WO2024191983A1

WO2024191983A1 - Methods of treating cancer with bispecific anti-cd22 x anti-cd28 molecules

Info

Publication number: WO2024191983A1
Application number: PCT/US2024/019506
Authority: WO
Inventors: Aafia CHAUDHRY; Hesham Mohamed
Original assignee: Regeneron Pharmaceuticals Inc
Current assignee: Regeneron Pharmaceuticals Inc
Priority date: 2023-03-13
Filing date: 2024-03-12
Publication date: 2024-09-19
Anticipated expiration: 2025-09-13
Also published as: TW202500582A; KR20250156813A; CN120916782A; MX2025010746A; IL323074A; AU2024235165A1

Abstract

The present disclosure provides methods for treating, reducing the severity, or inhibiting the growth of cancer. The methods, in some embodiments, comprise administering to a subject in need thereof a therapeutically effective amount of a bispecific antibody or antigen-binding fragment thereof that specifically binds CD22 and CD28, in combination with a bispecific antibody or antigen-binding fragment thereof that binds CD20 and CD3.

Description

Methods of Treating Cancer with Bispecific Anti-CD22 x Anti-CD28 Molecules

RELATED APPLICATION

[0001] This applicanion is related to and claims priority to U.S. Provisional Application No. 63/489,808, filed on March 13, 2023. The entire contents of the foregoing application, including all drawings and sequence listing, are expressly incorporated herein by reference.

FIELD

[0002] The present disclosure provides methods for treating, reducing the severity, or inhibiting the growth of cancer in a subject (e.g.. a human) in need thereof, comprising administering to the subject a therapeutically effective amount of a bispecific antibody or antigen-binding fragment thereof that specifically binds CD22 and CD28, in combination with a bispecific antibody or antigen-binding fragment thereof that binds CD20 and CD3.

SEQUENCE LISTING

[0003] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on March 5, 2024, is named 118003-59220.XML and is 39,470 bytes in size.

BACKGROUND

[0004] CD28 is a type I transmembrane protein expressed on the surface of T cells, which has a single extracellular Ig-V-like domain assembled as a homodimer. CD28 is the receptor for the CD80 (B7.1) and CD86 (B7.2) proteins and is activated by CD80 or CD86 expressed on antigen-presenting cells (APCs). The binding of CD28 to CD80 or CD86 provides co-stimulatory signals important for T cell activation and survival. T cell stimulation through CD28, in addition to the T-cell receptor (TCR), provides a potent signal for the production of various interleukins. CD28 also potentiates cellular signals such as pathways controlled by the NFKB transcription factor after TCR activation. The CD28 co-signal is important for effective T-cell activation such as T cell differentiation, proliferation, cytokine release and cell-death.

[0005] Anti-CD28 antibodies have been proposed for therapeutic purposes involving the activation of T cells. One particular anti-CD28 antibody, TGN1412 (anti-CD28 superagonist), was used in a clinical trial in 2006. Six healthy volunteers were dosed intravenously with TGN1412 (anti-CD28 superagonist) at a dose of 0.1 mg/kg. Within two hours, all six subjects had significant inflammatory responses (cytokine storm), and all subjects were in multi-organ failure within sixteen hours. Subjects were treated with corticosteriods, and cytokine levels returned to normal levels within 2-3 days. The starting dose of 0.1 mg/kg in a Phase 1 study (associated with CRS) was based on 500-fold multiple of cynomolgus “NOAEL” of 50 mg/kg (Suntharalingam, et al., Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412, NEJM 355:1018-1028 (2006)). Unfortunately, TGN1412 induced a cytokine storm, which was not predicted by toxicology studies in cynomolgus macaques or ex vivo human PBMC studies.

[0006] CD22 (also known as Siglec-2), a member of Siglec family, specifically recognizes a2,6 sialic acid, and is a transmembrane protein preferentially expressed on B lymphocytes (B cells). CD22 has a number of ascribed functions including, for example, B cell homeostasis, B cell survival and migration, dampening TLR and CD40 signaling, and inhibiting B cell receptor (BCR) signaling via recruitment of SH2 domain-containing phosphatases by phosphorylation of immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic region, as well as facilitation of adhesion between B cells and other cell types. CD22 is not found on the surface of B cells during the early stages of development, nor is it expressed in stem cells. However, 60-70% of all B-cell lymphomas and leukemias express CD22.

[0007] An anti-CD22 antibody for treating B-cell lymphomas and leukemias has been investigated. However, the monoclonal antibody, Epratuzumab, had limited success.

(Grant, et al. (2013) Cancer 119(21): 10.1002/cncr.28299)

[0008] Bispecific antigen-binding molecules that bind both CD28 and a target antigen (such as CD22) would be useful in therapeutic settings in which specific targeting and T cell- mediated killing of cells that express the target antigen is desired.

SUMMARY

[0009] The present disclosure provides a method for treating a B-cell proliferative disorder or a malignancy, e.g., a CD20-expressing cell malignancy, in a subject, the method comprising administering to the subject a therapeutically effective amount of a bispecific CD22xCD28 antibody or antigen-binding fragment thereof in combination with a bispecific CD3xCD20 antibody or antigen-binding fragment thereof, wherein the bispecific CD22xCD28 antibody or antigen-binding fragment thereof comprises a first antigen-binding domain that binds cluster of differentiation factor 28 (CD28) and a second antigen-binding domain that binds cluster of differentiation factor 22 (CD22), and the bispecific CD3xCD20 antibody or antigen-binding fragment thereof comprises a first antigen-binding domain that binds cluster of differentiation factor 3 (CD3) and a second antigen-binding domain that binds cluster of differentiation factor 20 (CD20), thereby treating the B-cell proliferative disorder or malignancy, e.g., CD20-expressing cell malignancy, in the subject.

[0010] In some embodiments, the B-cell proliferative disorder is a B-cell lymphoma. In some embodiments, the lymphoma is a B-cell non-Hodgkin lymphoma (B-NHL). In some embodiments, the non-Hodgkin lymphoma is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), high-grade B-cell lymphoma, Burkitt lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma.

[0011] In some embodiments, the method further comprises selecting a subject, wherein the subject has an aggressive B-NHL.

[0012] In some embodiments, the subject has at least one of the following criteria, or is selected on the basis of at least one of the following criteria: has CD20+ aggressive B-NHL; has progressed after at least 2 lines of systemic therapy containing a CD20 inhibitor and an alkylating agent; has measurable disease on cross sectional imaging has adequate bone marrow function and hepatic function; and/or has any of the following cancer types: DLBCL, primary mediastinal (thymic) large B-cell lymphoma, T-cell/histiocyte rich large B-cell lymphoma, follicular lymphoma grade 3b, and high-grade B-cell lymphoma (HGBL) with or without MYC, BCL2 or BCL6 translocations.

[0013] In some embodiments, the subject has been treated with a prior therapy and relapsed or the disorder progressed during or after the prior treatment. In some embodiments, the subject has received a CAR-T therapy.

[0014] In some embodiments, the subject has measurable CD20+ aggressive B-NHL that has progressed after >2 lines of systemic therapy containing at least a CD20 inhibitor and an alkylating agent.

[0015] In some embodiments, the CD20 inhibitor is an anti-CD20 antibody.

[0016] In some embodiments, the subject has been treated with CAR-T cell therapy.

[0017] In some embodiments, the subject has not been previously treated with a

CD3xCD20 bispecific antibody.

[0018] In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is administered at a dose of about 0.01 mg to about 400 mg.

[0019] In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is administered at a dose of about 0.01 mg, 0.03 mg, 0.05 mg, 0.1 mg, 0.3 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 200 mg, 240 mg, 280 mg, 300 mg, 320 mg, 350 mg, or 400 mg.

[0020] In some embodiments, the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered at a dose of about 0.1 mg to about 400 mg.

[0021] In some embodiments, the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered at a dose of about 0.1 mg, 0.2 mg, 0.3 mg, 0.5 mg, 0.7 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 200 mg, 240 mg, 280 mg, 300 mg, 320 mg, 350 mg, or 400 mg.

[0022] In some embodiments, the method comprises administering one or more doses of the bispecific CD22xCD28 antibody or antigen-binding fragment thereof in combination with one or more doses of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof. In some embodiments, each of the one or more doses of the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is about 0.01 mg to about 400 mg. In some embodiments, each of the one or more doses is about 0.01 mg, 0.03 mg, 0.05 mg, 0.1 mg, 0.3 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 200 mg, 240 mg, 280 mg, 300 mg, 320 mg, 350 mg, or 400 mg.

[0023] In some embodiments, each of the one or more doses of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is about 0.1 mg to about 400 mg. [0024] In some embodiments, each of the one or more doses of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is about 0.1 mg, 0.2 mg, 0.3 mg, 0.5 mg, 0.7 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 200 mg, 240 mg, 280 mg, 300 mg, 320 mg, 350 mg, or 400 mg.

[0025] In some embodiments, one or more doses of the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the one or more doses of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered 1 day to 8 weeks after the immediately preceding dose.

[0026] In some embodiments, each of the one or more doses of the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the one or more doses of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered once every week, once every two weeks, once every three weeks, once every four weeks, once every five weeks or once every six weeks.

[0027] In some embodiments, one or more doses of the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is administered once every week. In some embodiments, one or more doses of the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is administered once every two weeks.

[0028] In some embodiments, one or more doses of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered once every week. In some embodiments, one or more doses of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered once every two weeks. [0029] In some embodiments, a dose of the bispecific CD3xCD20 antibody or antigenbinding fragment thereof is administered in a single administration, or split and administered on two days that are no more than 3 days apart.

[0030] In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the bispecific CD3xCD20 antibody or antigen-binding fragment are administered intravenously. In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the bispecific CD3xCD20 antibody or antigenbinding fragment thereof are administered subcutaneously.

[0031] In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the bispecific CD3xCD20 antibody or antigen-binding fragment thereof are administered on the same day.

[0032] In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the bispecific CD3xCD20 antibody or antigen-binding fragment thereof are administered on different days. In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is administered before or after the bispecific CD3xCD20 antibody or antigen-binding fragment thereof. In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is administered one day before the bispecific CD3xCD20 antibody or antigen-binding fragment thereof.

[0033] In some embodiments, the method comprises the steps of: (i) administering to the subject the bispecific CD3xCD20 antibody or antigen-binding fragment thereof at a dose of 0.1 mg to 160 mg subcutaneously or intravenously every week for a period of monotherapy, wherein the period of monotherapy is at least 2 weeks; and (ii) administering to the subject the bispecific CD22xCD28 antibody or antigen-binding fragment thereof at a dose of 0.01 mg to 400 mg subcutaneously or intravenously every week, and administering to the subject the bispecific CD3xCD20 or antigen-binding fragment thereof at a dose of 80 mg to 160 mg intravenously or subcutaneously every week for a period of induction combination therapy.

[0034] In some embodiments, the period of monotherapy is at least 2 weeks, at least 3 weeks, at least 4 weeks, or at least 5 weeks.

[0035] In some embodiments, the dose of the bispecific CD3xCD20 antibody or antigenbinding fragment thereof during the period of monotherapy period is split and administered on two different days that are no more than 3 days apart, or administered in a single administration.

[0036] In some embodiments, the monotherapy period in step (i) comprises administering an initial dose of the bispecific CD3xCD20 antibody and increasing the dose of to a full dose by the end of the monotherapy period. In some embodiments, the full dose of the bispecific CD3xCD20 in step (i) is 80 or 160 mg. [0037] In some embodiments, the induction combination therapy period in step (ii) comprises: (a) administering an initial dose of the bispecifc CD22xCD28 antibody wherein the initial dose comprises 0.03mg to 2mg; (b) administering an intermediate dose comprising 0.1 mg to 20mg of the bispecifc CD22xCD28 antibody; and (c) administering a full dose of the bispecific CD22xCD28 wherein the full dose comprises 0.3mg to 160mg.

[0038] In some embodiments, during step (ii), the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered on a different day as the bispecific CD22xCD28 antibody or antigen-binding fragment thereof.

[0039] In some embodiments, the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered one day after the bispecific CD22xCD28 antibody or antigen-binding fragment thereof.

[0040] In some embodiments, during step (ii), the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered on the same day as the bispecific CD22xCD28 antibody or antigen-binding fragment thereof.

[0041] In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is administered in combination with the bispecific CD3xCD20 or antigenbinding fragment thereof in step (ii) for at least 9 weeks. In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is administered in combination with the bispecific CD3xCD20 antibody or antigen-binding fragment thereof in step (ii) for at least 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks or 15 weeks.

[0042] In some embodiments, the method further comprises: (iii) administering the bispecific CD22xCD28 antibody or antigen-binding fragment thereof in combination with 160 mg or 320 mg of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof after step (ii) every two or more weeks for a period of maintenance combination therapy.

[0043] In some embodiments, in step (iii), the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and the bispecific CD3xCD20 antibody or antigen-binding fragment are administered on the same day.

[0044] In some embodiments, in step (iii), the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and the bispecific CD3xCD20 or antigen-binding fragment are administered every two weeks or every four weeks.

[0045] In some embodiments, the method further comprises administering to the subject one or more additional agents to treat or prevent one or more symptoms of an adverse event.

[0046] In some embodiments, the bispecific antibodies are administered to the subject in combination with a second agent wherein the second agent is selected from the group consisting of dexamethasone, diphenhydramine, acetaminophen, a steroid, an antihistamine, a non-steroidal anti-inflammatory drug (NSAID), an IL-6 antagonist, and an IL- 6R antagonist.

[0047] In some embodiments, the subject has stable disease, partial response, or complete response upon administration of the bispecific CD22xCD28 antibody or antigenbinding fragment thereof for at least one week at a dose of about 0.01 mg to about 400 mg in combination with the bispecific CD3xCD20 antibody or antigen-binding fragment thereof. [0048] In some embodiments, the bispecific CD3xCD20 antibody or antigen-binding fragment thereof comprises: i) a CD3 binding arm comprising the heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 5 and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 6; and ii) a CD20 binding arm comprising the heavy chain complementarity determining regions (HCDR1, HCDR2 and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 4 and three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 6.

[0049] In some embodiments, the bispecific CD3xCD20 antibody or antigen-binding fragment thereof comprises i) a CD3 binding arm comprising three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 10; HCDR2 comprises the amino acid sequence of SEQ ID NO: 11; HCDR3 comprises the amino acid sequence of SEQ ID NO: 12; LCDR1 comprises the amino acid sequence of SEQ ID NO: 13; LCDR2 comprises the amino acid sequence of SEQ ID NO: 14; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 15; and ii) the CD20 binding arm comprising three HCDRs (HCDR1 , HCDR2 and HCDR3) and three LCDRs (LCDR1, LCDR2 and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 7; HCDR2 comprises the amino acid sequence of SEQ ID NO: 8; HCDR3 comprises the amino acid sequence of SEQ ID NO: 9; LCDR1 comprises the amino acid sequence of SEQ ID NO: 13; LCDR2 comprises the amino acid sequence of SEQ ID NO: 14; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 15.

[0050] In some embodiments, the HCVR of the CD3 binding arm comprises the amino acid sequence of SEQ ID NO: 5, the HCVR of the CD20 binding arm comprises the amino acid sequence of SEQ ID NO: 4, and the common LCVR comprises the amino acid sequence of SEQ ID NO: 6.

[0051] In some embodiments, the bispecific CD3xCD20 antibody or antigen-binding fragment thereof comprises a heavy chain of the CD3 binding arm comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain of the CD20 binding arm comprising the amino acid sequence of SEQ ID NO: 1, and a common light chain comprising the amino acid sequence of SEQ ID NO: 3.

[0052] In some embodiments, the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is odronextamab.

[0053] In some embodiments, the first antigen-binding domain that binds CD28 comprises three heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 20; and three light chain complementarity determining regions (LCDR1, LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 25, HCDR2 comprises the amino acid sequence of SEQ ID NO: 26, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 27. In some embodiments, LCDR1 comprises the amino acid sequence: of SEQ ID NO: 28, LCDR2 comprises the amino acid sequence of SEQ ID NO: 29, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 30.

[0054] In some embodiments, the first antigen-binding domain that binds CD28 comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 20, and a LCVR comprising the amino acid sequence of SEQ ID NO: 21.

[0055] In some embodiments, the second antigen binding domain that binds CD22 comprises three heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 19; and three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments, HCDR1 comprises the amino acid sequence of SEQ ID NO: 22, HCDR2 comprises the amino acid sequence of SEQ ID NO: 23, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 24. In some embodiments, LCDR1 comprises the amino acid sequence: of SEQ ID NO: 28, LCDR2 comprises the amino acid sequence of SEQ ID NO: 29, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 30.

[0056] In some embodiments, the second antigen-binding domain that binds CD22 comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 19, and a LCVR comprising the amino acid sequence of SEQ ID NO: 21.

[0057] In some embodiments, (a) the first antigen binding domain that binds human CD28 comprises a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 20, and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 21; and (b) the second antigen binding domain that binds CD22 comprises a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 19; and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 21.

[0058] In some embodiments, the bispecific CD22xCD28 antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 17.

[0059] In some embodiments, the bispecific CD22xCD28 antibody comprises a second heavy chain comprising the amino acid sequence of SEQ ID NO: 16.

[0060] In some embodiments, the bispecific CD22xCD28 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0061] In some embodiments, the bispecific CD22xCD28 antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 17, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 16, and a common light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0062] In some embodiments, the first antigen-binding domain comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and a light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0063] In some embodiments, the second antigen-binding domain comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 16 and a light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0064] In some embodiments, the bispecific CD22xCD28 antibody is REGN5837, or an antigen-binding fragment thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 shows a schematic representation of a combination therapy study with a 28-day screening period and an odronextamab monotherapy lead-in period, followed by combination with REGN5837. Each cycle in the induction period is 21 days, and each cycle in the maintenance period is 28 days. QW: every week. Q2W: every 2 weeks. Q4W: every 4 weeks.

[0066] Figure 2 shows a schematic representation of an example of combination dosing regimen for a subject at dose level 1 (DL1).

[0067] Figure 3 shows a schematic representation of pre-medication schedule for Cycle 1 to Cycle 3, from the initial odronextamab monotherapy to the combination treatment of REGN5837 with odronextamab.

DETAILED DESCRIPTION

[0068] Before the present disclosure is described, it is to be understood that this disclosure is not limited to particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.

[0069] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value may vary from the recited value by no more than 1 %. For example, as used herein, the expression "about 100" includes 99 and 1 01 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0070] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. All patents, applications and non-patent publications mentioned in this specification are incorporated herein by reference in their entireties.

Definitions

[0071] The expression “CD28,” as used herein, refers to an antigen which is expressed on T cells as a costimulatory receptor. Human CD28 comprises the amino acid sequence as set forth in NCBI accession No. NP_006130.1. All references to proteins, polypeptides and protein fragments herein are intended to refer to the human version of the respective protein, polypeptide or protein fragment unless explicitly specified as being from a non-human species. Thus, the expression "CD28" means human CD28 unless specified as being from a non-human species, e.g., "mouse CD28," "monkey CD28," etc.

[0072] As used herein, “an antibody that binds CD28” or an “anti-CD28 antibody” includes antibodies and antigen-binding fragments thereof that specifically recognize a monomeric CD28, as well as antibodies and antigen-binding fragments thereof that specifically recognize a dimeric CD28. The antibodies and antigen-binding fragments of the present disclosure may bind soluble CD28 and/or cell surface expressed CD28. Soluble CD28 includes natural CD28 proteins as well as recombinant CD28 protein variants such as, e.g., monomeric and dimeric CD28 constructs, that lack a transmembrane domain or are otherwise unassociated with a cell membrane.

[0073] As used herein, the expression “cell surface-expressed CD28” means one or more CD28 protein(s) that is/are expressed on the surface of a cell in vitro or in vivo, such that at least a portion of a CD28 protein is exposed to the extracellular side of the cell membrane and is accessible to an antigen-binding portion of an antibody. "Cell surface- expressed CD28" includes CD28 proteins contained within the context of a functional T cell costimulatory receptor in the membrane of a cell. The expression "cell surface-expressed CD28" includes CD28 protein expressed as part of a homodimer on the surface of a cell. A "cell surface-expressed CD28" can comprise or consist of a CD28 protein expressed on the surface of a cell which normally expresses CD28 protein. Alternatively, "cell surface- expressed CD28" can comprise or consist of CD28 protein expressed on the surface of a cell that normally does not express human CD28 on its surface but has been artificially engineered to express CD28 on its surface.

[0074] As used herein, the expression "anti-CD28 antibody" includes both monovalent antibodies with a single specificity, as well as bispecific antibodies comprising a first arm that binds CD28 and a second arm that binds a second (target) antigen, wherein the anti-CD28 arm comprises any of the HCVR/LCVR or CDR sequences as set forth in Table 1 herein. Examples of anti-CD28 bispecific antibodies are described elsewhere herein. The term "antigen-binding molecule" includes antibodies and antigen-binding fragments of antibodies, including, e.g., bispecific antibodies.

[0075] The term "CD22," as used herein, refers to the human CD22 protein unless specified as being from a non-human species (e.g., "mouse CD22," "monkey CD22," etc.). The human CD22 protein has the amino acid sequence as set forth in accession number CAA42006. The sequence of recombinant human CD22 ecto (D20-R687) with a myc hexahistidine tag is shown in accession number NP_001762.2. The hCD22 ectodomain (D20-R687).hFc, can also be purchased from R&D Systems, Catalog# 1968-SL-050.

[0076] As used herein, “an antibody that binds CD22” or an “anti-CD22 antibody” includes antibodies and antigen-binding fragments thereof that may bind soluble CD22 and/or cell surface expressed CD22. Soluble CD22 includes natural CD22 proteins as well as recombinant CD22 protein variants such as, e.g., CD22 constructs, that lack a transmembrane domain or are otherwise unassociated with a cell membrane.

[0077] As used herein, the expression "anti-CD22 antibody" includes both monovalent antibodies with a single specificity, as well as bispecific antibodies comprising a first arm that binds CD22 and a second arm that binds a second (target) antigen, wherein the anti-CD22 arm comprises any of the HCVR/LCVR or CDR sequences as set forth in Table 1 herein. Examples of anti-CD22 bispecific antibodies are described elsewhere herein. The term "antigen-binding molecule" includes antibodies and antigen-binding fragments of antibodies, including, e.g., bispecific antibodies.

[0078] The term "antigen-binding molecule" includes antibodies and antigen-binding fragments of antibodies, including, e.g., bispecific antibodies.

[0079] The term "antibody", as used herein, means any antigen-binding molecule or molecular complex comprising at least one complementarity determining region (CDR) that specifically binds to or interacts with a particular antigen (e.g., CD28). The term "antibody" includes immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1). The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1 , CDR1, FR2, CDR2, FR3, CDR3, FR4. In different embodiments of the disclosure, the FRs of the anti-CD28 antibody and/or anti-CD22 antibody (or antigen-binding portion thereof) may be identical to the human germ line sequences, or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.

[0080] The term "antibody", as used herein, also includes antigen-binding fragments of full antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and/or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

[0081] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments;

(ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalent nanobodies, bivalent nanobodies, etc.), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigenbinding fragment," as used herein.

[0082] An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a VH domain associated with a VL domain, the VH and VL domains may be situated relative to one another in any suitable arrangement. For example, the variable region may be dimeric and contain VH-VH, VH-VL or VL-VL dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain.

[0083] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present disclosure include: (i) VH-CH1 ; (ii) VH-CH2; (iii) VH-CH3; (iv) VH-CH1-CH2; (v) VH-CH1-CH2-CH3; (vi) VH-CH2-CH3; (vii) VH- CL; (viii) VL-CH1 ; (ix) VL-CH2; (x) VL-CH3; (xi) VL-CH1-CH2; (xii) VL-CH1-CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule. Moreover, an antigenbinding fragment may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and/or with one or more monomeric VH or VL domain (e.g., by disulfide bond(s)).

[0084] As with full antibody molecules, antigen-binding fragments may be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody will typically comprise at least two different variable domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, may be adapted for use in the context of an antigen-binding fragment of an antibody of the present disclosure using routine techniques available in the art.

[0085] The antibodies of the present disclosure may function through complementdependent cytotoxicity (CDC) or antibody-dependent cell-mediated cytotoxicity (ADCC). "Complement dependent cytotoxicity" (CDC) refers to lysis of antigen-expressing cells by an antibody of the disclosure in the presence of complement. "Antibody-dependent cell- mediated cytotoxicity" (ADCC) refers to a cell-mediated reaction in which nonspecific cytotoxic cells that express Fc receptors (FcRs) (e.g., Natural Killer (NK) cells, neutrophils, and macrophages) recognize bound antibody on a target cell and thereby lead to lysis of the target cell. CDC and ADCC can be measured using assays that are well known and available in the art. (See, e.g., U.S. Patent Nos. 5,500,362 and 5,821,337, and Clynes et al. (1998) Proc. Natl. Acad. Sci. (USA) 95:652- 656). The constant region of an antibody is important in the ability of an antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of an antibody may be selected on the basis of whether it is desirable for the antibody to mediate cytotoxicity.

[0086] In certain embodiments of the disclosure, the anti-CD28 antibodies and/or anti- CD22 antibodies of the disclosure (monospecific or bispecific) are human antibodies. The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germ line immunoglobulin sequences. The human antibodies of the disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in particular CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germ line of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0087] The antibodies of the disclosure may, in some embodiments, be recombinant human antibodies. The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germ line VH and VL sequences, may not naturally exist within the human antibody germ line repertoire in vivo.

[0088] Human antibodies can exist in two forms that are associated with hinge heterogeneity. In one form, an immunoglobulin molecule comprises a stable four chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond. In a second form, the dimers are not linked via interchain disulfide bonds and a molecule of about 75-80 kDa is formed composed of a covalently coupled light and heavy chain (half-antibody). These forms have been extremely difficult to separate, even after affinity purification.

[0089] The frequency of appearance of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human lgG4 hinge can significantly reduce the appearance of the second form (Angal et al. (1993) Molecular Immunology 30:105) to levels typically observed using a human lgG1 hinge. The instant disclosure encompasses antibodies having one or more mutations in the hinge, CH2 or CH3 region which may be desirable, for example, in production, to improve the yield of the desired antibody form.

[0090] The antibodies of the disclosure may be isolated antibodies. An "isolated antibody," as used herein, means an antibody that has been identified and separated and/or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an "isolated antibody" for purposes of the present disclosure. An isolated antibody also includes an antibody in situ within a recombinant cell. Isolated antibodies are antibodies that have been subjected to at least one purification or isolation step. According to certain embodiments, an isolated antibody may be substantially free of other cellular material and/or chemicals.

[0091]

[0092] The anti-CD28 antibodies and/or anti-CD22 antibodies herein, or the antigenbinding domains thereof, may comprise one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences from which the antigenbinding proteins or antigen-binding domains were derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present disclosure includes antibodies, and the antigen-binding domains thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as "germline mutations"). A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments, which comprise one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and/or CDR residues within the VH and/or VL domains are mutated back to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1 , CDR2 or CDR3. In other embodiments, one or more of the framework and/or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (/.e., a germline sequence that is different from the germline sequence from which the antibody was originally derived). Furthermore, the antibodies, or the antigen-binding domains thereof, of the present disclosure may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a particular germline sequence while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue of a different germline sequence. Once obtained, antibodies, or the antigen-binding fragments thereof, that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Antibodies, or the antigenbinding fragments thereof, obtained in this general manner are encompassed within the present disclosure.

[0093] The present disclosure also includes anti-CD28 antibodies and/or anti-CD22 antibodies and antigen-binding molecules comprising variants of any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein. Exemplary variants included within this aspect of the disclosure include variants of any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the present disclosure includes anti-CD28 antibodies and antigen-binding molecules having HCVR, LCVR, and/or CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the HCVR, LCVR, and/or CDR amino acid sequences set forth in Table 1 herein. [0094] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different areas on an antigen and may have different biological effects. Epitopes may be either conformational or linear. A conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. In certain circumstance, an epitope may include moieties of saccharides, phosphoryl groups, or sulfonyl groups on the antigen.

[0095] The term "substantial identity" or "substantially identical," when referring to a nucleic acid or fragment thereof, indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 95%, and more preferably at least about 96%, 97%, 98% or 99% of the nucleotide bases, as measured by any well-known algorithm of sequence identity, such as FASTA, BLAST or Gap, as discussed below. A nucleic acid molecule having substantial identity to a reference nucleic acid molecule may, in certain instances, encode a polypeptide having the same or substantially similar amino acid sequence as the polypeptide encoded by the reference nucleic acid molecule.

[0096] As applied to polypeptides, the term "substantial similarity" or "substantially similar" means that two peptide sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 95% sequence identity, even more preferably at least 98% or 99% sequence identity. Preferably, residue positions which are not identical differ by conservative amino acid substitutions. A "conservative amino acid substitution" is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well-known to those of skill in the art. See, e.g., Pearson (1994) Methods Mol. Biol. 24: 307-331.

Examples of groups of amino acids that have side chains with similar chemical properties include (1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; (2) aliphatic- hydroxyl side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartate and glutamate, and (7) sulfur-containing side chains are cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine.

Alternatively, a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al (1992) Science 256: 1443-1445. A "moderately conservative" replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.

[0097] Sequence similarity for polypeptides, which is also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For instance, GCG software contains programs such as Gap and Bestfit which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof. See, e.g., GCG Version 6.1.

Polypeptide sequences also can be compared using FASTA using default or recommended parameters, a program in GCG Version 6.1. FASTA (e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (2000) supra). Another preferred algorithm when comparing a sequence of the disclosure to a database containing a large number of sequences from different organisms is the computer program BLAST, especially BLASTP or TBLASTN, using default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215:403- 410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389-402.

[0098] The terms “cell proliferative disorder” and “proliferative disorder” refer to disorders that are associated with some degree of abnormal cell proliferation that would benefit from treatment with anti-CD28/anti-CD22 bispecific antigen-binding molecules or method of the disclosure. This includes chronic and acute disorders including those pathological conditions which predispose the mammal to the disorder in question. In one embodiment, the cell proliferative disorder is cancer, the physiological condition in mammals that is typically characterized by unregulated cell growth/proliferation.

[0099] “Tumor,” as used herein, refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” “cell proliferative disorder,” “proliferative disorder” and “tumor” are not mutually exclusive as referred to herein.

[0100] A “B-cell proliferative disorder” includes Hodgkin’s lymphoma, non-Hodgkin’s lymphoma (NHL), such as aggressive NHL, relapsed aggressive NHL, low grade/follicular NHL, small lymphocytic (SL) NHL, intermediate grade/follicular NHL, intermediate grade diffuse NHL, high grade immunoblastic NHL, high grade lymphoblastic NHL, high grade small non-cleaved cell NHL, bulky disease NHL, indolent NHL including relapsed indolent NHL and rituximab-refractory indolent NHL; refractory NHL, refractory indolent NHL, mantle cell lymphoma, AIDS-related lymphoma, and Waldenstrom's Macroglobulinemia, lymphocyte predominant Hodgkin's disease (LPHD), small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL); leukemia, including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hairy cell leukemia, chronic myeloblastic leukemia; and other hematologic malignancies.

[0101] The term “non-Hodgkin's lymphoma” or “NHL”, as used herein, refers to a cancer of the lymphatic system other than Hodgkin's lymphomas. Hodgkin's lymphomas can generally be distinguished from non-Hodgkin's lymphomas by the presence of Reed- Sternberg cells in Hodgkin's lymphomas and the absence of said cells in non-Hodgkin's lymphomas. Examples of non-Hodgkin's lymphomas encompassed by the term as used herein include any that would be identified as such by one skilled in the art (e.g., an oncologist or pathologist) in accordance with classification schemes known in the art, such as the Revised European-American Lymphoma (REAL) scheme as described in Color Atlas of Clinical Hematology (3rd edition), A. Victor Hoffbrand and John E. Pettit (eds.) (Harcourt Publishers Ltd., 2000). See, in particular, the lists in FIGS. 11.57, 11.58 and 11.59. More specific examples include, but are not limited to, relapsed or refractory NHL, front line low grade NHL, Stage lll/IV NHL, chemotherapy resistant NHL, precursor B lymphoblastic leukemia and/or lymphoma, small lymphocytic lymphoma, B cell chronic lymphocytic leukemia and/or prolymphocytic leukemia and/or small lymphocytic lymphoma, B-cell prolymphocytic lymphoma, immunocytoma and/or lymphoplasmacytic lymphoma, lymphoplasmacytic lymphoma, marginal zone B cell lymphoma, splenic marginal zone lymphoma, extranodal marginal zone — MALT lymphoma, nodal marginal zone lymphoma, hairy cell leukemia, plasmacytoma and/or plasma cell myeloma, low grade/follicular lymphoma, intermediate grade/follicular NHL, mantle cell lymphoma, follicle center lymphoma (follicular), intermediate grade diffuse NHL, diffuse large B-cell lymphoma, aggressive NHL (including aggressive front-line NHL and aggressive relapsed NHL), NHL relapsing after or refractory to autologous stem cell transplantation, primary mediastinal large B-cell lymphoma, primary effusion lymphoma, high grade immunoblastic NHL, high grade lymphoblastic NHL, high grade small non-cleaved cell NHL, bulky disease NHL, Burkitt's lymphoma, precursor (peripheral) large granular lymphocytic leukemia, mycosis fungoides and/or Sezary syndrome, skin (cutaneous) lymphomas, anaplastic large cell lymphoma, angiocentric lymphoma.

[0102] As used herein, the expression "in combination with" means that a first therapeutic agent, e.g., a bispecific CD22xCD28 antibody or antigen-binding fragment thereof, is administered before, after, or concurrent with a second therapeutic agent, e.g., a bispecific CD3xCD20 antibody or antigen-binding fragment thereof. The term "in combination with" also includes sequential or concomitant administration of a first therapeutic agent, e.g., a bispecific CD22xCD28 antibody or antigen-binding fragment thereof and a second therapeutic agent, e.g., a bispecific CD3xCD20 antibody or antigenbinding fragment thereof.

Combination Therapies and Formulations

[0103] The present disclosure includes methods for treating, ameliorating or reducing the severity of at least one symptom or indication, or inhibiting the growth of a cancer in a subject, comprising administering to a subject in need thereof a therapeutic composition comprising a multispecific (e.g. bispecific) antigen binding molecule that specifically binds CD28 and CD22 in combination with a bispecific antibody that binds CD3 and CD20, e.g. odronextamab. The therapeutic composition can comprise any of the multispecific antibodies or bispecific antigen-binding molecules as disclosed herein and a pharmaceutically acceptable carrier or diluent. As used herein, the expression "a subject in need thereof" means a human or non-human animal that exhibits one or more symptoms or indicia of cancer (e.g., a subject expressing a tumor or suffering from any of the cancers mentioned herein below), or who otherwise would benefit from an inhibition or reduction in CD22 activity or a depletion of CD22+ cells.

[0104] The antibodies and bispecific antigen-binding molecules of the disclosure (and therapeutic compositions comprising the same) are useful, inter alia, for treating any disease or disorder in which stimulation, activation and/or targeting of an immune response would be beneficial. In particular, the anti-CD28/anti-CD22 bispecific antigen-binding molecules of the present disclosure may be used for the treatment, prevention and/or amelioration of any disease or disorder associated with or mediated by CD22 expression or activity or the proliferation of CD22+ cells. The mechanism of action by which the therapeutic methods of the disclosure are achieved include killing of the cells expressing CD22 in the presence of effector cells, for example, T cells. Cells expressing CD22 which can be inhibited or killed using the bispecific antigen-binding molecules of the disclosure include, for example, cancerous B cells.

[0105] The antigen-binding molecules of the present disclosure may be used to treat, e.g., primary and/or metastatic tumors arising in the blood, bone marrow, lymph nodes (e.g., thymus, spleen), colon, liver, lung, breast, renal cancer, central nervous system, and bladder cancer. According to certain exemplary embodiments, the bispecific antigen binding molecules of the present disclosure are used to treat a B cell proliferative disorder.

[0106] In some embodiments the B-cell proliferative disorder is a B-cell lymphoma, e.g., B-cell non-Hodgkin lymphoma (B-NHL). In some embodiments, the B-cell lymphoma is diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), high-grade B-cell lymphoma, Burkitt lymphoma, primary mediastinal large B-cell lymphoma, or follicular lymphoma.

[0107] The present disclosure also includes methods for treating residual cancer in a subject. As used herein, the term "residual cancer" means the existence or persistence of one or more cancerous cells in a subject following treatment with an anti-cancer therapy. [0108] According to certain aspects, the present disclosure provides methods for treating a disease or disorder associated with CD22 expression (e.g., a B cell proliferative disorder) comprising administering one or more of the bispecific antigen-binding molecules described elsewhere herein to a subject after the subject has been shown to be non- responsive to other types of anti-cancer therapies.

[0109] For example, the present disclosure includes methods for treating a B cell proliferative disorder comprising administering an anti-CD28/anti-CD22 bispecific antigenbinding molecule in combination with an anti-CD3/anti-CD20 bispecific antigen binding molecule to a subject 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks or 4 weeks, 2 months, 4 months, 6 months, 8 months, 1 year, or more after the subject has received the standard of care for subjects suffering from cancer, e.g., a B cell proliferative disorder, such as DLBCL.

[0110] In certain embodiments, the administration of bispecific CD22xCD28 antibody or antigen-binding fragment thereof, in combination with bispecific CD3xCD20 antibody or antigen-binding fragment thereof, leads to increased cancer regression, tumor shrinkage and/or disappearance. In certain embodiments, the administration of a bispecific CD22xCD28 or antigen-binding fragment thereof and a bispecific CD3xCD20 antibody or antigen-binding fragment thereof leads to delay in tumor growth and development, e.g., tumor growth may be delayed by about 3 days, more than 3 days, about 7 days, more than 7 days, more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 1 year, more than 2 years, or more than 3 years as compared to an untreated subject or a subject treated with either antibody as monotherapy. In certain embodiments, administration of a bispecific CD22xCD28 or antigen-binding fragment thereof and a bispecific CD3xCD20 antibody or antigen-binding fragment thereof prevents cancer recurrence and/or increases duration of survival of the subject, e.g., increases duration of survival by more than 15 days, more than 1 month, more than 3 months, more than 6 months, more than 12 months, more than 18 months, more than 24 months, more than 36 months, or more than 48 months than an untreated subject or a subject which is administered either antibody as monotherapy.

[0111] In certain embodiments, administration of a bispecific CD22xCD28 or antigenbinding fragment thereof and a bispecific CD3xCD20 antibody or antigen-binding fragment thereof increases response and duration of response in a subject, e.g., by more than 2%, more than 3%, more than 4%, more than 5%, more than 6%, more than 7%, more than 8%, more than 9%, more than 10%, more than 20%, more than 30%, more than 40% or more than 50% over an untreated subject or a subject which has received either antibody as monotherapy.

[0112] In certain embodiments, administration of a bispecific CD22xCD28 or antigenbinding fragment thereof and a bispecific CD3xCD20 antibody or antigen-binding fragment thereof to a subject with a cancer leads to at least 30% or more decrease in tumor cells or tumor size (“partial response”). In certain embodiments, administration of a bispecific CD22xCD28 or antigen-binding fragment thereof and a bispecific CD3xCD20 antibody or antigen-binding fragment to a subject with a cancer leads to complete disappearance of all evidence of tumor cells (“complete response”). In certain embodiments, administration of a bispecific CD22xCD28 or antigen-binding fragment thereof and a bispecific CD3xCD20 antibody or antigen-binding fragment to a subject with a cancer leads to complete or partial disappearance of tumor cells/lesions including new measurable lesions. Tumor reduction can be measured by any of the methods known in the art, e.g., X-rays, positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), cytology, histology, or molecular genetic analyses.

[0113] In certain embodiments, administration of a bispecific CD22xCD28 or antigenbinding fragment thereof and a bispecific CD3xCD20 antibody or antigen-binding fragment thereof to a subject with a cancer leads to a reduction in lymphoma lesion size or number. [0114] In certain embodiments, administration of a bispecific CD22xCD28 or antigenbinding fragment thereof and a bispecific CD3xCD20 antibody or antigen-binding fragment thereof increases progression-free survival or overall survival.

[0115] In certain embodiments, the methods of the present disclosure comprise administering to a subject in need thereof a therapeutically effective amount of a bispecific CD22xCD28 or antigen-binding fragment thereof in combination with a bispecific CD3xCD20 antibody or antigen-binding fragment, wherein administration of the combination leads to increased overall survival (OS) or progression-free survival (PFS) of the patient as compared to a patient administered with a standard-of-care (SOC) therapy (e.g., chemotherapy, surgery or radiation). In certain embodiments, the PFS is increased by at least one month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 1 year, at least 2 years, or at least 3 years as compared to a patient administered with any one or more SOC therapies. In certain embodiments, the OS is increased by at least one month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 1 year, at least 2 years, or at least 3 years as compared to a patient administered with any one or more SOC therapies.

(i) Dosages and Timing

[0116] An “effective” or “therapeutically effective” dose of a bispecific CD22xCD28 antibody or antigen-binding fragment thereof, e.g., REGN5837, or a bispecific CD3xCD20 antibody or antigen-binding fragment thereof , e.g., odronextamab, for treating or preventing a cancer, such as a CD22-expressing cancer, is the amount of the antibody or antigenbinding fragment sufficient to alleviate one or more signs and/or symptoms of the disease in the treated subject, whether by inducing the regression or elimination of such signs and/or symptoms or by inhibiting the progression of such signs and/or symptoms.

[0117] The dose of antigen-binding molecule administered to a subject may vary depending upon the age and the size of the subject, target disease, conditions, route of administration, and the like. The preferred dose is typically calculated according to body weight or body surface area. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted.

[0118] In one embodiment, the antigen-binding molecule (e.g., a bispecific antigenbinding molecule that specifically binds CD22 and CD28) is administered to a subject as a weight-based dose. A "weight-based dose" (e.g., a dose in mg/kg) is a dose of the antibody or the antigen-binding fragment thereof or the bispecific antigen-binding molecule that will change depending on the subject's weight.

[0119] In another embodiment, an antibody or the antigen-binding fragment thereof or a bispecific antigen-binding molecule is administered to a subject as a fixed dose. A "fixed dose" (e.g., a dose in mg) means that one dose of the antibody or the antigen-binding fragment thereof or the bispecific antigen-binding molecule is used for all subjects regardless of any specific subject-related factors, such as weight. In one particular embodiment, a fixed dose of an antibody or the antigen-binding fragment thereof or a bispecific antigen-binding molecule of the disclosure is based on a predetermined weight or age.

[0120] In general, a suitable dose of the antigen binding molecule of the disclosure can be in the range of about 0.001 to about 200.0 milligram per kilogram body weight of the recipient, generally in the range of about 1 to 50 mg per kilogram body weight. For example, the antibody or the antigen-binding fragment thereof or the bispecific antigen-binding molecule can be administered at about 0.1 mg/kg, about 0.2 mg/kg, about 0.5 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 3 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 40 mg/kg, about 50 mg/kg per single dose. Values and ranges intermediate to the recited values are also intended to be part of this disclosure. [0121]

[0122] In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is administered at a dose of about 0.01 mg to about 400 mg. In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is administered at a dose of about 0.01 mg, 0.03 mg, 0.05 mg, 0.1 mg, 0.3 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 200 mg, 240 mg, 280 mg, 300 mg, 320 mg, 350 mg, or 400 mg.

[0123] In some embodiments, the bispecific CD22xCD28 antibody is administered intravenously (IV). In some embodiments, the IV infusion occurs over about 1 hour, 2 hours,

3 hours, or 4 hours. In some embodiments, the bispecific CD22xCD28 antibody is administered subcutaneously.

[0124] In some embodiments of the disclosure, a therapeutically effective dose of a bispecific CD22xCD28 antibody, e.g., REGN5837, is 0.01-400 mg IV or SC every week, every two weeks, or every four weeks.

[0125] In some embodiments, the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered at a dose of about 0.1 mg to about 400 mg. In some embodiments, the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered at a dose of about 0.1 mg, 0.2 mg, 0.3 mg, 0.5 mg, 0.7 mg, 1 mg, 2 mg, 3 mg,

4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 200 mg, 240 mg, 280 mg, 300 mg, 320 mg, 350 mg, or 400 mg.

[0126] In some embodiments, the bispecific CD3xCD20 antibody is administered intravenously (IV). In some embodiments, the IV infusion occurs over about 1 hour, 2 hours, 3 hours, or 4 hours. In some embodiments, the bispecific CD3xCD20 antibody is administered subcutaneously.

[0127] In some embodiments of the disclosure, a therapeutically effective dose of a bispecific CD3xCD20 antibody, e.g., odronextamab, is 0.1-320 mg IV or SC every week, every two weeks, or every four weeks.

[0128] In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding molecule is administered concurrently with the bispecific CD3xCD20 antibody or antigenbinding portion thereof. In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding molecule is administered the same day as the bispecific CD3xCD20 antibody or antigen-binding portion thereof. In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding molecule is administered prior to administration the bispecific CD3xCD20 antibody or antigen-binding portion thereof, e.g., 1 hour prior, 2 hours prior, 3 hours prior, 4 hours prior, 5 hours prior, 6 hours prior, 12 hours prior, 1 day prior, 2 days prior, 3 days prior, 4 days prior, 5 days prior, 6 days prior, 7 days prior, 8 days prior, 9 days prior, 10 days prior, 11 days prior, 12 days prior, 13 days prior, 14 days prior, 15 days prior, 16 days prior, 17 days prior, 18 days prior, 19 days prior, 20 days prior, or 21 days prior. In some embodiments, the bispecific CD3xCD20 antibody or antigen-binding molecule is administered prior to administration the bispecific CD22xCD28 antibody or antigen-binding portion thereof, e.g., 1 hour prior, 2 hours prior, 3 hours prior, 4 hours prior, 5 hours prior, 6 hours prior, 12 hours prior, 1 day prior, 2 days prior, 3 days prior, 4 days prior, 5 days prior, 6 days prior, 7 days prior, 8 days prior, 9 days prior, 10 days prior, 11 days prior, 12 days prior, 13 days prior, 14 days prior, 15 days prior, 16 days prior, 17 days prior, 18 days prior, 19 days prior, 20 days prior, or 21 days prior.

[0129] According to certain embodiments of the present disclosure, multiple doses of an antigen-binding molecule (e.g., a bispecific antigen-binding molecule that specifically binds CD22 and CD28) may be administered to a subject over a defined time course. The methods according to this aspect of the disclosure comprise sequentially administering to a subject multiple doses of an antigen-binding molecule of the disclosure. As used herein, "sequentially administering" means that each dose of an antigen-binding molecule is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present disclosure includes methods which comprise sequentially administering to the subject a single initial dose of an antigen-binding molecule, followed by one or more secondary doses of the antigen-binding molecule, and optionally followed by one or more tertiary doses of the antigen-binding molecule.

[0130] The terms "initial dose," "secondary doses," and "tertiary doses," refer to the temporal sequence of administration of the antigen-binding molecule of the disclosure. Thus, the "initial dose" is the dose which is administered at the beginning of the treatment regimen (also referred to as the "baseline dose"); the "secondary doses" (also called “intermediate doses”) are the doses which are administered after the initial dose; and the "tertiary doses" are the doses which are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of the antigen-binding molecule, but generally may differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of an antigen-binding molecule contained in the initial, secondary and/or tertiary doses varies from one another (e.g., adjusted up or down as appropriate) during the course of treatment. In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as "loading doses" followed by subsequent doses that are administered on a less frequent basis (e.g., "maintenance doses"). [0131] In one exemplary embodiment of the present disclosure, each secondary and/or tertiary dose is administered 1 to 26 (e.g., 1 , 114, 2, 214, 3, 314, 4, 414, 5, 514, 6, 614, 7, 714, 8, 8¹/₂, 9, 9¹/₂, 10, 10¹/₂, 11 , 1134, 12, 12¹/₂, 13, 13¹/₂, 14, 14¹/₂, 15, 15¹/₂, 16, 16¹/₂, 17, 17¹/₂, 18, 1814, 19, 1914, 20, 2014, 21 , 21¹/₂, 22, 22¹/₂, 23, 23¹/₂, 24, 24¹/₂, 25, 25¹/₂, 26, 26¹/₂, or more) weeks after the immediately preceding dose. The phrase "the immediately preceding dose," as used herein, means, in a sequence of multiple administrations, the dose of antigenbinding molecule which is administered to a subject prior to the administration of the very next dose in the sequence with no intervening doses.

[0132] The methods according to this aspect of the disclosure may comprise administering to a subject any number of secondary and/or tertiary doses of an antigenbinding molecule (e.g., an anti-CD28 antibody or a bispecific antigen-binding molecule that specifically binds CD22 and CD28). For example, in certain embodiments, only a single secondary dose is administered to the subject. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the subject. Likewise, in certain embodiments, only a single tertiary dose is administered to the subject. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the subject.

[0133] In embodiments involving multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the subject 1 to 2 weeks after the immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the subject 2 to 4 weeks after the immediately preceding dose. Alternatively, the frequency at which the secondary and/or tertiary doses are administered to a subject can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual subject following clinical examination. [0134] In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered at a small initial dose to observe subject’s tolerability to the antibody, and the amount of the antibody in one or more subsequent doses are increased up to the therapeutically effective dose as the subject tolerates the administration.

[0135] In some embodiment, a dose of the bispecific CD22xCD28 antibody or antigenbinding fragment thereof and/or the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered in a single administration. In some other embodiments, a dose of the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is split and administered in two or more days. In some embodiments, the split doses are administered in two different days no more than 3 days apart.

[0136] In some embodiments, the method of treatment comprises the steps of (i) administering to the subject the bispecific CD3xCD20 antibody or antigen-binding fragment thereof at a dose of 0.1 mg to 160 mg subcutaneously or intravenously every week for a period of monotherapy, wherein the period of monotherapy is at least 2 weeks; and (ii) administering to the subject the bispecific CD22xCD28 antibody or antigen-binding fragment thereof at a dose of 0.01 mg to 400 mg subcutaneously or intravenously every week, and administering to the subject the bispecific CD3xCD20 or antigen-binding fragment thereof at a dose of 80 mg to 160 mg intravenously or subcutaneously every week for a period of induction combination therapy.

[0137] In some embodiments, the period of monotherapy is at least 2 weeks, at least 3 weeks, at least 4 weeks, or at least 5 weeks.

[0138] In some embodiments, the monotherapy period in step (i) comprises increasing the dose of the bispecific CD3xCD20 from a small initial dose to a therapeutically effective dose by the end of the monotherapy period.

[0139] In some embodiments, the therapeutically effective dose of the bispecific CD3xCD20 in step (i) is 80 or 160 mg.

[0140] In some embodiments, the induction combination therapy period in step (ii) comprises increasing the dose of the bispecific CD22xCD28 from a small initial dose to a therapeutically effective dose.

[0141] In some embodiments, during step (ii), the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered on a different day (e.g., one day after) as the bispecific CD22xCD28 antibody or antigen-binding fragment thereof.

[0142] In some embodiments, during step (ii), the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered on the same day as the bispecific CD22xCD28 antibody or antigen-binding fragment thereof.

[0143] In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is administered in combination with the bispecific CD3xCD20 or antigenbinding fragment thereof in step (ii) for at least 9 weeks (e.g., at least at least 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks or 15 weeks).

[0144] In some embodiments, the method further comprises (iii) administering the bispecific CD22xCD28 antibody or antigen-binding fragment thereof in combination with 180 mg or 320 mg of the bispecific CD3xCD20 or antigen-binding fragment thereof after step (ii) every two or more weeks for a period of maintenance combination therapy.

[0145] In some embodiments, wherein in step (iii), the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and the bispecific CD3xCD20 or antigen-binding fragment are administered on the same day. In some embodiments, the bispecific the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and the bispecific CD3xCD20 or antigen-binding fragment are administered every two weeks or every four weeks.

(ii) Routes of Administration

[0146] The present disclosure provides methods for administering a bispecific CD22xCD28 antibody, e.g., REGN5837, or antigen-binding fragment thereof; or any combination of anti-CD22 HCVR pairing with an HCVR from any of the CD28 antibodies described herein, or a pharmaceutical composition thereof, alone or in combination with a bispecific CD3xCD20 antibody, e.g., odronextamab, or antigen-binding fragment thereof to a subject (e.g., a human for example, who suffers from a cancer), comprising introducing the antigen-binding protein or pharmaceutical composition into the body of the subject (e.g., a human), for example, intravenously or subcutaneously. For example, the method comprises piercing the body of the subject with a needle of a syringe and injecting the antigen-binding protein or pharmaceutical composition into the body of the subject, e.g., into the vein, artery, skin, tumor, muscular tissue or subcutis of the subject.

[0147] The mode of administration of an antibody or a pharmaceutical composition thereof can vary. Routes of administration include parenteral, non-parenteral, oral, rectal, transmucosal, intestinal, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, cutaneous, intraocular, intravitreal, transdermal or intra-arterial.

[0148] In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding portion thereof is administered intravenously, and the bispecific CD3xCD20 antibody or antigen-binding portion thereof is administered subcutaneously. In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding portion thereof is administered subcutaneously, and the CD3xCD20 antibody or antigen-binding portion thereof is administered intravenously. In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding portion thereof is administered intravenously, and the bispecific CD3xCD20 antibody or antigen-binding portion thereof is administered intravenously. In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding portion thereof is administered subcutaneously, and the bispecific CD3xCD20 or antigen-binding portion thereof is administered subcutaneously.

[0149] In some further embodiments, the bispecific CD22xCD28 antibody or antigenbinding fragment thereof and/or the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered into the body of the subject over about 10-300, 20-240, 30- 180, 45-150, or 60-120 minutes. In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the bispecific CD3xCD20 antibody or antigenbinding fragment thereof is administered into the body of the subject over about 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 120, 150, 180, 210, 240, 270, or 300 minutes.

[0150] In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered into the body of the subject over about 1 hour. In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered into the body of the subject over about 2 hours. In some embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered into the body of the subject over about 4 hours.

[0151] The present disclosure also provides a vessel (e.g., a plastic or glass vial or ampule, e.g., with a cap or a chromatography column, hollow bore needle or a syringe cylinder) comprising a bispecific CD22xCD28 antigen-binding protein of the present disclosure or a pharmaceutical composition thereof.

[0152] The present disclosure also provides an injection device comprising one or more antigen-binding proteins e.g., antibody or antigen-binding fragment) that bind specifically to CD22 and CD28 (CD22xCD28) or a pharmaceutical formulation thereof. The injection device may be packaged into a kit. An injection device is a device that introduces a substance into the body of a subject via a parenteral route, e.g., intramuscular, subcutaneous or intravenous. For example, an injection device may be a syringe or an autoinjector (e.g., pre-filled with the pharmaceutical formulation) which, for example, includes a cylinder or barrel for holding fluid to be injected (e.g., comprising the antibody or fragment or a pharmaceutical formulation thereof), a needle for piecing skin, blood vessels or other tissue for injection of the fluid; and a plunger for pushing the fluid out of the cylinder and through the needle bore and into the body of the subject.

[0153] A pre-filled syringe is a syringe which has been filled with a composition (e.g. a pharmaceutical composition comprising a multispecific antigen-binding protein and a pharmaceutically acceptable carrier) prior to sale or transfer to an end-user, e.g., a physician or care-giver, who is to administer the composition to a subject.

[0154] Pharmaceutical compositions are described in more detail below.

(iii) Subject Selection [0155] In some embodiments, the methods described herein further comprise one or more steps of selecting a subject. The patient may be selected, e.g., based on inclusion criteria, or may be excluded, e.g., based on exclusion criteria. Inclusion and exclusion criteria are described in more detail in Example 2, below.

[0156] In some embodiments, the method comprises selecting a subject with a disease or disorder related to CD22 expression.

[0157] In some embodiments, the method comprises selecting a subject with a B-cell proliferative disorder.

[0158] In some embodiments, the method comprises selecting a subject that has lymphoma. In some embodiments, the method comprises selecting a subject that as B-cell non-Hodgkin lymphoma (B-NHL).

[0159] In some embodiments, the subject has an aggressive B- NHL. In some embodiments, the aggressive B-NHL is selected from the group consisting of DLBCL, primary mediastinal (thymic) large B-cell lymphoma, T cell/histiocyte rich large B-cell lymphoma, follicular lymphoma grade 3b, and high grade B-cell lymphoma (HGBL) with and without MYC and BCL2 or BCL6 translocations.

[0160] In some embodiments, the subject has at least one of the following criteria, or is selected on the basis of at least one of the following criteria: (i) has CD20+ aggressive B- NHL; (ii) has progressed after at least 2 lines of systemic therapy containing an anti-CD20 antibody and an alkylating agent; (iii) has measurable disease on cross sectional imaging; (iv) has adequate bone marrow function and hepatic function; and/or (v) has any of the following cancer types: DLBCL, primary mediastinal (thymic) large B-cell lymphoma, T- cell/histiocyte rich large B-cell lymphoma, follicular lymphoma grade 3b, and high-grade B- cell lymphoma (HGBL).

[0161] In some embodiments, the subject has been treated with a prior therapy and relapsed or the disorder progressed during or after the prior treatment.

[0162] In some embodiments, the subject has received a CAR-T therapy.

(iv) Adverse Events

[0163] As used herein, “adverse event” is any unfavorable and unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally associated with the use of a study drug, whether or not considered related to the study drug.

[0164] In some embodiments, the subject develops one or more mild symptoms of an adverse event after administration of the bispecific CD22xCD28 antibody, alone or in combination with the bispecific CD3xCD20 antibody. In some embodiments, the one or more symptoms of an adverse event is a symptom of infusion reactions (IR) or cytokine release syndrome (CRS), or a combination thereof. [0165] In some embodiments, the symptom of infusion reactions is selected from the group consisting of sustained/severe cough, persistent rigors/chills, rash, pruritus (itching), urticaria (hives, welts, wheals), diaphoresis (sweating), hypotension, dyspnea (shortness of breath), vomiting, and flushing.

[0166] In some embodiments, the symptom of cytokine release syndrome is selected from the group consisting of fever, tachypnea, headache, tachycardia, hypotension, rash, and/or hypoxia

[0167] In some embodiments, the subject receives one or more additional treatments to treat the one or more symptoms of an adverse event.

[0168] In some embodiments, treatment with the bispecific CD22xCD28 antibody, alone or in combination with the bispecific CD3xCD20 antibody, is paused when the subject develops one or more mild symptoms of an adverse event and resumed when the one or more symptoms resolve.

Multispecific CD22xCD28 Antigen-Binding Molecules

[0169] The present disclosure provides methods of use of antigen-binding proteins which are multispecific (e.g., bispecific) and bind at least to CD28 and CD22 for treating cancer, in combination with an bispecific anti-CD3 and anti-CD20 antibody or antigenbinding fragment thereof, e.g., odronextamab.

[0170] Multispecific binding refers to binding to two or more different epitopes (CD22 and CD28 or more) which may be on the same or on different antigens. Multispecific includes bispecific, trispecific and tetraspecific. An antibody or fragment thereof can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment to produce a bi-specific or a multispecific antibody with a second binding specificity.

[0171] In certain embodiments, the multispecific antigen-binding proteins comprise bispecific antigen-binding proteins. As used herein, the expression "bispecific antigenbinding protein" means a protein, polypeptide or molecular complex (e.g., antibody or antigen-binding fragment thereof) comprising at least a first antigen-binding domain and a second antigen-binding domain. Each antigen-binding domain within the bispecific antigenbinding molecule comprises at least one CDR that alone, or in combination with one or more additional CDRs and/or FRs, specifically binds to a particular antigen. In the context of the present disclosure, the first antigen-binding domain specifically binds CD28, and the second antigen-binding domain specifically binds a CD22.

[0172] According to certain exemplary embodiments, the present disclosure includes bispecific antigen-binding molecules that specifically bind CD28 and CD22. Such molecules may be referred to herein as, e.g., "anti-CD28/anti-CD22," or "anti-CD28xCD22," or "CD28xCD22" or “anti-CD22/anti-CD28,” or “anti-CD22xCD28,” or “CD22xCD28” bispecific molecules, or “aCD22 x aCD28”, or “aCD28 x aCD22”, or other similar terminology.

[0173] According to certain exemplary embodiments, the bispecific antigen-binding molecules (e.g., bispecific antibody) may have an effector arm and a targeting arm. The effector arm may be the first antigen-binding domain (e.g., anti-CD28 antibody) that binds to the antigens on effector cells (e.g., T cells). The targeting arm may be the second antigen binding domain (e.g., anti-CD22 antibody) that binds to the antigens on target cells (e.g., tumor cells). According to certain exemplary embodiments, the effector arm binds to CD28 and the targeting arm binds to CD22. The bispecific anti-CD28/CD22 may provide costimulatory signal to effector cells (e.g., T cells). The effector arm has no effect to stimulate T cells without clustering. The effector arm alone has little effect to stimulate T cells unless in combination with the targeting arm. The tumor targeting arm may have imperfect tumor specificity. The antigen that is the target of the targeting arm (e.g., CD22) may be expressed on a fraction of tumor cells. The specificity of the tumor targeting arm may be increased by overlapping with combination with anti-CD3 bispecific antigen-binding molecules (e.g., anti- CD3/CD20 bispecific antibody).

[0174] As used herein, the expression "antigen-binding molecule" means a protein, polypeptide or molecular complex comprising or consisting of at least one complementarity determining region (CDR) that alone, or in combination with one or more additional CDRs and/or framework regions (FRs), specifically binds to a particular antigen. In certain embodiments, an antigen-binding molecule is an antibody or a fragment of an antibody, as those terms are defined elsewhere herein.

[0175] As used herein, the expression "bispecific antigen-binding molecule" means a protein, polypeptide or molecular complex comprising at least a first antigen-binding domain and a second antigen-binding domain. Each antigen-binding domain within the bispecific antigen-binding molecule comprises at least one CDR that alone, or in combination with one or more additional CDRs and/or FRs, specifically binds to a particular antigen. In the context of the present disclosure, the first antigen-binding domain specifically binds a first antigen (e.g., CD28), and the second antigen-binding domain specifically binds a second, distinct antigen (e.g., CD22).

[0176] In certain exemplary embodiments of the present disclosure, the bispecific antigen-binding molecule is a bispecific antibody. Each antigen-binding domain of a bispecific antibody comprises a heavy chain variable domain (HCVR) and a light chain variable domain (LCVR). In the context of a bispecific antigen-binding molecule comprising a first and a second antigen binding domain (e.g., a bispecific antibody), the CDRs of the first antigen-binding domain may be designated with the prefix "D1" and the CDRs of the second antigen-binding domain may be designated with the prefix "D2". Thus, the CDRs of the first antigen-binding domain may be referred to herein as D1-HCDR1, D1-HCDR2, and D1- HCDR3; and the CDRs of the second antigen-binding domain may be referred to herein as D2-HCDR1, D2-HCDR2, and D2-HCDR3.

[0177] The first antigen-binding domain and the second antigen-binding domain may be directly or indirectly connected to one another to form a bispecific antigen-binding molecule of the present disclosure. Alternatively, the first antigen-binding domain and the second antigen binding domain may each be connected to a separate multimerizing domain. The association of one multimerizing domain with another multimerizing domain facilitates the association between the two antigen-binding domains, thereby forming a bispecific antigenbinding molecule. As used herein, a "multimerizing domain" is any macromolecule, protein, polypeptide, peptide, or amino acid that has the ability to associate with a second multimerizing domain of the same or similar structure or constitution. For example, a multimerizing domain may be a polypeptide comprising an immunoglobulin CH3 domain. A non-limiting example of a multimerizing component is an Fc portion of an immunoglobulin (comprising a CH2-CH3 domain), e.g., an Fc domain of an IgG selected from the isotypes lgG1, lgG2, lgG3, and lgG4, as well as any allotype within each isotype group.

[0178] Bispecific antigen-binding molecules of the present disclosure will typically comprise two multimerizing domains, e.g., two Fc domains that are each individually part of a separate antibody heavy chain. The first and second multimerizing domains may be of the same IgG isotype such as, e.g., lgG1/lgG1, lgG2/lgG2, lgG4/lgG4. Alternatively, the first and second multimerizing domains may be of different IgG isotypes such as, e.g., lgG1/lgG2, lgG1/lgG4, lgG2/lgG4, etc.

[0179] In certain embodiments, the multimerizing domain is an Fc fragment or an amino acid sequence of 1 to about 200 amino acids in length containing at least one cysteine residue. In other embodiments, the multimerizing domain is a cysteine residue, or a short cysteine containing peptide. Other multimerizing domains include peptides or polypeptides comprising or consisting of a leucine zipper, a helix-loop motif, or a coiled-coil motif.

[0180] Any bispecific antibody format or technology may be used to make the bispecific antigen-binding molecules of the present disclosure. For example, an antibody or fragment thereof having a first antigen binding specificity can be functionally linked (e.g., by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody or antibody fragment having a second antigenbinding specificity to produce a bispecific antigen-binding molecule. Specific exemplary bispecific formats that can be used in the context of the present disclosure include, without limitation, e.g., scFv-based or diabody bispecific formats, IgG-scFv fusions, dual variable domain (OVO)-lg, Quadroma, knobs-into-holes, common light chain (e.g., common light chain with knobs-intoholes, etc.), CrossMab, CrossFab, (SEEO)body, leucine zipper, Duobody, lgG1/lgG2, dual acting Fab (OAF)-lgG, and Mab2 bispecific formats (see, e.g., Klein et al. 2012, mAbs 4:6, 1-11, and references cited therein, for a review of the foregoing formats).

[0181] In the context of bispecific antigen-binding molecules of the present disclosure, the multimerizing domains, e.g., Fc domains, may comprise one or more amino acid changes (e.g., insertions, deletions or substitutions) as compared to the wild-type, naturally occurring version of the Fc domain. For example, the disclosure includes bispecific antigenbinding molecules comprising one or more modifications in the Fc domain that results in a modified Fc domain having a modified binding interaction (e.g., enhanced or diminished) between Fc and FcRn. In one embodiment, the bispecific antigen-binding molecule comprises a modification in a CH2 or a CH3 region, wherein the modification increases the affinity of the Fc domain to FcRn in an acidic environment (e.g., in an endosome where pH ranges from about 5.5 to about 6.0). Non-limiting examples of such Fc modifications include, e.g., a modification at position 250 (e.g., E or Q); 250 and 428 (e.g., L or F); 252 (e.g., LN/FIW or T), 254 (e.g., S or T), and 256 (e.g., S/R/Q/EID or T); or a modification at position 428 and/or 433 (e.g., UR/S/P/Q or K) and/or 434 (e.g., H/F or V); or a modification at position 250 and/or 428; or a modification at position 307 or 308 (e.g., 308F, V308F), and 434. In one embodiment, the modification comprises a 428L (e.g., M428L) and 434S (e.g., N434S) modification; a 428L, 2591 (e.g., V2591), and 308F (e.g., V308F) modification; a 433K (e.g., H433K) and a 434 (e.g., 434Y) modification; a 252,254, and 256 (e.g., 252Y, 254T, and 256E) modification; a 250Q and 428L modification (e.g., T250Q and M428L); and a 307 and/or 308 modification (e.g., 308F or 308P).

[0182] The present disclosure also includes bispecific antigen-binding molecules comprising a first CH3 domain and a second Ig CH3 domain, wherein the first and second Ig CH3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bispecific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference. In one embodiment, the first Ig CH3 domain binds Protein A and the second Ig CH3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by Ell numbering). The second CH3 may further comprise a Y96F modification (by IMGT; Y436F by Ell). Further modifications that may be found within the second CH3 include: D16E, L 18M, N44S, K52N, V57M, and V821 (by IMGT; D356E, L358M, N384S, K392N, V397M, and V4221 by EU) in the case of lgG1 antibodies; N44S, K52N, and V821 (IMGT; N384S, K392N, and V4221 by EU) in the case of lgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V821 (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V4221 by EU) in the case of lgG4 antibodies. [0183] In certain embodiments, the Fc domain may be chimeric, combining Fc sequences derived from more than one immunoglobulin isotype. For example, a chimeric Fc domain can comprise part or all of a CH2 sequence derived from a human lgG1 , human lgG2 or human lgG4 CH2 region, and part or all of a CH3 sequence derived from a human lgG1, human lgG2 or human lgG4. A chimeric Fc domain can also contain a chimeric hinge region. For example, a chimeric hinge may comprise an "upper hinge" sequence, derived from a human lgG1, a human lgG2 or a human lgG4 hinge region, combined with a "lower hinge" sequence, derived from a human lgG1 , a human lgG2 or a human lgG4 hinge region. A particular example of a chimeric Fc domain that can be included in any of the antigenbinding molecules set forth herein comprises, from N- to C-terminus: [lgG4 CH1] - [lgG4 upper hinge] - [lgG2 lower hinge] - [lgG4 CH2] - [lgG4 CH3], Another example of a chimeric Fc domain that can be included in any of the antigen-binding molecules set forth herein comprises, from N- to C-terminus: [lgG1 CH1] - [lgG1 upper hinge] - [lgG2 lower hinge] - [lgG4 CH2] - [IgG 1 CH3], These and other examples of chimeric Fc domains that can be included in any of the antigen-binding molecules of the present disclosure are described in W02014/022540A1 , the entire contents of which are incorporated herein by reference. Chimeric Fc domains having these general structural arrangements, and variants thereof, can have altered Fc receptor binding, which in turn affects Fc effector function.

[0184] According to certain exemplary embodiments of the present disclosure, the bispecific CD22xCD28 antibody, or antigen-binding fragment thereof comprises heavy chain variable regions, light chain variable regions, and/or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the bispecific CD22xCD28 antibodies as set forth in US Patent Publication No. 11,396,544. In certain exemplary embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof that can be used in the context of the methods of the present disclosure comprises: (a) a first antigen-binding arm that binds to CD28, comprising the heavy chain complementarity determining regions (CD28-HCDR1, CD28-HCDR2 and CD28-HCDR3) of a heavy chain variable region (CD28-HCVR) comprising the amino acid sequence of SEQ ID NO: 20 and the light chain complementarity determining regions (CD28-LCDR1, CD28-LCDR2 and CD28-LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 21; and (b) a second antigen-binding arm that binds to CD22, comprising the heavy chain CDRs (CD22-HCDR1 , CD22-HCDR2 and CD22-HCDR3) of a HCVR (CD22- HCVR) comprising an amino acid sequence of SEQ ID NO: 19, and the light chain CDRs (CD22-LCDR1 , CD22-LCDR2 and CD22-LCDR3) of a LCVR (CD22-LCVR) comprising the amino acid sequence of SEQ ID NO: 21.

[0185] According to certain embodiments, the CD28-HCDR1 comprises the amino acid sequence of SEQ ID NO: 25; the CD28-HCDR2 comprises the amino acid sequence of SEQ ID NO: 26; the CD28-HCDR3 comprises the amino acid sequence of SEQ ID NO: 27; the CD28-LCDR1 comprises the amino acid sequence of SEQ ID NO: 28; the CD28-LCDR2 comprises the amino acid sequence of SEQ ID NO: 29; the CD28-LCDR3 comprises the amino acid sequence of SEQ ID NO: 30; the CD22-HCDR1 comprises the amino acid sequence of SEQ ID NO: 22, the CD28-HCDR2 comprises the amino acid sequence of SEQ ID NO: 23, and the CD28-HCDR3 comprises the amino acid sequence of SEQ ID NO: 24, and the CD22-LCDR1 comprises the amino acid sequence of SEQ ID NO: 28; the CD22- LCDR2 comprises the amino acid sequence of SEQ ID NO: 29; the CD22-LCDR3 comprises the amino acid sequence of SEQ ID NO: 30.

[0186] In yet other embodiments, the bispecific CD22xCD28 antibody or antigen-binding fragment thereof comprises: (a) a first antigen-binding arm comprising a HCVR (CD28- HCVR) comprising SEQ ID NO: 20 and a LCVR (CD28-LCVR) comprising SEQ ID NO: 21; and (b) a second antigen-binding arm comprising a HCVR (CD22-HCVR) comprising SEQ ID NO: 19, and a LCVR (CD22-LCVR) comprising SEQ ID NO: 21.

[0187] In certain exemplary embodiments, the bispecific CD22xCD28 antibody comprises a CD28-binding arm comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and a light chain comprising the amino acid sequence of SEQ ID NO: 18, and a CD22-binding arm comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 16 and a light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0188] An exemplary CD22xCD28 bispecific antibody used in the methods of the present disclosure that comprises a HCVR of the CD28 binding arm comprising the amino acid sequence of SEQ ID NO: 20, a HCVR of the CD22 binding arm comprising the amino acid sequence of SEQ ID NO: 19 and a common LCVR comprising the amino acid sequence of SEQ ID NO: 21. In one embodiment, the CD22xCD28 bispecific antibody is REGN5837, or an antigen-binding fragment thereof.

(i) Sequence Variants

[0189] The antibodies and bispecific antigen-binding molecules of the present disclosure may comprise one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences from which the individual antigen-binding domains were derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germ line sequences available from, for example, public antibody sequence databases. The antigen-binding molecules of the present disclosure may comprise antigen binding fragments which are derived from any of the exemplary amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as "germline mutations"). A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments which comprise one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and/or CDR residues within the VH and/or VL domains are mutated back to the residues found in the original germline sequence from which the antigen-binding domain was originally derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 or CDR3. In other embodiments, one or more of the framework and/or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (/.e., a germline sequence that is different from the germ line sequence from which the antigen-binding domain was originally derived). Furthermore, the antigen-binding domains may contain any combination of two or more germline mutations within the framework and/or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a particular germ line sequence while certain other residues that differ from the original germ line sequence are maintained or are mutated to the corresponding residue of a different germline sequence. Once obtained, antigen-binding domains that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Bispecific antigen-binding molecules comprising one or more antigenbinding domains obtained in this general manner are encompassed within the present disclosure.

[0190] The present disclosure also includes antigen-binding molecules wherein one or both antigen-binding domains comprise variants of any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the present disclosure includes antigen-binding molecules comprising an antigenbinding domain having HCVR, LCVR, and/or CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein. A "conservative amino acid substitution" is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. Examples of groups of amino acids that have side chains with similar chemical properties include (1) aliphatic side chains: glycine, alanine, valine, leucine and isoleucine; (2) aliphatic-hydroxyl side chains: serine and threonine; (3) amide-containing side chains: asparagine and glutamine; (4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; (5) basic side chains: lysine, arginine, and histidine; (6) acidic side chains: aspartate and glutamate, and (7) sulfur-containing side chains are cysteine and methionine. Preferred conservative amino acids substitution groups are: valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine, alanine-valine, glutamate-aspartate, and asparagine-glutamine. Alternatively, a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al. (1992) Science 256: 1443-1445. A "moderately conservative" replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.

[0191] The present disclosure also includes antigen-binding molecules comprising an antigen binding domain with an HCVR, LCVR, and/or CDR amino acid sequence that is substantially identical to any of the HCVR, LCVR, and/or CDR amino acid sequences disclosed herein. The term "substantial identity" or "substantially identical," when referring to an amino acid sequence means that two amino acid sequences, when optimally aligned, such as by the programs GAP or BESTFIT using default gap weights, share at least 95% sequence identity, even more preferably at least 98% or 99% sequence identity. Preferably, residue positions which are not identical differ by conservative amino acid substitutions. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well-known to those of skill in the art. See, e.g., Pearson (1994) Methods Mol. Biol. 24: 307-331.

[0192] Sequence similarity for polypeptides, which is also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For instance, GOG software contains programs such as Gap and Bestfit which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof. See, e.g., GOG Version 6.1. Polypeptide sequences also can be compared using FASTA using default or recommended parameters, a program in GOG Version 6.1. FASTA (e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (2000) supra). Another preferred algorithm when comparing a sequence of the disclosure to a database containing a large number of sequences from different organisms is the computer program BLAST, especially BLASTP or TBLASTN, using default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215:403- 410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389-402.

(ii) pH-Dependent Binding

[0193] The present disclosure includes anti-CD28/anti-CD22 bispecific antigen-binding molecules, with pH-dependent binding characteristics. For example, an anti-CD28 antibody of the present disclosure may exhibit reduced binding to CD28 at acidic pH as compared to neutral pH. Alternatively, anti-CD22 antibodies of the disclosure may exhibit enhanced binding to CD22 at acidic pH as compared to neutral pH. The expression "acidic pH" includes pH values less than about 6.2, e.g., about 6.0, 5.95, 5.9, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3, 5.25, 5.2, 5.15, 5.1, 5.05, 5.0, or less. As used herein, the expression "neutral pH" means a pH of about 7.0 to about 7.4. The expression "neutral pH" includes pH values of about 7.0, 7.05, 7.1, 7.15, 7.2, 7.25, 7.3, 7.35, and 7.4.

[0194] In certain instances, "reduced binding ... at acidic pH as compared to neutral pH" is expressed in terms of a ratio of the KD value of the antibody binding to its antigen at acidic pH to the KD value of the antibody binding to its antigen at neutral pH (or vice versa). For example, an antibody or antigen-binding fragment thereof may be regarded as exhibiting "reduced binding to CD28 at acidic pH as compared to neutral pH" for purposes of the present disclosure if the antibody or antigen-binding fragment thereof exhibits an acidic/neutral KD ratio of about 3.0 or greater. In certain exemplary embodiments, the acidic/neutral KD ratio for an antibody or antigen-binding fragment of the present disclosure can be about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 20.0. 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 100.0 or greater.

[0195] Antibodies with pH-dependent binding characteristics may be obtained, e.g., by screening a population of antibodies for reduced (or enhanced) binding to a particular antigen at acidic pH as compared to neutral pH. Additionally, modifications of the antigenbinding domain at the amino acid level may yield antibodies with pH-dependent characteristics. For example, by substituting one or more amino acids of an antigen-binding domain (e.g., within a CDR) with a histidine residue, an antibody with reduced antigenbinding at acidic pH relative to neutral pH may be obtained.

(iii) Antibodies Comprising Fc Variants [0196] According to certain embodiments of the present disclosure, anti-CD28/anti- CD22 bispecific antigen binding molecules are provided comprising an Fc domain comprising one or more mutations which enhance or diminish antibody binding to the FcRn receptor, e.g., at acidic pH as compared to neutral pH. For example, the present disclosure includes antibodies and antigen binding molecules comprising a mutation in the CH2 or a CH3 region of the Fc domain, wherein the mutation(s) increases the affinity of the Fc domain to FcRn in an acidic environment (e.g., in an endosome where pH ranges from about 5.5 to about 6.0). Such mutations may result in an increase in serum half-life of the antibody when administered to an animal. Non-limiting examples of such Fc modifications include, e.g., a modification at position 250 (e.g., E or Q); 250 and 428 (e.g., L or F); 252 (e.g., L/Y/F/W or T), 254 (e.g., S or T), and 256 (e.g., S/R/Q/E/D or T); or a modification at position 428 and/or 433 (e.g., H/L/R/S/P/Q or K) and/or 434 (e.g., H/F or Y); or a modification at position 250 and/or 428; or a modification at position 307 or 308 (e.g., 308F, V308F), and 434. In one embodiment, the modification comprises a 428L (e.g., M428L) and 434S (e.g., N434S) modification; a 428L, 259I (e.g., V259I), and 308F (e.g., V308F) modification; a 433K (e.g., H433K) and a 434 (e.g., 434Y) modification; a 252, 254, and 256 (e.g., 252Y, 254T, and 256E) modification; a 250Q and 428L modification (e.g., T250Q and M428L); and a 307 and/or 308 modification (e.g., 308F or 308P).

[0197] For example, the present disclosure includes anti-CD28/anti-CD22 bispecific antigen binding molecules comprising an Fc domain comprising one or more pairs or groups of mutations selected from the group consisting of: 250Q and 248L (e.g., T250Q and M248L); 252Y, 254T and 256E (e.g., M252Y, S254T and T256E); 428L and 434S (e.g., M428L and N434S); and 433K and 434F (e.g., H433K and N434F). All possible combinations of the foregoing Fc domain mutations, and other mutations within the antibody variable domains disclosed herein, are contemplated within the scope of the present disclosure.

Bispecific CD3xCD20 Antibodies and Antigen-Binding Fragments Thereof [0198] According to certain exemplary embodiments of the present disclosure, the methods comprise administering a therapeutically effective amount of a bispecific antigenbinding molecule or antigen-binding fragment thereof that binds CD3 and CD20, in combination with a bispecific CD22xCD28 antigen-binding molecule or antigen-binding fragment thereof.

[0199] CD3 is a homodimeric or heterodimeric antigen expressed on T cells in association with the T cell receptor complex (TCR) and is required for T cell activation. Functional CD3 is formed from the dimeric association of two of four different chains: epsilon, zeta, delta and gamma. The CD3 dimeric arrangements include gamma/epsilon, delta/epsilon and zeta/zeta. As used herein, a molecule that “binds CD3” includes antibodies and antigen-binding fragments thereof that specifically recognize a single CD3 subunit (e.g., epsilon, delta, gamma or zeta), as well as antibodies and antigen-binding fragments thereof that specifically recognize a dimeric complex of two CD3 subunits (e.g., gamma/epsilon, delta/epsilon, and zeta/zeta CD3 dimers). The bispecific CD3xCD20 antibodies and antigenbinding fragments used in the methods of the present disclosure may bind soluble CD3 and/or cell surface expressed CD3. Soluble CD3 includes natural CD3 proteins as well as recombinant CD3 protein variants such as, e.g., monomeric and dimeric CD3 constructs, that lack a transmembrane domain or are otherwise unassociated with a cell membrane.

[0200] CD20 is a non-glycosylated phosphoprotein expressed on the cell membranes of mature B cells. CD20 is considered a B cell tumor-associated antigen because it is expressed by more than 95% of B-cell non-Hodgkin lymphomas (NHLs) and other B-cell malignancies, but it is absent on precursor B-cells, dendritic cells and plasma cells.

[0201] An antibody that “specifically binds” CD3 or CD20, as used in the context of the present disclosure, includes antibodies or antigen-binding fragments thereof that bind CD3 or CD20 or portion thereof with a KD of less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM or less than about 0.5 nM, as measured in a surface plasmon resonance assay. An isolated antibody or antigen-binding fragment that specifically binds human CD3 or CD20 may, however, have cross-reactivity to other antigens, such as CD3 or CD20 molecules from other (non-human) species.

[0202] According to certain exemplary embodiments of the present disclosure, the bispecific CD3xCD20 antibody, or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR), light chain variable region (LCVR), and/or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the anti-CD3 antibodies and anti-CD20 as set forth in US Patent No. 9,657,102.

[0203] In certain exemplary embodiments, the CD3 binding arm of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof that can be used in the context of the methods of the present disclosure comprises the heavy chain complementarity determining regions (HCDRs) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 5 and the light chain complementarity determining regions (LCDRs) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 6. [0204] According to certain embodiments, the CD3 binding arm of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1 , HCDR2 and HCDR3) and three LCDRs (LCDR1 , LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 10; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 11 ; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 12; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 13; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 14; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 15.

[0205] In yet other embodiments, the CD3 binding arm of the bispecifc CD3xCD20 antibody or antigen-binding fragment thereof comprises an HCVR comprising SEQ ID NO: 5 and an LCVR comprising SEQ ID NO: 6. In certain embodiments, the methods of the present disclosure comprise the use of a bispecifc CD3xCD20 antibody, wherein the CD3 binding arm comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 2. In some embodiments, the CD3 binding arm comprises a light chain comprising the amino acid sequence of SEQ ID NO: 3.

[0206] In certain exemplary embodiments, the CD20 binding arm of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof that can be used in the context of the methods of the present disclosure comprises the heavy chain complementarity determining regions (HCDRs) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 4 and the light chain complementarity determining regions (LCDRs) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 6.

[0207] According to certain embodiments, the CD20 binding arm of the bispecifc CD3xCD20 antibody or antigen-binding fragment thereof comprises three HCDRs (HCDR1 , HCDR2 and HCDR3) and three LCDRs (LCDR1 , LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 7; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 8; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 9; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 13; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 14; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 15.

[0208] In yet other embodiments, the CD20 binding arm of the bispecifc CD3xCD20 antibody or antigen-binding fragment thereof comprises an HCVR comprising SEQ ID NO: 4 and an LCVR comprising SEQ ID NO: 6. In certain embodiments, the methods of the present disclosure comprise the use of a bispecifc CD3xCD20 antibody, wherein the CD20 binding arm comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 1. In some embodiments, the CD20 binding arm comprises a light chain comprising the amino acid sequence of SEQ ID NO: 3. [0209] An exemplary antibody comprising a HCVR of the CD3 binding arm comprising the amino acid sequence of SEQ ID NO: 5, a HCVR of the CD20 binding arm comprising the amino acid sequence of SEQ ID NO: 4 and a common LCVR comprising the amino acid sequence of SEQ ID NO: 6 is the antibody known as odronextamab (also known as REGN1979).

[0210] According to certain exemplary embodiments, the methods of the present disclosure comprise the use of odronextamab, or a bioequivalent thereof. The term “bioequivalent”, as used herein, refers to antigen-binding proteins that bind to CD3 and CD20 (e.g., antibody or antigen-binding fragment thereof) that are pharmaceutical equivalents or pharmaceutical alternatives whose rate and/or extent of absorption do not show a significant difference with that of odronextamab when administered at the same molar dose under similar experimental conditions, either single dose or multiple doses. In the context of the disclosure, the term refers to antigen-binding proteins that bind to CD3 and CD20 which do not have clinically meaningful differences with odronextamab in their safety, purity and/or potency.

Bioequivalents

[0211] The present disclosure encompasses antigen-binding molecules having amino acid sequences that vary from those of the described antibodies but that retain the ability to bind CD28 and CD22 or CD3 and CD20. Such variant molecules comprise one or more additions, deletions, or substitutions of amino acids when compared to parent sequence, but exhibit biological activity that is essentially equivalent to that of the described antigen-binding molecules. Likewise, the antigen binding molecules-encoding DNA sequences of the present disclosure encompass sequences that comprise one or more additions, deletions, or substitutions of nucleotides when compared to the disclosed sequence, but that encode an antigen binding molecule that is essentially bioequivalent to the described antigen-binding molecules of the disclosure. Examples of such variant amino acid and DNA sequences are discussed above.

[0212] The present disclosure includes antigen-binding molecules that are bioequivalent to any of the exemplary antigen-binding molecules set forth herein. Two antigen-binding proteins, or antibodies, are considered bioequivalent if, for example, they are pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose under similar experimental conditions, either single does or multiple dose. Some antibodies will be considered equivalents or pharmaceutical alternatives if they are equivalent in the extent of their absorption but not in their rate of absorption and yet may be considered bioequivalent because such differences in the rate of absorption are intentional and are reflected in the labeling, are not essential to the attainment of effective body drug concentrations on, e.g., chronic use, and are considered medically insignificant for the particular drug product studied.

[0213] In one embodiment, two antigen-binding proteins are bioequivalent if there are no clinically meaningful differences in their safety, purity, and potency.

[0214] In one embodiment, two antigen-binding proteins are bioequivalent if a subject can be switched one or more times between the reference product and the biological product without an expected increase in the risk of adverse effects, including a clinically significant change in immunogenicity, or diminished effectiveness, as compared to continued therapy without such switching.

[0215] In one embodiment, two antigen-binding proteins are bioequivalent if they both act by a common mechanism or mechanisms of action for the condition or conditions of use, to the extent that such mechanisms are known.

[0216] Bioequivalence may be demonstrated by in vivo and in vitro methods. Bioequivalence measures include, e.g., (a) an in vivo test in humans or other mammals, in which the concentration of the antibody or its metabolites is measured in blood, plasma, serum, or other biological fluid as a function of time; (b) an in vitro test that has been correlated with and is reasonably predictive of human in vivo bioavailability data; (c) an in vivo test in humans or other mammals in which the appropriate acute pharmacological effect of the antibody (or its target) is measured as a function of time; and (d) in a well-controlled clinical trial that establishes safety, efficacy, or bioavailability or bioequivalence of an antibody.

[0217] Bioequivalent variants of the exemplary bispecific antigen-binding molecules set forth herein may be constructed by, for example, making various substitutions of residues or sequences or deleting terminal or internal residues or sequences not needed for biological activity. For example, cysteine residues not essential for biological activity can be deleted or replaced with other amino acids to prevent formation of unnecessary or incorrect intramolecular disulfide bridges upon renaturation. In other contexts, bioequivalent antibodies may include the exemplary bispecific antigen-binding molecules set forth herein comprising amino acid changes which modify the glycosylation characteristics of the antibodies, e.g., mutations which eliminate or remove glycosylation.

Therapeutic Formulation and Administration

[0218] The present disclosure provides pharmaceutical compositions comprising the antigen binding molecules of the present disclosure. The pharmaceutical compositions of the disclosure are formulated with suitable carriers, excipients, and other agents that provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTINTM, Life Technologies, Carlsbad, CA), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311.

[0219] The dose of antigen-binding molecule administered to a subject may vary depending upon the age and the size of the subject, target disease, conditions, route of administration, and the like. The preferred dose is typically calculated according to body weight or body surface area. When a bispecific antigen-binding molecule of the present disclosure is used for therapeutic purposes in an adult subject, it may be advantageous to intravenously administer the bispecific antigen-binding molecule of the present disclosure normally at a single dose of about 0.01 to 400mg. Depending on the severity of the condition, the frequency and the duration of the treatment can be adjusted.

[0220] Various delivery systems are known and can be used to administer the pharmaceutical composition of the disclosure, e.g., encapsulation in liposomes, microparticles, microcapsules, recombinant cells capable of expressing the mutant viruses, receptor mediated endocytosis (see, e.g., Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local.

[0221] A pharmaceutical composition of the present disclosure can be delivered subcutaneously or intravenously with a standard needle and syringe. In addition, with respect to subcutaneous delivery, a pen delivery device readily has applications in delivering a pharmaceutical composition of the present disclosure. Such a pen delivery device can be reusable or disposable. A reusable pen delivery device generally utilizes a replaceable cartridge that contains a pharmaceutical composition. Once all of the pharmaceutical composition within the cartridge has been administered and the cartridge is empty, the empty cartridge can readily be discarded and replaced with a new cartridge that contains the pharmaceutical composition. The pen delivery device can then be reused. In a disposable pen delivery device, there is no replaceable cartridge. Rather, the disposable pen delivery device comes prefilled with the pharmaceutical composition held in a reservoir within the device. Once the reservoir is emptied of the pharmaceutical composition, the entire device is discarded.

[0222] Numerous reusable pen and autoinjector delivery devices have applications in the subcutaneous delivery of a pharmaceutical composition of the present disclosure. Examples include, but are not limited to AUTOPENTM (Owen Mumford, Inc., Woodstock, UK), DISETRONICTM pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25™ pen, HUMALOGTM pen, HUMALIN 70/30™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPENTM I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIORTM (Novo Nordisk, Copenhagen, Denmark), BDTM pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPENTM, OPTIPEN PROTM, OPTIPEN STARLETTM, and OPTICLIKTM (Sanofi-Aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present disclosure include, but are not limited to the SOLOSTARTM pen (Sanofi-Aventis), the FLEXPENTM (Novo Nordisk), and the KWIKPENTM (Eli Lilly), the SURECLICK™ Autoinjector (Amgen, Thousand Oaks, CA), the PENLET™ (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.), and the HUMIRA™ Pen (Abbott Labs, Abbott Park IL), to name only a few.

[0223] In certain situations, the pharmaceutical composition can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201). In another embodiment, polymeric materials can be used; see, Medical Applications of Controlled Release, Langer and Wise (eds.), 1974, CRC Pres., Boca Raton, Florida. In yet another embodiment, a controlled release system can be placed in proximity of the composition's target, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, 1984, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138). Other controlled release systems are discussed in the review by Langer, 1990, Science 249:1527-1533.

[0224] The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, drip infusions, etc. These injectable preparations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. The injection thus prepared is preferably filled in an appropriate ampoule.

[0225] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. The amount of the aforesaid antibody contained is generally about 5 to about 500 mg per dosage form in a unit dose; especially in the form of injection, it is preferred that the aforesaid antibody is contained in about 5 to about 100 mg and in about 10 to about 250 mg for the other dosage forms.

Additional Combination Therapies

[0226] The present disclosure includes methods for treating, ameliorating or reducing the severity of at least one symptom or indication, or inhibiting the growth of a cancer in a subject, comprising administering to a subject in need thereof a therapeutic composition comprising a multispecific {e.g. bispecific) antigen binding molecule that specifically binds CD28 and CD22, alone as a monotherapy or with a bispecific antibody that binds CD3 and CD20 {e.g. odronextamab) as a combination therapy, and optionally with one or more therapeutic agent(s), e.g., at least a third therapeutic agent or therapy.

[0227] Exemplary third therapeutic agents or therapies that may be combined with or administered in combination with an antigen-binding molecule of the present disclosure include, e.g., surgery, chemotherapy, radiation therapy, checkpoint inhibitors that target PD- 1 e.g., an anti-PD-1 antibody such as pembrolizumab, nivolumab, or cemiplimab), CTLA-4, LAG3, TIM3, and others, costimulatory agonist bivalent antibodies that target molecules such as GITR, 0X40, 4-1 BB, and others, CD3x bispecific antibodies (See for example US9,657,102, WO2017/053856A1, WO2014/047231 A1, WO2018/067331 A1 and

WO2018/058001 A1), other antibodies that target CD22 X CD3, CD22 X CD28, or that target CD20 X CD3, other costimulatory CD28x bispecific antibodies, oncolytic virus, cancer vaccines, tamoxifen, aromatase inhibitors, cytokine inhibitors including small-molecule cytokine inhibitors and antibodies that bind to cytokines such as IL-1, IL-2, IL-3, IL-4, IL-5, IL- 6, IL-8, IL-9, IL-11, IL-12, IL-13, IL-17, IL-18, or to their respective receptors. The anti- CD28/anti-CD22 antigen-binding molecules of the present disclosure {e.g., pharmaceutical compositions comprising an anti-CD28/anti-CD22 bispecific antigen-binding molecule as disclosed herein) may also be administered as part of a therapeutic regimen comprising one or more therapeutic combinations selected from "ICE": ifosfamide {e.g., Ifex®), carboplatin {e.g., Paraplatin®), etoposide {e.g., Etopophos®, Toposar®, VePesid®, VP-16); "DHAP": dexamethasone {e.g., Decadron®), cytarabine {e.g., Cytosar-U®, cytosine arabinoside, ara- C), cisplatin e.g., Platinol®-AQ); and "ESHAP": etoposide e.g., Etopophos®, Toposar®, VePesid®, VP-16), methylprednisolone {e.g., Medrol®), high-dose cytarabine, cisplatin {e.g., Platinol®-AQ).The anti-CD28/anti-CD22 antigen-binding molecules of the present disclosure may also be administered in combination with any of the antigen-binding molecules mentioned herein and an inhibitor of one or more of VEGF, Ang2, DLL4, EGFR, ErbB2, ErbB3, ErbB4, EGFRvlll, cMet, IGF1 R, B-raf, PDGFR-o, PDGFR-I3, FOLH1 , PRLR, STEAP1, STEAP2, TMPRSS2, MSLN, CA9, uroplakin, or any of the aforementioned cytokines, wherein the inhibitor is an aptamer, an antisense molecule, a ribozyme, an siRNA, a peptibody, a nanobody or an antibody fragment (e.g., Fab fragment; F(ab')2 fragment; Fd fragment; Fv fragment; scFv; dAb fragment; or other engineered molecules, such as diabodies, triabodies, tetrabodies, minibodies and minimal recognition units). The anti- CD28/anti-CD22 antigen-binding molecules of the disclosure may also be administered and/or co-formulated in combination with antivirals, antibiotics, analgesics, corticosteroids and/or NSAIDs. The antigen-binding molecules of the disclosure may also be administered as part of a treatment regimen that also includes radiation treatment and/or conventional chemotherapy, or treatment with a biologic, including checkpoint inhibitors or other bispecific antibodies.

[0228] The present disclosure includes compositions and therapeutic formulations comprising any of the antigen-binding molecules described herein in combination with one or more chemotherapeutic agents. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (Cytoxan™); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-Fll); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6- mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK™; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2, 2', 2"- trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, e.g. paclitaxel (Taxol™, Bristol-Myers Squibb Oncology, Princeton, N.J.) and docetaxel (Taxotere™; Aventis Antony, France); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included in this definition are anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene (Fareston); and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0229] The additional therapeutically active component(s) may be administered just prior to, concurrent with, or shortly after the administration of an antigen-binding molecules of the present disclosure; (for purposes of the present disclosure, such administration regimens are considered the administration of an antigen-binding molecule "in combination with" an additional therapeutically active component).

[0230] The present disclosure includes pharmaceutical compositions in which an antigen binding molecule of the present disclosure is co-formulated with one or more of the additional therapeutically active component(s) as described elsewhere herein.

EXAMPLES

[0231] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the disclosure, and are not intended to limit the scope of what the inventors regard as their disclosure.

Example 1 : Bispecific CD22xCD28 and CD3xCD20 Antibodies

[0232] Bispecific CD22xCD28 antibodies are described in WO 2020/132066, the entire contents of which are expressly incorporated herein by reference. The exemplary bispecific CD22xCD28 antibody used in the following Examples is REGN5837. [0233] Table 1 sets forth the amino acid sequence identifiers of the heavy and light chain variable regions and CDRs of REGN5837.

Table 1 : Amino Acid Sequences of REGN5837

[0234] Sequences of the heavy chain of the CD22 binding arm of REGN5837:

HCVR:

EVQLVQSGAEVKKPGESLKISCKGSGYNFATYWIAWVRQMPGKGLELMGIIYPGDSETTYN

PSFQGQVTISADKSISNAYLQWSSLKASDTAMYYCARVGGYCSGTSCHNWFDPWGLGTLV

TVSS (SEQ ID NO: 19)

HCDR1: GYNFATYW (SEQ ID NO: 22)

HCDR2: IYPGDSET (SEQ ID NO: 23)

HCDR3: ARVGGYCSGTSCHNWFDP (SEQ ID NO: 24)

HC:

EVQLVQSGAEVKKPGESLKISCKGSGYNFATYWIAWVRQMPGKGLELMGIIYPGDSETTYN

PSFQGQVTISADKSISNAYLQWSSLKASDTAMYYCARVGGYCSGTSCHNWFDPWGLGTLV

TVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL

QSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGP

SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS

TYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT

KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE

GNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 16)

[0235] Sequences of the heavy chain of the CD28 binding arm of REGN5837:

HCVR:

QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWSWIRQPPGKGLEWIGYIYYSGITHYNPS

LKSRVTISVDTSKIQFSLKLSSVTAADTAVYYCARWGVRRDYYYYGMDVWGQGTTVTVSS

(SEQ ID NO: 20)

HCDR1: GGSISSYY (SEQ ID NO: 25)

HCDR2: IYYSGIT (SEQ ID NO: 26)

HCDR3: ARWGVRRDYYYYGMDV (SEQ ID NO: 27) HCVR:

QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWSWIRQPPGKGLEWIGYIYYSGITHYNPS LKSRVTISVDTSKIQFSLKLSSVTAADTAVYYCARWGVRRDYYYYGMDVWGQGTTVTVSSA STKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGPSVFLFP PKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSL TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSC SVMHEALHNRFTQKSLSLSPGK (SEQ ID NO: 17)

[0236] Sequences of the common light chain of both CD22 and CD28 binding arms of

REGN5837:

LCVR:

EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDR FSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK (SEQ ID NO: 21) LCDR1 : QSVSSSY (SEQ ID NO: 28)

LCDR2: GAS (SEQ ID NO: 29)

LCDR3: QQYGSSPWT (SEQ ID NO: 30)

LC:

EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDR FSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 18)

[0237] Bispecific CD3xCD20 antibodies are described in US9,657,102, the entire contents of which are expressly incorporated herein by reference. The exemplary bispecific CD3xCD20 antibody used in the following Examples is REGN1979.

[0238] Table 2 sets forth the amino acid sequence identifiers of the heavy and light chain variable regions and CDRs of REGN1979.

Table 2: Amino Acid Sequences of REGN1979

[0239] Sequences of the heavy chain of the CD3 binding arm of REGN1979:

HCVR:

EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYTMHWVRQAPGKGLEWVSGISWNSGSIG

YADSVKGRFTISRDNAKKSLYLQMNSLRAEDTALYYCAKDNSGYGHYYYGMDVWGQGTT

VTVAS (SEQ ID NO: 5)

HCDR1: GFTFDDYT (SEQ ID NO: 10)

HCDR2: ISWNSGSI (SEQ ID NO: 11)

HCDR3: AKDNSGYGHYYYGMDV (SEQ ID NO: 12)

HC:

EVQLVESGGGLVQPGRSLRLSCAASGFTFDDYTMHWVRQAPGKGLEWVSGISWNSGSIG

YADSVKGRFTISRDNAKKSLYLQMNSLRAEDTALYYCAKDNSGYGHYYYGMDVWGQGTT

VTVASASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV

LQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPPVAGP

SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS

TYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMT

KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQE

GNVFSCSVMHEALHNRFTQKSLSLSLGK (SEQ ID NO: 2)

[0240] Sequences of the heavy chain of the CD20 binding arm of REGN1979:

HCVR:

EVQLVESGGGLVQPGRSLRLSCVASGFTFNDYAMHWVRQAPGKGLEWVSVISWNSDSIG

YADSVKGRFTISRDNAKNSLYLQMHSLRAEDTALYYCAKDNHYGSGSYYYYQYGMDVWG

QGTTVTVSS (SEQ ID NO: 4)

HCDR1: GFTFNDYA (SEQ ID NO: 7)

HCDR2: ISWNSDSI (SEQ ID NO: 8)

HCDR3: AKDNHYGSGSYYYYQYGMDV (SEQ ID NO: 9)

HC:

EVQLVESGGGLVQPGRSLRLSCVASGFTFNDYAMHWVRQAPGKGLEWVSVISWNSDSIG

YADSVKGRFTISRDNAKNSLYLQMHSLRAEDTALYYCAKDNHYGSGSYYYYQYGMDVWG

QGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHT

FPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPP

VAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREE

QFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQ

EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSR

WQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 1) [0241] Sequences of the common light chain of both CD3 and CD20 binding arms of REGN1979:

LCVR:

EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQHYINWPLTFGGGTKVEIKR (SEQ ID NO: 6) LCDR1 : QSVSSN (SEQ ID NO: 13)

LCDR2: GAS (SEQ ID NO: 14)

LCDR3: QHYINWPLT (SEQ ID NO: 15)

LC:

EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQHYI NWPLTFGGGTKVEI KRTVAAPSVFI FPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 3)

Example 2: Clinical Assessment of treatment with REGN5837 in combination with REGN1979

[0242] This Example describes a phase 1 clinical study of REGN5837 (CD22xCD28 Costimulatory Bispecific Antibody) in combination with REGN1979 (odronextamab) in subjects with relapsed or refractory aggressive B-cell non-Hodgkin lymphomas.

[0243] Primary Objectives of the study are to assess safety, tolerability, and doselimiting toxicities (DLTs) and to determine recommended phase 2 dose (RP2D) regimen(s) (defined as either a maximum tolerance dose (MTD) regimen or a lower dose regimen) of REGN5837 in combination with odronextamab in subjects with relapsed or refractory aggressive B-NHL.

[0244] Secondary Objectives of the study are: (i) To characterize the pharmacokinetics (PK) of REGN5837 when given in combination with REGN1979 (odronextamab); (ii) To evaluate the PK of REGN1979 (odronextamab) when given in combination with REGN5837; (iii) To assess the immunogenicity of REGN5837 and odronextamab; and (iv) To assess the preliminary anti-tumor activity of REGN5837 in combination with REGN1979 (odronextamab) in subjects with relapsed or refractory aggressive B-NHL.

[0245] Exploratory objectives of the study are: (i) To evaluate the association between clinical efficacy and safety with biomarkers of systemic immune activation (serum cytokine levels, T-cell counts and activation markers); (ii) To evaluate the association between disease response and/or relapse and the change from baseline in the count and phenotype of tumor-infiltrating T cells and tumor B cell target antigen (CD20, CD22) expression; (iii) To evaluate association of the molecular Minimal Residual Disease (MRD) status in subjects with a clinical complete response (CR) with progression-free survival (PFS) and overall survival (OS); (iv) To assess other biomarkers (pharmacodynamic, predictive, and prognostic) potentially related to REGN5837 in combination with REGN1979 (odronextamab) exposure, anti-tumor activity, and safety; and (v) To evaluate the relationships among pharmacodynamics, drug concentrations, and clinical safety and efficacy measures.

Study Design

[0246] The purpose of this phase 1, open-label, FIH study is to evaluate the safety, PK and pharmacodynamic properties, and preliminary clinical activity of the anti-CD22 x anti- CD28 bispecific antibody REGN5837 combined with the anti-CD20 x anti-CD3 bispecific antibody odronextamab (REGN1979) in subjects with relapsed or refractory aggressive B- NHL, excluding mantle cell lymphoma (MCL), hereafter referred to simply as ‘aggressive B- NHL’. There are two parts of the study, dose escalation and dose expansion.

[0247] To reduce the likelihood and severity of cytokine release, and to mitigate the risk of TLS, REGN1979 (odronextamab) will be introduced as monotherapy from cycle 1 day 1 to cycle 2 day 8. REGN5837 will start on cycle 2 day 15. REGN5837 will not begin until QW dose of odronextamab is administered as a single infusion the previous week without signs or symptoms of cytokine release syndrome (CRS), infusion-related reaction (IRR) or tumor lysis syndrome (TLS). The sequential introduction of REGN1979 (odronextamab) and REGN5837 allows for subjects who develop CRS, IRR or TLS with odronextamab monotherapy to recover before they receive REGN5837. Up to cycle 2 day 1 , the dose of odronextamab will be increased in a stepwise manner, with an initial dose on cycle 1 days 1 and 2, followed by an intermediate dose on cycle 1 days 8 and 9, a second intermediate dose on cycle 1 days 15 and 16, and a full weekly dose on cycle 2 day 1 and after. In ongoing studies with odronextamab, once subjects tolerate 2 full nominal doses of odronextamab, severe CRS has not been observed in subjects with diffuse large-B cell lymphoma (DLBCL).

[0248] To further reduce the risk of severe CRS, IRR or TLS when REGN5837 is introduced in the presence of odronextamab, following the same approach as step-up dosing with odronextamab, REGN5837 will also be administered using a step-up dosing regimen, with a lower initial dose on cycle 2 day 15, an intermediate dose on cycle 3 day 1 , and a full weekly dose on cycle 3 day 8.

[0249] Weekly dosing of REGN5837 and odronextamab continues until cycle 6 day 8, after which dosing changes to a every 2 week (Q2W) schedule. Every week (QW) dosing period will be the induction period (cycles 1 through 6) followed by Q2W dosing which will be the maintenance period. Subjects who have achieved and sustained a complete response (CR) for 9 months will transition to every 4 week (Q4W) dosing. Subjects must have received the assigned dose at the Q2W dosing schedule for at least 3 preceding doses before switching from Q2W to Q4W dosing. [0250] The dose escalation portion of the study will follow the Bayesian Optimal Interval Design (BOIN) to assess the safety of REGN5837 in combination with odronextamab and to select recommended phase 2 dose (RP2D) regimen(s) for REGN5837 in combination with odronextamab. The DLT observation period will be 35 days (nominally from cycle 2 day 15 to cycle 4 day 7) from the beginning of REGN5837 administration and will consist of at least 3 full doses of REGN5837 in combination with odronextamab.

[0251] For the dose expansion portion, there will be 2 expansion cohorts: A and B. Cohort A consists of subjects with aggressive B-NHL, who have not had prior chimeric antigen receptor T-cell (CAR-T) therapy. Cohort B consists of subjects with aggressive B- NHL who have progressed after failure of CAR-T therapy. Subjects enrolled to an expansion cohort will receive the RP2D of the combination treatment. Initial anti-tumor activity will be explored, and safety and tolerability, PK properties, and biomarker responses will be further characterized.

Study Duration

[0252] After a 28-day screening period, study treatment will be comprised of six 21 day cycles of induction dosing comprising of weekly therapy, which includes odronextamab monotherapy from cycle 1 day 1 to cycle 2 day 8 and then REGN5837 and odronextamab combination treatment from cycle 2 day 15 to cycle 6 day 8.

[0253] During the maintenance period, which follows a 28-day cycle schedule and starts 2 weeks after the last induction every week (QW) dose, REGN5837 in combination with odronextamab will be dosed every 2 weeks (Q2W). REGN5837 in combination with odronextamab will continue on a Q2W schedule until the time of disease progression or other protocol-defined reason for treatment discontinuation. Subjects who achieve and sustain a complete response (CR) for at least 9 months will change to a every 4 week (Q4W) schedule of REGN5837 and odronextamab until the time of disease progression or other protocol-defined reason for treatment discontinuation. Subjects must have received the assigned dose at the Q2W dosing schedule for at least 3 preceding doses before switching from Q2W to Q4W dosing.

[0254] Safety Follow-up: The safety follow-up period consists of three Q4W Safety Follow-up Visits with safety follow-up visits at 4 weeks following last dose (Safety Follow-up Visit 1), at 8 weeks following the last dose (Safety Follow up Visit 2) and at 12 weeks following the last dose (Safety Follow up Visit 3). Safety follow-up continues until all 3 visits are completed, or until start of a non-protocol anti-lymphoma therapy, or subject withdrawal of consent, whichever is sooner.

[0255] Extended Follow-up: The extended follow-up is for subjects who have discontinued study drug for any reason other than disease progression, start of non-protocol anti-lymphoma therapy, withdrawal of consent, or death. Disease response will be assessed until the time of disease progression, death, start of a non-protocol anti-lymphoma therapy, or subject withdrawal of consent for follow-up of disease status, whichever is sooner.

[0256] Survival Follow up: After the safety follow-up period and, if applicable, the extended follow-up period, all study subjects will be followed at Q12W intervals for survival until the time of death, loss to follow-up, subject withdrawal of consent for follow-up, or study termination by the sponsor, whichever is earlier. Survival follow-up status may be determined at clinic visits or remotely by the study site (such as by telephone).

[0257] The end of study for an individual subject will be at the time when the subject discontinues from the study, up to the end of the extended follow-up and prior to survival follow-up. All subjects will continue survival follow-up until death, loss to follow-up, withdrawal of consent for follow-up, or study termination, whichever is earlier.

[0258] The study and all follow-up will end when all study subjects have been discontinued from the study or at the time of study closure, whichever is earlier.

Induction Dosing Period

[0259] Odronextamab Monotherapy (Cycle 1 Day 1 to Cycle 2 Day 8): Sites should ensure that 2 doses of anti-l L6 therapy (e.g. tocilizumab) are available for each subject before any study drug is administered. From cycle 1 day 1 to cycle 2 day 8 of study treatment, odronextamab will be infused weekly as monotherapy. For the initial dose (0.7 mg split as 0.2 mg/0.5 mg), intermediate dose 1 (4 mg to be given as split infusions 2 mg/ 2 mg), and intermediate dose 2 (20 mg to be given as split infusions 10 mg/10 mg) doses, odronextamab will be administered as a split infusion, preferably on consecutive days but no more than 3 days apart, to improve tolerability and mitigate against CRS, IRR, and TLS. For example, odronextamab dosing days will be cycle 1 day 1 and cycle 1 day 2 for the initial dose and cycle 1 day 8, cycle 1 day 9 for the first intermediate dose, and cycle 1 day 15, cycle 1 day 16 for the second intermediate dose. Each split dose is administered over 4 hours on each of 2 days. The initial dose and both intermediate doses should always be split, even if in the event of treatment delays causing administration beyond cycle 1 day 15. In cycle 2, on day 1 the full dose of 160 mg (NOTE: 80 mg QW in DL1) will be administered as a single infusion over 4 hours. On cycle 2 day 8, another full dose of odronextamab will be administered. If the administration of the first full QW dose of odronextamab is tolerated as a single infusion, subsequent doses (nominally cycle 2 day 8 and after) may be administered as a single infusion over 1 to 4 hours depending on previous tolerability. To be able to proceed to combination therapy, the most recent odronextamab dose must have been tolerated as a single infusion and without any grade CRS, IRR, or TLS.

[0260] Subjects should be hospitalized during odronextamab infusion and for at least 24 hours after the end of infusion (including days of split dosing), until a full dose, without splitting, is administered without CRS. Each infusion should be administered over 4 hours. [0261] REGN5837/odronextamab Weekly Dosing (Cycle 2 Day 15 to Cycle 6 Day 8): Initiation of REGN5837 is on cycle 2 day 15. REGN5837 will also be administered with step- up dosing. All doses of REGN5837 will be administered as single infusion. For all dose levels, REGN5837 dosing will not begin until the subject has demonstrated tolerability to 2 full QW doses of odronextamab as defined for each respective dose level (DL) (Table 4). Additionally, the most recent odronextamab monotherapy QW dose must have been administered as a single infusion without any grade of CRS, IRR or TLS before a subject can start REGN5837. Given the risk that combination therapy of REGN5837 and odronextamab may exacerbate CRS, subjects who developed grade 3 CRS during the monotherapy lead-in period will not be eligible to be dosed with REGN5837 but may continue with single agent odronextamab for the duration of the study.

[0262] On cycle 2 day 15 of study treatment, REGN5837 will be introduced at a lower, initial dose followed by the QW dose of odronextamab on day 16. On cycle 3 day 1 , REGN5837 will be increased to an intermediate dose. On cycle 3 day 8, REGN5837 will be increased to a full dose. When combination therapy starts, REGN5837 will be administered one day prior to odronextamab dosing during cycle 2 and 3. This staggered administration period will include REGN5837 step-up dosing on cycle 2 day 15, cycle 3 day 1 and cycle 3 day 8 plus second full combination dose on cycle 3 day 15. If staggered administration is adequately tolerated without any grade 2 or higher CRS, same-day administration of REGN5837 and odronextamab will commence on cycle 4 day 1. However, if grade 2 or higher CRS occurs with staggered administration, same-day administration of the combination will be delayed until two full combination doses of REGN5837 and odronextamab have been tolerated without any such events. Same-day administration of REGN5837 and odronextamab, once initiated, will continue for the remainder of the study treatment. During same-day administration of combination therapy, REGN5837 will always be given first, followed by odronextamab initiation up to 60 minutes from the end of infusion of REGN5837.

[0263] For doses <1 mg, the duration of REGN5837 infusion is 1 hour and REGN5837 will be administered by syringe pump. For doses >1 mg, the duration of REGN5837 infusion is 2 hours by IV pump for the entire staggered administration period and also cycle 4 day 1 dose. If the subject does not experience IRR, CRS or TLS, the duration of REGN5837 infusions may be reduced to 1 hour starting on cycle 4 day 8. The duration of infusion may be extended based on clinical judgement. Odronextamab infusion times during REGN5837 step-up dosing period and the second QW full dose (cycle 2 day 15, cycle 3 day 1, cycle 3 day 8, and cycle 3 day 15) will remain consistent with cycle 2 day 8 infusion times.

[0264] Once combination therapy starts, subjects should be hospitalized for REGN5837 and odronextamab infusion until at least 48 hours after REGN5837 infusion is completed (24 hours after odronextamab infusion is completed). The observation period in the protocol will vary based on the rationale that the highest risk of occurrence of CRS is in the first 24 hours from the end of infusion of a bispecific antibody. During the hospitalization period, subjects should be monitored for IRR, CRS and TLS during and after each infusion per institutional guidelines for observation. Monitoring will include but is not limited to: vital signs (including temperature, blood pressure, and oxygen saturation); clinical and laboratory (including, at minimum, serum chemistry) assessments.

[0265] Hospitalization will continue for combination therapy administration until two full doses of the combination therapy are administered without CRS occurrence. From cycle 4 day 1 , hospitalization is not required as long as the subjects have received and tolerated the full dose of REGN5837 in combination with full-dose odronextamab. However, if subjects experience grade 2 or higher CRS on cycle 3 day 8 or beyond, they must be monitored in the hospital for at least 48 hours from the end of REGN5837 infusion until they have tolerated both study drugs without occurrence of grade 2 or higher CRS events.

[0266] From cycle 4 day 1 onwards or when hospitalization is no longer required (whichever is later), and for the first 4 weeks of outpatient infusion visits, subjects are required to be observed for at least 2 hours after the end of the last infusion; clinical status evaluations, including vital signs checks, are required to be performed with hourly frequency at minimum. A phone call to assess safety must be made to the subjects the day following the first 4 outpatient infusion visits.

[0267] If a subject cannot begin combination treatment with REGN5837 by cycle 3 day 15 due to the occurrence or persistence of safety events, odronextamab monotherapy may be continued at the assigned dose if the criteria for permanent discontinuation of odronextamab have not been met. In such an instance, there will be no further attempt to introduce REGN5837, and subjects in dose escalation cohorts may be replaced for DLT evaluation.

[0268] Subjects will receive 12 weekly doses of REGN5837 and odronextamab combination therapy during the REGN5837/odronextamab induction dosing period. Assuming that REGN5837 is introduced on cycle 2 day 15, this means that subjects will receive 17 total doses of odronextamab upon completion of the REGN5837/odronextamab weekly dosing period. If there are interruptions in dosing, the REGN5837/odronextamab weekly dosing period will be extended until subjects have received 12 doses of REGN5837 combined with odronextamab.

[0269] Pretreatments: Pretreatment medication requirements up to the step-up dosing completion for REGN5837 are explained in Figure 3 and below

[0270] The following premedications apply to the initial odronextamab monotherapy from the initial dose through the first full every week (QW) dose as a single infusion. If the subject has IRR and/or CRS of any grade with first full QW dose, continue premedications until the full QW dose is tolerated without experiencing IRR and/or CRS. a) 12 to 24 hours prior to planned start time of first split infusion or first QW full dose as a single infusion and prior to planned start of second split infusion if administered on non-consecutive days for each odronextamab dose: i. Dexamethasone 10 mg PO or equivalent dose of steroid* b) Premedication on each day of split infusion of odronextamab and on the day of QW full dose as a single infusion: i. Dexamethasone 20 mg IV 1 to 3 hours prior to start of infusion ii. Diphenhydramine 25 mg IV or PO 30 to 60 min before the infusion (can be replaced with another equivalent antihistamine) iii. Acetaminophen 650 mg PO 30 to 60 min before the infusion, unless the subject has received acetaminophen within the past 4 hours prior to infusion with odronextamab, or is allergic to acetaminophen c) 24 (±4) hours from the end of second split infusion or end of the first full QW dose as a single infusion: i. Dexamethasone 10 mg PO or equivalent dose of steroid*

[0271] The following premedications apply to odronextamab treatment day on cycle 2 day 8 (or second full dose of odronextamab), provided subject has not experienced an IRR and/or CRS of any grade during the previous 4 weeks of odronextamab monotherapy:

Premedication for day of odronextamab as a single infusion: i. Dexamethasone 10 mg IV 1 to 3 hours prior to start of infusion on the day of treatment ii. Diphenhydramine 25 mg IV or PO 30 to 60 min before (can be replaced with another equivalent antihistamine) iii. Acetaminophen 650 mg PO 30 to 60 min before, unless the subject has received it within the past 4 hours prior to infusion with odronextamab, or is allergic to acetaminophen

[0272] The following premedication’s apply to REGN5837 in combination with odronextamab during cycle 2 day 15 through cycle 3 day 8 (step-up dose for REGN5837 in combination with odronextamab) (Figure 3). If the subject has IRR and/or CRS of any grade with first full REGN5837 QW dose, continue premedication’s until the full QW dose is tolerated without experiencing IRR and/or CRS. a) 12 to 24 hours prior to planned start time of the REGN5837 infusion: i. Dexamethasone 10 mg PO or equivalent dose of steroid* b) Premedication on each day of REGN5837/odronextamab combination therapy: ii. Dexamethasone 10 mg IV 1 to 3 hours prior to start of REGN5837 and odronextamab infusion on the days of treatment iii. Diphenhydramine 25 mg IV or PO 30 to 60 min before REGN5837 and odronextamab infusion (can be replaced with another equivalent antihistamine) iv.Acetaminophen 650 mg PO 30 to 60 min before REGN5837 and odronextamab infusion, unless the subject has received acetaminophen within the past 4 hours prior to infusion with REGN5837 or odronextamab, or is allergic to acetaminophen c) 24 (±4) hours from the end of the odronextamab infusion: i. Dexamethasone 10 mg PO or equivalent dose of steroid*

*Dose of steroids equivalent to dexamethasone 10 mg include prednisone/prednisolone 60 mg or methylprednisolone 50 mg (PO dose only).

[0273] The following premedication’s apply to REGN5837 in combination with odronextamab during cycle 3 days 15 and 16 or for the second full combination doses of REGN5837 and odronextamab without any grade IRR and/or CRS, whichever is later: Premedication for each day of infusion: i. Dexamethasone 10 mg IV 1 to 3 hours prior to start of REGN5837 and odronextamab infusion on the days of treatment ii. Diphenhydramine 25 mg IV or PO 30 to 60 min before REGN5837 and odronextamab infusion (can be replaced with another equivalent antihistamine) iii. Acetaminophen 650 mg PO 30 to 60 min before REGN5837 and odronextamab infusion, unless the subject has received it within the past 4 hours prior to infusion with REGN5837 or odronextamab, or is allergic to acetaminophen

[0274] For subsequent doses of REGN5837 in combination with odronextamab: a) If the subject continues to adequately tolerate the combination treatment of REGN5837 and odronextamab without any grade IRR and/or CRS on dexamethasone doses as described above, discontinuation of the corticosteroid (along with diphenhydramine and acetaminophen) with subsequent REGN5837 and odronextamab combination administration is encouraged. b) If continued corticosteroid administration is warranted, another intermediate or long-acting corticosteroid (eg, methylprednisolone) may be substituted for dexamethasone. [0275] At any point in treatment, if a subject experiences CRS or IRR of any grade, premedications with acetaminophen/antihistamine are also required for the subsequent dose.

[0276] Additional premedication with antihistamine, acetaminophen, and/or corticosteroid equivalent may also be considered.

[0277] If 2 subjects experience a grade > 3 CRS event, the dose of oral dexamethasone (or equivalent) before and after dosing days for that cohort will be increased to 20 mg.

Maintenance Dosing Period

[0278] REGN5837/odronextamab Q2W and Q4W Dosing: After completion of the REGN5837/odronextamab weekly induction dosing period, subjects will advance to the Q2W treatment period and receive the designated QW REGN5837 dose and 320 mg odronextamab (or 160 mg odronextamab Q2W for DL1) Q2W. During the Q2W treatment period, REGN5837 should be administered on the same day as odronextamab (or in 2 consecutive days if this is necessary for reasons such as scheduling). REGN5837 in combination with odronextamab will continue on a Q2W schedule until the time of disease progression or other protocol-defined reason for treatment discontinuation. However, if a subject achieves a CR that is sustained for a minimum of 9 months, then the subject will shift to a Q4W schedule of dosing for both QW dose of REGN5837 and 320 mg odronextamab (NOTE: 160 mg for DL1). Subjects must have received the assigned

REGN5837/odronextamab doses at the Q2W dosing schedule for at least 3 preceding doses before switching from Q2W to Q4W dosing.

[0279] The safety of the Q4W dosing will be assessed in the first 16 subjects after receiving 2 combination doses at this frequency.

• If 4 or fewer subjects experience grade >2 CRS events, continue Q4W dosing in subsequent subjects

• If 5 or more subjects experience grade >2 CRS events, stop Q4W dosing and continue Q2W dosing in all subjects

[0280] This rule is based on the lower bound of the 1 sided 80% confidence interval. Transition from Q2W to Q4W will be paused if the lower bound of the 1-sided 80% confidence interval of the grade >2 CRS rate is >20%. Subjects who experience grade >2 CRS after the first dose of either study drug following transition from Q2W to Q4W dosing will be included in the analysis.

[0281]

Dose Escalation and Study Cohorts

[0282] The dose escalation rule will be based on the Bayesian Optimal Interval Design (BOIN) with the target dose limiting toxicity (DLT) rate of 28%. This target DLT rate corresponds to de-escalation boundary similar to 3+3 design. A minimum of 3 subjects will be enrolled in all dose levels. The decision rule at dose level j is summarized as follows:

• If observed DLT rate < 0.221, escalate to the dose level j+1; observed DLT rate is calculated by the number of subjects with DLTs divided by the number of DLT evaluable subjects in the dose level.

• If observed DLT rate > 0.334, de-escalate to the dose level j-1 ; 3 additional subjects will be enrolled at dose level j-1.

• If 0.221 < observed DLT rate < 0.334, stay at the dose level j, 3 additional subjects will be enrolled for further evaluation.

• If the number of subjects with DLTs in evaluable subjects reaches the boundary defined as the posterior probability of >0.95 that the true DLT rate is higher than target DLT rate, dose level j and above will be eliminated from the trial. The trial will be terminated if the first dose level is eliminated. The posterior probability can be evaluated on the basis of a beta-binomial mode, assuming a non-informative prior distribution of Beta (1 ,1).

[0283] The decision rule will be repeated until the prespecified maximum sample size of 54 subjects is exhausted. At that point, the MTD is selected as the dose for which the isotonic estimate of the DLT probability is closest to the target DLT rate of 28%.

[0284] Note that the actual number of evaluable subjects per cohort may be variable. The decision rule during the study applies as long as at least one subject is evaluable in a dose level (except DL1 and DL2 where at least 3 DLT-evaluable subjects will be required) and varies depending on the number of evaluable subjects at each dose level and the observed number of subjects with DLTs. In Table 3, the detailed decision rules at various number of subjects with DLTs and evaluable subjects are provided.

Table 3: Dose Escalation/De-Escalation Rule at the Current Dose Level J with Target DLT Rate 28%

first dose level is eliminated.

[0285] In the scenarios of the true toxicity probabilities (0.05, 0.15, 0.28, 0.45, 0.6), the operating characteristics based on 1000 simulated trials are:

• Selection percentage at each dose level (%): 1.2, 27.3, 50.6, 18.4, 2.5

• Number of subjects treated at each dose level: 3.954, 6.921 , 6.933, 2.817, 0.375

• Number of toxicities observed at each dose level: 0.177, 1.002, 1.910, 1.274, 0.226

• Average number of toxicities: 4.589

• Average number of subjects: 21

• Percentage of early stopping due to toxicity: 0.0%

• Risk of overdosing (>60% of subjects treated above the MTD): 0.0 %

• Risk of overdosing (>80% of subjects treated above the MTD): 0.0 %

Table 4: Dose Escalation Schedule

* Dose may be fixed at a lower level based on tolerability

**REGN5837 starts on cycle 2 day 15 or later and continues, with odronextamab, through disease progression

***For combination therapy during cycles 2 and 3, odronextamab administration will be staggered at least 24 hours after REGN5837 dose; Cycle 6 day 15 has no REGN5837 and odronextamab doses

[0286] If the initial (cycle 2 day 15) dose of REGN5837 for a dose escalation cohort is determined to be intolerable, the initial dose for subsequent cohorts will be decreased to the highest tolerable initial dose of REGN5837. Similarly, if continued escalation of the intermediate (cycle 3 day 1) dose of REGN5837 is not tolerated, then the cycle 3 day 1 dose will be fixed to the highest tolerable intermediate dose.

[0287] If the initial and/or intermediate doses of REGN5837 are fixed, the purpose of the DLT window will be to evaluate the safety of the full dose of REGN5837 in combination with odronextamab. A subject will be deemed unevaluable for DLTs if the subject experiences any toxicity that requires discontinuation prior to the first full dose of REGN5837 in combination with odronextamab. Adverse events occurring prior to the first full dose of REGN5837 in combination with odronextamab will inform the overall safety profile of REGN5837 in combination with odronextamab and will impact dose escalation as per dose escalation restriction rules (outlined below). Subjects deemed unevaluable for DLT may be replaced.

[0288] Doses of REGN5837 which follow the rule-based dose escalation guidelines and that are in between the values in Table 4, but not over the pre-specified maximum dose values, may be explored based on the safety events observed. Dose levels are defined by the cycle 3 day 8 dose. Safety events that occur at the designated dose of REGN5837 in cycle 2 day 15 that had been tolerated as the cycle 3 day 1 dose in prior dose levels will be discussed by the SSET and a decision may be made to reduce the cycle 2 day 15 dose. The cycle 2 day 15 dose may be fixed at a lower dose to allow for dose escalation to continue for the cycle 3 day 1 dose. Similarly, safety events that occur at the designated dose of REGN5837 in cycle 3 day 1 that had been tolerated as the cycle 3 day 8 dose in prior dose levels will be assessed and a decision may be made to reduce the cycle 3 day 1 dose. The cycle 3 day 1 dose may be fixed at a lower dose to allow for dose escalation to continue for the cycle 3 day 8 dose. In all cases, modifications will only be applied to implement a more conservative dose escalation between cohorts (eg, less steep increase between 2 consecutive DLs or splitting of initial or subsequent doses over 2 administrations).

[0289] Prior to escalation to dose level 3, the safety with a minimum of 3 DLT evaluable subjects in each cohort will be evaluated. Escalation to DL3 will only proceed if the safety profile is comparable between the DL1 and DL2 (including the frequency and severity of CRS/IRR events with combination therapy). However, if a higher proportion of subjects in DL2 experience grade 2 or higher CRS/IRR events with combination therapy compared to DL1, then dose escalation of REGN5837 from DL3 onwards will proceed in combination with odronextamab 80 mg QW. Preliminary pharmacodynamic data from DL1 and DL2 may also be evaluated once available but will not be factored into this decision.

[0290] The following dose increment limitations of REGN5837 will also be implemented: a) The maximum dose increment of REGN5837 will be limited to 100% including step- up doses and full treatment doses of the next dosing cohort if any subject in a given cohort experiences a Grade > 2 AE (except for AEs unequivocally due to the underlying disease or an extraneous cause) during the DLT period. b) The maximum dose increment of REGN5837 will be limited to 50% including step-up doses and full treatment doses of the next dosing cohort if 2 or more subjects in a given cohort experience Grade > 2 AEs (except for AEs unequivocally due to the underlying disease or an extraneous cause) during the DLT period. c) The maximum dose increment of REGN5837 will be limited to 50% including step-up doses and full treatment doses of the next dosing cohort if any subject in a given cohort experiences a DLT during the DLT period. d) The maximum dose increment of REGN5837 will be limited to 30% including step-up doses and full treatment doses of the next dosing cohort if 2 or more subjects in a given cohort experience DLTs during the DLT period.

[0291] The following AEs are commonly observed with odronextamab monotherapy and might be present at a low grade at the time REGN5837 dosing is introduced: asthenia, cytopenias, clinically significant electrolyte derangements, fatigue, loss of appetite, myalgias, arthralgias, nausea, vomiting, diarrhea, rash, headache. For these AEs, the dose increment limitations guidance # (a) and (b) above require the occurrence of Grade 3 or higher events rather that Grade 2 or higher events. In addition, rules (a) and (b) listed above do not apply for infections unless if grade 4 or for hepatic enzyme and bilirubin elevations that resolve within 72 hours.

[0292] No intra-subject dose escalation will be allowed (Table 4).

Dose-Limiting Toxicity (DLT)

[0293] A DLT will be defined as any of the toxicities listed below unless the event is clearly attributable to the underlying disease or to an extraneous cause (including concomitant medications).

[0294] The grade for these toxicities are defined according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, except for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) which are defined according to the American Society for T ransplantation and Cellular Therapy (ASTCT) criteria.

[0295] A DLT is defined as the following:

Non-Hematologic Toxicity:

• Any grade 5 toxicity

• Any grade seizure • Grade 4 alanine aminotransferase/ aspartate aminotransferase (ALT/AST) values sustained for >3 consecutive days

• Any other grade >3 non-hematologic toxicity, with the exception of: o Alopecia o Nausea, vomiting, fatigue, or diarrhea lasting < 72 hours with supportive care measures as prescribed by the treating physician o Grade 3 tumor lysis syndrome (TLS) o Grade 3 infusion-related reaction (IRR) or CRS that responds to medical management and acute effects, that resolve to grade 1 or baseline within 72 hours. NOTE: Associated lab abnormalities can be at same grade for 7 days provided there is no suggestion of persistent organ injury o Following isolated laboratory abnormalities in the absence of clinical symptoms: grade < 2 alkaline phosphatase, gamma glutamyl transferase, amylase, lipase, INR, activated partial thromboplastin time, hypertriglyceridemia, electrolyte abnormalities where hospitalization is not indicated

Hematologic Toxicity:

• Any grade 5 hematologic toxicity

• Grade 4 neutropenia lasting >7 days despite granulocyte colony stimulating factor (G CSF)

• Grade 4 febrile neutropenia

• Grade 4 thrombocytopenia lasting >7 days

• Grade >3 thrombocytopenia associated with > grade 2 bleeding (except for grade 2 epistaxis)

• Grade >3 neutropenia with documented infection

[0296] T reatment-emergent adverse events (TEAEs) that appear to meet the DLT definition will be assessed. The inability to administer 2 full doses of the combination of REGN5837 and odronextamab within 35 days due to study drug toxicity will also be discussed. The final decision of whether or not the TEAE meets the DLT definition will be based on a careful review of all relevant data.

[0297] Continued treatment may occur in subjects who do not fulfill protocol-defined criteria for permanent discontinuation only if it is determined that it is in the subject’s best interest to resume combination study treatment after the occurrence of a DLT.

Dose Expansion

[0298] A total of up to 37 subjects will be enrolled in the dose expansion phase at the RP2D determined in the dose escalation portion of the study across 2 expansion cohorts: A and B. Cohorts A and B will enroll subjects with aggressive B-NHL without prior CAR-T therapy and subjects who have progressed after failure of prior CAR-T therapy respectively, who are evaluable for safety and efficacy. The analysis of these subjects will be combined with the subjects treated at the recommended phase 2 dose regimen (RP2D) in the dose escalation portion to yield a total of 20 subjects in each cohort treated at the RP2D.

[0299] Subjects enrolled in dose expansion cohorts will receive the RP2D to further evaluate the preliminary anti-tumor activity, safety, PK properties, and biomarker changes associated with combination REGN5837 and odronextamab therapy.

[0300] Subjects in the dose expansion cohorts will not be replaced if they have received at least 1 dose of REGN5837.

Study Population

[0301] The study population will consist of subjects with aggressive B-NHL lymphoma according to the WHO criteria who have progressed after at least 2 lines of treatment including an anti-CD20 antibody and an alkylating agent.

Inclusion Criteria

[0302] A subject must meet the following criteria to be eligible for inclusion in the study:

1. Age 18 years or greater

2. Have documented CD20⁺ aggressive B-NHL, with disease that has progressed after at least 2 lines of systemic therapy containing an anti-CD20 antibody and an alkylating agent. Lymphoma subtyping is based on the World Health Organization (WHO) classification. Eligible subtypes include: DLBCL, primary mediastinal (thymic) large B-cell lymphoma, T-cell/histiocyte rich large B-cell lymphoma, follicular lymphoma grade 3b, and high-grade B-cell lymphoma (HGBL) with and without MYC and BCL2 or BCL6 translocation. Subjects must, in the judgement of the investigator, require systemic therapy for lymphoma at the time of study enrollment.

NOTES:

• Subjects who relapse after the most recent prior line, or subjects who progress during or after the prior treatment, are eligible.

• Subjects who have received CAR-T therapy are eligible. Ongoing studies have demonstrated that odronextamab can be tolerated by and provides efficacy in these subjects. CAR-T naive and post-CAR-T failure subjects are evaluated separately in Cohorts A and B respectively, in the dose expansion phase.

• DLBCL that is transformed from a lower grade neoplasm (eg, FL or CLL) may be enrolled. Subjects with DLBCL transformation from prior CLL can only be enrolled in the absence of a leukemic CLL component. For subjects with transformed DLBCL, prior systemic therapies administered for the lower grade neoplasm will not be considered among the prior lines of therapy for the purpose of determining eligibility.

3. Measurable disease on cross sectional imaging (defined as at least 1 bi dimensionally measurable nodal lesion of >1.5 cm in the greatest transverse diameter (GTD) regardless of the short axis diameter) documented by diagnostic imaging (computed tomography [CT], or magnetic resonance imaging [MRI])

4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

5. Adequate bone marrow function as documented by:. a. Platelet count >50 x 109/L. A subject may not have received platelet transfusion therapy within 7 days prior to first dose of odronextamab to meet the platelet eligibility criterion b. Hemoglobin >9.0 g/dL; transfusions to meet this criteria are allowed per protocol. c. Absolute neutrophil count (ANC) >1.0 x 109/L. A subject may not have received G CSF within 2 days prior to first dose of odronextamab in order to meet the ANC eligibility criterion

NOTE: Subjects with bone marrow involvement or splenic sequestration should meet the following hematologic parameters:

- Platelet count >25 x 109/L. A subject may not have received platelet transfusion therapy within 3 days prior to first dose of odronextamab in order to meet the platelet eligibility criterion

- Hemoglobin >7.0 g/dL

- Absolute neutrophil count (ANC) > 0.5 x 109/L. A subject may not have received G-CSF within 2 days prior to first dose of odronextamab in order to meet the ANC eligibility criterion

6. Adequate hepatic function: a. Total bilirubin <1.5 x upper limit of normal (ULN) (<3 x ULN if attributed to lymphoma infiltration of liver) b. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <3 x ULN (<5 x ULN if attributed to lymphoma infiltration of liver) c. Alkaline phosphatase (ALP) <2.5 x ULN (<5 x ULN if attributed to lymphoma infiltration of liver)

NOTES: irrespective of the presence of lymphoma infiltration of the liver, a subject with an AST >3 x ULN and/or ALT >3 x ULN concurrent with a total bilirubin >1.5 x ULN will be excluded *Subjects with known Gilbert syndrome will be excluded if the total bilirubin value is >4 x ULN for the local general population

7. Calculated creatinine clearance by Cockcroft-Gault formula >50 mL/min: NOTE: Subjects with a calculated creatinine clearance <50 mL/min may be considered for enrollment if a measured creatinine clearance (based on 24-hour urine collection or other reliable method) is >50 mL/min

8. During dose expansion phase of the study, subject should be willing to undergo mandatory tumor biopsies, if in the opinion of the investigator, the subject has an accessible lesion that can be biopsied without significant risk to the subject. In the absence of such a lesion at screening, archival tissue samples up to 6 months prior (and without intervening treatment) can be considered acceptable for subject’s study eligibility (after approval by the medical monitor).

9. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations).

10. Willing and able to comply with clinic visits and study-related procedures.

11. Provide informed consent signed by study subject or legally acceptable representative

Exclusion Criteria

[0303] A subject who meets any of the following criteria will be excluded from the study:

1. Prior treatments:

• Prior allogeneic stem cell transplantation or solid organ transplantation

• Subjects who have received prior treatment with anti-CD20 x anti-CD3 bispecific antibody, such as odronextamab

2. Diagnosis of mantle cell lymphoma (MCL)

3. Primary central nervous system (CNS) lymphoma or known involvement by non-primary CNS lymphoma (even if treated into complete remission). Suspected CNS lymphoma should be evaluated by lumbar puncture, as appropriate, in addition to the mandatory head CT or MRI.

4. T reatment with any systemic anti-lymphoma therapy within 5 half-lives or within 14 days prior to first administration of study drug, whichever is shorter

5. Standard radiotherapy within 14 days of first administration of study drug. NOTE: Palliative radiotherapy to a symptomatic lymph node/lesion is allowed provided the irradiated lesion(s) or node(s) is not included as a target lesion for tumor assessments

6. Continuous systemic corticosteroid treatment with more than 10 mg per day of prednisone or corticosteroid equivalent within 72 hours of start of odronextamab 7. Co-morbid conditions: a. History of neurodegenerative condition or CNS movement disorder. Subjects with a history of seizure within 12 months prior to study enrollment are excluded b. Another malignancy in the past 5 years, with the exception of any tumor that is localized (eg, non-melanoma skin cancer or in-situ cervical carcinoma) and effectively treated with definitive local control (with or without continued adjuvant hormonal therapy) c. Cardiac ejection fraction <40% by echocardiogram (ECHO) or multigated acquisition (MLIGA) scan d. Other significant concurrent disease or medical condition that, in the opinion of the investigator, could interfere with the conduct of the study or put the subject at significant risk, including but not limited to significant cardiovascular (eg, New York Heart Association Class III or IV cardiac disease, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina), pulmonary (eg, obstructive pulmonary disease and history of symptomatic bronchospasm), gastrointestinal, hepatic, renal, endocrine, hematologic, autoimmune, psychiatric or neurologic disorder

8. Infection: a. Any infection requiring hospitalization or treatment with IV anti infectives within 2 weeks of first administration of study drug b. Uncontrolled infection with human immunodeficiency virus (HIV), hepatitis B (HBV) or hepatitis C (HCV) infection; or other uncontrolled infection

- Subjects with HIV who have controlled infection (undetectable viral load and CD4 count above 350 cells/microliter either spontaneously or on a stable antiviral regimen) are permitted

- Subjects with hepatitis B (HepBsAg+) who have controlled infection (serum hepatitis B virus DNA polymerase chain reaction [PCR] that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted

- Subjects who are hepatitis C virus antibody positive (HCV Ab+) who have controlled infection (undetectable HCV RNA by PCR either spontaneously or in response to a successful prior course of anti-HCV therapy) are permitted

9. Cytomegalovirus infection as noted by detectable levels on peripheral blood PCR assay. Subjects who show detectable levels of CMV at screening will need to be treated with appropriate antiviral therapy and demonstrate at least 2 undetectable levels of CMV by PCR assay (at least 7 days apart) before being re-considered for eligibility. 10. Allergy/hypersensitivity: Known hypersensitivity to both allopurinol and rasburicase

11. History of severe allergic reaction attributed to compounds with a similar chemical or biologic composition as that of the study drug or excipient

12. Vaccination within 28 days prior to first study drug administration with a vector that has replicative potential

13. Member of the clinical site study team or his/her immediate family unless prior approval granted by the sponsor.

14. Women of childbearing potential (WOCBP) with a positive serum p-hCG pregnancy test.

15. Pregnant or breastfeeding women.

16. Women of childbearing potential* or men who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose. Sperm donation is prohibited during the study and for 6 months after the last dose of study drug. Highly effective contraceptive measures include: a. stable use of combined (estrogen and progesterone containing) hormonal contraception (oral, intravaginal, transdermal) or progesterone-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening b. intrauterine device (IUD); intrauterine hormone releasing system (IUS) c. bilateral tubal ligation d. vasectomized partnerf (provided that the male vasectomized partner is the sole sexual partner of the study participant and that the partner has obtained medical assessment of surgical success for the procedure). e. and/or sexual abstinence ^,§. f. Male study participants with WOCBP partners are required to use condoms unless they are vasectomizedf or practice sexual abstinence. :|:,§

* Women of childbearing potential are defined as women who are fertile following menarche until becoming post-menopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.

A post-menopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a post-menopausal state. The above definitions are according to Clinical Trial Facilitation Group (CTFG) guidance.

Pregnancy testing and contraception are not required for women with documented hysterectomy. t Vasectomized partner or vasectomized study participant must have received medical assessment of the surgical success. t Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.

§ Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.

17. Subjects who are committed to an institution by virtue of an order issued either by the judicial or the administrative authorities.

Study Treatments

[0304] REGN5837 and Odronextamab (REGN1979) drug products will be supplied as liquid in sterile, single use vials for administration by IV infusion.

[0305] A pharmacist or other qualified individual will be identified at each site to prepare REGN5837 and odronextamab for administration. The dose administered will be a fixed dose and will not be determined by subject weight or body surface area.

[0306] During the initial 5 weeks of study treatment, subjects will receive weekly odronextamab administered as monotherapy. Step-up dose consists of initial dose 0.7 mg, followed by the first intermediate dose of 4 mg, and a second intermediate dose of 20 mg. The initial and both intermediate doses are always split into 2 separate infusions, with initial dose split as 0.2 mg/0.5 mg, first intermediate dose split as 2 mg each infusion, and second intermediate dose split as 10 mg each infusion. Each split dose is administered over 4 hours on each of 2 days that are preferably consecutive but no more than 3 days apart (eg, cycle 1 day 1 and cycle 1 day 2 for the initial dose and cycle 1 day 8, cycle 1 day 9 for the first intermediate dose and cycle 1 day 15, cycle 1 day 16 for the second intermediate dose); these step-up doses should be split even if there are treatment delays causing administration beyond cycle 1 day 15. On cycle 2 day 1 , the full dose of 160 mg (NOTE: 80 mg QW in DL1) will be administered. On cycle 2 day 8 another full dose of odronextamab will be administered. The first QW dose will be administered as a single infusion on cycle 2 day 1 and continue as such thereafter.

[0307] Initiation of REGN5837 is on cycle 2 day 15 in order to allow subjects to tolerate odronextamab monotherapy prior to beginning combination therapy. REGN5837 will also be initially administered with step-up dosing. All doses of REGN5837 will be administered as single infusion. On cycle 2 day 15 of study treatment, REGN5837 will be introduced at a lower, initial dose in combination with 160 mg (NOTE: 80 mg in DL1) of odronextamab. On cycle 3 day 1, REGN5837 will be given at an intermediate dose. On cycle 3 day 8, REGN5837 will be stepped up to the full QW dose.

[0308] Prior to escalation to DL3, safety data from DL1 and DL2 will be assessed. Escalation to DL3 will only proceed if the safety profile is comparable between the DL1 and DL2. However, if the safety profile of DL2 is deemed to be worse, then the escalation of REGN5837 from DL3 onwards will proceed in combination with odronextamab 80 mg QW. [0309] Subjects will receive 12 doses of combination REGN5837 and odronextamab during the REGN5837/odronextamab induction period. Subjects will receive 17 total doses of odronextamab upon completion of the REGN5837/odronextamab induction period.

[0310] After completion of the REGN5837/odronextamab induction period, subjects will advance to the maintenance period where doses are Q2W, and subjects receive the designated QW REGN5837 dose and 320 mg odronextamab (160 mg for DL1).

Study Endpoints

[0311] Primary endpoints are:

• The incidence of DLTs from the first dose of REGN5837 in combination with odronextamab through the end of the DLT observation period

• The incidence and severity of treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESIs) during the treatment period with REGN5837 in combination with odronextamab

[0312] Secondary endpoints are:

• Concentrations of REGN5837 and odronextamab in the serum

• Immunogenicity as measured by anti-drug antibodies (ADA) to REGN5837 and odronextamab

• Overall response rate (ORR), which is the proportion of patients who achieve a best overall response CR or PR during or following study treatment, according to the Lugano Classification of response in malignant lymphoma assessed by investigator • Complete response (CR) rate, which is the proportion of patients who achieve a best overall response CR during or following study treatment, according to the Lugano Classification assessed by investigator

• Progression Free Survival (PFS) according to the Lugano Classification assessed by investigator, determined as time from the start of study treatment until the first date of progressive disease, or death due to any cause, whichever occurs first.

• Overall survival (OS), measured from the start of study treatment until deah due to any cause

• Duration of response (DOR) according to the Lugano Classification assessed by investigator, determined as time from the date of the first documented CR or PR until the first date of progressive disease, or death due to any cause, whichever occurs first

[0313] Exploratory endpoints are:

• Changes in absolute numbers of peripheral T-cells, including the activation and proliferation phenotype of T-cell subsets measured by multiparameter flow cytometry along with changes in serum cytokine levels

• Comparison of response (by the Lugano Classification) with both baseline levels and on-treatment I at relapse changes in lymph node T-cell density and expression of immune markers such as CD28, 41 BB, programmed death receptor-1 (PD-1), Lag3, GzmB, IFN-y, Ki67, along with B-cell markers (CD20, CD22), as measured by multiplex IHC and/or RNA Scope

• Fraction of molecular MRD negative subjects at clinical complete response by next generation sequencing and the correlation with PFS and OS

• Assessment of the relationship between clinical drug concentrations and pharmacodynamics, safety, and efficacy measures

Procedures and Assessments

[0314] Data will be summarized by dose level, disease subtype, and prior treatment group(s). Demographic and baseline characteristics will be summarized descriptively. Safety observations and measurements including drug exposure, adverse events, laboratory data, vital signs, and European Cooperative Oncology Group performance status will be summarized.

[0315] Treatments will be assessed using the following procedures and assessments

• Procedures Performed Only at the Screening/Baseline Visit

• Safety Procedures

• Immune Safety Assessments

• Laboratory Testing • Efficacy Procedures

• Drug Concentration and Measurements

• Immunogenicity Measurements and Samples

• Pharmacodynamic and Exploratory Biomarkers

• Future Biomedical Research (optional)

• Pharmacogenomic analysis (optional)

Statistical Plan and Analysis

[0316] This section provides the basis for the statistical analysis plan (SAP) for the study. The SAP will be revised prior to the end of the study to accommodate amendments to the clinical study protocol and to make changes to adapt to unexpected issues in study execution and data that may affect the planned analyses.

Justification of Sample Size

[0317] Up to total 91 subjects are planned to be enrolled.

[0318] Dose Escalation Portion: Up to 54 subjects are to be enrolled in the dose escalation portion, under the assumption that average 6 subjects per dose level may be enrolled across 9 dose levels. The actual sample size of these dose escalation cohorts will depend on the number of observed subjects with DLTs and number of dose levels implemented.

[0319] Dose Expansion Portion: There will be 2 dose expansion cohorts of subjects with aggressive B-NHL: 1 cohort with no prior CAR T therapy, and 1 cohort with subjects who progressed after failure of prior CAR-T therapy. In each cohort, 20 subjects are needed including 3 subjects treated at the RP2D in the dose escalation portion. Therefore, up to a total of 37 subjects will be enrolled in the dose expansion portion..

[0320] The sample size of 20 subjects in each cohort is determined to further explore the safety and to better understand the preliminary anti-tumor activity of the combination of REGN5837 with odronextamab in subjects treated at the RP2D.

[0321] Preliminary Evaluation of Anti-tumor Activity: The 20 subjects treated at RP2D in the Dose Escalation and Expansion portions will provide a preliminary evaluation of anti-tumor activity.

Analysis Sets

[0322] Efficacy Analysis Sets: The full analysis set (FAS) includes all subjects who received any study drug. Efficacy endpoints will be analyzed using the FAS. [0323] Safety Analysis Set: The safety analysis set (SAF) includes all subjects who received any study drug and will be based on the treatment received. Treatment compliance/administration and all clinical safety variables will be analyzed using the SAF. [0324] Pharmacokinetic Analysis Sets: The PK analysis set includes all subjects who received at least one dose of study drugs and who had at least one non-missing drug concentration result following the first dose of study drugs.

[0325] Immunogenicity Analysis Sets: The anti-drug antibody analysis sets (AAS) are defined for each study drug separately and include all treated subjects who received any amount of study drug (safety analysis set) and had at least one non missing ADA result following the first dose of the respective study drug.

[0326] Dose-Limiting Toxicity Analysis Set: The dose-limiting toxicity (DLT) analysis set includes all subjects enrolled in dose escalation, treated with REGN5837 and odronextamab and DLT evaluable, defined as the subjects who completed the DLT observation period, and those subjects who discontinued early due to the development of a DLT during the DLT observation period. This analysis set will be used for the assessment of DLTs for determination of dose escalation

Efficacy Analysis

[0327] Primary efficacy analysis: All the efficacy endpoints are secondary endpoints in this study.

[0328] Secondary efficacy analysis: The ORR and CR rate according to the Lugano Classification based on local investigator review will be summarized along with the 2-sided 95% confidence interval. Subjects who are not evaluable for the best overall response will be considered as non-responders. The other secondary efficacy endpoints, including DOR, PFS, and OS will be summarized by median and its 95% confidence interval using the Kaplan-Meier method, if applicable.

Example 3: Results

[0329] It is expected that administration of REGN5837 in combination with REGN1979 will lead to enhanced tumor regression and improved disease control. Further, it is expected that administration of REGN5837 in combination with REGN1979 will be safe with no increased incidence of adverse events and/or toxicity over monotherapy.

[0330] The trial is enrolling. Preliminary results indicate that administration of REGN5837 and REGN1979 is safe.

[0331] The present disclosure is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the disclosure in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying figures. Such modifications are intended to fall within the scope of the appended claims.

Claims

1. A method for treating a B-cell proliferative disorder or a CD20-expressing cell malignancy in a subject, the method comprising administering to the subject a therapeutically effective amount of a bispecific CD22xCD28 antibody or antigen-binding fragment thereof in combination with a bispecific CD3xCD20 antibody or antigen-binding fragment thereof, wherein the bispecific CD22xCD28 antibody or antigen-binding fragment thereof comprises a first antigen-binding domain that binds cluster of differentiation factor 28 (CD28) and a second antigen-binding domain that binds cluster of differentiation factor 22 (CD22), and the bispecific CD3xCD20 antibody or antigen-binding fragment thereof comprises a first antigen-binding domain that binds cluster of differentiation factor 3 (CD3) and a second antigen-binding domain that binds cluster of differentiation factor 20 (CD20), thereby treating the B-cell proliferative disorder or CD20-expressing cell malignancy in the subject.

2. The method of claim 1, wherein the B-cell proliferative disorder is a B-cell lymphoma.

3. The method of claim 2, wherein the lymphoma is a B-cell non-Hodgkin lymphoma (B-NHL).

4. The method of claim 3, wherein the non-Hodgkin lymphoma is selected from the group consisting of diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), high-grade B-cell lymphoma, Burkitt lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma.

5. The method of any one of claims 1-4, further comprising selecting a subject, wherein the subject has an aggressive B-NHL.

6. The method of any one of claims 1-5, wherein the subject has at least one of the following criteria, or is selected on the basis of at least one of the following criteria: a. has CD20+ aggressive B-NHL; b. has progressed after at least 2 lines of systemic therapy containing a CD20 inhibitor and an alkylating agent; c. has measurable disease on cross sectional imaging d. has adequate bone marrow function and hepatic function; and/or e. has any of the following cancer types: DLBCL, primary mediastinal (thymic) large B-cell lymphoma, T-cell/histiocyte rich large B-cell lymphoma, follicular lymphoma grade 3b, and high-grade B-cell lymphoma (HGBL) with or without MYC, BCL2 or BCL6 translocations.

7. The method of any one of claims 1-6, wherein the subject has been treated with a prior therapy and relapsed or the disorder progressed during or after the prior treatment.

8. The method of any one of claims 1-7, wherein the subject has received a CAR-T therapy.

9. The method of any one of claims 1-8, wherein the subject has measurable CD20+ aggressive B-NHL that has progressed after >2 lines of systemic therapy containing at least a CD20 inhibitor and an alkylating agent.

10. The method of claim 9, wherein the CD20 inhibitor is an anti-CD20 antibody.

11. The method of claim 9 or 10, wherein the subject has been treated with CAR-T cell therapy.

12. The method of any one of claims 9-11, wherein the subject has not been previously treated with a CD3 antibody, a CD3 bispecific antibody, or a CD3xCD20 bispecific antibody.

13. The method of any one of claims 1-12, wherein the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is administered at a dose of about 0.01 mg to about 400 mg.

14. The method of any one of claims 1-13, wherein the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is administered at a dose of about 0.01 mg, 0.03 mg, 0.05 mg, 0.1 mg, 0.3 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 200 mg, 240 mg, 280 mg, 300 mg, 320 mg, 350 mg, or 400 mg.

15. The method of any one of claims 1-14, wherein the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered at a dose of about 0.1 mg to about 400 mg.

16. The method of any one of claims 1-15, wherein the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered at a dose of about 0.1 mg, 0.2 mg, 0.3 mg, 0.5 mg, 0.7 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 200 mg, 240 mg, 280 mg, 300 mg, 320 mg, 350 mg, or 400 mg.

17. The method of any one of claims 1-16, wherein the method comprises administering one or more doses of the bispecific CD22xCD28 antibody or antigenbinding fragment thereof in combination with one or more doses of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof.

18. The method of claim 17, wherein each of the one or more doses of the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is about 0.01 mg to about 400 mg.

19. The method of claim 18, wherein each of the one or more doses is about 0.01 mg, 0.03 mg, 0.05 mg, 0.1 mg, 0.3 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 200 mg, 240 mg, 280 mg, 300 mg, 320 mg, 350 mg, or 400 mg.

20. The method of any one of claims 17-19, wherein each of the one or more doses of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is about 0.1 mg to about 400 mg.

21. The method of any one of claims 17-20, wherein each of the one or more doses of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is about 0.1 mg, 0.2 mg, 0.3 mg, 0.5 mg, 0.7 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 8 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 200 mg, 240 mg, 280 mg, 300 mg, 320 mg, 350 mg, or 400 mg.

22. The method of any one of claims 17-21, wherein one or more doses of the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the one or more doses of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered 1 day to 8 weeks after the immediately preceding dose.

23. The method of any one of claims 17-22, wherein each of the one or more doses of the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the one or more doses of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered once every week, once every two weeks, once every three weeks, once every four weeks, once every five weeks or once every six weeks.

24. The method of any one of claims 17-23, wherein one or more doses of the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is administered once every week.

25. The method of any one of claims 17-24, wherein one or more doses of the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is administered once every two weeks.

26. The method of any one of claims 17-25, wherein one or more doses of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered once every week.

27. The method of any one of claims 17-26, wherein one or more doses of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered once every two weeks.

28. The method of any one of claims 17-27, wherein a dose of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered in a single administration, or split and administered on two days that are no more than 3 days apart.

29. The method of any one of claims 1-28, wherein the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the bispecific CD3xCD20 antibody or antigen-binding fragment are administered intravenously.

30. The method of any one of claims 1-29, wherein the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the bispecific CD3xCD20 antibody or antigen-binding fragment thereof are administered subcutaneously.

31. The method of any one of claims 1-30, wherein the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the bispecific CD3xCD20 antibody or antigen-binding fragment thereof are administered on the same day.

32. The method of any one of claims 1-31, wherein the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and/or the bispecific CD3xCD20 antibody or antigen-binding fragment thereof are administered on different days.

33. The method of claim 32, wherein the bispecific CD22xCD28 antibody or antigenbinding fragment thereof is administered before or after the bispecific CD3xCD20 antibody or antigen-binding fragment thereof.

34. The method of claim 33, wherein the bispecific CD22xCD28 antibody or antigenbinding fragment thereof is administered one day before the bispecific CD3xCD20 antibody or antigen-binding fragment thereof.

35. The method of any one of claims 1-34, comprising the steps of:

(i) administering to the subject the bispecific CD3xCD20 antibody or antigenbinding fragment thereof at a dose of 0.1 mg to 160 mg subcutaneously or intravenously every week for a period of monotherapy, wherein the period of monotherapy is at least 2 weeks; and

(ii) administering to the subject the bispecific CD22xCD28 antibody or antigenbinding fragment thereof at a dose of 0.01 mg to 400 mg subcutaneously or intravenously every week, and administering to the subject the bispecific CD3xCD20 or antigen-binding fragment thereof at a dose of 80 mg to 160 mg intravenously or subcutaneously every week for a period of induction combination therapy.

36. The method of claim 35, wherein the period of monotherapy is at least 2 weeks, at least 3 weeks, at least 4 weeks, or at least 5 weeks.

37. The method of claim 36 or 37, wherein the dose of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof during the period of monotherapy period is split and administered on two different days that are no more than 3 days apart, or administered in a single administration.

38. The method of any one of claims 35-37, wherein the monotherapy period in step (i) comprises administering an initial dose of the bispecific CD3xCD20 antibody and increasing the dose of to a full dose by the end of the monotherapy period.

39. The method of claim 38, wherein the full dose of the bispecific CD3xCD20 in step (i) is 80 or 160 mg.

40. The method of any one of claims 35-39, wherein the induction combination therapy period in step (ii) comprises:

(a) administering an initial dose of the bispecific CD22xCD28 antibody wherein the initial dose comprises 0.03 mg to 2 mg;

(b) administering an intermediate dose comprising 0.1 mg to 20 mg of the bispecific CD22xCD28 antibody; and

(c) administering a full dose of the bispecific CD22xCD28 wherein the full dose comprises 0.3 mg to 160 mg.

41. The method of any one of claims 35-40, wherein, during step (ii), the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered on a different day as the bispecific CD22xCD28 antibody or antigen-binding fragment thereof.

42. The method of claim 41 , wherein the bispecific CD3xCD20 antibody or antigenbinding fragment thereof is administered one day after the bispecific CD22xCD28 antibody or antigen-binding fragment thereof.

43. The method of any one of claims 35-40, wherein, during step (ii), the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is administered on the same day as the bispecific CD22xCD28 antibody or antigen-binding fragment thereof.

44. The method of any one of claims 35-43, wherein the bispecific CD22xCD28 antibody or antigen-binding fragment thereof is administered in combination with the bispecific CD3xCD20 or antigen-binding fragment thereof in step (ii) for at least 9 weeks.

45. The method of claim 44, wherein the bispecific CD22xCD28 antibody or antigenbinding fragment thereof is administered in combination with the bispecific CD3xCD20 antibody or antigen-binding fragment thereof in step (ii) for at least 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks or 15 weeks.

46. The method of any one of claims 35-44, further comprising:

(iii) administering the bispecific CD22xCD28 antibody or antigen-binding fragment thereof in combination with 160 mg or 320 mg of the bispecific CD3xCD20 antibody or antigen-binding fragment thereof after step (ii) every two or more weeks for a period of maintenance combination therapy.

47. The method of claim 46, wherein in step (iii), the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and the bispecific CD3xCD20 antibody or antigenbinding fragment are administered on the same day.

48. The method of claim 46 or 47, wherein in step (iii), the bispecific CD22xCD28 antibody or antigen-binding fragment thereof and the bispecific CD3xCD20 or antigenbinding fragment are administered every two weeks or every four weeks.

49. The method of any one of claims 1-48, further comprising administering to the subject one or more additional agents to treat or prevent one or more symptoms of an adverse event.

50. The method of any one of claims 1-49, wherein the bispecific antibodies are administered to the subject in combination with a second agent wherein the second agent is selected from the group consisting of dexamethasone, diphenhydramine, acetaminophen, a steroid, an antihistamine, a non-steroidal anti-inflammatory drug (NSAID), an IL-6 antagonist, and an IL-6R antagonist.

51 . The method of any one of claims 1-50, wherein the subject has stable disease, partial response, or complete response upon administration of the bispecific CD22xCD28 antibody or antigen-binding fragment thereof for at least one week at a dose of about 0.01 mg to about 400 mg in combination with the bispecific CD3xCD20 antibody or antigenbinding fragment thereof.

52. The method of any one of claims 1-51 , wherein the bispecific CD3xCD20 antibody or antigen-binding fragment thereof comprises: i) a CD3 binding arm comprising the heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 5 and three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 6; and ii) a CD20 binding arm comprising the heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 4 and three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 6.

53. The method of any one of claims 1-52, wherein the bispecific CD3xCD20 antibody or antigen-binding fragment thereof comprises i) a CD3 binding arm comprising three HCDRs (HCDR1, HCDR2 and HCDR3) and three LCDRs (LCDR1 , LCDR2 and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 10; HCDR2 comprises the amino acid sequence of SEQ ID NO: 11; HCDR3 comprises the amino acid sequence of SEQ ID NO: 12; LCDR1 comprises the amino acid sequence of SEQ ID NO: 13; LCDR2 comprises the amino acid sequence of SEQ ID NO: 14; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 15; and ii) the CD20 binding arm comprising three HCDRs (HCDR1 , HCDR2 and HCDR3) and three LCDRs (LCDR1 , LCDR2 and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 7; HCDR2 comprises the amino acid sequence of SEQ ID NO: 8; HCDR3 comprises the amino acid sequence of SEQ ID NO: 9; LCDR1 comprises the amino acid sequence of SEQ ID NO: 13; LCDR2 comprises the amino acid sequence of SEQ ID NO: 14; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 15.

54. The method of claim 53, wherein the HCVR of the CD3 binding arm comprises the amino acid sequence of SEQ ID NO: 5, the HCVR of the CD20 binding arm comprises the amino acid sequence of SEQ ID NO: 4, and the common LCVR comprises the amino acid sequence of SEQ ID NO: 6.

55. The method of any one of claims 52-54, wherein the bispecific CD3xCD20 antibody or antigen-binding fragment thereof comprises a heavy chain of the CD3 binding arm comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain of the CD20 binding arm comprising the amino acid sequence of SEQ ID NO: 1, and a common light chain comprising the amino acid sequence of SEQ ID NO: 3.

56. The method of any one of claims 1-55, wherein the bispecific CD3xCD20 antibody or antigen-binding fragment thereof is odronextamab.

57. The method of any one of claims 1-56, wherein the first antigen-binding domain that binds CD28 comprises three heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 20; and three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 21.

58. The method of claim 57, wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 25, HCDR2 comprises the amino acid sequence of SEQ ID NO: 26, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 27.

59. The method of claim 58, wherein LCDR1 comprises the amino acid sequence: of SEQ ID NO: 28, LCDR2 comprises the amino acid sequence of SEQ ID NO: 29, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 30.

60. The method of any one of claims 57-59, wherein the first antigen-binding domain that binds CD28 comprises a HCVR comprising the amino acid sequence of SEQ ID NO:

20, and a LCVR comprising the amino acid sequence of SEQ ID NO: 21.

61. The method of any one of claims 1-60, wherein the second antigen binding domain that binds CD22 comprises three heavy chain complementarity determining regions (HCDR1 , HCDR2 and HCDR3) contained within a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 19; and three light chain complementarity determining regions (LCDR1 , LCDR2 and LCDR3) contained within a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:

21.

62. The method of claim 61 , wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 22, HCDR2 comprises the amino acid sequence of SEQ ID NO: 23, and HCDR3 comprises the amino acid sequence of SEQ ID NO: 24.

63. The method of claim 62, wherein LCDR1 comprises the amino acid sequence: of SEQ ID NO: 28, LCDR2 comprises the amino acid sequence of SEQ ID NO: 29, and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 30.

64. The method of any one of claims 61-63, wherein the second antigen-binding domain that binds CD22 comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 19, and a LCVR comprising the amino acid sequence of SEQ ID NO: 21.

65. The method of any one of claims 1-64, wherein:

(a) the first antigen binding domain that binds human CD28 comprises a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 20, and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 21; and

(b) the second antigen binding domain that binds CD22 comprises a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 19; and a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 21.

66. The method of any one of claims 57-65, wherein the bispecific CD22xCD28 antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 17.

67. The method of any one of claims 57-66, wherein the bispecific CD22xCD28 antibody comprises a second heavy chain comprising the amino acid sequence of SEQ ID NO: 16.

68. The method of any one of claims 57-67, wherein the bispecific CD22xCD28 antibody comprises a light chain comprising the amino acid sequence of SEQ ID NO: 18.

69. The method of any one of claims 57-68, wherein the bispecific CD22xCD28 antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 17, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 16, and a common light chain comprising the amino acid sequence of SEQ ID NO: 18.

70. The method of any one of claims 57-69, wherein the first antigen-binding domain comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 17 and a light chain comprising the amino acid sequence of SEQ ID NO: 18.

71. The method of any one of claims 57-70, wherein the second antigen-binding domain comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 16 and a light chain comprising the amino acid sequence of SEQ ID NO: 18.

72. The method of any one of claims 1-71 , wherein the bispecific CD22xCD28 antibody is REGN5837, or an antigen-binding fragment thereof.