.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 264; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 265; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 264. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 265.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 264 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 265.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody binds to an epitope on CD3 comprising amino acid residue Glu6 of CD3. In certain aspects, the invention features an anti-CD3 antibody, wherein the epitope further comprises one or more additional amino acid residues selected from the group consisting of Gln1, Asp2, and Met7 of CD3. In another aspect, the invention features an anti-CD3 antibody, wherein the epitope further comprises amino acid residues Gln1, Asp2, and Glu6 of CD3. In certain aspects, the invention features an anti-CD3 antibody, wherein the epitope comprises amino acid residues Gln1, Asp2, Glu6, and Met7 of CD3. In another aspect, the invention features an anti-CD3 antibody, wherein the epitope does not comprise amino acid residue Glu5 of CD3. In another aspect, the invention features an anti-CD3 antibody, wherein the epitope does not comprise amino acid residues Gly3 and Glu5 of CD3. In certain aspects, the invention features an anti-CD3 antibody, wherein the epitope consists of amino acid residues Gln1, Asp2, Glu6, and Met7 of CD3.

In a related aspect, the invention features an anti-CD3 antibody that binds to such an epitope and is a multispecific antibody. In some embodiments, the multispecific antibody is a bispecific antibody. In some embodiments, the bispecific antibody comprises a second binding domain that can bind to a second biomolecule, wherein the second biomolecule is a cell surface antigen. In some embodiments, the cell surface antigen is a tumor antigen. In some embodiments, the tumor antigen is selected from the group consisting of: CD20; FcRH5 (Fc receptor-like protein 5); HER2; LYPD1; Ly6G6D (lymphocyte antigen 6 complex, locus G61); Ly6-D; MEGT1); PMEL17 (silver homolog; SILV; D12S53E; PMEL17; (SI); (SIL); ME20; gp100); Ly6E (lymphocyte antigen 6 complex, locus E; Ly67, RIG-E, SCA-2, TSA-1); CD19; CD33; CD22 (B cell receptor CD22-B isoform); CD79a (CD79A, CD79a, immunoglobulin-related protein alpha; BMPR1B (bone marrow type IB receptor); shaped protein receptor); CD79b (CD79B, CD79β, 1Gb (immunoglobulin-related protein β), B29); EDR (exotropin A receptor); GFRA1 (GDNF-Ra1); MRP4 (multidrug resistance protein 4); RET; STEAP1 (six-transmembrane epithelial antigen of the prostate); TENB2 (putative transmembrane proteoglycan); E16 (LAT1, SLC7A5); 0772P (CA125, MUC16); MPF (MPF, MSLN, SMR, megakaryocyte-stimulating factor, mesothelin); Napi2b (NAPI-2B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate) member 2, sodium-dependent phosphate transporter type II 3b); Sema 5b; PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 genes); ETBR (endothelin type B receptor); MSG783 (RNF124, hypothetical protein FLJ20315); STEAP2; TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel protein subfamily M member 4); CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratoma-derived growth factor); CD21 (CR2 (complement receptor 2) or C3D R (C3d/Epstein-Barr virus receptor) or Hs.73792); FcRH2 (IFGP4, IRTA4, SPAP1A (phosphatase anchoring protein containing SH2 domain 1a), SPAP1B, SPAP1C); NCA; MDP; IL20Rα; brevirin; EphB2R; ASLG659; PSCA; GEDA; BAFF-R (B cell activating factor receptor, BLyS receptor 3, BR3); CXCR5 (Bertge's lymphoma receptor 1); HLA-DOB (MHC class II molecule beta subunit); P2X5 (purinergic receptor P2X ligand-gated ion channel 5; CD72 (B cell differentiation antigen CD72, Lyb-2); LY64 (lymphocyte antigen 64 (RP105), leucine-rich repeat (LRR) family type I membrane protein); FcRH1 (Fc receptor-like protein 1); IRTA2 (immunoglobulin superfamily receptor translocation-associated protein 2); TMEFF1; TMEM46 (shisa homolog 2 (African Xenopus); SHISA2); LGR5 (leucine-rich repeat-containing G protein-coupled receptor 5; GPR49, GPR67); LY6K (lymphocyte antigen 6 complex, locus K; LY6K; HSJ001348; FLJ35226); GPR19 (G protein-coupled receptor 19; Mm 4787); GPR54 (KISS1 receptor; KISS1R; GPR54; HOT7T175; AXOR12); ASPHD1 (aspartate beta-hydroxylase domain-containing protein 1; LOC253982); tyrosinase (TYR; OCAIA; OCA1A; tyrosinase; SHEP3); TMEM118 (RING finger protein, transmembrane protein 2; RNFT2; FLJ14627); GPR172A (G protein-coupled receptor 172A; GPCR41; FLJ11856; D15Ertd74) 7e); GPC3 (glypican 3); CLL1 (C-type lectin-like molecule 1); B7-H4 (B7x; B7S1); RNF43 (RING finger protein 43); CD70; CXORF61 (chromosome X open reading frame 61); HAVCR1; epiregulin; amphiregulin; EGFR; EGFR-L858R; EGFR-L861Q; EGFR-G719A; EGFR-G719S; EGFR-G719C; EGFR-T790M; EGFR-S768I; adipose differentiation-related Adipophilin; AIM-2; ALDH1A1; α-actinin-4; α-fetoprotein; ARTC1; B-RAF; BAGE-1; BCLX(L); BCR-ABL fusion protein (b3a2); β-catenin; BING-4; CALCA; CASP-5; CASP-8; CD45; Cdc27; CDK4; CDKN2A; CEA; CLPP; COA-1; CPSF; Cw6; cyclin D1; cyclin A1; dek-can fusion protein; DK K1; DR1; DR13; EFTUD2; elongation factor 2; ENAH (hMena); EpCAM; EphA3; ETV6-AML1 fusion protein; EZH2; FLT3-ITD; FN1; G250; MN; CAIX; GAGE-1; 2; 8; GAGE-3; 4; 5; 6; 7; glypican-3; GnTVf; gp100/Pmel17; GPNMB; HERV-K-MEL; hsp70-2; IDO1; IGF2B3; IL13Rα2; intestinal carboxylate enzymes; K-ras; vascular kallikrein 4; KIF20A; KK-LC-1; KM-HN-1; LAGE-1; LDLR-fucosyltransferase AS fusion protein; Lengsin; M-CSF; MAGE-A1; MAGE-A10; MAGE-A12; MAGE-A2; MAGE-A3; MAGE-A4; MAGE-A6; MAGE-A9; MAGE-C1; MAGE-C2; mammaglobin A; MART2; MCSP; mdm-2; ME1; Melan-A/ MART-1; Meloe; MMP-2; MMP-7; MUC1; MUC5AC; mucin; MUM-1f; MUM-2; MUM-3; class I myosin; N-ras; NA88-A; neo-PAP; NFYC; NY-BR-1; NY-ESO-1/LAGE-2; OA1; OGT; OS-9; p53; PAP; PAX5; PBF; pml-RARα fusion protein; PRAME; PRDX5; PSMA; PTPRK; RAB38/NY-MEL-1; RAG E-1; RBAF600; RGS5; RhoC; RNF43; RU2AS; SAGE; sequestering protein 1; SIRT2; SNRPD1; SOX10; Sp17; SSX-2; SSX-4; STEAP1; survivin; SYT-SSX1 or SYT-SSX2 fusion protein; TAG-1; TAG-2; telomerase; TGF-βRII; TRAG-3; triosephosphate isomerase; TRP-1/gp75; TRP-2; TRP2-INT2; tyrosinase; VEGF; WT1; XA GE-1b/GAGED2a; and SLC53SLC35D3. In some embodiments, the tumor antigen is selected from the group consisting of CD20, FcRH5, HER2, LYPD1, LY6G6D, PMEL17, LY6E, CD19, CD33, CD22, CD79A, CD79B, EDAR, GFRA1, MRP4, RET, Steap1, and TenB2. In preferred embodiments, the tumor antigen is selected from the group consisting of CD20, HER2, FcRH5, and LYPD1.

In some embodiments, the binding domain of any of the foregoing anti-CD3 antibodies binds to a human CD3 polypeptide or a cynomolgus monkey (cyno) CD3 polypeptide. In some embodiments, the human CD3 polypeptide or the cyno CD3 polypeptide is a human CD3ε polypeptide or a cyno CD3ε polypeptide, respectively. In some embodiments, the human CD3 polypeptide or the cyno CD3 polypeptide is a human CD3γ polypeptide or a cyno CD3γ polypeptide, respectively.

In some embodiments, any of the foregoing anti-CD3 antibodies binds to the human CD3ε polypeptide with a Kd of 250 nM or less. In some embodiments, the anti-CD3 antibody binds to the human CD3ε polypeptide with a Kd of 100 nM or less. In some embodiments, the anti-CD3 antibody binds to the human CD3ε polypeptide with a Kd of 15 nM or less. In some embodiments, the anti-CD3 antibody binds to the human CD3ε polypeptide with a Kd of 10 nM or less. In some embodiments, the anti-CD3 antibody binds to the human CD3ε polypeptide with a Kd of 5 nM or less.

In some embodiments, any of the aforementioned anti-CD3 antibodies may comprise a deglycosylation site mutation. In some embodiments, the deglycosylation site mutation is a substitution mutation. In some embodiments, the substitution mutation is at amino acid residues N297, L234, L235, and/or D265 (EU numbering). In some embodiments, the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, and D265A. In some embodiments, the substitution mutation is an N297G mutation. In some embodiments, the deglycosylation site mutation reduces the effector function of the anti-CD3 antibody. In some embodiments, the deglycosylation site mutation reduces the effector function of the anti-CD3 antibody. In some embodiments, the anti-CD3 antibody comprises a substitution mutation in the Fc region that can reduce effector function.

In some embodiments, any of the aforementioned anti-CD3 antibodies may be a monoclonal antibody, a human antibody, a humanized antibody, or a chimeric antibody. In some embodiments, any of the aforementioned anti-CD3 antibodies may be an antibody fragment that binds to CD3. In some embodiments, the antibody fragment is selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab') ₂ fragments. In other embodiments, the anti-CD3 antibody is a full-length antibody. In some embodiments, the anti-CD3 antibody is an IgG antibody (e.g., IgG1, IgG2, or IgG3 antibody). In some embodiments, the anti-CD3 antibody is a monospecific antibody. In some embodiments, the anti-CD3 antibody is a bispecific T cell engager antibody.

In some embodiments, the anti-CD3 antibody is a multispecific antibody. In some embodiments, the multispecific antibody is a bispecific antibody. In some embodiments, the bispecific antibody comprises a second binding domain that binds to a second biomolecule, wherein the second biomolecule is a cell surface antigen. In some embodiments, the cell surface antigen is a tumor antigen. In some embodiments, the tumor antigen is selected from the group consisting of: CD20; FcRH5 (Fc receptor-like protein 5); HER2; LYPD1; Ly6G6D (lymphocyte antigen 6 complex, locus G61); Ly6-D, MEGT1); PMEL17 (silver homolog; SILV; D12S53E; PMEL17; (SI); (SIL); ME20; gp100); Ly6E (lymphocyte antigen 6 complex, locus E; Ly67, RIG-E, SCA-2, TSA-1); CD19; CD33; CD22 (B cell receptor CD22-B isoform); CD79a (CD79A, CD79a, immunoglobulin-related protein alpha; BMPR1B (bone marrow type IB homolog); shaped protein receptor); CD79b (CD79B, CD79β, 1Gb (immunoglobulin-related protein β), B29); EDR (exotropin A receptor); GFRA1 (GDNF-Ra1); MRP4 (multidrug resistance protein 4); RET; STEAP1 (six-transmembrane epithelial antigen of the prostate); TENB2 (putative transmembrane proteoglycan); E16 (LAT1, SLC7A5); 0772P (CA125, MUC16); MPF (MPF, MSLN, SMR, megakaryocyte-stimulating factor, mesothelin); Napi2b (NAPI-2B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate) member 2, sodium-dependent phosphate transporter type II 3b); Sema 5b; PSCA hlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 genes); ETBR (endothelin type B receptor); MSG783 (RNF124, hypothetical protein FLJ20315); STEAP2; TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel protein subfamily M member 4); CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratoma-derived growth factor); CD21 (CR2 (complement receptor 2) or C3DR (C3d/Epstein-Barr virus receptor) or Hs.73792); FcRH2 (IFGP4, IRTA4, SPAP1A (phosphatase anchoring protein containing SH2 domain 1a), SPAP1B, SPAP1C); NCA; MDP; IL20Rα; brevirin; EphB2R; ASLG659; PSCA; GEDA; BAFF-R (B cell activating factor receptor, BLyS receptor 3, BR3); CXCR5 (Bertge's lymphoma receptor 1); HLA-DOB (MHC class II molecule beta subunit); P2X5 (purinergic receptor P2X ligand-gated ion channel 5; CD72 (B cell differentiation antigen CD72, Lyb-2); LY64 (lymphocyte antigen 64 (RP105), leucine-rich repeat (LRR) family type I membrane protein); FcRH1 (Fc receptor-like protein 1); IRTA2 (immunoglobulin superfamily receptor translocation-associated protein 2); TMEFF1; TMEM46 (shisa homolog 2 (African Xenopus); SHISA2); LGR5 (leucine-rich repeat-containing G protein-coupled receptor 5; GPR49, GPR67); LY6K (lymphocyte antigen 6 complex, locus K; LY6K; HSJ001348; FLJ35226); GPR19 (G protein-coupled receptor 19; Mm 4787); GPR54 (KISS1 receptor; KISS1R; GPR54; HOT7T175; AXOR12); ASPHD1 (aspartate beta-hydroxylase domain-containing protein 1; LOC253982); tyrosinase (TYR; OCAIA; OCA1A; tyrosinase; SHEP3); TMEM118 (RING finger protein, transmembrane protein 2; RNFT2; FLJ14627); GPR172A (G protein-coupled receptor 172A; GPCR41; FLJ11856; D 15Ertd747e); GPC3 (glypican 3); CLL1 (C-type lectin-like molecule 1); B7-H4 (B7x; B7S1); RNF43 (RING finger protein 43); CD70; CXORF61 (chromosome X open reading frame 61); HAVCR1; epiregulin; amphiregulin; EGFR; EGFR-L858R; EGFR-L861Q; EGFR-G719A; EGFR-G719S; EGFR-G719C; EGFR-T790M; E GFR-S768I; adipose differentiation-related protein; AIM-2; ALDH1A1; α-actinin-4; α-fetoprotein; ARTC1; B-RAF; BAGE-1; BCLX(L); BCR-ABL fusion protein (b3a2); β-catenin; BING-4; CALCA; CASP-5; CASP-8; CD45; Cdc27; CDK4; CDKN2A; CEA; CLPP; COA-1; CPSF; Cw6; cyclin D1; cyclin A1; dek -can fusion protein; DKK1; DR1; DR13; EFTUD2; elongation factor 2; ENAH (hMena); EpCAM; EphA3; ETV6-AML1 fusion protein; EZH2; FLT3-ITD; FN1; G250; MN; CAIX; GAGE-1; 2; 8; GAGE-3; 4; 5; 6; 7; glypican-3; GnTVf; gp100/Pmel17; GPNMB; HERV-K-MEL; hsp70-2; IDO1; IGF2B3; IL13Rα2; intestinal carboxylesterase; K-ras; vasokallikrein 4; KIF20A; KK-LC-1; KM-HN-1; LAGE-1; LDLR-fucosyltransferase AS fusion protein; Lengsin; M-CSF; MAGE-A1; MAGE-A10; MAGE-A12; MAGE-A2; MAGE-A3; MAGE-A4; MAGE-A6; MAGE-A9; MAGE-C1; MAGE-C2; mammaglobin A; MA RT2; MCSP; mdm-2; ME1; Melan-A/MART-1; Meloe; MMP-2; MMP-7; MUC1; MUC5AC; mucin; MUM-1f; MUM-2; MUM-3; class I myosin; N-ras; NA88-A; neo-PAP; NFYC; NY-BR-1; NY-ESO-1/LAGE-2; OA1; OGT; OS-9; p53; PAP; PAX5; PBF; pml-RARα fusion protein; PRAME; PRDX5; PSMA; PTPRK; RAB38/NY-MEL-1; RAGE-1; RBAF600; RGS5; RhoC; RNF43; RU2AS; SAGE; sequestering protein 1; SIRT2; SNRPD1; SOX10; Sp17; SSX-2; SSX-4; STEAP1; survivin; SYT-SSX1 or SYT-SSX2 fusion protein; TAG-1; TAG-2; telomerase; TGF-βRII; TRAG-3; triosephosphate isomerase; TRP-1/gp75; TRP-2; TRP2-INT2; tyrosinase; VEGF; WT1; XAGE-1b/GAGED2a; and SLC35D3. In some embodiments, the tumor antigen is selected from the group consisting of: CD20, FcRH5, HER2, LYPD1, LY6G6D, PMEL17, LY6E, CD19, CD33, CD22, CD79A, CD79B, EDAR, GFRA1, MRP4, RET, Steap1, and TenB2.

In some embodiments, the tumor antigen is CD20 and the second binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162. In some embodiments, the second binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 266. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 267.

In some embodiments, the tumor antigen is FcRH5 and the second binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168. In some embodiments, the second binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 268. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 269.

In some embodiments, the tumor antigen is HER2 and the second binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174. In some embodiments, the second binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 270. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 271.

In some embodiments, the tumor antigen is HER2 and the second binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586. In some embodiments, the second binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 593. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 594.

In some embodiments, the tumor antigen is HER2 and the second binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592. In some embodiments, the second binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 595. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 596.

In some embodiments, the tumor antigen is RET and the second binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618. In some embodiments, the second binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 619; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 620; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 619. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 620.

In some embodiments, the tumor antigen is LYPD1 and the second binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180. In some embodiments, the second binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 272. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 273.

In some aspects, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises a second binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 266 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 267; (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 268 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 269; (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 270 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 271; (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 272 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 273; (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 593 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 594; (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 595 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: NO: 596; or (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 619 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 620.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises an anti-CD3 arm comprising a first binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6; and an anti-CD20 arm comprising a second binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: NO:159; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:160; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:161; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:162.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises an anti-CD3 arm comprising a first binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 184 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 185; and an anti-CD20 arm comprising a second binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 266 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 267.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises an anti-CD3 arm comprising a first binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 184 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 185; and an anti-CD20 arm comprising a second binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 266 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 267, wherein the anti-CD3 antibody comprises an N297G substitution mutation.

In another aspect, the invention features an anti-CD3 antibody, wherein the anti-CD3 antibody comprises an anti-CD3 arm comprising a first binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 184 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 185; and an anti-CD20 arm comprising a second binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 266 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 267, wherein (a) the anti-CD3 arm comprises T366S, L368A, Y407V, and N297G substitution mutations, and (b) the anti-CD20 arm comprises T366W and N297G substitution mutations.

In some embodiments, any of the aforementioned anti-CD3 antibodies may comprise one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 ( _CH11 ) domain, a first CH2 ( _CH21 ) domain, a first CH3 ( _CH31 ) domain, a second CH1 ( _CH12 ) domain, a second CH2 ( _CH22 ) domain, and a second CH3 ( _CH32 ) domain. In some embodiments, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some embodiments, the _CH31 domain and the _CH32 domain each comprise a protuberance or a cavity, and the protuberance or cavity in the _CH31 domain may be located in the cavity or protuberance in the _CH32 domain, respectively. In some embodiments, the _CH31 domain and the _CH32 domain contact each other at the interface between the protuberance and the cavity. In some embodiments, the _CH2.1 domain and the _CH2.2 domain each comprise a protuberance or a cavity, and the protuberance or cavity in the _CH2.1 domain can be located in the cavity or protuberance in the _CH2.2 domain, respectively. In some embodiments, the _CH2.1 domain and the _CH2.2 domain contact each other at the interface between the protuberance and the cavity.

In some embodiments, any of the foregoing anti-CD3 antibodies may have a half-life of about 7 days.

In some embodiments, the present invention features an immunoconjugate comprising any of the aforementioned anti-CD3 antibodies conjugated to a cytotoxic agent. A composition comprising any of the aforementioned anti-CD3 antibodies is also provided. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition further comprises a PD-1 axis binding antagonist or another therapeutic agent. In another aspect, the present invention features an isolated nucleic acid encoding any of the anti-CD3 antibodies disclosed herein, comprising a vector (e.g., an expression vector) for expressing the antibody.

In another aspect, the invention features a host cell comprising the aforementioned nucleic acid and/or vector. In some embodiments, the host cell is a mammalian cell (e.g., a Chinese hamster ovary (CHO) cell). In other embodiments, the host cell is a prokaryotic cell (e.g., an E. coli cell). Also provided is a method of producing any of the aforementioned anti-CD3 antibodies, the method comprising culturing a host cell capable of producing the anti-CD3 antibody and recovering the anti-CD3 antibody from the host cell or culture medium.

In some aspects, any of the aforementioned anti-CD3 antibodies can be used as a medicament. In some embodiments, any of the aforementioned anti-CD3 antibodies can be used to treat or delay the progression of a cell proliferative disorder or an autoimmune disorder in an individual in need thereof. In some embodiments, any of the aforementioned anti-CD3 antibodies can be used to enhance immune function in an individual suffering from a cell proliferative disorder or an autoimmune disorder.

In some aspects, the invention features the use of any of the aforementioned anti-CD3 antibodies for the manufacture of a medicament for treating or delaying progression of a cell proliferative disorder or an autoimmune disorder. In some aspects, the invention features the use of any of the aforementioned anti-CD3 antibodies for the manufacture of a medicament for enhancing immune function in an individual with a cell proliferative disorder or an autoimmune disorder.

Another aspect of the present invention is a method for treating a cell proliferative disorder or an autoimmune disorder or delaying its progression in an individual in need thereof, the method comprising administering to the individual any one of the aforementioned anti-CD3 antibodies of an effective amount. In another aspect, the present invention is characterized by a method for enhancing immune function in an individual suffering from a cell proliferative disorder or an autoimmune disorder, the method comprising administering to the individual any one of the aforementioned anti-CD3 antibodies. In some embodiments, the anti-CD3 antibody binds to (a) a CD3 molecule located on an immune effector cell and (b) a second biomolecule located on a target cell other than the immune effector cell. In some embodiments, the anti-CD3 antibody activates the immune effector cell after binding (a) and (b). In some embodiments, the activated immune effector cell is able to exert a cytotoxic effect and/or apoptotic effect on the target cell. In some embodiments, the anti-CD3 antibody is administered to the individual at a dosage of about 0.01 mg/kg to about 10 mg/kg. In some embodiments, the anti-CD3 antibody is administered to the individual at a dosage of about 0.1 mg/kg to about 10 mg/kg. In some embodiments, the anti-CD3 antibody is administered to the subject at a dose of about 1 mg/kg. In some embodiments, the anti-CD3 antibody is administered subcutaneously, intravenously, intramuscularly, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some embodiments, the anti-CD3 antibody is administered subcutaneously. In some embodiments, the anti-CD3 antibody is administered intravenously.

In some embodiments, the method further comprises administering a PD-1 axis binding antagonist or another therapeutic agent to the individual. In some embodiments, the other therapeutic agent is administered before or after the administration of the anti-CD3 antibody. In some embodiments, the other therapeutic agent is administered simultaneously with the anti-CD3 antibody. In some embodiments, the PD-1 axis binding antagonist is selected from the group consisting of a PD-1 binding antagonist, a PD-L1 binding antagonist, and a PD-L2 binding antagonist. In some embodiments, the PD-1 axis binding antagonist is a PD-1 binding antagonist. In some embodiments, the PD-1 binding antagonist is selected from the group consisting of MDX-1106 (nivolumab), MK-3475 (lambrolizumab), CT-011 (pidilizumab), and AMP-224. In other embodiments, the PD-1 axis binding antagonist is a PD-L1 binding antagonist. In some embodiments, the PD-L1 binding antagonist is selected from the group consisting of: YW243.55.S70, MPDL3280A, MDX-1105, and MEDI4736. In other embodiments, the PD-1 axis binding antagonist is a PD-L2 binding antagonist. In some embodiments, the PD-L2 binding antagonist is an antibody or an immunoadhesin.

In some aspects, the invention features a method of treating or delaying progression of a cell proliferative disorder or an autoimmune disorder in an individual in need thereof, the method comprising administering to the individual an anti-CD3 antibody and a PD-1 axis binding antagonist, wherein the anti-CD3 antibody comprises an anti-CD3 arm and an anti-CD20 arm. In some aspects, the invention features a method of enhancing immune function in an individual with a cell proliferative disorder or an autoimmune disorder, the method comprising administering to the individual an anti-CD3 antibody and a PD-1 axis binding antagonist, wherein the anti-CD3 antibody comprises an anti-CD3 arm and an anti-CD20 arm (i.e., CD20 TDB). In some embodiments, (a) the anti-CD3 arm comprises a first binding domain comprising (i) a VH domain comprising the amino acid sequence of SEQ ID NO: 184 and (ii) a VL domain comprising the amino acid sequence of SEQ ID NO: 185; (b) the anti-CD20 arm comprises a second binding domain comprising (i) a VH domain comprising the amino acid sequence of SEQ ID NO: 266 and (ii) a VL domain comprising the amino acid sequence of SEQ ID NO: 267; and/or (c) the PD-1 axis binding antagonist is an anti-PD-L1 antibody.

In some embodiments, the anti-CD3 antibody comprises an anti-CD20 arm comprising an N297G substitution mutation. In some embodiments, the anti-CD3 antibody comprises an anti-CD3 arm comprising a T366S, L368A, Y407V and/or N297G substitution mutation and an anti-CD20 arm comprising a T366W and/or N297G substitution mutation. In some embodiments, the anti-CD3 antibody comprises an anti-CD3 arm comprising an N297G substitution mutation. In some embodiments, the anti-CD3 antibody comprises an anti-CD20 arm comprising a T366S, L368A, Y407V and/or N297G substitution mutation and an anti-CD3 arm comprising a T366W and/or N297G substitution mutation.

In some embodiments, the anti-CD3 antibody comprises an anti-HER2 arm comprising an N297G substitution mutation. In some embodiments, the anti-CD3 antibody comprises an anti-CD3 arm comprising a T366S, L368A, Y407V and/or N297G substitution mutation and an anti-HER2 arm comprising a N297G, N297A, L234A, L235A and/or D265A substitution mutation. In some embodiments, the anti-CD3 antibody comprises an anti-CD3 arm comprising an N297G substitution mutation. In some embodiments, the anti-CD3 antibody comprises an anti-HER2 arm comprising a T366S, L368A, Y407V and/or N297G substitution mutation and an anti-CD3 arm comprising a N297G, N297A, L234A, L235A and/or D265A substitution mutation.

In some embodiments, the method further comprises administering a glucocorticoid to the individual. In some embodiments, the glucocorticoid is selected from the group consisting of: dexamethasone, hydrocortisone, cortisone, prednisolone, prednisone, methylprednisone, triamcinolone, paramethasone, betamethasone, fludrocortisone, and pharmaceutically acceptable esters, salts, and complexes thereof. In some embodiments, the glucocorticoid is dexamethasone. In some embodiments, the glucocorticoid is a pharmaceutically acceptable ester, salt, or complex of dexamethasone.

In some embodiments, the method further comprises administering rituximab to the individual.

In some embodiments, the method further comprises administering obinutuzumab to the individual.

In some embodiments, the method further comprises administering to the individual an antibody-drug conjugate (ADC).

In any of the aforementioned uses or methods, the cell proliferative disorder can be cancer. In some embodiments, the cancer is selected from the group consisting of breast cancer, colorectal cancer, non-small cell lung cancer, non-Hodgkin's lymphoma (NHL), B cell lymphoma, B cell leukemia, multiple myeloma, kidney cancer, prostate cancer, liver cancer, head and neck cancer, melanoma, ovarian cancer, mesothelioma, glioblastoma, germinal center B cell-like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), Small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrom's macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt's lymphoma (BL), B-cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, unclassified splenic lymphoma/leukemia, splenic diffuse red pulp small B-cell lymphoma, hairy cell leukemia variant, Waldenstrom's macroglobulinemia, heavy chain disease, alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasma cell Myeloma, solitary plasmacytoma of bone, extraskeletal plasmacytoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma, pediatric nodular marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicle center lymphoma, T cell/histiocyte-rich large B cell lymphoma, primary DLBCL of the CNS, primary cutaneous DLBCL leg type, EBV-positive DLBCL of the elderly, DLBCL associated with chronic inflammation, lymphomatoid granulomatosis, primary Mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman's disease, primary effusion lymphoma: unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma, and unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin's lymphoma. In some embodiments, the preferred cancer is germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrom's macroglobulinemia (WM), central nervous system lymphoma (CNSL), or Burkitt's lymphoma (BL).

In any of the aforementioned uses or methods, the autoimmune disorder may be selected from the group consisting of rheumatoid arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus (SLE), Wegener's disease, inflammatory bowel disease, idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), autoimmune thrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgM polyneuropathy, myasthenia gravis, vasculitis, diabetes, Reynaud's syndrome, Sjorgen's syndrome, glomerulonephritis, neuromyelitis optica (NMO), and IgG neuropathy.

In another aspect, the invention features a kit comprising: (a) a composition comprising any of the aforementioned anti-CD3 antibodies and (b) a package insert including instructions for administering the composition to a subject to treat or delay progression of a cell proliferative disorder.

In any of the aforementioned uses or methods, the subject may be a human.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 shows the amino acid sequence of single-chain human CD3εγ with a 26-mer linker sequence (SEQ ID NO: 282) used in CD3 epitope mapping experiments.

Figure 2A is a table summarizing the characterization results of selected hybridoma clones. The table summarizes the results of the following experiments: ELISA CD3 binding assay using human and cyno CD3ε ^1-27 -Fc; FACS binding assay using human Jurkat T cells, human PBMCs, and cynoPBMCs; T cell activation assay using FACS analysis; and isotype determination assay.

FIG2B is a table summarizing the binding affinities (Kd values) of selected hybridoma clones to commercially available human CD3εγ antigen.

Figure 3A is a table summarizing the characterization results of selected hybridomas. The table summarizes the results of the following experiments: ELISA CD3 binding assay using human and cyno CD3ε ^1-27 -Fc; FACS binding assay using human Jurkat T cells, human PBMCs, and cyno PBMCs; T cell activation assay using FACS analysis; and isotype determination assay.

FIG3B and FIG3C are tables summarizing the binding affinities (Kd values) of selected hybridoma clones.

Figure 4A shows the amino acid sequences of the light chain variable domains of anti-CD3 antibodies. For each antibody, the HVR sequences are defined by indicated boxes.

FIG4B shows the amino acid sequence of the light chain variable domain of the anti-CD3 antibody.

FIG4C shows the amino acid sequence of the heavy chain variable domain of the anti-CD3 antibody.

FIG5A shows the amino acid sequence of the light chain variable domain of an anti-CD3 antibody.

FIG5B shows the amino acid sequence of the heavy chain variable domain of the anti-CD3 antibody.

FIG6A shows the amino acid sequences of the light chain variable domains of the anti-CD3 antibodies 21A9 and Rab17.

FIG6B shows the amino acid sequences of the heavy chain variable domains of the anti-CD3 antibodies 21A9 and Rab17.

FIG7 is a sequence alignment of the amino acid sequences of the light chain variable domain (top) and the heavy chain variable domain (bottom) of anti-CD3 antibodies, which shows that the consensus sequence 40G5c is derived from related cloned antibodies.

FIG8A is a sequence alignment of the amino acid sequences of the light chain variable domain (top) and heavy chain variable domain (bottom) of the anti-CD3 antibody 13A3 and its humanized variant (hu13A3).

FIG8B is a sequence alignment of the amino acid sequences of the light chain variable domain (top) and heavy chain variable domain (bottom) of the anti-CD3 antibody 30A1 and its humanized variant (hu30A1).

Figure 8C is a sequence alignment of the amino acid sequences of the light chain variable domain (top) and heavy chain variable domain (bottom) of the anti-CD3 antibody 41D9a and its humanized variant (hu41D9a).

FIG8D is a sequence alignment of the amino acid sequences of the light chain variable domain (top) and heavy chain variable domain (bottom) of the anti-CD3 antibody SP34 and its humanized variant (huSP34).

Figure 8E is a sequence alignment of the amino acid sequences of the light chain variable domain (top) and heavy chain variable domain (bottom) of the anti-CD3 antibody 38E4 and its humanized variant (hu38E4).

Figure 8F is a sequence alignment of the amino acid sequences of the light chain variable domain (top) and heavy chain variable domain (bottom) of the anti-CD3 antibody 40G5 and its humanized variant (hu40G5).

Figure 9A is a table summarizing selected humanized variants of the anti-CD3 antibody 13A3 and their binding affinities determined using commercially available CD3 epsilon (Creative Biomart, Shirley, NY; Catalog No. CD3E-2194H).

Figure 9B is a table summarizing selected humanized variants of the anti-CD3 antibody 30A1 and their binding affinities determined using commercially available CD3ε (Creative Biomart, Shirley, NY; Catalog No. CD3E-2194H).

Figure 9C is a table summarizing selected humanized variants of the anti-CD3 antibody 41D9a and their binding affinities determined using commercially available CD3ε (Creative Biomart, Shirley, NY; Catalog No. CD3E-2194H).

Figure 9D is a table summarizing selected humanized variants of the anti-CD3 antibody SP34 and their binding affinities determined using commercially available CD3ε (Creative Biomart, Shirley, NY; Catalog No. CD3E-2194H).

Figure 9E is a table summarizing selected humanized variants of the anti-CD3 antibody 38E4 and their binding affinities determined using commercially available CD3ε (Creative Biomart, Shirley, NY; Catalog No. CD3E-2194H).

Figure 9F is a table summarizing selected humanized variants of the anti-CD3 antibody 40G5c and their binding affinities determined using commercially available CD3ε (Creative Biomart, Shirley, NY; Catalog No. CD3E-2194H).

FIG10 is a table summarizing the binding affinities of humanized anti-CD3 antibodies to various CD3ε antigens.

Figure 11 is a table summarizing the binding affinities of humanized anti-CD3 antibodies 38E4v1 to 38E4v9 and 40G5c as measured by Biacore using human CD3 epsilon gamma on-chip and in flow-through format using anti-CD3 antibodies.

Figure 12A is a table summarizing the relative binding affinities of single alanine, serine, threonine, or glutamate mutants of humanized anti-CD3 antibody 38E4v1 having single mutations in HVR-L3 or HVR-H3 compared to 38E4v1 obtained using single-cycle or conventional multi-cycle kinetic Biacore analysis.

FIG12B shows the amino acid sequences of HVR-L3 (top) and HVR-H3 (bottom) of the humanized anti-CD3 antibody 38E4v1.

Figure 13A is a series of graphs showing relative binding of the indicated anti-CD3 antibodies to alanine variants of CD3ε ^1-27 -Fc.

Figure 13B is a graph showing the relative fraction of CD3εγ alanine scanning phagemid mutants that bind to anti-CD3 antibodies 38E4.v1, 40G5c, and SP34.v52 compared to wild-type CD3εγ phage binding.

Figure 13C is a series of graphs showing relative binding of anti-CD3 antibodies 38E4.v1, 40G5c, and SP34.v52 to selected CD3εγ alanine scanning phagemid mutants as a function of phage concentration.

Figure 13D is a series of tables showing the relative binding affinities of anti-CD3 antibodies SP34.v52 and 38E4v1 to selected CD3εγ alanine scanning mutants as assessed by Biacore. NB = no detectable binding.

Figure 14A shows the sequence of the 16-mer CD3ε polypeptide used in co-crystallization experiments with 38E4.v1 Fab.

Figures 14B-14F are a series of crystal structure renderings showing different views of the hu38E4.v1 Fab/CD3ε peptide complex.

Figure 14G shows an alignment of the amino acid sequences of the light chain variable domain (top) and heavy chain variable domain (bottom) of the anti-CD3 antibodies hu40G5c and hu38E4.v1, with the residues of each antibody important for binding to CD3 circled in the alignment (contact residues). The circled residues were found to be within the CD3 peptide as determined by crystallographic analysis. Δ indicates the cursor position (for references, see, e.g., Foote and Winter, JMB, 224:487, 1992); ^* indicates FW-HVR interactions (for references, see, e.g., Padlan et al., Mol. Immunol. 31:169, 1994); and ● indicates VH-VL interactions (for references, see, e.g., Padlan et al., Mol. Immunol. 31:169, 1994).

Figure 14H is a perspective view of the crystal structure of the CD3ε polypeptide bound by hu38E4.v1 Fab. All antigen-contacting residues are shown in yellow. All contact residues between hu38E4.v1 and hu40G5 are identical, except for G96 (shown in orange), which is S96 in hu40G5.

Figures 14I and 14J are ribbon diagram perspective views of the crystal structures of hu38E4.v1 Fab and SP34v52 Fab, respectively, in the same orientation and overlapping with the VL region, RMS = 2.24.

Figure 14K is a perspective view of a space-filling model of hu38E4.v1 Fab in complex with the CD3ε N-terminal peptide bound in the cleft between the heavy chain (cyan) and light chain (purple).

Figure 14L is a perspective view of a space-filling model of SP34v52 Fab and CD3ε N-terminal peptide superimposed in the same orientation as the CD3ε/hu38E4.v1 Fab complex shown in Figure 14K. Residues R50 and R52 (in orange) of HVR-H2 of SP34v52 Fab are critical for CD3 binding. Significant clashes between the CD3 peptide and SP34v52 Fab are indicated by arrows.

Figure 14M is a perspective view of the crystal structure of hu38E4.v1 in complex with the N-terminal peptide of CD3εγ and illustrates key intermolecular interactions involving the first pyroglutamine residue and the sixth residue (E6) in CD3εγ. Potential hydrogen bonds are shown as dashed lines.

Figure 14N is a perspective view of a space-filling model of the hu38E4.v1 Fab in complex with the CD3εγ N-terminal peptide bound in the cleft between the heavy chain (cyan) and the light chain (purple). As shown, the fifth residue (E5) points away from the interaction site of the sixth residue (E6) containing the CD3εγ N-terminal peptide-Fab complex.

Figure 15 shows a schematic overview of TDB antibody formation. The particular TDB shown is a full-length TDB in a knob-in-hole (KIH) format, which can have a deglycosylation mutation if produced by eukaryotic cells (e.g., CHO cells). In an alternative format, the knob-like structure can be present on the anti-CD3 arm, and the hole-like structure can be present on the anti-tumor antigen arm. If produced by eukaryotic cells (e.g., CHO cells), this format can also have a deglycosylation mutation.

Figure 16 is a graph showing the results of FACS in vitro binding assays of various CD3/CD20 TDBs with different combinations of UCHT1 series anti-CD3 arms and 2H7 series anti-CD20 arms. Bjab B tumor cell line binding (CD20 binding), left. Jurkat cell binding (CD3 binding), right.

Figure 17 is a set of tables summarizing the monovalent (upper) and (bivalent) binding affinities (Kd values) of various CD3/CD20 TDBs having different combinations of UCHT1 series anti-CD3 arms and 2H7 series anti-CD20 arms.

Figure 18 is a graph showing the results of in vitro Jurkat cell binding (CD3 binding) FACS analysis of various CD3/CD20 TDBs having different combinations of anti-CD3 arms with the anti-CD20 arms of 2H7v16.

Figure 19 is a graph showing the results of in vitro Jurkat cell binding (CD3 binding) FACS analysis of various CD3/CD20 TDBs having different combinations of anti-CD3 arms with the anti-CD20 arms of 2H7v16.

Figure 20 is a graph showing the results of in vitro Bjab cell binding (CD20 binding) FACS analysis of various CD3/CD20 TDBs having different combinations of anti-CD3 arms with the anti-CD20 arms of 2H7v16.

Figures 21A and 21B are graphs showing the results of in vitro Jurkat cell binding (CD3 binding) FACS analysis of various CD3/CD20 TDBs having different combinations of anti-CD3 arms and the anti-CD20 arms of 2H7v16.

FIG. 21C is a table summarizing the EC50 (μg/ml) of each CD3/CD20 TDB tested in FIG. 21A and 21B .

Figures 22A and 22B are graphs showing the results of in vitro Bjab cell binding (CD20 binding) FACS analysis of various CD3/CD20 TDBs having different combinations of anti-CD3 arms and the anti-CD20 arms of 2H7v16.

Figure 23 is a graph showing the results of in vitro Jurkat cell binding (CD3 binding) FACS analysis of various CD3/CD20 TDBs having different combinations of anti-CD3 arms with the anti-CD20 arms of 2H7v16.

Figure 24 is a table summarizing the binding affinities of various CD3/CD20 TDBs and Fabs as measured by Biacore analysis using human CD3εγ on-chip and using CD3/CD20 TDB or Fab in flow-through format.

Figure 25A is a graph showing the percentage of T cell activation as measured by CD69 and CD25 surface expression following 24 hours incubation of the indicated CD3/CD20 TDBs (2H7 series) with 20,000 Bjab cells and 5x purified hu CD8+ T cells.

25B is a graph showing the percentage of Bjab killing relative to non-TDB-treated controls following 24 hours of incubation of the indicated CD3/CD20 TDBs (2H7 series) with 20,000 Bjab cells and 5× purified huCD8+ T cells as measured by FACS analysis.

Figure 26A is a graph showing the percentage of T cell activation as measured by CD69 and CD25 surface expression following 24 hours incubation of the indicated CD3/CD20 TDBs (2H7 series) with 200,000 human PBMCs per well.

Figure 26B is a graph showing the percent endogenous (endo) B cell killing relative to non-TDB-treated controls following 24 hours of incubation of the indicated CD3/CD20 TDBs (2H7 series) with 200,000 human PBMCs per well as measured by FACS analysis.

Figure 27A is a graph showing the percentage of T cell activation as measured by CD69 and CD25 surface expression following 24 hours incubation of the indicated CD3/CD20 TDBs (UCHT1 series) with 20,000 Bjab cells and 5x purified hu CD8+ T cells.

27B is a graph showing the percentage of Bjab killing relative to non-TDB-treated controls following 24 hours of incubation of the indicated CD3/CD20 TDBs (UCHT1 series) with 20,000 Bjab cells and 5× purified huCD8+ T cells as measured by FACS analysis.

Figure 28A is a graph showing the percentage of T cell activation as measured by CD69 and CD25 surface expression following incubation of the indicated CD3/CD20 TDBs (UCHT1 series) with 200,000 human PBMCs per well for 24 hours.

Figure 28B is a graph showing the percent endogenous B cell killing relative to non-TDB-treated controls following 24 hours of incubation of the indicated CD3/CD20 TDBs (UCHT1 series) with 200,000 human PBMCs per well as measured by FACS analysis.

Figure 29A is a graph showing the percent endogenous B cell killing relative to a non-TDB-treated control group after incubation of various CD3/CD20 TDBs having different combinations of an anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor No. 3) per well for 24 hours as measured by FACS analysis.

29B is a graph showing the percentage of T cell activation, as measured by CD69 and CD25 surface expression and as measured by FACS analysis, after incubation of various CD3/CD20 TDBs having different combinations of the anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor No. 3) per well for 24 hours.

Figure 30A is a graph showing the percent endogenous B cell killing relative to a non-TDB-treated control group after incubation of various CD3/CD20 TDBs having different combinations of an anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor No. 4) per well for 24 hours as measured by FACS analysis.

30B is a graph showing the percentage of T cell activation, as measured by CD69 and CD25 surface expression and as measured by FACS analysis, after incubation of various CD3/CD20 TDBs having different combinations of the anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor No. 4) per well for 24 hours.

Figure 31A is a graph showing the percent endogenous B cell killing relative to a non-TDB-treated control group after incubation of various CD3/CD20 TDBs having different combinations of an anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 cyno PBMCs (isolated from Donor 2) per well for 24 hours as measured by FACS analysis.

31B is a graph showing the percentage of T cell activation, as measured by CD69 and CD25 surface expression and as measured by FACS analysis, after incubation of various CD3/CD20 TDBs having different combinations of the anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 cynoPBMCs (isolated from Donor No. 2) per well for 24 hours.

Figure 32A is a graph showing the percent endogenous B cell killing relative to a non-TDB-treated control group after incubation of various CD3/CD20 TDBs having different combinations of an anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 cyno PBMCs (isolated from Donor 3) per well for 24 hours as measured by FACS analysis.

32B is a graph showing the percentage of T cell activation, as measured by CD69 and CD25 surface expression and as measured by FACS analysis, after incubation of various CD3/CD20 TDBs having different combinations of the anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 cynoPBMCs (isolated from Donor No. 3) per well for 24 hours.

Figure 33A is a graph showing the percentage of Bjab cell killing relative to a non-TDB-treated control group following 24 hours incubation of various CD3/CD20 TDBs having different combinations of an anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 cyno PBMCs per well as measured by FACS analysis.

Figure 33B is a graph showing the percentage of T cell activation as measured by CD69 and CD25 surface expression and as measured by FACS analysis after incubation of various CD3/CD20 TDBs having different combinations of the anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 cynoPBMCs per well for 24 hours.

Figure 34A is a graph showing the percent endogenous B cell killing relative to a non-TDB-treated control group after incubation of various CD3/CD20 TDBs having different combinations of an anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor 2) per well for 24 hours as measured by FACS analysis.

34B is a graph showing the percentage of T cell activation, as measured by CD69 and CD25 surface expression and as measured by FACS analysis, after incubation of various CD3/CD20 TDBs having different combinations of the anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor 2) per well for 24 hours.

Figure 35A is a graph showing the percent endogenous B cell killing relative to a non-TDB-treated control group after incubation of various CD3/CD20 TDBs having different combinations of an anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor 3) per well for 24 hours as measured by FACS analysis.

35B is a graph showing the percentage of T cell activation, as measured by CD69 and CD25 surface expression and as measured by FACS analysis, after incubation of various CD3/CD20 TDBs having different combinations of the anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor #3) per well for 24 hours.

Figure 36A is a graph showing the percent endogenous B cell killing relative to a non-TDB-treated control group after incubation of various CD3/CD20 TDBs having different combinations of an anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor No. 4) per well for 24 hours as measured by FACS analysis.

36B is a graph showing the percentage of T cell activation, as measured by CD69 and CD25 surface expression and as measured by FACS analysis, after incubation of various CD3/CD20 TDBs having different combinations of the anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor No. 4) per well for 24 hours.

Figures 37A and 37B are graphs showing the percentage of T cell activation, as measured by CD69 and CD25 surface expression and as measured by FACS analysis, after incubation of various CD3/CD20 TDBs having different combinations of the anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor No. 1) per well for 24 hours.

FIG37C is a table summarizing the CD8+ T cell activation EC50 (ng/ml) for each CD3/CD20 TDB tested in FIG37A and FIG37B .

Figures 38A and 38B are graphs showing the percent endogenous B cell killing relative to a non-TDB-treated control group after incubation of various CD3/CD20 TDBs having different combinations of an anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor 1) per well for 24 hours as measured by FACS analysis.

FIG38C is a table summarizing the EC50 (ng/ml) for endogenous B cell killing for each CD3/CD20 TDB tested in FIG38A and FIG38B .

Figures 39A and 39B are graphs showing the percentage of T cell activation, as measured by CD69 and CD25 surface expression and as measured by FACS analysis, after incubation of various CD3/CD20 TDBs having different combinations of the anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor No. 1) per well for 48 hours.

FIG39C is a table summarizing the CD8+ T cell activation EC50 (ng/ml) for each CD3/CD20 TDB tested in FIG39A and FIG39B .

40A and 40B are graphs showing the percent endogenous B cell killing relative to a non-TDB-treated control group after incubation of various CD3/CD20 TDBs having different combinations of an anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor 1) per well for 48 hours as measured by FACS analysis.

FIG40C is a table summarizing the EC50 (ng/ml) for endogenous B cell killing for each CD3/CD20 TDB tested in FIG40A and FIG40B .

Figures 41A and 41B are graphs showing the percentage of T cell activation, as measured by CD69 and CD25 surface expression and as measured by FACS analysis, after incubation of various CD3/CD20 TDBs having different combinations of an anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor No. 2) per well for 24 hours.

FIG41C is a table summarizing the CD8+ T cell activation EC50 (ng/ml) for each CD3/CD20 TDB tested in FIG41A and FIG41B .

Figures 42A and 42B are graphs showing the percent endogenous B cell killing relative to a non-TDB-treated control group after incubation of various CD3/CD20 TDBs having different combinations of an anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor 2) per well for 24 hours as measured by FACS analysis.

FIG42C is a table summarizing the EC50 (ng/ml) for endogenous B cell killing for each CD3/CD20 TDB tested in FIG42A and FIG42B .

Figures 43A and 43B are graphs showing the percentage of T cell activation, as measured by CD69 and CD25 surface expression and as measured by FACS analysis, after incubation of various CD3/CD20 TDBs having different combinations of the anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor No. 2) per well for 48 hours.

FIG43C is a table summarizing the CD8+ T cell activation EC50 (ng/ml) for each CD3/CD20 TDB tested in FIG43A and FIG43B .

Figures 44A and 44B are graphs showing the percent endogenous B cell killing relative to a non-TDB-treated control group after incubation of various CD3/CD20 TDBs having different combinations of an anti-CD3 arm and the anti-CD20 arm of 2H7v16 with 200,000 human PBMCs (isolated from Donor 2) per well for 48 hours as measured by FACS analysis.

FIG44C is a table summarizing the EC50 (ng/ml) for endogenous B cell killing for each CD3/CD20 TDB tested in FIG44A and FIG44B .

FIG45A is a graph showing that certain CD3/CD20 TDBs, such as the TDB with an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of 72H6, exhibit no in vitro potency as assessed by the Bjab killing assay.

45B and 45C are graphs showing that certain CD3/CD20 TDBs, such as one with an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of 72H6, do not exhibit in vitro potency as assessed by endogenous B cell killing assays (B) and T cell activation assays (C).

FIG46A is a graph showing that certain CD3/CD20 TDBs, such as the TDB with an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of 13A3, exhibit lower potency in vitro as assessed by the Bjab killing assay.

FIG46B is a graph showing that certain CD3/CD20 TDBs, such as the TDB with an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of 30A1, exhibit lower in vitro potency as assessed by the Bjab killing assay.

Figure 46C is a graph showing that certain CD3/CD20 TDBs (such as one with an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of 41D9a) exhibited lower in vitro potency as assessed by the Bjab killing assay. The Bjab cell killing EC50 (ng/ml) value is shown for each CD3/CD20 TDB tested.

Figure 46D is a graph showing that certain CD3/CD20 TDBs (such as those with an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of 41D9a) exhibited lower in vitro potency as assessed by an endogenous B cell killing assay. The endogenous B cell killing EC50 (ng/ml) value is shown for each CD3/CD20 TDB tested.

FIG46E is a graph showing that certain CD3/CD20 TDBs, such as the TDB with an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of 41D9a, exhibit lower in vitro potency as assessed by a T cell activation assay.

FIG47A is a graph showing that certain CD3/CD20 TDBs, such as those with an anti-CD20 arm of 2H7v16 and anti-CD3 arms of UCHT1v9, 21A9, and 40G5c, exhibit higher potency in vitro as assessed by an endogenous B cell killing assay using 200,000 human PBMCs (isolated from Donor #1) per well and as measured by FACS analysis.

47B is a graph showing that certain CD3/CD20 TDBs, such as those with an anti-CD20 arm of 2H7v16 and anti-CD3 arms of UCHT1v9, 21A9, and 40G5c, exhibit higher in vitro potency as assessed by a T cell activation assay using 200,000 human PBMCs (isolated from Donor 1) per well and as measured by FACS analysis.

FIG48A is a graph showing that certain CD3/CD20 TDBs, such as those with an anti-CD20 arm of 2H7v16 and anti-CD3 arms of UCHT1v9, 21A9, and 40G5c, exhibit higher potency in vitro as assessed by an endogenous B cell killing assay using 200,000 human PBMCs (isolated from Donor #2) per well and as measured by FACS analysis.

48B is a graph showing that certain CD3/CD20 TDBs, such as those with an anti-CD20 arm of 2H7v16 and anti-CD3 arms of UCHT1v9, 21A9, and 40G5c, exhibit higher in vitro potency as assessed by a T cell activation assay using 200,000 human PBMCs (isolated from Donor #2) per well and as measured by FACS analysis.

49 is a table summarizing the in vitro potency of various CD3/CD20 TDBs having different combinations of an anti-CD3 arm with the anti-CD20 arm of 2H7v16.

Figure 50 shows the amino acid sequences of the light chain variable domain (top) and heavy chain variable domain (bottom) of the anti-CD20 antibody 2H7.v16.

FIG51 shows the amino acid sequences of the light chain variable domain (top) and heavy chain variable domain (bottom) of the anti-CD3 antibody hu40G5c.

Figures 52A and 52B show that the purified CD3/CD20 TDB (40G5c/2H7v16) had no detectable aggregate formation as determined by size exclusion chromatography (SEC) (A) and no detectable homodimer formation (i.e., CD3/CD3 or CD20/CD20 antibody formation) as assessed by mass spectrometry (B).

Figure 53A is a graph showing the pharmacokinetic profile of serum concentrations of CD3/CD20 TDB in Sprague Dawley (SD) rats at different doses over time (days) as assessed by General Immunoglobulin Pharmacokinetics (GRIP) or specific assays.

Figure 53B is a table summarizing the quantitative clearance (ml/d/kg) values for the CD3/CD20 TDB antibodies tested at each dose tested in Figure 53A.

Figure 54A is a graph showing that the F(ab') ₂ portion of the CD20 TDB retains the same in vitro B cell killing (Bjab killing) potency as the full-length IgG CD20 TDB. 20,000 Bjab cells and 200,000 PBMCs isolated from healthy donors were incubated with various concentrations of full-length CD20 TDB or F(ab')2CD20 TDB for 24 hours.

Figure 54B is a graph showing that the B cell killing activity of CD20 TDB is T cell dependent, as no B cell killing was detected in the presence of CD3+ T cell-depleted PBMCs. 20,000 Bjab cells isolated from healthy donors and 200,000 PBMCs or 200,000 CD3+ T cell-depleted PBMCs were incubated with various concentrations of CD20 TDB for 24 hours.

Figure 54C is a graph showing that comparable B cell killing can be achieved using CD4+ or CD8+ T cells as effectors. 20,000 Bjab cells and 100,000 purified CD8+ or CD4+ T cells were incubated with various concentrations of CD20 TDB for 24 hours. Cell killing and T cell activation marked as CD69+CD25+ were measured and calculated as described below.

Figure 54D is a graph showing that CD20 TDB can activate CD4+ and CD8+ T cells. 20,000 Bjab cells and 100,000 purified CD8+ T cells or CD4+ T cells were incubated with various concentrations of CD20 TDB for 24 hours. Cell killing and T cell activation labeled with CD69+CD25+ were measured and calculated as described below.

Figure 54E is a graph showing that granzyme upregulation is more prevalent in CD8+ T cells after addition of CD20 TDB. 20,000 Bjab cells and 100,000 purified CD8+ T cells or CD4+ T cells were incubated with various concentrations of CD20 TDB for 24 hours. Granzyme B induction was also detected by FACS.

Figure 54F is a graph showing that higher levels of perforin release are associated with CD8+ T cells after addition of CD20 TDB. 20,000 Bjab cells and 100,000 purified CD8+ T cells or CD4+ T cells were incubated with various concentrations of CD20 TDB for 24 hours. Perforin concentrations in the culture medium were measured by ELISA.

Figure 55 is a series of flow cytometry graphs showing that activated T cells are able to proliferate in the presence of CD20 TDB and Bjab cells.

FIG56A is a series of graphs showing dose-response B cell killing curves for eight B leukemia/lymphoma tumor cell lines (left) and CD20 expression levels of the indicated B cell lines under isotype control (grey) as measured by FACS. B cells were cultured in RPMI 1640 medium supplemented with 10% FBS. In the killing assay, 20,000 B cells were incubated with 200,000 PBMCs isolated from healthy donors and various concentrations of CD20 TDB for 24 hours.

FIG56B is a graph showing the wide range of average CD20 expression across the eight B cell lines tested in FIG56A. CFSE-labeled CD4+ or CD8+ T cells purified from healthy donor whole blood were first incubated for 24 hours with Bjab alone, Bjab alone, CD20 TDB alone, or Bjab and CD20 TDB. The cells were then washed and placed in fresh culture medium for an additional 48 hours. T cells were assayed for CFSE intensity by FACS, demonstrating T cell proliferation only in the presence of Bjab and CD20 TDB.

Figure 56C is a set of graphs showing that CD20 TDB is effective in killing all eight cell lines in a dose-dependent manner, with EC50 values (ng/ml) for B cell killing (top) and percentage of B cell killing (bottom) expressed as a function of CD20 expression on target B cells.

Figure 56D is a graph showing that TDBs targeting five different B cell antigens are comparable in mediating T cell killing of Bjab cells. B cells were cultured in RPMI 1640 medium supplemented with 10% FBS. In the killing assay, 20,000 Bjab cells were incubated with 100,000 purified CD8+ T cells from healthy donors and 1000 ng/ml of CD20 TDB (TDBA: 2H7v16/UCHT1v9) or TDBs targeting different B cell antigens (i.e., TDB B-E, each targeting a different B cell antigen) for 24 hours.

Figure 56E is a graph showing the extent of B cell killing of 10 B leukemia/lymphoma tumor cell lines. B cells were cultured in RPMI 1640 medium supplemented with 10% FBS. In the killing assay, 20,000 B cells were incubated with 100,000 purified CD8+ T cells from healthy donors and 1000 ng/ml CD20 TDB (2H7v16/UCHT1v9) for 24 hours.

Figure 56F is a graph showing dose-response killing curves for 8 random donors.

Figure 56G is a summary graph of EC50 (left) and extent of B cell killing (right) at 1000 ng/ml antibody in a 24 hour assay for 30 donors.

Figure 56H is a set of graphs showing that the extent of B cell killing within 24 hours by CD20 TDB is comparable to or greater than that by CD19 scFv. In autologous B cell killing, 200,000 PBMCs isolated from healthy donors were incubated with the indicated concentrations of CD20 TDB for 24 hours. The reported cell killing was calculated as described below.

Figure 56I is a set of graphs showing that the extent of B cell killing within 24 hours by CD20 TDB is comparable to or greater than that by CD19-TDB or CD22-TDB (upper graph) or by CD79a or CD79b (lower graph). In autologous B cell killing, 200,000 PBMCs isolated from healthy donors were incubated with 40,000 BJAB cells and the indicated concentrations of CD20, CD19, CD22, CD79a, or CD79b TDB for 24 hours. Reported cell killing was calculated as described below.

Figure 57A is a series of graphs showing the relative expression of human CD3 _epsilon detected in CD4+ T cells (left panel) and CD8+ T cells (middle panel) and human CD20 detected in CD19+ B cells (right panel) in mouse (mu) or human (hu) PBMCs as measured by FACS. Mouse PBMCs were derived from the blood of double transgenic huCD3/huCD20 mice; human PBMCs were derived from the blood of healthy donors.

Figure 57B is a graph showing that the CD20 TDB is unable to participate in the elimination of murine T cells by B cells in the absence of human CD3 expression in human CD20 transgenic mice. HuCD20 transgenic mice or huCD20/CD3 double transgenic mice were treated once intravenously with the indicated antibodies (10 mg/kg rituximab, 0.5 mg/kg CD20 TDB and HER2 TDB). Mouse spleens were harvested on day 7 (7 days after antibody treatment). The anti-human CD20 antibody rituximab was used as a positive control. The CD3/HER2 TDB was used as a negative isotype control.

Figure 57C is a graph showing that the CD20 TDB enables huCD3-expressing murine T cells to participate in the efficient elimination of huCD20-expressing murine B cells in human CD3/CD20 double transgenic mice. huCD20 transgenic mice or huCD20/CD3 double transgenic mice were treated once intravenously with the indicated antibodies (10 mg/kg rituximab, 0.5 mg/kg CD20 TDB and HER2 TDB). Mouse spleens were harvested on day 7 (7 days after antibody treatment). The CD3/HER2 TDB was used as a negative isotype control.

Figure 58A is a series of graphs showing that treatment with CD20 TDB resulted in sustained B cell depletion until D15 (15 days after dosing). huCD20/huCD3 double transgenic mice were treated once intravenously with different doses of CD20 TDB. Blood was collected from mice (D1, D8, and D15).

Figure 58B is a graph showing that near-complete B cell depletion in mouse spleens was achieved only after a single dose of 0.5 mg/kg on D7, while a lower dose of 0.05 mg/kg only partially resulted in splenic B cell depletion. huCD20/CD3 double transgenic mice were treated once intravenously with various doses of CD20 TDB. Spleens were harvested (D7).

Figure 58C is a graph showing that robust B cell depletion was observed in the circulation of double transgenic huCD3/huCD20 mice treated with CD20 TDB on D7. huCD20/huCD3 double transgenic mice were treated once with 0.5 mg/kg CD20 TDB intravenously. Blood was collected on D0-5 min (5 minutes after treatment), D0-2 h, D0-8 h, D1, D2, D3, and D7. B cells expressing huCD20 were measured by FACS.

Figure 58D is a series of graphs showing T cell activation in double transgenic huCD3/huCD20 mice treated with CD20 TDB. Treated double transgenic huCD3/huCD20 mice showed an increase of up to 80% in the count of CD8+ T cells expressing human _CD3ε 2 hours after CD20 TDB treatment and returned to baseline levels by D2 and D7 (top graph). Similarly, 2 hours after treatment with CD20 TDB, CD4+ T cells expressing human _CD3ε increased by 80% and then returned to baseline levels by D2. Double transgenic huCD3/huCD20 mice were treated once intravenously with 0.5 mg/kg CD20 TDB. Blood was collected at D0-5min (5 minutes after treatment), D0-2h, D0-8h, D1, D2, D3 and D7. CD4+ and CD8+ T cells expressing _CD3ε were measured by FACS.

FIG59A is a series of flow cytometry images showing that CD20 TDB effectively depletes marginal zone B cells (MZB) and follicular B cells (FOB) following administration of TDB to double transgenic huCD3/huCD20 mice. Two double transgenic animals (left and right panels, respectively) were treated with vehicle (top panel) or a single intravenous dose of 0.5 mg/kg TDB (bottom panel). Mouse spleens were harvested on day 7 and analyzed by FACS.

Figures 59B to 59E are a series of graphs showing that CD20 TDB equally effectively depletes marginal zone B cells (MZB) (B) and follicular B cells (FOB) (C) after a single intravenous dose of 0.5 mg/kg TDB, as well as CD8+ T cell activation (D) and CD8+ T cell proliferation (E) in the spleen at the indicated time points. Mouse spleens were harvested on D1, D2, D3, D5, D7, and D14.

Figure 60A is a graph showing that humanized NSG mice treated with 0.5 mg/kg CD20 TDB three times a week (repeat dose setting) exhibited depleted B cell levels in the blood on D7, with virtually no B cells detected on D21. Humanized NSG mice were treated intravenously with three doses of 0.5 mg/kg CD20 TDB weekly. Blood was collected on D-5 (5 days prior to treatment), D7, D14, and D21. Murine B cell counts in the blood were measured by FACS.

Figure 60B is a graph showing that robust B cell depletion was observed in the spleens of humanized NSG mice treated with CD20 TDB at D21. Humanized NSG mice were treated with 3 doses of 0.5 mg/kg CD20 TDB intravenously weekly. Spleens were harvested at D21. Murine B cell counts in the spleen were measured by FACS.

Figure 60C is a series of flow cytometry images showing the proliferation of huCD8+ T cells and the depletion of huCD19+ B cells 7 days (D7) after treatment of humanized NSG mice with CD20 TDB. Humanized NSG mice were treated with vehicle or 0.5 mg/kg CD20 TDB (2H7v16/UCHT1v9). Spleens from control and CD20 TDB-treated humanized NSG mice were harvested on D7. B cells expressing huCD19 and T cells expressing huCD8 were measured by FACS.

Figure 60D is a graph showing that humanized NSG mice treated with 0.5 mg/kg CD20 TDB three times a week (repeat dose setting) exhibited a 10-fold increase in CD8+ T cell counts on D7 and returned to baseline levels or lower by D14 and D21. Humanized NSG mice were treated with three doses of 0.5 mg/kg CD20 TDB intravenously weekly. Blood was collected on D-5 (5 days prior to treatment), D7, D14, and D21. Murine CD8+ T cell counts and T cell activation were measured in the blood by FACS.

FIG60E is a series of flow cytometry graphs showing baseline levels of huCD20+ B cells (center panel) and huCD8+ and huCD4+ T cells (right panel) from two humanized NSG mice as measured by FACS.

Figure 60F is a series of graphs showing the cell surface expression levels of _huCD3ε and CD20 expression levels on CD19+ B cells (left), CD8+ T cells (middle), and CD4+ T cells (right), as detected by FACS.

Figure 61A is a graph showing that CD20 TDB is effective in killing CLL B cells in the presence of autologous T cells. 200,000 PBMCs were incubated with various concentrations of CD20 TDB in RPMI medium supplemented with 10% FBS for 48 hours. Figure 61B is a graph showing that CD20 TDB is effective in inducing autologous T cell activation in the presence of CLL B cells. 200,000 PBMCs were incubated with various concentrations of CD20 TDB in RPMI medium supplemented with 10% FBS for 48 hours.

Figure 61C is a set of graphs showing that T cell counts are highly correlated with ex vivo killing of CLL B cells. 200,000 PBMCs were incubated for 48 hours with 1000 ng/ml CD20 TDB alone or with the addition of CD8+ T cells purified from healthy donors. The percentages of CD19+CD5+ B cells and CD8+ T cells in CLL PBMCs were 90/0.55 for sample A1645, 76/3.5 for A1957, 87/0.63 for A1978, and 69/1.3 for A1980. Cell killing, granzyme B induction, and T cell activation were measured by FACS as described below.

FIG62A is a set of graphs showing T cell activation (left) following administration of 0.1 mg/kg or 0.5 mg/kg CD20 TDB to NSG mice with transplanted CLL leukemia cells, correlated with efficient clearance of transplanted CLL B cells (right).

Figure 62B is a set of immunohistochemistry images of spleen sections from NSG mice engrafted with CLL leukemia cells, showing that very few B cells can be detected after CD20 TDB treatment. B cells and T cells were transplanted into NSG mice as described below. Mice were treated once intravenously with HER2 TDB and 0.5 mg/kg rituximab, 0.1 mg/kg and 0.5 mg/kg CD20 TDB, and spleens were harvested 14 days after treatment for FACS analysis.

Figure 63 is a graph showing the fitted tumor volume over time for Bjab-implanted tumors in the following groups of SCID mice: Group 1 (vehicle: 20 mM histidine/acetate pH 5.5, 240 mM sucrose, 0.02% Tween 20); Group 2 (CD20 TDB: 2H7v114/UCHT1.v9; 0.5 mg/kg); Group 3 (vehicle: 20 mM histidine/acetate pH 5.5, 240 mM sucrose, 0.02% Tween 20, PBMC); and Group 4 (CD20 TDB: CD20 2H7v114/CD3 UCHT1.v9; 0.5 mg/kg, PBMC). Effector cells were PBMCs derived from healthy human donors. Mice were treated once a week for two weeks.

Figure 64A is a graph showing the relative levels of CD20 expression on Bjab, NALM-6, SC-1, and OCI-LY 19 cells. B cells and T cells were transplanted into NSG mice as described below. Mice were treated once intravenously with HER2 TDB and 0.5 mg/kg rituximab, 0.1 mg/kg and 0.5 mg/kg CD20 TDB, and spleens were harvested 14 days after treatment for IHC analysis.

Figure 64B is a graph showing that rituximab and CD20 TDB are comparable in their efficacy in killing Bjab cells in vitro, which express high levels of CD20 on their cell surface. PBMCs isolated from healthy donors were depleted of B cells and used as effector cells in an in vitro cell killing assay. 20,000 B cells and 200,000 effector cells were incubated with various concentrations of CD20 TDB or rituximab for 24 hours. CD20 TDB expression was detected by FACS.

Figure 64C is a graph showing that CD20 TDB, but not rituximab, is able to kill NALM-6, SC-1, and OCI-LY19 cells, which have relatively low levels of CD20 on their cell surfaces. PBMCs isolated from healthy donors were depleted of B cells and used as effector cells in an in vitro cell killing assay. 20,000 B cells and 200,000 effector cells were incubated with various concentrations of CD20 TDB or rituximab for 24 hours. CD20 TDB expression was detected by FACS.

Figure 64D is a graph showing the level of B cell surface expression of unblocked CD20 antigen as measured by FACS as a function of rituximab-DANA concentration. CD20/CD3 double transgenic mice were treated with a single dose of vehicle or rituximab-DANA (10 mg/kg). Spleens were collected 5 days after treatment.

Figures 65A and 65B are graphs showing that CD20 TDB has in vitro B cell killing activity in the presence of high levels of rituximab (A) or dexamethasone (B). 200,000 PBMCs isolated from healthy donors were first incubated with the indicated concentrations of rituximab-DANA for 1 hour, followed by the addition of CD20 TDB and incubation for 24 hours. In the dexamethasone assay, cells were pretreated overnight with 1 μM dexamethasone before the addition of CD20 TDB. Cell killing was calculated as described below.

FIG66 is a set of graphs showing that CD20 TDB has the activity of depleting B cells in the blood (left) and spleen (right) of mice pretreated with rituximab-DANA. In single-agent treatment, huCD20/CD3 double-transgenic mice were treated once intravenously at the indicated doses; in combination treatment, mice were first treated intravenously with rituximab-DANA and 30 minutes later injected intravenously with CD20 TDB. Blood was collected on D-7, D0-2h (2 hours after TDB treatment), and D7; spleens were collected on D7. B cell counts were measured by FACS as described below.

Figure 67A is a set of graphs showing B cell (left), CD4+ T cell (center), and CD8+ T cell (right) counts in blood samples from three cynomolgus monkeys before and 7 days after treatment with a single intravenous dose of 1 mg/kg CD20 TDB. Three cynomolgus monkeys were treated once intravenously with 1 mg/kg CD20 TDB. Blood was collected on D-7 (7 days before dosing), D0-4h (4 hours after dosing), and D7.

Figure 67B is a set of graphs showing B cell, CD4+ T cell, and CD8+ T cell levels in the spleen (left), mandibular lymph nodes (center), and mesenteric lymph nodes (right) of three cynomolgus monkeys 7 days after treatment with a single intravenous dose of 1 mg/kg CD20 TDB. Three cynomolgus monkeys were treated once intravenously with 1 mg/kg CD20 TDB. Blood was collected on D-7 (7 days before dosing), D0-4h (4 hours after dosing), and D7.

Figure 67C is a set of graphs showing B cell, CD4+ T cell, and CD8+ T cell levels in the spleen (left), mandibular lymph nodes (center), and mesenteric lymph nodes (right) of three cynomolgus monkeys before treatment with a single intravenous dose of 1 mg/kg CD20 TDB. Three cynomolgus monkeys were treated once intravenously with 1 mg/kg CD20 TDB. Blood was collected on D-7 (7 days before dosing), D0-4h (4 hours after dosing), and D7.

Figure 67D is a set of graphs showing baseline levels of B cells and CD4+ and CD8+ T cells as a percentage of total lymphocytes detected in the spleen (left) and submandibular lymph nodes (right) in vehicle control treated animals.

FIG68A is a set of graphs showing CD20 TDB serum concentrations in blood and serum samples collected from four cynomolgus monkeys treated four times weekly with 1 mg/kg CD20 TDB via intravenous administration.

Figure 68B is a set of graphs showing CD20 TDB concentrations in serum samples collected from the animals described in Figures 65 and 66 A. Mean ± standard deviation are plotted.

FIG69A is a histogram showing PD-L1 expression on A20-huCD20 cells from A20-huCD20 syngeneic Balb/C mice as assessed by flow cytometry.

Figure 69B is a graph showing the relative tumor volume change over time for the following groups: Group 1 (vehicle); Group 2 (0.5 mg/kg CD20 TDB); Group 3 (10 mg/kg anti-PD-L1 antibody); and Group 4 (0.5 mg/kg CD20 TDB + anti-PD-L1 antibody).

Figure 70 is a graph showing the binding curves for each of the three test FcRH5 TDBs tested for in vitro binding to CD8+CD3 expressing T cells.

FIG. 71A is a graph showing the percentage of MOLP-2 target cell killing as a function of FcRH5 TDB concentration, wherein CD8+ T cells were purified from human PBMCs from donor #1.

FIG. 71B is a graph showing the percentage of MOLP-2 target cell killing as a function of FcRH5 TDB concentration, where CD8+ T cells were purified from human PBMCs from donor #2.

Figure 72A is a graph showing the percentage of CD8+CD69+ T cells as a function of FcRH5 TDB concentration as assessed by FACS analysis. Target cells were MOLP-2, and CD8+ T cells were purified from donor #1.

Figure 72B is a graph showing the percentage of CD8+CD107a+ T cells as a function of FcRH5 TDB concentration as assessed by FACS analysis. Target cells were MOLP-2, and CD8+ T cells were purified from donor #1.

Figure 72C is a graph showing the percentage of CD8+CD69+ T cells as a function of FcRH5 TDB concentration as assessed by FACS analysis. Target cells were MOLP-2, and CD8+ T cells were purified from donor #2.

Figure 72D is a graph showing the percentage of CD8+CD107a+ T cells as a function of FcRH5 TDB concentration as assessed by FACS analysis. Target cells were MOLP-2, and CD8+ T cells were purified from donor #2.

73 is a set of graphs showing binding curves for each of three HER2 TDBs tested for in vitro binding to Her2-expressing SKBR3 cells (top) and CD8+CD3-expressing T cells (bottom).

Figure 74A is a graph showing binding curves for in vitro binding of Trastuzumab (Bivalent), Trastuzumab (Fab), and HER2 TDB (UCHT1v9/hu4D5) (Bispecific) to Her2-expressing SKBR3 cells.

Figure 74B is a graph showing the percentage of viable SKBR3 cells as a function of Trastuzumab (Bivalent), Trastuzumab (Fab), and HER2 TDB (UCHT1v9/hu4D5) (Bispecific) concentrations as assessed by a luminescent cell viability assay.

Figure 74C is a graph showing the percentage of SKBR target cell killing mediated by antibody-dependent cell-mediated cytotoxicity (ADCC) in the presence of trastuzumab (T-mab), trastuzumab produced in E. coli (E. coli T-mab), and HER2 TDB (UCHT1v9/hu4D5), as assessed by lactate dehydrogenase (LDH) release from lysed cells.

FIG75 is a graph showing the percentage of SKBR3 target cell killing as a function of HER2 TDB (hu4D5-TDB, hu4D5.91A-TDB, and hu4D5.Y100A-TDB) concentration.

Figure 76A is a series of figures. The top figure is a perspective view of the crystal structure of the HER2 extracellular domain (ECD) bound by hu4D5Fab (trastuzumab), 2C4Fab (pertuzumab), and 7C2. The bottom figure is a ribbon structure of _CD3ε bound by 2C11, 38E4v1, and 40G5c.

Figure 76B is a table indicating the binding affinity of HER2-TDB to three different HER2 arms (i.e., hu4D5, 2C4, and 7C2) (expressed by the dissociation constant, _KD (nM)). The lower right panel is a table indicating the binding affinity of HER2-TDB to three different CD3 _epsilon arms (i.e., 38E4v1, 40G5c, and 2C11) (expressed by the dissociation constant, _KD (nM)).

Figure 76C is a graph showing the percentage killing of HER2-expressing MCF7 target cells as a function of HER2-TDB (hu4D5-TDB, 2C4-TDB, and 7C2-TDB) concentration. Cytotoxicity was measured by the release of lactate dehydrogenase (LDH).

Figure 77 is a graph showing that HER2 hu4D5 and 2C4 arms are potent mediators of cell killing, as shown by the maximum percentage of SKBR3 target cell killing achieved by treatment with the following HER2-TDB variants: hu4D5-38E4v1, hu4D5-40G5c, 2C4-38E4v1, 2C4-40G5c, 7C2-38E4v1, and 7C2-40G5c.

Figure 78 is a series of graphs showing the potency of HER2-TDB variants in killing HER2-expressing SKBR3 cell line (left) and HER2-expressing MCF7 cell line (right) in a dose-dependent manner as EC50 values (pM) for target cell killing.

79 is a series of graphs showing the percent killing of HER2-expressing SKBR3 target cells by various TDBs having a HER2 arm (hu4D5, 2C4, and 7C2) paired with either a high-affinity (38E4v1) or low-affinity (40G5c) CD3 arm as a function of TDB concentration (ng/mL).

Figure 80 is a series of graphs. The left graph shows the efficacy of HER2-TDB variants (hu4D5-38E4v1, 2C4-38E4v1, 7C2-38E4v1; hu4D5-40G5c, 2C4-40G5c, 7C2-40G5c) in killing HER2-expressing SKBR3 and HER2-expressing MCF7 cell lines in a dose-dependent manner as target cell killing EC50 values (pM). The right graph is a table showing the EC50 ratios of the specified HER2-TDB variants in MCF7 versus SKBR3 target cells across three experiments.

Figure 81 is a series of graphs. The top graph shows a table listing variants of the hu4D5 HER2 arm of the HER2-TDB (40G5c CD3 arm) (hu4D5v7, hu4D5v5, hu4D5v10, hu4D5v31, hu4D5.Y100A) and the corresponding SKBR3 target cell killing EC50 (ng/mL), HER2 binding affinity ( _KD , nM), and the ratio of the HER2 binding affinity _KD and SKBR3 target cell killing EC50 of the hu4D5 variants relative to that of hu4D5. The bottom graph shows the correlation between the SKBR3 EC50 ratios of the hu4D5 HER2-TDB variants (hu4D5, hu4D5v7, hu4D5v5, hu4D5v10, and hu4D5v31) and the relative _KD ratios of the hu4D5 HER2-TDB variants.

Figure 82 is a series of graphs showing the percentage of SKBR3 and MCF7 target cell killing as a function of the concentration of the following HER2-TDB variants: hu4D5-40G5c (upper left), hu4D5v7-40G5c (upper middle), hu4D5v5-40G5c (upper right), hu4D5v10-40G5c (lower left), hu4D5v31-40G5c (lower middle), hu4D5.Y100A-40G5c (lower right).

Figure 83 is a series of graphs. The left graph shows the percentage of target cell killing as a function of the concentration (μg/mL) of bivalent, monospecific HER2-blocking antibodies specific for the specified HER2 arm of the HER2-TDB. (HER2-blocking antibodies: bivalent, monospecific antibodies against hu4D5, 2C4, and 7C2. HER2-TDB: hu4D5-40G5c, 2C4-40G5c, and 7C2-38E4v1 at a fixed concentration (10 ng/mL).) The right graph shows the percentage of viable cells as a function of the concentration of the HER2 antibody (hu4D5) trastuzumab in the presence or absence of the HER2-TDB hu4D5-40G5c.

Figure 84 is a series of graphs. The top graph is a table providing the reactivity of HER2 arm variants with HER2 as measured by various binding assays, as well as the reactivity of HER2 clones with the hu4D5 antibody, trastuzumab. The bottom graph is a graph showing the percentage of target cell killing as a function of the concentration (pM) of the HER2 bispecific Fab of the indicated clones (hu4D5, 3H4, and 2H11). The EC50 value (pM) for each clone is provided.

FIG85 is a table providing affinity and reactivity information for variants of the HER2-TDB CD3 arm (38E4v1, 38E4, SP34, 40G5c, and 2C11).

Figure 86 is a graph showing the killing of HER2-expressing CT26 target cells as a function of the concentration (ng/mL) of HER2-TDB variants (hu4D5-2C11, hu4D5-SP34, 7C2-2C11, and 2C4-2C11). Effector cells: CD3-TG-derived T cells

Figure 87A is a graph showing tumor volume ( ^mm3 ) measured over time (days 0 to 5) in animals treated with vehicle or HER2-TDB (.5 mg/kg).

Figure 87B is a series of graphs. The upper left graph shows the percentage of peripheral CD45+ cells in every 5 cells detected on day 6 after treatment with vehicle or HER2-TDB (.5 mg/kg). The upper right graph shows the percentage of peripheral CD45+ cells detected as CD8+ cells on day 6 after treatment with vehicle or HER2-TDB (.5 mg/kg). The lower left graph shows the percentage of peripheral CD45+ cells detected as CD4+ on day 6 after treatment with vehicle or HER2-TDB (0.5 mg/kg). The lower right graph shows the percentage of peripheral CD8+ cells detected as IFN+ on day 6 after treatment with vehicle or HER2-TDB (.5 mg/kg).

Figure 88A is a series of graphs. The top graph shows a waterfall plot of the percent change in tumor volume for animals treated with vehicle or a HER2-TDB variant (hu4D5-SP34 or hu4D5-2C11; 0.5 mg/kg, intravenously, weekly for 5 weeks). The bottom graph shows a waterfall plot of the percent change in tumor volume for animals treated with a HER2-TDB variant (2C4-38E4; 0.5 mg/kg; IV, weekly for 5 weeks).

Figure 88B is a series of graphs. The upper graph shows the change in tumor volume (percent of baseline volume) over time (days) for animals treated with vehicle or HER2-TDB (hu4D5-SP34). The lower graph shows the change in tumor volume (percent of baseline volume) over time (days) for animals treated with vehicle or HER2-TDB (hu4D5-2C11). (HER2-TDB: 0.5 mg/kg; IV, weekly for 5 weeks).

Figure 89 is a graph showing the percentage of CD8+CD107a+ T cells as a function of HER2 TDB concentration (hu4D5-TDB, hu4D5.91A-TDB, and hu4D5.Y100A-TDB) as assessed by FACS analysis. Target cells were SKBR3 cells; effector cells were CD8+ T cells; effector cell:target cell ratio = 3:1.

Figure 90A is a graph showing the percentage of SKBR3 target cell killing as a function of HER2 TDB (UCHT1v9/hu4D5 and SP34/hu4D5) concentration.

Figure 90B is a graph showing the percentage of SKBR3 target cell killing as a function of HER2 TDB (SP34/hu4D5, 38E4c/hu4D5, and 40G5c/hu4D5) concentration.

FIG. 90C is a graph showing the percentage of SKBR3 target cell killing as a function of HER2 TDB (SP34/hu4D5, 38E4c/hu4D5, and 40G5c/hu4D5) concentration.

Figure 91A is a graph showing the binding curves for each of the three HER2-TDBs (SP34/hu4D5, 38E4c/hu4D5, and 40G5c/hu4D5) tested for in vitro binding to CD8+CD3 expressing T cells as assessed by FACS analysis.

Figure 91B is a graph showing the percentage of CD8+CD69+ T cells as a function of HER2-TDB (SP34/hu4D5, 38E4c/hu4D5, and 40G5c/hu4D5) concentrations.

FIG92A is a graph showing the binding curves of two HER2 TDBs (38E4c/hu4D5 and 38E4/hu4D5) tested for in vitro binding to CD8+CD3 expressing T cells as assessed by FACS analysis.

Figure 92B is a graph showing the binding curves of two HER2 TDBs (38E4c/hu4D5 and 38E4/hu4D5) tested for in vitro binding to Her2-expressing SKBR3 cells, as assessed by FACS analysis.

Figure 92C is a graph showing the percentage of SKBR3 target cell killing as a function of HER2 TDB (38E4c/hu4D5 and 38E4/hu4D5) concentration as assessed by FACS analysis. Effector cells were human CD8+ T cells; effector cell:target cell ratio = 3:1.

Figure 92D is a graph showing the percentage of CD8+CD69+ T cells as a function of HER2-TDB (38E4c/hu4D5 and 38E4/hu4D5) concentration.

Figure 93A is a graph showing the percentage of CD8+CD69+Granzyme B+T cells as a function of HER2TDB (UCHT1v9/hu4D5) concentration as assessed by FACS analysis. Target cells were SKBR3 cells; effector cells were CD8+T cells; effector cell:target cell ratio = 3:1.

Figure 93B is a series of graphs showing HER2 TDB (UCHT1v9/hu4D5) T cell-mediated target cell granule exocytosis and percentage of target cell killing as assessed by LDH release, as detected by ELISA for perforin and granzymes A and B. Target cells were SKBR3 cells; effector cells were PBMCs; effector cell:target cell ratio = 30:1.

Figure 93C is a series of graphs showing target cell apoptosis mediated by HER2 TDB (UCHT1v9/hu4D5) T cells as measured by caspase-3 and caspase-7 activity in the 3/7 assay, apoptosis in the cell death detection ELISA ^plus assay, and LDH release. Target cells are SKBR3 cells; effector cells are PBMCs; effector cell:target cell ratio = 10:1.

Figure 93D is a Western blot showing Her2 expression in 3T3 transfected cells (top) and a graph showing the percentage of target cell killing by activated T cells as measured by LDH release as a function of HER2 TDB (UCHT1v9/hu4D5) concentration (bottom). Target cells were 3T3-vector and 3T3-HER2; effector cells were PBMCs; effector cell:target cell ratio = 10:1.

Figure 93E is a graph showing the percentage of BT474 target cell killing as a function of HER2 TDB (UCHT1v9/hu4D5) concentration in the presence of trastuzumab Fab (T-Fab) or soluble HER2 extracellular domain (ECD) as assessed by LDH release. Effector cells were human CD8+ T cells; effector cell: target cell ratio = 5:1.

Figure 93F is a graph showing the percentage of SKBR3 target cell killing as a function of HER2 TDB (UCHT1v9/hu4D5) concentration following depletion of CD3+ cells from PBMC effector cell populations. Effector:target cell ratio = 20:1.

Figure 94A is a series of graphs showing the percentage of CD8+CD69+ T cells (left) and CD8+CD107a+ T cells (center) as a function of HER2 TDB (UCHT1v9/hu4D5) concentration and the percentage of SKBR3 target cell killing as a function of HER2 TDB (UCHT1v9/hu4D5) concentration (right), as assessed by FACS analysis. Target cells are SKBR3 cells; effector cells are CD8+ T cells; effector cell:target cell ratio = 3:1.

Figure 94B is a series of graphs showing the percentage of BT474 target cell killing as a function of HER2 TDB (UCHT1v9/hu4D5) concentration (left) and the percentage of CD8+CD69+ granzyme B+ T cells as a function of HER2 TDB (UCHT1v9/hu4D5) concentration (right), as assessed by FACS analysis. Target cells are BT474 cells; effector cells are CD8+ T cells; effector cell: target cell ratios are as indicated.

FIG. 95A is a series of histograms showing CFSE expression in CD8+ T cells in the presence of SKBR3 target cells and/or HER2 TDB (UCHT1v9/hu4D5).

Figure 95B is a graph showing the fold change in CD8+ cell number over time following incubation with SKBR3 target cells and HER2 TDB (UCHT1v9/hu4D5), as assessed by FACS analysis.

Figure 95C is a series of graphs showing the fold change in CD8+ cell number over time following incubation with SKBR3 target cells, HER2 TDB (UCHT1v9/hu4D5), and 20 ng/ml IL-2, as assessed by FACS analysis.

Figure 96A is a Western blot showing the expression levels of Her2 in a panel of human tumor cell lines.

Figure 96B is a graph showing the percentage of target cell killing as a function of HER2 TDB (UCHT1v9/hu4D5) concentration as assessed by LDH release. Target cells were BJAB, MDA435, MDA231, MCF7, MDA453, SKBR3, and BT474; effector cells were PBMCs; effector cell:target cell ratio = 25:1.

Figure 96C is a graph showing the percentage of target cell killing as a function of HER2 TDB (UCHT1v9/hu4D5) concentration as assessed by FACS analysis. Target cells were MCF7 and SKBR3; effector cells were PBMC; effector cell:target cell ratio = 20:1.

Figure 96D is a graph showing the percentage of target cell killing as a function of HER2 TDB (UCHT1v9/hu4D5) concentration as assessed by FACS analysis. Target cells were BJAB and SKBR3; effector cells were PBMCs; effector cell:target cell ratio = 20:1.

Figure 96E is a table showing the HER2 copy number of a small group of target cells and the HER2 TDB EC50 and HER2 occupancy percentage at each concentration. The target cells are MDA435, MDA231, MCF7, MDA453, BT474 and SKBR3.

Figure 97A is a graph showing the percentage of target cell killing as a function of HER2 TDB (UCHT1v9/hu4D5) concentration, as assessed by LDH release. Target cells were SKBR3, HCC1569, KPL4, HCC202, JIMT1, and CALU3; effector cells were PBMCs; effector cell:target cell ratio = 10:1.

Figure 97B is a graph showing the percentage of live target cells as a function of trastuzumab emtansine (T-DM1) concentration, as assessed by a luminescent cell viability assay. Target cells were parental BT474-M1 and T-DM1-resistant BT474-M1; effector cells were CD8+ T cells; effector cell:target cell ratio = 3:1.

Figure 97C is a graph showing the percentage of live target cells as a function of HER2 TDB (UCHT1v9/hu4D5) concentration as assessed by FACS analysis. Target cells were parental BT474-M1 and T-DM1-resistant BT474-M1; effector cells were CD8+ T cells; effector cell:target cell ratio = 3:1.

FIG. 98 is a graph and table showing the pharmacokinetic profile (PK) of HER2 TDB (UCHT1v9/hu4D5) in SD rats as assessed by ELISA.

Figure 99A is a graph showing the relative tumor volume changes over time for the following groups: Group 1 (0.5 mg/kg vehicle); Group 2 (PBMC(1) + 0.5 mg/kg vehicle); Group 3 (PBMC(1) + 0.5 mg/kg HER2 TDB(UCHT1v9/hu4D5)); Group 4 (PBMC(2) + 0.5 mg/kg vehicle); and Group 5 (PBMC(2) + 0.5 mg/kg HER2 TDB(UCHT1v9/hu4D5)).

Figure 99B is a graph showing the percent change in tumor volume over time for Group 1 (0.5 mg/kg vehicle) and Group 2 (0.5 mg/kg HER2 TDB (hu4D5/2C11)).

FIG. 99C is a histogram showing the percent change in relative tumor volume over time for Group 1 (0.5 mg/kg vehicle) and Group 2 (0.5 mg/kg HER2 TDB (hu4D5/2C11)).

Figure 99D is a graph showing the relative tumor volume over time for Group 1 (0.5 mg/kg vehicle) and Group 2 (0.5 mg/kg HER2 TDB (hu4D5/2C11)). Responders included tumors greater than 1000 ^mm3 at the start of treatment.

Figure 99E is a graph showing the percent change in tumor volume over time for Group 1 (0.5 mg/kg CD3 arm control HER2 TDB (hu4D5/SP34)) and Group 2 (0.5 mg/kg control TDB (2C11)).

Figure 99F is a graph showing the relative tumor volume changes over time for Group 1 (0.5 mg/kg vehicle) and Group 2 (0.5 mg/kg HER2 TDB (hu4D5/SP34)).

Figure 99G is a graph showing the relative tumor volume changes over time for Group 1 (0.5 mg/kg vehicle), Group 2 (0.5 mg/kg HER2 TDB (hu4D5/2C11)), Group 3 (0.5 mg/kg control TDB (2C11)), and Group 4 (15 mg/kg T-DM1).

FIG. 100A is a graph showing the relative tumor volume changes over time for Group 1 (untreated) and Group 2 (0.5 mg/kg HER2 TDB (UCHT1v9/hu4D5)). FIG.

Figure 100B is a graph showing the changes in relative tumor volume over time for Group 1 (0.5 mg/kg vehicle), Group 2 (PBMC(3) + 0.5 mg/kg vehicle), and Group 3 (PBMC(3) + 0.5 mg/kg control TDB(2C11)).

Figure 101A is a graph showing the binding affinity of CD3-UCHT1 antibodies tested for in vitro binding to human CD3 on human T cells, CD3 TG T cells, and BALB/c T cells as assessed by FACS analysis.

Figure 101B is a graph showing the binding affinity of CD3-2C11 antibodies tested for in vitro binding to mouse CD3 on CD3 TG T cells and BALB/c T cells as assessed by FACS analysis.

Figure 102A is a graph showing the percentage of CT26-HER2 target cell killing as a function of HER2 TDB (UCHT1v9/hu4D5) concentration as assessed by FACS analysis. Effector cells were human peripheral blood isolated T cells, huCD3 transgenic spleen T cells, and BALB/c spleen T cells.

Figure 102B is a graph showing the percentage of CT26-HER2 target cell killing as a function of HER2 TDB (hu4D5/2C11) concentration as assessed by FACS analysis. Effector cells were human peripheral blood isolated T cells, huCD3 transgenic spleen T cells, and BALB/c spleen T cells.

Figure 103 is a graph showing the relative tumor volume changes over time for Group 1 (0.5 mg/kg vehicle) and Group 2 (0.5 mg/kg HER2 TDB (hu4D5/SP34)).

Figure 104 is a graph showing the binding curves for each of the three LYPD1 TDBs tested for in vitro binding to CD8+CD3 expressing T cells.

Figure 105 is a graph showing the percentage of OVCAR3.Luc target cell killing as a function of LYPD1 TDB concentration.

Figure 106 is a set of graphs showing the percentage of CD8+CD69+ (left) and CD8+CD25+ (right) T cells as a function of LYPD1 TDB concentration as assessed by FACS analysis. Target cells were OVCAR3.Luc cells; effector cell:target cell ratio = 3:1.

Figure 107 shows the amino acid sequences of the light chain variable domain (top) and heavy chain variable domain (bottom) of the anti-RET antibody 41205.v6.

Figure 108A is a graph showing the change in tumor volume ( ^mm3 ) over time (days) for the following groups: Group 1 (Vehicle, qwx3, IV; n=9); Group 2 (CD20 TDB (2H7-mu2C11), 0.5 mg/kg, qwx3, IV; n=9); Group 3 (Anti-PD1 (mu8F11 DANA), 10 mg/kg, tiwx3, IP; n=9); and Group 4 (Anti-PD1 (mu8F11 DANA), 10 mg/kg, tiwx3, IP + CD20 TDB (2H7-mu2C11), 0.5 mg/kg, qwx3, IV; n=9).

Figure 108B is a graph showing the change in tumor volume ( ^mm3 ) over time (days) for Group 1 (Vehicle, qwx3, IV; n=9); Group 2 (CD20 TDB (2H7-mu2C11), 0.5 mg/kg, qwx3, IV; n=9); Group 3 (anti-PD1 (mu8F11 DANA), 10 mg/kg, tiwx3, IP; n=9); and Group 4 (anti-PD1 (mu8F11 DANA), 10 mg/kg, tiwx3, IP + CD20 TDB (2H7-mu2C11), 0.5 mg/kg, qwx3, IV; n=9). The bold solid line indicates the fitted tumor volume for the indicated group.

DETAILED DESCRIPTION

I. Definition

As used herein, the term "about" refers to the customary error range for respective values readily known to those skilled in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments for that value or parameter per se.

An "acceptor human framework" for the purposes of this document is a framework comprising the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human common framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human common framework may comprise the same amino acid sequence therefrom, or it may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework sequence is identical to the VL human immunoglobulin framework sequence or the human common framework sequence.

"Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding partner (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be represented by a dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

An "affinity mutant" antibody is one with one or more alterations in one or more hypervariable regions (HVRs) that result in an improvement in the affinity of the antibody for antigen, compared to a parent antibody that does not possess such alterations.

The terms "anti-CD3 antibody" and "antibody that binds to CD3" refer to an antibody that can bind to CD3 with sufficient affinity so that the antibody is useful as a diagnostic and/or therapeutic agent targeting CD3. In one embodiment, the extent of binding of the anti-CD3 antibody to unrelated, non-CD3 proteins is less than about 10% of the binding of the antibody to CD3, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, the antibody binds to CD3 with a dissociation constant (Kd) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 ⁻⁸ M or less, e.g., 10 ⁻⁸ M to 10 ⁻¹³ M, e.g., 10 ⁻⁹ M to 10 ⁻¹³ M). In certain embodiments, the anti-CD3 antibody binds to a CD3 epitope that is conserved between CD3s from different species.

The term "antibody" herein is used broadly and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (eg, bispecific antibodies), and antibody fragments, so long as they exhibit the desired antigen-binding activity.

An "antibody fragment" refers to a molecule that contains a portion of an intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab') ₂ ; bifunctional antibodies; linear antibodies; single-chain antibody molecules (e.g., scFv); and multispecific antibodies formed from antibody fragments.

"Binding domain" means a portion of a compound or molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Binding domains include, but are not limited to, antibodies (e.g., monoclonal, polyclonal, recombinant, humanized, and chimeric antibodies), antibody fragments or portions thereof (e.g., Fab fragments, Fab'2, scFv antibodies, SMIPs, domain antibodies, diabodies, minibodies, scFv-Fc, affibodies, nanobodies, and VH and/or VL domains of antibodies), receptors, ligands, aptamers, and other molecules with identified binding partners.

A "chemotherapeutic agent" is a compound useful in treating cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylmelamines including altretamine, triethyleneimine, and methylmelamines. amine, triethylenephosphoramide, triethylenethiophosphoramide, and tris(hydroxymethyl)melamine; polyacetogenins (especially bullatacin and bullatacinone); delta-9-tetrahydrocannabinol (dronabinol); beta-lapachone; lapachol; colchicine; betulinic acid; camptothecins (including the synthetic analog topotecan CPT-11 (irinotecan), acetylcamptothecin, scopolamine Scopolectin and 9-aminocamptothecin); bryostatin; callystatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); podophyllotoxin; podophyllinic acid; teniposide; scutellarin cryptophycin (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fo fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as enediyne antibiotics (e.g., calicheamicins, especially calicheamicin gamma 1I and calicheamicin omega 1I) (see, e.g., Nicolaou et al., Angew. Chem Intl. Ed. Engl., 33:183-186 (1994)); CDP323, oral alpha-4 integrin inhibitors preparations; dynemicins, including dynemicin A; esperamicin; and neocarcinogen chromophores and related chromoprotein enediyne antibiotic chromophores), aclacinomycins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, cararubicin, bicin), caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including N-morpholino doxorubicin, cyano(N-morpholino) doxorubicin, 2-pyrrolino doxorubicin, deoxydoxorubicin hydrochloride liposomal injection, liposomal doxorubicin TLC D-99 pegylated liposomal doxorubicin, and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins (such as mitomycin C), mycophenolic acid acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate, gemcitabine, tegafur, capecitabine bine) epothilone and 5-fluorouracil (5-FU); combretastatin; folic acid analogs such as dimethylfolate, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as cyclocytidine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, propionate, epitiostanol, mepitiostane, testolactone; anti-adrenal antibodies such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folinic acid; aceglucuronolide; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansines, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; 2-ethylhydrazide; procarbazine; polysaccharide complex (JHS Natural Products, Eugene, Oreg.; razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2'-trichlorotriethylamine; trichothecenes (particularly T-2 toxin, verracurin A, roridin A, and anguidine); urethan; vindesine; dacarbazine; mannitol mustard; dibromomannitol; dibromodulcitol; pipobroman; gacytosine; arabinoside ("Ara-C");thiotepa; taxanes, such as paclitaxel (Bristol-Myers Squibb); Squibb Oncology, Princeton, NJ), albumin-engineered nanoparticle formulations of paclitaxel (ABRAXANE ^™ ), and docetaxel (Rhome-Poulene Rorer, Antony, France); chlorambucil; 6-thioguanine; mercaptopurine; methotrexate; platinum agents, such as cisplatin, oxaliplatin (for example), and carboplatin; periwinkle drugs that prevent tubulin polymerization to form microtubules, including the vinca alkaloids vincristine, vindesine, and vinorelbine etoposide (VP-16); ifosfamide; mitoxantrone; leucovorin; novantrone; edatrexate; daunorubicin; aminopterin; ibandronate; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid, including bexarotene; bisphosphonates, such as clodronate (e.g., or etidronate), NE-58095, zoledronic acid/zoledronate; alendronate; pamidronate; tiludronate; or risedronate; troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides, particularly those that inhibit gene expression in signaling pathways involved in abnormal cell proliferation, such as, for example, PKC-α, Raf, H-Ras, and epidermal growth factor receptor (EGF-R) (e.g., erlotinib (Tarceva ^™ )). )); and VEGF-A that reduces cell proliferation; vaccines, such as vaccines and gene therapy vaccines, such as vaccines, vaccines and vaccines; topoisomerase 1 inhibitors (for example); rmRH (for example); BAY439006 (sorafenib; Bayer); SU-11248 (sunitinib, Pfizer); perifosine, COX-2 inhibitors (for example, celecoxib or etoricoxib), proteosome inhibitors (for example, PS341); bortezomib CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitors, such as oblimersen sodium EGFR inhibitors; tyrosine kinase inhibitors; serine-threonine kinase inhibitors, such as rapamycin (sirolimus); farnesyl transferase inhibitors, such as lonafarnib (SCH 6636, SARASAR ^™ ); and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing; and combinations of two or more thereof, such as CHOP, which is an abbreviation for the combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone; and FOLFOX, which is an abbreviation for the treatment regimen of oxaliplatin (ELOXATIN ^™ ) in combination with 5-FU and leucovorin, and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing; and combinations of two or more thereof.

Chemotherapeutic agents as defined herein include "antihormonal agents" or "endocrine therapeutic agents" used to modulate, reduce, block or inhibit the effects of hormones that promote cancer growth. They can be hormones themselves, including but not limited to: antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including tamoxifen), raloxifene, droloxifene, 4-hydroxytamoxifen, troloxifene, raloxifene, LY117018, onapristone and FARESTON.cndot.toremifene; aromatase inhibitors that inhibit the aromatase enzyme that regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazole, aminoglutethimide, megestrol acetate, exestane, formestanie, fadrozole, vorozole, letrozole and anastrozole; and antiandrogens, such as flutamide, nilutamide, bisoprolol, drolaz ... Calutamide, leuprorelin and goserelin; and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides, particularly those that inhibit gene expression in signaling pathways involved in abnormal cell proliferation, such as, for example, PKC-α, Raf and H-Ras; ribozymes, such as VEGF expression inhibitors (e.g., ribozymes) and HER2 expression inhibitors; vaccines, such as gene therapy vaccines, for example, vaccine, vaccine and vaccine; rIL-2; topoisomerase 1 inhibitors; rmRH; vinorelbine and esperamicin (see U.S. Patent No. 4,675,187), and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing; and combinations of two or more of the foregoing.

The term "chimeric" antibody refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.

Unless otherwise indicated, the term "cluster of differentiation 3" or "CD3" as used herein refers to any native CD3 from any vertebrate source, including mammals, such as primates (e.g., humans) and rodents (e.g., mice and rats), including, for example, CD3ε, CD3γ, CD3α, and CD3β chains. The term encompasses "full-length" unprocessed CD3 (e.g., unprocessed or unmodified CD3ε or CD3γ), as well as any form of CD3 produced by processing in cells. The term also encompasses naturally occurring CD3 variants, including, for example, splice variants or allelic variants. CD3 includes, for example, a human CD3ε protein (NCBI Reference Sequence No. NP_000724) having a length of 207 amino acids and a human CD3γ protein (NCBI Reference Sequence No. NP_000064) having a length of 182 amino acids.

The "class" of an antibody refers to the type of constant domain or region possessed by its heavy chain. There are five major antibody classes: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subclasses (isotypes), such as _IgG1 , _IgG2 , _IgG3 , _IgG4 , _IgA1 , and _IgA2 . The heavy chain constant domains corresponding to the different immunoglobulin classes are called α, δ, ε, γ, and μ, respectively.

It should be understood that aspects and embodiments of the present invention described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

As used herein, the term "cytotoxic agent" refers to a substance that inhibits or prevents cell function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioisotopes (e.g., At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² and radioisotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adrenaline, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agents); growth inhibitors; enzymes and fragments thereof, such as ribozymes; antibiotics; toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof; and various antitumor or anticancer agents disclosed below.

A "disorder" is any condition that would benefit from treatment, including but not limited to chronic and acute disorders or diseases, including pathological conditions that predispose a mammal to the disorder.

The terms "cell proliferative disorder" and "proliferative disorder" refer to disorders associated with some degree of abnormal cell proliferation. In one embodiment, the cell proliferative disorder is cancer. In one embodiment, the cell proliferative disorder is a tumor.

The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and leukemias or lymphoid malignancies. More specific examples of such cancers include, but are not limited to, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma); lung cancer, including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma; peritoneal cancer; hepatocellular carcinoma; gastric cancer, including gastrointestinal cancer and gastrointestinal stromal cancer; pancreatic cancer; glioblastoma; cervical cancer; ovarian cancer; liver cancer; bladder cancer; urethral cancer; hepatocellular carcinoma; breast cancer; colon cancer, rectal cancer, colorectal cancer; endometrial cancer or uterine cancer; salivary gland cancer; kidney cancer; prostate cancer; vulvar cancer; thyroid cancer; liver cancer; anal cancer; penile cancer; melanoma, superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanoma, nodular melanoma; multiple myeloid and B-cell lymphoma (including low-grade/follicular non- Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate/follicular NHL; intermediate diffuse NHL; high-grade immunoblastic NHL; high-grade lymphoblastic NHL; high-grade small non-cleaved cell NHL; bulky NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); hairy cell leukemia; chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with keloids, edema (such as that associated with brain tumors), Meigs' syndrome, brain cancer, and head and neck cancer and related metastases. In certain embodiments, cancers that can be treated with the antibodies of the invention include breast cancer, colorectal cancer, rectal cancer, non-small cell lung cancer, glioblastoma, non-Hodgkin's lymphoma (NHL), renal cell carcinoma, prostate cancer, liver cancer, pancreatic cancer, soft tissue sarcoma, Kaposi's sarcoma, carcinoid carcinoma, head and neck cancer, ovarian cancer, mesothelioma, and multiple myeloma. In some embodiments, the cancer is selected from the group consisting of small cell lung cancer, glioblastoma, neuroblastoma, melanoma, breast carcinoma, gastric cancer, colorectal cancer (CRC), and hepatocellular carcinoma. In some embodiments, the cancer is selected from the group consisting of non-small cell lung cancer, colorectal cancer, glioblastoma, and breast carcinoma, including metastatic forms of those cancers. In other embodiments, the cancer is selected from a class of mature B cell cancers excluding Hodgkin's lymphoma but including germinal center B cell-like (GCB) DLBCL, activated B cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (L L), Waldenstrom's macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt's lymphoma (BL), B-cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, unclassified splenic lymphoma/leukemia, splenic diffuse red pulp small B-cell lymphoma, hairy cell leukemia variant, Waldenstrom's macroglobulinemia, heavy chain disease, alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma DLBCL, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodal marginal zone lymphoma, pediatric nodular marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicle center lymphoma, T cell/histiocyte-rich large B cell lymphoma, primary DLBCL of the CNS, primary cutaneous DLBCL leg type, EBV-positive DLBCL of the elderly, DLBCL associated with chronic inflammation, lymphomatoid granulomatosis, primary mediastinal (thymic) large B B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman's disease, primary effusion lymphoma, unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma, and unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin's lymphoma.

As used herein, "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. As mentioned herein, the terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" are not mutually exclusive.

As used herein, the term "tumor antigen" may be understood as referring to those antigens presented on tumor cells. These antigens may be presented on the cell surface together with the extracellular portion, which is usually combined with the transmembrane and cytoplasmic portions of the molecule. These antigens may sometimes be presented only by tumor cells and never by normal cells. Tumor antigens may be specifically expressed on tumor cells compared to normal cells, or may represent tumor-specific mutations. In this case, they are referred to as tumor-specific antigens. More common are tumor antigens presented by tumor cells and normal cells, and they are referred to as tumor-associated antigens. These tumor-associated antigens may be overexpressed compared to normal cells, or may be easily bound to antibodies in tumor cells due to the lower structural density of tumor tissue compared to normal tissue. In one aspect, the tumor antigens are selected from those described in Table 1 below.

"Effector functions" refer to those biological activities attributable to the Fc region of an antibody and vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor); and B cell activation.

An "effective amount" of a compound, such as an anti-CD3 antibody of the present invention, or a composition thereof (e.g., a pharmaceutical composition) is at least the minimum amount required to achieve a desired therapeutic or prophylactic result, such as a measurable improvement or prevention of a particular disorder (e.g., a cell proliferative disorder such as cancer). The effective amount herein may vary depending on a number of factors, such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also an amount in which any toxic or adverse effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of disease, including biochemical, histological, and/or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes present during disease progression. For therapeutic use, beneficial or desired results include clinical results such as reducing one or more symptoms resulting from the disease, improving the quality of life of those suffering from the disease, reducing the dose of other drug treatments required to treat the disease, enhancing the effect of another drug treatment (e.g., through targeting), delaying disease progression, and/or prolonging survival. In the case of cancer or tumors, the effect that an effective amount of a drug may have is to reduce the number of cancer cells; reduce the size of the tumor; inhibit (i.e., slow down to some extent or ideally stop) the infiltration of cancer cells into peripheral organs; inhibit (i.e., slow down to some extent, and ideally stop) tumor metastasis; inhibit tumor growth to some extent; and/or alleviate one or more symptoms associated with the condition to some extent. An effective amount may be administered in one or more administrations. For the purposes of the present invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to achieve a preventive or therapeutic treatment, directly or indirectly. As understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an effective amount may be considered in the context of administering one or more therapeutic agents, and it may be considered that an effective amount of a single agent is administered, which, if combined with one or more other agents, may be or achieve a desired result.

The term "Fc region" herein is used to define the C-terminal region of at least a portion of an immunoglobulin heavy chain containing a constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, the human IgG heavy chain Fc region extends from Cys226 or Pro230 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) in the Fc region may or may not be present. Unless otherwise specified herein, the amino acid residues in the Fc region or constant region are numbered according to the EU numbering system, also referred to as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

"Framework" or "FR" refers to variable domain residues excluding hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Accordingly, HVR and FR sequences generally appear in the following order in VH (or VL): FR1-H1 (L1)-FR2-H2 (L2)-FR3-H3 (L3)-FR4.

The terms "full length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody that has a structure substantially similar to a native antibody structure or has heavy chains that contain an Fc region as defined herein.

"Growth inhibitor" as used herein refers to a compound or composition that inhibits cell growth in vitro or in vivo. In one embodiment, a growth inhibitor is a growth inhibitory antibody that prevents or reduces the proliferation of cells expressing an antigen to which the antibody binds. In another embodiment, a growth inhibitor may be a growth inhibitor that significantly reduces the percentage of cells in the S phase. Examples of growth inhibitors include agents that block cell cycle progression (at a site other than the S phase), such as agents that induce G1 arrest and M phase arrest. Classical M phase blockers include vinca (vincristine and vinblastine), taxanes, and topoisomerase II inhibitors, such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Those agents that block G1 also penetrate into the S phase arrest, such as DNA alkylating agents, such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C. Further information can be found in Mendelsohn and Israel (eds.), The Molecular Basis of Cancer, Chapter 1, Murakami et al., entitled "Cell cycle regulation, oncogenes, and antimetoplastic drugs" (W.B. Saunders, Philadelphia, 1995), e.g., page 13. Taxanes (paclitaxel and docetaxel) are anticancer drugs derived from the yew tree. Docetaxel (Rhone-Poulenc Rorer), derived from the European yew tree, is a semisynthetic analog of paclitaxel (Bristol-Myers Squibb). Paclitaxel and docetaxel promote the assembly of microtubules from tubulin dimers and stabilize microtubules by preventing depolymerization, thereby inhibiting mitosis in cells.

The term "HER2-positive" cancer includes cancer cells with higher than normal levels of HER2. Examples of HER2-positive cancers include HER2-positive breast cancer and HER2-positive gastric cancer. Optionally, the HER2-positive cancer has an immunohistochemistry (IHC) score of 2+ or 3+ and/or an in situ hybridization (ISH) amplification ratio of ≥2.0.

The terms "host cell," "host cell strain," and "host cell culture" are used interchangeably to refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," including the primary transformed cell and progeny derived therefrom, regardless of the number of subsequent generations. Progeny may not be completely identical in nucleic acid content to the parent cell and may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.

A "human antibody" is an antibody whose amino acid sequence corresponds to the amino acid sequence of an antibody produced by a human or human cell or derived from a non-human source using a human antibody repertoire or other human antibody encoding sequence. This definition of a human antibody specifically excludes humanized antibodies comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227: 381 (1991); Marks et al., J. Mol. Biol., 222: 581 (1991). Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147 (1): 86-95 (1991) methods described can also be used to prepare human monoclonal antibodies. See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5: 368-74 (2001). Human antibodies can be prepared by administering an antigen to a transgenic animal (e.g., an immune xenogeneic mouse) that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled (for XENOMOUSE ^™ technology, see, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584). See also, e.g., Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006), for human antibodies produced via human B cell hybridoma technology.

A "human common framework" is a framework that represents the amino acid residues that are most commonly present in a selection of human immunoglobulin VL or VH framework sequences. Generally, a human immunoglobulin VL or VH sequence is selected from a subset of variable domain sequences. Generally, a subset of sequences is a subset as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is subgroup κI as described in Kabat et al., supra. In one embodiment, for VH, the subgroup is subgroup III as described in Kabat et al., supra.

A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody will comprise substantially all of at least one and typically two variable domains, wherein all or substantially all of the HVRs (e.g., CDRs) correspond to the HVRs of a non-human antibody, and all or substantially all of the FRs correspond to the FRs of a human antibody. A humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has been humanized.

As used herein, the term "hypervariable region" or "HVR" refers to each region of an antibody variable domain that has sequence hypervariability ("complementarity determining regions" or "CDRs") and/or forms structurally defined loops ("hypervariable loops") and/or contains antigen-contacting residues ("antigen contacts"). Generally, antibodies comprise six HVRs: three in VH (H1, H2, H3) and three in VL (L1, L2, L3). Exemplary HVRs herein include:

(a) Hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987));

(b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991));

(c) Antigenic contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al., J. Mol. Biol. 262:732-745 (1996)); and

(d) A combination of (a), (b) and/or (c), comprising HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3) and 94-102 (H3).

Unless otherwise indicated, HVR residues and other residues in the variable domain (eg, FR residues) are numbered herein according to Kabat et al., supra.

An "immunoconjugate" is a conjugate of an antibody with one or more heterologous molecules, including but not limited to a cytotoxic agent.

A "subject" or "individual" is a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the individual is a human.

An "isolated" antibody is one that has been separated from the components of its natural environment. In some embodiments, the antibody is purified to a purity greater than 95% or 99%, as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reversed-phase HPLC). For a review of methods for assessing antibody purity, see, for example, Flatman et al., J. Chromatogr. B 848:79-87 (2007).

An "isolated" nucleic acid is one that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but where the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

"Isolated nucleic acid encoding an anti-CD3 antibody" refers to one or more nucleic acid molecules encoding the antibody heavy and light chains (or fragments thereof), including such nucleic acid molecules in a single vector or separate vectors, and such nucleic acid molecules are present at one or more locations in a host cell.

As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies constituting the population are identical and/or bind identical epi-positions, but except for possible variant antibodies, which for example contain naturally occurring mutations or occur during the preparation of monoclonal antibodies, and such variants are generally present in trace amounts. In contrast to polyclonal antibody preparations typically comprising different antibodies for different determinants (epi-positions), each monoclonal antibody of a monoclonal antibody preparation is directed to a single determinant on an antigen. Thus, the modifier "monoclonal" indicates that the characteristic of an antibody is obtained from a population of substantially homogeneous antibodies, and should not be considered as requiring antibody production by any ad hoc method. For example, the monoclonal antibody used in accordance with the present invention can be manufactured by various techniques, including but not limited to hybridoma methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of human immunoglobulin loci, such methods and other exemplary methods for the manufacture of monoclonal antibodies are described herein.

A "naked antibody" is an antibody that is not conjugated to a heterologous moiety (eg, a cytotoxic moiety) or a radiolabel. Naked antibodies can be present in pharmaceutical formulations.

"Natural antibodies" refer to naturally occurring immunoglobulin molecules with different structures. For example, natural IgG antibodies are heterotetrameric glycoproteins of about 150,000 daltons consisting of two identical light chains and two identical heavy chains bonded by disulfide bonds. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also referred to as a variable heavy chain domain or a heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also referred to as a variable light chain domain or a light chain variable domain, followed by a constant light chain (CL) domain. The light chain of an antibody can be divided into one of two types based on the amino acid sequence of its constant domain, referred to as κ (kappa) and λ (lambda).

The term "package insert" is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic products.

The term "PD-1 axis binding antagonist" refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with one or more of its binding partners to remove T cell dysfunction caused by signaling on the PD-1 signaling axis, resulting in restoration or enhancement of T cell function (e.g., proliferation, cytokine production, target cell killing). As used herein, PD-1 axis binding antagonists include PD-1 binding antagonists, PD-L1 binding antagonists, and PD-L2 binding antagonists.

The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, prevents or interferes with the signal transduction caused by the interaction of PD-1 with one or more of its binding partners (such as PD-L1, PD-L2). In some embodiments, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In a specific aspect, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that reduce, block, inhibit, prevent or interfere with the signal transduction caused by the interaction of PD-1 with PD-L1 and/or PD-L2. In one embodiment, the PD-1 binding antagonist reduces negative co-stimulatory signals mediated by or via cell surface proteins expressed on T lymphocytes that mediate signal transduction via PD-1, so as to alleviate the dysfunction of dysfunctional T cells (e.g., enhance effector responses to antigen recognition). In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. In one specific aspect, the PD-1 binding antagonist is MDX-1106 (nivolumab) as described herein. In another specific aspect, the PD-1 binding antagonist is MK-3475 (lanloizumab) as described herein. In another specific aspect, the PD-1 binding antagonist is CT-011 (picolizumab) as described herein. In another specific aspect, the PD-1 binding antagonist is AMP-224 as described herein.

The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, prevents or interferes with signal transduction caused by the interaction of PD-L1 with one or more of its binding partners (such as PD-1, B7-1). In some embodiments, the PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partner. In a specific aspect, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and/or B7-1. In some embodiments, the PD-L1 binding antagonist includes an anti-PD-L1 antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, an oligopeptide, and other molecules that reduce, block, inhibit, prevent or interfere with signal transduction caused by the interaction of PD-L1 with one or more of its binding partners (such as PD-1, B7-1). In one embodiment, the PD-L1 binding antagonist reduces negative co-stimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes that mediate signaling through PD-L1, so as to alleviate the dysfunction of dysfunctional T cells (e.g., enhance the effector response to antigen recognition). In some embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antibody. In a specific aspect, the anti-PD-L1 antibody is YW243.55.S70 described herein. In another specific aspect, the anti-PD-L1 antibody is MDX-1105 described herein. In another specific aspect, the anti-PD-L1 antibody is MPDL3280A described herein. In another specific aspect, the anti-PD-L1 antibody is MEDI4736 described herein.

The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, prevents or interferes with the signal transduction caused by the interaction of PD-L2 with one or more of its binding partners (such as PD-1). In some embodiments, the PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In a specific aspect, the PD-L2 binding antagonist inhibits the binding of PD-L2 to PD-1. In some embodiments, the PD-L2 antagonist includes anti-PD-L2 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that reduce, block, inhibit, prevent or interfere with the signal transduction caused by the interaction of PD-L2 with one or more of its binding partners (such as PD-1). In one embodiment, the PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or via cell surface proteins expressed on T lymphocytes that mediate signal transduction via PD-L2, so as to reduce the dysfunction of the dysfunctional T cells (e.g., enhance the effector response to antigen recognition). In some embodiments, the PD-L2 binding antagonist is an immunoadhesin.

Unless otherwise indicated, the term "protein" as used herein refers to any native protein from any vertebrate source, including mammals, such as primates (e.g., humans) and rodents (e.g., mice and rats). The term encompasses "full-length" unprocessed protein as well as any form of the protein produced by processing in cells. The term also encompasses naturally occurring variants of the protein, such as splice variants or allelic variants. Proteins according to the present invention include, for example, any of the proteins listed in Table 1.

"Percentage (%) of amino acid sequence identity" with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in the candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, after the candidate sequence and, if necessary, gaps are introduced to achieve the maximum percentage of sequence identity, and in the case where any conservative substitutions are not considered part of the sequence identity. Alignment for the purpose of determining percentage of amino acid sequence identity can be achieved in a variety of ways within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. One skilled in the art can determine the parameters suitable for aligning sequences, including any algorithm required to achieve maximum alignment over the full length of the compared sequences. However, for the purposes of this article, amino acid sequence identity % values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program is licensed by Genentech, Inc., and the source code has been submitted with user files to the U.S. Copyright Office (Washington D.C., 20559) and is deposited here with U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc. (South San Francisco, California) or can be compiled from source code. The ALIGN-2 program should be compiled for UNIX operating systems, including digital UNIX V4.0D. All sequence comparison parameters are set by the ALIGN-2 program and do not vary.

In the case of amino acid sequence comparison using ALIGN-2, the % amino acid sequence identity of a specified amino acid sequence A to, with, or relative to a specified amino acid sequence B (which can alternatively be expressed as a specified amino acid sequence A having or comprising a certain % amino acid sequence identity to, with, or relative to a specified amino acid sequence B) is calculated as follows:

100 × fraction X/Y

Wherein X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 when the program aligns A and B, and wherein Y is the total number of amino acid residues in B. It will be understood that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not be equal to the % amino acid sequence identity of B to A. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are obtained using the ALIGN-2 computer program as described in the preceding paragraph.

The term "pharmaceutical formulation" refers to a preparation that is in such form as to permit the biological activity of the active ingredient contained therein to be effective and that contains no additional ingredients that are unacceptably toxic to a subject to which the formulation would be administered.

"Pharmaceutically acceptable carrier" refers to a component of a pharmaceutical preparation other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

As used herein, "treatment" (and grammatical variations thereof) refers to clinical intervention that attempts to alter the natural course of the individual being treated, and can be performed for prevention or during the course of clinical pathology. Desirable therapeutic effects include, but are not limited to, preventing the onset or recurrence of the disease, alleviating symptoms, eliminating any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, ameliorating or slowing the disease state, and alleviating or improving prognosis. In some embodiments, the antibodies of the invention are used to delay disease development or slow disease progression.

As used herein, "delaying" the "progression" of a condition or disease means to slow, hinder, slow, postpone, stabilize, and/or postpone the development of a disease or condition (e.g., a cell proliferative disorder such as cancer). This delay can be of varying duration, depending on the medical history and/or the individual being treated. As will be apparent to one skilled in the art, a substantial or significant delay can actually encompass prevention, in that the individual does not develop the disease. For example, the development of advanced cancers, such as metastases, can be delayed.

"Reduce" or "inhibit" means being able to cause an overall decrease, for example, 20% or more, 50% or more, or 75%, 85%, 90%, 95% or more. In certain embodiments, reduction or inhibition may refer to antibody effector functions mediated by the Fc region of the antibody, specifically, such effector functions include complement dependent cytotoxicity (CDC), antibody dependent cellular cytotoxicity (ADCC) and antibody dependent cellular phagocytosis (ADCP).

The term "variable region" or "variable domain" refers to the domain of an antibody heavy chain or light chain involved in binding an antibody to an antigen. The variable domains of the heavy and light chains (VH and VL, respectively) of natural antibodies generally have a similar structure, with each domain comprising four conserved framework regions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindt et al., Kuby Immunology, 6th ed., W.H. Freeman and Co., p. 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. In addition, VH or VL domains from antibodies that bind to a specific antigen can be used to isolate antibodies that bind to that antigen to screen libraries of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150: 880-887 (1993); Clarkson et al., Nature 352: 624-628 (1991).

As used herein, the term "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes vectors in the form of self-replicating nucleic acid structures as well as vectors incorporated into the genome of a host cell into which they have been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors."

As used herein, "administering" refers to a method of administering a dose of a compound (e.g., an anti-CD3 antibody of the invention or a nucleic acid encoding an anti-CD3 antibody of the invention) or composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition comprising an anti-CD3 antibody of the invention) to a subject. The compositions utilized in the methods described herein can be administered, for example, intramuscularly, intravenously, intradermally, transdermally, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, locally, intratumorally, peritoneally, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, transdermally, topically, by inhalation, by injection, by infusion, by continuous infusion, by direct local perfusion bathing target cells, by catheter, by lavage, in a cream, or in a lipid composition. The method of administration can vary depending on various factors, such as the compound or composition being administered and the severity of the condition, disease, or disorder being treated.

II. Compositions and Methods

In one aspect, the present invention is based in part on anti-CD3 antibodies. In certain embodiments, the anti-CD3 antibodies are multispecific (e.g., bispecific) and bind to a second biomolecule (e.g., a cell surface antigen, such as a tumor antigen) in addition to CD3 or a fragment thereof. The antibodies of the present invention are useful, for example, in treating or delaying the progression of cell proliferative disorders (e.g., cancer) or autoimmune disorders, or in enhancing immune function in individuals suffering from such disorders.

A. Exemplary anti-CD3 antibodies

In one aspect, the invention provides isolated antibodies that bind CD3 (eg, CD3ε and/or CD3γ).

For example, in one aspect, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 301-304, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 305-308, respectively. In some instances, the anti-CD3 antibody may have a heavy chain variable (VH) domain that can include an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 184, and/or a light chain variable (VL) domain that includes an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 185. In other instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 293-296, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 297-300, respectively. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 186, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 187. In certain instances, the anti-CD3 antibody may be 40G5c or a derivative or clone thereof.

In another aspect, an antibody of the invention comprises (a) a VH domain comprising at least one, at least two, or all three VH HVR sequences selected from the group consisting of: (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2, and (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and (b) a VL domain comprising at least one, at least two, or all three VL HVR sequences selected from the group consisting of: (i) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5, and (iii) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6. In some instances, the anti-CD3 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 184 and a VL domain comprising the amino acid sequence of SEQ ID NO: 185. In some cases, the anti-CD3 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 186 and a VL domain comprising the amino acid sequence of SEQ ID NO: 187. In certain instances, the anti-CD3 antibody may be 40G5c or a derivative or clone thereof.

In one aspect, the present invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 181; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 182.

In certain embodiments, any one or more amino acids of an anti-CD3 antibody as provided above are substituted at the following HVR positions:

- in HVR-H3 (SEQ ID NO: 181): positions 1, 2, 5, 6 and 7; and

- in HVR-L3 (SEQ ID NO: 182): positions 1, 2, 4 and 5.

In certain embodiments, such substitutions are conservative substitutions as provided herein. In certain embodiments, any one or more of the following substitutions can be made in any combination:

- in HVR-H3 (SEQ ID NO: 181): D1T or S; S1D or T; T1D or S; G2A or S; A2G or S; S2A or G; R5N; N5R; Y6A; A6Y; A7Y; and Y7A; and

- in HVR-L3 (SEQ ID NO: 182): K1T; T1K; Q2A; A2Q; F4A; A4F; I5A and A5I.

For example, in some cases, the present invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:12. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 188, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 189. In certain instances, the anti-CD3 antibody may be 38E4v1 or a derivative or clone thereof.

In some instances, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:12. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 190, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 191. In certain instances, the anti-CD3 antibody may be 38E4v2 or a derivative or clone thereof.

In some instances, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:14. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 192, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 193. In certain instances, the anti-CD3 antibody may be 38E4v3 or a derivative or clone thereof.

In some instances, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:15. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 194, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 195. In certain instances, the anti-CD3 antibody may be 38E4v4 or a derivative or clone thereof.

In some instances, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:16. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 196, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 197. In certain instances, the anti-CD3 antibody may be 38E4v5 or a derivative or clone thereof.

In some instances, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 198, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 199. In certain instances, the anti-CD3 antibody may be 38E4v6 or a derivative or clone thereof.

In some instances, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:12. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 200, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 201. In certain instances, the anti-CD3 antibody may be 38E4v7 or a derivative or clone thereof.

In some instances, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:12. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 202, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 203. In certain instances, the anti-CD3 antibody may be 38E4v8 or a derivative or clone thereof.

In some instances, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:12. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 204, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 205. In certain instances, the anti-CD3 antibody may be 38E4v9 or a derivative or clone thereof.

In some instances, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 206, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 207. In certain instances, the anti-CD3 antibody may be 38E4c or a derivative or clone thereof.

In some cases, any of the 38E4v1-38E4v9 and 38E4c anti-CD3 antibodies can include at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 309-312, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 313-316, respectively.

In one aspect, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 183; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28.

In certain embodiments, any one or more amino acids of an anti-CD3 antibody as provided above are substituted at the following HVR positions:

- in HVR-H2 (SEQ ID NO: 183): positions 9, 12, 13, 14, 15 and 17.

In certain embodiments, such substitutions are conservative substitutions as provided herein. In certain embodiments, any one or more of the following substitutions can be made in any combination:

- in HVR-H2 (SEQ ID NO: 183): S9T; T9S; N12A; A12N; Q13D; D13Q; K14S; S14K; F15V; V15F; D17G; and G17D.

For example, in some cases, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 317-320, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 321-324, respectively. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 208, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 209. In certain instances, the anti-CD3 antibody may be UCHT1v9 or a derivative or clone thereof.

In some instances, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 325-328, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 329-332, respectively. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 210, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 211. In certain instances, the anti-CD3 antibody may be UCHT1v1 or a derivative or clone thereof.

In some instances, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 333-336, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 337-340, respectively. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 212, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 213. In certain instances, the anti-CD3 antibody may be UCHT1vM1 or a derivative or clone thereof.

In one aspect, the present invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 341-344, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 345-348, respectively. In some instances, the anti-CD3 antibody may have an amino acid sequence whose heavy chain variable (VH) domain comprises an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 214, and/or a light chain variable (VL) domain comprises an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 215. In other instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 349-352, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 353-356, respectively. In some instances, the anti-CD3 antibody may comprise a VH domain having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, 140%, 141%, 142%, 143%, 144%, 145%, 146%, 147%, 148%, 149%, 150%, 151%, 152%, 153%, 154%, 155%, 1

In certain instances, the anti-CD3 antibody may be SP34v52 or a derivative or clone thereof.

In one aspect, the present invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 357-360, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 361-364, respectively. In some instances, the anti-CD3 antibody may have an amino acid sequence whose heavy chain variable (VH) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 218, and/or a light chain variable (VL) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 219. In other instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 365-368, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 369-372, respectively. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 220, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 221. In certain instances, the anti-CD3 antibody may be 41D9a or a derivative or clone thereof.

In one aspect, the present invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 373-376, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 377-380, respectively. In some instances, the anti-CD3 antibody may have an amino acid sequence as a heavy chain variable (VH) domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 222, and/or a light chain variable (VL) domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 223. In other instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 381-384, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 385-388, respectively. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 226, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 227. In certain instances, the anti-CD3 antibody may be 13A3 or a derivative or clone related thereto.

In some instances, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5, or 6 HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 389-392, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 393-396, respectively. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 224, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 225. In certain instances, the anti-CD3 antibody may be 13A3.v2 or a derivative or clone thereof.

In one aspect, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 397-400, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 401-404, respectively. In some instances, the anti-CD3 antibody may have an amino acid sequence whose heavy chain variable (VH) domain comprises an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 228, and/or a light chain variable (VL) domain comprises an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 229. In other instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 405-408, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 409-412, respectively. In some instances, the anti-CD3 antibody may have a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 230, and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 231. In certain instances, the anti-CD3 antibody may be 30A1 or a derivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 413-416, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 417-420, respectively. In some instances, the anti-CD3 antibody may have a heavy chain variable (VH) domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 232, and/or a light chain variable (VL) domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 233. In certain instances, the anti-CD3 antibody may be 30A1.v2 or a derivative or clone thereof.

In one aspect, the present invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 421-424, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 425-428, respectively. In some instances, the anti-CD3 antibody may have an amino acid sequence whose heavy chain variable (VH) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 234, and/or a light chain variable (VL) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 235. In certain instances, the anti-CD3 antibody may be h21A9 or a derivative or clone thereof.

In one aspect, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 429-432, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 433-436, respectively. In some instances, the anti-CD3 antibody may have an amino acid sequence whose heavy chain variable (VH) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 236, and/or a light chain variable (VL) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 237. In certain instances, the anti-CD3 antibody may be 21B2 or a derivative or clone thereof.

In one aspect, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 437-440, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 441-444, respectively. In some instances, the anti-CD3 antibody may have a heavy chain variable (VH) domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 238, and/or a light chain variable (VL) domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 239. In certain instances, the anti-CD3 antibody may be 125A1 or a derivative or clone thereof.

In one aspect, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 445-448, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 449-452, respectively. In some instances, the anti-CD3 antibody may have a heavy chain variable (VH) domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 240, and/or a light chain variable (VL) domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 241. In certain instances, the anti-CD3 antibody may be 72H6 or a derivative or clone thereof.

In one aspect, the invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 453-456, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 457-460, respectively. In some instances, the anti-CD3 antibody may have a heavy chain variable (VH) domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 242, and/or a light chain variable (VL) domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 243. In certain instances, the anti-CD3 antibody may be 19B1 or a derivative or clone thereof.

In one aspect, the present invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 461-464, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 465-468, respectively. In some instances, the anti-CD3 antibody may have an amino acid sequence whose heavy chain variable (VH) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 244, and/or a light chain variable (VL) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 245. In certain instances, the anti-CD3 antibody may be 71H7 or a derivative or clone thereof.

In one aspect, the present invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 469-472, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 473-476, respectively. In some instances, the anti-CD3 antibody may have an amino acid sequence whose heavy chain variable (VH) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 246, and/or a light chain variable (VL) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 247. In certain instances, the anti-CD3 antibody may be 14C7 or a derivative or clone thereof.

In one aspect, the present invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 477-480, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 481-484, respectively. In some instances, the anti-CD3 antibody may have an amino acid sequence whose heavy chain variable (VH) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 248, and/or a light chain variable (VL) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 249. In certain instances, the anti-CD3 antibody may be 127B3 or a derivative or clone thereof.

In one aspect, the present invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 485-488, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 489-492, respectively. In some instances, the anti-CD3 antibody may have a heavy chain variable (VH) domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 250, and/or a light chain variable (VL) domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 251. In certain instances, the anti-CD3 antibody may be 18F12 or a derivative or clone thereof.

In one aspect, the present invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 493-496, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 497-500, respectively. In some instances, the anti-CD3 antibody may have a heavy chain variable (VH) domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 252, and/or a light chain variable (VL) domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 253. In certain instances, the anti-CD3 antibody may be 27H5-1 or a derivative or clone thereof.

In one aspect, the present invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 501-504, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 505-508, respectively. In some instances, the anti-CD3 antibody may have an amino acid sequence whose heavy chain variable (VH) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 254, and/or a light chain variable (VL) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 255. In certain instances, the anti-CD3 antibody may be 39B7 or a derivative or clone thereof.

In one aspect, the present invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 509-512, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 513-516, respectively. In some instances, the anti-CD3 antibody may have an amino acid sequence whose heavy chain variable (VH) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 256, and/or a light chain variable (VL) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 257. In certain instances, the anti-CD3 antibody may be 40D2 or a derivative or clonal relative thereof.

In one aspect, the present invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 517-520, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 521-524, respectively. In some instances, the anti-CD3 antibody may have an amino acid sequence whose heavy chain variable (VH) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 258, and/or a light chain variable (VL) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 259. In certain instances, the anti-CD3 antibody may be 79B7 or a derivative or clone thereof.

In one aspect, the present invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 525-528, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 529-532, respectively. In some instances, the anti-CD3 antibody may have a heavy chain variable (VH) domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 260, and/or a light chain variable (VL) domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 261. In certain instances, the anti-CD3 antibody may be 95A2 or a derivative or clonal relative thereof.

In one aspect, the present invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 533-536, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 537-540, respectively. In some instances, the anti-CD3 antibody may have an amino acid sequence whose heavy chain variable (VH) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 262, and/or a light chain variable (VL) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 263. In certain instances, the anti-CD3 antibody may be 118G9 or a derivative or clone thereof.

In one aspect, the present invention provides an anti-CD3 antibody having a binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156. In some instances, the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 541-544, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 545-548, respectively. In some instances, the anti-CD3 antibody may have an amino acid sequence whose heavy chain variable (VH) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 264, and/or a light chain variable (VL) domain comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 265. In certain instances, the anti-CD3 antibody may be Rabl7 or a derivative or clone thereof.

In any of the above embodiments, the anti-CD3 antibody is humanized.In one embodiment, the anti-CD3 antibody comprises HVRs as in any of the above embodiments, and further comprises an acceptor human framework, eg, a human immunoglobulin framework or a human common framework.

In another aspect, an anti-CD3 antibody is provided, wherein the antibody comprises a VH as in any of the embodiments provided above and a VL as in any of the embodiments provided above, wherein one or both of such variable domain sequences include a post-translational modification.

In another aspect, the present invention provides an antibody that binds to the same epitope as an anti-CD3 antibody provided herein. For example, in certain embodiments, the antibodies provided herein bind to the same epitope as an anti-CD3 antibody comprising the VH sequence of SEQ ID NO: 184 and the VL sequence of SEQ ID NO: 185. In certain embodiments, antibodies are provided that bind to an epitope within a fragment of CD3 (e.g., human CD3 epsilon) consisting of amino acids 1-26 (SEQ ID NO: 283) or 1-27 (SEQ ID NO: 278) of human CD3 epsilon.

In another aspect, the present invention provides an antibody that binds to a unique CD3 epitope. In certain embodiments, an anti-CD3 antibody of the invention forms unique contacts with amino acids in human CD3ε that are adjacent or closer to the epitope. In certain embodiments, the provided antibody binds to an epitope consisting of 1, 2, 3, 4, or 5 amino acids in human CD3ε that are adjacent or closer to the epitope. In one embodiment, an anti-CD3 antibody of the invention uniquely contacts amino acids in human CD3ε that are adjacent or closer to the epitope. In certain embodiments, the provided antibody binds to an epitope consisting of 1, 2, 3, 4, or 5 amino acids in human CD3ε that are adjacent or closer to the epitope. For example, in certain embodiments, the provided antibody binds to an epitope consisting of amino acids in human CD3ε selected from Gln1, Asp2, Asn4, Glu6, and Met7. In a specific embodiment, the anti-CD3 antibody binds to an epitope that specifically includes Glu6. In certain other embodiments, the provided antibody does not bind to an epitope that includes amino acid Glu5 in human CD3ε. In certain other embodiments, the provided antibody does not bind to an epitope that includes amino acids Gly3 and Glu5 in human CD3ε.

Anti-CD3 epitopes can be determined by binding of an anti-CD3 antibody to a peptide fragment of the epitope. Alternatively, the anti-CD3 epitope can be determined by alanine scanning mutagenesis. In one embodiment, a 20%, 30%, 50%, 80% or more reduction in binding of an anti-CD3 antibody to a mutant CD3 indicates that the mutated CD3 amino acid residue in the alanine scanning mutagenesis assay is an epitope residue of the anti-CD3 antibody. Alternatively, the anti-CD3 epitope can be determined by mass spectrometry. In some embodiments, the epitope is determined by crystallography (e.g., the crystallographic method described in the Examples).

In some embodiments, the epitope as determined by crystallography is determined using amino acids Q1-M7 of CD3. In some embodiments, the epitope as determined by crystallography is determined using amino acids QDGNEEMGGITQTPYK (SEQ ID NO: 284) of CD3.

In some embodiments, epitopes as determined by crystallography can be determined by combining anti-CD3 antibody Fab dissolved in 0.15 M NaCl, 25 mM tris pH 7.5 (10 mg/ml) with a 2-fold molar excess (1 mg) of CD3ε peptide and initially screening a sparse matrix of precipitates using a sitting-drop vapor diffusion format. Optimized crystals can be grown from a 1:1 mixture of a stock solution containing 70% v/v methylpentanediol and 0.1 M HEPES buffer, pH 7.5. This stock solution can be used as a cryoprotectant. Crystals can be transferred to extremely cold temperatures by sudden immersion in liquid nitrogen.

Diffraction data of the crystals were collected using a MAR300 CCD detector at an Advanced Photon Source beamline of 22 ID. The recorded diffractograms were integrated and scaled using the program HKL2000.

The structure was phased using the molecular replacement (MR) method using the Phaser program. For example, the MR search model was the Fab subunit (PDB code: 2R0L) derived from the HGFA/Fab complex crystal structure. The CD3ε peptide was incorporated into the structure based on the Fo-Fc spectrum. The structure was then refined using the REFMAC5 and PHENIX programs using a maximum probability objective function, anisotropic individual B-factor refinement, and TLS refinement until convergence.

In certain other embodiments, the antibodies provided include antibody determinants that bind to the same epitope as the anti-CD3 antibodies provided herein. For example, in certain embodiments, the antibodies provided bind to the same epitope as the anti-CD3 antibody determinants comprising amino acids that form contact at a distance of 1 or 2 or closer. In certain embodiments, the antibodies provided bind to the same epitope as the anti-CD3 antibody determinants consisting of amino acids in the anti-CD3 antibody VH region selected from the group comprising 33Tyr, 35His, 50Trp, 97Tyr and 98Ser. In certain embodiments, the antibodies provided bind to the same epitope as the anti-CD3 antibody determinants consisting of amino acids in the anti-CD3 antibody VH region selected from the group comprising 33Tyr, 35His, 50Trp, 97Tyr and 98Ser. In certain embodiments, the antibodies provided bind to the same epitope as an anti-CD3 antibody determinant consisting of an anti-CD3 antibody VL region amino acid selected from the group consisting of 27Arg, 27Asn, 30Lys, 32Tyr, 92Phe, 94Leu, and 96Arg. In certain embodiments, the antibodies provided bind to the same epitope as an anti-CD3 antibody determinant consisting of 1, 2, 3, 4, 5, 6, or 7 anti-CD3 antibody VL region amino acids selected from the group consisting of 27Arg, 27Asn, 30Lys, 32Tyr, 92Phe, 94Leu, and 96Arg. In an optional embodiment, the antibodies provided do not bind to the same epitope as an anti-CD3 antibody determinant consisting of a VL region amino acid comprising 91Ser. In another aspect of the invention, the anti-CD3 antibody according to any of the above embodiments is a monoclonal antibody, including a chimeric antibody, a humanized antibody, or a human antibody. In one embodiment, the anti-CD3 antibody is an antibody fragment, such as an Fv, Fab, Fab', scFv, diabody, or F(ab') ₂ fragment. In another embodiment, the antibody is a full-length antibody, such as an intact IgG antibody (e.g., an intact IgG1 antibody), or other antibody classes or isotypes as defined herein.

In another aspect, the anti-CD3 antibody according to any of the above embodiments may incorporate any single feature or combination thereof as described in Sections 1 to 7 below.

1. Antibody affinity

In certain embodiments, the dissociation constant (Kd) of an antibody provided herein is ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 ⁻⁸ M or less, e.g., 10 ⁻⁸ M to 10 ⁻¹³ M, e.g., 10 ⁻⁹ M to 10 ⁻¹³ M).

In one embodiment, Kd is measured by radiolabeled antigen binding assay (RIA). In one embodiment, RIA is performed using a Fab form of the relevant antibody and its antigen. For example, the solution binding affinity of Fab for antigen is measured by balancing Fab with a very low concentration of ( ¹²⁵ I) labeled antigen in the presence of a titration series of unlabeled antigen, followed by capturing the bound antigen with a plate coated with an anti-Fab antibody (see, for example, Chen et al., J. Mol. Biol. 293: 865-881 (1999)). In order to establish the conditions for this assay, a multiwell plate (ThermoScientific) was coated overnight with 50 mM sodium carbonate (pH 9.6) containing 5 μg/ml capture anti-Fab antibody (Cappel Labs), and then blocked for 2 to 5 hours at room temperature (about 23°C) with PBS containing 2% (w/v) bovine serum albumin. In a non-adsorbent plate (Nunc #269620), 100 pM or 26 pM [ ¹²⁵ I]-antigen is mixed with a serial dilution of the relevant Fab (e.g., as assessed for the anti-VEGF antibody Fab-12 in Presta et al., Cancer Res. 57:4593-4599 (1997)). The relevant Fab is then incubated overnight; however, the incubation can be continued for a longer period (e.g., about 65 hours) to ensure that equilibrium is reached. Thereafter, such a mixture is transferred to a capture plate for incubation at room temperature (e.g., 1 hour). The solution is then removed and the plate is washed 8 times with PBS containing 0.1% polysorbate 20. When the plate has dried, 150 μl/well scintillant (MICROSCINT-20 ^™ ; Packard) is added and the plate is counted for 10 minutes on a TOPCOUNT ^™ gamma counter (Packard). Concentrations of each Fab that provide less than or equal to 20% maximal binding are selected for competitive binding assays.

According to another embodiment, Kd is measured using a surface plasmon resonance assay. For example, an assay using or (BIAcore, Inc., Piscataway, NJ) is performed at 25°C with an immobilized antigen CM5 chip at approximately 10 response units (RU). In one embodiment, a carboxymethylated dextran biosensor chip (CM5, BIACORE, Inc.) is activated with N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the manufacturer's instructions. Antigen is diluted to 5 μg/ml (approximately 0.2 μM) with 10 mM sodium acetate, pH 4.8, and then injected at a flow rate of 5 μl/min to achieve approximately 10 response units (RU) of coupled protein. Following antigen injection, 1 M ethanolamine is injected to block unreacted groups. In kinetic measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) were injected into PBS containing 0.05% polysorbate 20 (TWEEN-20 ^™ ) surfactant (PBST) at 25° C. at a flow rate of approximately 25 μl/min. Association rates (k _on ) and dissociation rates (k _off ) were calculated using a simple one-to-one Langmuir binding model (Evaluation Software version 3.2) by simultaneously fitting the association and dissociation spectra. The equilibrium dissociation constant (Kd) was calculated as the ratio _kon /k _off . See, e.g., Chen et al., J. Mol. Biol. 293: 865-881 (1999). If the association rate obtained from the above surface plasmon resonance assay exceeds 10 ⁶ M ^-1 s ^-1 , the association rate can be determined by using a fluorescence quenching technique, which measures the increase or decrease in fluorescence emission intensity (excitation = 295 nm; emission = 340 nm, 16 nm bandpass) of 20 nM anti-antigen antibody (Fab form) in PBS pH 7.2 at 25°C in the presence of increasing antigen concentrations, as measured in a spectrometer such as a stopped-flow spectrometer (Aviv Instruments) or an 8000 series SLM-AMINCO ^™ spectrometer with a stirred cuvette (ThermoSpectronic).

2. Antibody fragments

In certain embodiments, the antibodies provided herein are antibody fragments. Antibody fragments include, but are not limited to, Fab, Fab', Fab'-SH, (Fab') ₂ , Fv and scFv fragments and other fragments described below. For a review of certain antibody fragments, see Hudson et al., Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, for example, Pluckthün, The Pharmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore, eds. (Springer-Verlag, New York), pp. 269-315 (1994); see also WO 93/16185; and U.S. Pat. Nos. 5,571,894 and 5,587,458. For a discussion of Fab and F(ab') ₂ fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Pat. No. 5,869,046.

Diabodies are antibody fragments with two antigen-binding sites that can be bivalent or bispecific. See, for example, EP 404,097; WO 1993/01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med. 9:129-134 (2003).

Single-domain antibodies are antibody fragments that contain all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In certain embodiments, the single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see, e.g., U.S. Patent No. 6,248,516 Bl).

Antibody fragments can be produced by a variety of techniques, including, but not limited to, proteolytic digestion of intact antibodies and production by recombinant host cells (eg, E. coli or phage) as described herein.

3. Chimeric and humanized antibodies

In certain embodiments, the antibodies provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81: 6851-6855 (1984). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or a non-human primate such as a monkey) and a human constant region. In another example, a chimeric antibody is a "class-switched" antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

In certain embodiments, chimeric antibodies are humanized antibodies. Typically, non-human antibodies are humanized to reduce immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibody. Generally speaking, humanized antibodies include one or more variable domains, wherein HVR, such as CDR, (or a portion thereof) are derived from non-human antibodies, and FR (or a portion thereof) are derived from human antibody sequences. Humanized antibodies optionally also will include at least a portion of a human constant region. In some embodiments, some FR residues in humanized antibodies are replaced with corresponding residues from non-human antibodies (e.g., antibodies that obtain HVR residues), for example, to repair or improve antibody specificity or affinity.

Humanized antibodies and methods for making them can be found, for example, in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and are further described, for example, in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S. Pat. Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing “surfacing”); Dall’Acqua et al., Methods 36:43-60 (2005) (describing “FR shuffling”); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing “guided selection” methods for FR shuffling).

Human framework regions that can be used for humanization include, but are not limited to, framework regions selected using the "best fit" method (see, e.g., Sims et al., J. Immunol. 151:2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al., Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al., J. Immunol., 151:2623 (1993)). 93)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci. 13: 1619-1633 (2008)); and framework regions obtained by screening FR libraries (see, e.g., Baca et al., J. Biol. Chem. 272: 10678-10684 (1997) and Rosok et al., J. Biol. Chem. 271: 22611-22618 (1996)).

4. Human Antibodies

In certain embodiments, the antibodies provided herein are human antibodies. Human antibodies can be produced using various techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opin. Immunol. 20: 450-459 (2008).

Human antibodies can be prepared by administering an immunogen to a modified transgenic animal to produce complete human antibodies or complete antibodies with human variable regions in response to an antigen attack. Such animals typically contain all or part of the human immunoglobulin locus, which replaces the endogenous immunoglobulin locus or is present outside the chromosome or randomly integrated into the animal chromosome. In such transgenic mice, the endogenous immunoglobulin locus is generally inactivated. For methods of obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23: 1117-1125 (2005). See also, for example, U.S. Patents 6,075,181 and 6,150,584 (describing XENOMOUSE ^™ technology); U.S. Patent 5,770,429 (describing technology); U.S. Patent 7,041,870 (describing KM technology); and U.S. Application Publication No. US 2007/0061900 (technology). Human variable regions obtained from intact antibodies produced by such animals can be further modified, for example, by combining with a different human constant region.

Human antibodies can also be produced by hybridoma-based methods. Human myeloma and mouse-human hybrid myeloma cell lines for producing human monoclonal antibodies have been described. (See, for example, Kozbor J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147:86 (1991).) Human antibodies produced by human B cell hybridoma technology are also described in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Other methods include, for example, those described in U.S. Pat. No. 7,189,826 (describing the production of monoclonal human IgM antibodies by hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing human-human hybridomas). Human hybridoma technology (Trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91 (2005).

Human antibodies can also be produced by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences can then be combined with desired human constant domains. The following describes techniques for selecting human antibodies from antibody libraries.

5. Library-derived antibodies

The antibodies of the present invention can be isolated by screening combinatorial libraries for antibodies with the desired activity. For example, various methods for generating phage display libraries and screening such libraries for antibodies with the desired binding characteristics are known in the art. Such methods can be found, for example, in Hoogenboom et al., Methods in Molecular Biology 178: 1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001), and are further described in, for example, the following literature: McCafferty et al., Nature 348: 552-554; Clackson et al., Nature 352: 624-628 (1991); Marks et al., J. Mol. Biol. 222: 581-597 (1992); Marks and Bradbury, Methods in Molecular Biology 248: 161-175 (Lo et al., ed., Human Press, Totowa, NJ, 2003); Sidhu et al., J. Mol. Biol. 338(2):299-310 (2004); Lee et al., J. Mol. Biol. 340(5):1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34):12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132 (2004).

In certain phage display methods, VH and VL gene repertoires are individually cloned by polymerase chain reaction (PCR) and randomly recombined in phage libraries, which can then be screened for antigen-binding phage as described in Winter et al., Ann. Rev. Immunol., 12: 433-455 (1994). Phage typically display antibody fragments as single-chain Fv (scFv) fragments or Fab fragments. Libraries from immune sources provide high-affinity antibodies to the immunogen without the need to construct hybridomas. Alternatively, natural repertoires (e.g., from humans) can be cloned as described in Griffiths et al., EMBO J, 12: 725-734 (1993) to provide a single source of antibodies against a wide range of non-self antigens as well as self antigens without any immunization. Finally, natural repertoires can also be produced synthetically by cloning unrearranged V gene segments from stem cells and using PCR primers containing random sequences to encode the hypervariable CDR3 regions and achieve in vitro rearrangement as described in Hoogenboom and Winter, J. Mol. Biol., 227:381-388 (1992). Patent publications describing human antibody phage repertoires include, for example, U.S. Patent No. 5,750,373 and U.S. Patent Publication Nos. 2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598, 2007/0237764, 2007/0292936, and 2009/0002360.

Antibodies or antibody fragments isolated from human antibody repertoires are considered herein to be human antibodies or human antibody fragments.

6. Multispecific Antibodies

In any of the above aspects, the anti-CD3 antibodies provided herein are multispecific antibodies, such as bispecific antibodies. Multispecific antibodies are monoclonal antibodies that have binding specificity for at least two different sites. In certain embodiments, bispecific antibodies can bind to two different epitopes of CD3 (e.g., CD3ε or CD3γ). In certain embodiments, one binding specificity is for CD3 (e.g., CD3ε or CD3γ), while the other binding specificity is for any other antigen (e.g., a second biomolecule, such as a cell surface antigen, such as a tumor antigen). Accordingly, bispecific anti-CD3 antibodies can have binding specificity for CD3 and a second biomolecule such as a second biomolecule (e.g., a tumor antigen) listed in Table 1 and described in U.S. Publication No. 2010/0111856.

Table 1. Tumor antigen targets of the bispecific anti-CD3 antibodies of the present invention

A bispecific anti-CD3 antibody, such as any of the anti-CD3 antibodies described above, can have binding specificity for CD3 and a second biomolecule, such as a human leukocyte antigen (HLA)-peptide complex presented by MHC on the surface of a cell. The bispecific anti-CD3 antibody (e.g., any of the anti-CD3 antibodies described above) can have binding specificity for CD3 and a second biomolecule comprising an HLA-peptide complex selected from the group consisting of: 0772P (CA125, MUC16; Genbank accession number AF36148); adipose differentiation-related protein (perilipin 2, adipose differentiation-related protein, ADRP, ADFP, MGC10598; NCBI reference sequence NP_001113.2); AIM-2 (absent in melanoma 2, PYHIN4, interferon-induced protein AIM2; NCBI reference sequence NP_004824.1); ALDH1A1 (aldehyde dehydrogenase 1 family member A1, ALDH1, PUMB1, retinal dehydrogenase 1, ALDC, ALDH-E1, ALHDII, RALDH1, EC 1.2.1.36, ALDH11, HEL-9, HEL-S-53e, HEL12, RALDH1, aldehyde dehydrogenase 1, aldehyde dehydrogenase 1, soluble aldehyde dehydrogenase, liver cytosolic antigen, class 1 ALDH, epididymal luminal protein 12, epididymal luminal protein 9, epididymal secretory seminal fluid binding protein Li 53e, retinal dehydrogenase 1, RaIDH1, aldehyde dehydrogenase family 1 member A1, aldehyde dehydrogenase, cytosolic antigen, EC 1.2.1; NCBI Reference Sequence NP_000680.2); α-actinin-4 (ACTN4, actinin, α4, FSGS1, focal segmental glomerulosclerosis 1, non-muscle α-actinin 4, F-actin cross-linking protein, FSGS, actinin-4, actinin α4 isoform, α-actinin-4; NCBI Reference Sequence: NP_004915.2); α-fetoprotein (AFP, HPAFP, FETA, α-1-fetoprotein, α-fetoprotein, α-1-fetoprotein, α-fetoprotein, HP; Gen Bank: AAB58754.1); amphiregulin (AREG, SDGF, Schwannoma-derived growth factor, colorectal cell-derived growth factor, AR, CRDGF; GenBank: AAA51781.1); ARTC1 (ART1, ADP-ribosyltransferase 1, mono(ADP-ribosyl)transferase 1, ADP-ribosyltransferase C2 and C3 toxin-like protein 1, ART2, CD296, RT6, ADP-ribosyltransferase 2, GPI-linked NAD(P)(+)-arginine ADP-ribosyltransferase 1, EC 2.4.2.31, CD296 antigen; NP); ASLG659; ASPHD1 (aspartate β-hydroxylase domain-containing protein 1, aspartate β-hydroxylase domain-containing protein 1, EC 1.14.11.-, EC 1.14.11; GenBank: AAI44153.1); B7-H4 (VTCN1, V-Set domain-containing T cell activation inhibitor 1, B7H4, B7 superfamily member 1, immune co-stimulatory protein B7-H4, B7h.5, T cell co-stimulatory molecule B7x, B7S1, B7X, VCTN1, H4, B7 family member, PRO1291, B7 family member, H4, T cell co-stimulatory molecule B7x, V-Set domain-containing T cell activation inhibitor 1, protein B7S1; GenBank: AAZ17406.1); BAFF-R (TN FRSF13C, tumor necrosis factor receptor superfamily member 13C, BAFFR, B cell-activating factor receptor, BAFF receptor, BLyS receptor 3, CVID4, BROMIX, CD268, B cell-activating factor receptor, prolixin, tumor necrosis factor receptor superfamily member 13C, BR3, CD268 antigen; NCBI Reference Sequence NP_443177.1); BAGE-1; BCLX(L); BCR-ABL fusion protein (b3a2); β-catenin (CTNNB1, catenin (cadherin-associated protein) β1 88kDa, CTNNB, MRD19, catenin (cadherin-related protein) β1 (88kD), armadillo catenin β-1; GenBank: CAA61107.1); BING-4 (WDR46, WD repeat domain 46, C6orf11, BING4, WD repeat-containing protein BING4, chromosome 6 open reading frame 11, FP221, UTP7, WD repeat-containing protein 46; NP); BMPR1B (bone morphogenetic protein receptor type IB, Genbank accession number NM_00120; NP); B-RAF (brevitin (BCAN, BEHAB, Genbank accession number AF22905); brevitin (BCAN, chondroitin sulfate proteoglycan 7, brain-enriched hyaluronan-binding protein, B EHAB, CSPG7, brevican, brevican core protein, chondroitin sulfate proteoglycan BEHAB; GenBank: AAH27971.1); CALCA (calcitonin-related polypeptide alpha, CALC1, calcitonin 1, calcitonin, alpha-type CGRP, calcitonin gene-related peptide I, CGRP-I, CGRP, CGRP1, CT, KC, calcitonin/calcitonin-related polypeptide alpha, calcium inhibitory peptide; NP); CASP-5 (CASP5, caspase 5, apoptosis-related cysteine peptidase, caspase 5, apoptosis-related cysteine protease, protease ICH-3, protease TY, ICE(rel)-III, ICE(rel)III, ICEREL-III, ICH-3, caspase-5, TY protease, EC 3.4.22.58, ICH3, EC 3.4.22; NP); CASP-8; CD19 (CD19 - B lymphocyte antigen CD19 isoform 2 precursor, B4, CVID3 [Homo sapiens], NCBI Reference Sequence NP_001761.3); CD20 (CD20 - B lymphocyte antigen CD20, transmembrane 4 domains, superfamily A, member 1, B1, Bp35, CD20, CVID5, LEU-16, MS4A2, S7; NCBI Reference Sequence NP_690605.1); CD21 (CD21 (CR2 (complement receptor or C3DR (C3d/Epstein-Barr virus receptor) or Hs.73792, Genbank accession number M2600); (CD22 (B cell receptor CD22-B isoform, BL-CAM, Lyb-8, Lyb8, SIGLEC-2, FLJ22814, Genbank accession number AK02646); CD22; CD33 (CD33 molecule, CD33 antigen (Gp67), sialic acid-binding Ig-like lectin 3, sialic acid-binding Ig-like lectin 3, SIGLEC 3, gp67, SIGLEC-3, myeloid cell surface antigen CD33, p67, Siglec-3, CD33 antigen; GenBank: AAH28152.1); CD45; CD70 (CD70-tumor necrosis factor (ligand) superfamily member 7; surface antigen CD70; Ki-24 antigen; CD27 ligand; CD27-L; tumor necrosis factor ligand superfamily member 7; NCBI reference sequence NP_001243.1 for Homo sapiens); CD72 (CD72 (B cell Differentiation antigen CD72, Lyb-; 359aa, pI: 8.66, MW: 40225, TM: 1[P] gene chromosome: 9p13.3, Genbank accession number NP_001773.); CD79a (CD79a (CD79A, CD79a, immunoglobulin-associated protein α, a B cell-specific protein that covalently interacts with Igβ (CD79B) and forms a complex with IgM molecules on the surface, transducing signals involved in B cell differentiation), pI: 4.84, MW: 25028 TM: 2[P] gene chromosome: 19q13.2, Genbank accession number NP_001774.1); CD79b (CD79b (CD79B, CD79b, IGb (immunoglobulin-related protein beta), B29, Genbank accession number NM_000626 or 1103867); Cdc27 (cyclin 27, D0S1430E, D17S978E, anaphase-promoting complex subunit 3, anaphase-promoting complex Anaphase-promoting complex, protein 3, cyclin 27 homolog, cyclin 27 homolog, Nuc2 homolog; GenBank: AAH11656.1); CDK4 (cyclin-dependent kinase 4, cell division protein kinase 4, PSK-J3, EC 2.7.11.22, CMM3, EC 2.7.11; NCBI Reference Sequence NP_000066.1); CDKN2A (cyclin-dependent kinase inhibitor 2A, MLM, CDKN2, MTS1, cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4), cyclin-dependent kinase 4 inhibitor A, multiple tumor suppressor 1, CDK4I, MTS-1, CMM2, p16, ARF, INK4, INK4A, p14, P14ARF, P16-INK4A, P16INK4, P16INK4A, p19, P19ARF, TP16, CDK4 inhibitor P16-INK4, cell cycle negative regulator protein β, p14ARF, p16-INK4, p16-INK4a, p1 6INK4A, p19ARF; NP); CEA; CLL1 (CLL-1 (CLEC12A, MICL and DCAL, encoding a member of the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily. Members of this family share a common protein fold and possess diverse functions, such as cell adhesion, cell-cell signaling, glycoprotein turnover and roles in inflammation and immune responses. The protein encoded by this gene is a negative regulator of granulocyte and monocyte function. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. This gene is closely linked to other CTL/CTLD superfamily members in the natural killer gene complex region on chromosome 12p13 (Drickamer et al. K Curr. Opin. Struct. Biol. 9: 585-90; van Rhenen A et al., Blood 110): 2659-66; Chen CH et al., Blood 107): 1459-67; Marshall AS et al., Eur. J. Immunol. 36): 2159-69; Bakker AB et al., Cancer Res. 64: 8443-50; Marshall AS et al., J. Biol. Chem. 279: 14792-80. CLL-1 has been shown to be a type II transmembrane receptor comprising a single C-type lectin-like domain (predicted not to bind calcium or sugar), a rod region, a transmembrane domain, and a short cytoplasmic tail containing an ITIM motif; CLPP (caseinolytic mitochondrial matrix peptidase proteolytic subunit, endopeptidase Clp, EC 3.4.21.92, PRLTS3, ATP-dependent protease ClpAP (Escherichia coli), ClpP (casein hydrolytic protease ATP-dependent proteolytic subunit, Escherichia coli) homolog, ClpP casein hydrolytic peptidase ATP-dependent proteolytic subunit homolog (Escherichia coli), ClpP casein hydrolytic protease ATP-dependent proteolytic subunit homolog (Escherichia coli), human proteolytic subunit, human ATP-dependent protease ClpAP proteolytic subunit, ClpP casein hydrolytic peptidase ATP-dependent mitochondrial proteolytic subunit, ClpP caseinolytic peptidase ATP-dependent proteolytic subunit homolog, ClpP caseinolytic protease ATP-dependent proteolytic subunit homolog, putative ATP-dependent Clp protease proteolytic subunit mitochondrial; NP); COA-1; CPSF; CRIPTO (CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratoma-derived growth factor, Genbank accession number NP_003203 or NM_00321); Cw6; CXCR5 CXCR5 (1, a G protein-coupled receptor activated by the CXCL13 chemokine, plays a role in lymphocyte migration and humoral defense, and plays a role in HIV-2 infection and possibly in AIDS, lymphoma, myeloma, and leukemia); 372 aa, pI: 8.54, MW: 41959 TM: 7[P] gene chromosome: 11q23.3, Genbank accession number NP_001707.); CXORF61 CXORF61 (chromosome X open reading frame 61 [Homo sapiens], NCBI Reference Sequence NP_001017978.1); cyclin D1 (CCND1, BCL1, PRAD1, D11S287E, B-cell CLL/lymphoma 1, B-cell lymphoma 1 protein, BCL-1 oncogene, PRAD1 oncogene, cyclin D1 (PRAD1: parathyroid adenoma gene 1), G1/S-specific cyclin D1, parathyroid adenoma gene 1, U21B31, G1/S-specific cyclin D1, BCL-1; NCBI Reference Sequence NP_444284.1); cyclin A1 (CCNA1, CT146, cyclin A1; GenBank: AAH36346.1); dek-can fusion protein; DKK1 (Dickkopf WNT signaling pathway inhibitor 1, SK, hDkk-1, Dickkopf (Xenopus laevis) homolog 1, Dickkopf 1 homolog (Xenopus laevis), DKK-1, Dickkopf 1 homolog, Dickkopf-related protein 1, Dickkopf-1-like protein; Dickkopf-like protein 1, Dickkopf-related protein 1, Dickkopf-1, Dkk-1; GenBank: AAQ89364.1); DR1 (transcription down-regulating protein 1, TBP-binding (negative cofactor 2), negative cofactor 2-β, TATA-binding protein-associated phosphoprotein, NC2, NC2-β, protein Dr1, NC2-β, transcription down-regulating protein 1; NCBI Reference Sequence NP_001929.1); DR13 (major histocompatibility complex, class II, DRβ1, HLA-DR1B, DRw10, DW2.2/DR2.2, SS1, DRB1, HLA-DRB, HLA class II histocompatibility antigen, DR-1β chain, human lymphocyte antigen DRB1, lymphocyte antigen DRB1, MHC class II antigen, MHC Class II HLA-DRβ1 chain, MHC class II HLA-DR-β cell surface glycoprotein, MHC class II HLA-DRw10-β, DR-1, DR-12, DR-13, DR-14, DR-16, DR-4, DR-5, DR-7, DR-8, DR-9, DR1, DR12, DR13, DR14, DR16, DR4, DR5, DR7, DR8, DR9, DRw11, DRw8, HLA-DRB2, clone P2-β-3, MHC class II antigen DRB1 ^* 1, MHC class II antigen DRB1 ^* 10, MHC class II antigen DRB1 ^* 11, MHC class II antigen DRB1 ^* 12, MHC class II antigen DRB1 ^* 13, MHC class II antigen DRB1 ^* 14, MHC class II antigen DRB1 ^* 15, MHC class II antigen DRB1 ^* 16, MHC class II antigen DRB1 ^* 3, MHC class II antigen DRB1 ^* 4, MHC class II antigen DRB1 ^* 7, MHC class II antigen DRB1 ^* 8, MHC class II antigen DRB1 ^* 9; NP); E16 (E16 (LAT1, SLC7A5, Genbank accession number NM_00348); EDA (EDAR - tumor necrosis factor receptor superfamily member EDA precursor, EDA-A1 receptor; dl homolog; exosome A receptor; ectodermal dysplasia receptor; anhidrotic ectodermal dysplasia receptor 1, DL; ECTD10A; ECTD10B; ED1R; ED3; ED5; EDA-A1R; EDA1R; EDA3; HRM1 [Homo sapiens]; NCBI reference sequence NP_071731.1); EFTUD2 (elongation factor Tu GTP-binding domain-containing 2, elongation factor Tu GTP-binding domain protein 2, hSNU114, SNU114 homolog, U5 SnRNP-specific protein, 116 KDa, MFDGA, KIAA0031, 116 KD, U5 SnRNP-specific protein, 116 KDa U5 small nuclear ribonucleoprotein component, MFDM, SNRNP116, Snrp116, Snu114, U5-116 KD, SNRP116, U5-116 KDa; GenBank: AAH02360.1); EGFR (epidermal growth factor receptor, ERBB, proto-oncogene C-ErbB-1, receptor tyrosine protein kinase ErbB-1, ERBB1, HER1, EC 2.7.10.1, epidermal growth factor receptor (avian erythroblastic leukemia virus (V-Erb-B) oncogene homolog), erythroblastic leukemia virus (V-Erb-B) oncogene homolog (avian), PIG61, avian erythroblastic leukemia virus (V-Erb-B) oncogene homolog, cytostatic protein 40, cell proliferation inducing protein 61, mENA, EC 2.7.10; GenBank: AAH94761.1); EGFR-G719A; EGFR-G719C; EGFR-G719S; EGFR-L858R; EGFR-L861Q; EGFR-S768I; EGFR-T790M; Elongation factor 2 (EEF2, eukaryotic translation elongation factor 2, EF2, polypeptidyl-tRNA translocase, EF-2, SCA26, EEF-2; NCBI Reference Sequence NP_001952.1); ENAH (hMena) (initiator homolog (Drosophila), MENA, mammalian initiator, ENA, NDPP1, protein initiator homolog; GenBank: AAH95481.1) - only for "ENAH" and not "ENAH" Results of "AH(hMena)"; EpCAM (epithelial cell adhesion molecule, M4S1, MIC18, tumor-associated calcium signaling protein 1, TACSTD1, TROP1, adenocarcinoma-associated antigen, cell surface glycoprotein Trop-1, epithelial glycoprotein 314, major gastrointestinal tumor-associated protein GA733-2, EGP314, KSA, DIAR5, HNPCC8, antigen identified by monoclonal antibody AUA1, EGP-2, EGP40, ESA, KS1/4, MK-1, human epithelial glycoprotein-2, membrane fraction, chromosome 4, surface marker (35kD glycoprotein), EGP, Ep-CAM, GA733-2, M1S2, CD326 antigen, epithelial cell surface antigen, hEGP314, KS 1/4 antigen, ACSTD1; GenBank: AAH14785.1); EphA3 (EPH receptor A3, ETK1, ETK, TYRO4, HEK, Eph-like tyrosine kinase 1, tyrosine-protein kinase receptor ETK1, EK4, EPH-like kinase 4, EC 2.7.10.1, EPHA3, HEK4, Ephrin type A receptor 3, human embryonic kinase 1, TYRO4 protein tyrosine kinase, hEK4, human embryonic kinase, tyrosine-protein kinase TYRO4, EC 2.7.10; GenBank: AAH63282.1); EphB2R; Epiregulin (EREG, ER, epiregulin; GenBank: AAI36405.1); ETBR (EDNRB, endothelin type B receptor, HSCR2, HSCR, nonselective endothelin receptor, ET-B, ET-BR, ETRB, ABCDS, WS4A, ETB, endothelin B receptor; NP); ETV6-AML1 fusion protein; EZH2 (Enhancer of Zeste homolog 2 (Drosophila), lysine N-methyltransferase 6, ENX-1, KMT6EC 2.1.1.43, EZH1, WVS, Enhancer of Zeste (Drosophila) homolog 2, ENX1, EZH2b, KMT6A, WVS2, histone-lysine N-methyltransferase EZH2, Enhancer of Zeste homolog 2, EC 2.1.1; GenBank: AAH10858.1); FcRH1 (FCRL1, Fc receptor-like protein 1, FCRH1, Fc receptor homolog 1, FcR-like protein 1, immune receptor translocation-associated protein 5, IFGP1, IRTA5, hIFGP1, IFGP family protein 1, CD307a, Fc receptor-like protein 1, immunoglobulin superfamily Fc receptor, Gp42, FcRL1, CD307a antigen; GenBank: AAH33690.1); FcRH2 (FCRL2, Fc receptor-like protein 2, SPAP1, SH2 domain-containing phosphatase anchoring protein 1, Fc receptor homolog 2, FcR-like protein 2, immunoglobulin receptor translocation-associated protein 4, FCRH2, IFGP4, IRTA4, IFGP family protein 4, SPAP1A, SPAP1B, SPAP1C, CD307b, F Fc receptor-like protein 2, immunoreceptor translocation-associated protein 4, immunoglobulin superfamily Fc receptor, Gp42, SH2 domain-containing phosphatase anchoring protein 1, FcRL2, CD307b antigen; GenBank: AAQ88497.1); FcRH5 (FCRL5, Fc receptor-like protein 5, IRTA2, Fc receptor homolog 5, FcR-like protein 5, immunoreceptor translocation-associated protein 2, BXMAS1, FCRH5, CD307, CD307e, PRO820, Fc receptor-like protein 5, immunoglobulin superfamily receptor translocation-associated protein 2 (IRTA2), FcRL5, CD307e antigen; GenBank: AAI01070.1); FLT3-ITD; FN1 (fibronectin 1, cold-insoluble globulin, FN, migration-stimulating factor, CIG, FNZ, GFND2, LETS, ED-B, FINC , GFND, MSF, fibronectin; GenBank: AAI43764.1); G250 (MN, CAIX, carbonic anhydrase IX, carbonic anhydrase, RCC-associated protein G250, carbonic anhydrase IX, membrane antigen MN, renal cell carcinoma-associated antigen G250, CA-IX, p54/58N, pMW1, RCC-associated antigen G250, carbonic anhydrase 9; NP; other results for "G250" instead of "G250/MN/CAIX"; GAGE-1, 2, 8; GAGE-3, 4, 5, 6, 7; GDNF-Ra1 (GDNF family receptor α1; GFRA1; GDNFR; GDNFRA; RETL1; TRNR1; RET1L; GDNFR-α1; GFR-α-; U95847; BC014962; NM_145793NM_005264); GEDA (Ge nbank accession number AY26076); GFRA1-GDNF family receptor alpha-1; GDNF receptor alpha-1; GDNFR-α-1; GFR-α-1; RET ligand 1; TGF-β-related neurotrophic factor receptor 1 [Homo sapiens]; ProtKB/Swiss-Prot: P56159.2; glypican-3 (GPC3, glypican 3, SDYS, glypican protein) Glycan 3, intestinal protein OCI-5, GTR2-2, MXR7, SGBS1, DGSX, OCI-5, SGB, SGBS, heparan sulfate proteoglycan, secretory glypican-3, OCI5; GenBank: AAH35972.1); GnTVf; gp100 (PMEL, premelanosomal protein, SILV, D12S53E, PMEL17, SIL, melanocyte protein Pmel 17, melanocyte lineage-specific antigen GP100, melanoma-associated ME20 antigen, silver locus protein homolog, ME20-M, ME20M, P1, P100, silver (mouse homolog)-like, silver homolog (mouse), ME20, SI, melanocyte protein Mel 17, melanocyte protein PMEL, melanosome matrix protein 17, silver, mouse, homolog; GenBank: AAC60634.1); GPC; GPNMB (glycoprotein (transmembrane) Nmb, glycoprotein NMB, glycoprotein Nmb-like protein, osteoclast, transmembrane glycoprotein HGFIN, HGFIN, NMB, transmembrane glycoprotein, transmembrane glycoprotein NMB; GenBank: AAH32783.1); GPR172A (G protein coupled GPR19 (G protein-coupled receptor 19; Mm.478; NP_006134.1; NM_006143.2); GPR54 (KISS1 receptor; KISS1R; GPR54; HOT7T175; AXOR1; NP_115940.2); NM_032551.4); HAVCR1 (hepatitis A virus cellular receptor 1, T cell immunoglobulin mucin family member 1, kidney injury molecule 1, KIM-1, KIM1, TIM, TIM-1, TIM1, TIMD-1, TIMD1, T cell immunoglobulin mucin receptor 1, T cell membrane protein 1, HAVCR, HAVCR-1, T cell immunoglobulin domain and mucin domain protein 1, HAVcr-1, T cell immunoglobulin and mucin domain-containing protein 1; GenBank: AAH13325.1); HER2 (ERBB2, V-Erb-B2 avian erythroblastic leukemia virus oncogene homolog 2, NGL, NEU, Neuro/glioblastoma-derived oncogene homolog, metastatic lymph node gene 19 protein, proto-oncogene C-ErbB-2, proto-oncogene Neu, tyrosine kinase-type cell surface receptor HER2, MLN 19, p185erbB2, EC 2.7.10.1, V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 2 (Neuro/glioblastoma-derived oncogene homolog), CD340, HER-2, HER-2/neu, TKR1, C-Erb B2/Neu protein, herstatin, neuroblastoma/glioblastoma-derived oncogene homolog, receptor tyrosine-protein kinase ErbB-2, V-Erb-B2 erythroblastic leukemia viral oncogene homolog 2, Neuro/glioblastoma-derived oncogene homolog, MLN19, CD340 antigen, EC 2.7.10; NP); HER-2/neu - alias for the above; HERV-K-MEL; HLA-DOB (MHC that binds and presents peptides to CD4+ T lymphocytes) β subunit of class II molecule (Ia antigen); 273 aa, pI: 6.56, MW: 30820. TM: 1 [P] gene chromosome: 6p21.3, Genbank accession number NP_002111); hsp70-2 (HSPA2, heat shock 70 kDa protein 2, heat shock 70 kD protein 2, HSP70-3, heat shock associated 70 kDa protein 2, heat shock 70 kDa protein 2; GenBank: AAD21815.1); IDO1 (indoleamine 2,3-dioxygenase 1, IDO, INDO, indoleamine-pyrrole 2,3-dioxygenase, IDO-1, indoleamine-pyrrole 2,3-dioxygenase, indoleamine 2,3-dioxygenase, indole 2,3-dioxygenase, EC 1.13.11.52; NCBI Reference Sequence NP_002155.1); IGF2B3; IL13Rα2 (IL13RA2, interleukin 13 receptor alpha 2, cancer/testis antigen 19, interleukin-13-binding protein, IL-13R-α-2, IL-13RA2, IL-13 receptor subunit alpha-2, IL-13R subunit alpha-2, CD213A2, CT19, IL-13R, IL13BP, interleukin 13 binding protein, interleukin 13 receptor alpha 2 chain, interleukin-13 receptor subunit alpha-2, IL13R, CD213 a2 antigen; NP); IL20Rα; intestinal carboxylesterase; IRTA2 (also known as FcRH5); vasokallikrein 4 (KLK4, vasokallikrein-related peptidase 4, PRSS17, EMSP1, enamel matrix serine protease 1, vasokallikrein-like protein 1, serine protease 17, KLK-L1, PSTS, AI2A1, vasokallikrein 4 (prostate enzyme, enamel matrix, prostate), ARM1, EMSP, androgen-regulated messenger 1, enamel matrix serine protease 1, vasokallikrein, vasokallikrein-4, prostate enzyme, EC 3.4.21-, prostate enzyme, EC 3.4.21; GenBank: AAX30051.1); KIF20A (kinesin family member 20A, RAB6KIFL, RAB6 interacting, kinesin-like (Rab kinesin 6), mitosis a; LAGE-1; LDLR-fucosyltransferase AS fusion protein; crystallin (LGSN, crystallin, crystallin with glutamate synthetase domain, GLULD1, glutamate-ammonia ligase domain-containing protein 1, LGS, glutamate-ammonia ligase (glutamate synthetase) domain-containing 1, glutamate-ammonia ligase domain-containing protein 1). Enzyme (glutamate synthase) domain 1, lensoid glutamate synthase; GenBank: AAF61255.1); LGR5 (leucine-rich repeat-containing G protein-coupled receptor 5; GPR49, GPR6; NP_003658.1; NM_003667.2; LY64 (lymphocyte antigen 64 (RP10, a leucine-rich repeat (LRR) family type I membrane protein that regulates B cell activation and apoptosis, loss of function is associated with increased disease activity in patients with systemic lupus erythematosus); 661 aa, pI: 6.20, MW: 74147 TM: 1[P] gene chromosome: 5q12, Genbank accession number NP_005573.; Ly6E (lymphocyte antigen 6 complex, locus E; Ly67, RIG-E, SCA-2, TSA-; NP_002337.1; NM_002346.2); Ly6G6D (lymphocyte antigen 6 complex, locus G6D; Ly6-D, MEGT; NP_067079.2; NM_ 021246.2); LY6K (lymphocyte antigen 6 complex, locus K; LY6K; HSJ001348; FLJ3522; NP_059997.3; NM_017527.3); LyPD1-LY6/PLAUR domain-containing 1, PHTS [Homo sapiens], GenBank: AAH17318.1); MAGE-A1 (melanoma antigen family A1 (guide antigen MZ2-E, Expression of MAGE1, melanoma antigen family A1, MAGEA1, melanoma antigen MAGE-1, melanoma-associated antigen 1, melanoma-associated antigen MZ2-E, antigen MZ2-E, cancer/testis antigen 1.1, CT1.1, MAGE-1 antigen, cancer/testis antigen family 1 member 1, cancer/testis antigen family 1 member 1, MAGE1A; NCBI Reference Sequence NP_004979.3); MAGE-A10 (MAGEA10, melanoma antigen family A10, MAGE10, MAGE-10 antigen, melanoma-associated antigen 10, cancer/testis antigen 1.10, CT1.10, cancer/testis antigen family 1 member 10, cancer/testis antigen family 1 member 10; NCBI Reference Sequence NP_001238757.1); MAGE-A12 (MAGEA12, melanoma antigen family A12, MAGE12, cancer/testis antigen MAGE-A2 (MAGEA2, melanoma antigen family A2, MAGE2, cancer/testis antigen 1.2, CT1.2, MAGEA2A, MAGE-2 antigen, cancer/testis antigen family 1 member 2, cancer/testis antigen family 1 member 2, melanoma antigen 2, melanoma-associated antigen 2; NCBI Reference Sequence NP_001269434.1); MAGE-A3 (MAGEA3, melanoma antigen family A3, MAGE3, MAGE-3 antigen, antigen MZ2-D, melanoma-associated antigen 3, cancer/testis antigen 1.3, CT1.3, cancer/testis antigen family 1 member 2 MAGE-A4 (MAGEA4, melanoma antigen family A4, MAGE4, melanoma-associated antigen 4, cancer/testis antigen 1.4, CT1.4, MAGE-4 antigen, MAGE-41 antigen, MAGE-X2 antigen, MAGE4A, MAGE4B, cancer/testis antigen family 1 member 4, MAGE-41, MAGE-X2, cancer/testis antigen family 1 member 4; NCBI Reference Sequence NP_001011550.1); MAGE-A6 (MAGEA6, melanoma antigen family A6, MAGE6, MAGE-6 antigen, melanoma-associated antigen 6, cancer/testis antigen 1.6, CT1.6, MAGE3B antigen, cancer/testis antigen family 1, melanoma antigen family A 6 member 6, MAGE-3b, MAGE3B, cancer/testis antigen family 1 member 6; NCBI Reference Sequence NP_787064.1); MAGE-A9 (MAGEA9, melanoma antigen family A9, MAGE9, MAGE-9 antigen, melanoma-associated antigen 9, cancer/testis antigen 1.9, CT1.9, cancer/testis antigen family 1 member 9, cancer/testis antigen family 1 member 9, MAGEA9A; NCBI Reference Sequence NP_005356.1); MAGE-C1 (MAGEC1, melanoma antigen family C1, cancer/testis antigen 7.1, CT7.1, MAGE-C1 antigen, cancer/testis antigen family 7 member 1, CT7, cancer/testis antigen family 7 member 1, melanoma-associated antigen C1; NCBI Reference Sequence NP_005453.2); MAGE-C2 (MAGEC 2, melanoma antigen family C2, MAGEE1, cancer/testis antigen 10, CT10, HCA587, melanoma antigen family E1, cancer/testis specific, hepatocellular carcinoma-associated antigen 587, MAGE-C2 antigen, MAGE-E1 antigen, hepatocellular carcinoma antigen 587, melanoma-associated antigen C2; NCBI Reference Sequence NP_057333.1); mammaglobin A (SCGB2A2, secretoglobulin family 2A member 2, MGB1, mammaglobin 1, UGB2, mammaglobin A, mammaglobin A, mammaglobin 1, secretoglobulin family 2A member 2; NP); MART2 (HHAT, hedgehog acyltransferase, SKI1, melanoma antigen recognized by T cells 2, Skinny hedgehog 1, Skn, melanoma antigen recognized by T cells 2, protein-cysteine N-palmitoyltransferase HHAT, EC 2.3.1.-; GenBank: AAH39071.1); M-CSF (CSF1, colony-stimulating factor 1 (macrophages), MCSF, CSF-1, lanimostim, macrophage colony-stimulating factor 1, lanimostim; GenBank: AAH21117.1); MCSP (SMCP, seminal fluid mitochondria-associated cysteine-rich protein, MCS, mitochondrial capsule selenoprotein, HSMCSGEN1, seminal fluid mitochondria-associated cysteine-rich protein; NCBI Reference Sequence NP_109588.2); XAGE-1b/GAGED2a; WT1 (Wilms tumor Tumor) 1, WAGR, GUD, WIT-2, WT33, the amino-terminal domain of EWS, NPHS4, the last three zinc fingers of the DNA-binding domain of WT1, AWT1, Wilms' tumor protein, EWS-WT1; GenBank: AAB33443.1); VEGF; tyrosinase (TYR; OCAIA; OCA1A; tyrosinase; SHEP; NP_000363.1; NM_000372.4; GenBank: AAB60319 .1); TrpM4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel protein subfamily M member 4, Genbank accession number NM_01763); TRP2-INT2; TRP-2; TRP-1/gp75 (tyrosinase-associated protein 1, 5,6-dihydroxyindole-2-carboxylic acid oxidase, CAS2, CATB, TYRP, OCA3, catalase B, β-PROTEIN, glycoprotein 75, EC 1.14.18., melanoma antigen Gp75, TYRP1, TRP, TYRRP, TRP1, SHEP11, DHICA oxidase, EC 1.14.18, GP75, EC 1.14.18.1; triosephosphate isomerase (triosephosphate isomerase 1, TPID, triosephosphate isomerase, HEL-S-49, TIM, epididymal secretory protein Li 49, TPI, triosephosphate isomerase, EC 5.3.1.1; TRAG-3 (CSAG family member 2, cancer/testis antigen family 24, CSAG3B member 2, CSAG family member 3B, cancer/testis antigen family 24 member 2, cancer/testis antigen 24.2, chondrosarcoma-related gene 2/3 protein, paclitaxel resistance-associated gene 3 protein, chondrosarcoma-related gene 2/3 protein, CT24.2, paclitaxel resistance-associated gene 3, TRAG-3, CSAG3A, TRAG3); TMEM46 (shisa homolog 2 (Xenopus laevis); SHISA; NP_001007539.1; NM_001007538.1; TMEM118 (transmembrane RING finger protein 2) ;RNFT2;FLJ1462;NP_001103373.1;NM_001109903.1;TMEFF1 (transmembrane protein with an EGF-like domain and two follistatin-like domains 1; tumourin-;H7365;C9orf2;C9ORF2;U19878;X83961;NM_080655;NM_003692;TGF-βRII (TGFBR2, transforming growth factor beta receptor II (70/80 kDa), TGFβ-RII, MFS2, tβR-II, TGFR-2, TGF-β receptor type IIB, TGF-β receptor type II, TGF-β receptor type 2, EC 2.7.11.30, transforming growth factor beta receptor type IIC, AAT3, TβR-II, transforming growth factor beta receptor II (70-80 kD), type II TGF-β receptor, FAA3, transforming growth factor beta receptor type II, LDS1B, HNPCC6, LDS2B, LDS2, RIIC, EC2.7.11, TAAD2; TENB2 (TMEFF2, tumor inhibitor, TPEF, HPP1, TR, putative transmembrane proteoglycan related to EGF/HRG family growth factors and follistatin); 374 aa, NCBI accession numbers: AAD55776, AAF91397, AAG49451, NCBI reference sequence: NP_057276; NCBI gene: 23671; OMIM: 605734; SwissProt Q9UIK5; Genbank accession number AF179274; AY358907, CAF85723, CQ782436; TAG-2; TAG-1 (contactin 2 (axonal), TAG-1, AXT, axonal glycoprotein-1 cell adhesion molecule, TAX, contactin 2 (transiently expressed), TAX1, contactin-2, axonal glycoprotein TAG-1, transiently expressed axonal glycoprotein, transient axonal glycoprotein, axonal glycoprotein-1, TAX-1, TAG1, FAME5; PRF: 444868); SYT-SS X1 or SYT-SSX2 fusion protein; survivin; STEAP2 (HGNC_8639, IPCA-1, PCANAP1, STAMP1, STEAP2, STMP, prostate cancer-associated gene 1, prostate cancer-associated protein 1, six-transmembrane epithelial antigen of the prostate 2, six-transmembrane prostate protein, Genbank accession number AF45513; STEAP1 (six-transmembrane epithelial antigen of the prostate, Genbank accession number NM_01244; SSX-4; SSX-2 (SSX2, synovial sarcoma, X breakpoint 2, X breakpoint 2, SSX, X breakpoint 2B, cancer/testis antigen 5.2, X chromosome-associated antigen 2, tumor antigen HOM-MEL-40, CT5.2, HD21, cancer/testis antigen family 5, HOM-MEL-40, isoform B, cancer/testis antigen family 5 member 2a, member 2a, protein SSX2, sarcoma, sarcoma, synovium, X chromosome-associated antigen 2, synovium, synovial sarcoma, X breakpoint 2B, synovial sarcoma, SSX2A; Sp17; SOX10 (SRY (sex determining region Y)-box 10), mouse, PCWH, DOM, WS4, WS 2E, WS4C, dominant megacolon, mouse, human homolog, dominant megacolon, SRY-related HMG-box gene 10, human homolog, transcription factor SOX-10; GenBank: CAG30470.1); SNRPD1 (small nuclear ribonucleoprotein D1, small nuclear ribonucleoprotein D1, polypeptide 16 kDa, polypeptide (16 kD), SNRPD, HsT2456, Sm-D1, SMD1, Sm-D autoantigen, small nuclear ribonucleoprotein D1 polypeptide 16 kDa pseudogene, SnRNP core protein D1, small nuclear ribonucleoprotein Sm D1; SLC35D3 (solute carrier protein family 35 member D3, FRCL1, marginal junction-like protein 1, bA55K22.3, Frc, marginal-like protein 1, solute carrier protein family 35 member D3; NCBI GenBank: NC_000006.11, NC_018917.2, NT_025741.16); SIRT2 (short-lived protein 2, NAD-dependent deacetylase longevity protein 2, SIRL2, silent information regulator protein 2, regulatory protein SIR2 homolog 2, Sir2-related protein type 2, SIR2-like protein 2, type 2 longevity protein, longevity protein (silent mating type information regulator protein 2 homolog) 2 (Saccharomyces cerevisiae), longevity protein-2, longevity protein (silent mating type information regulator protein 2, Saccharomyces cerevisiae, homolog) 2, EC 3.5.1., SIR2; GenBank: AAK51133.1); Sema 5b (FLJ10372, KIAA1445, Mm.42015, SEMA5B, SEMAG, semaphorin 5b homolog sema domain, seven thrombospondin repeats (type 1 and type 1-like), transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 5B, GenBank accession number AB04087); sequesterin 1 (SCRN1, SES1, KIAA0193, secerin-1; GenBank: EAL2 4458.1); SAGE (SAGE1, sarcoma antigen 1, cancer/testis antigen 14, CT14, putative tumor antigen; NCBI Reference Sequence NP_061136.2); RU2AS (KAAG1, kidney-associated antigen 1, RU2AS, RU2 antisense gene protein, kidney-associated antigen 1; GenBank: AAF23613.1); RNF43-E3 ubiquitin-protein ligase RNF43 precursor [Homo sapiens], RNF124; U RCC; NCBI Reference Sequence NP_060233.3; RhoC (; RGS5 (regulator of G protein signaling 5, MSTP032, regulator of G protein signaling 5, MSTP092, MST092, MSTP106, MST106, MSTP129, MST129; GenBank: AAB84001.1); RET (ret proto-oncogene; MEN2A; HSCR1; MEN2B; MT C1; PTC; CDHF12; Hs.168114; RET51; RET-ELE; NP_066124.1; NM_020975.4); RBAF600 (UBR4, ubiquitin-protein ligase E3 component N-recognition protein 4, zinc finger, type 1 UBR1, ZUBR1, E3 ubiquitin-protein ligase UBR4, RBAF600, 600 KDa retinoblastoma protein-associated factor, zinc finger UBR1 type protein 1, EC 6.3.2., N-recognition protein-4, KIAA0462, p600, EC 6.3.2, KIAA1307; GenBank: AAL83880.1); RAGE-1 (MOK, MOK protein kinase, renal tumor antigen, RAGE, MAPK/MAK/MRK overlapping kinase, renal tumor antigen 1, renal cell carcinoma antigen, RAGE-1, EC2.7.11.22, RAGE1; UniProtKB/Swiss-Prot: Q9UQ07.1); RAB38/NY-MEL-1 (RAB38, NY-MEL-1, RAB38, RAS oncogenic family member, melanoma antigen NY-MEL-1, Rab-related GTP-binding protein, Ras-related protein Rab-38, rrGTPbp; GenBank: AAH15808.1); PTPRK (DJ480J14.2.1 (protein tyrosine phosphatase receptor type, K R-PTP-κ, protein tyrosine phosphatase K, protein tyrosine phosphatase K), protein tyrosine phosphatase receptor type K, protein tyrosine phosphatase K, protein tyrosine phosphatase receptor type K, R-PTP-κ, receptor type tyrosine protein phosphatase K, EC3.1.3.48, PTPK; GenBank: AAI44514.1); PSMA; PSCAhlg (2700050C12Rik, C530008O16Rik, RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene, Genbank accession number AY358628); PSCA (prostate stem cell antigen precursor, Genbank accession number AJ29743; PRDX5 (peroxiredoxin 5, EC1.11.1.15, type VI TPx, B166, antioxidant enzyme B166, HEL-S-55, liver tissue 2D-Page Spot 71B, PMP20, peroxisomal antioxidant enzyme, PRDX6, thioredoxin peroxidase PMP20, PRXV, AOEB166, epididymal secretory protein Li 55, Alu corepressor 1, peroxiredoxin-5, mitochondria, peroxiredoxin V, prx-V, thioredoxin reductase, Prx-V, ACR1, Alu corepressor, PLP; GenBank: CAG33484.1); PRAME (preferentially expressed antigen in melanoma, preferentially expressed antigen in melanoma, MAPE, OIP-4, OIPA, CT130, cancer/testis antigen 130, preferentially expressed in tumors Melanoma antigen, Opa interacting protein 4, Opa interacting protein OIP4; GenBank: CAG30435.1); pml-RARα fusion protein; PMEL17 (silver homolog; SILV; D12S53E; PMEL17; SI; SIL); ME20; gp10BC001414; BT007202; M32295; M77348; NM_006928; PBF (ZNF395, zinc finger protein 39 5, PRF-1, Huntington's disease regulatory factor, HD gene regulatory region binding protein, region binding protein 2, protein 2, papillomavirus regulatory factor 1, HD regulatory factor 2, papillomavirus regulatory factor, PRF1, HDBP-2, Si-1-8-14, HDBP2, Huntington's disease gene regulatory region binding protein 2, HDRF-2, papillomavirus regulatory factor PRF-1, PBF; GenBank: AAH01237.1); PAX5 (paired box 5, Paired box homeotic gene 5, BSAP, paired box protein Pax-5, B-cell lineage-specific activator, paired domain gene 5, paired box gene 5 (B-cell lineage-specific activator protein), B-cell-specific transcription factor, paired box gene 5 (B-cell lineage-specific activator); PAP (REG3A, regenerating islet-derived 3 alpha, INGAP, PAP-H, enterohepatic pancreatin, PBBCGF, human proislet peptide, REG-III, pancreatitis-related protein 1, Reg3, Reg III-α, hepato-intestinal-pancreatic, regenerating islet-derived protein III-α, pancreatic beta-cell growth factor, HIP, PAP homologous protein, HIP/PAP, proliferation-inducing protein 34, PAP1, proliferation-inducing protein 42, REG-3-α, regenerating islet-derived protein 3-α, pancreatitis-associated protein; GenBank: AAH36776.1); p53 (TP53, tumor protein P53, TPR53, P53, cell tumor antigen P53, antigen NY-CO-13, mutant tumor protein 53, phosphoprotein P53, P53 tumor suppressor, BCC7, transformation-related protein 53, LFS1, tumor protein 53, Li-Fraumeni syndrome (Li-Fraumeni syndrome) Syndrome), tumor suppressor P53; P2X5 (purinergic receptor P2X ligand-gated ion channel 5, an ion channel gated by extracellular ATP, may be involved in synaptic transmission and neurogenesis, and its deficiency may contribute to the pathophysiology of idiopathic detrusor instability); 422aa), pI: 7.63, MW: 47206 TM:1[P] gene chromosome: 17p13.3, Genbank accession number NP_002552.; OGT (O-linked N-acetylglucosamine (GlcNAc) transferase, O-GlcNAc transferase P110 subunit, O-linked N-acetylglucosamine (GlcNAc) transferase (UDP-N-acetylglucosamine:polypeptide-N-acetylglucosaminyltransferase, DP-N-acetylglucosamine-peptide N-acetylglucosaminyltransferase 110 KDa subunit, UDP-N-acetylglucosamine:polypeptide-N-acetylglucosaminyltransferase, uridine diphosphate-N-acetylglucosamine:polypeptide β-N-acetylglucosaminyltransferase, O-GlcNAc transferase subunit P110, EC 2.4.1.255, O-linked N-acetylglucosamine transferase 110 KDa subunit, EC 2.4.1, HRNT1, EC 2.4.1.186, O-GLCNAC; GenBank: AAH38180.1); OA1 (Osteoarthritis QTL 1, OASD; GenBank: CAA88742.1); NY-ESO-1/LAGE-2 (Cancer/Testis Antigen 1B, CTAG1B, NY-ESO-1, LAGE-2, ESO1, CTAG1, CTAG, LAGE2B, Cancer/Testis Antigen 1, Autoimmunogenic Cancer/Testis Antigen NY-ESO-1, Cancer Antigen 3, Cancer/Testis Antigen 6.1, New York Esophageal Squamous Cell Carcinoma 1, L Antigen Family Member 2, LAGE2, CT6.1 , LAGE2A; GenBank: AAI30365.1); NY-BR-1 (ANKRD30A, ankyrin repeat domain 30A, breast cancer antigen NY-BR-1, serologically defined breast cancer antigen NY-BR-1, ankyrin repeat domain-containing protein 30A; NCBI Reference Sequence NP_443723.2); N-ras (NRAS, neuroblastoma RAS viral (V-Ras) oncogene homolog, NRAS1, transforming protein N-Ras, GTPase NRas, ALPS4, N-Ras protein part 4, NS6, oncogene homolog, HRAS1; GenBank: AAH05219.1); NFYC (nuclear transcription factor Y, gamma, HAP5, HSM, nuclear transcription factor Y subunit C, transactivator HSM-1/2, CCAAT-binding factor subunit C, NF-YC, CCAAT transcription binding factor subunit gamma, CAAT box DNA binding protein subunit C, histone H1 transcription factor large subunit 2A, CBFC, nuclear transcription factor Y subunit gamma, CBF-C, transactivator HSM-1, H1TF2A, transcription factor NF-Y, C subunit; neo-PAP (PAPOLG, poly(A) polymerase gamma, neo-poly(A) polymerase, nuclear poly(A) polymerase gamma, polynucleotide adenylyltransferase gamma, SRP RNA 3' adenylase/Pap2, PAPγ, neo-PAP, SRP RNA 3'-Adenylase, PAP2, EC 2.7.7.19, PAPG; NCBI Reference Sequence NP_075045.2); NCA (CEACAM6, Genbank Accession No. M1872); Napi3b (NAPI-3B, NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate) member 2, type II sodium-dependent phosphate transporter 3b, Genbank Accession No. NM_00642); class I myosin; MUM-3; MUM-2 (TRAPPC1, transport protein particle complex 1, BET5, BET5 homolog, MUM2, melanoma spread mutated 2, multiple melanoma protein 2, transport protein particle complex subunit 1); MUM-1f; mucins (MUC1, mucin 1, cell surface associated, PEMT, PUM, CA 15-3, MCKD1, ADMCKD, medullary cystic kidney disease 1 (autosomal dominant), ADMCKD1, mucin 1, transmembrane, CD227, breast cancer-associated antigen DF3, MAM6, cancer antigen 15-3, MCD, carcinoma-associated mucin, MCKD, interstitial lung disease-6, MUC-1/SEC, peanut-reactive urinary mucin, MUC1/ZD, tumor-associated epithelial membrane antigen, DF3 antigen, tumor-associated mucin, episialin, EMA, H23 antigen, H23AG, mucin-1, KL-6, tumor-associated epithelial mucin, MUC-1, Ep isialin, PEM, CD227 antigen; UniProtKB/Swiss-Prot: P15941.3); MUC5AC (mucin 5AC, oligomeric mucus/gel-forming, tracheobronchial mucin MUC5, TBM, mucin 5, isoforms A and C, tracheobronchial/gastric, leB, gastric mucin, mucin 5AC, oligomeric mucus/gel-forming pseudogene, Lewis B blood group antigen, LeB, major airway glycoprotein, MUC-5AC, mucin-5 isoform AC, tracheobronchial; MUC1 (mucin 1, cell surface associated, PEMT, PUM, CA 15-3, MCKD1, ADMCKD, medullary cystic kidney disease 1 (autosomal dominant), ADMCKD1, mucin 1, transmembrane, CD227, breast cancer-associated antigen DF3, MAM6, cancer antigen 15-3, MCD, cancer-associated mucin, MCKD, interstitial lung disease-6, MUC-1/SEC, peanut-reactive urinary mucin, MUC-1/X, polymorphic epithelial mucin, MUC1/ZD, tumor-associated epithelial membrane antigen, DF3 antigen, tumor-associated mucin, episialin, EMA, h23 antigen, H23AG, mucin-1, KL-6, tumor-associated epithelial mucin, MUC-1, episialin, PEM, CD227 antigen; MSG783 (RNF124, hypothetical protein FLJ20315, Genbank accession number NM_01776; MRP4 multidrug resistance-associated protein 4 isoform 3, MOAT-B; MOATB [Homo sapiens]; NCBI Reference Sequence NP_001288758.1; MPF (MPF, MSLN, SMR, megakaryocyte-stimulating factor, mesothelin, Genbank accession number NM_00582; MMP-7 (MMP7, matrix metalloproteinase, MPSL1, matrix metalloproteinase, matrix metalloproteinase, PUMP-1, EC3.24.23), uterine stromal leukemia cell cycle inhibitor, mesothelin). 3.4.24, PUMP-1; GenBank: AAC37543.1); MMP-2 (MMP2, matrix metalloproteinase 2 (gelatinase A, 72kDa gelatinase, 72kDa type IV collagenase), MONA, CLG4A, matrix metalloproteinase 2 (gelatinase A, 72kD gelatinase, 72kD type IV collagenase), CLG4, 72kDa gelatinase, 72kDa type IV collagenase), matrix metalloproteinase-2, MMP-II, 72KDa gelatinase, type IV collagenase-A, MMP-2, matrix metalloproteinase II, TBE-1, neutrophil gelatinase, EC 3.4.24.24, EC 3.4.24; GenBank: AAH02576.1); and Meloe.

For example, in some cases, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 557-560, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 561-564, respectively. In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c. The anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to CD79b may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-CD79b antibody 1G7. In some cases, the second binding domain that binds FcRH5 comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 565-568, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 569-572, respectively. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 549-552, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 553-556, respectively. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 270, or the sequence of SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 271, or the sequence of SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 597-600, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 601-604, respectively. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 605-608, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 609-612, respectively. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 comprises at least one (e.g., 1, 2, 3, or 4) of the heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequence of SEQ ID NOs: 573-576, respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequence of SEQ ID NOs: 577-580, respectively. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as 40G5c, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to CD79b may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-CD79b antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1. The anti-CD3 antibody may have a second binding domain that binds MRP4.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v1, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to CD79b may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-CD79b antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v2, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to CD79b may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-CD79b antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as 38E4v3, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to CD79b may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-CD79b antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4. The anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as 38E4v4, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to CD79b may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-CD79b antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as 38E4v5, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to CD79b may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-CD79b antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v6, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to CD79b may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-CD79b antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v7, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to CD79b may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-CD79b antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v8, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to CD79b may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-CD79b antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as 38E4v9, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to CD79b may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-CD79b antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c. The anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c. The anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as 38E4c, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9. The anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9. The anti-CD3 antibody may have a second binding domain that binds to MRP4.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v9, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, and the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1. The anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1. The anti-CD3 antibody may have a second binding domain that binds to MRP4.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1v1, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1. The anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such as UCHT1vM1, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b). In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as 41D9a, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3. The anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3. The anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3. The anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3. The anti-CD3 antibody may have a second binding domain that binds CD79A.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3. The anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as 13A3.v2, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as 30A1, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as 30A1. The anti-CD3 antibody may have a second binding domain that binds to FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as 30A1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as 30A1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as 30A1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:54, such as 30A1. The anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:54, such as 30A1, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:54, such as 30A1, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as 30A1, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as 30A1. The anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as 30A1. The anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as 30A1. The anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:54, such as 30A1, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as 30A1, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as 30A1, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:54, such as 30A1, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as 30A1. The anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as 30A1, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as 30A1. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:49; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:50; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:53; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:54, such as 30A1, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2. The anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2. The anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as 30A1.v2, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9. The anti-CD3 antibody may have a second binding domain that binds to FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9. The anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such as h21A9, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2. The anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2. The anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2. The anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2. The anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2. The anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as 21B2. The anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1. The anti-CD3 antibody may have a second binding domain that binds to FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1. The anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1. The anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1. The anti-CD3 antibody may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1. The anti-CD3 antibody may have a second binding domain that binds CD79A.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1. The anti-CD3 antibody may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as 125A1, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, and the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, the anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as 72H6, and the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1. The anti-CD3 antibody may have a second binding domain that binds to FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1. The anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1. The anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1. The anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1. The anti-CD3 antibody may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1. The anti-CD3 antibody may have a second binding domain that binds CD79A.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1. The anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1. The anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as 19B1. The anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, and the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO:91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as 71H7, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7. The anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7. The anti-CD3 antibody may have a second binding domain that binds MRP4.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102, such as 14C7, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3. The anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108, such as 127B3, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114, such as 18F12, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120, such as 27H5-1, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7. The anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7. The anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7. The anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7. The anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126, such as 39B7, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2. The anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2. The anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132, such as 40D2, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody is selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, and may have a second binding domain that binds to CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as 43H8, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7. The anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7. The anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7. The anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7. The anti-CD3 antibody may have a second binding domain that binds CD79A.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7. The anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7. The anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as 79B7, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2. The anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2. The anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2. The anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2. The anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2. The anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2. The anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2. The anti-CD3 antibody may have a second binding domain that binds CD22.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2. The anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2. The anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2. The anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as 95A2, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to FcRH5 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-FcRH5 antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds MRP4.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150, such as 118G9, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In another instance, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17, and the anti-CD3 antibody may have a second binding domain that binds CD20. The second binding domain that binds CD20 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the group consisting of: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900). In some cases, the second binding domain that binds CD20 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in (b), such as the binding domain possessed by the anti-CD20 antibody 2H7.v16 (described in U.S. Patent No. 7,799,900).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17, the anti-CD3 antibody may have a second binding domain that binds FcRH5. The second binding domain that binds to CD79b may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such as the binding domain possessed by the anti-CD79b antibody 1G7. In some cases, the second binding domain that binds FcRH5 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such as the binding domain possessed by the anti-HER2 antibody hu4D5. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such as the binding domain possessed by the anti-HER2 antibody 2C4. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 593, or the sequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 594, or the sequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17, the anti-CD3 antibody may have a second binding domain that binds HER2. The second binding domain that binds HER2 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such as the binding domain possessed by the anti-HER2 antibody 7C2. In some cases, the second binding domain that binds HER2 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17. The anti-CD3 antibody may have a second binding domain that binds LYPD1. The second binding domain that binds to LYPD1 may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such as the binding domain possessed by the anti-LYPD1 antibody YWO.49.H6. In some cases, the second binding domain that binds LYPD1 can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 272, or the sequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO: 273, or the sequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domain as in (b).

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17, the anti-CD3 antibody may have a second binding domain that binds LY6G6D.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17, the anti-CD3 antibody may have a second binding domain that binds PMEL17.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17, the anti-CD3 antibody may have a second binding domain that binds LY6E.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17, the anti-CD3 antibody may have a second binding domain that binds CD19.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17, the anti-CD3 antibody may have a second binding domain that binds CD33.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17, the anti-CD3 antibody may have a second binding domain that binds CD22.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17, the anti-CD3 antibody may have a second binding domain that binds CD79A.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17, the anti-CD3 antibody may have a second binding domain that binds CD79B.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17, the anti-CD3 antibody may have a second binding domain that binds EDAR.

In some instances, an anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17, the anti-CD3 antibody may have a second binding domain that binds GFRA1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17. The anti-CD3 antibody may have a second binding domain that binds MRP4.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17, the anti-CD3 antibody may have a second binding domain that binds RET. The second binding domain that binds RET may comprise, for example, at least 1, 2, 3, 4, 5 or 6 hypervariable regions (HVRs) selected from the following: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such as the binding domain possessed by the anti-RET antibody 41205.v6. In some cases, the second binding domain that binds RET can comprise, for example, (a) a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17. The anti-CD3 antibody may have a second binding domain that binds Steap1.

In some cases, the anti-CD3 antibody has a first binding domain comprising at least 1, 2, 3, 4, 5, or 6 hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156, such as Rab17, the anti-CD3 antibody may have a second binding domain that binds TenB2.

In some embodiments, bispecific antibodies can also be used to localize cytotoxic agents to cells expressing tumor antigens, such as those listed in Table 1 (e.g., CD20, FcRH5, HER2, LYPD1, LY6G6D, PMEL17, LY6E, CD19, CD33, CD22, CD79A, CD79B, EDAR, GFRA1, MRP4, RET, Steap1, or TenB2). Bispecific antibodies can also be prepared as full-length antibodies or antibody fragments.

Techniques for making multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs with different specificities (see Milstein and Cuello, Nature 305:537 (1983)); WO 93/08829; and Traunecker et al., EMBO J. 10:3655 (1991)) and "knob-into-hole" engineering (see, e.g., U.S. Patent No. 5,731,168). "Knob-into-hole" engineering of multispecific antibodies can be used to create a first arm containing a knob-like structure and a second arm containing a hole-like structure to which the knob-like structure of the first arm can bind. In one embodiment, the knob-like structure of the multispecific antibody of the present invention can be an anti-CD3 arm. Alternatively, in one embodiment, the knob-like structure of the multispecific antibody of the present invention can be an anti-target/antigen arm. In one embodiment, the hole-like structure of the multispecific antibody of the present invention can be an anti-CD3 arm. Alternatively, in one embodiment, the hole-like structure of the multispecific antibody of the present invention can be an anti-target/antigen arm. Multispecific antibodies can also be engineered using immunoglobulin exchange (also known as Fab domain exchange or CrossMab format) technology (see, for example, WO 2009/080253; Schaefer et al., Proc. Natl. Acad. Sci. USA, 108: 11187-11192 (2011)). Multispecific antibodies can also be made by the following techniques: engineering electrostatic steering effects for making antibody Fc heterodimeric molecules (WO 2009/089004A1); cross-linking two or more antibodies or fragments (see, for example, U.S. Patent No. 4,676,980 and Brennan et al., Science, 229: 81 (1985)); using leucine zippers to produce bispecific antibodies (see, for example, Kostelny et al., J. Immunol., 148 (5): 1547-1553 (1992)); using "diabody" technology to make bispecific Antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); and using single-chain Fv (sFv) dimers (see, e.g., Gruber et al., J. Immunol., 152:5368 (1994)); and trispecific antibodies as described, e.g., in Tutt et al., J. Immunol. 147:60 (1991).

Also included herein are engineered antibodies with three or more functional antigen binding sites, including "Octopus antibodies" (see, eg, US 2006/0025576A1).

Antibodies or antibody fragments thereof may also include "dual-acting FAbs" or "DAFs" comprising an antigen binding site that can bind CD3 as well as another, different antigen (eg, a second biomolecule) (see, eg, US 2008/0069820).

7. Antibody variants

In certain embodiments, amino acid sequence variants of the anti-CD3 antibodies of the invention (e.g., bispecific anti-CD3 antibodies of the invention that can bind to CD3 and a second biomolecule (e.g., a cell surface antigen, such as a tumor antigen), such as the TDB antibodies of the invention or variants thereof) are contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody. Amino acid sequence variants of the antibody can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions and/or insertions and/or substitutions of residues within the antibody amino acid sequence. Any combination of deletions, insertions, and substitutions can be made to obtain the final construct, provided that the final construct possesses the desired characteristics, such as antigen binding.

a. Substitution variants, insertion variants, and deletion variants

In certain embodiments, antibody variants having one or more amino acid substitutions are provided. Relevant sites for substitution-type mutagenesis include HVRs and FRs. Conservative substitutions are shown under the "Preferred Substitutions" heading in Table 2. More substantial changes are provided under the "Exemplary Substitutions" heading in Table 2 and are further described below with reference to amino acid side chain classes. Amino acid substitutions can be introduced into related antibodies and the products can be screened for desired activity (e.g., retaining/improving antigen binding, reducing immunogenicity, or improving ADCC or CDC).

Table 2. Exemplary amino acid substitutions and preferred amino acid substitutions

Amino acids can be grouped according to common side chain properties:

(1) Hydrophobicity: norleucine, Met, Ala, Val, Leu, Ile;

(2) Neutral hydrophilicity: Cys, Ser, Thr, Asn, Gln;

(3) Acidic: Asp, Glu;

(4) Basic: His, Lys, Arg;

(5) Residues that affect chain orientation: Gly, Pro;

(6) Aromatic: Trp, Tyr, Phe.

Non-conservative substitutions will necessarily entail exchanging a member of one of these classes for another class.

One type of substitution variant involves replacing one or more hypervariable region residues of a parent antibody (e.g., a humanized antibody or a human antibody). In general, the resulting variant selected for further study will be modified (e.g., improved) relative to the parent antibody in terms of certain biological properties (e.g., increasing affinity, reducing immunogenicity) and/or will substantially retain certain biological properties of the parent antibody. Exemplary substitution variants are affinity matured antibodies, which can be conveniently produced using, for example, affinity maturation techniques based on phage display (such as those described herein). In short, one or more HVR residues are mutated and the variant antibodies are displayed on phage and screened for specific biological activity (e.g., binding affinity).

Changes (e.g., substitutions) can be made in HVRs, for example, to improve antibody affinity. Such changes can be made in HVR "hot spots," i.e., residues encoded by codons that mutate at a higher frequency during somatic maturation (see, e.g., Chowdhury, Methods Mol. Biol. 207: 179-196 (2008)) and/or residues that contact the antigen, and the resulting variant VH or VL is tested for binding affinity. Affinity maturation by constructing a secondary library and reselecting from it has been described, for example, in the following literature: Hoogenboom et al., Methods in Molecular Biology 178: 1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some embodiments of affinity maturation, diversity is introduced into the variable genes selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity. Another method for introducing diversity includes an HVR-directed approach, in which several HVR residues are randomly selected (e.g., 4 to 6 residues at a time). HVR residues involved in antigen binding can be specifically identified by using, for example, alanine scanning mutagenesis or modeling. Specifically, CDR-H3 and CDR-L3 are typically targeted.

In certain embodiments, substitutions, insertions or deletions may occur within one or more HVRs, as long as such changes do not substantially impair the ability of the antibody to bind to the antigen. For example, conservative changes that do not substantially reduce binding affinity (e.g., conservative substitutions as provided herein) may be made in the HVRs. For example, such changes may be outside the antigen contact residues in the HVRs. In certain embodiments of the variant VH and VL sequences provided above, each HVR is unchanged or contains no more than 1, 2, or 3 amino acid substitutions.

A suitable method for identifying antibody residues or regions that can be targeted for mutagenesis is called "alanine scanning mutagenesis," as described by Cunningham and Wells (1989) Science, 244: 1081-1085. In this method, one or a group of target residues (e.g., charged residues such as arg, asp, his, lys, and glu) are identified and replaced with neutral or negatively charged amino acids (e.g., alanine or polyalanine) to determine whether the interaction between the antibody and the antigen is affected. Additional substitutions can be introduced at these amino acid positions to demonstrate functional sensitivity to the initial substitutions. Alternatively, or in addition, a crystal structure of the antigen-antibody complex identifies contact points between the antibody and the antigen. Such contact residues and adjacent residues can be targeted or eliminated as candidates for substitution. Variants can be screened to determine whether they contain the desired properties.

Amino acid sequence insertions include amino and/or carboxyl terminal fusions ranging in length from 1 residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include antibodies with an N-terminal methionyl residue. Other insertional variants of the antibody molecule include fusing the N- or C-terminus of the antibody to an enzyme (e.g., for ADEPT) or a polypeptide that increases the serum half-life of the antibody.

b. Glycosylation variants

In certain embodiments, an anti-CD3 antibody of the invention (e.g., a bispecific anti-CD3 antibody of the invention that binds to CD3 and a second biomolecule (e.g., a cell surface antigen, such as a tumor antigen), such as a TDB antibody of the invention or a variant thereof) can be altered to increase or decrease the degree of glycosylation of the antibody. Addition or deletion of glycosylation sites to an anti-CD3 antibody of the invention can be conveniently achieved by altering the amino acid sequence to create or remove one or more glycosylation sites.

In the case where the antibody comprises an Fc region, the carbohydrate connected thereto can be changed. Natural antibodies produced by mammalian cells typically comprise a branched biantennary oligosaccharide generally connected to the CH2 domain of the Fc region by an N-linkage. See, for example, Wright et al., TIBTECH 15: 26-32 (1997). Oligosaccharides may include various carbohydrates, such as mannose, N-acetylglucosamine (GlcNAc), galactose and sialic acid, and the fucose of the GlcNAc in the "stem" of the biantennary oligosaccharide structure. In some embodiments, the oligosaccharide in the antibody of the present invention may be modified to produce antibody variants with certain improved properties.

In one embodiment, an anti-CD3 antibody variant is provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to the Fc region. For example, the amount of fucose in such an antibody may be 1% to 80%, 1% to 65%, 5% to 65%, or 20% to 40%. For example, the amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297 as measured by MALDI-TOF mass spectrometry relative to the sum of all sugar structures (e.g., complex, mixed, and high mannose structures) attached to Asn297, as described in WO2008/077546. Asn297 refers to the asparagine residue located at approximately position 297 in the Fc region (EU numbering of Fc region residues); however, due to minor sequence variations in antibodies, Asn297 may also be located approximately ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300. Such fucosylation variants may have improved ADCC function. See, for example, US Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications relating to "defucosylated" or "fucose-deficient" antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; WO 2005/053742; WO 2002/031140; Okazaki et al., J. Mol. Biol. 336: 1239-1249 (2004); Yamane-Ohnuki et al., Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells lacking protein fucosylation (Ripka et al., Arch. Biochem. Biophys. 249: 533-545 (1986); U.S. Patent Application No. US 2003/0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al., particularly Example 11) and gene knockout cell lines, such as α-1,6-fucosyltransferase gene, FUT8, gene knockout CHO cells (see, e.g., Yamane-Ohnuki et al., Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4): 680-688 (2006); and WO 2003/085107).

Further provided are anti-CD3 antibody variants having bisected oligosaccharides, for example, wherein the biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, for example, in WO 2003/011878 (Jean-Mairet et al.); U.S. Patent No. 6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al.). Antibody variants in which at least one galactose residue in the oligosaccharide is attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, for example, in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).

c. Fc region variants

In certain embodiments, one or more amino acid modifications can be introduced into the Fc region of an anti-CD3 antibody of the invention (e.g., a bispecific anti-CD3 antibody of the invention that can bind to CD3 and a second biological molecule (e.g., a cell surface antigen, such as a tumor antigen), such as a TDB antibody of the invention or a variant thereof), thereby generating an Fc region variant (see, e.g., US 2012/0251531). The Fc region variant can comprise a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) comprising an amino acid modification (e.g., substitution) at one or more amino acid positions.

In certain embodiments, the present invention encompasses anti-CD3 antibody variants with some, but not all, effector functions, thereby making them ideal candidates for applications where the half-life of the antibody in vivo is very important and certain effector functions (such as complement and ADCC) are unnecessary or harmful. In vitro and/or in vivo cytotoxicity assays can be performed to confirm the reduction/elimination of CDC and/or ADCC activity. For example, Fc receptor (FcR) binding assays can be performed to ensure that the antibody lacks FcγR binding (and therefore may lack ADCC activity), but retains FcRn binding ability. Primary cells used to mediate ADCC, NK cells, express only FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9: 457-492 (1991). Non-limiting examples of in vitro assays for evaluating ADCC activity of related molecules are described in U.S. Pat. Nos. 5,500,362 (see, e.g., Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)); and Hellstrom, I. et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985); and 5,821,337 (see Bruggemann, M. et al., J. Exp. Med. 166:1351-1361 (1987)). Alternatively, non-radioactive assays can be employed (see, e.g., ACTI ^™ non-radioactive cytotoxicity assay for flow cytometry (Cell Technology, Inc. Mountain View, CA); and CytoTox non-radioactive cytotoxicity assay (Promega, Madison, WI)). Suitable effector cells for such assays include peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively, or in addition, ADCC activity of the relevant molecules can be assessed in vivo in, for example, animal models such as those disclosed in Clynes et al., Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). C1q binding assays can also be performed to confirm that the antibody cannot bind to C1q and therefore lacks CDC activity. See, for example, C1q and C3c binding ELISAs in WO 2006/029879 and WO 2005/100402. To assess complement activation, a CDC assay can be performed (see, e.g., Gazzano-Santoro et al., J. Immunol. Methods 202: 163 (1996); Cragg, MS et al. Blood. 101: 1045-1052 (2003); and Cragg, MS and MJ Glennie Blood. 103: 2738-2743 (2004)). FcRn binding and in vivo clearance/half-life assays can also be performed using methods known in the art (see, e.g., Petkova, SB et al., Int'l. Immunol. 18(12): 1759-1769 (2006)).

Antibodies with reduced effector function include those with substitutions of one or more of Fc region residues 238, 265, 269, 270, 297, 327, and 329 ( U.S. Pat. Nos. 6,737,056 and 8,219,149 ). Such Fc mutants include those with substitutions at two or more of amino acid positions 265, 269, 270, 297, and 327, including the so-called "DANA" Fc mutant in which residues 265 and 297 are substituted with alanine ( U.S. Pat. Nos. 7,332,581 and 8,219,149 ).

In certain embodiments, the proline at position 329 of the wild-type human Fc region in the antibody is substituted with glycine or arginine, or an amino acid residue of sufficient size to disrupt the proline sandwich structure within the Fc/Fcγ receptor interface formed between proline 329 of Fc and tryptophan residues Trp 87 and Trp 110 of FcgRIII (Sondermann et al.: Nature 406, 267-273 (July 20, 2000)). In certain embodiments, the antibody comprises at least one other amino acid substitution. In one embodiment, the additional amino acid substitution is S228P, E233P, L234A, L235A, L235E, N297A, N297D, or P331S, and in another embodiment, the at least one additional amino acid substitution is L234A and L235A in the human IgG1 Fc region or S228P and L235E in the human IgG4 Fc region (see, e.g., US 2012/0251531), and in another embodiment, the at least one additional amino acid substitution is L234A and L235A and P329G in the human IgG1 Fc region.

Certain antibody variants with improved or impaired FcR binding are described. (See, e.g., U.S. Patent No. 6,737,056; WO 2004/056312; and Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001).)

In certain embodiments, the antibody variant comprises an Fc region with one or more amino acid substitutions that improve ADCC, such as substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues).

In some embodiments, changes made in the Fc region alter (ie, improve or impair) C1q binding and/or complement dependent cytotoxicity (CDC), e.g., as described in U.S. Pat. No. 6,194,551, WO 99/51642, and Idusogie et al., J. Immunol. 164:4178-4184 (2000).

US 2005/0014934A1 (Hinton et al.) describes antibodies with increased half-life and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgG to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)). These antibodies comprise an Fc region having one or more substitutions therein that improve binding of the Fc region to FcRn. Such Fc variants include those having substitutions at one or more of the following Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424, or 434, such as substitutions at Fc region residue 434 (U.S. Pat. No. 7,371,826).

See also Duncan and Winter, Nature 322:738-40 (1988); U.S. Patent No. 5,648,260; U.S. Patent No. 5,624,821; and WO 94/29351 for other examples of Fc region variants.

In some aspects, an anti-CD3 antibody (eg, a bispecific anti-CD3 antibody) comprises an Fc region comprising an N297G mutation. In some embodiments, an anti-CD3 antibody comprising an N297G mutation comprises an anti-CD3 arm comprising a first binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6; and an anti-CD20 arm comprising a second binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: NO:159; (d) HVR-L1, which comprises the amino acid sequence of SEQ ID NO:160; (e) HVR-L2, which comprises the amino acid sequence of SEQ ID NO:161; and (f) HVR-L3, which comprises the amino acid sequence of SEQ ID NO:162.

In some embodiments, an anti-CD3 antibody comprising an N297G mutation comprises an anti-CD3 arm comprising a first binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 184 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 185; and an anti-CD20 arm comprising a second binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 266 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 267.

In some embodiments, an anti-CD3 antibody comprising an N297G mutation comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 ( _CH11 ) domain, a first CH2 ( _CH21 ) domain, a first CH3 ( _CH31 ) domain, a second CH1 ( _CH12 ) domain, a second CH2 ( _CH22 ) domain, and a second CH3 ( _CH32 ) domain. In some cases, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some cases, the _CH31 domain and the _CH32 domain each comprise a protuberance or a cavity, and wherein the protuberance or cavity in the CH31 _domain can be positioned within the cavity or protuberance in the _CH32 domain, respectively. In some cases, the _CH31 domain and the _CH32 domain touch at the interface between the protuberance and the cavity. In some cases, the _CH2.1 domain and the _CH2.2 domain each comprise a protuberance or a cavity, and the protuberance or cavity in the _CH2.1 domain can be located in the cavity or protuberance in the _CH2.2 domain, respectively. In other cases, the _CH2.1 domain and the _CH2.2 domain contact at the interface between the protuberance and the cavity. In some cases, the anti-CD3 antibody is an IgG1 antibody.

In other embodiments, an anti-CD3 antibody comprising an N297G mutation comprises an anti-CD3 arm comprising a first binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 184 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 185; and an anti-CD20 arm comprising a second binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 266 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 267, wherein (a) the anti-CD3 arm comprises T366S, L368A, Y407V, and N297G substitution mutations and (b) the anti-CD20 arm comprises T366W and N297G substitution mutations.

d. Cysteine-engineered antibody variants

In certain embodiments, it may be desirable to produce cysteine-engineered antibodies, such as "thioMAbs," in which one or more residues of an antibody are substituted with cysteine residues. In specific embodiments, such substituted residues are present at accessible sites of the antibody. By replacing those residues with cysteine, reactive thiol groups are thereby located at accessible sites of the antibody and can be used to bind the antibody to other moieties such as drug moieties or linker-drug moieties to produce immunoconjugates as further described herein. In certain embodiments, any one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of the light chain; A118 (EU numbering) of the heavy chain; and S400 (EU numbering) of the heavy chain Fc region. Cysteine-engineered antibodies can be produced as described, for example, in U.S. Patent No. 7,521,541.

e. Antibody derivatives

In certain embodiments, the anti-CD3 antibodies of the invention provided herein (e.g., bispecific anti-CD3 antibodies of the invention that can bind to CD3 and a second biomolecule (e.g., a cell surface antigen, such as a tumor antigen), such as the TDB antibodies of the invention or variants thereof) can be further modified to contain other non-proteinaceous moieties that are known in the art and readily available. Suitable moieties for derivatizing antibodies include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1,3-dioxane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymers, polyamino acids (homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone) polyethylene glycol, polypropylene glycol homopolymers, polypropylene oxide/ethylene oxide copolymers, polyether polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have manufacturing advantages due to its stability in water. The polymer can have any molecular weight and can be branched or unbranched. The number of polymers attached to the antibody can vary, and if more than one polymer is attached, they can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on a number of considerations, including but not limited to the specific antibody property or function to be improved, whether the antibody derivative will be used in therapy under specified conditions, etc.

In another embodiment, conjugates of antibodies and non-protein moieties are provided, such conjugates being selectively heated by exposure to radiation. In one embodiment, the non-protein moiety is a carbon nanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102: 11600-11605 (2005)). The radiation can be of any wavelength, including but not limited to wavelengths that do not harm normal cells but that heat the non-protein moiety to a temperature that kills cells adjacent to the antibody-non-protein moiety.

B. Recombinant Methods and Compositions

The anti-CD3 antibodies of the invention (e.g., bispecific anti-CD3 antibodies of the invention that can bind to CD3 and a second biomolecule (e.g., a cell surface antigen, e.g., a tumor antigen), such as the TDB antibodies of the invention or variants thereof) can be produced using recombinant methods and compositions, e.g., as described in U.S. Patent No. 4,816,567. In one embodiment, isolated nucleic acids encoding the anti-CD3 antibodies described herein are provided. Such nucleic acids can encode an amino acid sequence comprising the VL of the antibody (e.g., the light chain and/or heavy chain of the antibody) and/or an amino acid sequence comprising the VH thereof. In another embodiment, one or more vectors (e.g., expression vectors) comprising such nucleic acids are provided. In another embodiment, host cells comprising such nucleic acids are provided. In one such embodiment, the host cell comprises (e.g., is transformed with): (1) a vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and an amino acid sequence comprising the VH of the antibody; or (2) a first vector comprising a nucleic acid encoding an amino acid sequence comprising the VL of the antibody and a second vector comprising a nucleic acid encoding an amino acid sequence comprising the VH of the antibody. In one embodiment, the host cell is a eukaryotic cell, such as a Chinese hamster ovary (CHO) cell or a lymphoid cell (e.g., a Y0, NS0, Sp20 cell). In one embodiment, a method for producing an anti-CD3 antibody is provided, wherein the method comprises culturing a host cell comprising a nucleic acid encoding the antibody as provided above under conditions suitable for expression of the antibody, and optionally recovering the antibody from the host cell (or host cell culture medium).

To recombinantly produce an anti-CD3 antibody, nucleic acid encoding the antibody is isolated (e.g., as described above) and inserted into one or more vectors for further cloning and/or expression in a host cell. Such nucleic acid can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes capable of specifically binding to genes encoding the heavy and light chains of the antibody).

Suitable host cells for cloning or expressing antibody encoding vectors include prokaryotic cells or eukaryotic cells described herein. For example, antibodies can be produced in bacteria, especially when glycosylation and Fc effector functions are not required. For expressing antibody fragments and polypeptides in bacteria, see, for example, U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (B.K.C.Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, which describes expression of antibody fragments in Escherichia coli.) After expression, the antibodies in the soluble portion can be separated from the bacterial cell slurry and can be further purified.

In addition to prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeast are also suitable cloning or expression hosts for antibody encoding vectors, including fungal and yeast strains whose glycosylation pathways have been "humanized" to produce antibodies with partially or fully human glycosylation patterns. See Gerngross, Nat. Biotech. 22: 1409-1414 (2004); and Li et al., Nat. Biotech. 24: 210-215 (2006).

Suitable host cells for expressing glycosylated antibodies also come from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Many baculovirus strains have been identified that can be used to bind to insect cells, particularly for transfecting Spodoptera frugiperda cells.

Plant cell cultures can also be used as hosts. See, e.g., U.S. Patent Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429 (describing PLANTIBODIES ^™ technology for producing antibodies in transgenic plants).

Vertebrate cells can also be used as hosts. For example, mammalian cell lines adapted for growth in suspension may be suitable. Other examples of suitable mammalian host cell lines are monkey kidney CV1 cell line (COS-7) transformed by SV40; human embryonic kidney cell line (e.g., 293 or 293 cells as described in Graham et al., J. Gen Virol. 36:59 (1977)); baby hamster kidney cells (BHK); mouse Sertoli cells (e.g., TM4 cells as described in Mather, Biol. Reprod. 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma cells (HELA); canine kidney cells (MDCK); Buffalo rat liver cells (BRL3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); for example, as described in Mather et al., Annals of TRI cells described in NY Acad. Sci. 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other suitable mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR ^- CHO cells (Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines such as Y0, NS0, and Sp2/0. For a review of certain mammalian host cell lines suitable for producing antibodies, see, for example, Yazaki and Wu, Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

C. Determination

The anti-CD3 antibodies of the invention provided herein (e.g., bispecific anti-CD3 antibodies of the invention that can bind to CD3 and a second biological molecule (e.g., a cell surface antigen, e.g., a tumor antigen), such as the TDB antibodies of the invention or variants thereof) can be identified, screened, or characterized for their physical/chemical properties and/or biological activities using various assays known in the art.

1. Binding Assays and Other Assays

In one aspect, the anti-CD3 antibodies of the invention are tested for antigen binding activity, for example, by known methods such as ELISA, Western blotting, and the like.

In another aspect, competition assays can be used to identify antibodies that compete with the anti-CD3 antibodies of the invention for binding to CD3.

In an exemplary competition assay, immobilized CD3 is incubated in a solution comprising a first labeled antibody that binds to CD3 and a second unlabeled antibody that is tested to compete with the first antibody for binding to CD3. The second antibody can be present in the hybridoma supernatant. As a control, immobilized CD3 is incubated in a solution comprising the first labeled antibody but not the second unlabeled antibody. Following incubation under conditions permissive for binding of the first antibody to CD3, excess unbound antibody is removed, and the amount of label associated with immobilized CD3 is measured. If the amount of label associated with immobilized CD3 in the test sample is substantially reduced relative to the control sample, this indicates that the second antibody is competing with the first antibody for binding to CD3. See, e.g., Harlow and Lane (1988) Antibodies: A Laboratory Manual. Chapter 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).

2. Activity Assay

In one aspect, an assay is provided for identifying an anti-CD3 antibody having biological activity. Biological activity can include, for example, binding to CD3 (e.g., CD3 on a T cell surface) or a peptide fragment thereof in vivo, in vitro, or ex vivo. In the case of a multispecific (e.g., bispecific) anti-CD3 antibody of the present invention (e.g., a TDB antibody having an anti-CD3 arm and an arm that can recognize a second biomolecule (e.g., a cell surface antigen, e.g., a tumor antigen)), biological activity can also include, for example, effector cell activation (e.g., T cell (e.g., CD8+ and/or CD4+ T cell) activation), effector cell population expansion (i.e., an increase in T cell count), target cell population reduction (i.e., a decrease in the cell population expressing the second biomolecule on its cell surface), and/or target cell killing. Antibodies having such biological activity in vivo and/or in vitro are provided. In certain embodiments, such biological activity of antibodies of the present invention is tested as described below in the Examples.

In some embodiments, the activity includes the ability to support B cell killing and/or cytotoxic T cell activation. In certain embodiments, the biological activity of such B cells killing and/or activating T cell cytotoxic effects of anti-B cell targeting anti-CD3 antibodies (such as anti-CD20 TDB) of the present invention is tested by any method described herein (especially in the examples). In some embodiments of any one of these activity assays, PBMC can be separated from whole blood of healthy donors by Ficoll separation. Specifically, human blood can be collected in a heparinized syringe and PBMC can be separated using Leucosep and FicollPaque Plus. If necessary, the Miltenyi test kit can be used to separate CD4+T cells and CD8+T cells according to the manufacturer's instructions.

In addition, cells can be washed in RPMI medium containing 10% FBS and supplemented with GlutaMax, penicillin, and streptomycin, and approximately 200,000 suspended cells can be added to a 96-well U-bottom plate. Cells can be cultured in RPMI1640 supplemented with 10% FBS in a humidified standard cell culture incubator at 37°C. In the BJAB cell killing assay, 20,000 BJAB cells can be incubated with effector cells (as huPBMCs or purified T cells) at ratios indicated by the assay in the presence of various concentrations of TDB antibodies for 24 hours. In the endogenous B cell killing assay, 200,000 huPBMCs can be incubated with various concentrations of TDB antibodies for 24 hours.

After cultivation, cells can be washed with FACS buffer (PBS containing 0.5% BSA, 0.05% sodium azide). Cells can then be stained in FACS buffer, washed with FACS buffer and suspended in 100 μl of FACS buffer containing 1 μg/ml propidium iodide. Data can be collected on a FACSCalibur flow cytometer and analyzed using FlowJo. Live B cells can be gated out as PI-CD19+ or PI-CD20+ B cells by FACS, and absolute cell counts can be obtained using FITC beads added to the reaction mixture as internal counting controls. Cell killing percentage (%) can be calculated based on controls without TDB treatment. Anti-CD69-FITC and anti-CD25-PE can be used to detect activated T cells by CD69 and CD25 surface expression.

D. Immunoconjugates

The invention also provides immunoconjugates comprising an anti-CD3 antibody herein bound to one or more cytotoxic agents, such as chemotherapeutic agents or drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes.

In one embodiment, the immunoconjugate is an antibody-drug conjugate (ADC) in which the antibody is bound to one or more drugs, including but not limited to maytansine (see U.S. Pat. Nos. 5,208,020, 5,416,064 and European Patent EP 0 425). 235B1); auristatins, such as the monomethyl auristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Pat. Nos. 5,635,483 and 5,780,588 and 7,498,298); dolastatin; calicheamicin or its derivatives (see U.S. Pat. Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001 and 5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode ... Res. 58:2925-2928 (1998)); anthracyclines such as daunomycin or doxorubicin (see Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343 (2002); and U.S. Pat. No. 6,630,579); methotrexate; vindesine; taxanes, such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel; trichothecenes; and CC1065.

In another embodiment, the immunoconjugate comprises a conjugate of an anti-CD3 antibody as described herein and an enzymatically active toxin or fragment thereof, including but not limited to diphtheria A chain, a non-binding active fragment of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, α-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, Curcas curcas toxin, crotonin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the trichothecenes.

In another embodiment, the immunoconjugate comprises a reflective conjugate formed by combining an anti-CD3 antibody as described herein with a radioactive atom. A variety of radioisotopes can be used to produce radioconjugates. Examples include At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ²¹² and radioisotopes of Lu. When the radioconjugate is used for detection, it may comprise a radioactive atom for scintillation studies, such as tc 99m or I 123 ; or a spin label for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as iodine-123, iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron.

Conjugates of antibodies and cytotoxic agents can be made using a variety of bifunctional protein coupling agents, such as N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP), succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipate hydrochloride), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl)hexanediamine), bis-diazonium derivatives (such as bis(p-diazoniumbenzoyl)ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, ricin immunotoxins can be prepared as described in Vitetta et al., Science 238:1098 (1987). Carbon-14 labeled 1-isothiocyanate benzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for binding radionucleotides to antibodies. See WO94/11026. The linker can be a "cleavable linker" that helps release the cytotoxic drug in the cell. For example, an acid-labile linker, a peptidase-sensitive linker, a photolabile linker, a dimethyl linker, or a disulfide-containing linker can be used (Chari et al., Cancer Res. 52:127-131 (1992); U.S. Patent No. 5,208,020).

The immunoconjugates or ADCs herein specifically encompass, but are not limited to, such conjugates prepared with cross-linker reagents including, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and commercially available SVSB (succinimidyl-(4-vinylsulfone)benzoate) (e.g., from Pierce Biotechnology, Inc., Rockford, IL., U.S.A.).

E. Methods and compositions for diagnosis and detection

In certain embodiments, any of the anti-CD3 antibodies of the invention (e.g., bispecific anti-CD3 antibodies of the invention that can bind to CD3 and a second biological molecule (e.g., a cell surface antigen, such as a tumor antigen), such as the TDB antibodies of the invention or variants thereof) are suitable for detecting the presence of CD3 in a biological sample. As used herein, the term "detection" encompasses quantitative or qualitative detection. In certain embodiments, the biological sample comprises cells or tissue.

In one embodiment, an anti-CD3 antibody for use in a diagnostic or detection method is provided. In another aspect, a method for detecting the presence of CD3 in a biological sample is provided. In certain embodiments, the method comprises contacting the biological sample with an anti-CD3 antibody as described herein under conditions permissive for binding of the anti-CD3 antibody to CD3, and detecting whether a complex forms between the anti-CD3 antibody and CD3. Such methods can be in vitro or in vivo.

In certain embodiments, labeled anti-CD3 antibodies are provided. Labels include, but are not limited to, labels or moieties that are directly detected, for example, by enzymatic reactions or intermolecular interactions (such as fluorescent labels, chromogenic labels, electron-dense labels, chemiluminescent labels, and radioactive labels), as well as moieties that are indirectly detected, such as enzymes or ligands. Exemplary labels include, but are not limited to, radioisotopes ³² P, ¹⁴ C, ¹²⁵ I, ³ H, and ¹³¹ I; fluorophores such as rare earth chelates or fluorescein and its derivatives, rhodamine and its derivatives, dansyl, umbelliferone; luciferases such as firefly luciferase and bacterial luciferase (U.S. Pat. No. 4,737,456); luciferin; 2,3-dihydrophthalazinedione; horseradish peroxidase (HRP); alkaline phosphatase; β-galactosidase; glucoamylase; lysozyme; carbohydrate oxidases such as glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase; heterocyclic oxidases such as uricase and xanthine oxidase, such labels coupled to enzymes that utilize hydrogen peroxide to oxidize the dye precursor, such as HRP, lactoperoxidase, or microperoxidase, biotin/avidin, spin labels, phage labels, stable free radicals, and the like.

F. Pharmaceutical Preparations

Pharmaceutical preparations of the anti-CD3 antibodies of the present invention (e.g., bispecific anti-CD3 antibodies of the present invention that can bind to CD3 and a second biomolecule (e.g., a cell surface antigen, e.g., a tumor antigen), such as the TDB antibodies of the present invention or variants thereof) are prepared by mixing the antibody having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th edition, Osol, A. ed. (1980)) in the form of a lyophilized formulation or an aqueous solution. Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed and include, but are not limited to, buffers such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl alcohol, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 Residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamic acid, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, fucose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., zinc-protein complexes); and/or nonionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersants such as soluble neutral active hyaluronidase glycoprotein (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoprotein, such as rHuPH20 (Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in U.S. Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, sHASEGP is combined with one or more other glycosaminoglycanases, such as chondroitinase.

Exemplary lyophilized antibody formulations are described in US Patent No. 6,267,958. Aqueous antibody formulations include those described in US Patent No. 6,171,586 and WO 2006/044908, the latter formulations including a histidine-acetate buffer.

The preparations herein may also contain more than one active ingredient that must be present for the specific indication being treated, preferably with active ingredients that are complementary in nature and that do not adversely affect each other. For example, it may be necessary to further provide additional therapeutic agents (e.g., chemotherapeutic agents, cytotoxic agents, growth inhibitors and/or anti-hormonal agents, such as those described above). Such active ingredients are suitable for being present in an amount effective for a predetermined purpose in a combined form.

The active ingredient can be embedded in microcapsules prepared, for example, by coagulation techniques or by interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, embedded in colloidal drug delivery systems (such as liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th edition, Osol, A., ed. (1980).

Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, eg, films, or microcapsules.

Formulations intended for in vivo administration are generally sterile. Sterility can be readily accomplished, for example, by filtration through sterile filtration membranes.

G. Methods of Treatment and Compositions

Any of the anti-CD3 antibodies of the invention (e.g., bispecific anti-CD3 antibodies of the invention that can bind to CD3 and a second biomolecule (e.g., a cell surface antigen, such as a tumor antigen), such as the TDB antibodies of the invention or variants thereof) can be used in therapeutic methods.

In one aspect, an anti-CD3 antibody is provided, which is used as a medicament. In other aspects, an anti-CD3 antibody is provided, which is used to treat a cell proliferative disorder (e.g., cancer) or an autoimmune disorder (e.g., arthritis) or to delay its progression. In certain embodiments, an anti-CD3 antibody is provided, which is used for a method of treating a subject suffering from a cell proliferative disorder or an autoimmune disorder, the method comprising administering an effective amount of an anti-CD3 antibody to the subject. In one such embodiment, the method further comprises administering an effective amount of at least one additional therapeutic agent to the subject, for example, as described below. In other embodiments, the invention provides an anti-CD3 antibody, which is used to enhance immune function in a subject suffering from a cell proliferative disorder or an autoimmune disorder. In certain embodiments, the present invention provides an anti-CD3 antibody for use in a method of enhancing immune function in an individual suffering from a cell proliferative disorder or an autoimmune disorder, the method comprising administering to the individual an effective amount of the anti-CD3 antibody to activate effector cells (e.g., T cells, such as CD8+ and/or CD4+ T cells), expand (increase) the effector cell population, reduce the target cell population (e.g., cells expressing a second biomolecule recognized by an anti-CD3 antibody of the invention (such as a bispecific TDB antibody of the invention)), and/or kill the target cell (e.g., target tumor cell). The "individual" according to any of the above embodiments can be a human.

In another aspect, the present invention provides anti-CD3 antibodies for the manufacture or preparation of medicaments. In one embodiment, the medicament is used to treat cell proliferative disorders (e.g., cancer) or autoimmune disorders (e.g., arthritis). In another embodiment, the medicament is used to treat a method for treating a cell proliferative disorder or an autoimmune disorder, the method comprising administering an effective amount of the medicament to an individual suffering from a cell proliferative disorder or an autoimmune disorder. In one such embodiment, the method further comprises administering an effective amount of at least one additional therapeutic agent to the individual, e.g., as described below. In another embodiment, the medicament is used to activate effector cells (e.g., T cells, e.g., CD8+ and/or CD4+ T cells) in the individual, amplify (increase) effector cell colonies, reduce target cells (e.g., cells expressing a second biomolecule identified by an anti-CD3 antibody of the present invention (such as the bispecific TDB antibody of the present invention)) colony and/or kill target cells (e.g., target tumor cells). In another embodiment, the agent is used in a method of enhancing immune function in an individual suffering from a cell proliferative disorder or an autoimmune disorder, the method comprising administering to the individual an effective amount of the agent to activate effector cells (e.g., T cells, such as CD8+ and/or CD4+ T cells), expand (increase) the effector cell population, reduce the target cell population (e.g., cells expressing a second biomolecule recognized by an anti-CD3 antibody of the invention (such as a bispecific TDB antibody of the invention)) and/or kill the target cell (e.g., target tumor cell). The "individual" according to any of the above embodiments may be a human.

In another aspect, the present invention provides a method for treating a cell proliferative disorder (e.g., cancer) or an autoimmune disorder (e.g., arthritis). In one embodiment, the method comprises administering an effective amount of an anti-CD3 antibody to an individual suffering from such a cell proliferative disorder or autoimmune disorder. In one such embodiment, the method further comprises administering to the individual an effective amount of at least one additional therapeutic agent, e.g., as described below. The "individual" according to any of the above embodiments may be a human.

In another aspect, the present invention provides a method for enhancing immune function in an individual suffering from a cell proliferative disorder or an autoimmune disorder. In one embodiment, the method comprises administering to the individual an effective amount of an anti-CD3 antibody to activate effector cells (e.g., T cells, e.g., CD8+ and/or CD4+ T cells), amplify (increase) effector cell populations, reduce target cells (e.g., cells expressing a second biomolecule recognized by an anti-CD3 antibody of the present invention (such as a bispecific TDB antibody of the present invention)) populations and/or kill target cells (e.g., target tumor cells). In one embodiment, an "individual" is a human being.

In another aspect, the present invention provides a method for treating a hematological cancer such as a B cell cancer (e.g., a mature B cell lymphoma) by administering an effective amount of an anti-CD3 antibody of the invention, such as a bispecific TDB antibody of the invention, such as an anti-B cell targeting TDB, such as a CD20-TDB having an anti-CD3 arm and an anti-CD20 arm. In another aspect of this embodiment, the mature B cell lymphoma is a non-Hodgkin's lymphoma (NHL). In another aspect of this embodiment, the NHL is selected from the group consisting of germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrom macroglobulinemia (WM), central nervous system lymphoma (CNSL), Burkitt's lymphoma (Burkitt's lymphoma (BL), B-cell prolymphocytic leukemia, splenic marginal zone lymphoma, hairy cell leukemia, unclassified splenic lymphoma/leukemia, splenic diffuse red pulp small B-cell lymphoma, hairy cell leukemia variant, Waldenstrom's macroglobulinemia, heavy chain disease, alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasma cell myeloma, solitary plasmacytoma of bone, extraosseous plasmacytoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), nodular marginal zone lymphoma, pediatric nodular marginal zone lymphoma, pediatric follicular lymphoma, primary cutaneous follicle center lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, primary DL of the central nervous system BCL, primary cutaneous DLBCL leg type, EBV-positive DLBCL of the elderly, DLBCL associated with chronic inflammation, lymphomatoid granulomatosis, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman's disease, primary effusion lymphoma: unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma, and unclassified B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin's lymphoma. In a preferred embodiment of the invention, the method comprises treating a cancer comprising germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrom's macroglobulinemia (WM), central nervous system lymphoma (CNSL), or Burkitt's lymphoma (BL).

In one embodiment, the method comprises administering an effective amount of an anti-CD3 antibody of the invention, such as a bispecific TDB antibody, such as a CD20 TDB comprising an anti-CD20 targeting arm and an anti-CD3 targeting arm, to an individual suffering from such a hematological cancer (e.g., a B-cell cancer, such as a B-cell lymphoma). In other embodiments, the CD20 TDB is co-administered with one or more other therapeutic agents. In one embodiment, the therapeutic agent is an antibody targeting CD20. In one embodiment, the CD20 TDB is co-administered with one or more antibodies targeting CD20 selected from the chimeric monoclonal CD20 antibody rituximab or the monoclonal CD20 antibody obinutuzumab. In one embodiment, the CD20 TDB is co-administered with rituximab. In one embodiment, the CD20 TDB is co-administered with obinutuzumab. In one embodiment, the CD20 TDB is co-administered with obinutuzumab and rituximab.

In another embodiment, an anti-CD3 antibody of the invention (e.g., CD20 TDB) is administered with or without a CD20 monoclonal antibody in combination with another chemotherapeutic agent and/or antibody-drug conjugate (ADC). In one embodiment, CD20 TDB is co-administered with one or more additional chemotherapeutic agents selected from cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). In one embodiment, CD20 TDB is co-administered with ADC. In one embodiment, CD20 TDB is co-administered with CHOP, with ADC replacing vincristine. In one embodiment, the CD20 TDB is co-administered with an ADC selected from an anti-CD79b antibody drug conjugate (such as anti-CD79b-MC-vc-PAB-MMAE or the anti-CD79b antibody drug conjugates described in any one of U.S. 8,088,378 and/or US 2014/0030280, or polatuzumab vedotin), an anti-CD19 antibody drug conjugate, an anti-CD22 antibody drug conjugate, an anti-CD45 drug conjugate, and an anti-CD32 drug conjugate.

In one other embodiment, the therapeutic agent is a biomodulator. In one embodiment, CD20 TDB is co-administered with one or more biological modulators selected from the group consisting of: a BCL-2 inhibitor (such as GDC-0199/ABT-199); a lenalidomide PI3K-δ inhibitor (such as idelalisib); a PD-1 axis binding antagonist; an agonist (e.g., agonist antibody) directed against the following activating costimulatory molecules: for example, CD40, CD226, CD28, OX40 (e.g., AgonOX), GITR, CD137 (also known as TNFRSF9, 4-1BB, or ILA), CD27 (e.g., CDX-1127), HVEM, or CD127; an antagonist (e.g., antagonist antibody) directed against the following inhibitory costimulatory molecules: for example, CTLA-4 (also known as CD152), PD-1, TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO (e.g., 1-methyl-D-tryptophan (also known as 1 -D-MT)), TIGIT, MICA/B, GITR (e.g., TRX518) or arginase; ipilimumab (also known as MDX-010, MDX-101 or), tremelimumab (also known as ticilimumab or CP-675,206), urelumab (also known as BMS-663513); MGA271; antagonists to TGFβ, such as metelimumab (also known as CAT-192), fresolimumab (also known as GC1008), LY2157299k and adoptive transfer of T cells (e.g., cytotoxic T cells or CTLs) expressing a chimeric antigen receptor (CAR), such as adoptive transfer of T cells comprising a dominant-negative TGFβ receptor (e.g., a dominant-negative TGFβ type II receptor).

In one embodiment, the CD20 TDB is co-administered with rituximab and one or more chemotherapeutic agents. In one such embodiment, the CD20 TDB is co-administered with rituximab and CHOP. In one embodiment, the CD20 TDB is co-administered with rituximab and an ADC. In one embodiment, the CD20 TDB is co-administered with rituximab and CHOP, wherein vincristine is replaced with an ADC. In one embodiment, the CD20 TDB is co-administered with an ADC selected from an anti-CD79b antibody drug conjugate (such as anti-CD79b-MC-vc-PAB-MMAE or an anti-CD79b antibody drug conjugate described in any one of U.S. 8,088,378 and/or US 2014/0030280 or pertuzumab vedotin), an anti-CD19 antibody drug conjugate, an anti-CD22 antibody drug conjugate, an anti-CD45 drug conjugate, and an anti-CD32 drug conjugate. In one embodiment, the CD20 TDB is co-administered with an ADC selected from an anti-CD79b antibody drug conjugate (such as anti-CD79b-MC-vc-PAB-MMAE or an anti-CD79b antibody drug conjugate described in any one of U.S. 8,088,378 and/or US 2014/0030280 or pertuzumab vedotin), an anti-CD19 antibody drug conjugate, an anti-CD22 antibody drug conjugate, an anti-CD45 drug conjugate, and an anti-CD32 drug conjugate. TDB is co-administered with rituximab and one or more biological modulators selected from the group consisting of: a BCL-2 inhibitor (such as GDC-0199/ABT-199); a lenalidomide PI3K-delta inhibitor (such as idelacoxib); a PD-1 axis binding antagonist; an agonist (e.g., agonist antibody) to the following activating costimulatory molecules: for example, CD40, CD226, CD28, OX40 (e.g., AgonOX), GITR, CD137 (also known as TNFRSF9, 4-1BB, or ILA), CD27 (e.g., CDX-1127), HVEM, or CD127; an antagonist (e.g., antagonist antibody) to the following inhibitory costimulatory molecules: for example, CTLA-4 (also known as CD152), PD-1, TIM-3, BTLA, VISTA, LAG-3, B7-H3 , B7-H4, IDO (e.g., 1-methyl-D-tryptophan (also known as 1-D-MT)), TIGIT, MICA/B, GITR (e.g., TRX518) or arginase; ipilimumab (also known as MDX-010, MDX-101 or), tremelimumab (also known as tesimumab or CP-675,206), usrecirumab (also known as BMS-663513); MGA271; antagonists to TGFβ, such as metilimumab (also known as CAT-192), fusumumab (also known as GC1008), LY2157299k and adoptive transfer of T cells (e.g., cytotoxic T cells or CTLs) expressing a chimeric antigen receptor (CAR), such as adoptive transfer of T cells comprising a dominant-negative TGFβ receptor (e.g., a dominant-negative TGFβ type II receptor).

In one embodiment, the CD20 TDB is co-administered with rituximab, one or more chemotherapeutic agents, and one or more biological modulators selected from the group consisting of: a BCL-2 inhibitor (such as GDC-0199/ABT-199); a lenalidomide PI3K-delta inhibitor (such as idelacoxib); a PD-1 axis binding antagonist; an agonist (e.g., agonist antibody) to the following activating costimulatory molecules: e.g., CD40, CD226, CD28, OX40 (e.g., AgonOX), GITR, CD137 (also known as TNFRSF9, 4-1BB, or ILA), CD27 (e.g., CDX-1127), HVEM, or CD127; an antagonist (e.g., antagonist antibody) to the following inhibitory costimulatory molecules: e.g., CTLA-4 (also known as CD152), PD-1, TIM-3, BTLA, VISTA, LAG-3 , B7-H3, B7-H4, IDO (e.g., 1-methyl-D-tryptophan (also known as 1-D-MT)), TIGIT, MICA/B, GITR (e.g., TRX518) or arginase; ipilimumab (also known as MDX-010, MDX-101 or), tremelimumab (also known as tesimumab or CP-675,206), usrulumab (also known as BMS-663513); MGA271; antagonists to TGFβ, such as metilimumab (also known as CAT-192), fusumumab (also known as GC1008), LY2157299k and adoptive transfer of T cells (e.g., cytotoxic T cells or CTLs) expressing a chimeric antigen receptor (CAR), such as adoptive transfer of T cells comprising a dominant-negative TGFβ receptor (e.g., a dominant-negative TGFβ type II receptor).

In one embodiment, the CD20 TDB is co-administered with rituximab, an ADC, and one or more biological modulators selected from the group consisting of: a BCL-2 inhibitor (such as GDC-0199/ABT-199); a lenalidomide PI3K-δ inhibitor (such as idelacoxib); a PD-1 axis binding antagonist; an agonist (e.g., agonist antibody) to the following activating costimulatory molecules: for example, CD40, CD226, CD28, OX40 (e.g., AgonOX), GITR, CD137 (also known as TNFRSF9, 4-1BB, or ILA), CD27 (e.g., CDX-1127), HVEM, or CD127; an antagonist (e.g., antagonist antibody) to the following inhibitory costimulatory molecules: for example, CTLA-4 (also known as CD152), PD-1, TIM-3, BTLA, VISTA, LAG-3, B7- H3, B7-H4, IDO (e.g., 1-methyl-D-tryptophan (also known as 1-D-MT)), TIGIT, MICA/B, GITR (e.g., TRX518) or arginase; ipilimumab (also known as MDX-010, MDX-101 or), tremelimumab (also known as tesimumab or CP-675,206), usrecitabine (also known as BMS-663513); MGA271; antagonists to TGFβ, such as metilimumab (also known as CAT-192), fusumumab (also known as GC1008), LY2157299k and adoptive transfer of T cells (e.g., cytotoxic T cells or CTLs) expressing a chimeric antigen receptor (CAR), such as adoptive transfer of T cells comprising a dominant-negative TGFβ receptor (e.g., a dominant-negative TGFβ type II receptor).

In one embodiment, the CD20 TDB is co-administered with obinutuzumab and one or more chemotherapeutic agents. In one embodiment, the CD20 TDB is co-administered with obinutuzumab and CHOP. In one embodiment, the CD20 TDB is co-administered with obinutuzumab and an ADC. In one embodiment, the CD20 TDB is co-administered with obinutuzumab and CHOP, wherein vincristine is replaced with an ADC. In one embodiment, the CD20 TDB is co-administered with an ADC selected from an anti-CD79b antibody drug conjugate (such as anti-CD79b-MC-vc-PAB-MMAE or an anti-CD79b antibody drug conjugate described in any one of U.S. 8,088,378 and/or US 2014/0030280 or pertuzumab vedotin), an anti-CD19 antibody drug conjugate, an anti-CD22 antibody drug conjugate, an anti-CD45 drug conjugate, and an anti-CD32 drug conjugate. In one embodiment, the CD20 TDB is co-administered with an ADC selected from an anti-CD79b antibody drug conjugate (such as anti-CD79b-MC-vc-PAB-MMAE or an anti-CD79b antibody drug conjugate described in any one of U.S. 8,088,378 and/or US 2014/0030280 or pertuzumab vedotin), an anti-CD19 antibody drug conjugate, an anti-CD22 antibody drug conjugate, an anti-CD45 drug conjugate, and an anti-CD32 drug conjugate. TDB is co-administered with obinutuzumab and one or more biological modulators selected from the group consisting of: a BCL-2 inhibitor (such as GDC-0199/ABT-199); a lenalidomide PI3K-delta inhibitor (such as idelacoxib); a PD-1 axis binding antagonist; an agonist (e.g., agonist antibody) to the following activating costimulatory molecules: for example, CD40, CD226, CD28, OX40 (e.g., AgonOX), GITR, CD137 (also known as TNFRSF9, 4-1BB, or ILA), CD27 (e.g., CDX-1127), HVEM, or CD127; an antagonist (e.g., antagonist antibody) to the following inhibitory costimulatory molecules: for example, CTLA-4 (also known as CD152), PD-1, TIM-3, BTLA, VISTA, LAG-3, B7-H3 , B7-H4, IDO (e.g., 1-methyl-D-tryptophan (also known as 1-D-MT)), TIGIT, MICA/B, GITR (e.g., TRX518), or arginase; ipilimumab (also known as MDX-010, MDX-101, or), tremelimumab (also known as tesimumab or CP-675,206), usrulumab (also known as BMS-663513); MGA271; antagonists to TGFβ, such as metilimumab (also known as CAT-192), fusumumab (also known as GC1008), LY2157299k, and adoptive transfer of T cells (e.g., cytotoxic T cells or CTLs) expressing a chimeric antigen receptor (CAR), such as adoptive transfer of T cells comprising a dominant-negative TGFβ receptor (e.g., a dominant-negative TGFβ type II receptor).

In one embodiment, the CD20 TDB is co-administered with obinutuzumab, an ADC, and one or more biological modulators selected from the group consisting of: a BCL-2 inhibitor (such as GDC-0199/ABT-199); a lenalidomide PI3K-δ inhibitor (such as idelacoxib); a PD-1 axis binding antagonist; an agonist (e.g., agonist antibody) to the following activating costimulatory molecules: for example, CD40, CD226, CD28, OX40 (e.g., AgonOX), GITR, CD137 (also known as TNFRSF9, 4-1BB, or ILA), CD27 (e.g., CDX-1127), HVEM, or CD127; an antagonist (e.g., antagonist antibody) to the following inhibitory costimulatory molecules: for example, CTLA-4 (also known as CD152), PD-1, TIM-3, BTLA, VISTA, LAG-3, B7- H3, B7-H4, IDO (e.g., 1-methyl-D-tryptophan (also known as 1-D-MT)), TIGIT, MICA/B, GITR (e.g., TRX518) or arginase; ipilimumab (also known as MDX-010, MDX-101 or), tremelimumab (also known as tesimumab or CP-675,206), uslecitumomab (also known as BMS-663513); MGA271; antagonists to TGFβ, such as metilimumab (also known as CAT-192), fusumumab (also known as GC1008), LY2157299k and adoptive transfer of T cells (e.g., cytotoxic T cells or CTLs) expressing a chimeric antigen receptor (CAR), such as adoptive transfer of T cells comprising a dominant-negative TGFβ receptor (e.g., a dominant-negative TGFβ type II receptor).

In another aspect of the present invention, the additional therapy comprises an anti-CD20 antibody. In one embodiment, the anti-CD20 antibody is rituximab. In one embodiment, the anti-CD20 antibody is a humanized B-Ly1 antibody. In one embodiment, the humanized B-Ly1 antibody is obinituzumab. In one embodiment, the anti-CD20 antibody is ofatumumab, ublituximab, and/or ibritumomab tiuxetan.

In another aspect of the present invention, the additional therapy comprises an alkylating agent. In one embodiment, the alkylating agent is 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid and salts thereof. In one embodiment, the alkylating agent is bendamustine.

In another aspect of the present invention, the additional therapy includes a BCL-2 inhibitor. In one embodiment, the BCL-2 inhibitor is 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide and salts thereof. In one embodiment, the BCL-2 inhibitor is venetoclax (CAS No.: 1257044-40-8).

In another aspect of the present invention, the additional therapy includes a phosphoinositide 3-kinase (PI3K) inhibitor. In one embodiment, the PI3K inhibitor inhibits the delta isoform of PI3K (i.e., P110δ). In some embodiments, the PI3K inhibitor is 5-fluoro-3-phenyl-2-[(1S)-1-(7H-purine-6-ylamino)propyl]-4(3H)-quinazolinone and its salts. In some embodiments, the PI3K inhibitor is idarucizumab (CAS No.: 870281-82-6). In one embodiment, the PI3K inhibitor inhibits the α and δ isoforms of PI3K. In some embodiments, the PI3K inhibitor is 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide and salts thereof.

In another aspect of the present invention, the additional therapy includes a Bruton's tyrosine kinase (BTK) inhibitor. In one embodiment, the BTK inhibitor is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one and salts thereof. In one embodiment, the BTK inhibitor is ibrutinib (CAS No.: 936563-96-1).

In another aspect of the present invention, the additional therapy comprises thalidomide or a derivative thereof. In one embodiment, the thalidomide or a derivative thereof is (RS)-3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione and a salt thereof. In one embodiment, the thalidomide or a derivative thereof is lenalidomide (CAS No.: 191732-72-6).

In another aspect of the invention, the additional therapy comprises one or more of cyclophosphamide, doxorubicin, vincristine, or prednisolone (CHOP). In one embodiment, the additional therapy further comprises an anti-CD20 antibody as described above (e.g., GA-101 and/or ). Any of the above methods and therapies can be used, but is not limited to, for any cancer, including, for example, treatment of B-cell cancer or breast cancer.

In another aspect, the present invention provides a method for treating HER2-positive cancers. In one embodiment, the method comprises administering an effective amount of an anti-HER2 antibody of the present invention to an individual suffering from such cancer, such as a bispecific TDB antibody having an anti-HER2 targeting arm and an anti-CD3 targeting arm. In a preferred embodiment, the HER2-TDB has an acceptable toxicity profile when administered to a patient at an effective dose. In one embodiment, the CD3 arm of the HER2-TDB with an acceptable toxicity profile is a low-affinity CD3 arm. In one embodiment, the CD3 arm of the HER2-TDB with an acceptable toxicity profile is 40G5c.

In preferred embodiments, the HER2-positive cancer is HER2-positive breast cancer or HER2-positive gastric cancer. In one embodiment, HER2 TDB is co-administered with one or more additional therapeutic agents that target the HER pathway. In one embodiment, the therapeutic agent that targets the HER pathway is selected from an EGFR inhibitor, a HER2 inhibitor, a HER3 inhibitor, and/or a HER4 inhibitor. In one embodiment, HER2 TDB is co-administered with one or more additional therapeutic agents selected from trastuzumab T-DM1 and pertuzumab. In one embodiment, HER2 TDB is co-administered with trastuzumab. In one embodiment, HER2 TDB is co-administered with T-DM1. In one embodiment, HER2 TDB is co-administered with pertuzumab. In one embodiment, HER2 TDB is co-administered with trastuzumab and pertuzumab. In one embodiment, HER2 TDB is co-administered with T-DM1 and pertuzumab.

In another aspect, the present invention provides a pharmaceutical formulation comprising any of the anti-CD3 antibodies provided herein for use, for example, in any of the above-described methods of treatment. In one embodiment, the pharmaceutical formulation comprises any of the anti-CD3 antibodies provided herein and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical formulation comprises any of the anti-CD3 antibodies provided herein and at least one additional therapeutic agent, e.g., as described herein.

The antibodies of the present invention can be used in therapy alone or in combination with other agents. For example, the antibodies of the present invention can be co-administered with at least one additional therapeutic agent. In certain embodiments, the additional therapeutic agent is a chemotherapeutic agent, a growth inhibitor, a cytotoxic agent, an agent for radiotherapy, an anti-angiogenic agent, an apoptotic agent, an anti-tubulin agent or other agent, such as an epidermal growth factor receptor (EGFR) antagonist (e.g., a tyrosine kinase inhibitor), a HER1/EGFR inhibitor (e.g., erlotinib (Tarceva ^™ ), a platelet-derived growth factor inhibitor (e.g., Gleevec ^™ (imatinib mesylate)), a COX-2 inhibitor (e.g., celecoxib), an interferon, a cytokine, an antibody other than the anti-CD3 antibody of the present invention, such as an antibody in conjunction with one or more of the following targets: ErbB2, ErbB3, ErbB4, PDGFR-β, BlyS, APRIL, BCMA VEGF or VEGF receptor, TRAIL/Apo2, PD-1, PD-L1, PD-L2 or another bioactive agent or an organic chemical agent.

In some embodiments, the present invention provides a method wherein the additional therapeutic agent is a glucocorticoid. In one embodiment, the glucocorticoid is dexamethasone.

Such combination therapies noted above encompass both combined administration (where two or more therapeutic agents are included in the same or separate formulations) and separate administration, in which case the antibodies of the invention can be administered before, simultaneously with, and/or after the administration of the additional therapeutic agent. In one embodiment, administration of the anti-CD3 antibody and administration of the additional therapeutic agent are performed within about 1 month, or within about 1, 2, or 3 weeks, or within about 1, 2, 3, 4, 5, or 6 days of each other. The anti-CD3 antibodies of the invention (e.g., bispecific anti-CD3 antibodies of the invention that can bind to CD3 and a second biomolecule (e.g., a cell surface antigen, e.g., a tumor antigen) such as a TDB antibody of the invention or a variant thereof) can also be used in combination with radiation therapy.

The antibodies of the present invention (and/or any additional therapeutic agent) can be administered by any suitable method, including parenteral, intrapulmonary and intranasal administration, and intralesional administration when desired for local treatment. Parenteral infusion includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous infusion. In some embodiments, the antibody is administered by subcutaneous administration. In some embodiments, the anti-CD3 antibody administered by subcutaneous injection exhibits fewer toxic reactions in patients compared to the same anti-CD3 antibody administered by intravenous injection. Administration can be performed by any suitable route, for example by injection, such as intravenous or subcutaneous injection, depending in part on whether the administration is short-term or long-term. Various administration schedules are contemplated herein, including but not limited to single or multiple administrations, bolus administration, and pulsed infusions at different time points.

The antibodies of the present invention will be formulated, given, and administered in a manner consistent with good medical practice. Factors to be considered in this context include the specific condition being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the condition, the delivery site of the agent, the method of administration, the administration schedule, and other factors known to medical practitioners. The antibodies need not necessarily be formulated together with one or more agents currently used to prevent or treat the condition. The effective amount of such other agents depends on the amount of the antibody present in the formulation, the type of condition or treatment, and other factors discussed above. These are generally used in the same dosages and routes of administration as described herein, or in about 1% to 99% of the total dosage described herein, or in any dosage and any route determined to be appropriate empirically/clinically.

For the prevention or treatment of disease, the appropriate dosage of the antibodies of the invention (when used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease to be treated, the type of antibody, the severity and course of the disease, whether the antibody is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the judgment of the attending physician. The antibody is suitably administered to the patient at one time or over a series of treatments.

As a general rule, a therapeutically effective amount of a human anti-CD3 antibody administered will be in the range of about 0.01 to about 100 mg/kg of patient body weight, whether administered once or multiple times. In some embodiments, the antibody is administered daily, for example, at about 0.01 to about 45 mg/kg, about 0.01 to about 40 mg/kg, about 0.01 to about 35 mg/kg, about 0.01 to about 30 mg/kg, about 0.01 to about 25 mg/kg, about 0.01 to about 20 mg/kg, about 0.01 to about 15 mg/kg, about 0.01 to about 10 mg/kg, about 0.01 to about 5 mg/kg, or about 0.01 to about 1 mg/kg. In one embodiment, an anti-CD3 antibody described herein is administered to a human on day 1 of a 21-day cycle at a dose of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, or about 1400 mg. The dose may be administered as a single dose or as multiple doses (e.g., 2 or 3 doses), such as by infusion. For repeated administration over several days or longer, depending on the condition, treatment will generally continue until the desired suppression of disease symptoms occurs. An exemplary dose of the antibody will be in the range of about 0.05 mg/kg to about 10 mg/kg. Thus, one or more doses of about 0.5 mg/kg, 2.0 mg/kg, 4.0 mg/kg, or 10 mg/kg (or any combination thereof) may be administered to the patient. Such doses can be administered intermittently, for example, weekly or every three weeks (e.g., so that the patient receives about 2 to about 20 doses, or, for example, about 6 doses of the anti-CD3 antibody). An initial higher loading amount can be administered, followed by one or more lower doses. The progress of this therapy is easily monitored by conventional techniques and assays.

In some embodiments, such methods may further include additional therapy. The additional therapy may be radiotherapy, surgery, chemotherapy, gene therapy, DNA therapy, virotherapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy or a combination of the foregoing. The additional therapy may be in the form of adjuvant therapy or neoadjuvant therapy. In some embodiments, the additional therapy is the administration of small molecule enzyme inhibitors or anti-metastatic agents. In some embodiments, the additional therapy is the administration of side effect limiting agents (e.g., agents intended to reduce the occurrence and/or alleviate the severity of treatment side effects, such as anti-nausea agents, etc.). In some embodiments, the additional therapy is radiotherapy. In some embodiments, the additional therapy is surgery. In some embodiments, the additional therapy is a combination of radiotherapy and surgery. In some embodiments, the additional therapy is gamma irradiation. In some embodiments, the additional therapy may be the independent administration of one or more of the above-mentioned therapeutic agents.

H. Products

In another aspect of the present invention, an article containing materials suitable for treating, preventing and/or diagnosing the above-mentioned conditions is provided. The article comprises a container and a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, IV solution bags, and the like. Such containers can be formed from a variety of materials, such as glass or plastic. The container holds a composition that is effective for treating, preventing and/or diagnosing a condition, either by itself or in combination with another composition, and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic needle). At least one active agent in the composition is an antibody of the present invention. The label or package insert indicates that the composition is used to treat a selected condition. In addition, the article may comprise (a) a first container containing a composition comprising an antibody of the present invention; and (b) a second container containing a composition comprising another cytotoxic agent or other therapeutic agent. The article in this embodiment of the invention may further comprise a package insert indicating that such a composition can be used to treat a specific condition. Alternatively, or in addition, the article of manufacture may further comprise a second (or third) container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

III. Examples

The following are examples of methods and compositions of the present invention. It will be appreciated that various other embodiments may be practiced, given the general description provided above.

Example 1. Production of anti-CD3 antibodies

CD3ε antigen

A. Bispecific human and cyno CD3ε+CD3γ fused to mouse IgG2a-Fc (CD3εγ-muFc)

cDNA encoding the extracellular portion of human or cynomolgus monkey (cyno) CD3ε or CD3γ was fused to the C-terminus of mouse IgG2aFc to generate CD3-Fc fusions. Total RNA from peripheral blood mononuclear cells (PBMCs) activated with anti-CD3/anti-CD28 was used to generate cDNA encoding the extracellular domains of human or cyno CD3ε and CD3γ. Normal PBMCs were activated for 72 h in RPMI supplemented with 10% FBS by plate-fixed anti-CD3 and anti-CD28. Total mRNA was isolated using the RNeasy mini kit from Qiagen. The cDNA was cloned into a TOPO vector using gene-specific primers by RT-PCR using PCR products amplified with Taq polymerase according to the protocol provided with the TOPO TA cloning kit from Invitrogen. The resulting fragment was introduced into a mammalian expression vector containing the murine IgG2a Fc domain by unrestricted subcloning using Phusion High-Fidelity DNA Polymerase (New England Biolabs, catalog number M0530L). The CD3 fragment was thus amplified using the overlapping region contained in the template plasmid to target it directly downstream of the signal sequence and the murine Fc N-terminus.

For human and cyno constructs, a plasmid containing CD3ε-Fc was transiently co-expressed with a plasmid containing CD3γ-Fc in mammalian CHO cells. CD3ε/γ heterodimers were purified by protein A-agarose (Pharmacia Biotech).

B. N-terminal peptide-KLH conjugate (CD3ε-KLH)

A peptide fragment containing the N-terminal sequence of cyno and human CD3ε was synthesized. The fragment intended for immunization was conjugated to the widely used carrier protein keyhole limpet hemocyanin (KLH) to generate a significant immune response. Attachment of the naturally occurring cysteine at position 28 of cyno and human CD3ε allowed coupling of maleimide-activated KLH to the thiol-containing C-terminal cysteine.

C. Single-chain CD3ε-26-mer-CD3γ (CD3εγ)

cDNA encoding the extracellular portion of human CD3ε and CD3γ subunits was generated by PCR. A flexible peptide linker with 26 amino acids was used to connect amino acids 1-97 of human CD3ε and amino acids 1-81 of human CD3γ to form a CD3ε-26 polymer-CD3γ construct (CD3εγ) (Figure 1). The construct was cloned into an expression vector with a His tag using an alkaline phosphatase promoter and an STIII secretion signal sequence for secretion by Escherichia coli. CD3εγ was purified on a Ni column and subsequently refolded. The appropriately folded CD3εγ was then purified using an OKT3 affinity column.

Except for some binding experiments, commercially available CD3ε was purchased from Creative Biomart (Shirley, New York 11967) (Cat. No. CD3E-2194H).

immunity

A. Immunization of mice

BALB/c or C57BL/6 mice were immunized (2 μg or 10 μg/injection/mouse). Antigen suspended in monophosphoryl lipid A/trehalose dipyrrolidone adjuvant was injected into the footpad at 3-4 day intervals for a total of 12-15 boosts. Lymphocytes were collected from the spleen and lymph nodes of immunized mice 3 days after the last pre-fusion boost. Isolated mouse lymphocytes were fused with SP2/0-Ag14 myeloma cells (American Type Culture Collection) using a Cyto Pulse CEEF-50 instrument (Cyto Pulse Sciences). Briefly, after washing twice with Cytofusion Medium C (Cat. No. LCM-C), isolated spleen cells were mixed with SP2/0-Ag14 cells in a 1:1 ratio and then suspended in Cytofusion Medium C at 10,000,000 cells/ml for electrofusion according to the manufacturer's instructions. The fused cells were cultured overnight in ClonaCell-HY Medium C (Cat. No. 03803) at 37°C in a 7% _CO2 incubator. The next day, the fused cells were centrifuged and then suspended in 10 ml of ClonaCell-HY Medium C and then gently mixed with 90 ml of methylcellulose-based ClonaCell-HY Medium D (Cat. No. 03804) containing HAT components. The cells were plated in OmniTray plates (Thermo Scientific) and allowed to grow at 37°C in a 7% _CO2 incubator. After 6 to 7 days of incubation, single hybridoma clones were picked by ClonePix FL (Molecular Devices) and transferred to 96-well cell plates (No. 353075, Becton Dickinson) containing 200 μL/well ClonaCell-HY Medium E (Cat. No. 03805). The hybridoma culture medium was replaced before ELISA screening.

B. Rabbit immunization

Rabbits were immunized with CFA/IFA human and cyno CD3ε-KLH at 0.5 mg/injection every 2 weeks for 5 injections (d0, d14, d28, d42, d56). Blood was collected on days 52 and 66.

PEG fusion and screening were performed as follows. Clones were screened by ELISA for binding to the N-terminal portion of CD3ε that binds to thyroglobulin (THY). All positive clones were also found to cross-react with cyno CD3ε by ELISA, and 16 unique clones were selected for subcloning. Total RNA was extracted from frozen cell pellets and purified using the Qiagen RNeasy kit according to the manufacturer's instructions. First strand cDNA was synthesized using a one-step RT-PCR method (Qiagen). Rabbit VH and VL domains were further PCR amplified using the protocol described for generating rabbit immune libraries (Kontermann and Dubel. Antibody Engineering. 1: 115-123, 2010). Moderate degeneracy was designed to represent common rabbit germline immunoglobulin genes.

Antibody screening

A. Mouse Hybridoma Screening

Three days after the culture medium was changed, hybridoma supernatants were screened for binding to human and cyno CD3ε by ELISA as described below. All ELISA-positive clones were further screened for binding to human Jurkat T cells, human PBMCs, and cynoPBMCs by flow cytometry (Figures 2 and 3). Hybridoma supernatants were purified by protein A affinity chromatography, followed by sterile filtration (0.2 μm pore size, Nalge Nunc International, NY, USA) and stored in 4°C PBS. Purified mAbs were determined by ELISA and subsequently further tested in functional assays. mAb isotypes were determined using a mouse monoclonal antibody isotyping kit from Roche Diagnostics Corporation.

The amino acid sequences of the light and heavy chain variable domains of the anti-CD3 antibodies 13A3, 72H6, and 19B1 are shown in Figure 4A. Figure 4A also defines the HVR sequences for each of the three antibodies. Figures 4B, 4C, 5A, and 5B show additional amino acid sequences of the light and heavy chain variable domains of other anti-CD3 antibodies.

B. Screening after rabbit immunization

Eight unique heavy chain sequences and six unique light chain sequences were cloned from hybridoma cell lines. Figure 7 shows the heavy and light chain sequences of one of these antibodies, Rab17. High sequence similarity led to the decision to focus on six heavy and light chain pairings. The resulting six antibodies were expressed on a small scale (100 ml culture of 293S) as chimeric rabbit/human IgG and screened for binding to CD3 by ELISA.

Antibody Characterization - Binding Affinity and T Cell Activation Activity Analysis

A. CD3εγ Binding ELISA Assay

CD3εγ binding ELISA assays were performed overnight at 4°C in 96-well microtiter ELISA plates (Greiner, Germany) coated with 2 μg/ml of a conjugate of the N-terminal amino acid of human/cyno CD3ε and THY or a fusion of human/cyno CD3ε/γ and murine Fc in 0.05 M carbonate buffer (pH 9.6). After washing three times with wash buffer (PBS containing 0.05% Tween 20), the plates were blocked with 200 μL of ELISA assay diluent containing BSA. 100 μL of culture supernatant or diluted purified mAb was added and incubated at room temperature for 1 hour. The plates were washed three times and incubated with HRP-conjugated goat anti-mouse IgG Fc for 1 hour. After washing three times, bound enzyme was detected by adding 100 μL/well of TMB substrate (BioFX Laboratories, MD, USA) for 5 minutes. The reaction was stopped by adding 100 μL/well stop reagent (BioFX Laboratories, MD, USA), and the color was detected at A _{630 nm} .

B. Flow Cytometry Analysis

Human Jurkat T cells, human PBMCs, or cyno PBMCs were washed twice with FACS staining buffer (phosphate-buffered saline containing 1% fetal bovine serum) and then suspended in FACS staining buffer at a final concentration of 5×10 ⁶ cells/ml. 100 μl of cells were added to a U-bottom 96-well tissue plate (No. 353077, Becton Dickinson), and 100 μl of hybridoma supernatant or diluted purified mAb was added. After incubation on ice for 30 minutes, cells were washed twice with FACS staining buffer and then stained with a goat anti-mouse IgG antibody conjugated to FITC or allophycocyanin (APC) (No. 1012-11, Southern Biotech) at a 1:300 dilution for 30 minutes. After washing twice with FACS staining buffer, cells were analyzed by flow cytometry using a FACSCalibur (BD Biosciences). Data were analyzed using FlowJo software (Tree Star, Inc.).

C. Human T cell activation assay

Human blood was collected in heparinized syringes and PBMCs were isolated using Leucosep (Greiner Bio-one, catalog number 227290P) and Ficoll Paque Plus (GE Healthcare Biosciences, catalog number 95038-168) as recommended by the manufacturer. Cells were washed in RPMI medium containing 10% FBS and supplemented with GlutaMax (Gibco, catalog number 35050-061), penicillin, and streptomycin (Gibco, catalog number 15140-122), and approximately 200,000 suspended cells were added to a 96-well U-bottom plate. Anti-CD3 antibody was added at between 10 μg/ml and 0.01 μg/ml. After approximately 20 hours of culture, cells were washed with FACS buffer (PBS containing 0.5% BSA and 0.05% sodium azide). The cells were then stained with FACS buffer containing anti-CD69-FITC (BD, catalog number 555530), anti-CD25-PE (BD, catalog number 555432), anti-CD4-APC (BD, catalog number 555349) or anti-CD8-APC (BD, catalog number 555369), washed with FACS buffer and suspended in 100ul of FACS buffer containing 1μg/ml propidium iodide. Data were collected on a FACSCalibur flow cytometer and analyzed using FlowJo. The degree of T cell activation was determined by comparing the percentage of CD69+ and CD25+ populations in CD4+ or CD8+ T cells.

D. Cyno T cell activation assay

Cyno blood was collected in heparinized tubes. Red blood cells were lysed twice with ACK red blood cell lysis buffer (0.874% NHCl, 0.1% KHCO, 0.0036g disodium EDTA). Cells were washed in RPMI medium containing 10% FBS supplemented with GlutaMax (Gibco, catalog number 35050-061) and penicillin and streptomycin (Gibco, catalog number 15140-122). Approximately 200,000 suspended cells were added to 96-well U-bottom plates. 10 μg/ml anti-CD3 antibody was added. After approximately 20 hours of culture, cells were washed with FACS buffer (PBS containing 0.5% BSA and 0.05% sodium azide). The cells were then stained with FACS buffer containing anti-CD69-FITC (BD, catalog number 555530), anti-CD25-PE (BD, catalog number 555432), and anti-CD4-APC (BD, catalog number 551980), washed with FACS buffer, and suspended in 100 μg of FACS buffer containing 1 μg/ml propidium iodide. Data were collected on a FACSCalibur flow cytometer and analyzed using FlowJo. The degree of T cell activation was determined by comparing the percentage of CD69+ and CD25+ populations in CD4+ T cells.

Generation of anti-CD3 antibody variants

A. Cloning and sequencing of mouse CD3εγ human/cyno cross-reactive hybridomas

Total RNA was extracted from mouse hybridoma cells using the RNeasy kit (Qiagen), and the first strand cDNA was synthesized using the SuperScript III RT kit (Invitrogen). The antibody gene was amplified by error-proof Taq polymerase PCR using a 5' degenerate primer mix and 3' Cγ-, Cκ-, and Cλ-specific primers. The PCR products were purified and sequenced to obtain the variable regions of the antibody heavy and light chains. The variable regions of the antibody heavy and light chains were digested with appropriate restriction enzymes and cloned into the corresponding pRK expression vectors. The murine antibodies were expressed in 293 cells.

B. Humanization

The sequences of human/cyno CD3εγ cross-reactive hybridomas were aligned with the most homologous human common or germline light and heavy chain variable domains ( FIG. 7 ). The consensus sequence, designated mu40G5c, was derived from the light and heavy chain variable domains of related hybridoma clones ( FIG. 7 ). The hypervariable regions (HVRs) were engineered into the light and heavy chain human acceptor frameworks to generate humanized CDR grafts (see, e.g., FIG. 8A to FIG. 8F ). Humanized variants were evaluated in Fab fragment format or in IgG format. VL domain positions 24-34 (L1), 50-56 (L2), and 89-97 (L3) and VH domain positions 26-35 (H1), 50-65 (H2), and 95-102 (H3) were used for such grafts ( FIG. 8A to FIG. 8F ). Other variants comprising various combinations of one or more mouse cursor positions were also generated and tested for binding affinity (see, e.g., FIG. 9A to FIG. 9F ). The murine variable domain residues at the selected cursor positions were incorporated into the final humanized sequences based on their ability to improve binding affinity. The monovalent binding affinities of selected humanized antibodies to different CD3ε antigens are shown in Figure 10. The binding affinities for affinity variants of humanized anti-CD3 antibodies 38E4 (38E4v1-38E4v9) and 40G5c are shown in Figure 11.

C. Antibody Determinant Cluster Location

Kunkle mutagenesis was used to individually mutate residues in HVR-L3 and HVR-H3 of hu38E4 to alanine. Additionally, position 95 in HVR-H3 was mutated to serine, threonine, or glutamate. Variants harboring these single-point mutations were expressed as Fabs in HEK293 cells and screened using a single-cycle kinetic approach on a Biacore T100. Selected variants were also scaled up and purified for conventional multi-cycle kinetic analysis. In single-cycle kinetic analysis, a Biacore S-series CM5 sensor chip was immobilized with an anti-human Fab antibody (Human Fab Capture Kit, GE Healthcare). Each Fab was captured from the culture supernatant, and increasing concentrations of human CD3εγ (ranging from 3 nM to 250 nM in HBSP buffer) were sequentially injected in a single analytical cycle at a flow rate of 30 μl/min, with no surface regeneration between injections; a 10-min dissociation period was achieved between cycles. In conventional multi-cycle kinetic analysis, human CD3εγ, cyno CD3εγ or 27-mer peptides were immobilized on a Biacore S series CM5 sensor chip using an amine coupling kit derived from Biacore. Serial 3-fold dilutions of each Fab variant were injected at a flow rate of 30 μl/min. Each sample was analyzed using a 3-minute association and 3-minute dissociation protocol. In both methods, 10 mM glycine (pH 1.7) was used to regenerate the Biacore chip. The binding reaction was corrected by blank subtraction, and a 1:1 Languir model that simultaneously fitted _kon and _koff was used for kinetic analysis. The effects of these mutations summarized in Figure 12 indicate that light chain residue R96 and heavy chain residues Y97, R99 and F100b play an important role in binding to CD3εγ.

D. CD3 epitope mapping

Alanine mutations were introduced into CD3ε ^1-27 -Fc to assess epitope recognition by N-terminal binding anti-CD3ε antibodies. Each CD3ε ^1-27 -Fc variant was immobilized on Nunc Maxisorp plates at 2 μg/ml in PBS overnight at 4°C. After blocking the plates for 1 hour with 2% milk powder in PBS containing 0.05% Tween 20, 100 μl of 3 nM anti-CD3ε was added to each well and allowed to bind for 1 hour at 25°C. After washing six times with PBS containing 0.05% Tween 20, antibody binding was detected by adding an anti-mouse IgG-HRP secondary antibody, as shown in Figure 13A.

CD3εγ was subcloned into an M13 phagemid containing a C-terminal gD tag followed by an amber stop codon so that it could be displayed on phage or expressed in a non-suppressor strain of Escherichia coli. This CD3εγ phagemid was used as a template to induce single alanine mutations in CD3ε by Kunkel mutagenesis. Each CD3ε alanine mutant displayed on phage was determined by DNA sequencing, isolated from a single colony, grown overnight in 2YT/Carb+KO7 helper phage and purified by PEG precipitation. The effect of alanine mutations in CD3εγ on anti-CD3 antibody binding was assessed using phage ELISA. Each anti-CD3 antibody at 2 μg/ml in PBS buffer was immobilized on a NUNC maxisorp plate overnight at 4°C. Purified phage supernatant displaying the CD3εγ alanine variant (1.0 OD ₄₅₀ ) was added to the plate and allowed to bind for 1 hour at room temperature under shaking. After washing, bound phage were detected using anti-M13-HRP (GE Healthcare, catalog number 45-001-419). The binding of each CD3εγ alanine variant was compared to wild-type CD3εγ phage binding ( FIG13B ). Alanine variants that affect anti-CD3 antibody binding were further characterized by assessing binding as a function of phage concentration ( FIG13C ).

To quantify the effect of alanine mutations in CD3 on antibody binding, selected CD3 alanine mutants were expressed in a non-suppressive strain of E. coli. Secreted CD3εγ variants were captured from crude periplasmic fractions using the anti-CD3 antibody UCHT1v9. UCHT1v9 was immobilized on a CM5S series chip via amine coupling using an anti-human IgG (Fc) antibody capture kit (BR-1008-39) from GE Healthcare. SPR measurements were performed on a Biacore 4000 instrument using kinetic evaluation software. To measure monovalent binding affinity, an anti-CD3 bispecific antibody was used, in which one arm was the anti-CD3 to be tested and the other arm recognized an unrelated antigen. The bispecific anti-CD3 antibody was passed through the capture supernatant at a two-fold dilution series from 0.39 to 100 nM. The resulting kinetic properties were measured ( FIG. 13D ) and calculated using Biacore 4000 BIAevaluation software (product code 28-9664-57).

E. Structural mapping of the CD3ε binding site

1.Hu38E4.v1 Fab

Hu38E4.v1 Fab dissolved at 10 mg/ml in 0.15 M NaCl, 25 mM tris pH 7.5 was mixed with a 2-fold molar excess (1 mg) of the CD3ε peptide QDGNEEMGGITQTPYK (SEQ ID NO: 284) ( FIG. 14A ) and subjected to crystallization trials. A preliminary screen was performed using a sparse matrix of precipitates in a sessile drop vapor diffusion format. Optimized crystals were grown from a 1:1 mixture with a stock solution containing 70% v/v methylpentanediol and 0.1 M HEPES buffer, pH 7.5. This stock solution served as a cryoprotectant. Crystals were transferred to extremely cold temperatures by sudden immersion in liquid nitrogen.

Diffraction data of hu38E4.v1 Fab and CD3ε peptide co-crystals were collected using a MAR300 CCD detector at an Advanced Photon Source beamline of 22 ID. The recorded diffractograms were then integrated and scaled using the program HKL2000.

The structure was phased using the molecular replacement (MR) method using the Phaser program. The MR search model was the Fab subunit derived from the crystal structure of the HGFA/Fab complex (PDB code: 2R0L). The CD3ε peptide was incorporated into the structure based on the Fo-Fc spectrum. The structure was subsequently refined using the REFMAC5 and PHENIX programs using a maximum probability objective function, anisotropic individual B-factor refinement, and TLS refinement to convergence. Data and refinement statistics are shown in Table 3A.

Table 3A. Data collection and refinement statistics for the hu38E4.v1/CD3ε complex

^1The values in brackets have the highest resolution shell.

² Rsym＝Σ| _Ihi - _Ih |/ _ΣIhi , where _Ihi is the scaled intensity of the ith symmetry-related observation of reflectivity h, and _Ih is the average value.

³ Rcryst＝ _Σh |Fo _,h - _Fc,h |/ _{ΣhFo ,h} , where Fo _,h and Fc _,h are the observed and calculated structure factor amplitudes of the reflectivity h.

⁴ The value of R _free was calculated for 5% randomly selected reflectances and was not included in the refinement.

The crystal structure of the hu38E4.v1 Fab/CD3ε peptide complex was determined at 400 nm resolution. The structure shows that the CD3ε peptide forms a small turn and inserts deeply into the cleft between the heavy and light chains of the 38E4.v1 Fab (Figures 14B and 14C). The binding buries the solvent-accessible surface area between the peptide and the Fab fragment and involves an entangled network of hydrophobic hydrogen bonding and ionic interactions (Figure 14D). The N-terminal pyroglutamate (pyroglu) loop packs against heavy chain Tyr33 and forms a hydrogen bond with heavy chain His35 in HVR-H1. The bulky side chain of residue F100b in HVR-H3 facilitates the proper orientation of His35 for interaction with pyroglu and explains the observed loss of binding when F100b is mutated to the small side chain residue alanine. In addition, consistent with the alanine scanning results, R96 in CDR-L3 forms an important hydrogen bond with the carboxyl group in pyroglu, while Y97 in CDR-H3 forms a hydrogen bond with Met7 of the CD3ε peptide (Figure 14E). Interestingly, although the alanine substitution at R99 in CDR-H3 has a significant effect on antigen binding, the structure shows that this side chain points away from the CD3ε peptide and does not participate in any interaction with the peptide. Alternatively, R99 forms extensive contacts with several residues in CDR-H3, including hydrogen bonds with D101 and hydrophobic stacking against Y100a, thereby further affecting the cursor residue LC Y49 (Figure 14F). These interactions may be important for the support and overall arrangement of the CDR loops in the 38E4.v1 Fab by organizing the important central cleft between the heavy and light chains to enable CD3ε peptide binding.

Figure 14G indicates all residues in the 38E4.v1 Fab that were determined to be within the CD3ε peptide. These antigen-contacting residues are identical between hu38E4.v1 and hu40G5c, except that residue G96 of hu38E4.v1 is a serine residue (S96) in hu40G5 (see Figure 14H , which shows the location of the contact residue G96 of hu38E4.v1).

Contacts between anti-CD3 (38E4.v1) and the CD3 _{epsilon gamma} peptide were calculated based on alanine scanning. The epitope recognized by 38E4v1 anti-CD3 makes contacts at or nearer distances, as provided in Table 3B below. This analysis identified CD3 epitope Gln1 (PCA1, pyroglutamic acid), Asp2, Glu6, and Met7 as key contact-forming residues for the antibody determinants of both the light and heavy chain variable regions of the CD3 antibody.

Table 3B. CD3 contacts of hu38E4.v1/CD3ε complex

* indicates hydrogen bonding between two side chains.

Gray shaded cells indicate reliable hydrogen bonding contacts.

The bold contacts are hydrogen bonds formed between the side chains and the main chain backbone.

2.SP34v52 Fab

SP34v52 Fab was dissolved at 10 mg/mL in 0.25 M NaCl, 25 mM MES pH 5.5. A preliminary crystallization screen was performed using a sparse matrix (PEG II, Qiagen) screen in a sessile drop vapor diffusion format. Successful crystallization was observed in drops of a stock solution containing _0.2 M CaCl2, 0.1 M HEPES pH 7.5, and 30% w/v PEG 4000. Optimized crystals were grown from a mixture of 2 μL of protein and 2 μL of a stock solution containing 20%-23% w/v PEG 3350, 0.1 M HEPES pH 7.2, and 0.1 _M CaCl2. The final crystallization drop was incubated at 18°C using the hanging drop vapor diffusion method.

Diffraction data for SP34v52 Fab were collected using a PILATUS detector at Stanford Synchrotron Light Source beamline 12-2. The recorded diffractions were then integrated using the XDS program and calibrated using the SCALA program. The structure was phased using the molecular replacement (MR) method using the Phaser program. The MR search model was the Fab subunit derived from the HGFA/Fab complex (PDB code: 2R0L) crystal structure. The CD3ε peptide was incorporated into the structure based on _{the F-Fc spectrum} . The structure was then refined using the REFMAC5 and PHENIX programs using the maximum probability objective function, anisotropic individual B-factor refinement method, and TLS refinement method to achieve convergence. The data and refinement statistics are shown in Table 4 below.

Table 4. Data collection and refinement statistics for SP34v52

^1The values in brackets have the highest resolution shell.

² Rsym＝Σ| _Ihi - _Ih |/ _ΣIhi , where _Ihi is the scaled intensity of the ith symmetry-related observation of reflectivity h, and _Ih is the average value.

³ Rcryst＝ _Σh |Fo _,h - _Fc,h |/ _{ΣhFo ,h} , where Fo _,h and Fc _,h are the observed and calculated structure factor amplitudes of the reflectivity h.

⁴ The value of R _free was calculated for 5% randomly selected reflectances and was not included in the refinement.

In Figures 14I to 14L , the crystal structures of hu38E4.v1 Fab and SP34v52 Fab are compared in the same orientation. When the CD3ε peptide was superimposed on the SP34v52 Fab in the same orientation as in hu38E4.v1, a clear clash of the peptide with SP34v52 was observed ( Figure 14L ). HVR-H2 residues R50 and R52 of SP34v52 (which are absent in hu38E4.v1 or hu40G5c) were found to be critical for SP34v52 binding to CD3 ( Figure 14L ). These data suggest that hu38E4.v1 and hu40G5c bind CD3 differently from SP34v52.

Figures 14M and 14N show the crystal structure of hu38E4.v1 in complex with the N-terminal peptide of CD3 _epsilon gamma. Figure 14M provides a zoomed-in view of the key intermolecular interactions involved in contacting the sixth residue in CD3 _{epsilon gamma} . In a zoomed-out view, Figure 14N shows a space-filling model of the Fab/CD3 peptide complex, with the fifth residue pointing completely away from the interaction site. As shown, the sixth residue is involved in the interaction with the Fab and points toward the active site.

Example 2. Generation and selection of T cell-dependent bispecific (TDB) antibodies

One approach to exploiting the high cytotoxic potential of T cells in eliminating tumor cells has been to use T cell-dependent bispecific (TDB) antibodies. Molecules such as the CD19/CD3 bispecific BiTE antibody blinatumomab, which targets B cells, have been reported to promote clinical responses. However, the therapeutic prospects of many reported bispecific antibody formats are limited by unfavorable conditions (including unfavorable pharmacokinetic (PK), toxicity, and/or production issues). Therefore, we initially generated and characterized anti-CD3 TDB antibodies with different combinations of anti-CD3 arms and anti-tumor antigens (e.g., anti-CD20, anti-FcRH5, anti-HER2, anti-LYPD1, anti-LY6E, anti-LY6G6D, anti-PMEL17, anti-CD19, anti-CD22, anti-CD33, anti-CD79A, anti-CD79B, anti-EDAR, anti-GFRA1, anti-MRP4, anti-RET, anti-Steap1, anti-TenB2) arms, resulting in full-length antibodies in a knob-into-hole format. Unexpectedly, we found that specific combinations (pairings) of anti-CD3 arms with anti-tumor antigen arms resulted in TDBs that exhibited favorable activity compared to other TDBs.

The TDB antibodies produced are full-length antibodies in a knob-in-hole format, such as human IgG1, as previously described (Atwell et al., J. Mol. Biol. 270:26-35, 1997). Half antibodies are expressed in E. coli or Chinese hamster ovary (CHO) cells, purified by protein A affinity chromatography, and the appropriate half-antibody pairings are annealed in vitro as previously described (Spiess et al., Nat. Biotechnol. 2013). If the TDB antibodies are produced in CHO cells, the antibodies may include a deglycosylation mutation, for example, at residue N297 (e.g., N297G), rendering the TDB antibodies effector-free variants and unable to elicit antibody-dependent cell-mediated cytotoxicity (ADCC). FIG15 shows a schematic overview of CD3/CD20 TDB production.

After annealing, the CD3/CD20 TDB was purified by hydrophobic interaction chromatography (HIC) and characterized by analytical gel filtration, mass spectrometry, and polyacrylamide gel electrophoresis. The purified antibody ran as a single peak (>99% signal) in gel filtration with less than 0.2% aggregate. No homodimers were detected by mass spectrometry. The anti-CD20 arms tested in the generation of the CD3/CD20 TDB included 2H7v16, 2H7v114, 2H7v511, and GA101. The anti-CD3 arms tested in the generation of the CD3/CD20 TDB included UCHT1v1, UCHT1v9, UCHT1vM1, 72H6, 13A3, 30A1, 41D9a, SP34v52, 40G5c, 38E4v1-38E4v9, 21B2, 125A1, and 21A9. The CD3/CD20 TDB was tested for binding to CD3 and activity as assessed by in vitro B cell killing assays and T cell activation assays.

A. Binding affinity

As described above for anti-CD3 antibodies, the binding affinity of each CD3/CD20 TDB was tested by Biacore or FACS analysis. Briefly, in the Biacore binding assay, human CD3εγ was immobilized on a Biacore S series CM5 sensor chip using an amine coupling kit from Biacore, and the CD3/CD20 TDB or its Fab variant was flowed over. In the FACS binding assay, Bjab cells (for B cell antigens) or Jurkat cells (for CD3 antigens) were incubated with various concentrations of TDB antibodies for 30 minutes at 4°C, followed by washing and incubation with a secondary antibody (anti-huIgG-PE; BD Bioscience) for an additional 15 minutes, after which the cells were washed again and prepared for FACS analysis. FIG16 shows the results of an in vitro FACS binding assay for the CD3/CD20 TDB. The results show that specific combinations of an anti-CD3 antibody arm with an anti-tumor antigen arm (e.g., an anti-CD20 arm) produce TDB antibodies with more favorable binding properties. Figure 17 shows the monovalent and bivalent binding affinities of these specific CD3/CD20 TDBs. For example, a specific pairing of 2H7v16 with an anti-CD3 arm (e.g., UCHT1v9) yielded a CD3/CD20 TDB that exhibited unexpectedly strong binding to Bjab and Jurkat cells compared to other tested CD3/CD20 TDBs with different anti-CD20 arms. The binding affinities of other CD3/CD20 TDBs with the 2H7v16 anti-CD20 arm and various anti-CD3 arms were also tested (see Figures 18 to 24).

B. In vitro B cell killing and T cell activation assays

The generated CD3/CD20 TDBs were also tested for their ability to support B cell killing and activation of T cell cytotoxic effectors. In these assays, a B tumor cell line (Bjab) was obtained from ATCC, and PBMCs were isolated from whole blood of healthy donors by Ficoll separation. Where necessary, CD4+ T cells and CD8+ T cells were isolated using a Miltenyi kit according to the manufacturer's instructions. Cells were cultured in RPMI1640 supplemented with 10% FBS (Sigma-Aldrich) in a humidified standard cell culture incubator at 37°C. In the Bjab cell killing assay, 20,000 Bjab cells were incubated with effector cells (huPBMCs or purified T cells) at the ratios indicated for each assay in the presence of various concentrations of TDB antibodies for the indicated time periods for each assay. In the endogenous B cell killing assay, 200,000 huPBMCs were incubated with various concentrations of TDB antibodies for the indicated number of hours for each assay. At the end of each analysis, live B cells were gated out by FACS as PI-CD19+ or PI-CD20+ B cells, and absolute cell counts were obtained using FITC beads added to the reaction mixture as an internal counting control. Cell killing % was calculated based on controls not treated with TDB. Activated T cells were detected by CD69 and CD25 surface expression.

The varying potencies of the generated TDB antibodies with bispecificity for CD3 and a second biomolecule (in this case, CD20) emphasize the important and unpredictable contributions of the two antibody arms in generating exemplary TDBs with high potency (see Figures 25-49).

Example 3. Characterization of an Exemplary CD3/CD20 TDB (CD20 TDB)

We further characterized two of the exemplary CD3/CD20 TDBs (CD20 TDBs) described above, which showed high efficacy in in vitro B cell killing and T cell activation assays. The CD20 arm of each TDB antibody was the anti-CD20 clone 2H7.v16 (see FIG50 ), while the CD3 arm was clone UCHT1v9 (see, e.g., Zhu et al., Int. J. Cancer. 62:319-324, 1995) or the comparably active cyno-cross-reactive clone 40G5c (see, e.g., FIG51 ).

Materials and methods

A. Antibody Production

The T cell-dependent bispecific (TDB) antibodies generated are full-length antibodies, such as human IgG1, in a knob-in-hole format, as previously described (Atwell et al., J. Mol. Biol. 270:26-35, 1997). Half antibodies were expressed in E. coli and subsequently deglycosylated, purified by protein A affinity chromatography, and the appropriate half-antibody pairs were annealed in vitro as previously described (Spiess et al., Nat. Biotechnol. 2013). After annealing, the antibodies were purified by hydrophobic interaction chromatography (HIC) and characterized by analytical gel filtration, mass spectrometry, and polyacrylamide gel electrophoresis. The purified antibodies ran as a single peak (>99% signal) in gel filtration with no detectable aggregates (Figure 52A), and no homodimers were detected by mass spectrometry (Figure 52B).

B. In vitro B cell killing and T cell activation assays

B tumor cell lines were obtained from ATCC, and PBMCs were isolated from whole blood of healthy donors by Ficoll separation. CD4+ T cells and CD8+ T cells were separated using the Miltenyi kit according to the manufacturer's instructions. Cells were cultured in RPMI1640 supplemented with 10% FBS (Sigma-Aldrich). In the B cell killing assay, live B cells were gated out as PI-CD19+ B cells by FACS, and absolute cell counts were obtained using FITC beads added to the reaction mixture as an internal counting control. Activated T cells were detected by CD69 and CD25 surface expression. Intracellular granzyme B induction was detected by FACS. Perforin concentration in the culture medium was detected by ELISA (eBioscience). All antibodies were purchased from BD Bioscience.

C. In Vivo Efficacy Studies in Murine Models

Humanized NSG and SCID mice were purchased from Jackson Labs. Human CD20 and CD3 transgenic mice were generated as previously described (Gong et al., J. Immunol. 174:817-826, 2005; and de la Here et al., J. Exp. Med. 173:7-17, 1991), and human CD20/CD3 double-transgenic mice were generated by crossing the two single-transgenic mice. A human lymphoma mouse model was established by subcutaneously injecting 5×10 ⁶ Bjab luciferase cells, either alone or mixed with 10×10 ⁶ human donor PBMCs, into the right flank of 40 female mice in HBSS. One hour after inoculation and one week after the initial treatment, mice were treated intravenously with vehicle or 0.5 mg/kg CD20 TDB. Tumors were measured one to two times weekly, and body weights were measured twice weekly until 7 days after the final treatment. If weight loss was not observed, no further weight was obtained for a given animal. If the weight loss is greater than 15% of the total body weight, the affected mice are weighed daily and euthanized (or brought to the attention of veterinary staff) if the weight loss exceeds 20%. Clinical observations are performed twice a week throughout the duration of the study to monitor the health of the animals; any animal whose tumor size or condition may interfere with the animal's health or activity is euthanized. Otherwise, animals are euthanized 6 months after the initial treatment or when the tumor becomes ulcerated or its volume exceeds 2500 mm ³ .

A patient-derived chronic lymphocytic leukemia (CLL) mouse model was generated as previously described (Bagnara et al., Blood. 117: 5463-5472, 2011). Briefly, ⁵ × 10 activated T cells were purified from CLL PBMC and injected into NSG mice retroorbitally. After T cell transplantation, 2 × ¹⁰ CLL PBMC were injected retroorbitally. After 14 days, the circulation of transplanted B cells and T cells was determined by FACS analysis. Subsequently, after 3.5 weeks, the successfully transplanted animals were treated with TDB antibodies administered intravenously via tail vein injection. Animals were euthanized 6 or 14 days after treatment. Whole blood was collected using a heparinized pipette by retroorbital puncture while the animal was anesthetized and immediately transferred to a heparinized tube, or whole blood was collected with a heparinized syringe by terminal cardiac puncture after CO2 euthanasia. Spleens were collected after CO2 euthanasia. In each study, clinical observations were performed twice weekly to monitor the health of the animals. Animal weights were obtained at least once a week. PBMCs were isolated after hemolysis and analyzed by FACS for B cells (muCD45+CD19+) and T cells (muCD90.2+CD4+, or muCD90.2+CD8+). All antibodies used were purchased from BD Biosciences or eBiosciences.

D. PKPD Studies in Cynomolgus Monkeys

All cynomolgus monkey studies were conducted using purposefully bred natural cynomolgus monkeys from China. In the single-dose PKPD study, three male cynomolgus monkeys were administered a single slow bolus IV dose of 1 mg/kg of CD20 TDB; in the repeated-dose study, four cynomolgus monkeys were administered a slow bolus IV dose of 1 mg/kg of CD20 TDB once weekly for a total of four doses. Whole blood or tissue was collected at selected time points for B cell and T cell enumeration by FACS. Serum was collected and stored at -70°C until analyzed using ELISA to determine the amount of test article in each serum sample. Pharmacokinetic (PK) parameters were estimated using serum concentration-time curves from each animal using WinNonlin software (Pharsight; Mountain View, CA).

High-quality CD20 TDB produced as a full-length humanized IgG with conventional antibody PK properties

To explore targeting properties that may affect the efficacy of B cell-targeting TDBs, including antigen identity, extracellular domain size, and epitope distance from the cell membrane, we generated over 40 different TDBs targeting epitopes on _CD3ε , CD19, CD20, CD22, CD79a, and CD79b. Representative results are shown in Figure 56I. We found that the most effective TDBs were those targeting cancer target antigens with small extracellular domains (ECDs) and epitopes close to the target cell membrane. Among the best targets were CD20, CD79a, and CD79b, with an efficacy of approximately 10 ng/ml or 67 pM for autologous T cells killing normal donor B cells.

Anti-CD20/CD3 TDBs (CD20-TDBs) are described herein as proof-of-concept molecules demonstrating the pharmacological activity of these B cell-targeting TDBs. The generated CD20 TDBs are in the form of full-length, fully humanized IgGs that have the structure of native antibodies from bacteria, lacking homodimers and aggregates ( FIG52 ). The pharmacokinetic (PK) properties of the CD20 TDBs in rats (a non-binding species) are similar to those of other human IgG antibodies, with a half-life of approximately 7 days ( FIG53 ).

CD20 TDB-induced B cell killing via the granzyme-perforin pathway is T cell-dependent

To evaluate CD20 TDB as a potential therapy for cell proliferative disorders (such as CD20+ B cell malignancies), we first studied its mechanism of action as a bispecific T cell recruiting antibody. Unlike ADCC activity, which is the main mechanism of action of classical monoclonal antibody therapy, the activity of CD20 TDB does not require an Fc region. The F(ab')2 portion of CD20 TDB retains the same B cell killing potency as the full-length IgG CD20 TDB (Figure 54A). CD20 TDB is a conditional agonist whose activity requires target expression, T cells, and antibody. The B cell killing activity of CD20 TDB is T cell-dependent, as no B cell killing was detected with PBMCs that had been cleared of CD3+ T cells (Figure 54B). T cell activation requires target expression, as the absence of CD20 expression results in no activated T cells (Figure 54C). As measured by inducing CD69 and CD25 on T cells, CD20 TDB is able to activate CD4+ and CD8+ T cells (Figure 54D). Utilizing T cells as effectors can achieve comparable B cell killing, and CD8+T cells appear to be more effective in BJAB cell killing, as the degree of cell killing caused by CD8+T cells is higher than that of an equal number of CD4+T cells (Figure 54C). However, granzyme upregulation is more common in CD8+T cells (Figure 54E), and higher levels of perforin and granzyme A and B (not shown) release associated with CD8+T cells were detected in the culture medium by ELISA (Figure 54F). Activated T cells are able to proliferate (Figure 55). However, in vitro, in the presence of CD20 TDB and B cells, total T cell counts did not increase significantly after 24 hours in the absence of cytokine supplementation, which may be due to culture conditions. In vivo, stable T cell expansion was indeed observed in efficacy studies conducted in mouse models and in cynomolgus monkeys (Figures 58A and 67C).

CD20 TDB is effective in killing B leukemia/lymphoma cells in vitro and autologous B cells

The B cell killing efficacy of CD20 TDB was also tested in vitro using over a dozen B leukemia/lymphoma cell lines. To evaluate the efficacy of CD20-TDB, eight cell lines representing cells with a wide range of CD20 expression levels were selected ( FIG. 56B ). Dose-response B cell killing curves are shown for these eight cell lines, using PBMCs isolated from healthy donors as effector cells ( FIG. 56A ). Clearly, CD20-TDB was inactive against SU-DHL1 cells, which lack CD20 expression. The efficacy of CD20-TDB correlated somewhat with the various surface CD20 levels detected by flow cytometry ( FIG. 56A ). Despite this, CD20 TDB was effective in killing all eight cell lines in a dose-dependent manner, with EC50s ranging from 0.38 to 11 ng/ml in the 24-hour assay. In the 24-hour assay, the degree of cell killing varied somewhat from 60% to 90% with up to 1000 ng/ml of TDB ( FIG. 56C ). In general, complete B cell killing can be achieved using higher antibody concentrations or extended assay times. SU-DHL-1 cells were included in the killing assay as a CD20 negative control, where no cell killing was observed, demonstrating that target expression is required for CD20 TDB activity. CD20 TDB activity appears to require very low target expression levels, as both Nalm-6 and SC-1 cells were shown to have very low CD20 surface expression ( FIG56B ). The monovalent binding affinity of CD20 TDB for CD20 is weaker than the bivalent binding affinity of the parental anti-CD20, with a _K of 54 nM as determined by scatchard. Combining the _K value and CD20 TDB B cell killing potency, the receptor occupancy required for CD20 TDB activity is only less than 0.1%. As shown in Figure 56D , the generated TDBs targeting different B cell antigens were also effective in mediating B cell killing. TDBs targeting five different B cell antigens, including the CD20 TDB (TDB A: 2H7v16/UCHT1v9), killed 75% to 90% of B cells. The CD20 TDB further mediated killing of other B lymphoma cell lines expressing different CD20 surface antigens ( Figure 56E ).

CD20 TDB was also highly effective in killing autologous B cells tested with human PBMCs isolated from peripheral blood of healthy donors ( FIG. 56F ). Dose-response killing curves for 8 random donors are shown in FIG. 56F , along with a summary graph of the EC50 and extent of B cell killing at 1000 ng/ml of antibody in a 24-hour assay across 30 donors ( FIG. 56G ). Across the 30 samples tested, 57% to 96% of B cells were killed within 24 hours with up to 1000 ng/ml of antibody, with EC50s ranging from 0.43 to 135 ng/ml and a median of less than 3 ng/ml. The extent of B cell killing by CD20 TDB within 24 hours was comparable to or greater than that by anti-CD3/anti-CD19 scFv ( FIG. 56H ).

CD20 TDB is effective in depleting B cells in vivo in a murine model

Since the CD20 TDB we tested did not recognize the murine CD20 and CD3 antigens, we used human CD20 and human CD3 transgenic mice (as described above) to generate human CD3/CD20 double transgenic mice for subsequent in vivo efficacy studies. As shown in Figure 57A, human CD3/CD20 double transgenic mice expressed huCD3ε on the surface of CD4+ and CD8+ T cells and huCD20 on the surface of CD19+ B cells at detectable levels compared to human-derived T cells and B cells. In the case of human CD20 transgenic mice, only rituximab was able to eliminate B cells because the CD20 TDB was unable to engage murine T cells in the absence of human CD3 expression (Figure 57B). In the case of human CD3/CD20 double transgenic mice, the CD20 TDB was able to engage murine T cells expressing huCD3 and was effective in eliminating murine B cells expressing huCD20 (Figure 57C). The CD20 TDB appears to be more effective at depleting B cells in vivo, as fewer B cells were detected in the spleens of mice 7 days after a single IV dose of 0.5 mg/kg CD20 TDB compared to a single dose of 10 mg/kg rituximab. A HER2 TDB with the same CD3 arm but binding to HER2 with the other arm served as an isotype control and was shown to be inactive in cell depletion.

To investigate the lowest effective dose of CD20 TDB in B cell depletion using human CD3/CD20 double transgenic mice, mice were treated with single doses of CD20 TDB starting at 0.5 mg/kg and decreasing to 0.00005 mg/kg. Blood B cell counts were then monitored on D1 (24 hours post-dose), D8, and D15. A decrease in B cell counts was observed on D1, and B cell depletion continued until D15 after CD20 TDB treatment ( FIG58A ). Consistent with these blood B cell count observations, near-complete B cell depletion in the spleen of mice was achieved on D7 after a single dose of 0.5 mg/kg, while a lower dose of 0.05 mg/kg resulted in partial splenic B cell depletion and a similar ED50 dose level ( FIG58B ). Time course studies using double transgenic mice showed that B cell depletion in the spleen was nearly complete as early as three days after a single dose of 0.5 mg/kg, with no significant signs of B cell recovery until D14 ( FIG58A ). As shown in Figure 58C, CD20 TDB mediated B cell depletion in the periphery of the dual transgenic huCD20/huCD3, with this effect being detected in the blood as early as two hours after treatment and maintained until 7 days after treatment. In addition, activated CD8+ and CD4+ T cells were detected in the blood within two hours of CD20 TDB administration and then declined by two days after treatment (Figure 58D).

Furthermore, after a single IV dose of 0.5 mg/kg, CD20 TDB depleted marginal zone B cells (MZB) in mouse spleens (Figures 59A and 59B) with the same potency as follicular B cells (FOB) (Figures 59A and 59C). We observed a decrease in splenic B cells from baseline of approximately 50% by day 1 (24 hours post-dose) and continued to decline rapidly until reaching a nadir on day 3, where these levels were maintained throughout the study. This result differs significantly from previous reports on rituximab, in which the microenvironment was suggested to play a role in rituximab's effectiveness, suggesting that the in vivo mode of action of CD20 TDB differs from that of rituximab. Murine T cell activation was generally observed in the blood as early as 30 minutes after CD20 TDB treatment, and primarily in the spleen within the first 24 hours (Figures 59D and 59E). Following T cell activation, T cell counts were observed to increase around D2-D3 due to cell proliferation (Figures 59D and 59E). By day 2, most T cells were no longer CD69-positive, but the percentage of CD69+CD8+ cells remained in the 10% to 30% range for the remainder of the two-week study. However, T cell counts tended to decrease after the expansion phase, likely due to activation-induced cell death. T cell counts eventually recovered after TDB treatment, indicating that CD20 TDB treatment has no inhibitory effect on murine T cell regeneration.

Humanized NSG mice were also used to further validate the efficacy of CD20 TDB in B cell depletion in a murine model and under repeated dose conditions. The actual mice involved in the studies shown in Figures 60A to 60D had 35% to 80% human CD45+ cells in peripheral blood, and CD4+, CD8+, and CD20+ cells ranging from 12% to 25%, 2.1% to 8.7%, and 32% to 60%, respectively (percentages reported as a percentage of gated live leukocytes). A representative example of this baseline characterization is shown in Figure 60E. The levels of CD3 and CD20 target antigens obtained from these mice were compared with normal human donors and found to be no significant difference (Figure 60F). As shown in Figure 59, humanized NSG mice were treated with 0.5 mg/kg CD20 TDB three times a week. B cells in the blood were depleted on D7, with almost no B cells detected on D21 (Figure 60A). Robust B cell depletion was also observed in the spleens of TDB-treated mice on D21 ( FIG. 60B ). Furthermore, as shown in FIG. 60C , treatment of humanized NSG mice with CD20 TDB stimulated T cell proliferation and resulted in B cell depletion. For CD8+ T cells, their blood counts increased by as much as 10-fold on D7 and returned to baseline or lower on D14 and D21 ( FIG. 60D ). Similar trends were observed for CD4+ T cells.

CD20 TDB is effective in killing CLL B cells in vitro and in vivo

We also tested the efficacy of CD20 TDB in killing B leukemia cells in the presence of autologous T cells from CLL patients, where B tumor burden is typically high while T cell counts are low and T cell function may be impaired (Riches et al., Semin. Cancer Biol. 20(6):431-438, 2010). PBMCs isolated from peripheral blood of 9 CLL patients were incubated with a single high dose of 1000 ng/mL CD20 TDB for up to 48 hours. As shown in FIG61A , CD20 TDB was effective in killing CLL B cells in the presence of autologous T cells. For the two samples shown, the B leukemia tumor burden was 70% for patient sample 1 (8.4% CD8+ T cells in PBMC) and 80% for patient sample 2 (4.4% CD8+ T cells in PBMC). CD20 TDB appears to achieve effective B cell killing at very low effector-to-target ratios (1:8 and 1:18 for the two samples shown here). Killing of CLL B cells by CD20 TDB in the presence of autologous T cells was highly correlated with CD8+ T cell counts (Figure 61B). We found that T cell content varied significantly (between 0.4 and 8% of monocytes), and surprisingly, we observed that the extent of B cell lysis compared to pretreatment values was highly correlated with T cell content. By supplementing CLL PBMCs with purified CD8+ T cells, in which few autologous T cells were available, CD20 TDB effectively killed B leukemia cells in a T cell-dependent manner (Figure 61C).

CD20 TDB is also effective in clearing CLL leukemia cells transplanted into mice (Figure 62A). Briefly, NSG mice are transplanted with patient leukemia cells, followed by transplantation of patient-derived autologous activated T cells, and treatment is initiated after confirmation of leukemia graft formation. IHC staining of representative examples of mouse spleens shows that B leukemia cells and autologous T cells from CLL patients are successfully transplanted into NSG mice. After treatment with a single dose of 0.1 or 0.5 mg/kg of CD20-TDB, very few B cells can be detected. B cell clearance was also observed in the case of rituximab treatment, while no B cell clearance was detected in the case of HER2-TDB as an isotype control. (Figure 62B).

In the setting of tumor progression, CD20 TDB treatment effectively prevented B cell lymphoma tumor growth in the presence of human donor PBMCs. SCID (severe combined immunodeficiency) mice transplanted with human Bjab cells developed detectable tumors by day 12 post-inoculation when treated with vehicle or CD20 TDB alone. Furthermore, transplantation of PBMCs alone delayed tumor outgrowth, but these mice developed detectable tumors by day 25 post-inoculation. Thus, CD20 TDB effectively prevented tumor growth in vivo even in the presence of PBMC effector cells ( FIG. 63 ).

CD20 TDB efficacy requires very low CD20 expression levels

In addition to the fact that the requirement for the antibody Fc region for CD20 TDB activity is different from that of conventional anti-CD20 and may have a different tumor microenvironment dependency, CD20 TDB also appears to require lower levels of antigen expression to achieve effective B cell killing. For Bjab cells with high CD20 expression levels ( FIG. 64A ), comparable cell killing was achieved with rituximab and CD20 TDB ( FIG. 64B ). However, CD20 TDB only killed Nalm-6, SC-1, and OCI-Ly19 cells, which have greatly reduced CD20 expression levels ( FIG. 64A ), while no cell killing was detected with rituximab ( FIG. 64C ). Based on scatchard and FACS binding data (data not shown), the estimated CD20 copy number for these low CD20 cell lines was less than 500 compared to Bjab cells. In addition, the monovalent binding affinity of CD20-TDB for CD20 is approximately 50-100 nM, significantly less than the 1-5 nM affinity of rituximab (both measured by scatchard). Taken together, the potency of CD20-TDB is consistent with the idea that TCR triggering requires a low receptor occupancy of only 10 to 100 molecules (Purbhoo, M.A. et al., Nat Immunol 5:524-530, 2004; Irvine, D.J. et al., Nature 419:845-849, 2002; Sykulev, Y. et al., Immunity 4:565-571, 1996).

CD20 TDB is active in the presence of rituximab and steroids

Because rituximab and its combination with chemotherapy are widely used clinically to treat B-cell malignancies, it is important to explore how CD20 TDB can be used in such settings, as both CD20 TDB and rituximab target the same antigen. We utilized rituximab-DANA, a null rituximab variant containing alanine substitutions at residues 265 and 297 (the DANA mutation described in U.S. Patent Nos. 7,332,581 and 8,219,149), which binds to CD20 only in the absence of B-cell killing activity, as tested in human CD20/CD3 double-transgenic mice ( FIG64D ). Pretreatment of normal donor B cell targets with this inert rituximab molecule, which competes for binding to CD20-TDB, had very little effect in inactivating CD20-TDB activity. At concentrations up to 250 μg/ml rituximab-DANA (a 5000-fold excess relative to the 42 ng/ml EC50 dose level), we observed only modest changes in the in vitro dose-response curve (EC50 change less than 7-fold, 42 ng/ml vs. 320 ng/ml). Clearly, CD20 TDB remains active in this setting. Despite an approximately 7-fold increase in the EC50 of CD20-TDB at higher rituximab-DANA concentrations, the extent of B cell killing did not change significantly ( FIG. 65A ). This is consistent with our previous findings that CD20 TDB efficacy requires extremely low antigen expression levels or extremely low receptor occupancy. The in vitro observations were reproduced in vivo in CD3/CD20 double transgenic mice pretreated with 2 or 10 mg/kg rituximab-DANA protein and subsequently challenged with CD20-TDB. Here, we show in vivo that CD20 TDB remains active in depleting B cells in mice pretreated with rituximab-DANA ( FIG. 66 ). These results indicate the diversity of prospective combination therapies for B-cell malignancies.

CD20 TDB is a T cell recruiting antibody, and its efficacy depends on activated T cells. It was also tested to see whether steroid pretreatment, which may affect T cell immune responses, would affect CD20 TDB activity. In vitro, CD20 TDB remained active in killing B cells in the presence of high concentrations of dexamethasone (Figure 65B).

Preclinical validation of CD20 TDB as a potential therapy for CD20+ B-cell malignancies in cynomolgus monkeys

A pilot PKPD study of CD20 TDB was also conducted in cynomolgus monkeys. In a single-dose study in which 3 animals were treated once intravenously with 1 mg/kg CD20 TDB, complete B cell clearance was observed in the blood (Figure 67A) and spleen and lymph nodes (Figure 67B and Figure 67C) 7 days after antibody treatment. Historical vehicle controls are shown as the mean and standard deviation of 4 vehicle-treated animals (Figure 67D). When calculated as % lymphocytes, no significant T cell loss was observed because the levels of both CD8+ T cells and CD4+ T cells were comparable to or higher than the control. T cell activation was detected in the blood 4 hours after administration. No T cell loss was observed and 7 days after treatment, significantly higher CD8+ T cell counts were detected in the blood (Figure 67A).

The long-term effects of CD20 TDB treatment on immune cells were also tested using a 4-week repeat dose study followed by an 8-week recovery period. In blood from four animals treated with weekly doses of 1 mg/kg, B cell and T cell counts and CD20 TDB serum concentrations were measured for each individual animal over 77 days and plotted (Figure 68A). In all four animals, B cells were not detected in the blood shortly after treatment and did not recover as long as CD20 TDB serum concentrations remained above 100 ng/ml (animal 4502 vs. animals 4001, 4002, and 4503). CD8+ T cell counts, and to a lesser extent, CD4+ T cell counts, increased significantly after the first dose and gradually returned to within 25% to 150% of baseline values. In summary, CD20 TDB was highly active in depleting B cells without damaging T cells.

The PK properties of CD20 TDB are also summarized in Figure 68B, where CD20 TDB serum concentrations were measured from both studies. As shown for the repeated dose study, CD20 TDB maintained good exposure throughout, with CL of approximately 17 ml/day/kg during the first dose period (D0 to D7). Target-mediated clearance appeared high during the first dose period (D0-D7), as CL values decreased to approximately 6 ml/day/kg during the fourth dose period (D21-28).

Combination of CD20 TDB with PD-L1 antagonist in syngeneic tumor models

The in vivo efficacy of the combination of a CD20 TDB and a PD-L1 antagonist (murine IgG2a isotype anti-PD-L1 antibody 25A1 with a DANA mutation) in a syngeneic tumor model was also tested. In this study, A20-huCD20 mouse B lymphoma cells expressing human CD20 and mouse PD-L1 on the cell surface were used to generate a syngeneic tumor model (see, e.g., FIG69A ). The CD20 TDB used was a murine IgG2a isotype 2H7v16/2C11 TDB generated in a knob-into-hole (K&H) format (see, e.g., Atwell et al., J Mol Biol., 270:26-35, 1997), wherein the "knob" arm is anti-CD20 2H7v16 and the "hole" arm is anti-CD3 2C11 (Leo et al., Proc Natl Acad Sci USA, 84:1374-8, 1987). The PD-L1 antagonist used was a murine IgG2a isotype anti-PD-L1 antibody with the DANA Fc mutation (residues 265 and 297 substituted with alanine; see, e.g., U.S. Patent Nos. 7,332,581 and 8,219,149).

On day 7, 65 Balb/C mice were inoculated subcutaneously in the right thorax with 2,500,000 A20pRK-CD20-GFP cells in 100 μl of HBSS (not exceeding 200 μl). The mice were allowed to grow tumors. The mice were then weighed and measured 1-2 times per week until the tumors reached an average tumor volume of approximately 100-200 mm ³ (approximately 7 days after inoculation). The animals were then divided into the following four treatment groups: Group 1: 2,500,000 A20/CD20, vehicle, qwx3, IV, n=9; Group 2: 2,500,000 A20/CD20, anti-CD20xCD3K&H TDB (2H7v16-2C11 murine IgG2), 0.5 mg/kg, qwx3, IV, n=9; Group 3: 2,500,000 A20/CD20, aPDL1 (25A1, mIgG2a DANA), 10 mg/kg, tiwx3, IP, n=9; and Group 4: 2,500,000 A20/CD20, aPDL1 (25A1, mIgG2a DANA), 10 mg/kg, tiwx3, IP, n=9. DANA), 10 mg/kg, tiwx3, IP + anti-CD20xCD3K & HTDB (2H7-2C11 murine IgG2), 0.5 mg/kg, qwx3, IV, n=9. Mice that were not recruited into one of the above treatment groups due to dissimilar tumor volumes were euthanized. Treatment began on day 0, and all antibody administrations were performed intravenously in a volume of 100 ml as described above.

Tumors were measured 1 to 2 times per week. Body weights were measured twice per week until 7 days after the final treatment. If no weight loss was observed, no further weights were obtained. Affected mice were weighed daily if weight loss >15% was observed, and euthanized if weight loss was greater than or equal to 20%. Throughout the study, clinical observations were performed twice per week to monitor the health of the animals, and any animal whose tumor size or condition might interfere with the animal's health or activity was euthanized.

As shown in FIG69B , the combination treatment of CD20 TDB and anti-PD-L1 antibody (Group 4) exhibited an unexpected synergistic effect in inhibiting tumor growth when compared with treatment with CD20 TDB, anti-PD-L1 antibody, or vehicle alone.

Combination of CD20 TDB with PD-1 antagonists in syngeneic tumor models

In addition, the in vivo efficacy of the combination of a CD20 TDB and a PD-1 antagonist (murine IgG2 isotype anti-PD-1 antibody 8F11 with a DANA mutation) was also tested in the A20/huCD20 syngeneic B lymphoma mouse model. In this study, the CD20 TDB used was the murine IgG2a isotype 2H7v16/2C11 TDB, and the PD-1 antagonist used was a murine IgG2 isotype anti-PD-1 antibody with a DANA Fc mutation.

A20 mouse B lymphoma cells were transfected to express human CD20 and GFP and single cells were subsequently sorted for clonal selection and expansion for implantation. 8-10 week old female Balb/c mice (Charles River; Hollister, CA) were inoculated subcutaneously with 2,500,000 A20.hCD20-GFP cells in the right thorax. When tumors reached an average tumor volume of approximately 100-200 ^mm3 , mice were recruited and randomly divided into one of four treatment groups (n=9 mice/group) and antibody treatment began on the following day 1: Group 1 (2,500,000 A20/CD20, vehicle, qwx3, IV); Group 2 (2,500,000 A20/CD20, anti-CD20xCD3K&H TDB (2H7v16-2C11 murine IgG2), 0.5 mg/kg, qwx3, IV); Group 3 (2,500,000 A20/CD20, anti-PD1 (8F11, mIgG2a DANA), 10 mg/kg, tiwx3, IP); and Group 4 (2,500,000 A20/CD20, anti-PD1 (8F11, mIgG2a DANA), 10 mg/kg, tiwx3, IP). DANA), 10 mg/kg, tiwx3, IP + anti-CD20xCD3 K&H TDB (2H7v16-2C11 murine IgG2), 0.5 mg/kg, qwx3, IV).

Mice were treated with vehicle or CD20 TDB IV at 0.5 mg/kg weekly for 3 weeks and/or anti-PD-1 antibody IV at 10 mg/kg for the first dose followed by IP dosing 3 times per week for 3 weeks (N=9 mice/group).

As shown in FIG. 108A and FIG. 108B , the combination treatment of CD20 TDB and anti-PD-1 antibody (Group 4) exhibited an unexpected synergistic effect in inhibiting tumor growth when compared to treatment with CD20 TDB, anti-PD-1 antibody, or vehicle alone.

Example 4. Generation and Characterization of an Exemplary CD3/FcRH5 TDB (FcRH5 TDB)

We also explored the ability of TDB antibodies to recruit T cell cytotoxic activity to eradicate tumor cells by recognizing a different cell surface antigen, CD79b5. To this end, we generated and characterized a bispecific anti-CD3 antibody (CD79b5 TDB) with an anti-CD3 arm and an anti-CD79b5 arm. As described above, the generated CD79b5 TDB is a full-length antibody in a knob-in-hole format, such as human IgG1, as previously described (Atwell et al., J. Mol. Biol. 270:26-35, 1997). Half antibodies were expressed in E. coli, purified by protein A affinity chromatography, and annealed to the appropriate half-antibody pairing in vitro as previously described (Spiess et al., Nat. Biotechnol. 2013). After annealing, the CD79b5 TDB was purified by hydrophobic interaction chromatography (HIC) and characterized by analytical gel filtration, mass spectrometry, and polyacrylamide gel electrophoresis, as described above. The anti-CD795 arm used to generate the CD795 TDB was the anti-CD795 arm of the anti-CD795 antibody 1G7, which comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 268 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 269. Anti-CD3 arms tested in generating the CD795 TDB included UCHT1v9, 40G5c, and 38E4v1.

Specific FcRH5 TDBs were tested for binding to CD8+ T cells (CD3 binding) and activity as assessed by in vitro cytotoxicity assays and T cell activation assays.

A. Binding affinity

As described above for the CD20 TDB, the binding affinity of each CD795 TDB was tested by FACS analysis. Briefly, in the FACS binding assay, CD8+ T cells were incubated with various concentrations of CD795 TDB antibodies at 4°C for 30 minutes, followed by washing and incubation with a secondary antibody (anti-huIgG-PE; BD Bioscience) for an additional 15 minutes. The cells were then washed again and prepared for FACS analysis. FIG70 shows the results of an in vitro FACS binding assay of the CD795 TDB. The results show that the specific combination of the anti-CD3 antibody arm 38E4v1 paired with the anti-CD795 arm 1G7 produced a CD795 antibody with higher binding affinity for effector cells.

B. In vitro MOLP-2 target cell killing and T cell activation assays

The generated FcRH5 TDB was also tested for its ability to support the cytotoxic effects of killing FcRH5-expressing MOLP-2 target cells and activated T cells. In vitro cytotoxicity was monitored by flow cytometry. Target cells were labeled with CFSE according to the manufacturer's protocol (Invitrogen, No. C34554). Target cells labeled with carboxyfluorescein succinimidyl ester (CFSE) and purified CD8+ T cells from human PBMC were mixed at a 3:1 ratio for 48 hours with or without TDB. Cells were resuspended in an equal volume of PBS+2% FBS+1mM EDTA+propidium iodide (PI). Flow cytometry analysis was performed on a FACSCalibur in an automated format. The number of live target cells was counted by gating on CFSE+/PI-negative cells. Percent cytotoxicity was calculated as follows: % cytotoxicity (number of live target cells without TDB - number of live target cells with TDB)/(number of live target cells without TDB) × 100. As shown in FIG. 71A and FIG. 71B , FcRH5 TDBs with UCHT1v9 or 38E4v1 as their anti-CD3 arms showed robust in vitro MOLP-2 target cell killing compared to FcRH5 TDBs with 40G5c as their anti-CD3 arms.

When tested in T cell activation assays, Figures 72A to 72D show that CD79b TDBs with UCHT1v9 or 38E4v1 as their anti-CD3 arms were able to robustly induce in vitro T cell activity compared to CD79b TDBs with 40G5c as their anti-CD3 arms. In these assays, target cells were mixed with purified CD8+ T cells in the presence or absence of the TDBs, and T cell activation was analyzed by flow cytometry. At the end of the incubation period, cells were stained with CD8-FITC (BD Bioscience, 555634), CD69-PE (BD Bioscience, 555531), and CD107a-Alexa-Fluor 647 (eBioscience, 51-1079). Alternatively, after surface staining with CD8-FITC and CD69-PE, cells were fixed and permeabilized with Cytofix/CytoPerm solution (BD Bioscience, 554722) and intracellularly stained with anti-granzyme B-Alexa-Fluor 647 (BD Bioscience, 560212). T cell activation was assessed by the percentage of CD8+CD69+, CD8+CD107a+, and CD8+CD69+ granzyme B+ cells.

Example 5. Generation and Characterization of an Exemplary CD3/HER2 TDB (HER2 TDB)

We also explored the ability of TDB antibodies to recruit T cells' cytotoxic activity to eradicate tumor cells by recognizing different cell surface antigens HER2. To this end, we generated and characterized a bispecific anti-CD3 antibody (HER2 TDB) with an anti-CD3 arm and an anti-HER2 arm. As described above, the HER2 TDB produced is a full-length antibody in the form of a knob-in-hole, such as human IgG1, as previously described (Atwell et al., J. Mol. Biol. 270: 26-35, 1997). Half antibodies are expressed in Escherichia coli or Chinese hamster ovary (CHO) cells, purified by protein A affinity chromatography, and annealed to appropriate half-antibody pairs in vitro as previously described (Spiess et al., Nat. Biotechnol. 2013). If TDB antibodies are produced in CHO cells, the antibody includes a deglycosylation mutation, for example, at residue N297 (e.g., N297G), such that the TDB antibody is an effector-free variant and cannot induce antibody-dependent cell-mediated cytotoxicity (ADCC). As described above, after annealing, the HER2 TDB was purified by hydrophobic interaction chromatography (HIC) and characterized by analytical gel filtration, mass spectrometry, and polyacrylamide gel electrophoresis. One anti-HER2 arm used in generating the HER2 TDB was the anti-HER2 arm of the anti-HER2 antibody hu4D5, which comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 270 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 271. Other HER2 TDBs targeting different regions of the extracellular domain (ECD) of HER2 were generated. The anti-HER2 antibody 2C4 was used as the anti-Her2 arm, which comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 593 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 594. Another anti-HER2 antibody used as an anti-HER2 arm is the anti-HER2 arm of the anti-HER2 antibody 7C2, which comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 595 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 596. Other anti-HER2 arms used to generate the HER2 TDB include the hu4D5 affinity variants hu4D5.91A and hu4D5.Y100A (described in US 7,435,797).

Specific HER2 TDBs were tested for binding to CD8+ T cells (CD3 binding) and to SKBR3 cells (Her2 binding) and activity as assessed by in vitro cytotoxicity assays and T cell activation assays.

A. Binding affinity

As described above for CD20 TDB, the binding affinity of each HER2 TDB was tested by FACS analysis. Briefly, in FACS binding assays, Jurkat cells (for CD3 antigen), human CD8+ cells (for CD3 antigen) or SKBR3 (for Her2 antigen) were incubated with various concentrations of HER2 TDB antibodies at 4°C for 30 minutes, followed by washing the cells and incubating with a secondary antibody (anti-huIgG-PE; BD Bioscience; or anti-huIgG-AlexaFluor647, Southern Biotech) for another 15 minutes, followed by washing the cells again and preparing for FACS analysis. The geometric mean of fluorescence was read by flow cytometry. Figure 73, Figure 76A, Figures 78A to 78C, Figure 79A and Figures 80A to 80B show the results of the in vitro FACS binding assays of HER2 TDB. The combination of multiple HER2 arms in different regions of HER2 binding and multiple CD3 arms in different regions of CD3ε was tested to characterize the binding properties of each combination. Figure 76A provides the crystal structure of the HER2 ECD and CD3ε and highlights the regions to which the different HER2 and CD3 arms each bind. The hu4D5 HER2 antibody is called trastuzumab and binds to an epitope in domain IV of HER2, the region of the protein closest to the cell membrane. The recombinant humanized monoclonal antibody 2C4 (rhuMAb 2C4), also known as pertuzumab, binds to an epitope in domain II of HER2, located close to where hu4D5 binds. Pertuzumab (Genentech, Inc, South San Francisco) represents the first in a new class of agents known as HER dimerization inhibitors (HDIs) and functions by inhibiting the ability of HER2 to form active heterodimers or homodimers with other HER receptors, such as EGFR/HER1, HER2, HER3, and HER4 (Harari and Yarden. Oncogene 19:6102-6114, 2000; Yarden and Sliwkowski. Nat. Rev. Mol. Cell Biol. 2:127-137, 2001; Sliwkowski. Nat. Struct. Biol. 10:158-159, 2003; Cho et al., Nature 421:756-60, 2003; and Malik et al., Pro. Am. Soc. Cancer Res. 44:176-177, 2003). The anti-HER2 murine antibody 7C2 binds to an epitope in domain I of HER2 that is distal to the region of HER2 bound by hu4D5 (PCT Publication No. WO 98/17797) (FIG. 76A).

In addition, the binding affinity of the HER2 TDB was tested with multiple anti-CD3 arms. One of the designated anti-HER2 arms was combined with a high-affinity human CD3 targeting arm, such as SP34 and 38E4v1. Other HER2 TDB combinations included the low-affinity human CD3 targeting arm, 40G5c, or the murine CD3 targeting arm of 2C11. UCHT1v9, used as its anti-CD3 arm, and hu4D5, used as its anti-HER2 arm (referred to herein as HER2 TDB (UCHT1v9/hu4D5) or HER2 TDB), were compared with the anti-HER2 antibody trastuzumab and trastuzumab-Fab fragment in a competitive Scatchard assay (Ramirez-Carrozzi et al., Nature Immunology. 12: 1159-1166, 2011). In this assay, binding to SKBR-3 was determined by competitive binding of ¹²⁵ I-trastuzumab Fab with trastuzumab, trastuzumab-Fab, or the bispecific HER2 TDB. Figure 74A shows the results of an in vitro competitive Scatchard assay of HER2 TDB.

B. In vitro SKBR3 and MCF7 target cell killing and T cell activation assays

The ability of HER2 TDB combinations of one of the three anti-HER2 arms (hu4D5, 2C4, and 7C2) with either the high-affinity 38E4v1 or low-affinity 40G5c anti-CD3 arm to mediate target cell killing of HER2-expressing SKBR3 or MCF7 cells was tested in vitro (Figure 77). The in vitro activity of hu4D5 TDB with either the anti-CD3 arm was shown to be more effective than the 2C4 and 7C2 TDBs in mediating maximum SKBR3 and MCF7 cell killing, as measured by their EC50s (Figure 78). This killing activity also depended on the CD3 arm utilized. The combination of the anti-CD3 arm 38E4v1 with any of the anti-HER2 hu4D5, 2C4, or 7C2 was more effective than the 40G5c HER2 TDB combination (Figure 79). Further testing of the six HER2 TDB combinations showed that their target cell killing activity was independent of the HER2 expression level in the target cells. Figure 80 shows that the HER2 TDB is not selective for high HER2-expressing SKBR3 target cells relative to low HER2-expressing MCF7 target cells. Alternatively, the activity of the HER2 TDB depends on the affinity of the anti-HER2 arm for HER2 (Figure 81). The low HER2 affinity TDB retains activity against low HER2-expressing MCF7 cells and is unable to selectively kill HER2-amplified SKBR3 cells (Figure 82).

The specificity of the anti-HER2 arm of HER2 TDB to its individual HER2 epitope was also determined. When combined with increasing concentrations of trastuzumab (hu4D5), the killing activity of hu4D5-40G5cHER2-TDB was limited. However, the efficacy of trastuzumab was not affected by the combination of hu4D5TDB and hu4D5 antibodies (Figure 83). In contrast, target cell killing mediated by 2C4-40G5c or 7C2 38E4v1 was blocked by co-administration of bivalent monospecific antibodies Pertuzumab (2C4) or 7C2, respectively (Figure 83). When other anti-HER2 arms were tested in a multiple affinity analysis, all clones showing high or moderate HER2 TDB activity competed with trastuzumab or Pertuzumab (Figure 84). To identify candidate TDBs for in vivo testing, high-affinity CD3 arms (38E4v1, 38E4, and SP34) and low-affinity CD3 arms (40G5c and 2C11) were tested in vitro using mouse-derived humanized CD3+ T cells in combination with the hu4D5, 2C4, and 7C2 anti-HER2 arms (Figures 85-86). Based on this assay, three candidate TDBs were selected for further in vivo characterization based on their killing activity: hu4D5-SP34, hu4D5-2C11, and 2C4-38E4. Treatment of animals bearing HER2-expressing tumors with the hu4D5-2C11 HER2 TDB resulted in an increase in CD45+ and CD8+ cells in the tumors as early as 4 hours after treatment. Upon further analysis, tumors treated with the HER2-TDB showed an increase in IFNγ+ and PD1+CD8+ T cells, as well as an increased presence of T regulatory (Treg) cells (Figure 87B). Increased immune infiltrates detected in tumors were also associated with reduced tumor volume in animals treated with HER2-TDB compared to vehicle controls (Figure 87A). In Figure 88A, the combination of the anti-HER2 arm hu4D5 with either the low-affinity anti-CD3 arm 2C11 or the high-affinity anti-CD3 arm SP34 resulted in tumor regression in transgenic HER2 mice. However, this response was not observed with the combination of the low-affinity 2C4 anti-HER2 arm with the 38E4 high-affinity anti-CD3 arm (Figures 88A-88B).

The ability of the HER2 TDB to directly inhibit SKBR3 proliferation was also compared with that of bivalent trastuzumab and trastuzumab-Fab fragments. HER2-expressing SKBR3 target cells were plated in 96-well plates at a density of 5× ¹⁰ cells/well and cultured overnight to allow for cell attachment, followed by treatment with the indicated antibodies or fragment antibodies. Cell proliferation/viability was analyzed by a fluorescent cell viability assay (Promega, Madison, WI) after 6 days of treatment. The results of this assay are shown in FIG74B . In addition, an in vitro cytotoxicity assay was performed using trastuzumab, trastuzumab produced in E. coli, and the HER2 TDB to measure their ability to induce NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) (Jefferis Trends in Pharmacological Sciences. 30:356-362, 2009; Simmons et al. Journal of Immunological Methods. 263:133-147, 2002). Antibodies produced in E. coli are not glycosylated, which results in reduced FcγR binding required for ADCC. Cytotoxicity analysis was performed using the Cytotoxicity Detection Kit (LDH) (Roche, Mannheim, Germany) as described in Junttila et al. (Cancer Research. 70: 4481-4489, 2010). Briefly, lysed cells were detected by lactate dehydrogenase (LDH) release after 4 hours of treatment with the specified antibodies. The results are shown in Figure 74C.

The ability of the generated HER2 TDB to support the killing of HER2-expressing SKBR3 target cells and the cytotoxic effect of activated T cells was also tested. In vitro cytotoxicity was monitored by flow cytometry. Target cells were labeled using carboxyfluorescein succinimidyl ester (CFSE) according to the manufacturer's protocol (Invitrogen, No. C34554). With or without TDB, CFSE-labeled target cells and purified CD8+ T cells from human PBMC were mixed at a certain E:T ratio (as indicated in the legend) for 24 hours. At the end of the incubation, cells were lifted with trypsin and collected from the plate. The cells were resuspended in an equal volume of PBS+2% FBS+1mM EDTA+ propidium iodide (PI). Flow cytometry analysis was performed in an automated manner on a FACSCalibur. The number of live target cells was counted by gating CFSE+/PI negative cells. Percent cytotoxicity was calculated as follows: % cytotoxicity (number of live target cells without TDB - number of live target cells with TDB) / (number of live target cells without TDB) x 100. As shown in Figure 75, the HER2 TDBs showed robust in vitro killing of SKBR3 target cells compared to HER2 TDBs with hu4D5 affinity variants 91A or Y100A as their anti-HER2 arms (EC50 = 0.1 ng/ml for hu4D5/UCHT1v9 TDB; EC50 = 25.5 ng/ml for hu4D5.91A/UCHT1v9 TDB; EC50 = not determined for hu4D5.Y100A/UCHT1v9 TDB).

In addition, the anti-HER2 hu4D5 variant had a higher binding affinity for the HER2 extracellular domain (ECD) (0.4 nM) than the HER2 arms 2C4 (2.0 nM) and 7C2 (1.7 nM), as shown in Figure 76B. Furthermore, Figure 76C shows that hu4D5HER2-TDB was a more effective mediator of killing of MCF7 target cells than 2C4 HER2-TDB and 7C2 HER2-TDB. The kinetics of killing induced by HER2 TDB were also determined. As shown in Figure 94A, no significant killing activity was detected between 4 and 12 hours. Robust killing was detected at 24 hours, and killing activity increased over time. Further comparison of the anti-CD3 arms of hu4D5 HER2-TDB, as shown in Figures 90A to 90C and 92C, demonstrated the effectiveness of the different clones in mediating killing of SKBR3 cells expressing HER2. Specifically, surprisingly, two HER2 TDBs, hu4D5/38E4c and hu4D5/40G5c, were as effective or more effective than the HER2 TDB hu4D5/SP34 in mediating target cell killing (Figures 90B and 90C).

When tested in T cell activation assays, Figure 89 shows that HER2 TDB is able to stably induce T cell activity in vitro compared to HER2 TDBs with hu4D5 affinity variants 91A or Y100A as their anti-HER2 arms. As shown in Figure 91A, the 3 anti-CD3 arms (SP34, 38E4c, and 40G5c) of the analyzed hu4D5 HER2-TDB display different binding affinities for the CD3 antigen on human CD8+T cells. Despite this, all 3 HER2-TDBs are able to mediate CD8+T cell activation (Figure 91B). Additional analysis of the ability of the 38E4 and 38E4c anti-CD3 arms of hu4D5 HER2-TDB to mediate CD8+T cell activation is shown in Figure 92D. The kinetic properties of T cell activation induced by HER2 TDB are further determined. Early signs of T cell activation (CD69) appear 4 hours after initial HER2 TDB treatment. However, late activation markers (extracellular CD107a) were detected later at the 24-hour time point (Figure 94A). In addition, when CD8+ cells were incubated with HER2 TDB or target cells that do not express human HER2 (BJAB cells), no T cell activation was detected after 48 hours. Robust T cell activation was seen when HER2+SKBR3 cells were used as targets, accompanied by cytotoxic granule release (Figure 93A).

We also tested the ability of HER2 TDB to induce killing of BT474 target cells, and activated T cells were assayed for the following five ratios of effector CD8+ T cells to target cells: 1:5, 1:2, 1:1, 3:1, and 5: 1. This experiment showed that titration of effector cells significantly reduced cytotoxicity measured by LDH release; however, even at E:T ratios of ≤1:1, weak LDH signals and robust T cell activation were detected (Figure 94B).

In these assays, target cells are mixed with purified CD8+T cells in the presence or absence of TDB, and T cell activation is analyzed by flow cytometry. At the end of incubation, cells are stained with CD8-FITC (BD Bioscience, 555634), CD69-PE (BD Bioscience, 555531) and CD107a-Alexa-Fluor647 (eBioscience, 51-1079). Optionally, cells are stained with CD8-FITC and CD69-PE, wherein T cell activation is assessed by the CD8+CD69+ percentage in CD8+ cells. Alternatively, after surface staining with CD8-FITC and CD69-PE, cells are fixed and infiltrated with Cytofix/CytoPerm solution (BD Bioscience, 554722), and intracellular staining is performed with anti-granzyme B-Alexa-Fluor647 (BD Bioscience, 560212). T cell activation was assessed by the percentage of CD8+CD107a+ cells.

Another method for measuring T cell-mediated cytotoxicity against HER2 TDB (UCHT1v9/hu4D5) was a granule exocytosis assay. Figure 93B shows the results of soluble perforin (Cell Sciences), granzyme A, and granzyme B (eBioscience) detected in growth medium by ELISA according to the manufacturer's protocol. In this assay, a control TDB (10 ng/ml) or HER2 TDB (10 ng/ml) with the same CD3 arm as the HER2 TDB but with an irrelevant target arm was used. These antibodies were individually incubated for 18 hours with SKBR3 target cells and effector peripheral blood mononuclear cells (PBMCs) isolated from the blood of healthy volunteers using lymphocyte separation medium (MP Biomedicals, Solon, OH). In vitro cytotoxicity was measured by LDH release as described above. A series of apoptosis assays were performed using HER2 TDB (1 ng/ml), effector PBMCs, and SKBR3 target cells. After 24 hours of treatment, granule exocytosis coincided with a significant increase in HER2 TDB-induced caspase 3/7 activity (3/7 assay, Promega), apoptosis (cell death detection ELISA ^plus assay, Roche), and cytotoxicity measured by lactate dehydrogenase (LDH) release as described above (Figure 93C).

The ability of HER2 TDB-induced killing of 3T3 cells transfected with HER2 or vector was measured by the above-mentioned LDH cytotoxicity assay, wherein the killing of 3T3 cells transfected with vector was not detected after 19 hours; By contrast, 3T3 cells transfected with HER2 were killed very effectively (Figure 93 D). After 24 hours, the killing assay was modified to block HER2 arm binding using trastuzumab Fab (1 μg/ml) or soluble HER2 extracellular domain (HER2 ECD) (1 μg/ml), and killing activity was effectively suppressed (Figure 93 E). In order to determine the T cell dependence of killing, CD3+ microbeads (numbering 130-050-101) derived from Miltenyi were used to remove CD3+ cells from PBMC. Figure 93 F is presented in the presence of HER2 TDB, and after 19 hours, the removal resulted in target cell killing activity loss, as assessed by FACS analysis.

HER2 TDB induces T cell proliferation

In order to study whether HER2 TDB induces T cell proliferation, CD8+ T cells, target cells (SKBR3) and 0.1 μg/ml HER2 TDB were co-cultured, and T cell culture was subsequently performed in the absence of target cells and HER2 TDB. T cell proliferation was measured by flow cytometry on the 3rd day using a dilution of CFSE in CD8+/PI cells with cell division. After 3 days, 75% of the T cells and target cells to which HER2 TDB was pulsed had undergone cell division, as shown in Figure 95A. The number of T cells induced by HER2 TDB was determined by labeling purified CD8+ T cells with CFSE according to the manufacturer's protocol (Invitrogen, No. C34554). CFSE-labeled CD8+ T cells were incubated with target cells for 19 hours in the presence or absence of TDB. T cells were collected, washed, and cultured for 2 to 7 days (RPMI+10% FBS). The number of live CD8+ cells (CD8+/PI-) and the percentage of CFSE-fuzzy (dim) cells were detected by FACS. In Figure 95B, the number of cells did not increase. Further supplementation of the growth medium with IL-2 (20 ng/ml) provided a survival signal to the CD8+ cells, and robust T cell proliferation was detected in the T cells, but only when they were exposed to both the HER2 TDB and the target cells (Figure 95C). Importantly, no bystander effect on non-target expressing cells was detected under conditions that killed most of the HER2+ cells in the same culture medium. The HER2 TDB induced proliferation and polyclonal expansion of T cells, which is very important for the expansion of tumor infiltrating lymphocytes.

HER2 TDB activity is correlated with HER2 expression levels in target cells

In order to study the relationship between target copy number and TDB activity, a group of cancer cell lines with a predetermined number of HER2 receptors on the cell membrane were selected (Aguilar et al., Oncogene. 18: 6050-62, 1999). HER2 protein expression levels in HER2 negative cell lines (BJAB LUC), 3 low HER2 cell lines (MDA435, MDA231, MCF7) and 3 HER2 amplification/overexpression cell lines (MD453, SKBR3, BT474) were detected by Western blotting (Figure 96A). HER2 negative cell lines, low HER2 cell lines and HER2 overexpression cell lines were incubated with HER2 TDB and with effector PBMC at an E: T ratio of 25: 1 for 26 hours. At this time point, cytotoxicity was detected using LDH release assay. Figure 96B shows that HER2 amplified/overexpressing cells were significantly more sensitive to TDB-mediated killing (p=0.015, t-test) and effectively lysed at femtomolar to low picomolar concentrations (EC50=0.8-3pM). Cell lines expressing low levels of HER2 were significantly less sensitive to HER2 TDB antibodies (EC50=33-51pM). As low as <1000 copies of the target antigen were sufficient to support T cell killing.

In the studies performed in Figures 96C to 96D, MCF7 or BJAB cell lines were co-targeted with SKBR3 cells in the presence of HER2 TDB in the same killing assay. In this assay, MCF7 or BJAB cells were labeled with CFSE and mixed with SKBR3 and PBMC (E:T 20:1), then treated with HER2 TDB for 19 hours. Cells were stained with anti-HER2 APC and PI. Figure 96C shows the percentage of viable SKBR3 (high HER2, PI-) and MCF7 (CFSE+, PI-) cells detected by FACS and normalized for fluorescent beads. No MCF7 cell killing was detected at the EC50 for SKBR3 killing. The percentage of viable SKBR3 (high HER2, PI-) and BJAB (CFSE+PI-) cells detected by FACS and normalized for fluorescent beads is shown. No significant BJAB cell killing was detected at any HER2 TDB concentration (Figure 96D).

Very low target occupancy is sufficient for TDB activity

Next, the HER2 occupancy at the EC50 of the HER2 TDB was calculated using the formula [D]/[D]+ _KD (where D=drug and _KD for HER2 TDB = 5.4 nM). HER2 copy number has been previously reported (Aguilar et al., Oncogene. 18:6050-6062, 1999). EC50 values were calculated from the dose-response data in Figure 97B. Figure 96E shows that in all cell lines tested, less than 1% target occupancy was sufficient to achieve effective killing. In the case of high HER2 expressing cell lines, the required occupancy was even lower (0.01-0.05%). In low expressing cell lines, the calculated absolute number of HER2 TDBs bound by HER2 at the EC50 was as low as 10-150. These results show that the efficacy of HER2 TDB is extremely high and consistent with TCR triggering studies, which suggest that as few as 1-25 TCRs are required to trigger T cell responses (Irvine et al., Nature. 419: 845-849, 2002; Purbhoo et al., Nature Immunology. 5: 524-530, 2004; Sykulev et al., Immunity. 4: 565-571, 1996). The efficacy of HER2 TDB is consistent in the low picomolar to femtomolar range. In addition, as few as 10-500 HER2-binding TDBs are sufficient to induce significant in vitro cytotoxicity. As few as approximately 1000 HER2 copies on the serosal membrane are sufficient to induce killing. These studies also show a correlation between target expression levels and in vitro sensitivity to HER2 TDB.

HER2 TDB effectively kills HER2+ cancer cells that are refractory to anti-HER2 therapy

Next, we examined cell lines that had previously been shown to express high levels of HER2 but were insensitive to the direct cellular effects of trastuzumab and lapatinib in vitro (Junttila et al., Cancer Cell, 15:429-40, 2009; Junttila et al., Breast Cancer Res Treat, 2010). For some cell lines, resistance may result from activation of the PI3K pathway due to acquired activating mutations in the PI3K catalytic subunit (KPL4, HCC202) or loss of PTEN (HCC1596). LDH release (as a measure of cytotoxicity) was measured for 19 hours in a panel of six cell lines (5 chest, 1 lung) in the presence of effector PBMCs and HER2 TDB at a 10:1 ratio. The EC50 for HER2 TDB-mediated killing was in the femtomolar or low picomolar range (Figure 97A). Parental and T-DM1-resistant BT474-M1 clones were treated with T-DM1 for 3 days. At this time point, cell viability was measured using HER2 TDB (Figure 97B). The sensitivity of cell lines to T-DM1 has been previously reported (Junttila et al., Breast Cancer Res Treat. 2010; Lewis Phillips et al., Cancer Research. 68:9280-9290, 2008). In contrast, parental and T-DM1-resistant BT474-M1 clones were treated with HER2 TDB at a ratio of 3:1 for 24 hours in the presence of effector CD8+ T cells. Cytotoxicity was detected using FACS assay (Figure 97C). In addition, HER2 TDB can effectively kill HER2+ lung cancer cells. Using two independent cell line models, KPL4 and BT474 (Figures 97B to 97C), acquired resistance to T-DM1 did not affect sensitivity to HER2 TDB.

The killing activity of T cells recruited with the HER2 TDB depends on HER2 expression but is independent of the HER2 signaling pathway, suggesting that the HER2 TDB may be effective in treating tumors that are refractory to current anti-HER2 therapies. Thus, the data show equal activity in treating multiple trastuzumab/lapatinib-resistant cell lines compared to sensitive cells. Resistance in these cells arises from different mechanisms affecting the HER2 pathway. The data presented here suggest that switching to alternative mechanisms of action using the HER2 TDB can broadly enable overcoming resistance to antibody-drug conjugates (e.g., T-DM1), targeted small molecule inhibitors (e.g., lapatinib), and therapeutic monoclonal antibodies that block signaling in this pathway (e.g., trastuzumab).

Pharmacokinetic properties of HER2 TDB in rats

To evaluate the pharmacokinetic (PK) profile of HER2 TDB, SD rats were used. The animals were divided into the following two groups: Group 1: HER2 TDB (10 mg/kg, single IV, n=4); Group 2: trastuzumab (10 mg/kg, single IV, n=4). Samples were obtained from 4 rats in each group at multiple time points until 35 days after dosing. Approximately 0.2 ml of whole blood was collected via the jugular vein (under _CO2 / _O2 anesthesia). The samples were allowed to clot and centrifuged in a refrigerated chamber (5°C, 10 minutes, 2000×g) to obtain serum. Human IgG in serum samples was analyzed by ELISA, in which donkey anti-huFc coated on a microtiter plate was used to capture circulating humanized anti-HER2 antibodies and goat anti-huFc-HRP (mouse adsorbed) for detection. PK parameters were determined using a two-compartment method (Model 7) using version 5.2.1 (Pharsight Corp., Mountain View, CA). HER2 TDB does not cross-react with rat CD3 or rat HER2 and displays a biphasic profile typical of IgG1, with a short distribution phase and a slow elimination phase (Figure 98). In rats, the clearance and half-life of HER2 TDB are similar to those of trastuzumab and are within the expected range of a typical IgG1.

HER2 TDB inhibits tumor growth in immunocompromised mice in vivo

The in vivo efficacy of HER2 TDB was tested in NOD-SCID mice that lack endogenous functional T and B cells and have reduced levels of NK cells, DC cells, and macrophage types. In this experiment, NOD/SCID mice (NOD.CB17-Prkdcscid/J, Jackson Labs West) were implanted subcutaneously with 0.36 mg 60-day sustained-release estrogen pellets (Innovative Research of America) on the opposite side of tumor inoculation 1 to 3 days before cell inoculation. On day 0, 5×10 ⁶ MCF7-neo/HER2 cells were injected alone or with 10×10 ⁶ unstimulated human PBMCs (PBMC 1, 2) obtained from one of two healthy donors in HBSS matrigel in the right 2/3 mammary fat pad. The vaccinated mice were divided into the following five groups: Group 1: Vehicle (Control TDB, 0.5 mg/kg, qwk×3, IV, starting on day 0, n=5-10); Group 2: PBMC(1) (PBMC(1) + Control TDB, 0.5 mg/kg, qwk×3, IV, starting on day 0, n=5-10); Group 3: PBMC(1) + HER2 TDB (PBMC(1) + HER2 TDB, 0.5 mg/kg, qwk×3, IV, starting on day 0, n=5-10); Group 4: PBMC(2) (PBMC(2) + Control TDB, 0.5 mg/kg, qwk×3, IV, starting on day 0, n=5-10); and Group 5: PBMC(2) + HER2 TDB (PBMC(2) + HER2 TDB, 0.5 mg/kg, qwk×3, IV, starting on day 0, n=5-10). The first treatment was administered 2 hours after inoculation. Figure 99A shows the tumor volumes of individual mice and the fitted tumor volumes of the treatment groups, where HER2 TDB inhibited the growth of HER2-expressing tumors.

The dependence of HER2 TDB on human PBMCs was further tested in a similar immunocompromised mouse model. 5×10 6 MCF7-neo/HER2 cells, alone or together with 10×10 ⁶ unstimulated human PBMCs (PBMC 3) from healthy donors, were again injected in HBSS matrigel in the right ^2/3 mammary fat pad, and the first treatment was administered 2 hours after inoculation. In Figure 100A, inoculated mice were divided into the following two groups: Group 1: untreated (n=7); Group 2: HER2 TDB (HER2 TDB, 0.5 mg/kg, qwk×3, IV, starting on day 0, n=7). In Figure 100B, the inoculated mice were divided into the following three groups: Group 1: untreated (n = 7); Group 2: PBMC (3) (PBMC (3) + vehicle, 0.5 mg / kg, qwk × 3, IV, starting at day 0, n = 7); Group 3: PBMC (3) + control TDB (PBMC (3) + control TDB-2C11, 0.5 mg / kg, qwk × 3, IV, starting at day 0, n = 7). The obtained tumor volume measurements showed that there was no effect on tumor growth in animals treated with control TDB.

HER2 TDB leads to regression of large mammary tumors in huHER2 transgenic mice

To mimic the activity of the HER2 TDB in immunocompetent mice, human MMTV-huHER2 transgenic mice (Finkle et al., Clinical Cancer Research. 10:2499-2511; 2004) were used, and a surrogate HER2 TDB containing the murine IgG2ACD3-reactive antibody clone 2C11 (Leo et al., Proc Natl Acad Sci USA. 84:1374-1378, 1987) was generated to avoid immune responses against the TDB. For expression as muIgG2a, equivalent knob-into-hole mutations (Atwell et al., J Mol Biol. 270:26-35, 1997) were introduced into the Fc region, along with D265A and N297G (EU numbering) to abolish effector function. In the muIgG2a HER2 TDB, the "knob" arm is murine anti-HER2 hu4D5 and the "hole" is chimeric anti-murine CD3 2C11 (Leo et al., Proc Natl Acad Sci USA. 84:1374-1378, 1987) (TDB 2C11/hu4D5) or mouse anti-hu CD3 SP34 (Pessano et al., The EMBO Journal. 4:337-344, 1985) (TDB SP34/hu4D5). The muIgG2a bispecific antibody was expressed in CHO cells and assembled by in vitro assembly. The bispecific antibody was purified from contaminants by hydrophobic interaction chromatography (HIC) as described elsewhere (Speiss et al., Nat Biotechnology. 31:753-758, 2013). The resulting material was analyzed for endotoxin levels using a portable test system (Charles River, USA) and, when necessary, endotoxin content was reduced by washing the protein with 0.1% TRITON ^™ X-114. The in vitro activity of hu4D5/2C11-TDB was similar to that of human CD3-reactive HER2 TDB ( FIG. 101 ).

In Figures 99B to 99D, MMTV-huHER2 transgenic animals with established mammary tumors were divided into the following two groups: Group 1: Vehicle (0.5 mg/kg, qwk×5, IV, starting on day 0, n=7); and Group 2: HER2 TDB (HER2TDB(2C11/hu4D5), 0.5 mg/kg, qwk×5, IV, starting on day 0, n=7). Figure 99B shows that regression was detected in 57% of mice and 43% of mice had no detectable tumors after treatment. Figure 99C shows that HER2 TDB(2C11/hu4D5) produced more than 50% tumor regression, with the exception of one tumor. Responders included tumors >1000 mm ³ at the start of treatment, as observed in Figure 99D. In a similar experiment, two control TDBs were used: a CD3-arm control TDB (HER2 TDB (SP34/hu4D5)) that converted the murine-specific CD3 arm to a human-specific CD3 arm, and a control TDB (CTRL TDB-2C11) that had the same CD3 arm as the HER2 TDB (2C11/hu4D5) but an unrelated target arm. In Figure 99E, MMTV-huHER2 transgenic animals with established mammary tumors were divided into the following two groups: Group 1: CD3-arm control TDB (HER2 TDB (SP34/hu4D5), 0.5 mg/kg, qwk x 5, IV, starting on day 0, n=5); and Group 2: control TDB (control TDB-2C11, 0.5 mg/kg, qwk x 5, IV, starting on day 0, n=5). The growth of MMTV-huHER2 transgenic tumors was not affected by the control TDB.

The in vivo efficacy of HER2 TDB was further tested in huCD3 transgenic mice. Human CD3ε transgenic mice have been previously described ((huCD3 transgenic), de la Hera et al., J Exp Med. 173: 7-17, 1991). In this study, 100,000 CT26-HER2 cells were injected subcutaneously into huCD3 transgenic mice. After the CT26-HER2 tumor was established, the animals were divided into the following two groups: Group 1: vehicle (0.5 mg/kg, qwk×3, IV, starting on day 0, n=7); Group 2: HER2TDB (HER2 TDB (SP34/hu4D5), 0.5 mg/kg, qwk×3, IV, starting on day 0, n=7). HER2 TDB inhibited established tumor growth, but the effect was temporary and no complete response was seen (Figure 99F). This study shows the effective in vivo activity of HER2 TDB in MMTV-huHER2 transgenic mice, including significant responses.

In a similar experiment, the in vivo efficacy of a mouse-reactive HER2 TDB (2C11/hu4D5) was tested in Balb/c mice. Again, syngeneic tumors were established in Balb/c mice by subcutaneous injection of 1×10 ⁵ CT26-HER2 cells. Tumor-bearing animals were divided into one of the following four groups: Group 1: Vehicle (0.5 mg/kg, qwk×3, IV, starting on day 0, n=10); Group 2: HER2 TDB (HER2 TDB (2C11/hu4D5), 0.5 mg/kg, qwk×3, IV, starting on day 0, n=10); Group 3: Control TDB (CTRL TDB (2C11/hu4D5), 0.5 mg/kg, qwk×3, IV, starting on day 0, n=10); and Group 4: TDM-1 (TDM-1, 15 mg/kg, qwk×3, IV, starting on day 0, n=10). Figure 99G shows that despite the presence of incomplete responses, HER2 TDB significantly prolonged the time to tumor progression (log-rank p-value <0.0001). In contrast, the control TDB with an unrelated tumor arm had no effect on tumor growth. Additionally, the tumors were insensitive to TDM-1.

HER2 TDB inhibits the growth of established tumors in immunocompetent mice

Human CD3ε transgenic mice (de la Hera et al., J Exp Med. 173:7-17, 1991) were used to mimic the activity of HER2 TDB in immunocompetent mice. In this experiment, huCD3 transgenic T cells were extracted from the spleens of huCD3 transgenic mice and BALB/c mice or from the peripheral blood of healthy human donors. Cells were stained with mouse or human CD8 and human CD3 (clone UCHT1) in Figure 101A or mouse CD3 (clone 2C11) in Figure 101B. CD8+ cells were detected by flow cytometry. Figure 101A shows that huCD3 transgenic T cells express human CD3 at a level of approximately 50% of that of human T cells, and Figure 101B shows that huCD3 transgenic T cells express murine CD3 at a level of approximately 50% of that of BALB/c mice.

Next, the ability of huCD3 transgenic T cells to kill CT26 target cells expressing human HER2 in vitro was determined. In this study, T cells were extracted from the spleen of huCD3 transgenic mice, BALB/c mice, or from the peripheral blood of healthy human donors. The in vitro killing activity of CT26-HER2 cells was tested using the human CD3-specific HER2 TDB (UCHT1v9/hu4D5) in Figure 102A or the mouse CD3-specific HER2 TDB (2C11/hu4D5) in Figure 102B. Effector T cells were added to the target cells at a ratio of 20: 1 in the presence of a specified HER2 TDB and maintained for 40 hours. In vitro cytotoxicity was monitored by flow cytometry. Although the killing activity of mouse spleen T cells (EC50=2.4ng/ml) was always lower than that of human peripheral T cells (EC50=0.4ng/ml), huCD3 transgenic T cells killed target cells expressing human HER2 in vitro, as shown in Figure 102A. The mouse-specific HER2 TDB (2C11/hu4D5) induced target cell killing by T cells from both huCD3 transgenic mice (EC50 = 11 ng/ml) and BALB/c mice (EC50 = 10 ng/ml), as seen in FIG102B .

The T cell dependence of the anti-tumor activity of HER2 TDB was further analyzed in a syngeneic tumor model. As described above, 1×10 ⁵ CT26-HER2 cells were injected subcutaneously into BALB/c mice. Mice with established tumors were divided into one of the following two groups: Group 1: vehicle (n=10); Group 2: HER2 TDB (SP34/hu4D5) (HER2 TDB (SP34/hu4D5), 0.5 mg/kg, qwx3, IV, n=10). Figure 103 shows that the activity of HER2 TDB depends on T cells, because HER2 TDB has no effect in non-huCD3 transgenic mice. This study shows that huCD3 transgenic mice can be used as a novel efficacy model for huCD3 targeting molecules.

Example 6. Generation and Characterization of an Exemplary CD3/LYPD1 TDB (LYPD1 TDB)

We also explored the ability of TDB antibodies to recruit T cell cytotoxic activity to eradicate tumor cells by recognizing a different cell surface antigen, LYPD1. To this end, we generated and characterized a bispecific anti-CD3 antibody (LYPD1 TDB) with an anti-CD3 arm and an anti-LYPD1 arm. As described above, the LYPD1 TDB generated is a full-length antibody in a knob-in-hole format, such as human IgG1, as previously described (Atwell et al., J. Mol. Biol. 270: 26-35, 1997). Half antibodies were expressed in E. coli or Chinese hamster ovary (CHO) cells, purified by protein A affinity chromatography, and the appropriate half-antibody pairings were annealed in vitro as previously described (Spiess et al., Nat. Biotechnol. 2013). If the TDB antibody is produced in CHO cells, the antibody includes an aglycosylation mutation, for example, at residue N297 (e.g., N297G), rendering the TDB antibody a null effector variant and incapable of eliciting antibody-dependent cell-mediated cytotoxicity (ADCC). Following annealing, the LYPD1 TDB is purified by hydrophobic interaction chromatography (HIC) and characterized by analytical gel filtration, mass spectrometry, and polyacrylamide gel electrophoresis, as described above. The anti-LYPD1 arm used in generating the LYPD1 TDB is the anti-LYPD1 arm of the anti-LYPD1 antibody YWO.49.H6, which comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 272 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 273. Anti-CD3 arms tested in generating the LYPD1 TDB include UCHT1v9, 40G5, SP34, and 38E4v1.

Specific HER2 TDBs were tested for binding to CD8+ T cells (CD3 binding) and activity as assessed by in vitro cytotoxicity assays and T cell activation assays.

A. Binding affinity

As described above for the CD20 TDB, the binding affinity of each LYPD1 TDB was tested by FACS analysis. Briefly, in the FACS binding assay, CD8+ T cells were incubated with various concentrations of LYPD1 TDB antibodies at 4°C for 30 minutes, followed by washing and incubation with a secondary antibody (anti-huIgG-PE; BD Bioscience) for an additional 15 minutes. The cells were then washed again and prepared for FACS analysis. Figure 104 shows the results of an in vitro FACS binding assay for LYPD1 TDBs. Binding studies showed that LYPD1 TDBs with UCHT1v9 or 38E4v1 as their anti-CD3 arms exhibited higher binding affinity for the resulting effector cells.

B. In vitro OVCAR3.Luc target cell killing and T cell activation assays

The ability of the generated LYPD1 TDB to support the killing of LYPD1-expressing OVCAR3.Luc target cells and the cytotoxic effect of activated T cells was also tested. In vitro cytotoxicity was monitored by flow cytometry. Target cells were labeled with CFSE according to the manufacturer's protocol (Invitrogen, No. C34554). Target cells labeled with carboxyfluorescein succinimidyl ester (CFSE) and purified CD8+ T cells from human PBMC were mixed at a ratio of 3:1 for 48 hours with or without TDB. The cells were resuspended in an equal volume of PBS+2% FBS+1mM EDTA+propidium iodide (PI). Flow cytometry analysis was performed on a FACSCalibur in an automated format. The number of live target cells was counted by gating on CFSE+/PI-negative cells. The cytotoxicity percentage was calculated as follows: % cytotoxicity (number of live target cells without TDB - number of live target cells with TDB)/(number of live target cells without TDB) × 100. As shown in FIG105 , LYPD1 TDBs with UCHT1v9, 38E4v1, or SP34 as their anti-CD3 arms showed robust in vitro OVCAR3.Luc target cell killing compared to LYPD1 TDBs with 40G5 as their anti-CD3 arms.

When tested in a T cell activation assay, Figure 106 shows that LYPD1 TDBs with 38E4v1 and, to a lesser extent, UCHT1v9 and SP34 as their anti-CD3 arms are able to robustly induce in vitro T cell activity compared to LYPD1 TDBs with 40G5c as their anti-CD3 arms. In these analyses, target cells were mixed with purified CD8+ T cells in the presence or absence of TDBs, and T cell activation was analyzed by flow cytometry. At the end of the incubation period, cells were stained with CD8-FITC (BD Bioscience, 555634), CD69-PE (BD Bioscience, 555531), and CD107a-Alexa-Fluor 647 (eBioscience, 51-1079). Alternatively, after surface staining with CD8-FITC and CD69-PE, cells were fixed and permeabilized with Cytofix/CytoPerm solution (BD Bioscience, 554722) and intracellular staining was performed with anti-granzyme B-Alexa-Fluor 647 (BD Bioscience, 560212). T cell activation was assessed by the percentage of CD8+CD69+ and CD8+CD25+ cells.

Other implementation plans

Although the above invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, such description and example should not be construed as limiting the scope of the invention. The disclosures of all patents and scientific literature cited herein are expressly incorporated by reference in their entirety.

Claims (37)

1. A bispecific antibody that binds to CD20 and CD3, wherein the bispecific antibody comprises: (a) An anti-CD20 arm comprising a first binding domain, the first binding domain comprising: As shown in the amino acid sequence of SEQ ID NO:157, the hypervariable region (HVR)-H1, HVR-H2, as shown in the amino acid sequence of SEQ ID NO:158, HVR-H3, as shown in the amino acid sequence of SEQ ID NO:159, HVR-L1, as shown in the amino acid sequence of SEQ ID NO:160, HVR-L2, as shown in the amino acid sequence of SEQ ID NO:161, and HVR-L3, as shown in the amino acid sequence of SEQ ID NO:162; and (b) An anti-CD3 arm comprising a second binding domain, the second binding domain comprising: HVR-H1, as shown in the amino acid sequence of SEQ ID NO:1, HVR-H2, as shown in the amino acid sequence of SEQ ID NO:2, HVR-H3, as shown in the amino acid sequence of SEQ ID NO:3, HVR-L1, as shown in the amino acid sequence of SEQ ID NO:4, HVR-L2, as shown in the amino acid sequence of SEQ ID NO:5, and HVR-L3, as shown in the amino acid sequence of SEQ ID NO:6. 2. The bispecific antibody of claim 1, wherein The first binding domain includes: (a) a heavy chain variable (VH) domain amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:266; (b) a light chain variable (VL) domain amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:267; or (c) the VH domain in (a) and the VL domain in (b), and The second binding domain includes: (a) A VH domain amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:184; (b) A VL domain amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:185; or (c) the VH domain in (a) and the VL domain in (b). 3. The bispecific antibody of claim 1, wherein the second binding domain binds to human CD3ε polypeptide or cynomolgus monkey CD3ε polypeptide. 4. The bispecific antibody of claim 1, wherein the bispecific antibody comprises a substitution mutation in the Fc region that reduces effector function. 5. The bispecific antibody of claim 4, wherein the substitution mutation is a deglycosylation site mutation. 6. The bispecific antibody of claim 4, wherein the substitution mutation is located at amino acid residues N297, L234, L235, and/or D265 according to EU numbers. 7. The bispecific antibody of claim 6, wherein the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, and D265A. 8. The bispecific antibody of claim 1, wherein the bispecific antibody comprises a first CH1 (CH1 ₁ ) domain, a first CH2 (CH2 ₁ ) domain, a first CH3 (CH3 ₁ ) domain, a second CH1 (CH1 ₂ ) domain, a second CH2 (CH2 ₂ ) domain, and a second CH3 (CH3 ₂ ) domain, wherein: (i) The CH3 ₁ domain is paired with the CH3 ₂ domain, wherein each of the CH3 ₁ and CH3 ₂ domains contains a protrusion or a cavity, and wherein the protrusion or cavity in the CH3 ₁ domain may be located in the cavity or protrusion of the CH3 ₂ domain accordingly; or (ii) The CH2 ₁ domain is paired with the CH2 ₂ domain, wherein each of the CH2 ₁ and CH2 ₂ domains contains a protrusion or a cavity, and wherein the protrusion or cavity in the CH2 ₁ domain may be located in the cavity or protrusion of the CH2 ₂ domain. 9. The bispecific antibody of claim 1, wherein the bispecific antibody is a monoclonal antibody, a humanized antibody, or a chimeric antibody. 10. The bispecific antibody of claim 1, wherein the bispecific antibody is an antibody fragment that binds to CD20 and CD3. 11. The bispecific antibody of claim 1, wherein the bispecific antibody is a full-length antibody. 12. The bispecific antibody of claim 1, wherein: The first binding domain comprises (a) a VH domain as shown in the amino acid sequence of SEQ ID NO:266 and (b) a VL domain as shown in the amino acid sequence of SEQ ID NO:267; and The second binding domain comprises (a) a VH domain as shown in the amino acid sequence of SEQ ID NO:184 and (b) a VL domain as shown in the amino acid sequence of SEQ ID NO:185. 13. The bispecific antibody of claim 12, wherein (a) the anti-CD3 arm comprises T366S, L368A, Y407V, and N297G substitution mutations and (b) the anti-CD20 arm comprises T366W and N297G substitution mutations. 14. One or more isolated nucleic acids encoding the bispecific antibody of any one of claims 1-13. 15. A vector comprising one or more isolated nucleic acids of claim 14. 16. A host cell comprising the vector of claim 15. 17. The host cell of claim 16, wherein the host cell is a Chinese hamster ovary (CHO) cell. 18. A method for generating a bispecific antibody, wherein the bispecific antibody comprises: (a) An anti-CD20 arm comprising a first binding domain, the first binding domain comprising: HVR-H1, as shown in the amino acid sequence of SEQ ID NO:157, HVR-H2, as shown in the amino acid sequence of SEQ ID NO:158, HVR-H3, as shown in the amino acid sequence of SEQ ID NO:159, HVR-L1, as shown in the amino acid sequence of SEQ ID NO:160, HVR-L2, as shown in the amino acid sequence of SEQ ID NO:161, and HVR-L3, as shown in the amino acid sequence of SEQ ID NO:162; and (b) An anti-CD3 arm comprising a second binding domain, the second binding domain comprising: HVR-H1, as shown in the amino acid sequence of SEQ ID NO:1, HVR-H2, as shown in the amino acid sequence of SEQ ID NO:2, HVR-H3, as shown in the amino acid sequence of SEQ ID NO:3, HVR-L1, as shown in the amino acid sequence of SEQ ID NO:4, HVR-L2, as shown in the amino acid sequence of SEQ ID NO:5, and HVR-L3, as shown in the amino acid sequence of SEQ ID NO:6; The method includes culturing the host cell of claim 16 in a culture medium. 19. A composition comprising the bispecific antibody of any one of claims 1-13. 20. Use of the bispecific antibody of any one of claims 1-13 in the manufacture of a medicament for (a) treating or delaying the progression of a cell proliferative disorder or (b) enhancing immune function in a subject suffering from a cell proliferative disorder. 21. The use of claim 20, wherein the proliferative disease is lymphoma. 22. The use of claim 21, wherein the lymphoma is non-Hodgkin's lymphoma (NHL). 23. The use of claim 22, wherein the NHL is follicular lymphoma. 24. The use of claim 22, wherein the NHL is diffuse large B-cell lymphoma. 25. The use of claim 20, further comprising the use of a PD-1 axis binding antagonist and/or additional therapeutic agents in the manufacture of a medicament for (a) treating or delaying the progression of cellular proliferative disorders or (b) enhancing immune function in a subject suffering from cellular proliferative disorders. 26. The use of claim 25, wherein the PD-1 axis binding antagonist is selected from the group consisting of PD-1 binding antagonists, PD-L1 binding antagonists, and PD-L2 binding antagonists. 27. The use of claim 26, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist. 28. The use of claim 27, wherein the PD-L1 binding antagonist is selected from the group consisting of MPDL3280A, YW243.55.S70, MDX-1105, and MEDI4736. 29. The use of claim 26, wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist. 30. The use of claim 29, wherein the PD-1 binding antagonist is selected from the group consisting of MDX-1106 (nivolumab), MK-3475 (lambrolizumab), and AMP-224. 31. The use of claim 26, wherein the PD-1 axis binding antagonist is a PD-L2 binding antagonist. 32. The use of claim 31, wherein the PD-L2 binding antagonist is an antibody or an immunoadhesive. 33. The use of claim 25, further comprising the use of rituximab or obbituzumab in the manufacture of a medicament for (a) treating or delaying the progression of cellular proliferative disorders or (b) enhancing immune function in a subject suffering from cellular proliferative disorders. 34. The use of claim 25, further comprising the use of an antibody-drug conjugate (ADC) in the manufacture of a medicament for (a) treating or delaying the progression of a cell proliferative disorder or (b) enhancing immune function in a subject suffering from a cell proliferative disorder. 35. The use of claim 34, wherein the ADC is an anti-CD79b ADC. 36. The use of claim 35, wherein the anti-CD79b ADC is polatuzumab vedotin. 37. A medicine box comprising: (a) the composition of claim 19; and (b) A packaging insert containing instructions on administering the composition to a subject to treat a proliferative disease or delay its progression.