WO2019075392A1

WO2019075392A1 - Antigen-binding protein constructs and uses thereof

Info

Publication number: WO2019075392A1
Application number: PCT/US2018/055701
Authority: WO
Inventors: Alexander J. Nichols; Brian P. FISKE
Original assignee: Inevation LLC
Current assignee: Inevation LLC
Priority date: 2017-10-12
Filing date: 2018-10-12
Publication date: 2019-04-18
Anticipated expiration: 2020-04-12

Abstract

Provided herein are ph-dependent and conformation specific antigen-binding protein constructs directed to MHC 1 and uses of the same.

Description

ANTIGEN-BINDING PROTEIN CONSTRUCTS

AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application Serial No. 62/571,729, filed October 12, 2017, U.S. Provisional Patent Application Serial No.

62/571,735 filed October 12, 2017, and U.S. Provisional Patent Application Serial No. 62/571,733, filed October 12, 2017; the entire contents of which are herein incorporated by reference. SEQUENCE LISTING

This instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on October 12, 2018, is named Sequence Listing.txt and is 1,380,401 kilobytes in size. TECHNICAL FIELD

The present disclosure relates to the field of biotechnology, and more specifically, to antigen-binding molecules.

BACKGROUND

Antibody-drug-conjugates have been designed to combat a variety of diseases. One particular advantage of this approach is the ability for antibody-drug conjugates to have cytostatic or cytotoxic effects. Despite years of development, off-target effects of antibody- drug-conjugates remains an issue, and cause adverse effects in patients.

SUMMARY

The present invention is based on the concept that antigen-binding protein constructs and multi-specific antigen-binding protein constructs can be generated that display enhanced target cell selectivity and have reduced adverse effects and increased efficacy. The presently provided antigen-binding protein constructs and multi-specific antigen-binding constructs may provide for selective treatment of a cancer in a subject (e.g., a cancer characterized by having a population of cancer cells that have at least one of the following: (a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced level of MHCl or MHCl complex presentation on their surface, and/or a reduced level of MHCl in a cellular compartment as compared to a non-cancerous cell; (b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced level of TAP in the endoplasmic reticulum of a cell and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell; (c) a reduced level of expression of β2πι polypeptide, a reduced level of β2ιη polypeptide present on their surface, and/or a reduced level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ηι gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell).

The presently provided multi-specific antigen-binding constructs may provide for selective treatment of a cancer in a subject (e.g., a cancer characterized by having a population of cancer cells that (i) have the identifying antigen present on their surface, and (ii) have at least one of the following: (a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced level of MHCl or MHCl complex presentation on their surface, and'or a reduced level of MHCl in a cellular compartment as compared to a non-cancerous cell; (b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced level of TAP in the endoplasmic reticulum of a cell and/or a genetic lesion in a TAP gene as compared to a noncancerous cell; (c) a reduced level of expression of β2ιη polypeptide, a reduced level of β2ιη polypeptide present on their surface, and/or a reduced level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ηι gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell).

The presently provided antigen-binding protein constructs and multi-specific antigen- binding protein constructs may also provide a reduction in off-target cytotoxicity.

As used throughout this application, the term "multi-specific antigen-binding protein construct" or "multi-specific ABPC" refers to embodiments of an antigen-binding protein ABPC that includes:

(1) a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, where:

the first antigen-binding domain is capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell; and the second antigen-binding domain is capable of specifically binding to an epitope of a polypeptide complex, where the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2πι) polypeptide, where:

(a) the dissociation rate of the second antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or

(b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH is less than the KD at a neutral pH; and

the second antigen-binding domain comprises at least one paratope that comprises at least one histidine residue;

(2) a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, where:

the first antigen-binding domain is capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell; and

the second antigen-binding domain capable of specifically binding to an epitope of a polypeptide complex (PC), where the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ιη) polypeptide,

where the multi-specific ABPC has increased endosomal recycling in a mammalian cell that presents the PC on its surface or in a cellular compartment as compared to a control ABPC;

(3) a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, where:

the second antigen-binding domain is capable of specifically binding an epitope of a beta 2-microglobulin (β2ιη) polypeptide, where:

the second antigen-binding domain comprises at least one paratope that comprises at least one histidine residue; or (4) a first antigen-binding domain capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell;

(b) a second antigen-binding domain capable of specifically binding to an epitope of a polypeptide complex (PC), where the polypeptide complex comprises (i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and (ii) a beta 2-microglobulin (β2ιη) polypeptide; and

(c) a conjugated toxin, radioisotope, or drug,

where the multi-specific ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC complex on its surface or in a cellular compartment as compared to a control ABPC .

As used throughout this application, the term "antigen-binding protein construct" or "ABPC" refers to embodiments of an antigen-binding protein ABPC that includes:

(1) a first antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex, where the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2πι) polypeptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain, where:

(a) the dissociation rate of the first antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or

(b) the dissociation constant (KD) of the first antigen-binding domain at an acidic pH is less than the KD at a neutral pH; and

the first antigen-binding domain comprises at least one paratope that comprises at least one histidine residue, and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC in vivo;

(2) a first antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex (PC), where the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ιη) polypeptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain, wherein:

the ABPC has increased endosomal recycling in a mammalian cell that presents the PC on its surface or in a cellular compartment as compared to a control ABPC, and optionally, the half-life of the ABPC in vivo is increased as compared to the half- life of a control ABPC in vivo;

(3) a first antigen-binding domain that is capable of specifically binding to an epitope of a beta 2-microglobulin (β2ιη) polypeptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain, where:

(b) the dissociation constant (KD) of the first antigen-binding domain at an acidic pH is less than the KD at a neutral pH;

the first antigen-binding domain comprises at least one paratope that comprises at least one histidine residue, and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC in vivo; or

(4) a first antigen-binding domain that is capable of specifically binding to an epitope of a polypeptide complex (PC), where the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ηι) polypeptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain,

where the ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC complex on its surface or in a cellular

compartment as compared to a control ABPC, and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC in vivo. Provided herein are pharmaceutical compositions that include an effective amount of an antigen-binding protein construct (ABPC) that include: a first antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex, wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA- A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ηι) polypeptide; and one or both of a conjugated toxin, radioisotope, or drug, and an additional antigen-binding domain, wherein: (a) the dissociation rate of the first antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or (b) the dissociation constant (KD) of the first antigen- binding domain at an acidic pH is less than the KD at a neutral pH; and the first antigen- binding domain includes at least one paratope that includes at least one histidine residue, and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC in vivo.

Provided herein are pharmaceutical compositions that include an effective amount of an antigen-binding protein construct (ABPC) that include: a first antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex (PC), wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA- A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2πι) polypeptide; and one or both of: a conjugated toxin, radioisotope, or drug, and an additional antigen-binding domain, wherein: the ABPC has increased endosomal recycling in a mammalian cell that presents the PC on its surface or in a cellular compartment as compared to a control ABPC; and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC in vivo.

Provided herein are pharmaceutical compositions that include an effective amount of an antigen-binding protein construct (ABPC) that include: a first antigen-binding domain that is capable of specifically binding to an epitope of a beta 2-microglobulin (β2ιη) polypeptide; and one or both of a conjugated toxin, radioisotope, or drug, and an additional antigen- binding domain, wherein: (a) the dissociation rate of the first antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or (b) the dissociation constant (KD) of the first antigen-binding domain at an acidic pH is less than the Kx> at a neutral pH; the first antigen-binding domain includes at least one paratope that includes at least one histidine residue; and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC in vivo.

Provided herein are pharmaceutical compositions that include an effective amount of an antigen-binding protein construct (ABPC) that include: a first antigen-binding domain that is capable of specifically binding to an epitope of a polypeptide complex (PC), where the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA- A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ηι) polypeptide; and one or both of: a conjugated toxin, radioisotope, or drug, and an additional antigen-binding domain, where: the ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC complex on its surface or in a cellular compartment as compared to a control ABPC, and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC in vivo. In some embodiments of any of the pharmaceutical compositions described herein that include any of the antigen-binding protein constructs described herein, the ABPC further includes a second antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex, wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ιη) polypeptide, wherein: (a) the dissociation rate of the second antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or (b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH is less than the KD at a neutral pH, and wherein the second antigen-binding domain includes at least one paratope that includes at least one histidine residue.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the ABPC further includes a second antigen-binding domain that is capable of specifically binding an epitope of a beta 2- microglobulin (β2ηι) polypeptide, wherein: (a) the dissociation rate of the second antigen- binding domain at an acidic pH is slower than the disassociation rate at a neutral pH; or (b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH is less than the KD at a neutral pH; and wherein the second antigen-binding domain includes at least one paratope that includes at least one histidine residue.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the additional antigen-binding domain is capable of specifically binding to a soluble antigen or an antigen that is presented on the surface or in a cellular compartment of a target cell, or an antigen that is pericellular to a target cell. In some embodiments, the additional antigen-binding domain of any of the antigen-binding protein constructs described herein is capable of specifically binding to an antigen of an infectious disease, an antigen present on a surface of a target cell, or a therapeutic target antigen.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the first antigen-binding domain and the second antigen-binding domain, if present, specifically bind(s) an epitope that includes at least one amino acid of the polypeptide encoded by the HLA gene selected from the group consisting of HLA-A, HL A-B, and HLA-C, and at least one amino acid of the β2ιη polypeptide. In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the first antigen-binding domain and the second antigen-binding domain, if present, specifically bind(s) an epitope of a polypeptide encoded by the HLA gene selected from HLA-A, HLA-B, and HLA-C, when the polypeptide encoded by the HLA gene is bound to the β2ιη peptide.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the epitope of the PC is an at least partially a monomorphic epitope.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the second antigen-binding domain specifically binds an epitope of the β2ιτι polypeptide, when the β2πι polypeptide is bound to a polypeptide encoded by an HLA gene selected from the group consisting of HLA-A, HLA-B, and HLA-C.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-A variant polypeptide-beta 2-microglobulin (β2πι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen- binding domain, respectively, for the polypeptide encoded by the HLA-A gene-beta 2- microglobulin (β2ηι) polypeptide complex, wherein the HLA-A variant polypeptide is identical to the polypeptide encoded by the HLA-A gene except at one or more residues which both: (i) are located in the HLA-A epitope bound by the first antigen-binding domain or the second antigen-binding domain, respectively, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-A gene.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-B variant polypeptide-beta 2-microglobulin (β2ιη) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen- binding domain, respectively, for the polypeptide encoded by the HLA-B gene-beta 2- microglobulin (β2ηι) polypeptide complex, wherein the HLA-B variant polypeptide is identical to the polypeptide encoded by the HLA-B gene except at one or more residues which both: (i) are located in the HLA-B epitope bound by the first antigen-binding domain or the second antigen-binding domain, respectively, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-B gene.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-C variant polypeptide-beta 2-microglobulin (β2ηι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen- binding domain, respectively, for the polypeptide encoded by the HLA-C gene-beta 2- microglobulin (β2πι) poly peptide complex, wherein the HLA-C variant polypeptide is identical to the polypeptide encoded by the HLA-C gene except at one or more residues which both: (i) are located in the HLA-C epitope bound by the first antigen-binding domain or the second antigen-binding domain, respectively, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-C gene.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the first antigen-binding domain, and, if present, the second antigen-binding domain or the additional antigen-binding domain is/are capable of specifically binding to an epitope present on the surface or in a cellular compartment of human cells and an epitope that is present on the surface or in a cellular compartment of cells from an Old World Monkey.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the dissociation rate of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is/are at least 10% slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the dissociation rate of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 3-fold or 10-fold slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH. In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 10% less than the Kx> of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 3-fold or 10-fold less than the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the first antigen-binding domain and the second antigen-binding domain, if present, are each independently selected from the group of: a VHH domain, a VNAR domain, and a scFv.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the additional antigen-binding domain has a KD that is increased at an acidic pH as compared to the KD of the additional antigen-binding domain at a neutral pH.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the additional antigen-binding domain has a KD at an acidic pH that is at least 10% increased as compared to the KD of the additional antigen-binding domain at a neutral pH.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the additional antigen-binding domain has a KD at an acidic pH that is at least 3-fold or 10-fold greater than the KD of the additional antigen-binding domain at a neutral pH.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs described herein, the pH dependency is dictated by charge-charge interactions by the paratope and epitope of the first antigen-binding domain and the second antigen-binding domain, if present.

Provided herein are pharmaceutical compositions that include an effective amount of a multi-specific antigen-binding protein construct (multi-specific ABPC) that include: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, wherein: the first antigen-binding domain is capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell; and the second antigen-binding domain is capable of specifically binding to an epitope of a polypeptide complex, wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ιη) polypeptide, wherein: (a) the dissociation rate of the second antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or (b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH is less than the KD at a neutral pH; and the second antigen-binding domain includes at least one paratope that includes at least one histidine residue.

Also provided herein are pharmaceutical compositions that include an effective amount of a multi-specific antigen-binding protein construct (multi-specific ABPC) that includes: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, wherein: the first antigen-binding domain is capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell; and the second antigen-binding domain capable of specifically binding to an epitope of a polypeptide complex (PC), wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2πι) poly peptide, wherein the multi-specific ABPC has increased endosomal recycling in a mammalian cell that presents the PC on its surface or in a cellular compartment as compared to a control ABPC.

Also provided herein are pharmaceutical compositions that include an effective amount of a multi-specific antigen-binding protein construct (multi-specific ABPC) that includes: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, wherein: the first antigen-binding domain is capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell; and the second antigen-binding domain is capable of specifically binding an epitope of a beta 2-microglobulin (β2πι) polypeptide, wherein: (a) the dissociation rate of the second antigen- binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or (b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH is less than the KD at a neutral pH; and the second antigen-binding domain includes at least one paratope that includes at least one histidine residue. Also provided herein are pharmaceutical compositions that include an effective amount of a multi-specific antigen-binding protein construct (multi-specific ABPC) that includes: (a) a first antigen-binding domain that is capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell; (b) a second antigen- binding domain capable of specifically binding to an epitope of a polypeptide complex (PC), wherein the polypeptide complex includes (i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and (ii) a beta 2-microglobulin ( 2m)

polypeptide; and (c) a conjugated toxin, radioisotope, or drug, wherein the multi-specific ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC complex on its surface or in a cellular compartment as compared to a control ABPC.

In some embodiments of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, the second antigen- binding domain specifically binds to an epitope that includes at least one amino acid of the polypeptide encoded by the HLA gene selected from the group consisting of HLA-A, HLA- B, and HLA-C, and at least one amino acid of the β2πι polypeptide.

In some embodiments of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, the epitope of the PC is an at least partially monomorphic epitope.

In some embodiments of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, the second antigen- binding domain specifically binds to an epitope of a polypeptide encoded by the HLA gene selected from HLA-A, HLA-B, and HLA-C, when the polypeptide encoded by the HLA gene is bound to the β2πι polypeptide.

In some embodiments of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, the second antigen- binding domain specifically binds to an epitope of the β2πι polypeptide when the β2πι polypeptide is bound to a polypeptide encoded by an HLA gene selected from the group consisting of HLA-A, HL A-B, and HLA-C.

In some embodiments of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain for an HLA-A variant polypeptide-beta 2-microglobulin (β2ιη) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the second antigen-binding domain for the polypeptide encoded by the HLA-A gene-beta 2- microglobulin (β2ηι) polypeptide complex, and wherein the HLA-A variant polypeptide is identical to the polypeptide encoded by the HLA-A gene except at one or more residues which both: (i) are located in the HLA-A epitope bound by the second antigen-binding domain, wherein the epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-A gene.

In some embodiments of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain for an HLA-B variant polypeptide-beta 2-microglobulin (β2ηι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the second antigen-binding domain for the polypeptide encoded by the HLA-B gene-beta 2- microglobulin (β2πι) poly peptide complex, and wherein the HLA-B variant polypeptide is identical to the polypeptide encoded by the HLA-B gene except at one or more residues which both: (i) are located in the HLA-B epitope bound by the second antigen-binding domain, wherein the epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-B gene.

In some embodiments of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain for an HLA-C variant polypeptide-beta 2-microglobulin (β2ιη) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the second antigen-binding domain for the polypeptide product of the HLA-C gene-beta 2- microglobulin (β2ιη) poly peptide complex, and wherein the HLA-C variant polypeptide is identical to the polypeptide encoded by the HLA-C gene except at one or more residues which both: (i) are located in the HLA-C epitope bound by the second antigen-binding domain, wherein the epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-C gene.

In some embodiments of any of the pharmaceutical compositions including any of the multi-specific antigen-binding protein constructs described herein, the pH dependent binding is dictated through charge-charge interactions between the epitope and the paratope of the first antigen-binding domain and/or the second antigen-binding domain.

In some embodiments of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, the first antigen- binding domain and the second binding domain, is/are capable of specifically binding to an epitope present on the surface or in a cellular compartment of human cells and an epitope that is present on the surface or in a cellular compartment of cells from an Old World Monkey.

In some embodiments of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, the dissociation rate of the second antigen-binding domain at an acidic pH is at least 10% slower than the dissociation rate of the second antigen-binding domain at a neutral pH.

In some embodiments of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, the dissociation rate of the second antigen-binding domain at an acidic pH is at least 3-fold or 10-fold slower than the dissociation rate of the second antigen-binding domain at a neutral pH.

In some embodiments of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain at an acidic pH is at least 10% less than the KD of the second antigen-binding domain at a neutral pH

In some embodiments of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain at an acidic pH is at least 3-fold or 10-fold less than the KD of the second antigen-binding domain at a neutral pH.

In some embodiments of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, the identifying antigen is a protein, a carbohydrate, or a lipid, or a combination thereof. In some embodiments of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, the identifying antigen is an antigen that is expressed on a surface of a cancer cell and the first target mammalian cell is the cancer cell. In some embodiments of any of the pharmaceutical compositions that include any of the multi- specific antigen-binding protein constructs described herein, the identifying antigen is an epithelial-derived growth factor receptor (EGFR) antigen.

In some embodiments of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, the first antigen- binding domain and the second antigen-binding domain are each independently selected from the group consisting of: a VHH domain, a VNAR domain, and a scFv.

In some embodiments of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs, the first antigen-binding domain has a KD that is increased (e.g., at least 10% increased) at an acidic pH as compared to the KD of the first antigen-binding domain at a neutral pH.

In some embodiments of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs, the first antigen-binding domain has a KD at an acidic pH that is at least 3 -fold or 10-fold greater than the KD of the first antigen- binding domain at a neutral pH.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, the HLA-A gene is selected from the group consisting of: a A*24:02 gene, a A*24: 144 gene, a A* 02: 01 gene, a A*02:09 gene, a A*02:43N gene, a A*02:66 gene, a A*02:75 gene, a A*02:83N gene, a A*02: 89 gene, a A*02:97 gene, a A*02: 132 gene, a A*02: 134 gene, a A*02: 140 gene, a A* 02: 241 gene, a A*02:252 gene, a A*02:256 gene, a A*02:266 gene, a A*02:291 gene, a A*02:294 gene, a A*02:305N gene, a A* 11 :01 gene, a A* l 1 : 102 gene, a A*11 :21N gene, a A*11 :69N gene, a A* 11 :86 gene, a A*01 :01 gene, a A*01 :04N gene, a A*01 :22N gene, a A*01:32 gene, a A*01 :37 gene, a A*01 :45 gene, a A*01 :56N gene, a A*01 :81 gene, a A*01:87N gene, a A*33:03 gene, a A*33: 15 gene, a A*33:25 gene, a A*33:31 gene, a A*33:39 gene, a A*33:44 gene, a A*34:01 gene, a A*03:01 gene, a A*03:20 gene, a A*03:21N gene, a A* 03: 26 gene, a A*03:37 gene, a A*03:45 gene, a A*03:78 gene, a A*03: 112 gene, a A*03: 118 gene, a A*24:07 gene, a A*23:01 gene, a A*23:07N gene, a A*23: 17 gene, a A* 23: 18 gene, a A*23:20 gene, a A* 02: 07 gene, a A*02: 15N gene, a A*02:265 gene, a A* 02: 03 gene, a A*02:253 gene, a A*02:264 gene, a A*31 :01 gene, a A*31 : 14N gene, a A*31 :23 gene, a A*31 :46 gene, a A*31 :48 gene, a A*26:01 gene, a A*26:24 gene, a A*26:26 gene, a A*26:56 gene, a A*29:01 gene, a A*02:06 gene, a A*02: 126 gene, a A*30:01 gene, a A*30:24 gene, a A*30:02 gene, a A*30:33 gene, a A*68:01 gene, a A*68: l lN gene, a A*68:33 gene, a A*68:02 gene, a A*29:02 gene, a A*29:26 gene, a A*74:01 gene, a A*74:02 gene, a A*02: 11 gene, a A*02:69 gene, a A*32:01 gene, a A*02:02 gene, a A*34:02 gene, a A*36:01 gene, a A*33:01 gene, a A*l 1:02 gene, a A*l l :77 gene, a A*26:03 gene, a A*02:05 gene, a A*02: 179 gene, a A*25:01 gene, a A*25:07 gene, a A*24:03 gene, a A*24:33 gene, a A*26:02 gene, a A*68:03 gene, a A*03:02 gene, a A*66:01 gene, a A*66:08 gene, a A*30:04 gene, a A*02: 17 gene, a A*66:02 gene, a A*24: 10 gene, a A*02:04 gene, a A*24: 17 gene, a A*80:01 gene, a A*69:01 gene, a A*24:20 gene, a A*01 :02 gene, a A*68:05 gene, a A*02: 10 gene, a A*30: 10 gene, a A*34:05 gene, a A*02:131 gene, a A* 02: 16 gene, a A* 02: 104 gene, a A* 02: 22 gene, a A*02:20 gene, a A*01:03 gene, a A*66:03 gene, a A*l 1:04 gene, aA*24:25 gene, a A*24:23 gene, and a A*02:60 gene.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, the HLA-B gene is selected from the group consisting of: a B*40:01 gene, aB*40:55 gene, aB*40:141 gene, aB*40:150 gene, a 6*40: 151 gene, a B*15:02 gene, aB*15:214 gene, aB*46:01 gene, aB*46:15N gene, aB*46:24 gene, a B*07:02 gene, a B*07:44 gene, a B*07:49N gene, a B*07:58 gene, a B*07:59 gene, a B*07:61 gene, aB*07:120 gene, aB*07:128 gene, aB*07:129 gene, a B*07: 130 gene, a B*53:01 gene, aB*38:02 gene, aB*38:18 gene, aB*08:01 gene, aB*08:19N gene, a B*52:01 gene, aB*52:07 gene, aB*35:01 gene, aB*35:40N gene, aB*35:42 gene, a B*35:57 gene, aB*35:94 gene, aB*35:134N gene, aB*35:161 gene, aB*44:02 gene, a B*44:27 gene, aB*44:66 gene, aB*44:118 gene, aB*51:01 gene, aB*51:llN gene, a B*51:30gene, aB*51:32 gene, aB*51:48gene, aB*51:51 gene, aB*40:06 gene, aB*44:03 gene, aB*58:01 gene, aB*58:ll gene, aB*58:31N gene, a B* 15:01 gene, aB*15:102 gene, a 6*15: 104 gene, a 6*15: 140 gene, aB*15:146 gene, aB*15:201 gene, aB*35:05 gene, a B*07:05 gene, aB*07:06 gene, aB*15:35 gene, aBⁱ40:02 gene, aB*40:56 gene, aB*40:97 gene, aB*40:144Ngene, aB*54:01 gene, aB*54:17 gene, aB*18:01 gene, aB*18:17N gene, aB*18:53 gene, aB*35:03 gene, aB*35:70 gene, aB*57:01 gene, aB*57:29 gene, a B*57:37 gene, aB*15:03 gene, aB*15:103 gene, aB*13:01 gene, aB*27:05 gene, a B*27:13 gene, aB*42:01 gene, aB*15:25 gene, aB*45:01 gene, aB*45:07 gene, aB*45:13 gene, aB*14:02 gene, aB*58:02 gene, aB*49:01 gene, aB*15:10 gene, aB*38:01 gene, a B*48:01 gene, aB*48:09 gene, aB*57:03 gene, aB*37:01 gene, aB*37:23 gene, aB*39:01 gene, a B*39:46 gene, aB*39:59 gene, aB*35:02 gene, a B* 15:21 gene, a B*39:05 gene, a B*13:02 gene, aB*13:38gene, aB*50:01 gene, aB*39:06 gene, aB*55:02 gene, aB*41:01 gene, a B*27:06 gene, aB*15:13 gene, aB*59:01 gene, aB*35:12 gene, a B*55:01 gene, a B*15:12gene, aB*15:19 gene, aB*15:16 gene, aB*81:01 gene, aB*81:02 gene, aB*81:03 gene, a B*51:06 gene, aB*27:04 gene, aB*27:68 gene, aBⁱ27:69 gene, a B*35:43 gene, a B*35:67 gene, aB*35:79 gene, aB*15:ll gene, aB*35:08 gene, aB*15:18 gene, a B*15:198 gene, aB*15:17 gene, aB*51:02 gene, aB*14:01 gene, aB*39:10gene, a B*56:04 gene, aB*15:27 gene, aB*35:17 gene, aB*15:15 gene, aB*15:07 gene, aB*67:01 gene, aB*78:01 gene, aB*56:01 gene, aB*56:24 gene, aB*41:02 gene, aB*40:05 gene, a B*42:02 gene, aB*40:03 gene, aB*40:10 gene, aB*57:02 gene, aB*15:30 gene, aB*27:02 gene, aB*18:02 gene, aB*39:02 gene, aB*39:08 gene, aB*27:07 gene, aB*48:03 gene, a B*51:08 gene, aB*39:09 gene, aB*15:05 gene, aB*27:03 gene, aB*35:04 gene, aB*40:04 gene, aB*44:05 gene, aB*40:08 gene, aB*15:08 gene, aB*15:04 gene, aB*48:04 gene, a B*39:ll gene, aB*35:14 gene, aB*47:01 gene, aB*82:01 gene, aB*73:01 gene, aB*14:03 gene, a B*35:20 gene, a B*15:29 gene, a B*50:02 gene, a B*57:04 gene, a B*48:02 gene, a B*15:40 gene, aB*15:06 gene, aB*51:05 gene, aBⁱ40:ll gene, aB*56:03 gene, aB*51:07 gene, aB*39:04 gene, aB*44:10 gene, aB*39:15 gene, a B* 15:38 gene, aB*15:32 gene, a B*51:09 gene, aB*39:24 gene, aB*15:39 gene, aB*40:12 gene, aB*40:27 gene, aB*35:10 gene, aB*35:ll gene, aB*15:09 gene, aB*47:03 gene, and aB*48:07 gene.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, the HLA-C gene is selected from the group consisting of: a C*07:02 gene, a C*07:50 gene, a C*07:66 gene, a C*07:74 gene, a C*07: 159 gene, a C*07:160 gene, a C*07:167 gene, a C*04:01 gene, a C*04:09N gene, a C*04:28 gene, a

C*04:30 gene, aC*04:41 gene, aC*04:79 gene, aC*04:82 gene, aC*04:84 gene, aC*01:02 gene, a C*01 :25 gene, a C*01:44 gene, a C*08:01 gene, a C*08:20 gene, a C*08:22 gene, a C*08:24 gene, aC*07:01 gene, aC*07:06 gene, aC*07:18 gene, aC*07:52 gene, a C*07:153 gene, a C*07:166 gene, a C*03:03 gene, a C*03:20N gene, a C*03:62 gene, a C*06:02 gene, a C*06:46N gene, a C*06:55 gene, a C*03:04 gene, a C*03:100 gene, a C*03:101 gene,aC*03:105 gene, a C*03:106 gene, aC*15:02 gene, a C*15:13 gene, a C*15:47 gene, aC*12:02 gene, aC*16:01 gene, aC*05:01 gene, aC*05:03 gene, aC*05:37 gene, a C*05:53 gene, a C*12:03 gene, a C*12:23 gene, a C*02:02 gene, a C*02:10 gene, a C*02:29 gene, aC*03:02 gene, aC*14:02 gene, aC*14:23 gene, aC*14:31 gene, aC*15:05 gene, a C*15:29 gene, a C*17:01 gene, a C*17:02 gene, a C*17:03 gene, a C*14:03 gene, a C*04:03 gene, aC*08:02 gene, aC*18:01 gene, aC*18:02 gene, aC*16:02 gene, aC*07:04 gene, a C*07:l 1 gene, a C*03:05 gene, a C*12:04 gene, a C*08:03 gene, a C*08:40 gene, a C*04:06 gene, aC*16:04 gene, aC*08:04 gene, a 0*03:06 gene, a C* 04: 04 gene, a C*07:26 gene, aC*15:09 gene, aC*01:03 gene, aC*01:24 gene, aC*15:04 gene, andaC*04:07 gene.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, the PC further includes a peptide of about 8-12 amino acids in length that is bound to the PC.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, the ABPC or the multi-specific ABPC is cytotoxic or cytostatic to a cancer cell.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, the ABPC or the multi-specific ABPC includes a single polypeptide.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, the ABPC or the multi-specific ABPC is a BiTe, a (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH- CL-scFv, a HSAbody, scDiabody -HAS, or a tandem-scFv.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, the ABPC or the multi-specific ABPC includes two or more polypeptides.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, the ABPC or the multi-specific ABPC is selected from the group of an antibody , a VHH-scAb, a VHH-Fab, a Dual scFab, a F(ab')2, a diabody, a crossMab, a DAF (two-in-one), a DAF (four-in-one), a DutaMab, a DT-IgG, a knobs -in-holes common light chain, a knobs-in-holes assembly, a charge pair, a Fab-arm exchange, a SEEDbody, a LUZ-Y, a Fcab, a κλ-body, an orthogonal Fab, a DVD-IgG, a IgG(H)-scFv, a scFv-(H)IgG, IgG(L)-scFv, scFv-(L)I_gG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, Diabody -CH3, a triple body, a miniantibody, a minibody, a TriBi minibody, scFv-CH3 KIH, Fab-scFv, a F(ab')2-scFv2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody -Fc, a Diabody -Fc, a tandem scFv-Fc, an Intrabody, a dock and lock, an ImmTAC, an IgG-IgG conjugate, a Cov-X-Body, and a scFvl-PEG-scFv2. In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, at least one protein of the ABPC or the multi-specific ABPC is conjugated to the toxin, the radioisotope, or the drug via a cleavable linker.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific protein constructs described herein, at least one protein of the ABPC or the multi-specific ABPC is conjugated to the toxin, the radioisotope, or the drug via a non-cleavable linker.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific protein constructs described herein, the ABPC or the multi-specific ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC on its surface or in a cellular compartment as compared to a control ABPC.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, the half-life of the ABPC or the multi-specific ABPC in vivo is increased about 10% to about 400% as compared to the half-life of a control ABPC in vivo.

In some embodiments of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, the half-life of the ABPC or the multi-specific ABPC in vivo is increased about 0.5-fold to about 4-fold (e.g., about 1-fold to about 4-fold, about 1.5-fold to about 4-fold, about 2-fold to about 4-fold, or about 2.5-fold to about 4-fold) as compared to the half-life of a control ABPC in vivo.

Also provided herein are kits that include at least one dose of any of the

pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein. Provided herein are antigen-binding protein constructs (ABPCs) that include: a first antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex, wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA- A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ηι) polypeptide; and one or both of: a conjugated toxin, radioisotope, or drug, and an additional antigen-binding domain wherein: (a) the dissociation rate of the first antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or (b) the dissociation constant (KD) of the first antigen-binding domain at an acidic pH is less than the KD at a neutral pH; and wherein: the first antigen-binding domain includes at least one paratope that includes at least one histidine residue; and optionally, the half-life of the ABPC in vivo is increased as compared to the half- life of a control ABPC in vivo.

Provided herein are antigen-binding protein constructs (ABPCs) that include: a first antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex (PC), wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ιη) polypeptide; and one or both of: a conjugated toxin, radioisotope, or drug, and an additional antigen-binding domain wherein: the ABPC has increased endosomal recycling in a mammalian cell that presents the PC on its surface or in a cellular compartment as compared to a control ABPC; and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC in vivo.

Provided herein are antigen-binding protein constructs (ABPCs) that include: a first antigen-binding domain that is capable of specifically binding to an epitope of a beta 2- microglobulin (β2ιη) polypeptide; and one or both of: a conjugated toxin, radioisotope, or drug, and an additional antigen-binding domain wherein: (a) the dissociation rate of the first antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or (b) the dissociation constant (KD) of the first antigen-binding domain at an acidic pH is less than the KD at a neutral pH; and the first antigen-binding domain includes at least one paratope that includes at least one histidine residue; and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC in vivo.

Provided herein are antigen-binding protein constructs (ABPCs) that include: a first antigen-binding domain that is capable of specifically binding to an epitope of a polypeptide complex (PC), where the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ηι) polypeptide; and one or both of: a conjugated toxin, radioisotope, or drug, and an additional antigen-binding domain, where: the ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC complex on its surface or in a cellular compartment as compared to a control ABPC, and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC in vivo.

In some embodiments of any of the antigen-binding protein constructs described herein, the ABPC further comprises a second antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex, wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA- C, and ii) a beta 2-microglobulin (β2ηι) polypeptide, wherein: (a) the dissociation rate of the second antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or (b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH is less than the KD at a neutral pH, and wherein the second antigen-binding domain includes at least one paratope that includes at least one histidine residue.

In some embodiments of any of the antigen-binding protein constructs described herein, the ABPC further includes a second antigen-binding domain that is capable of specifically binding an epitope of a beta 2-microglobulin (β2πι) polypeptide, where: (a) the dissociation rate of the second antigen-binding domain at an acidic pH is slower than the disassociation rate at a neutral pH; or (b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH is less than the KD at a neutral pH, and wherein the second antigen-binding domain includes at least one paratope that includes at least one histidine residue.

In some embodiments of any of the antigen-binding protein constructs described herein, the additional antigen-binding domain is capable of specifically binding to a soluble antigen or an antigen that is presented on the surface or in a cellular compartment of a target cell, or an antigen that is pericellular to a target cell. In some embodiments of any of the antigen-binding protein constructs described herein, the additional antigen-binding domain is capable of specifically binding to an antigen of an infectious agent (e.g., a viral antigen, a fungal antigen, or a bacterial antigen), an antigen present on a surface of a target cell, or a therapeutic target antigen.

In some embodiments of any of the antigen-binding protein constructs, the additional antigen-binding domain is capable of specifically binding to an antigen of an infectious agent (e.g., a viral antigen, a fungal antigen, or a bacterial antigen), an antigen present on a surface of a target cell, or an antigen in a cellular compartment, or a therapeutic target antigen. In some embodiments of any of the antigen-binding protein constructs described herein, the additional antigen-binding domain is capable of specifically binding to an antigen selected from the group consisting of: sclerostin and hepatitis C E2 glycoprotein. In some embodiments of any of the antigen-binding protein constructs described herein, the additional antigen-binding domain does not bind an identifying antigen (e.g., an EGFR antigen) that is present on the surface of a cancer cell. In some embodiments of any of the antigen-binding protein constructs described herein, the first antigen-binding domain and the second antigen-binding domain, if present, specifically bind(s) an epitope that includes at least one amino acid of the polypeptide encoded by the HLA gene selected from the group consisting of HLA-A, HLA-B, and HLA- C, and at least one amino acid of the β2πι polypeptide.

In some embodiments of any of the antigen-binding protein constructs described herein, the first antigen-binding domain and the second antigen-binding domain, if present, specifically bind(s) an epitope of the polypeptide encoded by the HLA gene selected from HLA-A, HLA-B, and HLA-C, when the polypeptide encoded by the HLA gene is bound to the 2m peptide.

In some embodiments of any of the antigen-binding protein complexes described herein, the pH dependency is dictated by charge-charge interactions by the paratope and epitope of the first antigen-binding domain and the second antigen-binding domain, if present.

In some embodiments of any of the antigen-binding protein constructs described herein, the second antigen-binding domain specifically binds an epitope of the β2πι polypeptide, when the β2πι polypeptide is bound to a polypeptide encoded by an HLA gene selected from the group consisting of HLA-A, HLA-B, and HLA-C.

In some embodiments of any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain and the second antigen-binding domain, if present, for an HLA-A variant polypeptide-beta 2-microglobulin (β2ηι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-A gene-beta 2-microglobulin (β2πι) polypeptide complex, wherein the HLA-A variant polypeptide is identical to the polypeptide encoded by the HLA-A gene except at one or more residues which both: (i) are located in the HLA-A epitope bound by the first antigen- binding domain or the second antigen-binding domain, respectively, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-A gene.

In some embodiments of any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-B variant polypeptide-beta 2-microglobulin (β2ηι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-B gene-beta 2-microglobulin (β2ιη) polypeptide complex, wherein the HLA-B variant polypeptide is identical to the polypeptide encoded by the HLA-B gene except at one or more residues which both: (i) are located in the HLA-B epitope bound by the first antigen- binding domain or the second antigen-binding domain, respectively, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-B gene.

In some embodiments of any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-C variant polypeptide-beta 2-microglobulin (β2ηι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-C gene-beta 2-microglobulin (β2ιη) polypeptide complex, wherein the HLA-C variant polypeptide is identical to the polypeptide encoded by the HLA-C gene except at one or more residues which both: (i) are located in the HLA-C epitope bound by the first antigen- binding domain or the second antigen-binding domain, respectively, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-C gene.

In some embodiments of any of the antigen-binding protein constructs described herein, the first antigen-binding domain, and, if present, the second antigen-binding domain or the additional antigen-binding domain is/are capable of specifically binding to an epitope present on the surface or in a cellular compartment of human cells and an epitope that is present on the surface or in a cellular compartment of cells from an Old World Monkey.

In some embodiments of any of the antigen-binding protein constructs described herein, the dissociation rate of the first antigen-binding domain and the second antigen- binding domain, if present, at an acidic pH is/are at least 10% slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

In some embodiments of any of the antigen-binding protein constructs described herein, the dissociation rate of the first antigen-binding domain and the second antigen- binding domain, if present, at an acidic pH is at least 3-fold or 10-fold slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH. In some embodiments of any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 10% less than the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

In some embodiments of any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 3-fold or 10-fold less than the KD of the first antigen- binding domain or the second antigen-binding domain, respectively, at a neutral pH.

In some embodiments of any of the antigen-binding protein constructs described herein, the first antigen-binding domain and the second antigen-binding domain, if present, are each independently selected from the group of: a VHH domain, a VNAR domain, and a scFv.

In some embodiments of any of the antigen-binding protein constructs described herein, the additional antigen-binding domain has a KD that is increased at an acidic pH as compared to the KD of the additional antigen-binding domain at a neutral pH.

In some embodiments of any of the antigen-binding protein constructs described herein, the additional antigen-binding domain has a KD at an acidic pH that is at least 10% increased as compared to the KD of the additional antigen-binding domain at a neutral pH.

In some embodiments of any of the antigen-binding protein constructs described herein, the additional antigen-binding domain has a KD at an acidic pH that is at least 3-fold or 10-fold greater than the KD of the additional antigen-binding domain at a neutral pH.

Provided herein are multi-specific antigen-binding protein constructs (multi-specific ABPC) that include: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, where: the first antigen-binding domain is capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell; and the second antigen-binding domain is capable of specifically binding to an epitope of a polypeptide complex, wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ιη) polypeptide, wherein: (a) the dissociation rate of the second antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or (b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH is less than the KD at a neutral pH; and the second antigen-binding domain includes at least one paratope that includes at least one histidine residue. Provided herein are multi-specific antigen-binding protein constructs (multi-specific ABPCs) that include: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, wherein: the first antigen-binding domain is capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell; and the second antigen-binding domain capable of specifically binding an epitope of a polypeptide complex (PC), wherein the polypeptide complex includes) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ιη) polypeptide, wherein the multi-specific ABPC has increased endosomal recycling in a mammalian cell that presents the PC on its surface or in a cellular compartment as compared to a control ABPC.

Provided herein are multi-specific antigen-binding protein constructs (multi-specific ABPCs) that include: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, wherein: the first antigen-binding domain is capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell; and the second antigen-binding domain is capable of specifically binding an epitope of a beta 2-microglobulin (β2πι) polypeptide, wherein: (a) the dissociation rate of the second antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or

(b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH is less than the KD at a neutral pH; and the second antigen-binding domain includes at least one paratope that includes at least one histidine residue.

Provided herein are multi-specific antigen-binding protein constructs (multi-specific ABPCs) that include: (a) a first antigen-binding domain is capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell; (b) a second antigen- binding domain capable of specifically binding to an epitope of a polypeptide complex (PC), wherein the polypeptide complex includes(i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and (ii) a beta 2-microglobulin (β2ιη) polypeptide; and

(c) a conjugated toxin, radioisotope, or drug, wherein the multi-specific ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC complex on its surface or in a cellular compartment as compared to a control ABPC.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the second antigen-binding domain specifically binds to an epitope that includes at least one amino acid of the polypeptide product of the HLA gene selected from the group consisting of HLA-A, HLA-B, and HLA-C, and at least one amino acid of the β2πι polypeptide.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the second antigen-binding domain specifically binds to an epitope of a polypeptide encoded by the HLA gene selected from HLA-A, HLA-B, and HLA-C, when the polypeptide encoded by the HLA gene is bound to the β2ιη polypeptide.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the second antigen-binding domain specifically binds to an epitope of the β2ηι polypeptide when the β2ηι polypeptide is bound to a polypeptide encoded by an HLA gene selected from the group consisting of HLA-A, HLA-B, and HLA-C.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain for an HLA-A variant polypeptide-beta 2-microglobulin (β2πι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the second antigen-binding domain for the polypeptide encoded by the HLA-A gene-beta 2-microglobulin (β2πι) polypeptide complex, and wherein the HLA-A variant poly peptide is identical to the polypeptide encoded by the HLA-A gene except at one or more residues which both: (i) are located in the HLA-A epitope bound by the second antigen-binding domain, wherein the epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-A gene.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain for an HLA-B variant polypeptide-beta 2-microglobulin (β2ηι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the second antigen-binding domain for the polypeptide encoded by the HLA-B gene-beta 2-microglobulin (β2πι) polypeptide complex, and wherein the HLA-B variant polypeptide is identical to the polypeptide encoded by the HLA-B gene except at one or more residues which both: (i) are located in the HLA-B epitope bound by the second antigen-binding domain, wherein the epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-B gene.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain for an HLA-C variant polypeptide-beta 2-microglobulin (β2ηι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the second antigen-binding domain for the polypeptide product of the HLA-C gene-beta 2-microglobulin (β2πι) polypeptide complex, and wherein the HLA-C variant polypeptide is identical to the polypeptide encoded by the HLA-C gene except at one or more residues which both: (i) are located in the HLA-C epitope bound by the second antigen-binding domain, wherein the epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-C gene.

In some embodiments of any of the multi-specific antigen-binding protein complexes described herein, the first antigen-binding domain and the second-antigen binding domain is/are capable of specifically binding to an epitope present on the surface or in a cellular compartment of human cells and an epitope that is present on the surface or in a cellular compartment of cells from an Old World Monkey.

fn some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the dissociation rate of the second antigen-binding domain at an acidic pH is at least 10% slower than the dissociation rate of the second antigen-binding domain at a neutral pH.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the dissociation rate of the second antigen-binding domain at an acidic pH is at least 3-fold or at least 10-fold slower than the dissociation rate of the second antigen- binding domain at a neutral pH.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain at an acidic pH is at least 10% less than the KD of the second antigen-binding domain at a neutral pH.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain at an acidic pH is at least 3- fold less than the KD of the second antigen-binding domain at a neutral pH.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain at an acidic pH is at least 10- fold less than the KD of the second antigen-binding domain at a neutral pH.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the identifying antigen is a protein, a carbohydrate, or a lipid, or a combination thereof.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the identifying antigen is an antigen that is present on a surface of a cancer cell and the target mammalian cell is the cancer cell. In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the identifying antigen is an epithelial-derived growth factor receptor (EGFR) antigen.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the multi-specific antigen-binding protein construct is cytotoxic or cytostatic to the mammalian target cell.

In some embodiments of any of the multi-specific antigen-binding protein constructs, the first antigen-binding domain and the second antigen-binding domain are each

independently selected from the group consisting of: a VHH domain, a VNAR domain, and a scFv.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the first antigen-binding domain has a KD that is increased at an acidic pH as compared to the KD of the first antigen-binding domain at a neutral pH.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the first antigen-binding domain has a KD at an acidic pH that is at least 10% increased as compared to the KD of the first antigen-binding domain at a neutral pH.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the first antigen-binding domain has a KD at an acidic pH that is at least 3- fold or at least 10-fold greater than the KD of the first antigen-binding domain at a neutral pH.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the pH dependency is dictated by charge-charge interactions by the epitope and paratope of the first antigen-binding domain and the second antigen-binding domain.

In some embodiments of any of the antigen-binding protein constructs described herein or any of the multi-specific antigen-binding protein constructs described herein, the epitope of the PC is an at least partially monomorphic epitope.

In some embodiments of any of the antigen-binding protein constructs described herein or any of the multi-specific antigen-binding protein constructs described herein, the HLA-A gene is selected from the group consisting of: a A*24:02 gene, a A*24: 144 gene, a A*02:01 gene, a A*02:09 gene, a A*02:43N gene, a A*02:66 gene, a A*02:75 gene, a A*02:83N gene, a A*02:89 gene, a A*02:97 gene, a A*02: 132 gene, a A*02: 134 gene, a A*02: 140 gene, a A*02:241 gene, a A*02:252 gene, a A*02:256 gene, a A*02:266 gene, a A*02:291 gene, a A*02:294 gene, a A*02:305N gene, a A*l l:01 gene, a A*l l : 102 gene, a A* 11 :21N gene, a A*11 :69N gene, a A* 11 :86 gene, a A*01:01 gene, a A*01 :04N gene, a A*01:22N gene, a A*01:32 gene, a A*01:37 gene, a A*01:45 gene, a A*01:56N gene, a A*01:81 gene, a A*01:87Ngene, a A*33:03 gene, a A*33:15 gene, a A*33:25 gene, a A*33:31 gene, a A*33:39 gene, a A*33:44 gene, a A*34:01 gene, aA*03:01 gene, a A*03:20 gene, a A* 03: 2 IN gene, a A*03:26 gene, a A*03:37 gene, a A*03:45 gene, a A*03:78 gene, a A*03:112 gene, a A*03:118 gene, a A*24:07 gene, a A*23:01 gene, a A*23:07N gene, a A*23:17 gene, a A*23:18 gene, a A*23:20 gene, a A*02:07 gene, a A*02:15N gene, a A*02:265 gene, a A*02:03 gene, a A*02:253 gene, a A*02:264 gene, a A*31:01 gene, a A*31:14Ngene, a A*31:23 gene, a A*31:46 gene, a A*31:48 gene, a A*26:01 gene, a A*26:24 gene, a A*26:26 gene, a A*26:56 gene, a A*29:01 gene, a A*02:06 gene, a A*02: 126 gene, a A*30:01 gene, a A*30:24 gene, a A*30:02 gene, a A*30:33 gene, a A*68:01 gene, a A*68:11N gene, a A*68:33 gene, a A*68:02 gene, a A*29:02 gene, a A*29:26 gene, a A*74:01 gene, a A*74:02 gene, a A*02:ll gene, a A*02:69 gene, a A*32:01 gene, a A*02:02 gene, a A*34:02 gene, a A*36:01 gene, a A*33:01 gene, a A*ll:02 gene, a A*ll:77 gene, a A*26:03 gene, aA*02:05 gene, a A*02:179gene, aA*25:01 gene, aA*25:07 gene, a A*24:03 gene, aA*24:33 gene, a A*26:02 gene, a A*68:03 gene, a A*03:02 gene, a A*66:01 gene, aA*66:08 gene, a A*30:04 gene, a A*02: 17 gene, a A*66:02 gene, a A*24: 10 gene, a A*02:04 gene, a A*24:17 gene, a A*80:01 gene, a A*69:01 gene, a A*24:20 gene, a A*01:02 gene, a A*68:05 gene, a A*02:10 gene, a A*30:10 gene, a A*34:05 gene, aA*02:131 gene, a A*02:16 gene, a A* 02: 104 gene, a A* 02: 22 gene, a A*02:20 gene, a A*01:03 gene, a A*66:03 gene, a A* 11:04 gene, a A*24:25 gene, a A*24:23 gene, and a A*02:60 gene.

In some embodiments of any of the antigen-binding protein constructs described herein or any of the multi-specific antigen-binding protein constructs described herein, the HLA-B gene is selected from the group consisting of: a B*40:01 gene, a B*40:55 gene, a B*40:141 gene, aB*40:150 gene, aB*40:151 gene, aB*15:02 gene, aB*15:214gene, a B*46:01 gene, aB*46:15N gene, aB*46:24 gene, aB*07:02 gene, aB*07:44 gene, a B*07:49N gene, a B*07:58 gene, a B*07:59 gene, a B*07:61 gene, a B*07: 120 gene, a B*07:128 gene, a B* 07: 129 gene, aB*07:130 gene, aB*53:01 gene, aB*38:02 gene, a B*38:18 gene, aB*08:01 gene, aB*08:19N gene, aB*52:01 gene, aB*52:07 gene, a B*35:01 gene, aB*35:40N gene, aB*35:42 gene, aB*35:57 gene, aB*35:94 gene, a B*35:134N gene, aB*35:161 gene, aB*44:02 gene, aB*44:27 gene, a B* 44: 66 gene, a B*44: 118 gene, a B*51 : 01 gene, a B*51 : 1 IN gene, a B*51 : 30 gene, a B*51 : 32 gene, a B*51:48 gene, aB*51:51 gene, aB*40:06 gene, aB*44:03 gene, aB*58:01 gene, aB*58:ll gene, aB*58:31N gene, aB*15:01 gene, aB*15:102 gene, aB*15:104 gene, aB*15:140 gene, aB*15:146 gene, aB*15:201 gene, aB*35:05 gene, aB*07:05 gene, aB*07:06 gene, a B* 15:35 gene, aB*40:02 gene, aB*40:56 gene, aB*40:97 gene, aB*40:144Ngene, a B*54:01 gene, aB*54:17 gene, aB*18:01 gene, aB*18:17N gene, aB*18:53 gene, a B*35:03 gene, aB*35:70 gene, aB*57:01 gene, aB*57:29 gene, aB*57:37 gene, aB*15:03 gene, aB*15:103 gene, aB*13:01 gene, aB*27:05 gene, aB*27:13 gene, aB*42:01 gene, a B*15:25 gene, aB*45:01 gene, aB*45:07 gene, aBⁱ45:13 gene, aB*14:02 gene, aB*58:02 gene, aB*49:01 gene, aB*15:10 gene, aB*38:01 gene, aB*48:01 gene, aB*48:09 gene, a B*57:03 gene, a B*37:01 gene, a B*37:23 gene, a B*39:01 gene, a B*39:46 gene, a B*39:59 gene, aB*35:02 gene, aB*15:21 gene, aB*39:05 gene, a B* 13:02 gene, aB*13:38 gene, a B*50:01 gene, aB*39:06 gene, aB*55:02 gene, aB*41:01 gene, aB*27:06 gene, aB*15:13 gene, a B*59:01 gene, aB*35:12 gene, aB*55:01 gene, a B* 15: 12 gene, a B*15:19 gene, a B*15:16gene, aB*81:01 gene, aB*81:02 gene, aB*81:03 gene, aB*51:06 gene, aB*27:04 gene, a B*27:68 gene, aB*27:69 gene, aB*35:43 gene, aB*35:67 gene, a B*35:79 gene, a B*15:ll gene, aB*35:08gene, aB*15:18gene, aB*15:198 gene, a B* 15: 17 gene, a

B*51:02 gene, aB*14:01 gene, aB*39:10 gene, aB*56:04 gene, aB*15:27 gene, aB*35:17 gene, aB*15:15 gene, aB*15:07 gene, aB*67:01 gene, aBⁱ78:01 gene, aB*56:01 gene, a B*56:24 gene, aB*41:02 gene, aB*40:05 gene, aBⁱ42:02 gene, aB*40:03 gene, aB*40:10 gene, aB*57:02 gene, aB*15:30 gene, aB*27:02 gene, aB*18:02 gene, aB*39:02 gene, a B*39:08 gene, aB*27:07 gene, aB*48:03 gene, aB*51:08 gene, aB*39:09 gene, aB*15:05 gene, a B*27:03 gene, a B*35:04 gene, a B*40:04 gene, a B*44:05 gene, a B*40:08 gene, a B*15:08 gene, aB*15:04 gene, aB*48:04 gene, aB*39:ll gene, aB*35:14 gene, aB*47:01 gene, a B*82:01 gene, aB*73:01 gene, aB*14:03 gene, aB*35:20 gene, a B*15:29 gene, a B*50:02 gene, aB*57:04 gene, aB*48:02 gene, aB*15:40 gene, aB*15:06 gene, aB*51:05 gene, a B*40:ll gene, aB*56:03 gene, aB*51:07 gene, aB*39:04 gene, a B*44:10 gene, a B*39:15 gene, aB*15:38gene, aB^!|:15:32 gene, aB*51:09 gene, aB*39:24 gene, aB*15:39 gene, a B*40:12 gene, aB*40:27 gene, aB*35:10 gene, aB*35:ll gene, a B* 15:09 gene, a B*47:03 gene, and a B*48:07 gene.

In some embodiments of any of the antigen-binding protein constructs described herein or any of the multi-specific antigen-binding protein constructs described herein, the HLA-C gene is selected from the group consisting of: a C*07:02 gene, a 0*07:50 gene, a C*07:66 gene, a C*07:74 gene, a C*07: 159 gene, a C*07: 160 gene, a C*07: 167 gene, a C*04:01 gene, a C*04:09N gene, a C*04:28 gene, a C*04:30 gene, a C*04:41 gene, a C*04:79 gene, a C*04:82 gene, a C*04:84 gene, a C*01 :02 gene, a C*01 :25 gene, a C*01 :44 gene, a C*08:01 gene, a C*08:20 gene, a C*08:22 gene, a C*08:24 gene, a C*07:01 gene, a C*07:06 gene, a C*07: 18 gene, a C*07:52 gene, a C*07: 153 gene, a C*07: 166 gene, a C*03:03 gene, a C*03:20N gene, a C*03:62 gene, a C*06:02 gene, a C*06:46N gene, a C*06:55 gene, a C*03:04 gene, a C*03: 100 gene, a C*03: 101 gene, a C*03: 105 gene, a C*03: 106 gene, a C* 15:02 gene, a C*15: 13 gene, a C*15:47 gene, a C*12:02 gene, a C*16:01 gene, a C*05:01 gene, a C*05:03 gene, a C*05:37 gene, a C*05:53 gene, a C*12:03 gene, a C*12:23 gene, a C*02:02 gene, a C*02: 10 gene, a C*02:29 gene, a C*03:02 gene, a C*14:02 gene, a C*14:23 gene, a C*14:31 gene, a C* 15:05 gene, a C*15:29 gene, a C*17:01 gene, a C*17:02 gene, a C*17:03 gene, a C*14:03 gene, a C*04:03 gene, a C*08:02 gene, a C*18:01 gene, a C*18:02 gene, a C*16:02 gene, a C*07:04 gene, a C*07: l l gene, a C*03:05 gene, a C*12:04 gene, a C*08:03 gene, a C*08:40 gene, a C*04:06 gene, a C*16:04 gene, a C*08:04 gene, a C*03:06 gene, a C*04:04 gene, a C*07:26 gene, a C*15:09 gene, a C*01 :03 gene, a C*01 :24 gene, a C*15:04 gene, and a C*04:07 gene.

In some embodiments of any of the antigen-binding protein constructs described herein or any of the multi-specific antigen-binding protein constructs described herein, the PC further includes a peptide of about 8-12 amino acids in length that is bound to the PC.

In some embodiments of any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, the ABPC or the multi- specific ABPC is less cytotoxic or cytostatic to a non-cancerous cell.

In some embodiments of any of the antigen-binding protein constructs or of any of the multi-specific antigen-binding protein constructs described herein, the ABPC or the multi- specific ABPC is cytotoxic or cytostatic to a cancer cell (e.g., a cancer cell that does not present the PC on its surface).

In some embodiments of any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, the ABPC comprises a single polypeptide.

In some embodiments, the antigen-binding protein construct or the multi-specific antigen-binding protein construct is a BiTe, a (scFv)2, a nanobody, a nanobody-HS A, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH-CL-scFv, a HSAbody, scDiabody-HAS, or a tandem-scFv. In some embodiments of any of the antigen-binding protein constructs and any of the multi-specific antigen-binding protein constructs described herein, the ABPC or the multi- specific ABPC comprises two or more polypeptides.

In some embodiments in any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, the ABPC or the multi- specific ABPC is selected from the group of an antibody, a VHH-scAb, a VHH-Fab, a Dual scFab, a F(ab')2, a diabody, a crossMab, a DAF (two-in-one), a DAF (four-in-one), a DutaMab, a DT-IgG, a knobs-in-holes common light chain, a knobs-in-holes assembly, a charge pair, a Fab-arm exchange, a SEEDbody, a LUZ-Y, a Fcab, a κλ-body, an orthogonal Fab, a DVD-IgG, a IgG(H)-scFv, a scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KM IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4- Ig, Zybody, DVI-IgG, Diabody-CH3, a triple body, a miniantibody, a minibody, a TriBi minibody, scFv-CH3 KJH, Fab-scFv, a F(ab')2-scFv2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a Diabody-Fc, a tandem scFv-Fc, an Intrabody, a dock and lock, an ImmTAC, an IgG-IgG conjugate, a Cov-X-Body, and a scFvl-PEG-scFv2.

In some embodiments of any of the antigen-binding protein constructs or of any of the multi-specific antigen-binding protein constructs described herein, at least one protein of the ABPC or at least one protein of the multi-specific ABPC is conjugated to the toxin, the radioisotope, or the drug via a cleavable linker.

In some embodiments of any of the antigen-binding protein constructs or of any of the multi-specific antigen-binding protein constructs described herein, at least one protein of the ABPC or at least one protein of the multi-specific ABPC is conjugated to the toxin, the radioisotope, or the drug via a non-cleavable linker.

In some embodiments of any of the antigen-binding protein constructs or of any of the multi-specific antigen-binding protein constructs described herein, the ABPC or the multi- specific ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC on its surface or in a cellular compartment as compared to a control ABPC.

In some embodiments of any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, the half-life of the ABPC or the multi-specific ABPC in vivo is increased about 10% to about 400% as compared to the half-life of a control ABPC in vivo. In some embodiments of any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, the half-life of the ABPC in vivo is increased about 0.5-fold to about 4-fold (e.g., about 1-fold to about 4-fold, about 1.5-fold to about 4-fold, about 2-fold to about 4-fold, or about 2.5-fold to about 4-fold) as compared to the half-life of a control ABPC in vivo.

Also provided herein are kits that include any of the antigen-binding protein constructs described herein or any of the multi-specific antigen-binding protein constructs described herein.

Provided herein are methods of treating a cancer characterized by having a population of cancer cells that have at least one of the following: (a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced level of MHCl or MHCl complex presentation on their surface, and/or a reduced level of MHCl in a cellular compartment as compared to a non-cancerous cell; (b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced level of TAP in the endoplasmic reticulum of a cell and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell; (c) a reduced level of expression of β2ιη polypeptide, a reduced level of β2πι polypeptide present on their surface, and/or a reduced level of β2ιη polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ιη gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, or any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein to a subject identified as having a cancer characterized by having the population of cancer cells.

Provided herein are methods of treating a cancer characterized by having a population of cancer cells that (i) have the identifying antigen present on their surface, and (ii) have at least one of the following: (a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced level of MHCl or MHCl complex presentation on their surface, and/or a reduced level of MHC 1 in a cellular compartment as compared to a non-cancerous cell; (b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced level of TAP in the endoplasmic reticulum of a cell and/or a genetic lesion in a TAP gene as compared to a non- cancerous cell; (c) a reduced level of expression of β2ηι polypeptide, a reduced level of β2ιη polypeptide present on their surface, and/or a reduced level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ιη gene and/or a HLA gene selected from the group consisting of: HLA- A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, or any of the multi-specific antigen- binding protein constructs described herein to a subject identified as having a cancer characterized by having the population of cancer cells.

Provided herein are methods of reducing the volume of a tumor in a subject, wherein the tumor is characterized by having a population of cancer cells that have at least one of the following: (a) a reduced level of expression of a poly peptide encoded by a HLA- A, HLA-B, or HLA-C gene, a reduced level of MHC1 or MHC1 complex presentation on their surface, and/or a reduced level of MHC1 in a cellular compartment as compared to a non-cancerous cell; (b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced lev el of TAP in the endoplasmic reticulum of a cell and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell; (c) a reduced level of expression of β2ιη polypeptide, a reduced level of β2πι polypeptide present on their surface, and/or a reduced level of β2ιη polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ηι gene and/or a HLA gene selected from the group consisting of: HLA- A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi- specific antigen-binding protein constructs described herein, or any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, to a subject identified as having a cancer characterized by having the population of cancer cells.

Provided herein are methods of reducing the volume of a tumor in a subject, wherein the tumor is characterized by having a population of cancer cells that: (i) have the identifying antigen present on their surface, and (ii) have at least one of the following: (a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced level of MHC1 or MHC1 complex presentation on their surface, and/or a reduced level of MHC1 in a cellular compartment as compared to a non-cancerous cell; (b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced level of TAP in the endoplasmic reticulum of a cell and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell; (c) a reduced level of expression of β2πι polypeptide, a reduced level of β2ιη polypeptide present on their surface, and/or a reduced level of β2πι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ηι gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include:

administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, or any of the multi-specific antigen-binding protein constructs described herein, to a subject identified as having a cancer characterized by having the population of cancer cells

Provided herein are methods of inducing cell death in a cancer cell in a subject, wherein the cancer cell has at least one of the following: (a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced level of MHCl or MHC 1 complex presentation on their surface, and/or a reduced level of MHC 1 in a cellular compartment as compared to a non-cancerous cell; (b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced level of TAP in the endoplasmic reticulum of a cell and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell; (c) a reduced level of expression of β2ιη polypeptide, a reduced level of β2ηι polypeptide present on their surface, and/or a reduced level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ιη gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, or any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein to a subject identified as having a cancer characterized by having the population of cancer cells.

Provided herein are methods of inducing cell death in a cancer cell in a subject, wherein the cancer cell (i) has the identifying antigen present on its surface, and (ii) has at least one of the following: (a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced level of MHCl or MHCl complex presentation on their surface, and/or a reduced level of MHCl in a cellular compartment as compared to a non-cancerous cell; (b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced level of TAP in the endoplasmic reticulum of a cell and/or a genetic lesion in a TAP gene as compared to a noncancerous cell; (c) a reduced level of expression of β2πι polypeptide, a reduced level of β2ιη polypeptide present on their surface, and/or a reduced level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ηι gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, or any of the multi-specific antigen- binding protein constructs described herein to a subject identified as having a cancer characterized by having the population of cancer cells.

In some embodiments of any of the methods described herein, the cancer is a primary tumor.

In some embodiments of any of the methods described herein, the cancer is a metastasis.

In some embodiments of any of the methods described herein, the cancer is a non-T- cell-infiltrating tumor. In some embodiments of any of the methods described herein, the cancer is a T-cell-infiltrating tumor.

Provided herein are methods of decreasing the risk of developing a metastasis or decreasing the risk of developing an additional metastasis in a subject having a cancer, wherein the cancer is characterized by having a population of cancer cells that have at least one of the following: (a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced level of MHCl or MHCl complex presentation on their surface, and/or a reduced level of MHCl in a cellular compartment as compared to a noncancerous cell; (b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced level of TAP in the endoplasmic reticulum of a cell and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell; (c) a reduced level of expression of β2ιη polypeptide, a reduced level of β2ιη polypeptide present on their surface, and/or a reduced level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ηι gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of the multi-specific antigen-binding protein constructs described herein, or any of the antigen-binding protein constructs or any of the multi-specific antigen- binding protein constructs described herein, to a subject identified as having a cancer characterized by having the population of cancer cells.

Provided herein are methods of decreasing the risk of developing a metastasis or decreasing the risk of developing an additional metastasis in a subject having a cancer, wherein the cancer is characterized by having a population of cancer cells that (1) have the identifying antigen on their surface, and (ii) have at least one of the following: (a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced level of MHCl or MHCl complex presentation on their surface, and/or a reduced level of MHCl in a cellular compartment as compared to a non-cancerous cell; (b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced level of TAP in the endoplasmic reticulum of a cell and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell; (c) a reduced level of expression of β2πι polypeptide, a reduced level of β2πι polypeptide present on their surface, and/or a reduced level of β2πι polypeptide in a cellular compartment as compared to a noncancerous cell; and (d) a genetic lesion in a β2ηι gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, or any of the multi-specific antigen-binding protein constructs described herein, to a subject identified as having a cancer characterized by having the population of cancer cells.

Provided herein are methods of increasing the level of an ABPC or multi-specific

ABPC in a cellular compartment of a cancer cell in a subject as compared to the level of the ABPC or multi-specific ABPC, respectively, in the cellular compartment of a non-cancerous cell, wherein the cancer cell has at least one of the following: (a) a reduced level of expression of a poly peptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced level of MHCl or MHCl complex presentation on their surface, and/or a reduced level of MHCl in a cellular compartment as compared to a non-cancerous cell; (b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced level of TAP in the endoplasmic reticulum of a cell and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell; (c) a reduced level of expression of β2πι polypeptide, a reduced level of β2ιη polypeptide present on their surface, and/or a reduced level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ηι gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include:

administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the antigen-binding protein constructs or any of antigen-binding protein constructs described herein, or any of pharmaceutical compositions including any of the multi-specific antigen-binding protein constructs described herein or any of the multi-specific antigen-binding protein constructs described herein, respectively, to a subj ect identified as having a cancer characterized by having a population of the cancer cells.

Provided herein are methods of increasing the level of a multi-specific ABPC in a cellular compartment of a cancer cell in a subject as compared to the level of the multi- specific ABPC in the cellular compartment of a non-cancerous cell, wherein the cancer cell (i) has the identifying antigen present on its surface, and (ii) has at least one of the following: (a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced level of MHC1 or MHC1 complex presentation on their surface, and/or a reduced level of MHC1 in a cellular compartment as compared to a non-cancerous cell; (b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced level of TAP in the endoplasmic reticulum of a cell and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell; (c) a reduced level of expression of β2ιη polypeptide, a reduced level of β2ιη polypeptide present on their surface, and/or a reduced level of β2πι polypeptide in a cellular compartment as compared to a noncancerous cell; and (d) a genetic lesion in a β2πι gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein, or any of the multi-specific antigen-binding protein constructs described herein, to a subject identified as having a cancer characterized by having a population of the cancer cells.

Also provided herein are methods of decreasing the level of an ABPC or a multi- specific ABPC in a cellular compartment of a non-cancerous cell in a subject as compared to the level of the ABPC or multi-specific ABPC, respectively, in the cellular compartment of a cancerous cell in the subject, wherein the cancer cell has at least one of the following: (a) a reduced level of expression of a polypeptide encoded by a HLA- A, HLA-B, or HLA-C gene, a reduced level of MHC1 or MHC1 complex presentation on their surface, and/or a reduced level of MHC1 in a cellular compartment as compared to a non-cancerous cell; (b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced level of TAP in a cellular compartment and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell; (c) a reduced level of expression of p2m polypeptide, a reduced level of β2ιη polypeptide present on their surface, and/or a reduced level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ιη gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include:

administering a therapeutically effective amount of any of the pharmaceutical compositions that includes any of the antigen-binding protein constructs or any of the antigen-binding protein constructs described herein, or any of the pharmaceutical compositions that include any of the multi-specific antigen-binding protein constructs described herein or any of the multi-specific antigen-binding protein constructs described herein, respectfully, to a subject identified as having a cancer characterized by having a population of the cancer cells.

Also provided herein are methods of decreasing the level of a multi-specific ABPC in a cellular compartment of a non-cancerous cell in a subject as compared to the level of the multi-specific ABPC in the cellular compartment of a cancerous cell in the subject, wherein the cancer cell (i) has the identifying antigen present on its surface, and (ii) has at least one of the following: (a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA- B, or HLA-C gene, a reduced level of MHC1 or MHC1 complex presentation on their surface, and/or a reduced level of MHC1 in a cellular compartment as compared to a non- cancerous cell; (b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced level of TAP in a cellular compartment and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell; (c) a reduced level of expression of β2ιη polypeptide, a reduced level of β2ηι polypeptide present on their surface, and/or a reduced level of β2ιη polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ιη gene and'or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that includes any of the multi-specific antigen-binding protein constructs described herein, or any of the multi-specific antigen-binding protein constructs described herein, to a subject identified as having a cancer characterized by having a population of the cancer cells.

In some embodiments of any of the methods described herein, the cellular compartment is part of the endosomal/lysosomal pathway.

In some embodiments of any of the methods described herein, the cellular compartment is an endosome.

As used herein, the term "antigen-binding protein construct" is (l) a single polypeptide that includes at least one antigen-binding domain or (ii) a complex of two or more polypeptides (e.g., the same or different polypeptides) that together form at least one antigen-binding domain. Non-limiting examples and aspects of antigen-binding protein constructs are described herein. Additional examples and aspects of antigen-binding protein constructs are known in the art.

In some examples, an antigen-binding protein construct or a multi-specific antigen- binding protein construct can be a single polypeptide that includes at least two different antigen-binding domains or (ii) a complex of two or more polypeptides (e.g., the same or different polypeptides) that together form at least two different antigen-binding domains.

A "multi-specific antigen-binding protein construct" is an antigen-binding protein construct that includes two or more different antigen-binding domains that collectively specifically bind two or more different epitopes. The two or more different epitopes may be epitopes on the same antigen (e.g., a single polypeptide present on the surface of a cell) or on different antigens (e.g., different proteins present on the surface of the same cell or present on the surface of different cells). In some aspects, the antigen is present on the surface of the cell. In some aspects, the antigen is present or in a cellular compartment. In some aspects, a multi-specific antigen-binding protein construct binds two different epitopes (i.e., a

"bispecific antigen-binding protein construct"). In some aspects, a multi-specific antigen- binding protein construct binds three different epitopes (i.e., a "trispecific antigen-binding protein construct"). In some aspects, a multi-specific antigen-binding protein construct binds four different epitopes (i.e., a "quadspecific antigen-binding protein construct"). In some aspects, a multi-specific antigen-binding protein construct binds five different epitopes (i.e., a "quintspecific antigen-binding protein construct"). Each binding specificity may be present in any suitable valency. Non-limiting examples of multi-specific antigen-binding protein constructs are described herein.

An "antigen-binding domain" is one or more protein domain(s) (e.g., formed from amino acids from a single polypeptide or formed from amino acids from two or more polypeptides (e.g., the same or different polypeptides) that is capable of specifically binding to one or more different antigen(s) (e.g., an identifying antigen, an epitope of a beta 2- microglobulin (β2πι) poly peptide, or an epitope of a polypeptide complex (PC), wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA- A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ηι) polypeptide). In some examples, an antigen-binding domain can bind to an antigen or epitope with specificity and affinity similar to that of naturally-occurring antibodies. In some embodiments, the antigen- binding domain can be an antibody or a fragment thereof. In some embodiments, an antigen- binding domain can include an alternative scaffold (e.g., a DARPin). Non-limiting examples of antigen-binding domains are described herein. Additional examples of antigen-binding domains are known in the art. In some examples, an antigen-binding domain can bind to a single antigen (e.g., an identifying antigen, an epitope of a beta 2-microglobulin (β2πι) polypeptide, or an epitope of a polypeptide complex (PC), wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA- C, and ii) a beta 2-microglobulin (β2ηι) polypeptide).

The term "antibody" is used herein in its broadest sense and includes certain types of immunoglobulin molecules that include one or more antigen-binding domains that specifically bind to an antigen or epitope. An antibody specifically includes, e.g., intact antibodies (e.g., intact immunoglobulins), antibody fragments, and multi-specific antibodies. One example of an antigen-binding domain is an antigen-binding domain formed by a VH - VL dimer. Additional examples of an antibody are described herein. Additional examples of an antibody are known in the art.

The term "identifying antigen" is an antigen that is present on the surface of a target mammalian cell (e.g., a cancer cell).

The term "cellular compartment" refers to a structure within a cell that is confined within a single or double-lipid layer membrane. In some embodiments, the cellular compartment is an organelle (e.g., a mitochondrion, a Golgi apparatus, a lysosome, an endoplasmic reticulum, a vacuole). In some embodiments, the cellular compartment is part of the endosomal/lysosomal pathway.

Many cellular compartments are known in the art and can be purified from cells and tissues. See, e.g., Satori et A., Anal. Chim. Acta. 753:8-18, 2012; Pasquah et al, J. Chrom. B Biomed. Sci. Appl. 722(1 -2): 89-102, 1999; Olson et A., Anal. Bioanal. Chem. 382(4):906-17, 2005; Aniento et al., Curr. Prot. 1mm. , Chapter 8, Unit 8.1C, 2003; Walker et al., Cell.

Biosci. 6: 1, 2016; Worthington Biochemical, Worthington Tissue Dissociation Guide (website worthington-biochem.com/tissuedissociation/optimization.html). Once a cellular component is purified or isolated, assays for a target protein (e.g., an antigen-binding protein construct or a multi-specific antigen-binding protein construct described herein) can be performed using methods known in the art (ELISA, Western blot, immunofluorescence, and immunoprecipitation followed by an assay for protein concentration), and can be used to determine the concentration or relative level of the target protein in the cellular compartment. Alternatively, a cellular component can be imaged using immunofluorescence microscopy using an fiuorophore-labelled antibody that specifically binds to a characteristic protein present in the cellular component (e.g., EEA1 for early endosomes) and a fiuorophore- labelled antibody that specifically binds to the protein of interest (e.g., an antigen-binding protein construct or a multi-specific antigen-binding protein construct), and the level of the target protein in the cellular component can be determined by quantitation of the overlap in the fluorescence emissions of the two different antibodies.

The phrase "endosomal/lysosomal pathway" refers to a network of endosomes (early endosomes, multi-vesicular bodies, late endosomes, and lysosomes) in the cytoplasm of a mammalian cell, wherein molecules internalized through cell-mediated internalization processes, e.g., pinocytosis, micropinocytosis, receptor-mediated endocytosis, and/or phagocytosis, are sorted.

The term "acidic pH" refers to a pH of about pH 4.0 to about pH 6.5. In some embodiments, an antigen-binding domain described herein can bind to its epitope at an acidic pH. In some embodiments, an acidic pH can be a pH that is similar to the pH of an early endosome in the endocytic pathway in vivo and in vitro (e.g., a pH of about 6.0 to about 6.5). In some embodiments, the acidic pH can be about pH 4.5 to about 5.5, which is similar to the pH of a late endosome in the endocytic pathway and the pH of a lysosome in vivo and in vitro. In some embodiments, the acidic pH can be about 4.0 to about 4.5, about 4.5 to about 5.0, about pH 5.0 to about 5.5, about 5.5 to about 6.0, or about 6.0 to about 6.5. The term "neutral pH" refers to a pH of about 7.0 to about 10.0. In some embodiments, an antigen-binding protein construct or a multi-specific antigen binding protein construct described herein can bind to its epitope at a neutral pH. In some embodiments, the neutral pH is similar to a physiological pH in vivo (e.g., a pH of about 7.0 to about 8.0). In some embodiments, the neutral pH is similar to the pH of mammalian blood in vivo (e.g., a pH of about 7.35 to 7.45). In some embodiments, the neutral pH is about 7.0 to about 7.5, about 7.5 to about 8.0, about 8.0 to about 8.5, about 8.5 to about 9.0, about 9.0 to about 9.5, or about 9.5 to about 10.0.

The phrase "pericellular to a cell" or the "pericellular space of a cell" refers to a specific microenvironment surrounding a cell in the tissue of a mammal (e.g., a human). For example, the phrase "pericellular to a cell" can mean a distance of less than 50 nm (e.g., less than 45 nm, less than 40 nm, less than 35 nm, less than 30 nm, less than 25 nm, less than 20 nm, less than 15 nm, less than 10 nm, less than 9 nm, less than 8 nm, less than 7 nm, less than 6 nm, less than 5 nm, less than 4 nm, less than 3 nm, less than 2 nm, or less than 1 nm) from any specific location on the plasma membrane of the cell in the tissue of the mammal.

The term "population" when used before a noun means two or more of the specific noun. For example, the phrase "a population of cancer cells" means "two or more cancer cells." Non-limiting examples of cancer cells are described herein.

The phrase "cytostatic to a cell" refers to a direct or indirect decrease in the proliferation (cell division) of the cell (e.g., a cancer cell) in vivo or in vitro. When an agent is cytostatic to a cell, the agent can, e.g., directly or indirectly result in cell cycle arrest of the cell (e.g., a cancer cell). In some examples, an agent that is cytostatic to a cell can reduce the number of cells in a population of the cells that are in S phase (as compared to the number of cells in a population of the cells that are in S phase prior to contact with the agent). In some examples, an agent that is cytostatic to a cell can reduce the percentage of the cells in S phase by at least 20%, at least 40%, at least 60%, or at least 80% (e.g., as compared to the percentage of cells in a population of the cells that are in S phase prior to contact with the agent).

The phrase "cytotoxic to a cell" refers to the inducement, directly or indirectly, in the death (e.g., necrosis or apoptosis) of the cell (e.g., a mammalian cell, e.g., a cancer cell).

"Affinity" refers to the strength of the sum total of non-covalent interactions between an antigen-binding site and its binding partner (e.g., an antigen or epitope). Unless indicated otherwise, as used herein, "affinity" refers to intrinsic binding affinity, which reflects a 1 : 1 interaction between members of an antigen-binding domain and an antigen or epitope. The affinity of a molecule X for its partner Y can be represented by the dissociation equilibrium constant (KD). Affinity can be measured by common methods known in the art, including those described herein. Affinity can be determined, for example, using surface plasmon resonance (SPR) technology (e.g., BIACORE®) or biolayer interferometry (e.g.,

FORTEBIO®). Additional methods for determining the affinity for an antigen-binding domain and its corresponding antigen or epitope are known in the art.

The term "epitope" means a portion of an antigen that is specifically bound by an antigen-binding domain through a set of physical interactions between: (i) all monomers (e.g. individual amino acid residues, sugar side chains, and post-translationally modified amino acid residues) on the portion of the antigen-binding domain that specifically binds the antigen and (ii) all monomers (e.g. individual amino acid residues, sugar side chains, post- translationally modified amino acid residues) on the portion of the antigen that is specifically bound by the antigen-binding domain. Epitopes can, e.g., consist of surface-accessible amino acid residues, sugar side chains, phosphorylated amino acid residues, methylated amino acid residues, and/or acetylated amino acid residues and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non- conformational epitopes are distinguished in that the binding to the former, but not the latter, may be lost in the presence of denaturing solvents. In some embodiments, an epitope is defined by a linear amino acid sequence of at least about 3 to 6 amino acids, or about 10 to 15 amino acids. In some embodiments, an epitope refers to a portion of a full-length protein or a portion thereof that is defined by a three-dimensional structure (e.g., protein folding). In some embodiments, an epitope is defined by a discontinuous amino acid sequence that is brought together via protein folding. In some embodiments, an epitope is defined by a discontinuous amino acid sequence that is brought together by quaternary structure (e.g., a cleft formed by the interaction of two different polypeptide chains). The amino acid sequences between the residues that define the epitope may not be critical to three- dimensional structure of the epitope. A conformational epitope may be determined and screened using assays that compare binding of antigen-binding protein construct to a denatured version of the antigen, such that a linear epitope is generated. An epitope may include amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding. Methods for identifying an epitope to which an antigen-binding domain specifically binds are known in the art, e.g., structure-based analysis (e.g. X-ray crystallography, NMR, and/or electron microscopy) (e.g. on the antigen and/or the antigen-antigen binding domain complex) and/or mutagenesis-based analysis (e.g. alanine scanning mutagenesis, glycine scanning mutagenesis, and homology scanning mutagenesis) wherein mutants are measured in a binding assay with a binding partner, many of which are known in the art.

The term "paratope" means a portion of an antigen-binding domain that specifically binds to an antigen through a set of physical interactions between: (i) all monomers (e.g. individual amino acid residues, sugar side chains, posttranslationally modified amino acid residues) on the portion of the antigen-binding domain that specifically binds the antigen and (ii) all monomers (e.g. individual amino acid residues, sugar side chains, posttranslationally modified amino acid residues) on the portion of the antigen that is specifically bound by the antigen-binding domain. Paratopes can, e.g. consist of surface-accessible amino acid residues and may have specific three-dimensional structural characteristics, as well as specific charge characteristics. In some embodiments, a paratope refers to a portion of a full- length antigen-binding domain or a portion thereof that is defined by a three-dimensional structure (e.g., protein folding). In some embodiments, a paratope is defined by a discontinuous amino acid sequence that is brought together via protein folding. In some embodiments, an epitope is defined by a discontinuous amino acid sequence that is brought together by quaternary structure (e.g., a cleft formed by the interaction of two different polypeptide chains). The amino acid sequences between the residues that define the paratope may not be critical to three-dimensional structure of the paratope. A paratope may comprise amino acid residues that are directly involved in the binding, and other amino acid residues, which are not directly involved in the binding.

Methods for identifying a paratope to which an antigen-binding domain specifically binds are known in the art, e.g., structure-based analysis (e.g., X-ray crystallography, NMR, and/or electron microscopy) (e.g. on the antigen-binding domain, and/or the antigen binding domain-antigen complex), and/or mutagenesis-based analysis (e.g., alanine scanning mutagenesis, glycine scanning mutagenesis, and homology scanning mutagenesis) wherein mutants are measured in a binding assay with a binding partner, many of which are known in the art.

The term "at least partially monomorphic epitope" refers to an epitope that is presented on the surface, present in a cellular compartment and/or comprises amino acids encoded by the HLA-A, HLA-B, HLA-C, and/or β2ηι gene of cells in more than 1 % of a population or sub-population of a specific mammalian species. In some embodiments, an at least partially monomorphic antigen is present on the surface of cells in about 1% to about 100% (e.g., about 1% to about 99%, about 1% to about 95%, about 1% to about 90%, about 1% to about 85%, about 1% to about 80%, about 1% to about 75%, about 1% to about 70%, about 1% to about 65%, about 1 % to about 70%, about 1% to about 65%, about 1% to about 60%, about 1% to about 55%, about 1 % to about 50%, about 1% to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1 % to about 25%, about 1% to about 20%, about 1% to about 1 %, or about 1 % to about 10%) of a population or sub- population of a specific mammalian species.

The phrase "present on the surface of a mammalian cell" means (1) an antigen that physically attached to or at least partially embedded in the plasma membrane of a mammalian cell (e.g., a transmembrane protein, a peripheral membrane protein, a lipid-anchored protein (e.g., a GPI-anchor), an N-myristolyated protein, or a S-palmitoylated protein) or (2) an antigen that is stably bound to its cognate receptor, where the cognate receptor is physically attached to the plasma membrane of a mammalian cell (e.g., a ligand bound to its cognate receptor, where the cognate receptor is physically attached to the plasma membrane). Non- limiting methods for determining the presence of antigen on the surface of a mammalian cell include fluorescence-activated cell sorting (FACS), immunohistochemistry, cell-fractionation assays and Western blotting.

The phrase "MHC1" or "MHC1 complex" means a complex of polypeptide comprising l) a peptide encoded by a HLA-A gene, a HLA-B gene, a HLA-C gene, a HLA-E gene, a HLA-F gene, a HLA- gene, or a HLA-L gene, or a variant thereof; ii) a peptide encoded by a 2-microglobulin gene or a variant thereof; and, optionally, iii) an organic molecule (e.g., a peptide) that is presented within the groove formed between the al and 2 domains of the polypeptide encoded by the HLA-A gene, the HLA-B gene, the HLA-C gene, the HLA-E gene, the HLA-F gene, the HLA-K gene, or the HLA-L gene.

The phrase "control ABPC" or "control antigen-binding protein construct" means an antigen-binding protein construct or multi-specific ABPC that has at least a 10-fold increase in the KD for any of the polypeptide complexes (PCs) described herein or the beta 2- microglobulin (β2ηι) polypeptide at an acidic pH as compared to the KD of the first antigen- binding domain or second antigen-binding domain of any of the antigen-binding protein constructs described herein or the second antigen-binding domain of any of the multi-specific ABPCs described herein, respectively, for the same polypeptide complex or beta 2- microglobulin polypeptide at the acidic pH, or is not pH selective. In some embodiments, the control ABPC is not pH selective. In some embodiments, the control ABPC has the same Fc and/or idiotype characteristics as the ABPC or the multi-specific ABPC.

In some embodiments, the control ABPC has at least a 100-fold, at least a 200-fold, at least a 500-fold, or at least a 1000-fold increase in the KD for any of the polypeptide complexes (PCs) described herein or the beta 2-microglobulin (f>2m) polypeptide at an acidic pH as compared to the KD of the first antigen-binding domain of any of the antigen-binding constructs described herein or second antigen-binding domain of any of the multi-specific ABPCs described herein, for the same polypeptide complex or beta 2-microglobulin polypeptide at the acidic pH.

In some embodiments, the control ABPC does not bind specifically to any of the polypeptide complexes described herein or beta 2-microglobulin (β2ηι) polypeptide. In some embodiments, the control ABPC does not bind specifically to any of the polypeptide complexes described herein at an acidic pH and does not bind specifically to beta 2- microglobulin polypeptide at an acidic pH.

In some embodiments, the control ABPC for any of the multi-specific antigen-binding protein constructs described herein does not bind specifically to an identifying antigen, while the multi-specific antigen-binding protein construct binds specifically to the identifying antigen.

In some embodiments, the control ABPC has an antigen-binding domain that has the same sequence as the first antigen-binding domain of any of the antigen-binding protein constructs provided herein, except that is has one, two, three, four, or five amino acid substitutions in the paratope of the first antigen-binding domain. In some embodiments, the control ABPC has an antigen-binding domain that has the same sequence as the second antigen-binding domain of any of the multi-specific antigen-binding protein complexes provided herein, except that is has one, two, three, four, or five amino acid substitutions in the paratope of the second antigen-binding domain. In some embodiments, the control ABPC has an antigen-binding domain that has the same sequence as the second antigen-binding domain of any of the multi-specific ABPCs provided herein, except that it has been mutated to remove one, two, three, or four histidines from the paratope of the second antigen-binding domain, and optionally, the first antigen-binding domain has the same sequence as the first antigen-binding domain of the multi-specific ABPC. In some embodiments, the control ABPC has a first antigen-binding domain that has the same sequence as the first antigen- binding domain of any of the antigen-binding protein constructs provided herein, except that it has been mutated to remove one, two, three, or four histidines from the paratope of the first antigen-binding domain, except that it has been mutated to remove one, two, three, or four histidines.

The phrase "a reduced level" or "a decreased level" can be a reduction or decrease of at least a 1% (e.g., at least 2%, at least 4%, at least 6%, at least 8%, at least 10%, at least 12%, at least 14%, at least 16%, at least 18%, at least 20%, at least 22%, at least 24%, at least 26%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) reduction as compared to a reference level or value.

The phrase 'Old World Monkey" means a monkey of the Cercopithecoidea family. The Cercopithecoidea family includes, e.g., the following genuses: Allenopithecus,

Miopithecus, Erythrocebus, Chlorocebus, Cercopithecus, Macaca, Lophocebus.

Rungwecebus, Papio, Theropithecus, Cercocebus, Mandrillus, Colobus, Piliocolobus,

Procolobus, Semnopithecus, Trachypithecus, Pre bytis_m Pygathrix, Rhinopithecus, Nasalis, Simias, mdMesopithecus. Representative species that fall within the Cercopithecoidea family are known in the art.

The term "cell killing potency" refers to the ability of an agent (e.g., any of the antigen-binding protein constructs described herein, or any of the multi-specific antigen- binding protein constructs described herein) to induce, directly or indirectly, the apoptosis and/or necrosis of a mammalian cell (e.g., a cancer cell). Methods for determining the cell killing potency of a cell are known in the art (e.g., trypan blue staining, microscopy, fluorescence-assisted cell sorting, and assays to detect markers of apoptosis).

The term "toxin liberation" refers to the ability of a mammalian cell (e.g., a noncancerous mammalian cell or a cancer cell) to internalize (e.g., via pinocytosis and/or receptor-mediated endocytosis) any of the ABPCs or multi-specific ABPCs described herein (e.g., any of antigen-binding protein complexes, any of the multi-specific antibody-protein complexes, or any of the control ABPCs described herein) that are conjugated to a toxin, and subsequently release the toxin conjugated to the ABPC, thereby mediating cell killing. Toxin liberation can be assessed using ELISA, immunofluorescence, cell killing assays, mass spectrometry, and/or an isotope-labeled toxin. The term "endosomal recycling" refers to the ability of a mammalian cell (e.g., a noncancerous mammalian cell or a cancer cell) to endocytose (e.g., via pinocytosis and/or receptor-mediated endocytosis) any of the antigen-binding protein constructs, any of the multi-specific antigen-binding protein complexes, or any of the control ABPCs described herein, and subsequently recycle the ABPC, the multi-specific ABPC, or control ABPC back into the extracellular space. Endosomal recycling can be assessed using

immunofluorescence, ELISA, western blot, immunoprecipitation or an isotope-labeled ABPC, multi-specific ABPC, or control ABPC. Endosomal recycling can be determined by determining the rate of the subsequent release of any of the ABPCs, multi-specific ABPCs, or control ABPCs described herein after it has been endocytosed (taken up) by the mammalian cell (e.g., using pulse-labeling).

The phrase "half-life" refers to the half-life of an ABPC or a multi-specific ABPC in the circulation (e.g., blood, serum, or plasma) of a subject (e.g., any of the subjects described herein, e.g., any mammal) and is represented by the time required for 50% of an ABPC or a multi-specific ABPC to be cleared from the circulation at a time subsequent to the administration of a single initial dose of the ABPC or the multi-specific ABPC to the subject. In some embodiments, an alteration in half-life (e.g., an increase in half-life or a decrease in half-life of an ABPC or a multi-specific ABPC) is determined by comparing the half-life of an ABPC or a multi-specific ABPC in a subject to the half-life of a control ABPC in a similar subject.

In some embodiments, the half-life of an ABPC or a multi-specific ABPC in a subject is determined by measuring the level of the ABPC or the multi-specific ABPC in samples obtained from a subject (e.g., a blood sample, a plasma sample) at different time points following an initial, single administration of the ABPC or the multi-specific ABPC to the subject. In some embodiments, the level of the ABPC or the multi-specific ABPC in samples obtained from a subject is determined using enzyme-linked immunosorbent assay (ELISA) or another assay known to the art, and the determined level of the ABPC or the multi-specific ABPC in the samples is plotted as a function of time using a software program (e.g., GraphPad Prism).

Unless otherwise defined, 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 invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.

BRIEF DESCRIPTION OF DRAWINGS

FIGURE 1. SDS PAGE for W6/32 histidine scanning. Expi293 cell culture supematants post-harvest were loaded on non-reduced SDS PAGE gels to confirm expression of chimeric W6/32 Fab and histidine scanning variants. Arrows show the corresponding size for a Fab on a non-reduced SDS PAGE gel. MYT0064 (top left, first two lanes) is chimeric W6/32 Fab and the rest of the lanes(MYT0065-MYT0102) are chimeric W6/32 heavy chain histidine scanning variants.

FIGURE 2. Histidine Scanning of W6/32 heavy chain. pH-dependent binding of

W6/32 histidine scanning variants to HeLa cells. pH normalized cell culture supematants of chimeric W6-32 Fab (MYT0064), a pH dependent control (TAM0165) and histidine scanning variants (MYT0075, MYT0080, MYT0094, and MYT0098) were incubated with HeLa cells and detected via an anti-myc-tag mouse mAb (9B11) Alexa Fluor 488 conjugate. pH 5.8 is in gray, pH 7.4 is in black and secondary antibody only signal is in white, histograms were normalized to mode.

FIGURE 3. Binding of W6/32 his scan candidates to various HLA-C alleles. pH 5.8 normalized cell culture supematants from chimeric W6/32 Fab control (MYT0064) and histidine scanning variants (MYT0075, MYT0080, MYT0094, and MYT0098) were incubated with HLA-C beads corresponding to eight different alleles and a negative control and detected via an anti-myc-tag mouse mAb (9B11) Alexa Fluor 488 conjugate. Secondary only control is shown with a dashed histogram, all samples and controls are shown with filled histograms.

FIGURE 4. Characterization of recombinant HLA-A and HLA-B antigens. Non reduced (NR) and reduced (R) SDS PAGE analysis of purified HLA-A and HLA-B expressed as monovalent human Fc fusions i.e., MYT0002 and MYT0003, and HLA-A expressed as bivalent mouse Fc fusion MYT0051 is shown on the left. Size exclusion chromatography traces for the corresponding proteins are shown on the right. FIGURE 5. Antigen characterization for phage display selections. MYT0002(left) or MYT0003(right) were immobilized on a biosensor and characterized for binding to allele specific antibodies BB7.1 (HLA-B7 specific), and BB7.2 (HLA-A2 specific), as well as beta2m specific antibody BBM.1. Both antigens show binding to BBM.1 and their respective allele specific antibody in the association step. Top curve shows binding of the antibody, bottom two curves are baseline conditions.

FIGURE 6. Binding of anti-HLA-A VH domains (k_on and k₀ff selection) to MYT0002 by phage ELISA. Phage particles expressing TAM0039, TAM0121, TAM0146 and

TAM0165 in pH 5.8 and pH 7.4 buffers were tested against immobilized MYT0002 (HLA- A2-Fc), human Fc, and streptavidin. Background subtracted absorbance at 450 nm was plotted on the y-axis. pH 5.8 samples are in gray bars and pH 7.4 samples are in black bars.

FIGURES 7A and 7B. Binding of purified anti-HLA-A VH domains (k_on and k₀ff selection) to MYT0002 by biolayer interferometry. A) MYT0002 or human Fc was captured on an anti-human Fc biosensor and 50 μg/mL of purified TAM0039, TAM0146 or TAM0165 in pH 5.8 (gray) or pH 7.4 (black) was associated for 300 seconds. Dissociation step was carried out in the corresponding pH for 600 seconds. B) MYT0003 was captured on an anti- human Fc biosensor and 50 μg/mL of purified TAM0039, TAM0146 or TAM0165 in pH 5.8 (gray) or pH 7.4 (black) was associated for 300 seconds. Dissociation step was carried out in the corresponding pH for 300 seconds.

FIGURES 8A and 8B. Characterization of purified anti-HLA-A VH-Fc fusions. A)

Non-reduced and reduced SDS PAGE gel analysis for MYT0061, MYT0062, and

MYT0063. B) Purified MYT00061, MYT0062 or MYT0063 was captured on an anti-human Fc biosensor and 50 nM of MYT0051 (HLA-A-mouse Fc) was associated for 300 seconds in either pH 5.8 (gray) or pH 7.4 (black). Dissociation step was carried out in the corresponding pH for 600 seconds.

FIGURE 9. Selectivity of anti-HLA-A VH-Fc to fcMHCl over nfcMHCl . Binding of MYT0061, MYT0062, MYT0063, W6/32 (a fcMHCl binding control antibody), HC-10 and HCA-2 (nfcMHCl binding control antibodies) and a human IgGl isotype control antibody was tested to NCIH526, NCIH1693 and THP-1 cells with or without acid strip. MYT0061, MYT0062 and MYT0063 all show reduced binding to cells treated with an acid strip confirming that they are specific to fcMHCl . Acid strip cells are shown in gray bars and non- acid strip samples are shown in black bars. FIGURE 10. Binding of anti-HLA-A VH domains (k₀ff selection only) to MYT0002 by phage ELISA. Phage supematants expressing anti-HLA VH domains in pH 5.8 and pH 7.4 buffers were tested against immobilized MYT0002 (HLA-A2-Fc), human Fc, and streptavidin. Background subtracted absorbance at 450 nm was plotted on the y-axis. pH 5.8 samples are in gray bars and pH 7.4 samples are in black bars.

FIGURE 11. Binding of anti-HLA-B VH domains (k₀ff selection only) to MYT0003 by phage ELISA. Phage supematants expressing anti-HLA VH domains in pH 5.8 and pH 7.4 buffers were tested against immobilized MYT0002 (HLA-A2-Fc), human Fc, and streptavidin. Background subtracted fold over background ratio of absorbance at 450 nm was plotted on the y-axis. pH 5.8 samples are in gray bars and pH 7.4 samples are in black bars.

FIGURE 12. Quantitative staining of fcMHCl+ cell lines. Three cell lines (HeLa, NCIH82 and NCIH69) and primar human NK cells were stained with MYT0061,

MYT0062, MYT0063, and W6/32 ( a fcMHCl binding control) to quantify fcMHCl receptor numbers. A non-stained cells only control is shown as "NS".

FIGURE 13. Affinity determination of W6/32 at pH 5.8 and pH 7.4. HeLa cells were stained with increasing concentrations of labeled W6/32 from 80 pM to 600 nM in pH 5.8 (gray) and pH 7.4 (black). W6/32 was found to be a non pH dependent antibody.

FIGURE 14. pH dependent binding on HeLa and THP-1 cells. HeLa and THP-1 cells were labeled with MYT0061, MYT0062, and MYT0063 in either pH 5.8 or pH 7.4 assay buffer, followed by staining with a rat anti -human Fc-AF488 secondary antibody. No stain and secondary only controls were also performed. All constructs showed labeling of both cell lines at pH5.8, and MYT0063 on HeLa cells showed the greatest disparity in pH dependent binding.

FIGURE 15. Release assay at pH 7.4. HeLa cells were stained with the indicated protein constructs at either pH 5.8 or pH 7.4 at 500nM. To test if the constructs could be released by switching from pH 5.8 to 7.4, the cells were washed and incubated for 30 minutes in lxPBS pH 7.4. Secondary staining was done at the same pH as the primary. As demonstrated by the MFI levels for each condition, all constructs except for MYT0052 and the W6/32 control (MYT0064) showed pH-dependent binding, weak to no binding at pH 7.4, and release at pH 7.4. Secondary only staining and hlgG isotype control did not show staining.

FIGURE 16. Recycling of W6/32. HeLa cells were plated with 166nM of anti-HLA (clone W6/32) and incubated overnight. The following day the cells were stripped of their surface bound antibody with pH 2.7 assay buffer and then returned to 37 degrees C with for either various time points. After, all conditions were placed at 4 degrees C and stained with goat anti-mouse Fc-AF488 secondary antibody. Recycled antibody on the surface was read by flow cytometry.

FIGURE 17. Schematic of bispecific constructs. A series of thirteen fcMHCl bispecific constructs were generated in different formats, combining pH-dependent fcMHCl antigen-binding domains (TAM0039, TAM0146, and TAM0165) and second antigen-binding domains (pH-dependent anti-IL6R, pH-dependent anti-TNFa, anti-EGFR, anti-RANKL, anti- CEA, and anti-SOST) in different valencies and orientations, with and without an Fc domain: Fab-VH-Fc, KiH VH-Fc, KiH VH-tandem VH-Fc, tandem VH-Fc, and tandem VH.

FIGURE 18. SDS-PAGE of bispecific constructs. Non reduced (NR) and reduced (R) SDS PAGE was performed on purified MYT0045, MYT0046, MYT0047, MYT0048, MYT0049, MYT0052 ("52"), MYT0053 ("53"), MYT0054 ("54"), MYT0055 ("55"), MYT0056 ("56"), MYT0057 ("57"), MYT0058 ("58"), and MYT0059 ("59") using methods known in the art, and the resulting gel images are shown.

FIGURES 19A, 19B and 19C. Binding of bispecific antibodies to HLA-A and second antigen by biolayer interferometry. A) MYT0045-MYT0049 were captured on anti-human Fc biosensors and associated with MYT0051 at pH 5.8 (gray) or pH 7.4 (black). In a separate experiment binding to the corresponding second antigen was tested. MYT0045-MYT0049 captured on anti-human Fc biosensors were associated with either IL6R or TNFalpha or EGFR or RANKL or EGFR at pH 5.8 (gray) or pH 7.4(black). Binding of MYT0048 to RANKL was only tested at pH 7.4. B) MYT0052-MYT0055 were captured on anti-human Fc biosensors and associated with MYT0051 at pH 5.8 (gray) or pH 7.4 (black). In a separate experiment binding to the corresponding second antigen was tested. MYT0052-MYT0055 was captured on anti-human Fc biosensors were associated with either TNFalpha or CEA or EGFR at pH 5.8 (gray ) or pH 7.4(black). Binding of MYT0053 to CEA was only tested at pH 7.4 C) MYT0002 was captured on an anti-human Fc sensor and associated with either MYT0056, MYT0057, MYT0058 or MYT0059 at pH 5.8 (gray) and 7.4 (black). In another experiment, EGFR-Fc or IL6R-Fc was immobilized on an anti-human Fc sensor and associated with MYT0057 or MYT0058 respectively at pH 5.8 (gray) or pH 7.4(black). MYT0059 was captured on an anti-penta-his sensor and associated with SOST at either pH 5.8 (gray) or pH 7.4(black). Some figures show one or more flat bottom curve(s), which represent baseline conditions. FIGURE 20. Expression of EGFR/CEA and IL6R. HeLa and H82 cells were stained with anti-EGFR-PE, anti-IL-6R-PE, and purified anti-CEA, followed by goat anti-mouse- AF488 for anti-CEA primary stain only. H82 cells did not express any of these receptors while HeLa cells expressed very low levels of EGFR and low levels of CEA.

FIGURE 21. Recycling of bispecifics. HeLa and H82 cells were plated with 500nM of anti-HLA constructs and incubated overnight. The following day the cells were stripped of their surface bound antibody with pH 8.0 assay buffer and then returned to 37 degrees C at pH 5.8 with for either 0, lhr, or 2 hr. Next, all conditions were placed at 4 degrees C and stained with rat anti-human Fc secondary antibody. Recycled antibody on the surface was read by flow cytometry as mean fluorescence intensity, and the 0 hour timepoint mean fluorescence intensity was subtracted from the 1 hour timepoint mean fluorescence intensity to calculate a delta, which was then plotted as shown. MYT0047 and MYT0049 showed approximately 2-fold greater recycling than non-binding IgGl isotype control, whereas MYT0052, MYT0053, MYT0054, and MYT0055 showed approximately 5-fold to 18-fold greater recycling than non-binding IgGl isotype control.

FIGURE 22. SEC chromatography data for bispecifics. Size exclusion

chromatography was performed using methods known in the art, and size exclusion chromatography traces for MYT0045, MYT0046, MYT0047, MYT0048, MYT0049 are shown. Percent monomer was calculated from the peak with the expected retention time for monomer.

FIGURE 23: Construct identifier to SEQ ID NO correspondence table. Constructs are listed in the first column of the table, SEQ ID NOs are listed and correspond to constructs on the left and the appropriate heavy chain, light chain, and CDR categories along the top. For constructs with more than one heavy chain, a heavy chain "A" and "B" are denoted. For heavy chains with more than one antigen-binding domain, corresponding to more than one set of CDRs, a "set 1" and "set 2" are denoted.

DETAILED DESCRIPTION

Provided herein are antigen-binding protein constructs (ABPCs) that include: a first antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex, wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA- A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ηι) polypeptide; and one or both of a conjugated toxin, radioisotope, or drug, and an additional antigen-binding domain, wherein: (a) the dissociation rate of the first antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or (b) the dissociation constant (KD) of the first antigen-binding domain at an acidic pH is less than the KD at a neutral pH, and wherein the first antigen-binding domain includes at least one paratope that includes at least one histidine residue, and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC (e.g., any of the control ABPCs described herein) in vivo.

Also provided herein are antigen-binding protein constructs (ABPCs) that include: a first antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex (PC), wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2πι) polypeptide; and one or both of: a conjugated toxin, radioisotope, or drug, and an additional antigen-binding domain, wherein the ABPC has increased endosomal recycling in a mammalian cell that presents the PC on its surface or in a cellular compartment as compared to a control ABPC (e.g., any of the control ABPCs described herein), and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of the control ABPC in vivo.

Also provided herein are antigen-binding protein constructs (ABPC) that include: a first antigen-binding domain that is capable of specifically binding to an epitope of a beta 2- microglobulin (β2ηι) polypeptide; and one or both of: a conjugated toxin, radioisotope, or drug, and an additional antigen-binding domain, wherein the first antigen-binding domain includes at least one paratope that includes at least one histidine residue, and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC in vivo.

Also provided herein are antigen-binding protein constructs (ABPCs) that include: a first antigen-binding domain that is capable of specifically binding to an epitope of a polypeptide complex (PC), wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2ηι) polypeptide; and one or both of: a conjugated toxin, radioisotope, or drug, and an additional antigen-binding domain, wherein the ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC complex on its surface or in a cellular compartment as compared to a control ABPC (e.g., any of the control ABPCs described herein), and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of the control ABPC in vivo.

In some embodiments of any of the antigen-binding protein constructs described herein, the ABPC further includes a second antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex, wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA- C, and ii) a beta 2-microglobulin (β2πι) polypeptide, wherein: (a) the dissociation rate of the second antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or (b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH is less than the KD at a neutral pH, and wherein the second antigen-binding domain includes at least one paratope that includes at least one histidine residue.

In some embodiments of any of the antigen-binding protein constructs described herein, the ABPC further includes a second antigen-binding domain that is capable of specifically binding an epitope of a beta 2-microglobulin (β2πι) polypeptide, wherein: (a) the dissociation rate of the second antigen-binding domain at an acidic pH is slower than the disassociation rate at a neutral pH; or (b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH is less than the KD at a neutral pH, and wherein the second antigen-binding domain includes at least one paratope that includes at least one histidine residue.

Also provided herein are multi-specific antigen-binding protein constructs (multi- specific ABPCs) that include: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, wherein: the first antigen-binding domain is capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell; and the second antigen-binding domain is capable of specifically binding to an epitope of a polypeptide complex, wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ηι) polypeptide, wherein: (a) the dissociation rate of the second antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or (b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH is less than the KD at a neutral pH; and the second antigen-binding domain includes at least one paratope that includes at least one histidine residue.

Also provided herein are multi-specific antigen-binding protein constructs (multi- specific ABPCs) that include: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, wherein: the first antigen-binding domain is capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell; and the second antigen-binding domain capable of specifically binding to an epitope of a polypeptide complex (PC), wherein the polypeptide complex includes) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA- C, and ii) a beta 2-microglobulin (β2ιη) polypeptide, wherein the multi-specific ABPC has increased endosomal recycling in a mammalian cell that presents the PC on its surface or in a cellular compartment as compared to a control ABPC (e.g., any of the control ABPCs described herein).

Also provided herein are multi-specific antigen-binding protein constructs (multi- specific ABPCs) that include: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, wherein: the first antigen-binding domain is capable of specifically binding to an identify ing antigen present on a surface of a mammalian target cell; and the second antigen-binding domain is capable of specifically binding to an epitope of a beta 2-microglobulin (β2πι) polypeptide, wherein: (a) the dissociation rate of the second antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or (b) the dissociation constant (KD) of the second antigen- binding domain at an acidic pH is less than the KD at a neutral pH; and the second antigen- binding domain includes at least one paratope that includes at least one histidine residue.

Provided herein are multi-specific antigen-binding protein constructs (multi-specific

ABPCs) that include: (a) a first antigen-binding domain that is capable of specifically binding an identifying antigen present on a surface of a mammalian target cell; (b) a second antigen- binding domain capable of specifically binding to an epitope of a polypeptide complex (PC), wherein the polypeptide complex includes (i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and (ii) a beta 2-microglobulin (β2ιη) polypeptide; and (c) a conjugated toxin, radioisotope, or drug, wherein the multi-specific ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC complex on its surface or in a cellular compartment as compared to a control ABPC (e.g., any of the control ABPCs described herein).

The data in the specification showing increased recycling of the claimed ABPCs and multi-specific ABPCs indicates that the claimed ABPCs and multi-specific ABPCs would have an increased half-life in vivo. The data in the specification showing increased endocytosis of the claimed ABPCs and multi-specific ABPCs indicates that an ABPC or multi-specific ABPC that is conjugated to a cytotoxic drug or radioisotope would have increased toxin release and lead to increased toxicity in target cells (e.g., target cancer cells), e.g., relative to non-cancer cells.

Non-limiting aspects of these methods are described below, and can be used in any combination without limitation. Additional aspects of these methods are known in the art.

Exemplary Aspects of Antigen-Binding Protein Constructs and Multi-Specific Antigen- Binding Protein Constructs

Any of the antigen-binding protein constructs (ABPCs) or any of the multi-specific antigen-binding protein constructs described herein can be a single polypeptide, or can include two, three, four, five, six, seven, eight, nine, or ten (the same or different) polypeptides.

In some embodiments where the antigen-binding protein construct is a single polypeptide, the ABPC can include a single antigen-binding domain or two antigen-binding domains. In some embodiments where the antigen-binding protein construct is a single polypeptide and includes two antigen-binding domains, the first and additional antigen- binding domains can be identical or different from each other (and can specifically bind to the same or different antigens or epitopes). In some embodiments where the antigen-binding protein construct is a single polypeptide, the first antigen-binding domain and the additional antigen-binding domain (if present) can each be independently selected from the group of: a VHH domain, a VNAR domain, and a scFv. In some embodiments where the antigen- binding protein construct is a single polypeptide, the antigen-binding protein construct can be a BiTe, a (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH-CL-scFv, a HSAbody, scDiabody -HAS, or a tandem-scFv.

Additional examples of antigen-binding domains that can be used when the antigen-binding protein construct is a single polypeptide are known in the art.

In some embodiments where the multi-specific antigen-binding protein complex is a single polypeptide, the first and second antigen-binding domains are different from each other.

In some embodiments where the multi-specific antigen-binding protein construct is a single polypeptide, the first antigen-binding domain and the second antigen-binding domain can each be independently selected from the group of: a VHH domain, a VNAR domain, and a scFv. In some embodiments where the multi-specific ABPC is a single polypeptide, the antigen-binding protein construct can be a BiTe, a (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH-CL-scFv, a HSAbody, scDiabody-HAS, or a tandem-scFv. Additional examples of antigen-binding domains that can be used when the multi-specific antigen-binding protein complex is a single polypeptide are known in the art.

In some embodiments where the multi-specific antigen-binding protein construct is a single polypeptide and includes antigen-binding two domains, the first antigen-binding domain and the second antigen-binding domain can both be VHH domains, or at least one antigen-binding domain can be a VHH domain. In some embodiments where the multi- specific antigen-binding protein construct is a single polypeptide and includes two antigen binding domains, the first antigen-binding domain and the second antigen-binding domain are both VNAR domains, or at least one antigen-binding domain is a VNAR domain. In some embodiments where the multi-specific antigen-binding protein construct is a single polypeptide, the first antigen-binding domain is a scFv domain. In some embodiments where the multi-specific antigen-binding protein construct is a single polypeptide and includes two antigen binding domains, the first antigen-binding domain and the second antigen-binding domain can both be scFv domains, or at least one antigen-binding domain can be a scFv domain.

In some embodiments where the antigen-binding protein complex is a single polypeptide and includes two antigen-binding domains, the first antigen-binding domain and the additional antigen-binding domain can both be VHH domains, or at least one antigen- binding domain can be a VHH domain. In some embodiments where the antigen-binding protein complex is a single polypeptide and includes two antigen-binding domains, the first antigen-binding domain and the additional antigen-binding domain are both VNAR domains, or at least one antigen-binding domain is a VNAR domain. In some embodiments where the antigen-binding protein complex is a single polypeptide, the first antigen-binding domain is a scFv domain. In some embodiments where the antigen-binding protein complex is a single polypeptide and includes two antigen-binding domains, the first antigen-binding domain and the additional antigen-binding domain can both be scFv domains, or at least one antigen- binding domain can be a scFv domain.

In some embodiments where the antigen-binding protein construct or the multi- specific antigen-binding protein construct includes two or more polypeptides, two, three, four, five or six of the polypeptides of the two or more polypeptides can be identical. In some embodiments where the antigen-binding protein construct or multi-specific antigen-binding protein construct includes two or more polypeptides (e.g., two, three, four, five, six, seven, eight, nine, or ten polypeptides), two or more of the polypeptides of the ABPC or the multi-specific ABPC can assemble (e.g., non-covalently assemble) to form an antigen-binding domain, e.g., an antigen-binding fragment of an antibody (e.g., any of the antigen-binding fragments of an antibody described herein), a VHH-scAb, a VHH-Fab, a Dual scFab, a F(ab')2, a diabody, a crossMab, a DAF (two-in-one), a DAF (four-in-one), a DutaMab, a DT-IgG, a knobs-in-holes common light chain, a knobs-in-holes assembly, a charge pair, a Fab-arm exchange, a SEEDbody, a LUZ-Y, a Fcab, a κλ-body, an orthogonal Fab, a DVD-IgG, a IgG(H)-scFv, a scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4- Ig, Zybody, DVI-IgG, Diabody-CH3, a triple body, a miniantibody, a minibody, a TriBi minibody, scFv-CH3 KJH, Fab-scFv, a F(ab')2-scFv2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a Diabody-Fc, a tandem scFv-Fc, an Intrabody, a dock and lock, an ImmTAC, an IgG-IgG conjugate, a Cov-X-Body, and a scFvl-PEG-scFv2. See, e.g., Spiess et al., Mol. Immunol. 67:95-106, 2015, incorporated in its entirety herewith, for a description of these elements.

Non-limiting examples of an antigen-binding fragment of an antibody include an Fv fragment, a Fab fragment, a F(ab')2 fragment, and a Fab' fragment. Additional examples of an antigen-binding fragment of an antibody is an antigen-binding fragment of an IgG (e.g., an antigen-binding fragment of IgGl, IgG2, IgG3, or IgG4) (e.g., an antigen-binding fragment of a human or humanized IgG, e.g., human or humanized IgGl, IgG2, IgG3, or IgG4); an antigen-binding fragment of an IgA (e.g., an antigen-binding fragment of IgAl or IgA2) (e.g., an antigen-binding fragment of a human or humanized IgA, e.g., a human or humanized IgAl or IgA2); an antigen-binding fragment of an IgD (e.g., an antigen-binding fragment of a human or humanized IgD); an antigen-binding fragment of an IgE (e.g., an antigen-binding fragment of a human or humanized IgE); or an antigen-binding fragment of an IgM (e.g., an antigen-binding fragment of a human or humanized IgM).

In some embodiments of any of the antigen-binding protein constructs or multi- specific antigen-binding protein constructs described herein, the antigen-binding protein constructs or multi-specific antigen-binding protein constructs can be a Fab-Vh-Fc, KiH Vh- Fc, KiH Vh-tandem Vh-Fc, tandem Vh-Fc, or a tandem Vh. In some embodiments of any of the antigen-binding protein constructs described herein, the antigen-binding protein construct can be a Vh-Fc.

A VHH domain is a single monomeric variable antibody domain that can be found in camelids. A VNAR domain is a single monomeric variable antibody domain that can be found in cartilaginous fish. Non-limiting aspects of VHH domains and VNAR domains are described in, e.g., Cromie et al., Curr. Top. Med. Chem. 15:2543-2557, 2016; De Genst et al., Dev. Comp. Immunol. 30: 187-198, 2006; De Meyer et al., Trends Biotechnol. 32:263-270, 2014; Kijanka et al., Nanomedicine 10: 161-174, 2015; ovaleva et al., Expert. Opin. Biol. Ther. 14: 1527-1539, 2014; Krah et al., Immunopharmacol. Immunotoxicol. 38:21-28, 2016; Mujic- Delic et al., Trends Pharmacol. Sci. 35:247-255, 2014; Muyldermans, J. Biotechnol. 74:277- 302, 2001 ; Muyldermans et al., Trends Biochem. Sci. 26:230-235, 2001; Muyldermans, ^™. Rev. Biochem. 82:775-797, 2013; Rahbanzadeh et al, Immunol. Invest. 40:299-338, 2011; Van Audenhove et al, EBioMedicine 8:40-48, 2016; Van Bockstaele et al, Curr. Opin.

Investig. Drugs 10: 1212-1224, 2009; Vincke et al., Methods Mol. Biol 911 : 15-26, 2012; and Wesolowski et al, Med. Microbiol. Immunol. 198: 157-174, 2009.

A "Fv" fragment includes a non-covalently -linked dimer of one heavy chain variable domain and one light chain variable domain.

A "Fab" fragment includes, the constant domain of the light chain and the first constant domain (CHI) of the heavy chain, in addition to the heavy and light chain variable domains of the Fv fragment.

A "F(ab')2" fragment includes two Fab fragments joined, near the hinge region, by disulfide bonds.

A "dual variable domain immunoglobulin" or "DVD-Ig" refers to multivalent and multispecific binding proteins as described, e.g., in DiGiammarino et al, Methods Mol. Biol. 899: 145-156, 2012; Jakob et al, MABs 5:358-363, 2013; and U.S. Patent Nos. 7,612,181; 8,258,268; 8,586,714; 8,716,450; 8,722,855; 8,735,546; and 8,822,645, each of which is incorporated by reference in its entirety.

DARTs are described in, e.g., Garber, Nature Reviews Drug Discovery 13:799-801,

2014.

Additional aspects of antigen-binding protein constructs and multi-specific antigen- binding protein constructs are known in the art. Exemplary Aspects of Antigen-Binding Protien Constructs

In some embodiments of any of the antigen-binding protein constructs (ABPCs) described herein, the first antigen-binding domain is capable of specifically binding to an epitope of a polypeptide complex, wherein the polypeptide complex includes i) a poly peptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2πι) poly peptide, wherein: (a) the dissociation rate of the first antigen- binding domain at an acidic pH (e.g., any of the acidic pHs described herein) is slower than the dissociation rate at a neutral pH (e.g., any of the neutral pHs described herein); or (b) the dissociation constant (KD) of the first antigen-binding domain at an acidic pH (e.g., any of the acidic pHs described herein) is less than the KD at a neutral pH (e.g., any of the neutral pHs described herein), and wherein the first antigen-binding domain includes at least one paratope that includes at least one (e.g., 1, 2, 3, 4, or 5) histidine residue, and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC (e.g., any of the control ABPCs described herein) in vivo.

In some embodiments of any of the antigen-binding protein constructs (ABPCs) described herein, the first antigen-binding domain is capable of specifically binding an epitope of a polypeptide complex (PC), wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ιη) polypeptide, wherein the ABPC has increased (e.g., at least a 1% increase, at least a 2% increase, at least a 4% increase, at least a 6% increase, at least a 8% increase, at least a 10% increase, at least a 12% increase, at least a 14% increase, at least a 16% increase, at least a 18% increase, at least a 20% increase, at least a 25% increase, at least a 30% increase, at least a 35% increase, at least a 40% increase, at least a 45% increase, at least a 50% increase, at least a 55% increase, at least a 60% increase, at least a 65% increase, at least a 70% increase, at least a 75% increase, at least a 80% increase, at least a 85% increase, at least a 90% increase, at least a 95% increase, at least a 100% increase, at least a 110% increase, at least a 120% increase, at least a 130% increase, at least a 140% increase, at least a 150% increase, at least a 160% increase, at least a 170% increase, at least a 180% increase, at least a 190% increase, at least a 200% increase, at least a 210% increase, at a least a 220% increase, at least a 230% increase, at least a 240% increase, at least a 250% increase, at least a 260% increase, at least a 270% increase, at least a 280% increase, at least at a 290% increase, or at least a 300% increase) endosomal recycling in a mammalian cell that presents the PC on its surface or in a cellular compartment as compared to a control ABPC (e.g., any of the control ABPCs described herein), and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of the control ABPC in vivo.

In some embodiments of any of the antigen-binding protein constructs described herein, the first antigen-binding domain is capable of specifically binding to an epitope of a polypeptide complex (PC), wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2ηι) poly peptide, where the ABPC has reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 32% reduced, at least 34% reduced, at least 36% reduced, at least 38% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) toxin liberation and/or reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 32% reduced, at least 34% reduced, at least 36% reduced, at least 38% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) cell killing potency in a mammalian cell presenting the PC complex on its surface or in a cellular compartment as compared to a control ABPC (e.g., any of the control ABPCs described herein), and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of the control ABPC in vivo.

In some embodiments of any of the antigen-binding protein constructs described herein, the first antigen-binding domain is capable of specifically binding an epitope of a beta 2-microglobulin (β2ηι) polypeptide, wherein: (a) the dissociation rate of the second antigen- binding domain at an acidic pH (e.g., any of the acidic pHs described herein) is slower than the dissociation rate at a neutral pH (e.g., any of the neutral pHs described herein); or (b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH (e.g., any of the acidic pHs described herein) is less than the KD at a neutral pH (e.g., any of the neutral pHs described herein); and the first antigen-binding domain includes at least one paratope that includes at least one (e.g., 1, 2, 3, 4, or 5) histidine residue., and optionally, the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC in vivo.

In some embodiments of any of the antigen-binding protein constructs described herein, the ABPC further includes a second antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex, wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA- C, and ii) a beta 2-microglobulin (β2ηι) polypeptide, wherein: (a) the dissociation rate of the second antigen-binding domain at an acidic pH (e.g., any of the acidic pHs described herein) is slower than the dissociation rate at a neutral pH (e.g., any of the neutral pHs described herein); or (b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH (e.g., any of the acidic pHs described herein) is less than the KD at a neutral pH (e.g., any of the neutral pHs described herein), and wherein the second antigen-binding domain includes at least one paratope that includes at least one histidine residue.

In some embodiments of any of the antigen-binding protein constructs described herein, the ABPC further includes a second antigen-binding domain that is capable of specifically binding an epitope of a beta 2-microglobulin (β2ηι) polypeptide, wherein: (a) the dissociation rate of the second antigen-binding domain at an acidic pH (e.g., any of the acidic pHs described herein) is slower than the disassociation rate at a neutral pH (e.g., any of the neutral pHs described herein); or (b) the dissociation constant (KD) of the second antigen- binding domain at an acidic pH (e.g., any of the acidic pHs described herein) is less than the KD at a neutral pH (e.g., any of the neutral pHs described herein), and wherein the second antigen-binding domain includes at least one paratope that includes at least one histidine residue.

In some embodiments of any of the antigen-binding protein constructs described herein, the PC further includes a peptide of about 8-12 amino acids in length that is bound to the PC.

In some embodiments of any of the antigen-binding protein constructs described herein, the first antigen-binding domain and, if present, the second antigen-binding domain or the additional binding domain, can be capable of specifically binding to an epitope expressed on the surface or in a cellular compartment of human cells and an epitope that is expressed on the surface or in a cellular compartment of cell from an Old World Monkey (e.g., any of the Old World Monkeys described herein).

In some embodiments of any of the antigen-binding protein constructs described herein, the second antigen-binding domain specifically binds to an epitope that includes at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) amino acid of a polypeptide encoded by an HLA gene selected from the group of HLA-A, HLA-B, and HLA-C, and at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) amino acid of a β2ιη polypeptide.

In some embodiments of any of the antigen-binding protein constructs described herein, the epitope of the PC is an at least partially monomorphic epitope.

In some embodiments of any of the antigen-binding protein constructs described herein, the second antigen-binding domain specifically binds to an epitope of a polypeptide encoded by the HLA gene selected from HLA-A, HLA-B, and HLA-C, when the polypeptide encoded by the HLA gene is bound to the β2πι polypeptide.

In some embodiments of any of the antigen-binding protein constructs described herein, the second antigen-binding domain specifically binds to an epitope of the β2πι polypeptide when the β2ιη polypeptide is bound to the polypeptide encoded by the HLA gene selected from the group of HLA-A, HLA-B, and HLA-C.

In some embodiments of the antigen-binding protein constructs described herein, the first antigen-binding domain and, if present, the second antigen-binding domain, can bind to an epitope of a polypeptide complex (PC) (e.g., any of the polypeptide complexes described herein) or an epitope of a beta 2-microglobulin (β2ιη) polypeptide at an acidic pH (e.g., any of the acidic pHs described herein) or at neutral pH (e.g., any of the neutral pHs described herein) with a dissociation equilibrium constant (KD) of less than 1 x 10^"3 M, less than 1 x 10^" ⁴ M, less than 1 x 10^"5 M, less than 1 x 10^"6 M, less than 1 x 10^"7 M, less than 1 x 10^"8 M, less than 1 x 10^"9 M, less than 1 x 10^"10 M, less than 1 x 10^"11 M, less than 1 x 10^"12 M, or less than 1 x 10^"13 M.

In some embodiments of the antigen-binding protein constructs that include a first antigen-binding domain and a second antigen-binding domain, the first and second antigen- binding domains are identical or are at least 95% identical (e.g., at least 96%, at least 97%, at least 98%, or at least 99% identical) in amino acid sequence to each other. In some embodiments, the antigen-binding protein constructs that include a first antigen-binding domain and a second antigen-binding domain, the first antigen-binding domain and the second antigen-binding domain have a sequence that is less than 80% identical to each other. In some embodiments of antigen-binding protein constructs that include a first and a second antigen-binding domain, the first and second antigen-binding domain binds two different epitopes (e.g., two different epitopes on the same PC (e.g., any of the PCs described herein or p2m polypeptide); or one epitope from any of the PCs described herein and the other an epitope of β2ιη polypeptide).

In some embodiments of any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain and, if present, the second antigen-binding domain, at an acidic pH (e.g., any of the acidic pHs described herein) is between about 1 pM to about 250 nM (e.g., about 1 pM to about 240 nM, about 1 pM to about 230 nM, about 1 pM to about 220 nM, about 1 pM to about 210 nM, about 1 pM to about 200 nM, about 1 pM to about 190 nM, about 1 pM to about 180 nM, about 1 pM to about 170 nM, about 1 pM to about 160 nM, about 1 pM to about 150 nM, about 1 pM to about 140 nM, about 1 pM to about 130 nM, about 1 pM to about 120 nM, about 1 pM to about 110 nM, about 1 pM to about 100 nM, about 1 pM to about 95 nM, about 1 pM to about 90 nM, about 1 pM to about 85 nM, about 1 pM to about 80 nM, about 1 pM to about 75 nM, about 1 pM to about 70 nM, about 1 pM to about 65 nM, about 1 pM to about 60 nM, about 1 pM to about 55 nM, about 1 pM to about 50 nM, about 1 pM to about 45 nM, about 1 pM to about 40 nM, about 1 pM to about 35 nM, about 1 pM to about 30 nM, about 1 pM to about 25 nM, about 1 pM to about 20 nM, about 1 pM to about 15 nM, about 1 pM to about 10 nM, about 1 pM to about 5 nM, about 1 pM to about 2 nM, about 1 pM to about 1 nM, about 1 pM to about 950 pM, about 1 pM to about 900 pM, about 1 pM to about 850 pM, about 1 pM to about 800 pM, about 1 pM to about 750 pM, about 1 pM to about 700 pM, about 1 pM to about 650 pM, about 1 pM to about 600 pM, about 1 pM to about 550 pM, about 1 pM to about 500 pM, about 1 pM to about 450 pM, about 1 pM to about 400 pM, about 1 pM to about 350 pM, about 1 pM to about 300 pM, about 1 pM to about 250 pM, about 1 pM to about 200 pM, about 1 pM to about 150 pM, about 1 pM to about 100 pM, about 1 pM to about 90 pM, about 1 pM to about 80 pM, about 1 pM to about 70 pM, about 1 pM to about 60 pM, about 1 pM to about 50 pM, about 1 pM to about 40 pM, about 1 pM to about 30 pM, about 1 pM to about 20 pM, about 1 pM to about 10 pM, about 1 pM to about 5 pM, about 1 pM to about 4 pM, about 1 pM to about 3 pM, about 1 pM to about 2 pM, about 2 pM to about 250 nM, about 2 pM to about 240 nM, about 2 pM to about 230 nM, about 2 pM to about 220 nM, about 2 pM to about 210 nM, about 2 pM to about 200 nM, about 2 pM to about 190 nM, about 2 pM to about 180 nM, about 2 pM to about 170 nM, about 2 pM to about 160 nM, about 2 pM to about 150 nM, about 2 pM to about 140 nM, about 2 pM to about 130 nM, about 2 pM to about 120 nM, about 2 pM to about 110 nM, about 2 pM to about 100 nM, about 2 pM to about 95 nM, about 2 pM to about 90 nM, about 2 pM to about 85 nM, about 2 pM to about 80 nM, about 2 pM to about 75 nM, about 2 pM to about 70 nM, about 2 pM to about 65 nM, about 2 pM to about 60 nM, about 2 pM to about 55 nM, about 2 pM to about 50 nM, about 2 pM to about 45 nM, about 2 pM to about 40 nM, about 2 pM to about 35 nM, about 2 pM to about 30 nM, about 2 pM to about 25 nM, about 2 pM to about 20 nM, about 2 pM to about 15 nM, about 2 pM to about 10 nM, about 2 pM to about 5 nM, about 2 pM to about 2 nM, about 2 pM to about 1 nM, about 2 pM to about 950 pM, about 2 pM to about 900 pM, about 2 pM to about 850 pM, about 2 pM to about 800 pM, about 2 pM to about 750 pM, about 2 pM to about 700 pM, about 2 pM to about 650 pM, about 2 pM to about 600 pM, about 2 pM to about 550 pM, about 2 pM to about 500 pM, about 2 pM to about 450 pM, about 2 pM to about 400 pM, about 2 pM to about 350 pM, about 2 pM to about 300 pM, about 2 pM to about 250 pM, about 2 pM to about 200 pM, about 2 pM to about 150 pM, about 2 pM to about 100 pM, about 2 pM to about 90 pM, about 2 pM to about 80 pM, about 2 pM to about 70 pM, about 2 pM to about 60 pM, about 2 pM to about 50 pM, about 2 pM to about 40 pM, about 2 pM to about 30 pM, about 2 pM to about 20 pM, about 2 pM to about 10 pM, about 2 pM to about 5 pM, about 2 pM to about 4 pM, about 2 pM to about 3 pM, about 5 pM to about 250 nM, about 5 pM to about 240 nM, about 5 pM to about 230 nM, about 5 pM to about 220 nM, about 5 pM to about 210 nM, about 5 pM to about 200 nM, about 5 pM to about 190 nM, about 5 pM to about 180 nM, about 5 pM to about 170 nM, about 5 pM to about 160 nM, about 5 pM to about 150 nM, about 5 pM to about 140 nM, about 5 pM to about 130 nM, about 5 pM to about 120 nM, about 5 pM to about 110 nM, about 5 pM to about 100 nM, about 5 pM to about 95 nM, about 5 pM to about 90 nM, about 5 pM to about 85 nM, about 5 pM to about 80 nM, about 5 pM to about 75 nM, about 5 pM to about 70 nM, about 5 pM to about 65 nM, about 5 pM to about 60 nM, about 5 pM to about 55 nM, about 5 pM to about 50 nM, about 5 pM to about 45 nM, about 5 pM to about 40 nM, about 5 pM to about 35 nM, about 5 pM to about 30 nM, about 5 pM to about 25 nM, about 5 pM to about 20 nM, about 5 pM to about 15 nM, about 5 pM to about 10 nM, about 5 pM to about 5 nM, about 5 pM to about 2 nM, about 5 pM to about 1 nM, about 5 pM to about 950 pM, about 5 pM to about 900 pM, about 5 pM to about 850 pM, about 5 pM to about 800 pM, about 5 pM to about 750 pM, about 5 pM to about 700 pM, about 5 pM to about 650 pM, about 5 pM to about 600 pM, about 5 pM to about 550 pM, about 5 pM to about 500 pM, about 5 pM to about 450 pM, about 5 pM to about 400 pM, about 5 pM to about 350 pM, about 5 pM to about 300 pM, about 5 pM to about 250 pM, about 5 pM to about 200 pM, about 5 pM to about 150 pM, about 5 pM to about 100 pM, about 5 pM to about 90 pM, about 5 pM to about 80 pM, about 5 pM to about 70 pM, about 5 pM to about 60 pM, about 5 pM to about 50 pM, about 5 pM to about 40 pM, about 5 pM to about 30 pM, about 5 pM to about 20 pM, about 5 pM to about 10 pM, about 10 pM to about 250 nM, about 10 pM to about 240 nM, about 10 pM to about 230 nM, about 10 pM to about 220 nM, about 10 pM to about 210 nM, about 10 pM to about 200 nM, about 10 pM to about 190 nM, about 10 pM to about 180 nM, about 10 pM to about 170 nM, about 10 pM to about 160 nM, about 10 pM to about 150 nM, about 10 pM to about 140 nM, about 10 pM to about 130 nM, about 10 pM to about 120 nM, about 10 pM to about 110 nM, about 10 pM to about 100 nM, about 10 pM to about 95 nM, about 10 pM to about 90 nM, about 10 pM to about 85 nM, about 10 pM to about 80 nM, about 10 pM to about 75 nM, about 10 pM to about 70 nM, about 10 pM to about 65 nM, about 10 pM to about 60 nM, about 10 pM to about 55 nM, about 10 pM to about 50 nM, about 10 pM to about 45 nM, about 10 pM to about 40 nM, about 10 pM to about 35 nM, about 10 pM to about 30 nM, about 10 pM to about 25 nM, about 10 pM to about 20 nM, about 10 pM to about 15 nM, about 10 pM to about 10 nM, about 10 pM to about 5 nM, about 10 pM to about 2 nM, about 10 pM to about 1 nM, about 10 pM to about 950 pM, about 10 pM to about 900 pM, about 10 pM to about 850 pM, about 10 pM to about 800 pM, about 10 pM to about 750 pM, about 10 pM to about 700 pM, about 10 pM to about 650 pM, about 10 pM to about 600 pM, about 10 pM to about 550 pM, about 10 pM to about 500 pM, about 10 pM to about 450 pM, about 10 pM to about 400 pM, about 10 pM to about 350 pM, about 10 pM to about 300 pM, about 10 pM to about 250 pM, about 10 pM to about 200 pM, about 10 pM to about 150 pM, about 10 pM to about 100 pM, about 10 pM to about 90 pM, about 10 pM to about 80 pM, about 10 pM to about 70 pM, about 10 pM to about 60 pM, about 10 pM to about 50 pM, about 10 pM to about 40 pM, about 10 pM to about 30 pM, about 10 pM to about 20 pM, about 15 pM to about 250 nM, about 15 pM to about 240 nM, about 15 pM to about 230 nM, about 15 pM to about 220 nM, about 15 pM to about 210 nM, about 15 pM to about 200 nM, about 15 pM to about 190 nM, about 15 pM to about 180 nM, about 15 pM to about 170 nM, about 15 pM to about 160 nM, about 15 pM to about 150 nM, about 15 pM to about 140 nM, about 15 pM to about 130 nM, about 15 pM to about 120 nM, about 15 pM to about 110 nM, about 15 pM to about 100 nM, about 15 pM to about 95 nM, about 15 pM to about 90 nM, about 15 pM to about 85 nM, about 15 pM to about 80 nM, about 15 pM to about 75 nM, about 15 pM to about 70 nM, about 15 pM to about 65 nM, about 15 pM to about 60 nM, about 15 pM to about 55 nM, about 15 pM to about 50 nM, about 15 pM to about 45 nM, about 15 pM to about 40 nM, about 15 pM to about 35 nM, about 15 pM to about 30 nM, about 15 pM to about 25 nM, about 15 pM to about 20 nM, about 15 pM to about 15 nM, about 15 pM to about 10 nM, about 15 pM to about 5 nM, about 15 pM to about 2 nM, about 15 pM to about 1 nM, about 15 pM to about 950 pM, about 15 pM to about 900 pM, about 15 pM to about 850 pM, about 15 pM to about 800 pM, about 15 pM to about 750 pM, about 15 pM to about 700 pM, about 15 pM to about 650 pM, about 15 pM to about 600 pM, about 15 pM to about 550 pM, about 15 pM to about 500 pM, about 15 pM to about 450 pM, about 15 pM to about 400 pM, about 15 pM to about 350 pM, about 15 pM to about 300 pM, about 15 pM to about 250 pM, about 15 pM to about 200 pM, about 15 pM to about 150 pM, about 15 pM to about 100 pM, about 15 pM to about 90 pM, about 15 pM to about 80 pM, about 15 pM to about 70 pM, about 15 pM to about 60 pM, about 15 pM to about 50 pM, about 15 pM to about 40 pM, about 15 pM to about 30 pM, about 15 pM to about 20 pM, about 20 pM to about 250 nM, about 20 pM to about 240 nM, about 20 pM to about 230 nM, about 20 pM to about 220 nM, about 20 pM to about 210 nM, about 20 pM to about 200 nM, about 20 pM to about 190 nM, about 20 pM to about 180 nM, about 20 pM to about 170 nM, about 20 pM to about 160 nM, about 20 pM to about 150 nM, about 20 pM to about 140 nM, about 20 pM to about 130 nM, about 20 pM to about 120 nM, about 20 pM to about 110 nM, about 20 pM to about 100 nM, about 20 pM to about 95 nM, about 20 pM to about 90 nM, about 20 pM to about 85 nM, about 20 pM to about 80 nM, about 20 pM to about 75 nM, about 20 pM to about 70 nM, about 20 pM to about 65 nM, about 20 pM to about 60 nM, about 20 pM to about 55 nM, about 20 pM to about 50 nM, about 20 pM to about 45 nM, about 20 pM to about 40 nM, about 20 pM to about 35 nM, about 20 pM to about 30 nM, about 20 pM to about 25 nM, about 20 pM to about 20 nM, about 20 pM to about 15 nM, about 20 pM to about 10 nM, about 20 pM to about 5 nM, about 20 pM to about 2 nM, about 20 pM to about 1 nM, about 20 pM to about 950 pM, about 20 pM to about 900 pM, about 20 pM to about 850 pM, about 20 pM to about 800 pM, about 20 pM to about 750 pM, about 20 pM to about 700 pM, about 20 pM to about 650 pM, about 20 pM to about 600 pM, about 20 pM to about 550 pM, about 20 pM to about 500 pM, about 20 pM to about 450 pM, about 20 pM to about 400 pM, about 20 pM to about 350 pM, about 20 pM to about 300 pM, about 20 pM to about 250 pM, about 20 pM to about 20 pM, about 200 pM to about 150 pM, about 20 pM to about 100 pM, about 20 pM to about 90 pM, about 20 pM to about 80 pM, about 20 pM to about 70 pM, about 20 pM to about 60 pM, about 20 pM to about 50 pM, about 20 pM to about 40 pM, about 20 pM to about 30 pM, about 30 pM to about 250 nM, about 30 pM to about 240 nM, about 30 pM to about 230 nM, about 30 pM to about 220 nM, about 30 pM to about 210 nM, about 30 pM to about 200 nM, about 30 pM to about 190 nM, about 30 pM to about 180 nM, about 30 pM to about 170 nM, about 30 pM to about 160 nM, about 30 pM to about 150 nM, about 30 pM to about 140 nM, about 30 pM to about 130 nM, about 30 pM to about 120 nM, about 30 pM to about 110 nM, about 30 pM to about 100 nM, about 30 pM to about 95 nM, about 30 pM to about 90 nM, about 30 pM to about 85 nM, about 30 pM to about 80 nM, about 30 pM to about 75 nM, about 30 pM to about 70 nM, about 30 pM to about 65 nM, about 30 pM to about 60 nM, about 30 pM to about 55 nM, about 30 pM to about 50 nM, about 30 pM to about 45 nM, about 30 pM to about 40 nM, about 30 pM to about 35 nM, about 30 pM to about 30 nM, about 30 pM to about 25 nM, about 30 pM to about 20 nM, about 30 pM to about 15 nM, about 30 pM to about 10 nM, about 30 pM to about 5 nM, about 30 pM to about 2 nM, about 30 pM to about 1 nM, about 30 pM to about 950 pM, about 30 pM to about 900 pM, about 30 pM to about 850 pM, about 30 pM to about 800 pM, about 30 pM to about 750 pM, about 30 pM to about 700 pM, about 30 pM to about 650 pM, about 30 pM to about 600 pM, about 30 pM to about 550 pM, about 30 pM to about 500 pM, about 30 pM to about 450 pM, about 30 pM to about 400 pM, about 30 pM to about 350 pM, about 30 pM to about 300 pM, about 30 pM to about 250 pM, about 30 pM to about 200 pM, about 30 pM to about 150 pM, about 30 pM to about 100 pM, about 30 pM to about 90 pM, about 30 pM to about 80 pM, about 30 pM to about 70 pM, about 30 pM to about 60 pM, about 30 pM to about 50 pM, about 30 pM to about 40 pM, about 40 pM to about 250 nM, about 40 pM to about 240 nM, about 40 pM to about 230 nM, about 40 pM to about 220 nM, about 40 pM to about 210 nM, about 40 pM to about 200 nM, about 40 pM to about 190 nM, about 40 pM to about 180 nM, about 40 pM to about 170 nM, about 40 pM to about 160 nM, about 40 pM to about 150 nM, about 40 pM to about 140 nM, about 40 pM to about 130 nM, about 40 pM to about 120 nM, about 40 pM to about 110 nM, about 40 pM to about 100 nM, about 40 pM to about 95 nM, about 40 pM to about 90 nM, about 40 pM to about 85 nM, about 40 pM to about 80 nM, about 40 pM to about 75 nM, about 40 pM to about 70 nM, about 40 pM to about 65 nM, about 40 pM to about 60 nM, about 40 pM to about 55 nM, about 40 pM to about 50 nM, about 40 pM to about 45 nM, about 40 pM to about 40 nM, about 40 pM to about 35 nM, about 40 pM to about 30 nM, about 40 pM to about 25 nM, about 40 pM to about 30 nM, about 40 pM to about 15 nM, about 40 pM to about 10 nM, about 40 pM to about 5 nM, about 40 pM to about 2 nM, about 40 pM to about 1 nM, about 40 pM to about 950 pM, about 40 pM to about 900 pM, about 40 pM to about 850 pM, about 40 pM to about 800 pM, about 40 pM to about 750 pM, about 40 pM to about 700 pM, about 40 pM to about 650 pM, about 40 pM to about 600 pM, about 40 pM to about 550 pM, about 40 pM to about 500 pM, about 40 pM to about 450 pM, about 40 pM to about 400 pM, about 40 pM to about 350 pM, about 40 pM to about 300 pM, about 40 pM to about 250 pM, about 40 pM to about 200 pM, about 40 pM to about 150 pM, about 40 pM to about 100 pM, about 40 pM to about 90 pM, about 40 pM to about 80 pM, about 40 pM to about 70 pM, about 40 pM to about 60 pM, about 40 pM to about 50 pM, about 50 pM to about 250 nM, about 50 pM to about 240 nM, about 50 pM to about 230 nM, about 50 pM to about 220 nM, about 50 pM to about 210 nM, about 50 pM to about 200 nM, about 50 pM to about 190 nM, about 50 pM to about 180 nM, about 50 pM to about 170 nM, about 50 pM to about 160 nM, about 50 pM to about 150 nM, about 50 pM to about 140 nM, about 50 pM to about 130 nM, about 50 pM to about 120 nM, about 50 pM to about 110 nM, about 50 pM to about 100 nM, about 50 pM to about 95 nM, about 50 pM to about 90 nM, about 50 pM to about 85 nM, about 50 pM to about 80 nM, about 50 pM to about 75 nM, about 50 pM to about 70 nM, about 50 pM to about 65 nM, about 50 pM to about 60 nM, about 50 pM to about 55 nM, about 50 pM to about 50 nM, about 50 pM to about 45 nM, about 50 pM to about 40 nM, about 50 pM to about 35 nM, about 50 pM to about 30 nM, about 50 pM to about 25 nM, about 50 pM to about 30 nM, about 50 pM to about 15 nM, about 50 pM to about 10 nM, about 50 pM to about 5 nM, about 50 pM to about 2 nM, about 50 pM to about 1 nM, about 50 pM to about 950 pM, about 50 pM to about 900 pM, about 50 pM to about 850 pM, about 50 pM to about 800 pM, about 50 pM to about 750 pM, about 50 pM to about 700 pM, about 50 pM to about 650 pM, about 50 pM to about 600 pM, about 50 pM to about 550 pM, about 50 pM to about 500 pM, about 50 pM to about 450 pM, about 50 pM to about 400 pM, about 50 pM to about 350 pM, about 50 pM to about 300 pM, about 50 pM to about 250 pM, about 50 pM to about 200 pM, about 50 pM to about 150 pM, about 50 pM to about 100 pM, about 50 pM to about 90 pM, about 50 pM to about 80 pM, about 50 pM to about 70 pM, about 0 pM to about 60 pM, about 60 pM to about 250 nM, about 60 pM to about 240 nM, about 60 pM to about 230 nM, about 60 pM to about 220 nM, about 60 pM to about 210 nM, about 60 pM to about 200 nM, about 60 pM to about 190 nM, about 60 pM to about 180 nM, about 60 pM to about 170 nM, about 60 pM to about 160 nM, about 60 pM to about 150 nM, about 60 pM to about 140 nM, about 60 pM to about 130 nM, about 60 pM to about 120 nM, about 60 pM to about 110 nM, about 60 pM to about 100 nM, about 60 pM to about 95 nM, about 60 pM to about 90 nM, about 60 pM to about 85 nM, about 60 pM to about 80 nM, about 60 pM to about 75 nM, about 60 pM to about 70 nM, about 60 pM to about 65 nM, about 60 pM to about 60 nM, about 60 pM to about 55 nM, about 60 pM to about 50 nM, about 60 pM to about 45 nM, about 60 pM to about 40 nM, about 60 pM to about 35 nM, about 60 pM to about 30 nM, about 60 pM to about 25 nM, about 60 pM to about 20 nM, about 60 pM to about 15 nM, about 60 pM to about 10 nM, about 60 pM to about 5 nM, about 60 pM to about 2 nM, about 60 pM to about 1 nM, about 60 pM to about 950 pM, about 60 pM to about 900 pM, about 60 pM to about 850 pM, about 60 pM to about 800 pM, about 60 pM to about 750 pM, about 60 pM to about 700 pM, about 60 pM to about 650 pM, about 60 pM to about 600 pM, about 60 pM to about 550 pM, about 60 pM to about 500 pM, about 60 pM to about 450 pM, about 60 pM to about 400 pM, about 60 pM to about 350 pM, about 60 pM to about 300 pM, about 60 pM to about 250 pM, about 60 pM to about 200 pM, about 60 pM to about 150 pM, about 60 pM to about 100 pM, about 60 pM to about 90 pM, about 60 pM to about 80 pM, about 60 pM to about 70 pM, about 70 pM to about 250 nM, about 70 pM to about 240 nM, about 70 pM to about 230 nM, about 70 pM to about 220 nM, about 70 pM to about 210 nM, about 70 pM to about 200 nM, about 70 pM to about 190 nM, about 70 pM to about 180 nM, about 70 pM to about 170 nM, about 70 pM to about 160 nM, about 70 pM to about 150 nM, about 70 pM to about 140 nM, about 70 pM to about 130 nM, about 70 pM to about 120 nM, about 70 pM to about 110 nM, about 70 pM to about 100 nM, about 70 pM to about 95 nM, about 70 pM to about 90 nM, about 70 pM to about 85 nM, about 70 pM to about 80 nM, about 70 pM to about 75 nM, about 70 pM to about 70 nM, about 70 pM to about 65 nM, about 70 pM to about 60 nM, about 70 pM to about 55 nM, about 70 pM to about 50 nM, about 70 pM to about 45 nM, about 70 pM to about 40 nM, about 70 pM to about 35 nM, about 70 pM to about 30 nM, about 70 pM to about 25 nM, about 70 pM to about 20 nM, about 70 pM to about 15 nM, about 70 pM to about 10 nM, about 70 pM to about 5 nM, about 70 pM to about 2 nM, about 70 pM to about 1 nM, about 70 pM to about 950 pM, about 70 pM to about 900 pM, about 70 pM to about 850 pM, about 70 pM to about 800 pM, about 70 pM to about 750 pM, about 70 pM to about 700 pM, about 70 pM to about 650 pM, about 70 pM to about 600 pM, about 70 pM to about 550 pM, about 70 pM to about 500 pM, about 70 pM to about 450 pM, about 70 pM to about 400 pM, about 70 pM to about 350 pM, about 70 pM to about 300 pM, about 70 pM to about 250 pM, about 70 pM to about 200 pM, about 70 pM to about 150 pM, about 70 pM to about 100 pM, about 70 pM to about 90 pM, about 70 pM to about 80 pM, about 80 pM to about 250 nM, about 80 pM to about 240 nM, about 80 pM to about 230 nM, about 80 pM to about 220 nM, about 80 pM to about 210 nM, about 80 pM to about 200 nM, about 80 pM to about 190 nM, about 80 pM to about 180 nM, about 80 pM to about 170 nM, about 80 pM to about 160 nM, about 80 pM to about 150 nM, about 80 pM to about 140 nM, about 80 pM to about 130 nM, about 80 pM to about 120 nM, about 80 pM to about 110 nM, about 80 pM to about 100 nM, about 80 pM to about 95 nM, about 80 pM to about 90 nM, about 80 pM to about 85 nM, about 80 pM to about 80 nM, about 80 pM to about 75 nM, about 80 pM to about 70 nM, about 80 pM to about 65 nM, about 80 pM to about 60 nM, about 80 pM to about 55 nM, about 80 pM to about 50 nM, about 80 pM to about 45 nM, about 80 pM to about 40 nM, about 80 pM to about 35 nM, about 80 pM to about 30 nM, about 80 pM to about 25 nM, about 80 pM to about 20 nM, about 80 pM to about 15 nM, about 80 pM to about 10 nM, about 80 pM to about 5 nM, about 80 pM to about 2 nM, about 80 pM to about 1 nM, about 80 pM to about 950 pM, about 80 pM to about 900 pM, about 80 pM to about 850 pM, about 80 pM to about 800 pM, about 80 pM to about 750 pM, about 80 pM to about 700 pM, about 80 pM to about 650 pM, about 80 pM to about 600 pM, about 80 pM to about 550 pM, about 80 pM to about 500 pM, about 80 pM to about 450 pM, about 80 pM to about 400 pM, about 80 pM to about 350 pM, about 80 pM to about 300 pM, about 80 pM to about 250 pM, about 80 pM to about 200 pM, about 80 pM to about 150 pM, about 80 pM to about 100 pM, about 80 pM to about 90 pM, about 90 pM to about 250 nM, about 90 pM to about 240 nM, about 90 pM to about 230 nM, about 90 pM to about 220 nM, about 90 pM to about 210 nM, about 90 pM to about 200 nM, about 90 pM to about 190 nM, about 90 pM to about 180 nM, about 90 pM to about 170 nM, about 90 pM to about 160 nM, about 90 pM to about 150 nM, about 90 pM to about 140 nM, about 90 pM to about 130 nM, about 90 pM to about 120 nM, about 90 pM to about 110 nM, about 90 pM to about 100 nM, about 90 pM to about 95 nM, about 90 pM to about 90 nM, about 90 pM to about 85 nM, about 90 pM to about 80 nM, about 90 pM to about 75 nM, about 90 pM to about 70 nM, about 90 pM to about 65 nM, about 90 pM to about 60 nM, about 90 pM to about 55 nM, about 90 pM to about 50 nM, about 90 pM to about 45 nM, about 90 pM to about 40 nM, about 90 pM to about 35 nM, about 90 pM to about 30 nM, about 90 pM to about 25 nM, about 90 pM to about 30 nM, about 90 pM to about 15 nM, about 90 pM to about 10 nM, about 90 pM to about 5 nM, about 90 pM to about 2 nM, about 90 pM to about 1 nM, about 90 pM to about 950 pM_: about 90 pM to about 900 pM, about 90 pM to about 850 pM, about 90 pM to about 800 pM_; about 90 pM to about 750 pM, about 90 pM to about 700 pM, about 90 pM to about 650 pM, about 90 pM to about 600 pM, about 90 pM to about 550 pM, about 90 pM to about 500 pM, about 90 pM to about 450 pM, about 90 pM to about 400 pM, about 90 pM to about 350 pM_; about 90 pM to about 300 pM, about 90 pM to about 250 pM, about 90 pM to about 200 pM_; about 90 pM to about 150 pM, about 90 pM to about 100 pM, about 100 pM to about 30 nM, about 100 pM to about 25 nM, about 100 pM to about 250 nM, about 100 pM to about 240 nM, about 100 pM to about 230 nM, about 100 pM to about 220 nM, about 100 pM to about 210 nM, about 100 pM to about 200 nM, about 100 pM to about 190 nM, about 100 pM to about 180 nM, about 100 pM to about 170 nM, about 100 pM to about 160 nM, about 100 pM to about 150 nM, about 100 pM to about 140 nM, about 100 pM to about 130 nM, about 100 pM to about 120 nM, about 100 pM to about 110 nM, about 100 pM to about 100 nM, about 100 pM to about 95 nM, about 100 pM to about 90 nM, about 100 pM to about 85 nM, about 100 pM to about 80 nM, about 100 pM to about 75 nM, about 100 pM to about 70 nM, about 100 pM to about 65 nM, about 100 pM to about 60 nM, about 100 pM to about 55 nM, about 100 pM to about 50 nM, about 100 pM to about 45 nM, about 100 pM to about 40 nM, about 100 pM to about 35 nM, about 100 pM to about 30 nM, about 100 pM to about 15 nM, about 100 pM to about 10 nM, about 100 pM to about 5 nM, about 100 pM to about 2 nM, about 100 pM to about 1 nM, about 100 pM to about 950 pM, about 100 pM to about 900 pM, about 100 pM to about 850 pM, about 100 pM to about 800 pM, about 100 pM to about 750 pM, about 100 pM to about 700 pM, about 100 pM to about 650 pM, about 100 pM to about 600 pM, about 100 pM to about 550 pM, about 100 pM to about 500 pM, about 100 pM to about 450 pM, about 100 pM to about 400 pM, about 100 pM to about 350 pM, about 100 pM to about 300 pM, about 100 pM to about 250 pM, about 100 pM to about 200 pM, about 100 pM to about 150 pM, about 150 pM to about 250 nM, about 150 pM to about 240 nM, about 150 pM to about 230 nM, about 150 pM to about 220 nM, about 150 pM to about 210 nM, about 150 pM to about 200 nM, about 150 pM to about 190 nM, about 150 pM to about 180 nM, about 150 pM to about 170 nM, about 150 pM to about 160 nM, about 150 pM to about 150 nM, about 150 pM to about 140 nM, about 150 pM to about 130 nM, about 150 pM to about 120 nM, about 150 pM to about 110 nM, about 150 pM to about 100 nM, about 150 pM to about 95 nM, about 150 pM to about 90 nM, about 150 pM to about 85 nM, about 150 pM to about 80 nM, about 150 pM to about 75 nM, about 150 pM to about 70 nM, about 150 pM to about 65 nM, about 150 pM to about 60 nM, about 150 pM to about 55 nM, about 150 pM to about 50 nM, about 150 pM to about 45 nM, about 150 pM to about 40 nM, about 150 pM to about 35 nM, about 150 pM to about 30 nM, about 150 pM to about 25 nM, about 150 pM to about 30 nM, about 150 pM to about 15 nM, about 150 pM to about 10 nM, about 150 pM to about 5 nM, about 150 pM to about 2 nM, about 150 pM to about 1 nM, about 150 pM to about 950 pM, about 150 pM to about 900 pM, about 150 pM to about 850 pM, about 150 pM to about 800 pM, about 150 pM to about 750 pM, about 150 pM to about 700 pM, about 150 pM to about 650 pM, about 150 pM to about 600 pM, about 150 pM to about 550 pM, about 150 pM to about 500 pM, about 150 pM to about 450 pM, about 150 pM to about 400 pM, about 150 pM to about 350 pM, about 150 pM to about 300 pM, about 150 pM to about 250 pM, about 150 pM to about 200 pM, about 200 pM to about 250 nM, about 200 pM to about 240 nM, about 200 pM to about 230 nM, about 200 pM to about 220 nM, about 200 pM to about 210 nM, about 200 pM to about 200 nM, about 200 pM to about 190 nM, about 200 pM to about 180 nM, about 200 pM to about 170 nM, about 200 pM to about 160 nM, about 200 pM to about 150 nM, about 200 pM to about 140 nM, about 200 pM to about 130 nM, about 200 pM to about 120 nM, about 200 pM to about 110 nM, about 200 pM to about 100 nM, about 200 pM to about 95 nM, about 200 pM to about 90 nM, about 200 pM to about 85 nM, about 200 pM to about 80 nM, about 200 pM to about 75 nM, about 200 pM to about 70 nM, about 200 pM to about 65 nM, about 200 pM to about 60 nM, about 200 pM to about 55 nM, about 200 pM to about 50 nM, about 200 pM to about 45 nM, about 200 pM to about 40 nM, about 200 pM to about 35 nM, about 200 pM to about 30 nM, about 200 pM to about 25 nM, about 200 pM to about 30 nM, about 200 pM to about 15 nM, about 200 pM to about 10 nM, about 200 pM to about 5 nM, about 200 pM to about 2 nM, about 200 pM to about 1 nM, about 200 pM to about 950 pM, about 200 pM to about 900 pM, about 200 pM to about 850 pM, about 200 pM to about 800 pM, about 200 pM to about 750 pM, about 200 pM to about 700 pM, about 200 pM to about 650 pM, about 200 pM to about 600 pM, about 200 pM to about 550 pM, about 200 pM to about 500 pM, about 200 pM to about 450 pM, about 200 pM to about 400 pM, about 200 pM to about 350 pM, about 200 pM to about 300 pM, about 200 pM to about 250 pM, about 300 pM to about 30 nM, about 300 pM to about 25 nM, about 300 pM to about 250 nM, about 300 pM to about 240 nM, about 300 pM to about 230 nM, about 300 pM to about 220 nM, about 300 pM to about 210 nM, about 300 pM to about 200 nM, about 300 pM to about 190 nM, about 300 pM to about 180 nM, about 300 pM to about 170 nM, about 300 pM to about 160 nM, about 300 pM to about 150 nM, about 300 pM to about 140 nM, about 300 pM to about 130 nM, about 300 pM to about 120 nM, about 300 pM to about 110 nM, about 300 pM to about 100 nM, about 300 pM to about 95 nM, about 300 pM to about 90 nM, about 300 pM to about 85 nM, about 300 pM to about 80 nM, about 300 pM to about 75 nM, about 300 pM to about 70 nM, about 300 pM to about 65 nM, about 300 pM to about 60 nM, about 300 pM to about 55 nM, about 300 pM to about 50 nM, about 300 pM to about 45 nM, about 300 pM to about 40 nM, about 300 pM to about 35 nM, about 300 pM to about 30 nM, about 300 pM to about 15 nM, about 300 pM to about 10 nM, about 300 pM to about 5 nM, about 300 pM to about 2 nM, about 300 pM to about 1 nM, about 300 pM to about 950 pM, about 300 pM to about 900 pM, about 300 pM to about 850 pM, about 300 pM to about 800 pM, about 300 pM to about 750 pM, about 300 pM to about 700 pM, about 300 pM to about 650 pM, about 300 pM to about 600 pM, about 300 pM to about 550 pM, about 300 pM to about 500 pM, about 300 pM to about 450 pM, about 300 pM to about 400 pM, about 300 pM to about 350 pM, about 400 pM to about 250 nM, about 400 pM to about 240 nM, about 400 pM to about 230 nM, about 400 pM to about 220 nM, about 400 pM to about 210 nM, about 400 pM to about 200 nM, about 400 pM to about 190 nM, about 400 pM to about 180 nM, about 400 pM to about 170 nM, about 400 pM to about 160 nM, about 400 pM to about 150 nM, about 400 pM to about 140 nM, about 400 pM to about 130 nM, about 400 pM to about 120 nM, about 400 pM to about 110 nM, about 400 pM to about 100 nM, about 400 pM to about 95 nM, about 400 pM to about 90 nM, about 400 pM to about 85 nM, about 400 pM to about 80 nM, about 400 pM to about 75 nM, about 400 pM to about 70 nM, about 400 pM to about 65 nM, about 400 pM to about 60 nM, about 400 pM to about 55 nM, about 400 pM to about 50 nM, about 400 pM to about 45 nM, about 400 pM to about 40 nM, about 400 pM to about 35 nM, about 400 pM to about 30 nM, about 400 pM to about 25 nM, about 400 pM to about 20 nM, about 400 pM to about 15 nM, about 400 pM to about 10 nM, about 400 pM to about 5 nM, about 400 pM to about 2 nM, about 400 pM to about 1 nM, about 400 pM to about 950 pM, about 400 pM to about 900 pM, about 400 pM to about 850 pM, about 400 pM to about 800 pM, about 400 pM to about 750 pM, about 400 pM to about 700 pM, about 400 pM to about 650 pM, about 400 pM to about 600 pM, about 400 pM to about 550 pM, about 400 pM to about 500 pM, about 500 pM to about 250 nM, about 500 pM to about 240 nM, about 500 pM to about 230 nM, about 500 pM to about 220 nM, about 500 pM to about 210 nM, about 500 pM to about 200 nM, about 500 pM to about 190 nM, about 500 pM to about 180 nM, about 500 pM to about 170 nM, about 500 pM to about 160 nM, about 500 pM to about 150 nM, about 500 pM to about 140 nM, about 500 pM to about 130 nM, about 500 pM to about 120 nM_: about 500 pM to about 110 nM, about 500 pM to about 100 nM, about 500 pM to about 95 nM, about 500 pM to about 90 nM, about 500 pM to about 85 nM, about 500 pM to about 80 nM, about 500 pM to about 75 nM, about 500 pM to about 70 nM, about 500 pM to about 65 nM, about 500 pM to about 60 nM, about 500 pM to about 55 nM, about 500 pM to about 50 nM, about 500 pM to about 45 nM, about 500 pM to about 40 nM, about 500 pM to about 35 nM, about 500 pM to about 30 nM, about 500 pM to about 25 nM, about 500 pM to about 20 nM, about 500 pM to about 15 nM, about 500 pM to about 10 nM, about 500 pM to about 5 nM, about 500 pM to about 2 nM, about 500 pM to about 1 nM, about 500 pM to about 950 pM, about 500 pM to about 900 pM, about 500 pM to about 850 pM, about 500 pM to about 800 pM, about 500 pM to about 750 pM, about 500 pM to about 700 pM, about 500 pM to about 650 pM, about 500 pM to about 600 pM, about 500 pM to about 550 pM, about 600 pM to about 250 nM, about 600 pM to about 240 nM, about 600 pM to about 230 nM, about 600 pM to about 220 nM, about 600 pM to about 210 nM, about 600 pM to about 200 nM, about 600 pM to about 190 nM, about 600 pM to about 180 nM, about 600 pM to about 170 nM, about 600 pM to about 160 nM, about 600 pM to about 150 nM, about 600 pM to about 140 nM, about 600 pM to about 130 nM, about 600 pM to about 120 nM, about 600 pM to about 110 nM, about 600 pM to about 100 nM, about 600 pM to about 95 nM, about 600 pM to about 90 nM, about 600 pM to about 85 nM, about 600 pM to about 80 nM, about 600 pM to about 75 nM, about 600 pM to about 70 nM, about 600 pM to about 65 nM, about 600 pM to about 60 nM, about 600 pM to about 55 nM, about 600 pM to about 50 nM, about 600 pM to about 45 nM, about 600 pM to about 40 nM, about 600 pM to about 35 nM, about 600 pM to about 30 nM, about 600 pM to about 25 nM, about 600 pM to about 20 nM, about 600 pM to about 15 nM, about 600 pM to about 10 nM, about 600 pM to about 5 nM, about 600 pM to about 2 nM, about 600 pM to about 1 nM, about 600 pM to about 950 pM, about 600 pM to about 900 pM, about 600 pM to about 850 pM, about 600 pM to about 800 pM, about 600 pM to about 750 pM, about 600 pM to about 700 pM, about 600 pM to about 650 pM, about 700 pM to about 250 nM, about 700 pM to about 240 nM, about 700 pM to about 230 nM, about 700 pM to about 220 nM, about 700 pM to about 210 nM, about 700 pM to about 200 nM, about 700 pM to about 190 nM, about 700 pM to about 180 nM, about 700 pM to about 170 nM, about 700 pM to about 160 nM, about 700 pM to about 150 nM, about 700 pM to about 140 nM, about 700 pM to about 130 nM, about 700 pM to about 120 nM, about 700 pM to about 110 nM, about 700 pM to about 100 nM, about 700 pM to about 95 nM, about 700 pM to about 90 nM, about 700 pM to about 85 nM, about 700 pM to about 80 nM, about 700 pM to about 75 nM, about 700 pM to about 70 nM, about 700 pM to about 65 nM, about 700 pM to about 60 nM, about 700 pM to about 55 nM, about 700 pM to about 50 nM, about 700 pM to about 45 nM, about 700 pM to about 40 nM, about 700 pM to about 35 nM, about 700 pM to about 30 nM, about 700 pM to about 25 nM, about 700 pM to about 20 nM, about 700 pM to about 15 nM, about 700 pM to about 10 nM, about 700 pM to about 5 nM, about 700 pM to about 2 nM, about 700 pM to about 1 nM, about 700 pM to about 950 pM, about 700 pM to about 900 pM, about 700 pM to about 850 pM, about 700 pM to about 800 pM, about 700 pM to about 750 pM, about 800 pM to about 250 nM, about 800 pM to about 240 nM, about 800 pM to about 230 nM, about 800 pM to about 220 nM, about 800 pM to about 210 nM, about 800 pM to about 200 nM, about 800 pM to about 190 nM, about 800 pM to about 180 nM, about 800 pM to about 170 nM, about 800 pM to about 160 nM, about 800 pM to about 150 nM, about 800 pM to about 140 nM, about 800 pM to about 130 nM, about 800 pM to about 120 nM, about 800 pM to about 110 nM, about 800 pM to about 100 nM, about 800 pM to about 95 nM, about 800 pM to about 90 nM, about 800 pM to about 85 nM, about 800 pM to about 80 nM, about 800 pM to about 75 nM, about 800 pM to about 70 nM, about 800 pM to about 65 nM, about 800 pM to about 60 nM, about 800 pM to about 55 nM, about 800 pM to about 50 nM, about 800 pM to about 45 nM, about 800 pM to about 40 nM, about 800 pM to about 35 nM, about 800 pM to about 30 nM, about 800 pM to about 25 nM, about 800 pM to about 20 nM, about 800 pM to about 15 nM, about 800 pM to about 10 nM, about 800 pM to about 5 nM, about 800 pM to about 2 nM, about 800 pM to about 1 nM, about 800 pM to about 950 pM, about 800 pM to about 900 pM, about 800 pM to about 850 pM, about 900 pM to about 250 nM, about 900 pM to about 240 nM, about 900 pM to about 230 nM, about 900 pM to about 220 nM, about 900 pM to about 210 nM, about 900 pM to about 200 nM, about 900 pM to about 190 nM, about 900 pM to about 180 nM, about 900 pM to about 170 nM, about 900 pM to about 160 nM, about 900 pM to about 150 nM, about 900 pM to about 140 nM, about 900 pM to about 130 nM, about 900 pM to about 120 nM, about 900 pM to about 110 nM, about 900 pM to about 100 nM, about 900 pM to about 95 nM, about 900 pM to about 90 nM, about 900 pM to about 85 nM, about 900 pM to about 80 nM, about 900 pM to about 75 nM, about 900 pM to about 70 nM, about 900 pM to about 65 nM, about 900 pM to about 60 nM, about 900 pM to about 55 nM, about 900 pM to about 50 nM, about 900 pM to about 45 nM, about 900 pM to about 40 nM, about 900 pM to about 35 nM, about 900 pM to about 30 nM, about 900 pM to about 25 nM, about 900 pM to about 20 nM, about 900 pM to about 15 nM, about 900 pM to about 10 nM, about 900 pM to about 5 nM, about 900 pM to about 2 nM, about 900 pM to about 1 nM, about 900 pM to about 950 pM, about 1 nM to about 250 nM, about 1 nM to about 240 nM, about 1 nM to about 230 nM, about 1 nM to about 220 nM, about 1 nM to about 210 nM, about 1 nM to about 200 nM, about 1 nM to about 190 nM, about 1 nM to about 180 nM, about 1 nM to about 170 nM, about 1 nM to about 160 nM, about 1 nM to about 150 nM, about 1 nM to about 140 nM, about 1 nM to about 130 nM, about 1 nM to about 120 nM, about 1 nM to about 110 nM, about 1 nM to about 100 nM, about 1 nM to about 95 nM, about 1 nM to about 90 nM, about 1 nM to about 85 nM, about 1 nM to about 80 nM, about 1 nM to about 75 nM, about 1 nM to about 70 nM, about 1 nM to about 65 nM, about 1 nM to about 60 nM, about 1 nM to about 55 nM, about 1 nM to about 50 nM, about 1 nM to about 45 nM, about 1 nM to about 40 nM, about 1 nM to about 35 nM, about 1 nM to about 30 nM, about 1 nM to about 25 nM, about 1 nM to about 20 nM, about 1 nM to about 15 nM, about 1 nM to about 10 nM, about 1 nM to about 5 nM, about 2 nM to about 250 nM, about 2 nM to about 240 nM, about 2 nM to about 230 nM, about 2 nM to about 220 nM, about 2 nM to about 210 nM, about 2 nM to about 200 nM, about 2 nM to about 190 nM, about 2 nM to about 180 nM, about 2 nM to about 170 nM, about 2 nM to about 160 nM, about 2 nM to about 150 nM, about 2 nM to about 140 nM, about 2 nM to about 130 nM, about 2 nM to about 120 nM, about 2 nM to about 110 nM, about 2 nM to about 100 nM, about 2 nM to about 95 nM, about 2 nM to about 90 nM, about 2 nM to about 85 nM, about 2 nM to about 80 nM, about 2 nM to about 75 nM, about 2 nM to about 70 nM, about 2 nM to about 65 nM, about 2 nM to about 60 nM, about 2 nM to about 55 nM, about 2 nM to about 50 nM, about 2 nM to about 45 nM, about 2 nM to about 40 nM, about 2 nM to about 35 nM, about 2 nM to about 30 nM, about 2 nM to about 25 nM, about 2 nM to about 20 nM, about 2 nM to about 15 nM, about 2 nM to about 10 nM, about 2 nM to about 5 nM, about 4 nM to about 250 nM, about 4 nM to about 240 nM, about 4 nM to about 230 nM, about 4 nM to about 220 nM, about 4 nM to about 210 nM, about 4 nM to about 200 nM, about 4 nM to about 190 nM, about 4 nM to about 180 nM, about 4 nM to about 170 nM, about 4 nM to about 160 nM, about 4 nM to about 150 nM, about 4 nM to about 140 nM, about 4 nM to about 130 nM, about 4 nM to about 120 nM, about 4 nM to about 110 nM, about 4 nM to about 100 nM, about 4 nM to about 95 nM, about 4 nM to about 90 nM, about 4 nM to about 85 nM, about 4 nM to about 80 nM, about 4 nM to about 75 nM, about 4 nM to about 70 nM, about 4 nM to about 65 nM, about 4 nM to about 60 nM, about 4 nM to about 55 nM, about 4 nM to about 50 nM, about 4 nM to about 45 nM, about 4 nM to about 40 nM, about 4 nM to about 35 nM, about 4 nM to about 30 nM, about 4 nM to about 25 nM, about 4 nM to about 20 nM, about 4 nM to about 15 nM, about 4 nM to about 10 nM, about 4 nM to about 5 nM, about 5 nM to about 250 nM, about 5 nM to about 240 nM, about 5 nM to about 230 nM, about 5 nM to about 220 nM, about 5 nM to about 210 nM, about 5 nM to about 200 nM, about 5 nM to about 190 nM, about 5 nM to about 180 nM, about 5 nM to about 170 nM, about 5 nM to about 160 nM, about 5 nM to about 150 nM, about 5 nM to about 140 nM, about 5 nM to about 130 nM, about 5 nM to about 120 nM, about 5 nM to about 110 nM, about 5 nM to about 100 nM, about 5 nM to about 95 nM, about 5 nM to about 90 nM, about 5 nM to about 85 nM, about 5 nM to about 80 nM, about 5 nM to about 75 nM, about 5 nM to about 70 nM, about 5 nM to about 65 nM, about 5 nM to about 60 nM, about 5 nM to about 55 nM, about 5 nM to about 50 nM, about 5 nM to about 45 nM, about 5 nM to about 40 nM, about 5 nM to about 35 nM, about 5 nM to about 30 nM, about 5 nM to about 25 nM, about 5 nM to about 20 nM, about 5 nM to about 15 nM, about 5 nM to about 10 nM, about 10 nM to about 250 nM, about 10 nM to about 240 nM, about 10 nM to about 230 nM, about 10 nM to about 220 nM, about 10 nM to about 210 nM, about 10 nM to about 200 nM, about 10 nM to about 190 nM, about 10 nM to about 180 nM, about 10 nM to about 170 nM, about 10 nM to about 160 nM, about 10 nM to about 150 nM, about 10 nM to about 140 nM, about 10 nM to about 130 nM, about 10 nM to about 120 nM, about 10 nM to about 110 nM, about 10 nM to about 100 nM, about 10 nM to about 95 nM, about 10 nM to about 90 nM, about 10 nM to about 85 nM, about 10 nM to about 80 nM, about 10 nM to about 75 nM, about 10 nM to about 70 nM, about 10 nM to about 65 nM, about 10 nM to about 60 nM, about 10 nM to about 55 nM, about 10 nM to about 50 nM, about 10 nM to about 45 nM, about 10 nM to about 40 nM, about 10 nM to about 35 nM, about 10 nM to about 30 nM, about 10 nM to about 25 nM, about 10 nM to about 20 nM, about 10 nM to about 15 nM, about 15 nM to about 250 nM, about 15 nM to about 240 nM, about 15 nM to about 230 nM, about 15 nM to about 220 nM, about 15 nM to about 210 nM, about 15 nM to about 200 nM, about 15 nM to about 190 nM, about 15 nM to about 180 nM, about 15 nM to about 170 nM, about 15 nM to about 160 nM, about 15 nM to about 150 nM, about 15 nM to about 140 nM, about 15 nM to about 130 nM, about 15 nM to about 120 nM, about 15 nM to about 110 nM, about 15 nM to about 100 nM, about 15 nM to about 95 nM, about 15 nM to about 90 nM, about 15 nM to about 85 nM, about 15 nM to about 80 nM, about 15 nM to about 75 nM, about 15 nM to about 70 nM, about 15 nM to about 65 nM, about 15 nM to about 60 nM, about 15 nM to about 55 nM, about 15 nM to about 50 nM, about 15 nM to about 45 nM, about 15 nM to about 40 nM, about 15 nM to about 35 nM, about 15 nM to about 30 nM, about 15 nM to about 25 nM, about 15 nM to about 20 nM, about 20 nM to about 250 nM, about 20 nM to about 240 nM, about 20 nM to about 230 nM, about 20 nM to about 220 nM, about 20 nM to about 210 nM, about 20 nM to about 200 nM, about 20 nM to about 190 nM, about 20 nM to about 180 nM, about 20 nM to about 170 nM, about 20 nM to about 160 nM, about 20 nM to about 150 nM, about 20 nM to about 140 nM, about 20 nM to about 130 nM, about 20 nM to about 120 nM, about 20 nM to about 110 nM, about 20 nM to about 100 nM, about 20 nM to about 95 nM, about 20 nM to about 90 nM, about 20 nM to about 85 nM, about 20 nM to about 80 nM, about 20 nM to about 75 nM, about 20 nM to about 70 nM, about 20 nM to about 65 nM, about 20 nM to about 60 nM, about 20 nM to about 55 nM, about 20 nM to about 50 nM, about 20 nM to about 45 nM, about 20 nM to about 40 nM, about 20 nM to about 35 nM, about 20 nM to about 30 nM, about 20 nM to about 25 nM, about 25 nM to about 250 nM, about 25 nM to about 240 nM, about 25 nM to about 230 nM, about 25 nM to about 220 nM, about 25 nM to about 210 nM, about 25 nM to about 200 nM, about 25 nM to about 190 nM, about 25 nM to about 180 nM, about 25 nM to about 170 nM, about 25 nM to about 160 nM, about 25 nM to about 150 nM, about 25 nM to about 140 nM, about 25 nM to about 130 nM, about 25 nM to about 120 nM, about 25 nM to about 110 nM, about 25 nM to about 100 nM, about 25 nM to about 95 nM, about 25 nM to about 90 nM, about 25 nM to about 85 nM, about 25 nM to about 80 nM, about 25 nM to about 75 nM, about 25 nM to about 70 nM, about 25 nM to about 65 nM, about 25 nM to about 60 nM, about 25 nM to about 55 nM, about 25 nM to about 50 nM, about 25 nM to about 45 nM, about 25 nM to about 40 nM, about 25 nM to about 35 nM, about 25 nM to about 30 nM, about 25 nM to about 250 nM, about 25 nM to about 240 nM, about 25 nM to about 230 nM, about 25 nM to about 220 nM, about 25 nM to about 210 nM, about 25 nM to about 200 nM, about 25 nM to about 190 nM, about 25 nM to about 180 nM, about 25 nM to about 170 nM, about 25 nM to about 160 nM, about 25 nM to about 150 nM, about 25 nM to about 140 nM, about 25 nM to about 130 nM, about 25 nM to about 120 nM, about 25 nM to about 110 nM, about 25 nM to about 100 nM, about 25 nM to about 95 nM, about 25 nM to about 90 nM, about 25 nM to about 85 nM, about 25 nM to about 80 nM, about 25 nM to about 75 nM, about 25 nM to about 70 nM, about 25 nM to about 65 nM, about 25 nM to about 60 nM, about 25 nM to about 55 nM, about 25 nM to about 50 nM, about 25 nM to about 45 nM, about 25 nM to about 40 nM, about 25 nM to about 35 nM, about 30 nM to about 250 nM, about 30 nM to about 240 nM, about 30 nM to about 230 nM, about 30 nM to about 220 nM, about 30 nM to about 210 nM, about 30 nM to about 200 nM, about 30 nM to about 190 nM, about 30 nM to about 180 nM, about 30 nM to about 170 nM, about 30 nM to about 160 nM, about 30 nM to about 150 nM, about 30 nM to about 140 nM, about 30 nM to about 130 nM, about 30 nM to about 120 nM, about 30 nM to about 110 nM, about 30 nM to about 100 nM, about 30 nM to about 95 nM, about 30 nM to about 90 nM, about 30 nM to about 85 nM, about 30 nM to about 80 nM, about 30 nM to about 75 nM, about 30 nM to about 70 nM, about 30 nM to about 65 nM, about 30 nM to about 60 nM, about 30 nM to about 55 nM, about 30 nM to about 50 nM, about 30 nM to about 45 nM, about 30 nM to about 40 nM, about 30 nM to about 35 nM, about 30 nM to about 250 nM, about 30 nM to about 240 nM, about 30 nM to about 230 nM, about 30 nM to about 220 nM, about 30 nM to about 210 nM, about 30 nM to about 200 nM, about 30 nM to about 190 nM, about 30 nM to about 180 nM, about 30 nM to about 170 nM, about 30 nM to about 160 nM, about 30 nM to about 150 nM, about 30 nM to about 140 nM, about 30 nM to about 130 nM, about 30 nM to about 120 nM, about 30 nM to about 110 nM, about 30 nM to about 100 nM, about 30 nM to about 95 nM, about 30 nM to about 90 nM, about 30 nM to about 85 nM, about 30 nM to about 80 nM, about 30 nM to about 75 nM, about 30 nM to about 70 nM, about 30 nM to about 65 nM, about 30 nM to about 60 nM, about 30 nM to about 55 nM, about 30 nM to about 50 nM, about 30 nM to about 45 nM, about 30 nM to about 40 nM, about 30 nM to about 35 nM, about 40 nM to about 250 nM, about 40 nM to about 240 nM, about 40 nM to about 230 nM, about 40 nM to about 220 nM, about 40 nM to about 210 nM, about 40 nM to about 200 nM, about 40 nM to about 190 nM, about 40 nM to about 180 nM, about 40 nM to about 170 nM, about 40 nM to about 160 nM, about 40 nM to about 150 nM, about 40 nM to about 140 nM, about 40 nM to about 130 nM, about 40 nM to about 120 nM, about 40 nM to about 110 nM, about 40 nM to about 100 nM, about 40 nM to about 95 nM, about 40 nM to about 90 nM, about 40 nM to about 85 nM, about 40 nM to about 80 nM, about 40 nM to about 75 nM, about 40 nM to about 70 nM, about 40 nM to about 65 nM, about 40 nM to about 60 nM, about 40 nM to about 55 nM, about 40 nM to about 50 nM, about 40 nM to about 45 nM, about 50 nM to about 250 nM, about 50 nM to about 240 nM, about 50 nM to about 230 nM, about 50 nM to about 220 nM, about 50 nM to about 210 nM, about 50 nM to about 200 nM, about 50 nM to about 190 nM, about 50 nM to about 180 nM, about 50 nM to about 170 nM, about 50 nM to about 160 nM, about 50 nM to about 150 nM, about 50 nM to about 140 nM, about 50 nM to about 130 nM, about 50 nM to about 120 nM, about 50 nM to about 110 nM, about 50 nM to about 100 nM, about 50 nM to about 95 nM, about 50 nM to about 90 nM, about 50 nM to about 85 nM, about 50 nM to about 80 nM, about 50 nM to about 75 nM, about 50 nM to about 70 nM, about 50 nM to about 65 nM, about 50 nM to about 60 nM, about 50 nM to about 55 nM, about 60 nM to about 250 nM, about 60 nM to about 240 nM, about 60 nM to about 230 nM, about 60 nM to about 220 nM, about 60 nM to about 210 nM, about 60 nM to about 200 nM, about 60 nM to about 190 nM, about 60 nM to about 180 nM, about 60 nM to about 170 nM, about 60 nM to about 160 nM, about 60 nM to about 1 0 nM, about 60 nM to about 140 nM, about 60 nM to about 130 nM, about 60 nM to about 120 nM, about 60 nM to about 110 nM, about 60 nM to about 100 nM, about 60 nM to about 95 nM, about 60 nM to about 90 nM, about 60 nM to about 85 nM, about 60 nM to about 80 nM, about 60 nM to about 75 nM, about 60 nM to about 70 nM, about 60 nM to about 65 nM, about 70 nM to about 250 nM, about 70 nM to about 240 nM, about 70 nM to about 230 nM, about 70 nM to about 220 nM, about 70 nM to about 210 nM, about 70 nM to about 200 nM, about 70 nM to about 190 nM, about 70 nM to about 180 nM, about 70 nM to about 170 nM, about 70 nM to about 160 nM, about 70 nM to about 150 nM, about 70 nM to about 140 nM, about 70 nM to about 130 nM, about 70 nM to about 120 nM, about 70 nM to about 110 nM, about 70 nM to about 100 nM, about 70 nM to about 95 nM, about 70 nM to about 90 nM, about 70 nM to about 85 nM, about 70 nM to about 80 nM, about 70 nM to about 75 nM, about 80 nM to about 250 nM, about 80 nM to about 240 nM, about 80 nM to about 230 nM, about 80 nM to about 220 nM, about 80 nM to about 210 nM, about 80 nM to about 200 nM, about 80 nM to about 190 nM, about 80 nM to about 180 nM, about 80 nM to about 170 nM, about 80 nM to about 160 nM, about 80 nM to about 150 nM, about 80 nM to about 140 nM, about 80 nM to about 130 nM, about 80 nM to about 120 nM, about 80 nM to about 110 nM, about 80 nM to about 100 nM, about 80 nM to about 95 nM, about 80 nM to about 90 nM, about 80 nM to about 85 nM, about 90 nM to about 250 nM, about 90 nM to about 240 nM, about 90 nM to about 230 nM, about 90 nM to about 220 nM, about 90 nM to about 210 nM, about 90 nM to about 200 nM, about 90 nM to about 190 nM, about 90 nM to about 180 nM, about 90 nM to about 170 nM, about 90 nM to about 160 nM, about 90 nM to about 150 nM, about 90 nM to about 140 nM, about 90 nM to about 130 nM, about 90 nM to about 120 nM, about 90 nM to about 110 nM, about 90 nM to about 100 nM, about 90 nM to about 95 nM, about 100 nM to about 250 nM, about 100 nM to about 240 nM, about 100 nM to about 230 nM, about 100 nM to about 220 nM, about 100 nM to about 210 nM, about 100 nM to about 200 nM, about 100 nM to about 190 nM, about 100 nM to about 180 nM, about 100 nM to about 170 nM, about 100 nM to about 160 nM, about 100 nM to about 150 nM, about 100 nM to about 140 nM, about 100 nM to about 130 nM, about 100 nM to about 120 nM, about 100 nM to about 110 nM, about 110 nM to about 250 nM, about 110 nM to about 240 nM, about 110 nM to about 230 nM, about 110 nM to about 220 nM, about 110 nM to about 210 nM, about 110 nM to about 200 nM, about 110 nM to about 190 nM, about 110 nM to about 180 nM, about 110 nM to about 170 nM, about 110 nM to about 160 nM, about 110 nM to about 150 nM, about 110 nM to about 140 nM, about 110 nM to about 130 nM, about 110 nM to about 120 nM, about 120 nM to about 250 nM, about 120 nM to about 240 nM, about 120 nM to about 230 nM, about 120 nM to about 220 nM, about 120 nM to about 210 nM, about 120 nM to about 200 nM, about 120 nM to about 190 nM, about 120 nM to about 180 nM, about 120 nM to about 170 nM, about 120 nM to about 160 nM, about 120 nM to about 150 nM, about 120 nM to about 140 nM, about 120 nM to about 130 nM, about 130 nM to about 250 nM, about 130 nM to about 240 nM, about 130 nM to about 230 nM, about 130 nM to about 220 nM, about 130 nM to about 210 nM, about 130 nM to about 200 nM, about 130 nM to about 190 nM, about 130 nM to about 180 nM, about 130 nM to about 170 nM, about 130 nM to about 160 nM, about 130 nM to about 150 nM, about 130 nM to about 140 nM, about 140 nM to about 250 nM, about 140 nM to about 240 nM, about 140 nM to about 230 nM, about 140 nM to about 220 nM, about 140 nM to about 210 nM, about 140 nM to about 200 nM, about 140 nM to about 190 nM, about 140 nM to about 180 nM, about 140 nM to about 170 nM, about 140 nM to about 160 nM, about 140 nM to about 150 nM, about 150 nM to about 250 nM, about 150 nM to about 240 nM, about 150 nM to about 230 nM, about 150 nM to about 220 nM, about 150 nM to about 210 nM, about 150 nM to about 200 nM, about 150 nM to about 190 nM, about 150 nM to about 180 nM, about 150 nM to about 170 nM, about 150 nM to about 160 nM, about 160 nM to about 250 nM, about 160 nM to about 240 nM, about 160 nM to about 230 nM, about 160 nM to about 220 nM, about 160 nM to about 210 nM, about 160 nM to about 200 nM, about 160 nM to about 190 nM, about 160 nM to about 180 nM, about 160 nM to about 170 nM, about 170 nM to about 250 nM, about 170 nM to about 240 nM, about 170 nM to about 230 nM, about 170 nM to about 220 nM, about 170 nM to about 210 nM, about 170 nM to about 200 nM, about 170 nM to about 190 nM, about 170 nM to about 180 nM, about 180 nM to about 250 nM, about 180 nM to about 240 nM, about 180 nM to about 230 nM, about 180 nM to about 220 nM, about 180 nM to about 210 nM, about 180 nM to about 200 nM, about 180 nM to about 190 nM, about 190 nM to about 250 nM, about 190 nM to about 240 nM, about 190 nM to about 230 nM, about 190 nM to about 220 nM, about 190 nM to about 210 nM, about 190 nM to about 200 nM, about 200 nM to about 250 nM, about 200 nM to about 240 nM, about 200 nM to about 230 nM, about 200 nM to about 220 nM, about 200 nM to about 210 nM, about 210 nM to about 250 nM, about 210 nM to about 240 nM, about 210 nM to about 230 nM, about 210 nM to about 220 nM, about 220 nM to about 250 nM, about 220 nM to about 240 nM, about 220 nM to about 230 nM, about 230 nM to about 250 nM_; about 230 nM to about 240 nM, or about 240 nM to about 250 nM).

In some embodiments of any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain and, if present, the second antigen-binding domain, at a neutral pH (e.g., any of the neutral pHs described herein) is between about 1 nM to about 30 nM (e.g., about 1 nM to about 30 nM, about 1 nM to about 25 nM, about 1 nM to about 20 nM, about 1 nM to about 15 nM, about 1 nM to about 10 nM, about 1 nM to about 5 nM, about 2 nM to about 30 nM, about 2 nM to about 25 nM, about 2 nM to about 20 nM, about 2 nM to about 15 nM, about 2 nM to about 10 nM, about 2 nM to about 5 nM, about 4 nM to about 30 nM, about 4 nM to about 25 nM, about 4 nM to about 20 nM, about 4 nM to about 15 nM, about 4 nM to about 10 nM, about 4 nM to about 5 nM, about 5 nM to about 30 nM, about 5 nM to about 25 nM, about 5 nM to about 20 nM, about 5 nM to about 15 nM, about 5 nM to about 10 nM, about 10 nM to about 30 nM, about 10 nM to about 25 nM, about 10 nM to about 20 nM, about 10 nM to about 15 nM, about 15 nM to about 30 nM, about 15 nM to about 25 nM, about 15 nM to about 20 nM, about 20 nM to about 30 nM, or about 20 nM to about 25 nM).

In some embodiments of any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain and, if present, the second antigen-binding domain, at a neutral pH (e.g., any of the neutral pHs described herein) can be between about 1 nM to about 1 mM (e.g., about 1 nM to about 900 μΜ, about 1 nM to about 800 μΜ, about 1 nM to about 700 μΜ, about 1 nM to about 600 μΜ, about 1 nM to about 500 μΜ, about 1 nM to about 400 μΜ, about 1 nM to about 300 μΜ, about 1 nM to about 200 μΜ, about 1 nM to about 100 uM, about 1 nM to about 90 uM, about 1 nM to about 80 μΜ, about 1 nM to about 70 uM, about 1 nM to about 60 uM, about 1 nM to about 50 uM, about 1 nM to about 40 μΜ, about 1 nM to about 30 μΜ, about 1 nM to about 20 μΜ, about 1 nM to about 10 μΜ, about 1 nM to about 5 μΜ, about 1 nM to about 4 μΜ, about 1 nM to about 2 μΜ, about 1 nM to about 1 μΜ, about 1 nM to about 900 nM, about 1 nM to about 800 nM, about 1 nM to about 700 nM, about 1 nM to about 600 nM, about 1 nM to about 500 nM, about 1 nM to about 400 nM, about 1 nM to about 300 nM, about 1 nM to about 200 nM, about 1 nM to about 100 nM, about 1 nM to about 90 nM, about 1 nM to about 80 nM, about 1 nM to about 70 nM, about 1 nM to about 60 nM, about 1 nM to about 50 nM, about 1 nM to about 40 nM, about 1 nM to about 30 nM, about 2 nM to about 1 mM, about 2 nM to about 900 uM, about 2 nM to about 800 μΜ, about 2 nM to about 700 μΜ, about 2 nM to about 600 μΜ, about 2 nM to about 500 μΜ, about 2 nM to about 400 μΜ, about 2 nM to about 300 μΜ, about 2 nM to about 200 uM, about 2 nM to about 100 μΜ, about 2 nM to about 90 μΜ, about 2 nM to about 80 μΜ, about 2 nM to about 70 uM, about 2 nM to about 60 uM, about 2 nM to about 50 μΜ, about 2 nM to about 40 μΜ, about 2 nM to about 30 μΜ, about 2 nM to about 20 μΜ, about 2 nM to about 10 μΜ, about 2 nM to about 5 μΜ, about 2 nM to about 4 μΜ, about 2 nM to about 2 μΜ, about 2 nM to about 1 μΜ, about 2 nM to about 900 nM, about 2 nM to about 800 nM, about 2 nM to about 700 nM, about 2 nM to about 600 nM, about 2 nM to about 500 nM, about 2 nM to about 400 nM, about 2 nM to about 300 nM, about 2 nM to about 200 nM, about 2 nM to about 100 nM, about 2 nM to about 90 nM, about 2 nM to about 80 nM, about 2 nM to about 70 nM, about 2 nM to about 60 nM, about 2 nM to about 50 nM, about 2 nM to about 40 nM, about 2 nM to about 30 nM, about 5 nM to about 1 mM, about 5 nM to about 900 μΜ, about 5 nM to about 800 μΜ, about 5 nM to about 700 μΜ, about 5 nM to about 600 μΜ, about 5 nM to about 500 μΜ, about 5 nM to about 400 μΜ, about 5 nM to about 300 μΜ, about 5 nM to about 200 μΜ, about 5 nM to about 100 μΜ, about 5 nM to about 90 μΜ, about 5 nM to about 80 μΜ, about 5 nM to about 70 μΜ, about 5 nM to about 60 μΜ, about 5 nM to about 50 μΜ, about 5 nM to about 40 μΜ, about 5 nM to about 30 μΜ, about 5 nM to about 20 μΜ, about 5 nM to about 10 uM, about 5 nM to about 5 μΜ, about 5 nM to about 4 μΜ, about 5 nM to about 2 μΜ, about 5 nM to about 1 μΜ, about 5 nM to about 900 nM, about 5 nM to about 800 nM, about 5 nM to about 700 nM, about 5 nM to about 600 nM, about 5 nM to about 500 nM, about 5 nM to about 400 nM, about 5 nM to about 300 nM, about 5 nM to about 200 nM, about 5 nM to about 100 nM, about 5 nM to about 90 nM, about 5 nM to about 80 nM, about 5 nM to about 70 nM, about 5 nM to about 60 nM, about 5 nM to about 50 nM, about 5 nM to about 40 nM, about 5 nM to about 30 nM, about 10 nM to about 1 mM, about 10 nM to about 900 μΜ, about 10 nM to about 800 μΜ, about 10 nM to about 700 uM, about 10 nM to about 600 μΜ, about 10 nM to about 500 μΜ, about 10 nM to about 400 uM, about 10 nM to about 300 μΜ, about 10 nM to about 200 μΜ, about 10 nM to about 100 μΜ, about 10 nM to about 90 μΜ, about 10 nM to about 80 μΜ, about 10 nM to about 70 μΜ, about 10 nM to about 60 μΜ, about 10 nM to about 50 μΜ, about 10 nM to about 40 μΜ, about 10 nM to about 30 μΜ, about 10 nM to about 20 μΜ, about 10 nM to about 10 μΜ, about 10 nM to about 5 μΜ, about 10 nM to about 4 μΜ, about 10 nM to about 2 uM, about 10 nM to about 1 μΜ, about 10 nM to about 900 nM, about 10 nM to about 800 nM, about 10 nM to about 700 nM, about 10 nM to about 600 nM, about 10 nM to about 500 nM, about 10 nM to about 400 nM, about 10 nM to about 300 nM, about 10 nM to about 200 nM, about 10 nM to about 100 nM, about 10 nM to about 90 nM, about 10 nM to about 80 nM, about 10 nM to about 70 nM, about 10 nM to about 60 nM, about 10 nM to about 50 nM, about 10 nM to about 40 nM, about 10 nM to about 30 nM, about 20 nM to about 1 mM, about 20 nM to about 900 μΜ, about 20 nM to about 800 μΜ, about 20 nM to about 700 μΜ, about 20 nM to about 600 μΜ, about 20 nM to about 500 μΜ, about 20 nM to about 400 μΜ, about 20 nM to about 300 μΜ, about 20 nM to about 200 μΜ, about 20 nM to about 100 μΜ, about 20 nM to about 90 μΜ, about 20 nM to about 80 μΜ, about 20 nM to about 70 uM, about 20 nM to about 60 μΜ, about 20 nM to about 50 μΜ, about 20 nM to about 40 uM, about 20 nM to about 30 μΜ, about 20 nM to about 20 μΜ, about 20 nM to about 10 uM, about 20 nM to about 5 μΜ, about 20 nM to about 4 uM, about 20 nM to about 2 μΜ, about 20 nM to about 1 μΜ, about 20 nM to about 900 nM, about 20 nM to about 800 nM, about 20 nM to about 700 nM, about 20 nM to about 600 nM, about 20 nM to about 500 nM, about 20 nM to about 400 nM, about 20 nM to about 300 nM, about 20 nM to about 200 nM, about 20 nM to about 100 nM, about 20 nM to about 90 nM, about 20 nM to about 80 nM, about 20 nM to about 70 nM, about 20 nM to about 60 nM, about 20 nM to about 50 nM, about 20 nM to about 40 nM, about 20 nM to about 30 nM; about 1 μΜ to about 1 mM, about 1 μΜ to about 900 μΜ, about 1 μΜ to about 800 μΜ, about 1 μΜ to about 700 μΜ, about 1 μΜ to about 600 μΜ, about 1 μΜ to about 500 uM, about 1 μΜ to about 400 μΜ, about 1 μΜ to about 300 μΜ, about 1 μΜ to about 200 uM, about 1 μΜ to about 100 μΜ, about 1 μΜ to about 90 μΜ, about 1 μΜ to about 80 μΜ, about 1 μΜ to about 70 μΜ, about

1 μΜ to about 60 μΜ, about 1 μΜ to about 50 μΜ, about 1 μΜ to about 40 μΜ, about 1 μΜ to about 30 μΜ, about 1 μΜ to about 20 μΜ, about 1 μΜ to about 10 μΜ, about 1 μΜ to about 5 μΜ, about 1 μΜ to about 4 μΜ, about 1 μΜ to about 3 uM, about 1 μΜ to about 2 μΜ, about 2 μΜ to about 1 mM, about 2 μΜ to about 900 μΜ, about 2 μΜ to about 800 uM, about 2 μΜ to about 700 μΜ, about 2 μΜ to about 600 uM, about 2 μΜ to about 500 μΜ, about 2 μΜ to about 400 μΜ, about 2 μΜ to about 300 μΜ, about 2 μΜ to about 200 μΜ, about 2 μΜ to about 100 μΜ, about 2 μΜ to about 90 μΜ, about 2 μΜ to about 80 μΜ, about

2 μΜ to about 70 μΜ, about 2 μΜ to about 60 μΜ, about 2 μΜ to about 50 μΜ, about 2 μΜ to about 40 μΜ, about 2 μΜ to about 30 μΜ, about 2 μΜ to about 20 μΜ, about 2 μΜ to about 10 μΜ, about 2 μΜ to about 5 μΜ, about 2 μΜ to about 4 μΜ, about 2 μΜ to about 3 μΜ, about 5 μΜ to about 1 mM, about 5 μΜ to about 900 μΜ about 5 μΜ to about 800 μΜ, about 5 μΜ to about 700 μΜ, about 5 μΜ to about 600 μΜ, about 5 μΜ to about 500 μΜ, about 5 μΜ to about 400 μΜ, about 5 μΜ to about 300 μΜ, about 5 μΜ to about 200 μΜ, about 5 μΜ to about 100 μΜ, about 5 μΜ to about 90 μΜ, about 5 μΜ to about 80 μΜ, about 5 μΜ to about 70 μΜ, about 5 μΜ to about 60 μΜ_; about 5 μΜ to about 50 μΜ, about 5 μΜ to about 40 μΜ, about 5 μΜ to about 30 μΜ, about 5 μΜ to about 20 μΜ, about 5 μΜ to about 10 μΜ, about 10 μΜ to about 1 mM, about 10 μΜ to about 900 μΜ, about 10 μΜ to about 800 μΜ, about 10 μΜ to about 700 μΜ, about 10 μΜ to about 600 μΜ, about 10 μΜ to about 500 μΜ, about 10 μΜ to about 400 uM, about 10 μΜ to about 300 μΜ, about 10 μΜ to about 200 μΜ, about 10 μΜ to about 100 uM, about 10 μΜ to about 90 μΜ, about 10 μΜ to about 80 μΜ, about 10 μΜ to about 70 μΜ, about 10 μΜ to about 60 μΜ, about 10 μΜ to about 50 μΜ, about 10 μΜ to about 40 μΜ, about 10 μΜ to about 30 μΜ, about 10 μΜ to about 20 μΜ, about 20 μΜ to about 1 mM, about 20 μΜ to about 900 μΜ, about 20 μΜ to about 800 μΜ, about 20 μΜ to about 700 μΜ, about 20 μΜ to about 600 μΜ, about 20 μΜ to about 500 μΜ, about 20 μΜ to about 400 μΜ, about 20 μΜ to about 300 μΜ, about 20 μΜ to about 200 μΜ, about 20 μΜ to about 100 μΜ, about 20 μΜ to about 90 μΜ, about 20 μΜ to about 80 μΜ, about 20 μΜ to about 70 μΜ, about 20 μΜ to about 60 μΜ, about 20 μΜ to about 50 μΜ, about 20 μΜ to about 40 μΜ, about 20 μΜ to about 30 μΜ, about 30 μΜ to about 1 mM, about 30 μΜ to about 900 μΜ, about 30 μΜ to about 800 μΜ, about 30 μΜ to about 700 μΜ, about 30 μΜ to about 600 μΜ, about 30 μΜ to about 500 μΜ, about 30 μΜ to about 400 μΜ, about 30 μΜ to about 300 μΜ, about 30 μΜ to about 200 μΜ, about 30 μΜ to about 100 μΜ, about 30 μΜ to about 90 μΜ, about 30 μΜ to about 80 uM, about 30 μΜ to about 70 μΜ, about 30 μΜ to about 60 μΜ, about 30 μΜ to about 50 μΜ, about 30 μΜ to about 40 μΜ, about 40 μΜ to about 1 mM, about 40 μΜ to about 900 μΜ, about 40 μΜ to about 800 μΜ, about 40 μΜ to about 700 μΜ, about 40 μΜ to about 600 μΜ, about 40 μΜ to about 500 μΜ, about 40 μΜ to about 400 μΜ, about 40 μΜ to about 300 μΜ, about 40 μΜ to about 200 μΜ, about 40 μΜ to about 100 μΜ, about 40 μΜ to about 90 μΜ, about 40 μΜ to about 80 μΜ, about 40 μΜ to about 70 μΜ, about 40 μΜ to about 60 μΜ, about 40 μΜ to about 50 μΜ, about 50 μΜ to about 1 mM, about 50 μΜ to about 900 μΜ, about 50 μΜ to about 800 μΜ, about 50 μΜ to about 700 μΜ, about 50 μΜ to about 600 μΜ, about 50 μΜ to about 500 μΜ, about 50 μΜ to about 400 μΜ, about 50 μΜ to about 300 μΜ, about 50 μΜ to about 200 μΜ, about 50 μΜ to about 100 μΜ, about 50 μΜ to about 90 μΜ, about 50 uM to about 80 μΜ, about 50 μΜ to about 70 μΜ, about 50 μΜ to about 60 μΜ, about 60 μΜ to about 1 mM, about 60 μΜ to about 900 uM, about 60 μΜ to about 800 μΜ, about 60 μΜ to about 700 μΜ, about 60 μΜ to about 600 μΜ, about 60 μΜ to about 500 μΜ, about 60 μΜ to about 400 μΜ, about 60 μΜ to about 300 μΜ, about 60 μΜ to about 200 μΜ, about 60 μΜ to about 100 μΜ, about 60 μΜ to about 90 μΜ, about 60 μΜ to about 80 uM, about 60 μΜ to about 70 μΜ, about 70 μΜ to about 1 mM, about 70 μΜ to about 900 μΜ, about 70 uM to about 800 uM, about 70 μΜ to about 700 uM, about 70 μΜ to about 600 μΜ, about 70 μΜ to about 500 μΜ, about 70 μΜ to about 400 μΜ, about 70 μΜ to about 300 μΜ, about 70 μΜ to about 200 μΜ, about 70 μΜ to about 100 uM, about 70 μΜ to about 90 μΜ, about 70 μΜ to about 80 μΜ, about 80 μΜ to about 1 mM, about 80 μΜ to about 900 μΜ, about 80 μΜ to about 800 uM, about 80 μΜ to about 700 uM, about 80 μΜ to about 600 μΜ, about 80 μΜ to about 500 uM, about 80 μΜ to about 400 uM, about 80 μΜ to about 300 μΜ, about 80 μΜ to about 200 uM, about 80 μΜ to about 100 uM, about 80 μΜ to about 90 uM, about 90 uM to about 1 mM, about 90 μΜ to about 900 uM, about 90 μΜ to about 800 μΜ, about 90 μΜ to about 700 uM, about 90 μΜ to about 600 uM, about 90 μΜ to about 500 μΜ, about 90 μΜ to about 400 μΜ, about 90 μΜ to about 300 uM, about 90 μΜ to about 200 μΜ, about 90 μΜ to about 100 uM, about 100 μΜ to about 1 mM, about 100 μΜ to about 900 uM, about 100 μΜ to about 800 μΜ, about 100 μΜ to about 700 μΜ, about 100 μΜ to about 600 μΜ, about 100 μΜ to about 500 μΜ, about 100 μΜ to about 400 μΜ, about 100 μΜ to about 300 μΜ, about 100 μΜ to about 200 μΜ, about 200 μΜ to about 1 mM, about 200 μΜ to about 900 μΜ, about 200 μΜ to about 800 μΜ, about 200 μΜ to about 700 μΜ, about 200 μΜ to about 600 μΜ, about 200 μΜ to about 500 μΜ, about 200 μΜ to about 400 μΜ, about 200 μΜ to about 300 μΜ, about 300 μΜ to about 1 mM, about 300 μΜ to about 900 μΜ, about 300 μΜ to about 800 μΜ, about 300 μΜ to about 700 μΜ, about 300 μΜ to about 600 μΜ, about 300 μΜ to about 500 μΜ, about 300 μΜ to about 400 μΜ, about 400 μΜ to about 1 mM, about 400 μΜ to about 900 μΜ, about 400 μΜ to about 800 μΜ, about 400 μΜ to about 700 μΜ, about 400 μΜ to about 600 μΜ, about 400 μΜ to about 500 uM, about 500 μΜ to about 1 mM, about 500 μΜ to about 900 μΜ, about 500 μΜ to about 800 μΜ, about 500 μΜ to about 700 uM, about 500 μΜ to about 600 μΜ, about 600 μΜ to about 1 mM, about 600 μΜ to about 900 μΜ, about 600 μΜ to about 800 μΜ, about 600 μΜ to about 700 μΜ, about 700 μΜ to about 1 mM, about 700 μΜ to about 900 μΜ, about 700 μΜ to about 800 μΜ, about 800 μΜ to about 1 mM, about 800 μΜ to about 900 μΜ, or about 900 μΜ to about 1 mM).

In some embodiments of any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain and, if present, the second antigen-binding domain, for an HLA-A variant polypeptide-beta 2-microglobulin (β2ιη) polypeptide complex at an acidic pH (e.g., any of the acidic pHs described herein) is at least 10% (e.g., at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 150%, at least 200%, at least 250%, or at least 300%) increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-A gene-beta 2-microglobulin (β2ιη) polypeptide complex, and wherein the HLA-A variant polypeptide is identical to the polypeptide encoded by the HLA-A gene except at one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) residues which both: (i) are located in the HLA-A epitope bound by the second antigen-binding domain, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-A gene.

In some embodiments of any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain and, if present, the second antigen-binding domain, for an HLA-B variant polypeptide-beta 2-microglobulin (β2πι) polypeptide complex at an acidic pH (e.g., any of the acidic pHs described herein) is at least 10% (e.g., at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 150%, at least 200%, at least 250%, or at least 300%) increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-B gene-beta 2-microglobulin (β2ιη) polypeptide complex, and wherein the HLA-B variant polypeptide is identical to the polypeptide encoded by the HLA-B gene except at one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) residues which both: (i) are located in the HLA-B epitope bound by the second antigen-binding domain, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-B gene.

In some embodiments of any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain and, if present, the second antigen-binding domain, for an HLA-C variant polypeptide-beta 2-microglobulin (β2ηι) polypeptide complex at an acidic pH (e.g., any of the acidic pHs described herein) is at least 10% (e.g., at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 150%, at least 200%, at least 250%, or at least 300%) increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide product of the HLA-C gene-beta 2-microglobulin (β2ιη) polypeptide complex, and wherein the HLA-C variant polypeptide is identical to the polypeptide encoded by the HLA-C gene except at one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) residues which both: (i) are located in the HLA-C epitope bound by the second antigen-binding domain, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-C gene.

In some embodiments of any of the antigen-binding protein constructs described herein, the dissociation rate of the first antigen-binding domain and, if present, the second antigen-binding domain, at an acidic pH (e.g., any of the acidic pHs described herein) is at least 10% (e.g., at least 15% , at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH (e.g., any of the neutral pHs described herein).

In some embodiments of any of the antigen-binding protein constructs described herein, the dissociation rate of the first antigen-binding domain and, if present, the second antigen-binding domain, at an acidic pH (e.g., any of the acidic pHs described herein) is at least 1-fold (e.g., at least 1.5-fold, at least 2-fold slower, at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, at least 5.5-fold, at least 6-fold, at least 6.5-fold, at least 7-fold, at least 7.5-fold, at least 8-fold, at least 8.5-fold, at least 9- fold, at least 9.5-fold, at least 10-fold, at least 10.5-fold, at least 11-fold, at least 11.5-fold, at least 12-fold, at least 12.5-fold, at least 13-fold, at least 13.5-fold, at least 14-fold, at least 14.5-fold, at least 15-fold, at least 15.5-fold, at least 16-fold, at least 16.5-fold, at least 17- fold, at least 17.5-fold, at least 18-fold, at least 18.5-fold, at least 19-fold, at least 19.5-fold, or at least 20-fold) slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH (e.g., any of the neutral pHs described herein).

In some embodiments of any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain and, if present, the second antigen-binding domain, at an acidic pH (e.g., any of the acidic pHs described herein) can be 10% (e.g., at least 15% , at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) less than the KD of the first antigen- binding domain or the second antigen-binding domain, respectively, at a neutral pH (e.g., any of the neutral pHs described herein).

In some embodiments of any of the antigen-binding protein constructs described herein, the KD of the first antigen-binding domain and, if present, the second antigen-binding domain, at an acidic pH (e.g., any of the acidic pHs described herein) is at least 1-fold (e.g., at least 1.5-fold, at least 2-fold, at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4- fold, at least 4.5-fold, at least 5-fold, at least 5.5-fold, at least 6-fold, at least 6.5-fold, at least 7-fold, at least 7.5-fold, at least 8-fold, at least 8.5 -fold, at least 9-fold, at least 9.5-fold, at least 10-fold, at least 10.5-fold, at least 11 -fold, at least 11.5-fold, at least 12-fold, at least 12.5-fold, at least 13-fold, at least 13.5-fold, at least 14-fold, at least 14.5-fold, at least 15- fold, at least 15.5-fold, at least 16-fold, at least 16.5-fold, at least 17-fold, at least 17.5-fold, at least 18-fold, at least 18.5-fold, at least 19-fold, at least 19.5 -fold, or at least 20-fold) less than the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH (e.g., any of the neutral pHs described herein).

A variety of different methods known in the art can be used to determine the KD values of any of the antigen-binding protein constructs described herein (e.g., an

electrophoretic mobility shift assay, a filter binding assay, surface plasmon resonance, and a biomolecular binding kinetics assay, etc.).

In some embodiments of any of the antigen-binding protein constructs, the first antigen-binding domain and/or the second antigen-binding domain (if present), can each independently include a set of three or six CDRs selected from the group consisting of:

(1) a light chain CDR1 of SEQ ID NO: 448, a light chain CDR2 of SEQ ID NO: 449, a light chain CDR3 of SEQ ID NO: 450, a heavy chain CDR1 of SEQ ID NO: 454, a heavy chain CDR2 of SEQ ID NO: 455, and a heavy chain CDR3 of SEQ ID NO: 456;

(2) a light chain CDR1 of SEQ ID NO: 448, a light chain CDR2 of SEQ ID NO: 449, a light chain CDR3 of SEQ ID NO: 450, a heavy chain CDR1 of SEQ ID NO: 458, a heavy chain CDR2 of SEQ ID NO: 459, and a heavy chain CDR3 of SEQ ID NO: 460; (3) a light chain CDRl of SEQ ID NO: 448, a light chain CDR2 of SEQ ID NO: 449, a light chain CDR3 of SEQ ID NO: 450, a heavy chain CDRl of SEQ ID NO: 462, a heavy chain CDR2 of SEQ ID NO: 463, and a heavy chain CDR3 of SEQ ID NO: 464;

(4) a light chain CDRl of SEQ ID NO: 448, a light chain CDR2 of SEQ ID NO: 449, a light chain CDR3 of SEQ ID NO: 450, a heavy chain CDRl of SEQ ID NO: 466, a heavy chain CDR2 of SEQ ID NO: 467, and a heavy chain CDR3 of SEQ ID NO: 468;

(5) a heavy chain CDRl of SEQ ID NO: 477, a heavy chain CDR2 of SEQ ID NO: 478, and a heavy chain CDR3 of SEQ ID NO: 479;

(6) a heavy chain CDRl of SEQ ID NO: 480, a heavy chain CDR2 of SEQ ID NO: 481, and a heavy chain CDR3 of SEQ ID NO: 482;

(7) a heavy chain CDRl of SEQ ID NO: 483, a heavy chain CDR2 of SEQ ID NO: 484, and a heavy chain CDR3 of SEQ ID NO: 485;

(8) a a heavy chain CDRl of SEQ ID NO: 486, a heavy chain CDR2 of SEQ ID NO: 487, and a heavy chain CDR3 of SEQ ID NO: 488;

(9) a heavy chain CDRl of SEQ ID NO: 497, a heavy chain CDR2 of SEQ ID NO:

498, and a heavy chain CDR3 of SEQ ID NO: 499;

(10) a heavy chain CDRl of SEQ ID NO: 503, a heavy chain CDR2 of SEQ ID NO: 504, and a heavy chain CDR3 of SEQ ID NO: 505;

(11) a heavy chain CDRl of SEQ ID NO: 509, a heavy chain CDR2 of SEQ ID NO: 510, and a heavy chain CDR3 of SEQ ID NO: 511;

(12) a heavy chain CDRl of SEQ ID NO: 517, a heavy chain CDR2 of SEQ ID NO: 518, and a heavy chain CDR3 of SEQ ID NO: 519;

(13) a heavy chain CDRl of SEQ ID NO: 520, a heavy chain CDR2 of SEQ ID NO: 521, and a heavy chain CDR3 of SEQ ID NO: 522;

(14) a heavy chain CDRl of SEQ ID NO: 523, a heavy chain CDR2 of SEQ ID NO:

524, and a heavy chain CDR3 of SEQ ID NO: 525; and

(15) a heavy chain CDRl of SEQ ID NO: 529, a heavy chain CDR2 of SEQ ID NO: 530, and a heavy chain CDR3 of SEQ ID NO: 531.

In some embodiments of any of the antigen-binding protein constructs, the first antigen-binding domain and/or the second antigen-binding domain (if present), can each independently include a heavy chain variable domain, or a light chain variable domain and a heavy chain variable domain selected from the group consisting of: (1) a light chain variable domain of SEQ ID NO: 452 and a heavy chain variable domain of SEQ ID NO: 453;

(2) a light chain variable domain of SEQ ID NO: 452 and a heavy chain variable domain of SEQ ID NO: 457;

(3) a light chain variable domain of SEQ ID NO: 452 and a heavy chain variable domain of SEQ ID NO: 461 ;

(4) a light chain variable domain of SEQ ID NO: 452 and a heavy chain variable domain of SEQ ID NO: 465;

(5) a heavy chain variable domain of SEQ ID NO: 473;

(6) a heavy chain variable domain of SEQ ID NO: 474;

(7) a heavy chain variable domain of SEQ ID NO: 475;

(8) a heavy chain variable domain of SEQ ID NO: 476;

(9) a heavy chain variable domain of SEQ ID NO: 492;

(10) a heavy chain variable domain of SEQ ID NO: 494;

(11) a heavy chain variable domain of SEQ ID NO: 496;

(12) a heavy chain variable domain of SEQ ID NO: 512;

(13) a heavy chain variable domain of SEQ ID NO: 513;

(14) a heavy chain variable domain of SEQ ID NO: 514; and

(15) a heavy chain variable domain of SEQ ID NO: 516.

In some embodiments of any of the antigen-binding protein constructs described herein, the additional antigen-binding domain is capable of specifically binding to a soluble target antigen (e.g., an antigen that is pericellular to a target cell) or an antigen presented on the surface or in a cellular compartment of a target cell. In some embodiments of any of the antigen-binding protein constructs described herein, the additional antigen-binding domain is capable of specifically binding to an antigen of an infectious agent (e.g., a viral antigen, a fungal antigen, or a bacterial antigen), an antigen present on a surface of a target cell, or an antigen in a cellular compartment, or a therapeutic target antigen. In some embodiments of any of the antigen-binding protein constructs described herein, the additional antigen-binding domain is capable of specifically binding to an antigen selected from the group consisting of: sclerostin and hepatitis C E2 glycoprotein. In some embodiments of any of the antigen- binding protein constructs described herein, the additional antigen-binding domain does not bind an identifying antigen (e.g., an EGFR antigen) that is present on the surface of a cancer cell. In some embodiments of any of the antigen-binding protein constructs described herein, the additional antigen-binding domain can bind to an antigen (e.g., any of the antigens described herein) at an acidic pH (e.g., any of the acidic pHs described herein) and/or at a neutral pH (e.g., any of the neutral pHs described herein) with a dissociation equilibrium constant (KD) of less than 1 x 10^"7 M, less than 1 x 10^"8 M, less than 1 x 10^"9 M, less than 1 x 10^"10 M, less than 1 x 10^"11 M, less than 1 x 10^"12 M, or less than 1 x 10^"13 M. In some embodiments, any of the antigen-binding protein constructs described herein, the additional antigen-binding domain can bind to an antigen (e.g., any of the antigens described herein) with a KD of about 1 x 10^"3 M to about 1 x 10^"5 M, 1 x lO^"4 M to about 1 x 10^"6 M, about 1 x 10^"5 M to about 1 x 10^"7 M, about 1 x 10^"6 M to about 1 x 10^"8 M, about 1 x 10^"7 M to about 1 x lO^"9 M, about 1 x 10^"8 M to about 1 x 10^"10 M, or about 1 x 10^"9 M to about 1 x 10^"11 M (inclusive).

In some embodiments of any of the antigen-binding protein constructs described herein, the KD of the additional antigen-binding domain at a neutral pH (e.g., any of the neutral pHs described herein) and/or an acidic pH (e.g., any of the acidic pHs described herein) is between about 250 nM to about lmM (e.g., about 250 nM to about 900 μΜ, about 250 nM to about 800 μΜ, about 250 nM to about 700 μΜ, about 250 nM to about 600 μΜ, about 250 nM to about 500 μΜ, about 250 nM to about 400 μΜ, about 250 nM to about 300 μΜ, about 250 nM to about 200 μΜ, about 250 nM to about 100 μΜ, about 250 nM to about 90 μΜ, about 250 nM to about 80 μΜ, about 250 nM to about 70 μΜ, about 250 nM to about 60 μΜ, about 250 nM to about 50 μΜ, about 250 nM to about 40 μΜ, about 250 nM to about 30 μΜ, about 250 nM to about 20 μΜ, about 250 nM to about 10 μΜ, about 250 nM to about 5 μΜ, about 250 nM to about 4 μΜ, about 250 nM to about 2 μΜ, about 250 nM to about 1 μΜ, about 250 nM to about 900 nM, about 250 nM to about 800 nM, about 250 nM to about 700 nM, about 250 nM to about 600 nM, about 250 nM to about 500 nM, about 250 nM to about 400 nM, about 250 nM to about 300 nM, about 300 nM to about 900 μΜ, about 300 nM to about 800 μΜ, about 300 nM to about 700 μΜ, about 300 nM to about 600 uM, about 300 nM to about 500 μΜ, about 300 nM to about 400 μΜ, about 300 nM to about 300 μΜ, about 300 nM to about 200 μΜ, about 300 nM to about 100 μΜ, about 300 nM to about 90 μΜ, about 300 nM to about 80 μΜ, about 300 nM to about 70 μΜ, about 300 nM to about 60 μΜ, about 300 nM to about 50 μΜ, about 300 nM to about 40 μΜ, about 300 nM to about 30 μΜ, about 300 nM to about 20 μΜ, about 300 nM to about 10 μΜ, about 300 nM to about 5 μΜ, about 300 nM to about 4 μΜ, about 300 nM to about 2 μΜ, about 300 nM to about 1 μΜ, about 300 nM to about 900 nM, about 300 nM to about 800 nM, about 300 nM to about 700 nM, about 300 nM to about 600 nM, about 300 nM to about 500 nM, about 300 nM to about 400 nM, about 400 nM to about 900 μΜ, about 400 nM to about 800 μΜ, about 400 nM to about 700 μΜ, about 400 nM to about 600 μΜ, about 400 nM to about 500 uM, about 400 nM to about 400 μΜ, about 400 nM to about 300 μΜ, about 400 nM to about 200 μΜ, about 400 nM to about 100 μΜ, about 400 nM to about 90 μΜ, about 400 nM to about 80 μΜ, about 400 nM to about 70 μΜ, about 400 nM to about 60 μΜ, about 400 nM to about 50 μΜ, about 400 nM to about 40 μΜ, about 400 nM to about 30 μΜ, about 400 nM to about 20 μΜ, about 400 nM to about 10 μΜ, about 400 nM to about 5 μΜ, about 400 nM to about 4 μΜ, about 400 nM to about 2 μΜ, about 400 nM to about 1 μΜ, about 400 nM to about 900 nM, about 400 nM to about 800 nM, about 400 nM to about 700 nM, about 400 nM to about 600 nM, about 400 nM to about 500 nM, about 500 nM to about 900 μΜ, about 500 nM to about 800 μΜ, about 500 nM to about 700 μΜ, about 500 nM to about 600 μΜ, about 500 nM to about 500 μΜ, about 500 nM to about 400 μΜ, about 500 nM to about 300 μΜ, about 500 nM to about 200 μΜ, about 500 nM to about 100 μΜ, about 500 nM to about 90 μΜ, about 500 nM to about 80 μΜ, about 500 nM to about 70 μΜ, about 500 nM to about 60 μΜ, about 500 nM to about 50 μΜ, about 500 nM to about 40 μΜ, about 500 nM to about 30 μΜ, about 500 nM to about 20 μΜ, about 500 nM to about 10 μΜ, about 500 nM to about 5 μΜ, about 500 nM to about 4 μΜ, about 500 nM to about 2 μΜ, about 500 nM to about 1 μΜ, about 500 nM to about 900 nM, about 500 nM to about 800 nM, about 500 nM to about 700 nM, about 500 nM to about 600 nM, about 1 μΜ to about 1 mM, about 1 μΜ to about 900 μΜ, about 1 μΜ to about 800 μΜ, about 1 μΜ to about 700 μΜ, about 1 μΜ to about 600 μΜ, about 1 μΜ to about 500 μΜ, about 1 μΜ to about 400 μΜ, about 1 μΜ to about 300 μΜ, about 1 μΜ to about 200 μΜ, about 1 μΜ to about 100 μΜ, about 1 μΜ to about 90 μΜ, about 1 μΜ to about 80 μΜ, about 1 μΜ to about 70 μΜ, about 1 μΜ to about 60 μΜ, about

1 μΜ to about 50 μΜ, about 1 μΜ to about 40 μΜ, about 1 μΜ to about 30 μΜ, about 1 μΜ to about 20 μΜ, about 1 μΜ to about 10 μΜ, about 1 μΜ to about 5 μΜ, about 1 μΜ to about 4 μΜ, about 1 μΜ to about 3 μΜ, about 1 μΜ to about 2 μΜ, about 2 μΜ to about 1 mM, about 2 μΜ to about 900 μΜ, about 2 μΜ to about 800 μΜ, about 2 μΜ to about 700 μΜ, about 2 μΜ to about 600 μΜ, about 2 μΜ to about 500 μΜ, about 2 μΜ to about 400 μΜ, about 2 μΜ to about 300 μΜ, about 2 μΜ to about 200 μΜ, about 2 μΜ to about 100 μΜ, about 2 μΜ to about 90 μΜ, about 2 μΜ to about 80 μΜ, about 2 μΜ to about 70 μΜ, about

2 μΜ to about 60 μΜ, about 2 μΜ to about 50 μΜ, about 2 μΜ to about 40 μΜ, about 2 μΜ to about 30 μΜ, about 2 μΜ to about 20 μΜ, about 2 μΜ to about 10 μΜ, about 2 μΜ to about 5 μΜ, about 2 μΜ to about 4 μΜ, about 2 μΜ to about 3 μΜ, about 5 μΜ to about 1 mM, about 5 μΜ to about 900 μΜ, about 5 uM to about 800 μΜ, about 5 μΜ to about 700 μΜ, about 5 μΜ to about 600 uM, about 5 μΜ to about 500 μΜ, about 5 μΜ to about 400 μΜ, about 5 μΜ to about 300 uM, about 5 μΜ to about 200 μΜ_; about 5 μΜ to about 100 μΜ, about 5 μΜ to about 90 μΜ, about 5 μΜ to about 80 μΜ, about 5 μΜ to about 70 μΜ, about 5 μΜ to about 60 μΜ, about 5 μΜ to about 50 μΜ, about 5 μΜ to about 40 μΜ, about 5 μΜ to about 30 μΜ, about 5 μΜ to about 20 μΜ, about 5 μΜ to about 10 μΜ, about 10 μΜ to about 1 mM, about 10 μΜ to about 900 μΜ, about 10 μΜ to about 800 μΜ, about 10 μΜ to about 700 μΜ, about 10 μΜ to about 600 μΜ, about 10 μΜ to about 500 μΜ, about 10 uM to about 400 μΜ, about 10 μΜ to about 300 μΜ, about 10 μΜ to about 200 μΜ, about 10 uM to about 100 μΜ, about 10 μΜ to about 90 μΜ, about 10 μΜ to about 80 μΜ, about 10 μΜ to about 70 μΜ, about 10 μΜ to about 60 μΜ, about 10 μΜ to about 50 μΜ, about 10 μΜ to about 40 μΜ, about 10 μΜ to about 30 μΜ, about 10 μΜ to about 20 μΜ, about 20 μΜ to about 1 mM, about 20 μΜ to about 900 μΜ, about 20 μΜ to about 800 μΜ, about 20 μΜ to about 700 μΜ, about 20 μΜ to about 600 μΜ, about 20 μΜ to about 500 μΜ, about 20 μΜ to about 400 μΜ, about 20 μΜ to about 300 μΜ, about 20 μΜ to about 200 μΜ, about 20 μΜ to about 100 μΜ, about 20 μΜ to about 90 μΜ, about 20 μΜ to about 80 μΜ, about 20 μΜ to about 70 μΜ, about 20 μΜ to about 60 μΜ, about 20 μΜ to about 50 μΜ, about 20 μΜ to about 40 μΜ, about 20 μΜ to about 30 μΜ, about 30 μΜ to about 1 mM, about 30 μΜ to about 900 μΜ, about 30 μΜ to about 800 μΜ, about 30 μΜ to about 700 μΜ, about 30 μΜ to about 600 μΜ, about 30 μΜ to about 500 μΜ, about 30 μΜ to about 400 μΜ, about 30 μΜ to about 300 μΜ, about 30 μΜ to about 200 μΜ, about 30 μΜ to about 100 μΜ, about 30 μΜ to about 90 μΜ, about 30 μΜ to about 80 μΜ, about 30 μΜ to about 70 μΜ, about 30 μΜ to about 60 μΜ, about 30 μΜ to about 50 μΜ, about 30 μΜ to about 40 μΜ, about 40 μΜ to about 1 mM, about 40 μΜ to about 900 μΜ, about 40 μΜ to about 800 μΜ, about 40 μΜ to about 700 μΜ, about 40 μΜ to about 600 μΜ, about 40 μΜ to about 500 μΜ, about 40 μΜ to about 400 μΜ, about 40 μΜ to about 300 μΜ, about 40 μΜ to about 200 μΜ, about 40 μΜ to about 100 μΜ, about 40 μΜ to about 90 μΜ, about 40 μΜ to about 80 μΜ, about 40 μΜ to about 70 μΜ, about 40 μΜ to about 60 μΜ, about 40 μΜ to about 50 μΜ, about 50 μΜ to about 1 mM, about 50 μΜ to about 900 μΜ, about 50 μΜ to about 800 μΜ, about 50 μΜ to about 700 μΜ, about 50 μΜ to about 600 μΜ, about 50 μΜ to about 500 μΜ, about 50 μΜ to about 400 μΜ, about 50 μΜ to about 300 μΜ, about 50 μΜ to about 200 μΜ, about 50 μΜ to about 100 uM, about 50 μΜ to about 90 μΜ, about 50 μΜ to about 80 uM, about 50 μΜ to about 70 uM, about 50 μΜ to about 60 μΜ, about 60 μΜ to about 1 mM, about 60 μΜ to about 900 μΜ, about 60 μΜ to about 800 uM, about 60 μΜ to about 700 uM, about 60 μΜ to about 600 μΜ, about 60 μΜ to about 500 uM, about 60 μΜ to about 400 μΜ, about 60 μΜ to about 300 μΜ, about 60 μΜ to about 200 uM, about 60 μΜ to about 100 μΜ, about 60 μΜ to about 90 uM, about 60 μΜ to about 80 μΜ, about 60 μΜ to about 70 μΜ, about 70 μΜ to about 1 mM, about 70 μΜ to about 900 μΜ, about 70 μΜ to about 800 μΜ, about 70 μΜ to about 700 μΜ, about 70 μΜ to about 600 μΜ, about 70 μΜ to about 500 μΜ, about 70 μΜ to about 400 μΜ, about 70 μΜ to about 300 uM, about 70 μΜ to about 200 μΜ, about 70 μΜ to about 100 μΜ, about 70 μΜ to about 90 μΜ, about 70 μΜ to about 80 uM, about 80 μΜ to about 1 mM, about 80 μΜ to about 900 uM, about 80 μΜ to about 800 μΜ, about 80 μΜ to about 700 μΜ, about 80 μΜ to about 600 uM, about 80 μΜ to about 500 uM, about 80 μΜ to about 400 μΜ, about 80 μΜ to about 300 μΜ, about 80 μΜ to about 200 μΜ, about 80 μΜ to about 100 μΜ, about 80 μΜ to about 90 μΜ, about 90 μΜ to about 1 mM, about 90 μΜ to about 900 μΜ, about 90 μΜ to about 800 uM, about 90 μΜ to about 700 uM, about 90 μΜ to about 600 μΜ, about 90 μΜ to about 500 uM, about 90 μΜ to about 400 μΜ, about 90 μΜ to about 300 μΜ, about 90 μΜ to about 200 μΜ, about 90 μΜ to about 100 μΜ, about 100 μΜ to about 1 mM, about 100 μΜ to about 900 μΜ, about 100 μΜ to about 800 μΜ, about 100 μΜ to about 700 μΜ, about 100 μΜ to about 600 μΜ, about 100 μΜ to about 500 uM, about 100 μΜ to about 400 μΜ, about 100 μΜ to about 300 μΜ, about 100 μΜ to about 200 uM, about 200 μΜ to about 1 mM, about 200 μΜ to about 900 μΜ, about 200 μΜ to about 800 μΜ, about 200 μΜ to about 700 μΜ, about 200 μΜ to about 600 μΜ, about 200 μΜ to about 500 μΜ, about 200 μΜ to about 400 μΜ, about 200 μΜ to about 300 μΜ, about 300 μΜ to about 1 mM, about 300 μΜ to about 900 μΜ, about 300 μΜ to about 800 μΜ, about 300 μΜ to about 700 μΜ, about 300 μΜ to about 600 μΜ, about 300 μΜ to about 500 μΜ, about 300 μΜ to about 400 μΜ, about 400 μΜ to about 1 mM, about 400 μΜ to about 900 uM, about 400 μΜ to about 800 μΜ_; about 400 μΜ to about 700 μΜ, about 400 μΜ to about 600 μΜ, about 400 μΜ to about 500 μΜ, about 500 μΜ to about 1 mM, about 500 μΜ to about 900 μΜ, about 500 μΜ to about 800 μΜ, about 500 μΜ to about 700 μΜ, about 500 μΜ to about 600 μΜ, about 600 μΜ to about 1 mM, about 600 μΜ to about 900 μΜ, about 600 μΜ to about 800 μΜ, about 600 μΜ to about 700 μΜ, about 700 μΜ to about 1 mM, about 700 μΜ to about 900 μΜ, about 700 μΜ to about 800 μΜ, about 800 μΜ to about 1 mM, about 800 μΜ to about 900 μΜ, or about 900 μΜ to about 1 mM). In some embodiments of any of the antigen-binding protein constructs described herein, the KD of the additional antigen-binding domain for the antigen at an acidic pH (e.g., any of the acidic pHs described herein) and/or at a neutral pH (e.g., any of the neutral pHs described herein) can be between about 1 pM to about 250 nM (e.g., about 1 pM to about 240 nM, about 1 pM to about 230 nM, about 1 pM to about 220 nM, about 1 pM to about 210 nM, about 1 pM to about 200 nM, about 1 pM to about 190 nM, about 1 pM to about 180 nM, about 1 pM to about 170 nM, about 1 pM to about 160 nM, about 1 pM to about 1 0 nM, about 1 pM to about 140 nM, about 1 pM to about 130 nM, about 1 pM to about 120 nM, about 1 pM to about 110 nM, about 1 pM to about 100 nM, about 1 pM to about 95 nM, about 1 pM to about 90 nM, about 1 pM to about 85 nM, about 1 pM to about 80 nM, about 1 pM to about 75 nM, about 1 pM to about 70 nM, about 1 pM to about 65 nM, about 1 pM to about 60 nM, about 1 pM to about 55 nM, about 1 pM to about 50 nM, about 1 pM to about 45 nM, about 1 pM to about 40 nM, about 1 pM to about 35 nM, about 1 pM to about 30 nM, about 1 pM to about 25 nM, about 1 pM to about 20 nM, about 1 pM to about 15 nM, about 1 pM to about 10 nM, about 1 pM to about 5 nM, about 1 pM to about 2 nM, about 1 pM to about 1 nM, about 1 pM to about 950 pM, about 1 pM to about 900 pM, about 1 pM to about 850 pM, about 1 pM to about 800 pM, about 1 pM to about 750 pM, about 1 pM to about 700 pM, about 1 pM to about 650 pM, about 1 pM to about 600 pM, about 1 pM to about 550 pM, about 1 pM to about 500 pM, about 1 pM to about 450 pM, about 1 pM to about 400 pM, about 1 pM to about 350 pM, about 1 pM to about 300 pM, about 1 pM to about 250 pM, about 1 pM to about 200 pM, about 1 pM to about 150 pM, about 1 pM to about 100 pM, about 1 pM to about 90 pM, about 1 pM to about 80 pM, about 1 pM to about 70 pM, about 1 pM to about 60 pM, about 1 pM to about 50 pM, about 1 pM to about 40 pM, about 1 pM to about 30 pM, about 1 pM to about 20 pM, about 1 pM to about 10 pM, about 1 pM to about 5 pM, about 1 pM to about 4 pM, about 1 pM to about 3 pM, about 1 pM to about 2 pM, about 2 pM to about 250 nM, about 2 pM to about 240 nM, about 2 pM to about 230 nM, about 2 pM to about 220 nM, about 2 pM to about 210 nM, about 2 pM to about 200 nM, about 2 pM to about 190 nM, about 2 pM to about 180 nM, about 2 pM to about 170 nM, about 2 pM to about 160 nM, about 2 pM to about 150 nM, about 2 pM to about 140 nM, about 2 pM to about 130 nM, about 2 pM to about 120 nM, about 2 pM to about 110 nM, about 2 pM to about 100 nM, about 2 pM to about 95 nM, about 2 pM to about 90 nM, about 2 pM to about 85 nM, about 2 pM to about 80 nM, about 2 pM to about 75 nM, about 2 pM to about 70 nM, about 2 pM to about 65 nM, about 2 pM to about 60 nM, about 2 pM to about 55 nM, about 2 pM to about 50 nM, about 2 pM to about 45 nM, about 2 pM to about 40 nM, about 2 pM to about 35 nM, about 2 pM to about 30 nM, about 2 pM to about 25 nM, about 2 pM to about 20 nM, about 2 pM to about 15 nM, about 2 pM to about 10 nM, about 2 pM to about 5 nM, about 2 pM to about 2 nM, about 2 pM to about 1 nM, about 2 pM to about 950 pM, about 2 pM to about 900 pM, about 2 pM to about 850 pM, about 2 pM to about 800 pM, about 2 pM to about 750 pM, about 2 pM to about 700 pM, about 2 pM to about 650 pM, about 2 pM to about 600 pM, about 2 pM to about 550 pM, about 2 pM to about 500 pM, about 2 pM to about 450 pM, about 2 pM to about 400 pM, about 2 pM to about 350 pM, about 2 pM to about 300 pM, about 2 pM to about 250 pM, about 2 pM to about 200 pM, about 2 pM to about 150 pM, about 2 pM to about 100 pM, about 2 pM to about 90 pM, about 2 pM to about 80 pM, about 2 pM to about 70 pM, about 2 pM to about 60 pM, about 2 pM to about 50 pM, about 2 pM to about 40 pM, about 2 pM to about 30 pM, about 2 pM to about 20 pM, about 2 pM to about 10 pM, about 2 pM to about 5 pM, about 2 pM to about 4 pM, about 2 pM to about 3 pM, about 5 pM to about 250 nM, about 5 pM to about 240 nM, about 5 pM to about 230 nM, about 5 pM to about 220 nM, about 5 pM to about 210 nM, about 5 pM to about 200 nM, about 5 pM to about 190 nM, about 5 pM to about 180 nM, about 5 pM to about 170 nM, about 5 pM to about 160 nM, about 5 pM to about 1 0 nM, about 5 pM to about 140 nM, about 5 pM to about 130 nM, about 5 pM to about 120 nM, about 5 pM to about 110 nM, about 5 pM to about 100 nM, about 5 pM to about 95 nM, about 5 pM to about 90 nM, about 5 pM to about 85 nM, about 5 pM to about 80 nM, about 5 pM to about 75 nM, about 5 pM to about 70 nM, about 5 pM to about 65 nM, about 5 pM to about 60 nM, about 5 pM to about 55 nM, about 5 pM to about 50 nM, about 5 pM to about 45 nM, about 5 pM to about 40 nM, about 5 pM to about 35 nM, about 5 pM to about 30 nM, about 5 pM to about 25 nM, about 5 pM to about 20 nM, about 5 pM to about 15 nM, about 5 pM to about 10 nM, about 5 pM to about 5 nM, about 5 pM to about 2 nM, about 5 pM to about 1 nM, about 5 pM to about 950 pM. about 5 pM to about 900 pM, about 5 pM to about 850 pM, about 5 pM to about 800 pM, about 5 pM to about 750 pM, about 5 pM to about 700 pM, about 5 pM to about 650 pM, about 5 pM to about 600 pM, about 5 pM to about 550 pM, about 5 pM to about 500 pM, about 5 pM to about 450 pM, about 5 pM to about 400 pM, about 5 pM to about 350 pM, about 5 pM to about 300 pM, about 5 pM to about 250 pM, about 5 pM to about 200 pM, about 5 pM to about 150 pM, about 5 pM to about 100 pM, about 5 pM to about 90 pM, about 5 pM to about 80 pM, about 5 pM to about 70 pM, about 5 pM to about 60 pM, about 5 pM to about 50 pM, about 5 pM to about 40 pM, about 5 pM to about 30 pM, about 5 pM to about 20 pM, about 5 pM to about 10 pM, about 10 pM to about 250 nM, about 10 pM to about 240 nM, about 10 pM to about 230 nM, about 10 pM to about 220 nM, about 10 pM to about 210 nM, about 10 pM to about 200 nM, about 10 pM to about 190 nM, about 10 pM to about 180 nM, about 10 pM to about 170 nM, about 10 pM to about 160 nM, about 10 pM to about 150 nM, about 10 pM to about 140 nM, about 10 pM to about 130 nM, about 10 pM to about 120 nM, about 10 pM to about 110 nM, about 10 pM to about 100 nM, about 10 pM to about 95 nM, about 10 pM to about 90 nM, about 10 pM to about 85 nM, about 10 pM to about 80 nM, about 10 pM to about 75 nM, about 10 pM to about 70 nM, about 10 pM to about 65 nM, about 10 pM to about 60 nM, about 10 pM to about 55 nM, about 10 pM to about 50 nM, about 10 pM to about 45 nM, about 10 pM to about 40 nM, about 10 pM to about 35 nM, about 10 pM to about 30 nM, about 10 pM to about 25 nM, about 10 pM to about 20 nM, about 10 pM to about 15 nM, about 10 pM to about 10 nM, about 10 pM to about 5 nM, about 10 pM to about 2 nM, about 10 pM to about 1 nM, about 10 pM to about 950 pM, about 10 pM to about 900 pM. about 10 pM to about 850 pM, about 10 pM to about 800 pM, about 10 pM to about 750 pM, about 10 pM to about 700 pM, about 10 pM to about 650 pM, about 10 pM to about 600 pM, about 10 pM to about 550 pM, about 10 pM to about 500 pM, about 10 pM to about 450 pM, about 10 pM to about 400 pM, about 10 pM to about 350 pM, about 10 pM to about 300 pM, about 10 pM to about 250 pM, about 10 pM to about 200 pM, about 10 pM to about 150 pM, about 10 pM to about 100 pM, about 10 pM to about 90 pM, about 10 pM to about 80 pM, about 10 pM to about 70 pM, about 10 pM to about 60 pM, about 10 pM to about 50 pM, about 10 pM to about 40 pM, about 10 pM to about 30 pM, about 10 pM to about 20 pM, about 15 pM to about 250 nM, about 15 pM to about 240 nM, about 15 pM to about 230 nM, about 15 pM to about 220 nM, about 15 pM to about 210 nM, about 15 pM to about 200 nM, about 15 pM to about 190 nM, about 15 pM to about 180 nM, about 15 pM to about 170 nM, about 15 pM to about 160 nM, about 15 pM to about 150 nM, about 15 pM to about 140 nM, about 15 pM to about 130 nM, about 15 pM to about 120 nM, about 15 pM to about 110 nM, about 15 pM to about 100 nM, about 15 pM to about 95 nM, about 15 pM to about 90 nM, about 15 pM to about 85 nM, about 15 pM to about 80 nM, about 15 pM to about 75 nM, about 15 pM to about 70 nM, about 15 pM to about 65 nM, about 15 pM to about 60 nM, about 15 pM to about 55 nM, about 15 pM to about 50 nM, about 15 pM to about 45 nM, about 15 pM to about 40 nM, about 15 pM to about 35 nM, about 15 pM to about 30 nM, about 15 pM to about 25 nM, about 15 pM to about 20 nM, about 15 pM to about 15 nM, about 15 pM to about 10 nM, about 15 pM to about 5 nM, about 15 pM to about 2 nM, about 15 pM to about 1 nM, about 15 pM to about 950 pM, about 15 pM to about 900 pM, about 15 pM to about 850 pM, about 15 pM to about 800 pM, about 15 pM to about 750 pM, about 15 pM to about 700 pM, about 15 pM to about 650 pM, about 15 pM to about 600 pM, about 15 pM to about 550 pM, about 15 pM to about 500 pM, about 15 pM to about 450 pM, about 15 pM to about 400 pM, about 15 pM to about 350 pM, about 15 pM to about 300 pM, about 15 pM to about 250 pM, about 15 pM to about 200 pM, about 1 pM to about 150 pM, about 15 pM to about 100 pM, about 15 pM to about 90 pM, about 15 pM to about 80 pM, about 15 pM to about 70 pM, about 15 pM to about 60 pM, about 15 pM to about 50 pM, about 15 pM to about 40 pM, about 15 pM to about 30 pM, about 15 pM to about 20 pM, about 20 pM to about 250 nM, about 20 pM to about 240 nM, about 20 pM to about 230 nM, about 20 pM to about 220 nM, about 20 pM to about 210 nM, about 20 pM to about 200 nM, about 20 pM to about 190 nM, about 20 pM to about 180 nM, about 20 pM to about 170 nM, about 20 pM to about 160 nM, about 20 pM to about 150 nM, about 20 pM to about 140 nM, about 20 pM to about 130 nM, about 20 pM to about 120 nM, about 20 pM to about 110 nM, about 20 pM to about 100 nM, about 20 pM to about 95 nM, about 20 pM to about 90 nM, about 20 pM to about 85 nM, about 20 pM to about 80 nM, about 20 pM to about 75 nM, about 20 pM to about 70 nM, about 20 pM to about 65 nM, about 20 pM to about 60 nM, about 20 pM to about 55 nM, about 20 pM to about 50 nM, about 20 pM to about 45 nM, about 20 pM to about 40 nM, about 20 pM to about 35 nM, about 20 pM to about 30 nM, about 20 pM to about 25 nM, about 20 pM to about 20 nM, about 20 pM to about 15 nM, about 20 pM to about 10 nM, about 20 pM to about 5 nM, about 20 pM to about 2 nM, about 20 pM to about 1 nM, about 20 pM to about 950 pM, about 20 pM to about 900 pM, about 20 pM to about 850 pM, about 20 pM to about 800 pM, about 20 pM to about 750 pM, about 20 pM to about 700 pM, about 20 pM to about 650 pM, about 20 pM to about 600 pM, about 20 pM to about 550 pM, about 20 pM to about 500 pM, about 20 pM to about 450 pM, about 20 pM to about 400 pM, about 20 pM to about 350 pM, about 20 pM to about 300 pM, about 20 pM to about 250 pM, about 20 pM to about 20 pM, about 200 pM to about 150 pM, about 20 pM to about 100 pM, about 20 pM to about 90 pM, about 20 pM to about 80 pM, about 20 pM to about 70 pM, about 20 pM to about 60 pM, about 20 pM to about 50 pM, about 20 pM to about 40 pM, about 20 pM to about 30 pM, about 30 pM to about 250 nM, about 30 pM to about 240 nM, about 30 pM to about 230 nM, about 30 pM to about 220 nM, about 30 pM to about 210 nM, about 30 pM to about 200 nM, about 30 pM to about 190 nM, about 30 pM to about 180 nM, about 30 pM to about 170 nM, about 30 pM to about 160 nM, about 30 pM to about 150 nM, about 30 pM to about 140 nM, about 30 pM to about 130 nM, about 30 pM to about 120 nM, about 30 pM to about 110 nM, about 30 pM to about 100 nM, about 30 pM to about 95 nM, about 30 pM to about 90 nM, about 30 pM to about 85 nM, about 30 pM to about 80 nM, about 30 pM to about 75 nM, about 30 pM to about 70 nM, about 30 pM to about 65 nM, about 30 pM to about 60 nM, about 30 pM to about 55 nM, about 30 pM to about 50 nM, about 30 pM to about 45 nM, about 30 pM to about 40 nM, about 30 pM to about 35 nM, about 30 pM to about 30 nM, about 30 pM to about 25 nM, about 30 pM to about 20 nM, about 30 pM to about 15 nM, about 30 pM to about 10 nM, about 30 pM to about 5 nM, about 30 pM to about 2 nM, about 30 pM to about 1 nM, about 30 pM to about 950 pM, about 30 pM to about 900 pM, about 30 pM to about 850 pM, about 30 pM to about 800 pM, about 30 pM to about 750 pM, about 30 pM to about 700 pM, about 30 pM to about 650 pM, about 30 pM to about 600 pM, about 30 pM to about 550 pM, about 30 pM to about 500 pM, about 30 pM to about 450 pM, about 30 pM to about 400 pM, about 30 pM to about 350 pM, about 30 pM to about 300 pM, about 30 pM to about 250 pM, about 30 pM to about 200 pM, about 30 pM to about 150 pM, about 30 pM to about 100 pM, about 30 pM to about 90 pM, about 30 pM to about 80 pM, about 30 pM to about 70 pM, about 30 pM to about 60 pM, about 30 pM to about 50 pM, about 30 pM to about 40 pM, about 40 pM to about 250 nM, about 40 pM to about 240 nM, about 40 pM to about 230 nM, about 40 pM to about 220 nM, about 40 pM to about 210 nM, about 40 pM to about 200 nM, about 40 pM to about 190 nM, about 40 pM to about 180 nM, about 40 pM to about 170 nM, about 40 pM to about 160 nM, about 40 pM to about 150 nM, about 40 pM to about 140 nM, about 40 pM to about 130 nM, about 40 pM to about 120 nM, about 40 pM to about 110 nM, about 40 pM to about 100 nM, about 40 pM to about 95 nM, about 40 pM to about 90 nM, about 40 pM to about 85 nM, about 40 pM to about 80 nM, about 40 pM to about 75 nM, about 40 pM to about 70 nM, about 40 pM to about 65 nM, about 40 pM to about 60 nM, about 40 pM to about 55 nM, about 40 pM to about 50 nM, about 40 pM to about 45 nM, about 40 pM to about 40 nM, about 40 pM to about 35 nM, about 40 pM to about 30 nM, about 40 pM to about 25 nM, about 40 pM to about 30 nM, about 40 pM to about 15 nM, about 40 pM to about 10 nM, about 40 pM to about 5 nM, about 40 pM to about 2 nM, about 40 pM to about 1 nM, about 40 pM to about 950 pM, about 40 pM to about 900 pM, about 40 pM to about 850 pM, about 40 pM to about 800 pM, about 40 pM to about 750 pM, about 40 pM to about 700 pM, about 40 pM to about 650 pM, about 40 pM to about 600 pM, about 40 pM to about 550 pM, about 40 pM to about 500 pM_: about 40 pM to about 450 pM, about 40 pM to about 400 pM, about 40 pM to about 350 pM_; about 40 pM to about 300 pM, about 40 pM to about 250 pM, about 40 pM to about 200 pM, about 40 pM to about 150 pM, about 40 pM to about 100 pM, about 40 pM to about 90 pM, about 40 pM to about 80 pM, about 40 pM to about 70 pM, about 40 pM to about 60 pM, about 40 pM to about 50 pM, about 50 pM to about 250 nM, about 50 pM to about 240 nM, about 50 pM to about 230 nM, about 50 pM to about 220 nM, about 50 pM to about 210 nM, about 50 pM to about 200 nM, about 50 pM to about 190 nM, about 50 pM to about 180 nM, about 50 pM to about 170 nM, about 50 pM to about 160 nM, about 50 pM to about 150 nM, about 50 pM to about 140 nM, about 50 pM to about 130 nM, about 50 pM to about 120 nM, about 50 pM to about 110 nM, about 50 pM to about 100 nM, about 50 pM to about 95 nM, about 50 pM to about 90 nM, about 50 pM to about 85 nM, about 50 pM to about 80 nM, about 50 pM to about 75 nM, about 50 pM to about 70 nM, about 50 pM to about 65 nM, about 50 pM to about 60 nM, about 50 pM to about 55 nM, about 50 pM to about 50 nM, about 50 pM to about 45 nM, about 50 pM to about 40 nM, about 50 pM to about 35 nM, about 50 pM to about 30 nM, about 50 pM to about 25 nM, about 50 pM to about 30 nM, about 50 pM to about 15 nM, about 50 pM to about 10 nM, about 50 pM to about 5 nM, about 50 pM to about 2 nM, about 50 pM to about 1 nM, about 50 pM to about 950 pM, about 50 pM to about 900 pM, about 50 pM to about 850 pM, about 50 pM to about 800 pM, about 50 pM to about 750 pM, about 50 pM to about 700 pM, about 50 pM to about 650 pM, about 50 pM to about 600 pM, about 50 pM to about 550 pM, about 50 pM to about 500 pM, about 50 pM to about 450 pM, about 50 pM to about 400 pM, about 50 pM to about 350 pM, about 50 pM to about 300 pM, about 50 pM to about 250 pM, about 50 pM to about 200 pM, about 50 pM to about 150 pM, about 50 pM to about 100 pM, about 50 pM to about 90 pM, about 50 pM to about 80 pM, about 50 pM to about 70 pM, about 50 pM to about 60 pM, about 60 pM to about 250 nM, about 60 pM to about 240 nM, about 60 pM to about 230 nM, about 60 pM to about 220 nM, about 60 pM to about 210 nM, about 60 pM to about 200 nM, about 60 pM to about 190 nM, about 60 pM to about 180 nM, about 60 pM to about 170 nM, about 60 pM to about 160 nM, about 60 pM to about 150 nM, about 60 pM to about 140 nM, about 60 pM to about 130 nM, about 60 pM to about 120 nM, about 60 pM to about 110 nM, about 60 pM to about 100 nM, about 60 pM to about 95 nM, about 60 pM to about 90 nM, about 60 pM to about 85 nM, about 60 pM to about 80 nM, about 60 pM to about 75 nM, about 60 pM to about 70 nM, about 60 pM to about 65 nM, about 60 pM to about 60 nM, about 60 pM to about 55 nM, about 60 pM to about 50 nM, about 60 pM to about 45 nM, about 60 pM to about 40 nM, about 60 pM to about 35 nM, about 60 pM to about 30 nM, about 60 pM to about 25 nM, about 60 pM to about 20 nM, about 60 pM to about 15 nM, about 60 pM to about 10 nM, about 60 pM to about 5 nM, about 60 pM to about 2 nM, about 60 pM to about 1 nM, about 60 pM to about 950 pM, about 60 pM to about 900 pM, about 60 pM to about 850 pM, about 60 pM to about 800 pM, about 60 pM to about 750 pM, about 60 pM to about 700 pM, about 60 pM to about 650 pM, about 60 pM to about 600 pM, about 60 pM to about 550 pM, about 60 pM to about 500 pM, about 60 pM to about 450 pM, about 60 pM to about 400 pM, about 60 pM to about 350 pM, about 60 pM to about 300 pM, about 60 pM to about 250 pM, about 60 pM to about 200 pM, about 60 pM to about 150 pM, about 60 pM to about 100 pM, about 60 pM to about 90 pM, about 60 pM to about 80 pM, about 60 pM to about 70 pM, about 70 pM to about 250 nM, about 70 pM to about 240 nM, about 70 pM to about 230 nM, about 70 pM to about 220 nM, about 70 pM to about 210 nM, about 70 pM to about 200 nM, about 70 pM to about 190 nM, about 70 pM to about 180 nM, about 70 pM to about 170 nM, about 70 pM to about 160 nM, about 70 pM to about 150 nM, about 70 pM to about 140 nM, about 70 pM to about 130 nM, about 70 pM to about 120 nM, about 70 pM to about 110 nM, about 70 pM to about 100 nM, about 70 pM to about 95 nM, about 70 pM to about 90 nM, about 70 pM to about 85 nM, about 70 pM to about 80 nM, about 70 pM to about 75 nM, about 70 pM to about 70 nM, about 70 pM to about 65 nM, about 70 pM to about 60 nM, about 70 pM to about 55 nM, about 70 pM to about 50 nM, about 70 pM to about 45 nM, about 70 pM to about 40 nM, about 70 pM to about 35 nM, about 70 pM to about 30 nM, about 70 pM to about 25 nM, about 70 pM to about 20 nM, about 70 pM to about 15 nM, about 70 pM to about 10 nM, about 70 pM to about 5 nM, about 70 pM to about 2 nM, about 70 pM to about 1 nM, about 70 pM to about 950 pM, about 70 pM to about 900 pM, about 70 pM to about 850 pM, about 70 pM to about 800 pM, about 70 pM to about 750 pM, about 70 pM to about 700 pM, about 70 pM to about 650 pM, about 70 pM to about 600 pM, about 70 pM to about 550 pM, about 70 pM to about 500 pM, about 70 pM to about 450 pM, about 70 pM to about 400 pM, about 70 pM to about 350 pM, about 70 pM to about 300 pM, about 70 pM to about 250 pM, about 70 pM to about 200 pM, about 70 pM to about 150 pM, about 70 pM to about 100 pM, about 70 pM to about 90 pM, about 70 pM to about 80 pM, about 80 pM to about 250 nM, about 80 pM to about 240 nM, about 80 pM to about 230 nM, about 80 pM to about 220 nM, about 80 pM to about 210 nM, about 80 pM to about 200 nM, about 80 pM to about 190 nM, about 80 pM to about 180 nM, about 80 pM to about 170 nM, about 80 pM to about 160 nM, about 80 pM to about 150 nM, about 80 pM to about 140 nM, about 80 pM to about 130 nM, about 80 pM to about 120 nM, about 80 pM to about 110 nM, about 80 pM to about 100 nM, about 80 pM to about 95 nM, about 80 pM to about 90 nM, about 80 pM to about 85 nM, about 80 pM to about 80 nM, about 80 pM to about 75 nM, about 80 pM to about 70 nM, about 80 pM to about 65 nM, about 80 pM to about 60 nM, about 80 pM to about 55 nM, about 80 pM to about 50 nM, about 80 pM to about 45 nM, about 80 pM to about 40 nM, about 80 pM to about 35 nM, about 80 pM to about 30 nM, about 80 pM to about 25 nM, about 80 pM to about 20 nM, about 80 pM to about 15 nM, about 80 pM to about 10 nM, about 80 pM to about 5 nM, about 80 pM to about 2 nM, about 80 pM to about 1 nM, about 80 pM to about 950 pM, about 80 pM to about 900 pM, about 80 pM to about 850 pM, about 80 pM to about 800 pM, about 80 pM to about 750 pM, about 80 pM to about 700 pM, about 80 pM to about 650 pM, about 80 pM to about 600 pM, about 80 pM to about 550 pM, about 80 pM to about 500 pM, about 80 pM to about 450 pM, about 80 pM to about 400 pM, about 80 pM to about 350 pM, about 80 pM to about 300 pM, about 80 pM to about 250 pM, about 80 pM to about 200 pM, about 80 pM to about 150 pM, about 80 pM to about 100 pM, about 80 pM to about 90 pM, about 90 pM to about 250 nM, about 90 pM to about 240 nM, about 90 pM to about 230 nM, about 90 pM to about 220 nM, about 90 pM to about 210 nM, about 90 pM to about 200 nM, about 90 pM to about 190 nM, about 90 pM to about 180 nM, about 90 pM to about 170 nM, about 90 pM to about 160 nM, about 90 pM to about 1 0 nM, about 90 pM to about 140 nM, about 90 pM to about 130 nM, about 90 pM to about 120 nM, about 90 pM to about 110 nM, about 90 pM to about 100 nM, about 90 pM to about 95 nM, about 90 pM to about 90 nM, about 90 pM to about 85 nM, about 90 pM to about 80 nM, about 90 pM to about 75 nM, about 90 pM to about 70 nM, about 90 pM to about 65 nM, about 90 pM to about 60 nM, about 90 pM to about 55 nM, about 90 pM to about 50 nM, about 90 pM to about 45 nM, about 90 pM to about 40 nM, about 90 pM to about 35 nM, about 90 pM to about 30 nM, about 90 pM to about 25 nM, about 90 pM to about 30 nM, about 90 pM to about 15 nM, about 90 pM to about 10 nM, about 90 pM to about 5 nM, about 90 pM to about 2 nM, about 90 pM to about 1 nM, about 90 pM to about 950 pM, about 90 pM to about 900 pM, about 90 pM to about 850 pM, about 90 pM to about 800 pM, about 90 pM to about 750 pM, about 90 pM to about 700 pM, about 90 pM to about 650 pM, about 90 pM to about 600 pM, about 90 pM to about 550 pM, about 90 pM to about 500 pM, about 90 pM to about 450 pM, about 90 pM to about 400 pM, about 90 pM to about 350 pM, about 90 pM to about 300 pM, about 90 pM to about 250 pM, about 90 pM to about 200 pM, about 90 pM to about 150 pM, about 90 pM to about 100 pM, about 100 pM to about 30 nM, about 100 pM to about 25 nM, about 100 pM to about 250 nM, about 100 pM to about 240 nM, about 100 pM to about 230 nM, about 100 pM to about 220 nM, about 100 pM to about 210 nM, about 100 pM to about 200 nM, about 100 pM to about 190 nM, about 100 pM to about 180 nM, about 100 pM to about 170 nM, about 100 pM to about 160 nM, about 100 pM to about 150 nM, about 100 pM to about 140 nM, about 100 pM to about 130 nM, about 100 pM to about 120 nM, about 100 pM to about 110 nM, about 100 pM to about 100 nM, about 100 pM to about 95 nM, about 100 pM to about 90 nM, about 100 pM to about 85 nM, about 100 pM to about 80 nM, about 100 pM to about 75 nM, about 100 pM to about 70 nM, about 100 pM to about 65 nM, about 100 pM to about 60 nM, about 100 pM to about 55 nM, about 100 pM to about 50 nM, about 100 pM to about 45 nM, about 100 pM to about 40 nM, about 100 pM to about 35 nM, about 100 pM to about 30 nM, about 100 pM to about 15 nM, about 100 pM to about 10 nM, about 100 pM to about 5 nM, about 100 pM to about 2 nM, about 100 pM to about 1 nM, about 100 pM to about 950 pM, about 100 pM to about 900 pM, about 100 pM to about 850 pM, about 100 pM to about 800 pM, about 100 pM to about 750 pM, about 100 pM to about 700 pM, about 100 pM to about 650 pM, about 100 pM to about 600 pM, about 100 pM to about 550 pM, about 100 pM to about 500 pM, about 100 pM to about 450 pM, about 100 pM to about 400 pM, about 100 pM to about 350 pM, about 100 pM to about 300 pM, about 100 pM to about 250 pM, about 100 pM to about 200 pM, about 100 pM to about 150 pM, about 150 pM to about 250 nM, about 150 pM to about 240 nM, about 150 pM to about 230 nM, about 150 pM to about 220 nM, about 150 pM to about 210 nM, about 150 pM to about 200 nM, about 150 pM to about 190 nM, about 150 pM to about 180 nM, about 150 pM to about 170 nM, about 150 pM to about 160 nM, about 150 pM to about 150 nM, about 150 pM to about 140 nM, about 150 pM to about 130 nM, about 150 pM to about 120 nM, about 150 pM to about 110 nM, about 150 pM to about 100 nM, about 150 pM to about 95 nM, about 150 pM to about 90 nM, about 150 pM to about 85 nM, about 150 pM to about 80 nM, about 150 pM to about 75 nM, about 150 pM to about 70 nM, about 150 pM to about 65 nM, about 150 pM to about 60 nM, about 150 pM to about 55 nM, about 150 pM to about 50 nM, about 150 pM to about 45 nM, about 150 pM to about 40 nM, about 150 pM to about 35 nM, about 150 pM to about 30 nM, about 150 pM to about 25 nM, about 150 pM to about 30 nM, about 150 pM to about 15 nM, about 150 pM to about 10 nM, about 150 pM to about 5 nM, about 150 pM to about 2 nM, about 150 pM to about 1 nM, about 150 pM to about 950 pM, about 150 pM to about 900 pM, about 150 pM to about 850 pM, about 150 pM to about 800 pM, about 150 pM to about 750 pM, about 150 pM to about 700 pM, about 150 pM to about 650 pM, about 150 pM to about 600 pM, about 150 pM to about 550 pM, about 150 pM to about 500 pM, about 150 pM to about 450 pM, about 150 pM to about 400 pM, about 150 pM to about 350 pM, about 150 pM to about 300 pM, about 150 pM to about 250 pM, about 150 pM to about 200 pM_; about 200 pM to about 250 nM, about 200 pM to about 240 nM, about 200 pM to about 230 nM, about 200 pM to about 220 nM, about 200 pM to about 210 nM, about 200 pM to about 200 nM, about 200 pM to about 190 nM, about 200 pM to about 180 nM, about 200 pM to about 170 nM, about 200 pM to about 160 nM, about 200 pM to about 150 nM, about 200 pM to about 140 nM, about 200 pM to about 130 nM, about 200 pM to about 120 nM, about 200 pM to about 110 nM, about 200 pM to about 100 nM, about 200 pM to about 95 nM, about 200 pM to about 90 nM, about 200 pM to about 85 nM, about 200 pM to about 80 nM, about 200 pM to about 75 nM, about 200 pM to about 70 nM, about 200 pM to about 65 nM, about 200 pM to about 60 nM, about 200 pM to about 55 nM, about 200 pM to about 50 nM, about 200 pM to about 45 nM, about 200 pM to about 40 nM, about 200 pM to about 35 nM, about 200 pM to about 30 nM, about 200 pM to about 25 nM, about 200 pM to about 30 nM, about 200 pM to about 15 nM, about 200 pM to about 10 nM, about 200 pM to about 5 nM, about 200 pM to about 2 nM, about 200 pM to about 1 nM, about 200 pM to about 950 pM, about 200 pM to about 900 pM, about 200 pM to about 850 pM, about 200 pM to about 800 pM, about 200 pM to about 750 pM, about 200 pM to about 700 pM, about 200 pM to about 650 pM, about 200 pM to about 600 pM, about 200 pM to about 550 pM, about 200 pM to about 500 pM, about 200 pM to about 450 pM, about 200 pM to about 400 pM, about 200 pM to about 350 pM, about 200 pM to about 300 pM, about 200 pM to about 250 pM, about 300 pM to about 30 nM, about 300 pM to about 25 nM, about 300 pM to about 250 nM, about 300 pM to about 240 nM, about 300 pM to about 230 nM, about 300 pM to about 220 nM, about 300 pM to about 210 nM, about 300 pM to about 200 nM, about 300 pM to about 190 nM, about 300 pM to about 180 nM, about 300 pM to about 170 nM, about 300 pM to about 160 nM, about 300 pM to about 150 nM, about 300 pM to about 140 nM, about 300 pM to about 130 nM, about 300 pM to about 120 nM, about 300 pM to about 110 nM, about 300 pM to about 100 nM, about 300 pM to about 95 nM, about 300 pM to about 90 nM, about 300 pM to about 85 nM, about 300 pM to about 80 nM, about 300 pM to about 75 nM, about 300 pM to about 70 nM, about 300 pM to about 65 nM, about 300 pM to about 60 nM, about 300 pM to about 55 nM, about 300 pM to about 50 nM, about 300 pM to about 45 nM, about 300 pM to about 40 nM, about 300 pM to about 35 nM, about 300 pM to about 30 nM, about 300 pM to about 15 nM, about 300 pM to about 10 nM, about 300 pM to about 5 nM, about 300 pM to about 2 nM, about 300 pM to about 1 nM, about 300 pM to about 950 pM, about 300 pM to about 900 pM, about 300 pM to about 850 pM, about 300 pM to about 800 pM, about 300 pM to about 750 pM, about 300 pM to about 700 pM, about 300 pM to about 650 pM, about 300 pM to about 600 pM, about 300 pM to about 550 pM, about 300 pM to about 500 pM, about 300 pM to about 450 pM, about 300 pM to about 400 pM, about 300 pM to about 350 pM, about 400 pM to about 250 nM, about 400 pM to about 240 nM, about 400 pM to about 230 nM, about 400 pM to about 220 nM, about 400 pM to about 210 nM, about 400 pM to about 200 nM, about 400 pM to about 190 nM, about 400 pM to about 180 nM, about 400 pM to about 170 nM, about 400 pM to about 160 nM, about 400 pM to about 150 nM, about 400 pM to about 140 nM, about 400 pM to about 130 nM, about 400 pM to about 120 nM, about 400 pM to about 110 nM, about 400 pM to about 100 nM, about 400 pM to about 95 nM, about 400 pM to about 90 nM, about 400 pM to about 85 nM, about 400 pM to about 80 nM, about 400 pM to about 75 nM, about 400 pM to about 70 nM, about 400 pM to about 65 nM, about 400 pM to about 60 nM, about 400 pM to about 55 nM, about 400 pM to about 50 nM, about 400 pM to about 45 nM, about 400 pM to about 40 nM, about 400 pM to about 35 nM, about 400 pM to about 30 nM, about 400 pM to about 25 nM, about 400 pM to about 20 nM, about 400 pM to about 15 nM, about 400 pM to about 10 nM, about 400 pM to about 5 nM, about 400 pM to about 2 nM, about 400 pM to about 1 nM, about 400 pM to about 950 pM, about 400 pM to about 900 pM, about 400 pM to about 850 pM, about 400 pM to about 800 pM, about 400 pM to about 750 pM, about 400 pM to about 700 pM, about 400 pM to about 650 pM, about 400 pM to about 600 pM, about 400 pM to about 550 pM, about 400 pM to about 500 pM, about 500 pM to about 250 nM, about 500 pM to about 240 nM, about 500 pM to about 230 nM, about 500 pM to about 220 nM, about 500 pM to about 210 nM, about 500 pM to about 200 nM, about 500 pM to about 190 nM, about 500 pM to about 180 nM, about 500 pM to about 170 nM, about 500 pM to about 160 nM, about 500 pM to about 150 nM, about 500 pM to about 140 nM, about 500 pM to about 130 nM, about 500 pM to about 120 nM, about 500 pM to about 110 nM, about 500 pM to about 100 nM, about 500 pM to about 95 nM, about 500 pM to about 90 nM, about 500 pM to about 85 nM, about 500 pM to about 80 nM, about 500 pM to about 75 nM, about 500 pM to about 70 nM, about 500 pM to about 65 nM, about 500 pM to about 60 nM, about 500 pM to about 55 nM, about 500 pM to about 50 nM, about 500 pM to about 45 nM, about 500 pM to about 40 nM, about 500 pM to about 35 nM, about 500 pM to about 30 nM, about 500 pM to about 25 nM, about 500 pM to about 20 nM, about 500 pM to about 15 nM, about 500 pM to about 10 nM, about 500 pM to about 5 nM, about 500 pM to about 2 nM, about 500 pM to about 1 nM, about 500 pM to about 950 pM, about 500 pM to about 900 pM, about 500 pM to about 850 pM, about 500 pM to about 800 pM, about 500 pM to about 750 pM, about 500 pM to about 700 pM, about 500 pM to about 650 pM_; about 500 pM to about 600 pM, about 500 pM to about 550 pM, about 600 pM to about 250 nM, about 600 pM to about 240 nM, about 600 pM to about 230 nM, about 600 pM to about 220 nM, about 600 pM to about 210 nM, about 600 pM to about 200 nM, about 600 pM to about 190 nM, about 600 pM to about 180 nM, about 600 pM to about 170 nM, about 600 pM to about 160 nM, about 600 pM to about 150 nM, about 600 pM to about 140 nM, about 600 pM to about 130 nM, about 600 pM to about 120 nM, about 600 pM to about 110 nM, about 600 pM to about 100 nM, about 600 pM to about 95 nM, about 600 pM to about 90 nM, about 600 pM to about 85 nM, about 600 pM to about 80 nM, about 600 pM to about 75 nM, about 600 pM to about 70 nM, about 600 pM to about 65 nM, about 600 pM to about 60 nM, about 600 pM to about 55 nM, about 600 pM to about 50 nM, about 600 pM to about 45 nM, about 600 pM to about 40 nM, about 600 pM to about 35 nM, about 600 pM to about 30 nM, about 600 pM to about 25 nM, about 600 pM to about 20 nM, about 600 pM to about 15 nM, about 600 pM to about 10 nM, about 600 pM to about 5 nM, about 600 pM to about 2 nM, about 600 pM to about 1 nM, about 600 pM to about 950 pM, about 600 pM to about 900 pM, about 600 pM to about 850 pM, about 600 pM to about 800 pM, about 600 pM to about 750 pM, about 600 pM to about 700 pM, about 600 pM to about 650 pM, about 700 pM to about 250 nM, about 700 pM to about 240 nM, about 700 pM to about 230 nM, about 700 pM to about 220 nM, about 700 pM to about 210 nM, about 700 pM to about 200 nM, about 700 pM to about 190 nM, about 700 pM to about 180 nM, about 700 pM to about 170 nM, about 700 pM to about 160 nM, about 700 pM to about 150 nM, about 700 pM to about 140 nM, about 700 pM to about 130 nM, about 700 pM to about 120 nM, about 700 pM to about 110 nM, about 700 pM to about 100 nM, about 700 pM to about 95 nM, about 700 pM to about 90 nM, about 700 pM to about 85 nM, about 700 pM to about 80 nM, about 700 pM to about 75 nM, about 700 pM to about 70 nM, about 700 pM to about 65 nM, about 700 pM to about 60 nM, about 700 pM to about 55 nM, about 700 pM to about 50 nM, about 700 pM to about 45 nM, about 700 pM to about 40 nM, about 700 pM to about 35 nM, about 700 pM to about 30 nM, about 700 pM to about 25 nM, about 700 pM to about 20 nM, about 700 pM to about 15 nM, about 700 pM to about 10 nM, about 700 pM to about 5 nM, about 700 pM to about 2 nM, about 700 pM to about 1 nM, about 700 pM to about 950 pM, about 700 pM to about 900 pM, about 700 pM to about 850 pM, about 700 pM to about 800 pM, about 700 pM to about 750 pM, about 800 pM to about 250 nM, about 800 pM to about 240 nM, about 800 pM to about 230 nM, about 800 pM to about 220 nM, about 800 pM to about 210 nM, about 800 pM to about 200 nM, about 800 pM to about 190 nM, about 800 pM to about 180 nM, about 800 pM to about 170 nM, about 800 pM to about 160 nM, about 800 pM to about 150 nM, about 800 pM to about 140 nM, about 800 pM to about 130 nM, about 800 pM to about 120 nM, about 800 pM to about 110 nM, about 800 pM to about 100 nM, about 800 pM to about 95 nM, about 800 pM to about 90 nM, about 800 pM to about 85 nM, about 800 pM to about 80 nM, about 800 pM to about 75 nM, about 800 pM to about 70 nM, about 800 pM to about 65 nM, about 800 pM to about 60 nM, about 800 pM to about 55 nM, about 800 pM to about 50 nM, about 800 pM to about 45 nM, about 800 pM to about 40 nM, about 800 pM to about 35 nM, about 800 pM to about 30 nM, about 800 pM to about 25 nM, about 800 pM to about 20 nM, about 800 pM to about 15 nM, about 800 pM to about 10 nM, about 800 pM to about 5 nM, about 800 pM to about 2 nM, about 800 pM to about 1 nM, about 800 pM to about 950 pM, about 800 pM to about 900 pM, about 800 pM to about 850 pM, about 900 pM to about 250 nM, about 900 pM to about 240 nM, about 900 pM to about 230 nM, about 900 pM to about 220 nM, about 900 pM to about 210 nM, about 900 pM to about 200 nM, about 900 pM to about 190 nM, about 900 pM to about 180 nM, about 900 pM to about 170 nM, about 900 pM to about 160 nM, about 900 pM to about 150 nM, about 900 pM to about 140 nM, about 900 pM to about 130 nM, about 900 pM to about 120 nM, about 900 pM to about 110 nM, about 900 pM to about 100 nM, about 900 pM to about 95 nM, about 900 pM to about 90 nM, about 900 pM to about 85 nM, about 900 pM to about 80 nM, about 900 pM to about 75 nM, about 900 pM to about 70 nM, about 900 pM to about 65 nM, about 900 pM to about 60 nM, about 900 pM to about 55 nM, about 900 pM to about 50 nM, about 900 pM to about 45 nM, about 900 pM to about 40 nM, about 900 pM to about 35 nM, about 900 pM to about 30 nM, about 900 pM to about 25 nM, about 900 pM to about 20 nM, about 900 pM to about 15 nM, about 900 pM to about 10 nM, about 900 pM to about 5 nM, about 900 pM to about 2 nM, about 900 pM to about 1 nM, about 900 pM to about 950 pM, about 1 nM to about 250 nM, about 1 nM to about 240 nM, about 1 nM to about 230 nM, about 1 nM to about 220 nM, about 1 nM to about 210 nM, about 1 nM to about 200 nM, about 1 nM to about 190 nM, about 1 nM to about 180 nM, about 1 nM to about 170 nM, about 1 nM to about 160 nM, about 1 nM to about 150 nM, about 1 nM to about 140 nM, about 1 nM to about 130 nM, about 1 nM to about 120 nM, about 1 nM to about 110 nM, about 1 nM to about 100 nM, about 1 nM to about 95 nM, about 1 nM to about 90 nM, about 1 nM to about 85 nM, about 1 nM to about 80 nM, about 1 nM to about 75 nM, about 1 nM to about 70 nM, about 1 nM to about 65 nM, about 1 nM to about 60 nM, about 1 nM to about 55 nM, about 1 nM to about 50 nM, about 1 nM to about 45 nM, about 1 nM to about 40 nM, about 1 nM to about 35 nM, about 1 nM to about 30 nM, about 1 nM to about 25 nM, about 1 nM to about 20 nM, about 1 nM to about 15 nM, about 1 nM to about 10 nM, about 1 nM to about 5 nM, about 2 nM to about 250 nM, about 2 nM to about 240 nM, about 2 nM to about 230 nM, about 2 nM to about 220 nM, about 2 nM to about 210 nM, about 2 nM to about 200 nM, about 2 nM to about 190 nM, about 2 nM to about 180 nM, about 2 nM to about 170 nM, about 2 nM to about 160 nM, about 2 nM to about 150 nM, about 2 nM to about 140 nM, about 2 nM to about 130 nM, about 2 nM to about 120 nM, about 2 nM to about 110 nM, about 2 nM to about 100 nM, about 2 nM to about 95 nM, about 2 nM to about 90 nM, about 2 nM to about 85 nM, about 2 nM to about 80 nM, about 2 nM to about 75 nM, about 2 nM to about 70 nM, about 2 nM to about 65 nM, about 2 nM to about 60 nM, about 2 nM to about 55 nM, about 2 nM to about 50 nM, about 2 nM to about 45 nM, about 2 nM to about 40 nM, about 2 nM to about 35 nM, about 2 nM to about 30 nM, about 2 nM to about 25 nM, about 2 nM to about 20 nM, about 2 nM to about 15 nM, about 2 nM to about 10 nM, about 2 nM to about 5 nM, about 4 nM to about 250 nM, about 4 nM to about 240 nM, about 4 nM to about 230 nM, about 4 nM to about 220 nM, about 4 nM to about 210 nM, about 4 nM to about 200 nM, about 4 nM to about 190 nM, about 4 nM to about 180 nM, about 4 nM to about 170 nM, about 4 nM to about 160 nM, about 4 nM to about 150 nM, about 4 nM to about 140 nM, about 4 nM to about 130 nM, about 4 nM to about 120 nM, about 4 nM to about 110 nM, about 4 nM to about 100 nM, about 4 nM to about 95 nM, about 4 nM to about 90 nM, about 4 nM to about 85 nM, about 4 nM to about 80 nM, about 4 nM to about 75 nM, about 4 nM to about 70 nM, about 4 nM to about 65 nM, about 4 nM to about 60 nM, about 4 nM to about 55 nM, about 4 nM to about 50 nM, about 4 nM to about 45 nM, about 4 nM to about 40 nM, about 4 nM to about 35 nM, about 4 nM to about 30 nM, about 4 nM to about 25 nM, about 4 nM to about 20 nM, about 4 nM to about 15 nM, about 4 nM to about 10 nM, about 4 nM to about 5 nM, about 5 nM to about 250 nM, about 5 nM to about 240 nM, about 5 nM to about 230 nM, about 5 nM to about 220 nM, about 5 nM to about 210 nM, about 5 nM to about 200 nM, about 5 nM to about 190 nM, about 5 nM to about 180 nM, about 5 nM to about 170 nM, about 5 nM to about 160 nM, about 5 nM to about 150 nM, about 5 nM to about 140 nM, about 5 nM to about 130 nM, about 5 nM to about 120 nM, about 5 nM to about 110 nM, about 5 nM to about 100 nM, about 5 nM to about 95 nM, about 5 nM to about 90 nM, about 5 nM to about 85 nM, about 5 nM to about 80 nM, about 5 nM to about 75 nM, about 5 nM to about 70 nM, about 5 nM to about 65 nM, about 5 nM to about 60 nM, about 5 nM to about 55 nM, about 5 nM to about 50 nM, about 5 nM to about 45 nM, about 5 nM to about 40 nM, about 5 nM to about 35 nM, about 5 nM to about 30 nM, about 5 nM to about 25 nM, about 5 nM to about 20 nM, about 5 nM to about 15 nM, about 5 nM to about 10 nM, about 10 nM to about 250 nM, about 10 nM to about 240 nM, about 10 nM to about 230 nM, about 10 nM to about 220 nM, about 10 nM to about 210 nM, about 10 nM to about 200 nM, about 10 nM to about 190 nM, about 10 nM to about 180 nM, about 10 nM to about 170 nM, about 10 nM to about 160 nM, about 10 nM to about 150 nM, about 10 nM to about 140 nM, about 10 nM to about 130 nM, about 10 nM to about 120 nM, about 10 nM to about 110 nM, about 10 nM to about 100 nM, about 10 nM to about 95 nM, about 10 nM to about 90 nM, about 10 nM to about 85 nM, about 10 nM to about 80 nM, about 10 nM to about 75 nM, about 10 nM to about 70 nM, about 10 nM to about 65 nM, about 10 nM to about 60 nM, about 10 nM to about 55 nM, about 10 nM to about 50 nM, about 10 nM to about 45 nM, about 10 nM to about 40 nM, about 10 nM to about 35 nM, about 10 nM to about 30 nM, about 10 nM to about 25 nM, about 10 nM to about 20 nM, about 10 nM to about 1 nM, about 15 nM to about 250 nM, about 15 nM to about 240 nM, about 15 nM to about 230 nM, about 15 nM to about 220 nM, about 15 nM to about 210 nM, about 15 nM to about 200 nM, about 15 nM to about 190 nM, about 15 nM to about 180 nM, about 15 nM to about 170 nM, about 15 nM to about 160 nM, about 15 nM to about 150 nM, about 15 nM to about 140 nM, about 15 nM to about 130 nM, about 15 nM to about 120 nM, about 15 nM to about 110 nM, about 15 nM to about 100 nM, about 15 nM to about 95 nM, about 15 nM to about 90 nM, about 15 nM to about 85 nM, about 15 nM to about 80 nM, about 15 nM to about 75 nM, about 15 nM to about 70 nM, about 15 nM to about 65 nM, about 15 nM to about 60 nM, about 15 nM to about 55 nM, about 15 nM to about 50 nM, about 15 nM to about 45 nM, about 15 nM to about 40 nM, about 15 nM to about 35 nM, about 15 nM to about 30 nM, about 15 nM to about 25 nM, about 15 nM to about 20 nM, about 20 nM to about 250 nM, about 20 nM to about 240 nM, about 20 nM to about 230 nM, about 20 nM to about 220 nM, about 20 nM to about 210 nM, about 20 nM to about 200 nM, about 20 nM to about 190 nM, about 20 nM to about 180 nM, about 20 nM to about 170 nM, about 20 nM to about 160 nM, about 20 nM to about 150 nM, about 20 nM to about 140 nM, about 20 nM to about 130 nM, about 20 nM to about 120 nM, about 20 nM to about 110 nM, about 20 nM to about 100 nM, about 20 nM to about 95 nM, about 20 nM to about 90 nM, about 20 nM to about 85 nM, about 20 nM to about 80 nM, about 20 nM to about 75 nM, about 20 nM to about 70 nM, about 20 nM to about 65 nM, about 20 nM to about 60 nM, about 20 nM to about 55 nM, about 20 nM to about 50 nM, about 20 nM to about 45 nM, about 20 nM to about 40 nM, about 20 nM to about 35 nM, about 20 nM to about 30 nM, about 20 nM to about 25 nM, about 25 nM to about 250 nM, about 25 nM to about 240 nM, about 25 nM to about 230 nM, about 25 nM to about 220 nM, about 25 nM to about 210 nM, about 25 nM to about 200 nM, about 25 nM to about 190 nM, about 25 nM to about 180 nM, about 25 nM to about 170 nM, about 25 nM to about 160 nM, about 25 nM to about 150 nM, about 25 nM to about 140 nM, about 25 nM to about 130 nM, about 25 nM to about 120 nM, about 25 nM to about 110 nM, about 25 nM to about 100 nM, about 25 nM to about 95 nM, about 25 nM to about 90 nM, about 25 nM to about 85 nM, about 25 nM to about 80 nM, about 25 nM to about 75 nM, about 25 nM to about 70 nM, about 25 nM to about 65 nM, about 25 nM to about 60 nM, about 25 nM to about 55 nM, about 25 nM to about 50 nM, about 25 nM to about 45 nM, about 25 nM to about 40 nM, about 25 nM to about 35 nM, about 25 nM to about 30 nM, about 25 nM to about 250 nM, about 25 nM to about 240 nM, about 25 nM to about 230 nM, about 25 nM to about 220 nM, about 25 nM to about 210 nM, about 25 nM to about 200 nM, about 25 nM to about 190 nM, about 25 nM to about 180 nM, about 25 nM to about 170 nM, about 25 nM to about 160 nM, about 25 nM to about 150 nM, about 25 nM to about 140 nM, about 25 nM to about 130 nM, about 25 nM to about 120 nM, about 25 nM to about 110 nM, about 25 nM to about 100 nM, about 25 nM to about 95 nM, about 25 nM to about 90 nM, about 25 nM to about 85 nM, about 25 nM to about 80 nM, about 25 nM to about 75 nM, about 25 nM to about 70 nM, about 25 nM to about 65 nM, about 25 nM to about 60 nM, about 25 nM to about 55 nM, about 25 nM to about 50 nM, about 25 nM to about 45 nM, about 25 nM to about 40 nM, about 25 nM to about 35 nM, about 30 nM to about 250 nM, about 30 nM to about 240 nM, about 30 nM to about 230 nM, about 30 nM to about 220 nM, about 30 nM to about 210 nM, about 30 nM to about 200 nM, about 30 nM to about 190 nM, about 30 nM to about 180 nM, about 30 nM to about 170 nM, about 30 nM to about 160 nM, about 30 nM to about 150 nM, about 30 nM to about 140 nM, about 30 nM to about 130 nM, about 30 nM to about 120 nM, about 30 nM to about 110 nM, about 30 nM to about 100 nM, about 30 nM to about 95 nM, about 30 nM to about 90 nM, about 30 nM to about 85 nM, about 30 nM to about 80 nM, about 30 nM to about 75 nM, about 30 nM to about 70 nM, about 30 nM to about 65 nM, about 30 nM to about 60 nM, about 30 nM to about 55 nM, about 30 nM to about 50 nM, about 30 nM to about 45 nM, about 30 nM to about 40 nM, about 30 nM to about 35 nM, about 30 nM to about 250 nM, about 30 nM to about 240 nM, about 30 nM to about 230 nM, about 30 nM to about 220 nM, about 30 nM to about 210 nM, about 30 nM to about 200 nM, about 30 nM to about 190 nM, about 30 nM to about 180 nM, about 30 nM to about 170 nM, about 30 nM to about 160 nM, about 30 nM to about 150 nM, about 30 nM to about 140 nM, about 30 nM to about 130 nM, about 30 nM to about 120 nM, about 30 nM to about 110 nM, about 30 nM to about 100 nM, about 30 nM to about 95 nM, about 30 nM to about 90 nM, about 30 nM to about 85 nM, about 30 nM to about 80 nM, about 30 nM to about 75 nM, about 30 nM to about 70 nM, about 30 nM to about 65 nM, about 30 nM to about 60 nM, about 30 nM to about 55 nM, about 30 nM to about 50 nM, about 30 nM to about 45 nM, about 30 nM to about 40 nM, about 30 nM to about 35 nM, about 40 nM to about 250 nM, about 40 nM to about 240 nM, about 40 nM to about 230 nM, about 40 nM to about 220 nM, about 40 nM to about 210 nM, about 40 nM to about 200 nM, about 40 nM to about 190 nM, about 40 nM to about 180 nM, about 40 nM to about 170 nM, about 40 nM to about 160 nM, about 40 nM to about 150 nM, about 40 nM to about 140 nM, about 40 nM to about 130 nM, about 40 nM to about 120 nM, about 40 nM to about 110 nM, about 40 nM to about 100 nM, about 40 nM to about 95 nM, about 40 nM to about 90 nM, about 40 nM to about 85 nM, about 40 nM to about 80 nM, about 40 nM to about 75 nM, about 40 nM to about 70 nM, about 40 nM to about 65 nM, about 40 nM to about 60 nM, about 40 nM to about 55 nM, about 40 nM to about 50 nM, about 40 nM to about 45 nM, about 50 nM to about 250 nM, about 50 nM to about 240 nM, about 50 nM to about 230 nM, about 50 nM to about 220 nM, about 50 nM to about 210 nM, about 50 nM to about 200 nM, about 50 nM to about 190 nM, about 50 nM to about 180 nM, about 50 nM to about 170 nM, about 50 nM to about 160 nM, about 50 nM to about 150 nM, about 50 nM to about 140 nM, about 50 nM to about 130 nM, about 50 nM to about 120 nM, about 50 nM to about 110 nM, about 50 nM to about 100 nM, about 50 nM to about 95 nM, about 50 nM to about 90 nM, about 50 nM to about 85 nM, about 50 nM to about 80 nM, about 50 nM to about 75 nM, about 50 nM to about 70 nM, about 50 nM to about 65 nM, about 50 nM to about 60 nM, about 50 nM to about 55 nM, about 60 nM to about 250 nM, about 60 nM to about 240 nM, about 60 nM to about 230 nM, about 60 nM to about 220 nM, about 60 nM to about 210 nM, about 60 nM to about 200 nM, about 60 nM to about 190 nM, about 60 nM to about 180 nM, about 60 nM to about 170 nM, about 60 nM to about 160 nM, about 60 nM to about 150 nM, about 60 nM to about 140 nM, about 60 nM to about 130 nM, about 60 nM to about 120 nM, about 60 nM to about 110 nM, about 60 nM to about 100 nM, about 60 nM to about 95 nM, about 60 nM to about 90 nM, about 60 nM to about 85 nM, about 60 nM to about 80 nM, about 60 nM to about 75 nM, about 60 nM to about 70 nM, about 60 nM to about 65 nM, about 70 nM to about 250 nM, about 70 nM to about 240 nM, about 70 nM to about 230 nM, about 70 nM to about 220 nM, about 70 nM to about 210 nM, about 70 nM to about 200 nM, about 70 nM to about 190 nM, about 70 nM to about 180 nM, about 70 nM to about 170 nM, about 70 nM to about 160 nM, about 70 nM to about 150 nM, about 70 nM to about 140 nM, about 70 nM to about 130 nM, about 70 nM to about 120 nM, about 70 nM to about 110 nM, about 70 nM to about 100 nM, about 70 nM to about 95 nM, about 70 nM to about 90 nM, about 70 nM to about 85 nM, about 70 nM to about 80 nM, about 70 nM to about 75 nM, about 80 nM to about 250 nM, about 80 nM to about 240 nM, about 80 nM to about 230 nM, about 80 nM to about 220 nM, about 80 nM to about 210 nM, about 80 nM to about 200 nM, about 80 nM to about 190 nM, about 80 nM to about 180 nM, about 80 nM to about 170 nM, about 80 nM to about 160 nM, about 80 nM to about 150 nM, about 80 nM to about 140 nM, about 80 nM to about 130 nM, about 80 nM to about 120 nM, about 80 nM to about 110 nM, about 80 nM to about 100 nM, about 80 nM to about 95 nM, about 80 nM to about 90 nM, about 80 nM to about 85 nM, about 90 nM to about 250 nM, about 90 nM to about 240 nM, about 90 nM to about 230 nM, about 90 nM to about 220 nM, about 90 nM to about 210 nM, about 90 nM to about 200 nM, about 90 nM to about 190 nM, about 90 nM to about 180 nM, about 90 nM to about 170 nM, about 90 nM to about 160 nM, about 90 nM to about 150 nM, about 90 nM to about 140 nM, about 90 nM to about 130 nM, about 90 nM to about 120 nM, about 90 nM to about 110 nM, about 90 nM to about 100 nM, about 90 nM to about 95 nM, about 100 nM to about 250 nM, about 100 nM to about 240 nM, about 100 nM to about 230 nM, about 100 nM to about 220 nM, about 100 nM to about 210 nM, about 100 nM to about 200 nM, about 100 nM to about 190 nM, about 100 nM to about 180 nM, about 100 nM to about 170 nM, about 100 nM to about 160 nM, about 100 nM to about 150 nM, about 100 nM to about 140 nM, about 100 nM to about 130 nM, about 100 nM to about 120 nM, about 100 nM to about 110 nM, about 110 nM to about 250 nM, about 110 nM to about 240 nM, about 110 nM to about 230 nM, about 110 nM to about 220 nM, about 110 nM to about 210 nM, about 110 nM to about 200 nM, about 110 nM to about 190 nM, about 110 nM to about 180 nM, about 110 nM to about 170 nM, about 110 nM to about 160 nM, about 110 nM to about 150 nM, about 110 nM to about 140 nM, about 110 nM to about 130 nM, about 110 nM to about 120 nM, about 120 nM to about 250 nM, about 120 nM to about 240 nM, about 120 nM to about 230 nM, about 120 nM to about 220 nM, about 120 nM to about 210 nM, about 120 nM to about 200 nM, about 120 nM to about 190 nM, about 120 nM to about 180 nM, about 120 nM to about 170 nM, about 120 nM to about 160 nM, about 120 nM to about 150 nM, about 120 nM to about 140 nM, about 120 nM to about 130 nM, about 130 nM to about 250 nM, about 130 nM to about 240 nM, about 130 nM to about 230 nM, about 130 nM to about 220 nM, about 130 nM to about 210 nM, about 130 nM to about 200 nM, about 130 nM to about 190 nM, about 130 nM to about 180 nM, about 130 nM to about 170 nM, about 130 nM to about 160 nM, about 130 nM to about 150 nM, about 130 nM to about 140 nM, about 140 nM to about 250 nM, about 140 nM to about 240 nM, about 140 nM to about 230 nM, about 140 nM to about 220 nM, about 140 nM to about 210 nM, about 140 nM to about 200 nM, about 140 nM to about 190 nM, about 140 nM to about 180 nM, about 140 nM to about 170 nM, about 140 nM to about 160 nM, about 140 nM to about 150 nM, about 150 nM to about 250 nM, about 150 nM to about 240 nM, about 150 nM to about 230 nM, about 150 nM to about 220 nM, about 150 nM to about 210 nM, about 150 nM to about 200 nM, about 150 nM to about 190 nM, about 150 nM to about 180 nM, about 150 nM to about 170 nM, about 150 nM to about 160 nM, about 160 nM to about 250 nM, about 160 nM to about 240 nM, about 160 nM to about 230 nM, about 160 nM to about 220 nM, about 160 nM to about 210 nM, about 160 nM to about 200 nM, about 160 nM to about 190 nM, about 160 nM to about 180 nM, about 160 nM to about 170 nM, about 170 nM to about 250 nM, about 170 nM to about 240 nM, about 170 nM to about 230 nM, about 170 nM to about 220 nM, about 170 nM to about 210 nM, about 170 nM to about 200 nM, about 170 nM to about 190 nM, about 170 nM to about 180 nM, about 180 nM to about 250 nM, about 180 nM to about 240 nM, about 180 nM to about 230 nM, about 180 nM to about 220 nM, about 180 nM to about 210 nM, about 180 nM to about 200 nM, about 180 nM to about 190 nM, about 190 nM to about 250 nM, about 190 nM to about 240 nM, about 190 nM to about 230 nM, about 190 nM to about 220 nM, about 190 nM to about 210 nM, about 190 nM to about 200 nM, about 200 nM to about 250 nM, about 200 nM to about 240 nM, about 200 nM to about 230 nM, about 200 nM to about 220 nM, about 200 nM to about 210 nM, about 210 nM to about 250 nM, about 210 nM to about 240 nM, about 210 nM to about 230 nM, about 210 nM to about 220 nM, about 220 nM to about 250 nM, about 220 nM to about 240 nM, about 220 nM to about 230 nM, about 230 nM to about 250 nM, about 230 nM to about 240 nM, or about 240 nM to about 250 nM). In some embodiments of any of the antigen-binding protein constructs described herein, the additional antigen-binding domain has a KD for the antigen that is increased at an acidic pH (e.g., any of the acidic pHs described herein) as compared to the KD of the additional antigen-binding domain for the antigen at a neutral pH (e.g., any of the neutral pHs described herein). In some embodiments of any of the antigen-binding protein constructs described herein, the additional antigen-binding domain has a KD for the antigen at an acidic pH (e.g., any of the acidic pHs described herein) that is at least 10% increased (e.g., at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%) as compared to the KD of the additional antigen-binding domain at a neutral pH (e.g., any of the neutral pHs described herein).

In some embodiments of any of the antigen-binding protein constructs described herein, the additional antigen-binding domain has a KD for the antigen at an acidic pH (e.g., any of the acidic pHs described herein) that is at least 1-fold greater (e.g., at least 1.5-fold, at least 2-fold, at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, at least 5.5-fold, at least 6-fold, at least 6.5-fold, at least 7-fold, at least 7.5- fold, at least 8-fold, at least 8.5-fold, at least 9-fold, at least 9.5-fold, at least 10-fold, at least 10.5-fold, at least 11-fold, at least 11.5-fold, at least 12-fold, at least 12.5-fold, at least 13- fold, at least 13.5-fold, at least 14-fold, at least 14.5-fold, at least 15-fold, at least 15.5-fold, at least 16-fold, at least 16.5-fold, at least 17-fold, at least 17.5-fold, at least 18-fold, at least 18.5-fold, at least 19-fold, at least 19.5-fold, or at least 20-fold) than the KD of the additional antigen-binding domain at a neutral pH (e.g., any of the neutral pHs described herein).

In some embodiments of any of the antigen-binding protein constructs described herein, the dissociation rate of the additional antigen-binding domain for the antigen at an acidic pH (e.g., any of the acidic pHs described herein) is at least 10% (e.g., at least 15% , at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%) increased as compared to the dissociation rate of the additional antigen-binding domain for the antigen at a neutral pH (e.g., any of the neutral pHs described herein).

In some embodiments of any of the antigen-binding protein constructs described herein, the dissociation rate of the additional antigen-binding domain for the antigen at an acidic pH (e.g., any of the acidic pHs described herein) is at least 2-fold (e.g., at least 2.5- fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, at least 5.5-fold, at least 6-fold, at least 6.5-fold, at least 7-fold, at least 7.5-fold, at least 8-fold, at least 8.5-fold, at least 9-fold, at least 9.5-fold, at least 10-fold, at least 10.5-fold, at least 11.0- fold, at least 11.5-fold, at least 12.0-fold, at least 12.5-fold, at least 13.0-fold, at least 13.5- fold, at least 14.0-fold, at least 14.5-fold, or at least 15.0-fold) increased as compared to the dissociation rate of the additional antigen-binding domain for the antigen at a neutral pH (e.g., any of the neutral pHs described herein).

Exemplary Aspects of Multi-Specific Antigen-Binding Protein Constructs

Provided herein are multi-specific antigen-binding protein constructs (multi-ABPCs) comprising: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, where: the first antigen-binding domain is capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell; and the second antigen-binding domain is capable of specifically binding to an epitope of a polypeptide complex, wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ιη) polypeptide, where: (a) the dissociation rate of the second antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or (b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH is less than the KD at a neutral pH; and the second antigen-binding domain comprises at least one paratope that comprises at least one histidine residue.

Provided herein are multi-specific antigen-binding protein constructs (multi-specific ABPC) comprising: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, where: the first antigen-binding domain is capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell; and the second antigen-binding domain capable of specifically binding to an epitope of a polypeptide complex (PC), where the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2ι^η) poly peptide, where the multi-specific ABPC has increased endosomal recycling in a mammalian cell that presents the PC on its surface or in a cellular compartment as compared to a control ABPC.

Provided herein are multi-specific antigen-binding protein construct (ABPC) comprising: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, where: the first antigen-binding domain is capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell; and the second antigen-binding domain is capable of specifically binding an epitope of a beta 2-microglobulin (β2πι) polypeptide, where: (a) the dissociation rate of the second antigen- binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or (b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH is less than the KD at a neutral pH; and the second antigen-binding domain comprises at least one paratope that comprises at least one histidine residue.

Also provided herein are multi-specific antigen-binding protein construct (ABPC) comprising: (a) a first antigen-binding domain capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell; (b) a second antigen- binding domain capable of specifically binding to an epitope of a polypeptide complex (PC), where the polypeptide complex comprises (i) a polypeptide encoded by an HLA gene selected from HLA- A, HLA-B, and HLA-C, and (ii) a beta 2-microglobulin (β2ιη) polypeptide; and (c) a conjugated toxin, radioisotope, or drug, where the multi-specific ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC complex on its surface or in a cellular compartment as compared to a control ABPC. First Antigen-Binding Domains

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the identifying antigen is selected from the group consisting of: a protein, a carbohydrate, or a lipid, or a combination thereof. In some embodiments of any of the multi- specific antigen-binding protein constructs described herein, the identifying antigen is an antigen that is present on a surface of a cancer cell (e.g., EGFR) and the first target mammalian cell is the cancer cell, or the identifying antigen is another antigen that is present on the surface of a target mammalian cell.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the identifying antigen is selected from the group consisting of: trophoblast glycoprotein precursor (TPBG), guanylate cyclase 2C (GUCY2C), and lymphocyte antigen 6 family member E (LY6E).

The cDNA sequence and protein sequence of human EGFR is, e.g., provided in SEQ ID NO: 415 and SEQ ID NO: 416, respectively. The nucleic acid sequence and protein sequence of human TPBG is, e.g., provided in SEQ ID NO: 417 and SEQ ID NO: 418, respectively. The nucleic acid sequence and protein sequence of human GUCY2C is, e.g., provided in SEQ ID NO: 419 and SEQ ID NO: 420, respectively.

The nucleic acid sequence and protein sequence of human LY6E is, e.g., provided in

SEQ ID NO: 421 and SEQ ID NO: 422, respectively.

In some embodiments, any of the multi-specific antigen-binding protein constructs or control ABPCs described herein can bind to an identifying antigen at an acidic pH (e.g., any of the acidic pHs described herein) and/or at a neutral pH (e.g., any of the neutral pHs described herein) with a dissociation equilibrium constant (KD) of less than 1 x 10^"7 M, less than 1 x 10^"8 M, less than 1 x 10^"9 M, less than 1 x 10-¹⁰ M, less than 1 x 10^"11 M, less than 1 x 10^"12 M, or less than 1 x 10^"13 M. In some embodiments, any of the multi-specific antigen- binding protein constructs or control ABPCs described herein can bind to an identifying antigen with a KD of about 1 x 10^"3 M to about 1 x 10^"5 M, 1 x 10^"4 M to about 1 x 10^"6 M, about 1 x 10^"5 M to about 1 x 10^"7 M, about 1 x 10^"6 M to about 1 x 10^"8 M, about 1 x 10^"7 M to about 1 x lO^"9 M, about 1 x 10^"8 M to about 1 x lO ⁰ M, or about 1 x 10^"9 M to about 1 x 10^_11 M (inclusive).

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the KD of the first antigen-binding domain at a neutral pH (e.g., any of the neutral pHs described herein) and/or an acidic pH (e.g., any of the acidic pHs described herein) is between about 1 pM to about 250 nM (e.g., about 1 pM to about 245 nM, about 1 pM to about 240 nM, about 1 pM to about 235 nM, about 1 pM to about 230 nM, about 1 pM to about 225 nM, about 1 pM to about 220 nM, about 1 pM to about 215 nM, about 1 pM to about 210 nM, about 1 pM to about 205 nM, about 1 pM to about 200 nM, about 1 pM to about 195 nM, about 1 pM to about 190 nM, about 1 pM to about 185 nM, about 1 pM to about 180 nM, about 1 pM to about 175 nM, about 1 pM to about 170 nM, about 1 pM to about 165 nM, about 1 pM to about 160 nM, about 1 pM to about 155 nM, about 1 pM to about 150 nM, about 1 pM to about 145 nM, about 1 pM to about 140 nM, about 1 pM to about 135 nM, about 1 pM to about 130 nM, about 1 pM to about 125 nM, about 1 pM to about 120 nM, about 1 pM to about 115 nM, about 1 pM to about 110 nM, about 1 pM to about 105 nM, about 1 pM to about 100 nM, about 1 pM to about 95 nM, about 1 pM to about 90 nM, about 1 pM to about 85 nM, about 1 pM to about 80 nM, about 1 pM to about 75 nM, about 1 pM to about 70 nM, about 1 pM to about 65 nM, about 1 pM to about 60 nM, about 1 pM to about 55 nM, about 1 pM to about 50 nM, about 1 pM to about 45 nM, about 1 pM to about 40 nM, about 1 pM to about 35 nM, about 1 pM to about 30 nM, about 1 pM to about 25 nM, about 1 pM to about 20 nM, about 1 pM to about 15 nM, about 1 pM to about 10 nM, about 1 pM to about 5 nM, about 1 pM to about 2 nM, about 1 pM to about 1 nM, about 1 pM to about 950 pM, about 1 pM to about 900 pM, about 1 pM to about 850 pM, about 1 pM to about 800 pM, about 1 pM to about 750 pM, about 1 pM to about 700 pM, about 1 pM to about 650 pM, about 1 pM to about 600 pM, about 1 pM to about 550 pM, about 1 pM to about 500 pM, about 1 pM to about 450 pM, about 1 pM to about 400 pM, about 1 pM to about 350 pM, about 1 pM to about 300 pM, about 1 pM to about 250 pM, about 1 pM to about 200 pM, about 1 pM to about 150 pM, about 1 pM to about 100 pM, about 1 pM to about 90 pM, about 1 pM to about 80 pM, about 1 pM to about 70 pM, about 1 pM to about 60 pM, about 1 pM to about 50 pM, about 1 pM to about 40 pM, about 1 pM to about 30 pM, about 1 pM to about 20 pM, about 1 pM to about 10 pM, about 1 pM to about 5 pM, about 1 pM to about 4 pM, about 1 pM to about 3 pM, about 1 pM to about 2 pM, about 2 pM to about 250 nM, about 2 pM to about 245 nM, about 2 pM to about 240 nM, about 2 pM to about 235 nM, about 2 pM to about 230 nM, about 2 pM to about 225 nM, about 2 pM to about 220 nM, about 2 pM to about 215 nM, about 2 pM to about 210 nM, about 2 pM to about 205 nM, about 2 pM to about 200 nM, about 2 pM to about 195 nM, about 2 pM to about 190 nM, about 2 pM to about 185 nM, about 2 pM to about 180 nM, about 2 pM to about 175 nM, about 2 pM to about 170 nM, about 2 pM to about 165 nM, about 2 pM to about 160 nM, about 2 pM to about 155 nM, about 2 pM to about 150 nM, about 2 pM to about 145 nM, about 2 pM to about 140 nM, about 2 pM to about 135 nM, about 2 pM to about 130 nM, about 2 pM to about 125 nM, about 2 pM to about 120 nM, about 2 pM to about 115 nM, about 2 pM to about 110 nM, about 2 pM to about 105 nM, about 2 pM to about 100 nM, about 2 pM to about 95 nM, about 2 pM to about 90 nM, about 2 pM to about 85 nM, about 2 pM to about 80 nM, about 2 pM to about 75 nM, about 2 pM to about 70 nM, about 2 pM to about 65 nM, about 2 pM to about 60 nM, about 2 pM to about 55 nM, about 2 pM to about 50 nM, about 2 pM to about 45 nM, about 2 pM to about 40 nM, about 2 pM to about 35 nM, about 2 pM to about 30 nM, about 2 pM to about 25 nM, about 2 pM to about 20 nM, about 2 pM to about 15 nM, about 2 pM to about 10 nM, about 2 pM to about 5 nM, about 2 pM to about 2 nM, about 2 pM to about 1 nM, about 2 pM to about 950 pM, about 2 pM to about 900 pM, about 2 pM to about 850 pM, about 2 pM to about 800 pM, about 2 pM to about 750 pM, about 2 pM to about 700 pM, about 2 pM to about 650 pM, about 2 pM to about 600 pM, about 2 pM to about 550 pM, about 2 pM to about 500 pM, about 2 pM to about 450 pM, about 2 pM to about 400 pM, about 2 pM to about 350 pM, about 2 pM to about 300 pM, about 2 pM to about 250 pM, about 2 pM to about 200 pM, about 2 pM to about 150 pM, about 2 pM to about 100 pM, about 2 pM to about 90 pM, about 2 pM to about 80 pM, about 2 pM to about 70 pM, about 2 pM to about 60 pM, about 2 pM to about 50 pM, about 2 pM to about 40 pM, about 2 pM to about 30 pM, about 2 pM to about 20 pM, about 2 pM to about 10 pM, about 2 pM to about 5 pM, about 2 pM to about 4 pM, about 2 pM to about 3 pM, about 5 pM to about 250 nM, about 5 pM to about 245 nM, about 5 pM to about 240 nM, about 5 pM to about 235 nM, about 5 pM to about 230 nM, about 5 pM to about 225 nM, about 5 pM to about 220 nM, about 5 pM to about 215 nM, about 5 pM to about 210 nM, about 5 pM to about 205 nM, about 5 pM to about 200 nM, about 5 pM to about 195 nM, about 5 pM to about 190 nM, about 5 pM to about 185 nM, about 5 pM to about 180 nM, about 5 pM to about 175 nM, about 5 pM to about 170 nM, about 5 pM to about 165 nM, about 5 pM to about 160 nM, about 5 pM to about 155 nM, about 5 pM to about 150 nM, about 5 pM to about 145 nM, about 5 pM to about 140 nM, about 5 pM to about 135 nM, about 5 pM to about 130 nM, about 5 pM to about 125 nM, about 5 pM to about 120 nM, about 5 pM to about 115 nM, about 5 pM to about 110 nM, about 5 pM to about 105 nM, about 5 pM to about 100 nM, about 5 pM to about 95 nM, about 5 pM to about 90 nM, about 5 pM to about 85 nM, about 5 pM to about 80 nM, about 5 pM to about 75 nM, about 5 pM to about 70 nM, about 5 pM to about 65 nM, about 5 pM to about 60 nM, about 5 pM to about 55 nM, about 5 pM to about 50 nM, about 5 pM to about 45 nM, about 5 pM to about 40 nM, about 5 pM to about 35 nM, about 5 pM to about 30 nM, about 5 pM to about 25 nM, about 5 pM to about 20 nM, about 5 pM to about 15 nM, about 5 pM to about 10 nM, about 5 pM to about 5 nM, about 5 pM to about 2 nM, about 5 pM to about 1 nM, about 5 pM to about 950 pM, about 5 pM to about 900 pM, about 5 pM to about 850 pM, about 5 pM to about 800 pM, about 5 pM to about 750 pM, about 5 pM to about 700 pM, about 5 pM to about 650 pM, about 5 pM to about 600 pM, about 5 pM to about 550 pM, about 5 pM to about 500 pM, about 5 pM to about 450 pM, about 5 pM to about 400 pM, about 5 pM to about 350 pM, about 5 pM to about 300 pM, about 5 pM to about 250 pM, about 5 pM to about 200 pM, about 5 pM to about 1 0 pM, about 5 pM to about 100 pM, about 5 pM to about 90 pM, about 5 pM to about 80 pM, about 5 pM to about 70 pM, about 5 pM to about 60 pM, about 5 pM to about 50 pM, about 5 pM to about 40 pM, about 5 pM to about 30 pM, about 5 pM to about 20 pM, about 5 pM to about 10 pM, about 10 pM to about 250 nM_: about 10 pM to about 245 nM, about 10 pM to about 240 nM, about 10 pM to about 235 nM, about 10 pM to about 230 nM, about 10 pM to about 225 nM, about 10 pM to about 220 nM, about 10 pM to about 215 nM, about 10 pM to about 210 nM, about 10 pM to about 205 nM, about 10 pM to about 200 nM, about 10 pM to about 195 nM, about 10 pM to about 190 nM, about 10 pM to about 185 nM, about 10 pM to about 180 nM, about 10 pM to about 175 nM, about 10 pM to about 170 nM, about 10 pM to about 165 nM, about 10 pM to about 160 nM, about 10 pM to about 155 nM, about 10 pM to about 150 nM, about 10 pM to about 145 nM, about 10 pM to about 140 nM, about 10 pM to about 135 nM, about 10 pM to about 130 nM, about 10 pM to about 125 nM, about 10 pM to about 120 nM, about 10 pM to about 115 nM, about 10 pM to about 110 nM, about 10 pM to about 105 nM, about 10 pM to about 100 nM, about 10 pM to about 95 nM, about 10 pM to about 90 nM, about 10 pM to about 85 nM, about 10 pM to about 80 nM, about 10 pM to about 75 nM, about 10 pM to about 70 nM, about 10 pM to about 65 nM, about 10 pM to about 60 nM, about 10 pM to about 55 nM, about 10 pM to about 50 nM, about 10 pM to about 45 nM, about 10 pM to about 40 nM, about 10 pM to about 35 nM, about 10 pM to about 30 nM, about 10 pM to about 25 nM, about 10 pM to about 20 nM, about 10 pM to about 15 nM, about 10 pM to about 10 nM, about 10 pM to about 5 nM, about 10 pM to about 2 nM, about 10 pM to about 1 nM, about 10 pM to about 950 pM, about 10 pM to about 900 pM, about 10 pM to about 850 pM, about 10 pM to about 800 pM, about 10 pM to about 750 pM, about 10 pM to about 700 pM, about 10 pM to about 650 pM, about 10 pM to about 600 pM, about 10 pM to about 550 pM, about 10 pM to about 500 pM, about 10 pM to about 450 pM, about 10 pM to about 400 pM, about 10 pM to about 350 pM, about 10 pM to about 300 pM, about 10 pM to about 250 pM, about 10 pM to about 200 pM, about 10 pM to about 150 pM, about 10 pM to about 100 pM, about 10 pM to about 90 pM, about 10 pM to about 80 pM, about 10 pM to about 70 pM, about 10 pM to about 60 pM, about 10 pM to about 50 pM, about 10 pM to about 40 pM, about 10 pM to about 30 pM, about 10 pM to about 20 pM, about 15 pM to about 250 nM, about 15 pM to about 245 nM, about 15 pM to about 240 nM, about 15 pM to about 235 nM, about 15 pM to about 230 nM, about 1 pM to about 225 nM, about 15 pM to about 220 nM, about 15 pM to about 215 nM, about 15 pM to about 210 nM, about 15 pM to about 205 nM, about 15 pM to about 200 nM, about 1 pM to about 195 nM, about 15 pM to about 190 nM, about 15 pM to about 185 nM, about 15 pM to about 180 nM, about 15 pM to about 175 nM, about 15 pM to about 170 nM, about 15 pM to about 165 nM, about 15 pM to about 160 nM, about 15 pM to about 155 nM, about 15 pM to about 150 nM, about 15 pM to about 145 nM, about 15 pM to about 140 nM, about 15 pM to about 135 nM, about 15 pM to about 130 nM, about 15 pM to about 125 nM, about 15 pM to about 120 nM, about 15 pM to about 115 nM, about 15 pM to about 110 nM, about 15 pM to about 105 nM, about 15 pM to about 100 nM, about 15 pM to about 95 nM, about 15 pM to about 90 nM, about 15 pM to about 85 nM, about 15 pM to about 80 nM, about 15 pM to about 75 nM, about 15 pM to about 70 nM, about 15 pM to about 65 nM, about 15 pM to about 60 nM, about 15 pM to about 55 nM, about 15 pM to about 50 nM, about 15 pM to about 45 nM, about 15 pM to about 40 nM, about 15 pM to about 35 nM, about 15 pM to about 30 nM, about 15 pM to about 25 nM, about 15 pM to about 20 nM, about 15 pM to about 15 nM, about 15 pM to about 10 nM, about 15 pM to about 5 nM, about 15 pM to about 2 nM, about 15 pM to about 1 nM, about 15 pM to about 950 pM, about 15 pM to about 900 pM, about 15 pM to about 850 pM, about 15 pM to about 800 pM, about 15 pM to about 750 pM, about 15 pM to about 700 pM, about 15 pM to about 650 pM, about 15 pM to about 600 pM, about 15 pM to about 550 pM, about 15 pM to about 500 pM, about 15 pM to about 450 pM, about 15 pM to about 400 pM, about 15 pM to about 350 pM, about 15 pM to about 300 pM, about 15 pM to about 250 pM, about 15 pM to about 200 pM, about 15 pM to about 150 pM, about 15 pM to about 100 pM, about 15 pM to about 90 pM, about 15 pM to about 80 pM, about 15 pM to about 70 pM, about 15 pM to about 60 pM, about 15 pM to about 50 pM, about 15 pM to about 40 pM, about 15 pM to about 30 pM, about 15 pM to about 20 pM, about 20 pM to about 250 nM, about 20 pM to about 245 nM, about 20 pM to about 240 nM, about 20 pM to about 235 nM, about 20 pM to about 230 nM, about 20 pM to about 225 nM, about 20 pM to about 220 nM, about 20 pM to about 215 nM, about 20 pM to about 210 nM, about 20 pM to about 205 nM, about 20 pM to about 200 nM, about 20 pM to about 195 nM, about 20 pM to about 190 nM, about 20 pM to about 185 nM, about 20 pM to about 180 nM, about 20 pM to about 175 nM, about 20 pM to about 170 nM, about 20 pM to about 165 nM, about 20 pM to about 160 nM, about 20 pM to about 155 nM, about 20 pM to about 150 nM, about 20 pM to about 145 nM, about 20 pM to about 140 nM, about 20 pM to about 135 nM, about 20 pM to about 130 nM, about 20 pM to about 125 nM, about 20 pM to about 120 nM, about 20 pM to about 115 nM, about 20 pM to about 110 nM, about 20 pM to about 105 nM, about 20 pM to about 100 nM, about 20 pM to about 95 nM, about 20 pM to about 90 nM, about 20 pM to about 85 nM, about 20 pM to about 80 nM, about 20 pM to about 75 nM, about 20 pM to about 70 nM, about 20 pM to about 65 nM, about 20 pM to about 60 nM, about 20 pM to about 55 nM, about 20 pM to about 50 nM, about 20 pM to about 45 nM, about 20 pM to about 40 nM, about 20 pM to about 35 nM, about 20 pM to about 30 nM, about 20 pM to about 25 nM, about 20 pM to about 20 nM, about 20 pM to about 15 nM, about 20 pM to about 10 nM, about 20 pM to about 5 nM, about 20 pM to about 2 nM, about 20 pM to about 1 nM, about 20 pM to about 950 pM, about 20 pM to about 900 pM, about 20 pM to about 850 pM, about 20 pM to about 800 pM, about 20 pM to about 750 pM, about 20 pM to about 700 pM, about 20 pM to about 650 pM, about 20 pM to about 600 pM, about 20 pM to about 550 pM, about 20 pM to about 500 pM, about 20 pM to about 450 pM, about 20 pM to about 400 pM, about 20 pM to about 350 pM, about 20 pM to about 300 pM, about 20 pM to about 250 pM, about 20 pM to about 20 pM, about 200 pM to about 150 pM, about 20 pM to about 100 pM, about 20 pM to about 90 pM, about 20 pM to about 80 pM, about 20 pM to about 70 pM, about 20 pM to about 60 pM, about 20 pM to about 50 pM, about 20 pM to about 40 pM, about 20 pM to about 30 pM, about 30 pM to about 250 nM, about 30 pM to about 245 nM, about 30 pM to about 240 nM, about 30 pM to about 235 nM, about 30 pM to about 230 nM, about 30 pM to about 225 nM, about 30 pM to about 220 nM, about 30 pM to about 215 nM, about 30 pM to about 210 nM, about 30 pM to about 205 nM, about 30 pM to about 200 nM, about 30 pM to about 195 nM, about 30 pM to about 190 nM, about 30 pM to about 185 nM, about 30 pM to about 180 nM, about 30 pM to about 175 nM, about 30 pM to about 170 nM, about 30 pM to about 165 nM, about 30 pM to about 160 nM, about 30 pM to about 155 nM, about 30 pM to about 150 nM, about 30 pM to about 145 nM, about 30 pM to about 140 nM, about 30 pM to about 135 nM, about 30 pM to about 130 nM, about 30 pM to about 125 nM, about 30 pM to about 120 nM, about 30 pM to about 115 nM, about 30 pM to about 110 nM, about 30 pM to about 105 nM, about 30 pM to about 100 nM, about 30 pM to about 95 nM, about 30 pM to about 90 nM, about 30 pM to about 85 nM, about 30 pM to about 80 nM, about 30 pM to about 75 nM, about 30 pM to about 70 nM, about 30 pM to about 65 nM, about 30 pM to about 60 nM, about 30 pM to about 55 nM, about 30 pM to about 50 nM, about 30 pM to about 45 nM, about 30 pM to about 40 nM, about 30 pM to about 35 nM, about 30 pM to about 30 nM, about 30 pM to about 25 nM, about 30 pM to about 20 nM, about 30 pM to about 15 nM, about 30 pM to about 10 nM, about 30 pM to about 5 nM, about 30 pM to about 2 nM, about 30 pM to about 1 nM, about 30 pM to about 950 pM, about 30 pM to about 900 pM, about 30 pM to about 850 pM, about 30 pM to about 800 pM, about 30 pM to about 750 pM, about 30 pM to about 700 pM, about 30 pM to about 650 pM, about 30 pM to about 600 pM, about 30 pM to about 550 pM, about 30 pM to about 500 pM, about 30 pM to about 450 pM, about 30 pM to about 400 pM, about 30 pM to about 350 pM, about 30 pM to about 300 pM, about 30 pM to about 250 pM, about 30 pM to about 200 pM, about 30 pM to about 150 pM, about 30 pM to about 100 pM, about 30 pM to about 90 pM, about 30 pM to about 80 pM, about 30 pM to about 70 pM, about 30 pM to about 60 pM, about 30 pM to about 50 pM, about 30 pM to about 40 pM, about 40 pM to about 250 nM, about 40 pM to about 245 nM, about 40 pM to about 240 nM, about 40 pM to about 235 nM, about 40 pM to about 230 nM, about 40 pM to about 225 nM, about 40 pM to about 220 nM, about 40 pM to about 215 nM, about 40 pM to about 210 nM, about 40 pM to about 205 nM, about 40 pM to about 200 nM, about 40 pM to about 195 nM, about 40 pM to about 190 nM, about 40 pM to about 185 nM, about 40 pM to about 180 nM, about 40 pM to about 175 nM, about 40 pM to about 170 nM, about 40 pM to about 165 nM, about 40 pM to about 160 nM, about 40 pM to about 155 nM, about 40 pM to about 150 nM, about 40 pM to about 145 nM, about 40 pM to about 140 nM, about 40 pM to about 135 nM, about 40 pM to about 130 nM, about 40 pM to about 125 nM, about 40 pM to about 120 nM, about 40 pM to about 115 nM, about 40 pM to about 110 nM, about 40 pM to about 105 nM, about 40 pM to about 100 nM, about 40 pM to about 95 nM, about 40 pM to about 90 nM, about 40 pM to about 85 nM, about 40 pM to about 80 nM, about 40 pM to about 75 nM, about 40 pM to about 70 nM, about 40 pM to about 65 nM, about 40 pM to about 60 nM, about 40 pM to about 55 nM, about 40 pM to about 50 nM, about 40 pM to about 45 nM, about 40 pM to about 40 nM, about 40 pM to about 35 nM, about 40 pM to about 30 nM, about 40 pM to about 25 nM, about 40 pM to about 20 nM, about 40 pM to about 15 nM, about 40 pM to about 10 nM, about 40 pM to about 5 nM, about 40 pM to about 2 nM, about 40 pM to about 1 nM, about 40 pM to about 950 pM, about 40 pM to about 900 pM, about 40 pM to about 850 pM, about 40 pM to about 800 pM, about 40 pM to about 750 pM, about 40 pM to about 700 pM, about 40 pM to about 650 pM, about 40 pM to about 600 pM, about 40 pM to about 550 pM, about 40 pM to about 500 pM, about 40 pM to about 450 pM, about 40 pM to about 400 pM, about 40 pM to about 350 pM, about 40 pM to about 300 pM, about 40 pM to about 250 pM, about 40 pM to about 200 pM, about 40 pM to about 150 pM, about 40 pM to about 100 pM, about 40 pM to about 90 pM, about 40 pM to about 80 pM, about 40 pM to about 70 pM, about 40 pM to about 60 pM, about 40 pM to about 50 pM, about 50 pM to about 250 nM, about 50 pM to about 245 nM, about 50 pM to about 240 nM, about 50 pM to about 235 nM, about 50 pM to about 230 nM, about 50 pM to about 225 nM, about 50 pM to about 220 nM, about 50 pM to about 215 nM, about 50 pM to about 210 nM, about 50 pM to about 205 nM, about 50 pM to about 200 nM, about 50 pM to about 195 nM, about 50 pM to about 190 nM, about 50 pM to about 185 nM, about 50 pM to about 180 nM, about 50 pM to about 175 nM, about 50 pM to about 170 nM, about 50 pM to about 165 nM, about 50 pM to about 160 nM, about 50 pM to about 155 nM, about 50 pM to about 150 nM, about 50 pM to about 145 nM, about 50 pM to about 140 nM, about 50 pM to about 135 nM, about 50 pM to about 130 nM, about 50 pM to about 125 nM, about 50 pM to about 120 nM, about 50 pM to about 115 nM, about 50 pM to about 110 nM, about 50 pM to about 105 nM, about 50 pM to about 100 nM, about 50 pM to about 95 nM, about 50 pM to about 90 nM, about 50 pM to about 85 nM, about 50 pM to about 80 nM, about 50 pM to about 75 nM, about 50 pM to about 70 nM, about 50 pM to about 65 nM, about 50 pM to about 60 nM, about 50 pM to about 55 nM, about 50 pM to about 50 nM, about 50 pM to about 45 nM, about 50 pM to about 40 nM, about 50 pM to about 35 nM, about 50 pM to about 30 nM, about 50 pM to about 25 nM, about 50 pM to about 20 nM, about 50 pM to about 15 nM, about 50 pM to about 10 nM, about 50 pM to about 5 nM, about 50 pM to about 2 nM, about 50 pM to about 1 nM, about 50 pM to about 950 pM, about 50 pM to about 900 pM, about 50 pM to about 850 pM, about 50 pM to about 800 pM, about 50 pM to about 750 pM, about 50 pM to about 700 pM, about 50 pM to about 650 pM, about 50 pM to about 600 pM, about 50 pM to about 550 pM, about 50 pM to about 500 pM, about 50 pM to about 450 pM, about 50 pM to about 400 pM, about 50 pM to about 350 pM, about 50 pM to about 300 pM, about 50 pM to about 250 pM, about 50 pM to about 200 pM, about 50 pM to about 150 pM, about 50 pM to about 100 pM, about 50 pM to about 90 pM, about 50 pM to about 80 pM, about 50 pM to about 70 pM, about 50 pM to about 60 pM, about 60 pM to about 250 nM, about 60 pM to about 245 nM, about 60 pM to about 240 nM, about 60 pM to about 235 nM, about 60 pM to about 230 nM, about 60 pM to about 225 nM, about 60 pM to about 220 nM, about 60 pM to about 215 nM, about 60 pM to about 210 nM, about 60 pM to about 205 nM, about 60 pM to about 200 nM, about 60 pM to about 195 nM, about 60 pM to about 190 nM, about 60 pM to about 185 nM, about 60 pM to about 180 nM, about 60 pM to about 175 nM, about 60 pM to about 170 nM, about 60 pM to about 165 nM, about 60 pM to about 160 nM, about 60 pM to about 155 nM, about 60 pM to about 150 nM, about 60 pM to about 145 nM, about 60 pM to about 140 nM, about 60 pM to about 135 nM, about 60 pM to about 130 nM, about 60 pM to about 125 nM, about 60 pM to about 120 nM, about 60 pM to about 115 nM, about 60 pM to about 110 nM, about 60 pM to about 105 nM, about 60 pM to about 100 nM, about 60 pM to about 95 nM, about 60 pM to about 90 nM, about 60 pM to about 85 nM, about 60 pM to about 80 nM, about 60 pM to about 75 nM, about 60 pM to about 70 nM, about 60 pM to about 65 nM, about 60 pM to about 60 nM, about 60 pM to about 55 nM, about 60 pM to about 50 nM, about 60 pM to about 45 nM, about 60 pM to about 40 nM, about 60 pM to about 35 nM, about 60 pM to about 30 nM, about 60 pM to about 25 nM, about 60 pM to about 20 nM, about 60 pM to about 15 nM, about 60 pM to about 10 nM, about 60 pM to about 5 nM, about 60 pM to about 2 nM, about 60 pM to about 1 nM, about 60 pM to about 950 pM, about 60 pM to about 900 pM, about 60 pM to about 850 pM, about 60 pM to about 800 pM, about 60 pM to about 750 pM, about 60 pM to about 700 pM, about 60 pM to about 650 pM, about 60 pM to about 600 pM, about 60 pM to about 550 pM, about 60 pM to about 500 pM, about 60 pM to about 450 pM, about 60 pM to about 400 pM, about 60 pM to about 350 pM, about 60 pM to about 300 pM, about 60 pM to about 250 pM, about 60 pM to about 200 pM, about 60 pM to about 150 pM, about 60 pM to about 100 pM, about 60 pM to about 90 pM, about 60 pM to about 80 pM, about 60 pM to about 70 pM, about 70 pM to about 250 nM, about 70 pM to about 245 nM, about 70 pM to about 240 nM, about 70 pM to about 235 nM, about 70 pM to about 230 nM, about 70 pM to about 225 nM, about 70 pM to about 220 nM, about 70 pM to about 215 nM, about 70 pM to about 210 nM, about 70 pM to about 205 nM, about 70 pM to about 200 nM, about 70 pM to about 195 nM, about 70 pM to about 190 nM, about 70 pM to about 185 nM, about 70 pM to about 180 nM, about 70 pM to about 175 nM, about 70 pM to about 170 nM, about 70 pM to about 165 nM, about 70 pM to about 160 nM, about 70 pM to about 155 nM, about 70 pM to about 150 nM, about 70 pM to about 145 nM, about 70 pM to about 140 nM, about 70 pM to about 135 nM, about 70 pM to about 130 nM, about 70 pM to about 125 nM, about 70 pM to about 120 nM, about 70 pM to about 115 nM, about 70 pM to about 110 nM, about 70 pM to about 105 nM, about 70 pM to about 100 nM, about 70 pM to about 95 nM, about 70 pM to about 90 nM, about 70 pM to about 85 nM, about 70 pM to about 80 nM, about 70 pM to about 75 nM, about 70 pM to about 70 nM, about 70 pM to about 65 nM, about 70 pM to about 60 nM, about 70 pM to about 55 nM, about 70 pM to about 50 nM, about 70 pM to about 45 nM, about 70 pM to about 40 nM, about 70 pM to about 35 nM, about 70 pM to about 30 nM, about 70 pM to about 25 nM, about 70 pM to about 20 nM, about 70 pM to about 15 nM, about 70 pM to about 10 nM, about 70 pM to about 5 nM, about 70 pM to about 2 nM, about 70 pM to about 1 nM, about 70 pM to about 950 pM, about 70 pM to about 900 pM, about 70 pM to about 850 pM, about 70 pM to about 800 pM, about 70 pM to about 750 pM, about 70 pM to about 700 pM, about 70 pM to about 650 pM, about 70 pM to about 600 pM, about 70 pM to about 550 pM, about 70 pM to about 500 pM, about 70 pM to about 450 pM, about 70 pM to about 400 pM, about 70 pM to about 350 pM, about 70 pM to about 300 pM, about 70 pM to about 250 pM, about 70 pM to about 200 pM, about 70 pM to about 150 pM, about 70 pM to about 100 pM, about 70 pM to about 90 pM, about 70 pM to about 80 pM, about 80 pM to about 250 nM, about 80 pM to about 245 nM, about 80 pM to about 240 nM, about 80 pM to about 235 nM, about 80 pM to about 230 nM, about 80 pM to about 225 nM, about 80 pM to about 220 nM, about 80 pM to about 215 nM, about 80 pM to about 210 nM, about 80 pM to about 205 nM, about 80 pM to about 200 nM, about 80 pM to about 195 nM, about 80 pM to about 190 nM, about 80 pM to about 185 nM, about 80 pM to about 180 nM, about 80 pM to about 175 nM, about 80 pM to about 170 nM, about 80 pM to about 165 nM, about 80 pM to about 160 nM, about 80 pM to about 155 nM, about 80 pM to about 150 nM, about 80 pM to about 145 nM, about 80 pM to about 140 nM, about 80 pM to about 135 nM, about 80 pM to about 130 nM, about 80 pM to about 125 nM, about 80 pM to about 120 nM, about 80 pM to about 115 nM, about 80 pM to about 110 nM, about 80 pM to about 105 nM, about 80 pM to about 100 nM, about 80 pM to about 95 nM, about 80 pM to about 90 nM, about 80 pM to about 85 nM, about 80 pM to about 80 nM, about 80 pM to about 75 nM, about 80 pM to about 70 nM, about 80 pM to about 65 nM, about 80 pM to about 60 nM, about 80 pM to about 55 nM, about 80 pM to about 50 nM, about 80 pM to about 45 nM, about 80 pM to about 40 nM, about 80 pM to about 35 nM, about 80 pM to about 30 nM, about 80 pM to about 25 nM, about 80 pM to about 20 nM, about 80 pM to about 15 nM, about 80 pM to about 10 nM, about 80 pM to about 5 nM, about 80 pM to about 2 nM, about 80 pM to about 1 nM, about 80 pM to about 950 pM, about 80 pM to about 900 pM, about 80 pM to about 850 pM, about 80 pM to about 800 pM, about 80 pM to about 750 pM, about 80 pM to about 700 pM, about 80 pM to about 650 pM, about 80 pM to about 600 pM, about 80 pM to about 550 pM, about 80 pM to about 500 pM, about 80 pM to about 450 pM, about 80 pM to about 400 pM, about 80 pM to about 350 pM, about 80 pM to about 300 pM, about 80 pM to about 250 pM, about 80 pM to about 200 pM, about 80 pM to about 150 pM, about 80 pM to about 100 pM, about 80 pM to about 90 pM, about 90 pM to about 250 nM, about 90 pM to about 245 nM, about 90 pM to about 240 nM, about 90 pM to about 235 nM, about 90 pM to about 230 nM, about 90 pM to about 225 nM, about 90 pM to about 220 nM, about 90 pM to about 215 nM, about 90 pM to about 210 nM, about 90 pM to about 205 nM, about 90 pM to about 200 nM, about 90 pM to about 195 nM, about 90 pM to about 190 nM, about 90 pM to about 185 nM, about 90 pM to about 180 nM, about 90 pM to about 175 nM, about 90 pM to about 170 nM, about 90 pM to about 165 nM, about 90 pM to about 160 nM, about 90 pM to about 155 nM, about 90 pM to about 150 nM, about 90 pM to about 145 nM, about 90 pM to about 140 nM, about 90 pM to about 135 nM, about 90 pM to about 130 nM, about 90 pM to about 125 nM, about 90 pM to about 120 nM, about 90 pM to about 115 nM, about 90 pM to about 110 nM, about 90 pM to about 105 nM, about 90 pM to about 100 nM, about 90 pM to about 95 nM, about 90 pM to about 90 nM, about 90 pM to about 85 nM, about 90 pM to about 80 nM, about 90 pM to about 75 nM, about 90 pM to about 70 nM, about 90 pM to about 65 nM, about 90 pM to about 60 nM, about 90 pM to about 55 nM, about 90 pM to about 50 nM, about 90 pM to about 45 nM, about 90 pM to about 40 nM, about 90 pM to about 35 nM, about 90 pM to about 30 nM, about 90 pM to about 25 nM, about 90 pM to about 20 nM, about 90 pM to about 15 nM, about 90 pM to about 10 nM, about 90 pM to about 5 nM, about 90 pM to about 2 nM, about 90 pM to about 1 nM, about 90 pM to about 950 pM, about 90 pM to about 900 pM, about 90 pM to about 850 pM, about 90 pM to about 800 pM, about 90 pM to about 750 pM, about 90 pM to about 700 pM, about 90 pM to about 650 pM, about 90 pM to about 600 pM, about 90 pM to about 550 pM, about 90 pM to about 500 pM, about 90 pM to about 450 pM, about 90 pM to about 400 pM, about 90 pM to about 350 pM, about 90 pM to about 300 pM, about 90 pM to about 250 pM, about 90 pM to about 200 pM, about 90 pM to about 150 pM, about 90 pM to about 100 pM, about 100 pM to about 250 nM, about 100 pM to about 245 nM, about 100 pM to about 240 nM, about 100 pM to about 235 nM, about 100 pM to about 230 nM, about 100 pM to about 225 nM, about 100 pM to about 220 nM, about 100 pM to about 215 nM, about 100 pM to about 210 nM, about 100 pM to about 205 nM, about 100 pM to about 200 nM, about 100 pM to about 195 nM, about 100 pM to about 190 nM, about 100 pM to about 185 nM, about 100 pM to about 180 nM, about 100 pM to about 175 nM, about 100 pM to about 170 nM, about 100 pM to about 165 nM, about 100 pM to about 160 nM, about 100 pM to about 155 nM, about 100 pM to about 150 nM, about 100 pM to about 145 nM, about 100 pM to about 140 nM, about 100 pM to about 135 nM, about 100 pM to about 130 nM, about 100 pM to about 125 nM, about 100 pM to about 120 nM, about 100 pM to about 115 nM, about 100 pM to about 110 nM, about 100 pM to about 105 nM, about 100 pM to about 100 nM, about 100 pM to about 95 nM, about 100 pM to about 90 nM, about 100 pM to about 85 nM, about 100 pM to about 80 nM, about 100 pM to about 75 nM, about 100 pM to about 70 nM, about 100 pM to about 65 nM, about 100 pM to about 60 nM, about 100 pM to about 55 nM, about 100 pM to about 50 nM, about 100 pM to about 45 nM, about 100 pM to about 40 nM, about 100 pM to about 35 nM, about 100 pM to about 30 nM, about 100 pM to about 25 nM, about 100 pM to about 20 nM, about 100 pM to about 15 nM, about 100 pM to about 10 nM, about 100 pM to about 5 nM, about 100 pM to about 2 nM, about 100 pM to about 1 nM, about 100 pM to about 950 pM, about 100 pM to about 900 pM, about 100 pM to about 850 pM, about 100 pM to about 800 pM, about 100 pM to about 750 pM, about 100 pM to about 700 pM, about 100 pM to about 650 pM, about 100 pM to about 600 pM, about 100 pM to about 550 pM, about 100 pM to about 500 pM, about 100 pM to about 450 pM, about 100 pM to about 400 pM, about 100 pM to about 350 pM, about 100 pM to about 300 pM, about 100 pM to about 250 pM, about 100 pM to about 200 pM, about 100 pM to about 150 pM, about 150 pM to about 250 nM, about 150 pM to about 245 nM, about 150 pM to about 240 nM, about 150 pM to about 235 nM, about 150 pM to about 230 nM, about 150 pM to about 225 nM, about 150 pM to about 220 nM, about 150 pM to about 215 nM, about 150 pM to about 210 nM, about 150 pM to about 205 nM, about 150 pM to about 200 nM, about 150 pM to about 195 nM, about 150 pM to about 190 nM, about 150 pM to about 185 nM, about 150 pM to about 180 nM, about 150 pM to about 175 nM, about 150 pM to about 170 nM, about 150 pM to about 165 nM, about 150 pM to about 160 nM, about 150 pM to about 155 nM, about 150 pM to about 150 nM, about 150 pM to about 145 nM, about 150 pM to about 140 nM, about 150 pM to about 135 nM, about 150 pM to about 130 nM, about 150 pM to about 125 nM, about 150 pM to about 120 nM, about 150 pM to about 115 nM, about 150 pM to about 110 nM, about 150 pM to about 105 nM, about 150 pM to about 100 nM, about 150 pM to about 95 nM, about 150 pM to about 90 nM, about 150 pM to about 85 nM, about 150 pM to about 80 nM, about 150 pM to about 75 nM, about 150 pM to about 70 nM, about 150 pM to about 65 nM, about 150 pM to about 60 nM, about 150 pM to about 55 nM, about 150 pM to about 50 nM, about 150 pM to about 45 nM, about 150 pM to about 40 nM, about 150 pM to about 35 nM, about 150 pM to about 30 nM, about 150 pM to about 25 nM, about 150 pM to about 20 nM, about 150 pM to about 15 nM, about 150 pM to about 10 nM, about 150 pM to about 5 nM, about 150 pM to about 2 nM, about 150 pM to about 1 nM, about 150 pM to about 950 pM, about 150 pM to about 900 pM, about 150 pM to about 850 pM, about 150 pM to about 800 pM, about 150 pM to about 750 pM, about 150 pM to about 700 pM, about 150 pM to about 650 pM, about 150 pM to about 600 pM, about 150 pM to about 550 pM, about 150 pM to about 500 pM, about 150 pM to about 450 pM, about 150 pM to about 400 pM, about 150 pM to about 350 pM, about 150 pM to about 300 pM, about 150 pM to about 250 pM, about 150 pM to about 200 pM, about 200 pM to about 250 nM, about 200 pM to about 245 nM, about 200 pM to about 240 nM, about 200 pM to about 235 nM, about 200 pM to about 230 nM, about 200 pM to about 225 nM, about 200 pM to about 220 nM_: about 200 pM to about 215 nM, about 200 pM to about 210 nM, about 200 pM to about 205 nM, about 200 pM to about 200 nM, about 200 pM to about 195 nM, about 200 pM to about 190 nM, about 200 pM to about 185 nM, about 200 pM to about 180 nM, about 200 pM to about 175 nM, about 200 pM to about 170 nM, about 200 pM to about 165 nM, about 200 pM to about 160 nM, about 200 pM to about 155 nM, about 200 pM to about 150 nM, about 200 pM to about 145 nM, about 200 pM to about 140 nM, about 200 pM to about 135 nM, about 200 pM to about 130 nM, about 200 pM to about 125 nM, about 200 pM to about 120 nM, about 200 pM to about 115 nM, about 200 pM to about 110 nM, about 200 pM to about 105 nM, about 200 pM to about 100 nM, about 200 pM to about 95 nM, about 200 pM to about 90 nM, about 200 pM to about 85 nM, about 200 pM to about 80 nM, about 200 pM to about 75 nM, about 200 pM to about 70 nM, about 200 pM to about 65 nM, about 200 pM to about 60 nM, about 200 pM to about 55 nM, about 200 pM to about 50 nM, about 200 pM to about 45 nM, about 200 pM to about 40 nM, about 200 pM to about 35 nM, about 200 pM to about 30 nM, about 200 pM to about 25 nM, about 200 pM to about 20 nM, about 200 pM to about 15 nM, about 200 pM to about 10 nM, about 200 pM to about 5 nM, about 200 pM to about 2 nM, about 200 pM to about 1 nM, about 200 pM to about 950 pM, about 200 pM to about 900 pM, about 200 pM to about 850 pM, about 200 pM to about 800 pM, about 200 pM to about 750 pM, about 200 pM to about 700 pM, about 200 pM to about 650 pM, about 200 pM to about 600 pM, about 200 pM to about 550 pM, about 200 pM to about 500 pM, about 200 pM to about 450 pM, about 200 pM to about 400 pM, about 200 pM to about 350 pM, about 200 pM to about 300 pM, about 200 pM to about 250 pM, about 300 pM to about 250 nM, about 300 pM to about 245 nM, about 300 pM to about 240 nM, about 300 pM to about 235 nM, about 300 pM to about 230 nM, about 300 pM to about 225 nM, about 300 pM to about 220 nM, about 300 pM to about 215 nM, about 300 pM to about 210 nM, about 300 pM to about 205 nM, about 300 pM to about 200 nM, about 300 pM to about 195 nM, about 300 pM to about 190 nM, about 300 pM to about 185 nM, about 300 pM to about 180 nM, about 300 pM to about 175 nM, about 300 pM to about 170 nM, about 300 pM to about 165 nM, about 300 pM to about 160 nM, about 300 pM to about 155 nM, about 300 pM to about 150 nM, about 300 pM to about 145 nM, about 300 pM to about 140 nM, about 300 pM to about 135 nM, about 300 pM to about 130 nM, about 300 pM to about 125 nM, about 300 pM to about 120 nM, about 300 pM to about 115 nM, about 300 pM to about 110 nM, about 300 pM to about 105 nM, about 300 pM to about 100 nM, about 300 pM to about 95 nM, about 300 pM to about 90 nM, about 300 pM to about 85 nM, about 300 pM to about 80 nM, about 300 pM to about 75 nM, about 300 pM to about 70 nM, about 300 pM to about 65 nM, about 300 pM to about 60 nM, about 300 pM to about 55 nM, about 300 pM to about 50 nM, about 300 pM to about 45 nM, about 300 pM to about 40 nM, about 300 pM to about 35 nM, about 300 pM to about 30 nM, about 300 pM to about 25 nM, about 300 pM to about 20 nM, about 300 pM to about 15 nM, about 300 pM to about 10 nM, about 300 pM to about 5 nM, about 300 pM to about 2 nM, about 300 pM to about 1 nM, about 300 pM to about 950 pM, about 300 pM to about 900 pM, about 300 pM to about 850 pM, about 300 pM to about 800 pM, about 300 pM to about 750 pM, about 300 pM to about 700 pM, about 300 pM to about 650 pM, about 300 pM to about 600 pM, about 300 pM to about 550 pM, about 300 pM to about 500 pM, about 300 pM to about 450 pM, about 300 pM to about 400 pM, about 300 pM to about 350 pM, about 400 pM to about 250 nM, about 400 pM to about 245 nM, about 400 pM to about 240 nM, about 400 pM to about 235 nM, about 400 pM to about 230 nM, about 400 pM to about 225 nM, about 400 pM to about 220 nM, about 400 pM to about 215 nM, about 400 pM to about 210 nM, about 400 pM to about 205 nM, about 400 pM to about 200 nM, about 400 pM to about 195 nM, about 400 pM to about 190 nM, about 400 pM to about 185 nM, about 400 pM to about 180 nM, about 400 pM to about 175 nM, about 400 pM to about 170 nM, about 400 pM to about 165 nM, about 400 pM to about 160 nM, about 400 pM to about 155 nM, about 400 pM to about 150 nM, about 400 pM to about 145 nM, about 400 pM to about 140 nM, about 400 pM to about 135 nM, about 400 pM to about 130 nM, about 400 pM to about 125 nM, about 400 pM to about 120 nM, about 400 pM to about 115 nM, about 400 pM to about 110 nM, about 400 pM to about 105 nM, about 400 pM to about 100 nM, about 400 pM to about 95 nM, about 400 pM to about 90 nM, about 400 pM to about 85 nM, about 400 pM to about 80 nM, about 400 pM to about 75 nM, about 400 pM to about 70 nM, about 400 pM to about 65 nM, about 400 pM to about 60 nM, about 400 pM to about 55 nM, about 400 pM to about 50 nM, about 400 pM to about 45 nM, about 400 pM to about 40 nM, about 400 pM to about 35 nM, about 400 pM to about 30 nM, about 400 pM to about 25 nM, about 400 pM to about 20 nM, about 400 pM to about 15 nM, about 400 pM to about 10 nM, about 400 pM to about 5 nM, about 400 pM to about 2 nM, about 400 pM to about 1 nM, about 400 pM to about 950 pM, about 400 pM to about 900 pM, about 400 pM to about 850 pM, about 400 pM to about 800 pM, about 400 pM to about 750 pM, about 400 pM to about 700 pM, about 400 pM to about 650 pM, about 400 pM to about 600 pM, about 400 pM to about 550 pM, about 400 pM to about 500 pM, about 500 pM to about 250 nM, about 500 pM to about 245 nM, about 500 pM to about 240 nM, about 500 pM to about 235 nM, about 500 pM to about 230 nM, about 500 pM to about 225 nM, about 500 pM to about 220 nM, about 500 pM to about 215 nM, about 500 pM to about 210 nM, about 500 pM to about 205 nM, about 500 pM to about 200 nM, about 500 pM to about 195 nM, about 500 pM to about 190 nM, about 500 pM to about 185 nM, about 500 pM to about 180 nM, about 500 pM to about 175 nM, about 500 pM to about 170 nM, about 500 pM to about 165 nM, about 500 pM to about 160 nM, about 500 pM to about 155 nM, about 500 pM to about 150 nM, about 500 pM to about 145 nM, about 500 pM to about 140 nM, about 500 pM to about 135 nM, about 500 pM to about 130 nM, about 500 pM to about 125 nM, about 500 pM to about 120 nM, about 500 pM to about 115 nM, about 500 pM to about 110 nM, about 500 pM to about 105 nM, about 500 pM to about 100 nM, about 500 pM to about 95 nM, about 500 pM to about 90 nM, about 500 pM to about 85 nM, about 500 pM to about 80 nM, about 500 pM to about 75 nM, about 500 pM to about 70 nM, about 500 pM to about 65 nM, about 500 pM to about 60 nM, about 500 pM to about 55 nM, about 500 pM to about 50 nM, about 500 pM to about 45 nM, about 500 pM to about 40 nM, about 500 pM to about 35 nM, about 500 pM to about 30 nM, about 500 pM to about 25 nM, about 500 pM to about 20 nM, about 500 pM to about 15 nM, about 500 pM to about 10 nM, about 500 pM to about 5 nM, about 500 pM to about 2 nM, about 500 pM to about 1 nM, about 500 pM to about 950 pM, about 500 pM to about 900 pM, about 500 pM to about 850 pM, about 500 pM to about 800 pM, about 500 pM to about 750 pM, about 500 pM to about 700 pM, about 500 pM to about 650 pM, about 500 pM to about 600 pM, about 500 pM to about 550 pM, about 600 pM to about 250 nM, about 600 pM to about 245 nM, about 600 pM to about 240 nM, about 600 pM to about 235 nM, about 600 pM to about 230 nM, about 600 pM to about 225 nM, about 600 pM to about 220 nM, about 600 pM to about 215 nM, about 600 pM to about 210 nM, about 600 pM to about 205 nM, about 600 pM to about 200 nM, about 600 pM to about 195 nM, about 600 pM to about 190 nM, about 600 pM to about 185 nM, about 600 pM to about 180 nM, about 600 pM to about 175 nM, about 600 pM to about 170 nM, about 600 pM to about 165 nM, about 600 pM to about 160 nM, about 600 pM to about 155 nM, about 600 pM to about 150 nM, about 600 pM to about 145 nM, about 600 pM to about 140 nM, about 600 pM to about 135 nM, about 600 pM to about 130 nM, about 600 pM to about 125 nM, about 600 pM to about 120 nM, about 600 pM to about 115 nM, about 600 pM to about 110 nM, about 600 pM to about 105 nM, about 600 pM to about 100 nM, about 600 pM to about 95 nM, about 600 pM to about 90 nM, about 600 pM to about 85 nM, about 600 pM to about 80 nM, about 600 pM to about 75 nM, about 600 pM to about 70 nM, about 600 pM to about 65 nM, about 600 pM to about 60 nM, about 600 pM to about 55 nM, about 600 pM to about 50 nM, about 600 pM to about 45 nM, about 600 pM to about 40 nM, about 600 pM to about 35 nM, about 600 pM to about 30 nM, about 600 pM to about 25 nM, about 600 pM to about 20 nM, about 600 pM to about 15 nM, about 600 pM to about 10 nM, about 600 pM to about 5 nM, about 600 pM to about 2 nM, about 600 pM to about 1 nM, about 600 pM to about 950 pM, about 600 pM to about 900 pM, about 600 pM to about 850 pM, about 600 pM to about 800 pM, about 600 pM to about 750 pM, about 600 pM to about 700 pM, about 600 pM to about 650 pM, about 700 pM to about 250 nM, about 700 pM to about 245 nM, about 700 pM to about 240 nM, about 700 pM to about 235 nM, about 700 pM to about 230 nM, about 700 pM to about 225 nM, about 700 pM to about 220 nM, about 700 pM to about 215 nM, about 700 pM to about 210 nM, about 700 pM to about 205 nM, about 700 pM to about 200 nM, about 700 pM to about 195 nM, about 700 pM to about 190 nM, about 700 pM to about 185 nM, about 700 pM to about 180 nM, about 700 pM to about 175 nM, about 700 pM to about 170 nM, about 700 pM to about 165 nM, about 700 pM to about 160 nM, about 700 pM to about 155 nM, about 700 pM to about 150 nM, about 700 pM to about 145 nM, about 700 pM to about 140 nM, about 700 pM to about 135 nM, about 700 pM to about 130 nM, about 700 pM to about 125 nM, about 700 pM to about 120 nM, about 700 pM to about 115 nM, about 700 pM to about 110 nM, about 700 pM to about 105 nM, about 700 pM to about 100 nM, about 700 pM to about 95 nM, about 700 pM to about 90 nM, about 700 pM to about 85 nM, about 700 pM to about 80 nM, about 700 pM to about 75 nM, about 700 pM to about 70 nM, about 700 pM to about 65 nM, about 700 pM to about 60 nM, about 700 pM to about 55 nM, about 700 pM to about 50 nM, about 700 pM to about 45 nM, about 700 pM to about 40 nM, about 700 pM to about 35 nM, about 700 pM to about 30 nM, about 700 pM to about 25 nM, about 700 pM to about 20 nM, about 700 pM to about 15 nM, about 700 pM to about 10 nM, about 700 pM to about 5 nM, about 700 pM to about 2 nM, about 700 pM to about 1 nM, about 700 pM to about 950 pM, about 700 pM to about 900 pM, about 700 pM to about 850 pM, about 700 pM to about 800 pM, about 700 pM to about 750 pM, about 800 pM to about 250 nM, about 800 pM to about 245 nM, about 800 pM to about 240 nM, about 800 pM to about 235 nM, about 800 pM to about 230 nM, about 800 pM to about 225 nM, about 800 pM to about 220 nM, about 800 pM to about 215 nM, about 800 pM to about 210 nM, about 800 pM to about 205 nM, about 800 pM to about 200 nM, about 800 pM to about 195 nM, about 800 pM to about 190 nM, about 800 pM to about 185 nM, about 800 pM to about 180 nM, about 800 pM to about 175 nM, about 800 pM to about 170 nM_: about 800 pM to about 165 nM, about 800 pM to about 160 nM, about 800 pM to about 155 nM, about 800 pM to about 150 nM, about 800 pM to about 145 nM, about 800 pM to about 140 nM, about 800 pM to about 135 nM, about 800 pM to about 130 nM, about 800 pM to about 125 nM, about 800 pM to about 120 nM, about 800 pM to about 115 nM, about 800 pM to about 110 nM, about 800 pM to about 105 nM, about 800 pM to about 100 nM, about 800 pM to about 95 nM, about 800 pM to about 90 nM, about 800 pM to about 85 nM, about 800 pM to about 80 nM, about 800 pM to about 75 nM, about 800 pM to about 70 nM, about 800 pM to about 65 nM, about 800 pM to about 60 nM, about 800 pM to about 55 nM, about 800 pM to about 50 nM, about 800 pM to about 45 nM, about 800 pM to about 40 nM, about 800 pM to about 35 nM, about 800 pM to about 30 nM, about 800 pM to about 25 nM, about 800 pM to about 20 nM, about 800 pM to about 15 nM, about 800 pM to about 10 nM, about 800 pM to about 5 nM, about 800 pM to about 2 nM, about 800 pM to about 1 nM, about 800 pM to about 950 pM, about 800 pM to about 900 pM, about 800 pM to about 850 pM, about 900 pM to about 250 nM, about 900 pM to about 245 nM, about 900 pM to about 240 nM, about 900 pM to about 235 nM, about 900 pM to about 230 nM, about 900 pM to about 225 nM, about 900 pM to about 220 nM, about 900 pM to about 215 nM, about 900 pM to about 210 nM, about 900 pM to about 205 nM, about 900 pM to about 200 nM, about 900 pM to about 195 nM, about 900 pM to about 190 nM, about 900 pM to about 185 nM, about 900 pM to about 180 nM, about 900 pM to about 175 nM, about 900 pM to about 170 nM, about 900 pM to about 165 nM, about 900 pM to about 160 nM, about 900 pM to about 155 nM, about 900 pM to about 150 nM, about 900 pM to about 145 nM, about 900 pM to about 140 nM, about 900 pM to about 135 nM, about 900 pM to about 130 nM, about 900 pM to about 125 nM, about 900 pM to about 120 nM, about 900 pM to about 115 nM, about 900 pM to about 110 nM, about 900 pM to about 105 nM, about 900 pM to about 100 nM, about 900 pM to about 95 nM, about 900 pM to about 90 nM, about 900 pM to about 85 nM, about 900 pM to about 80 nM, about 900 pM to about 75 nM, about 900 pM to about 70 nM, about 900 pM to about 65 nM, about 900 pM to about 60 nM, about 900 pM to about 55 nM, about 900 pM to about 50 nM, about 900 pM to about 45 nM, about 900 pM to about 40 nM, about 900 pM to about 35 nM, about 900 pM to about 30 nM, about 900 pM to about 25 nM, about 900 pM to about 20 nM, about 900 pM to about 15 nM, about 900 pM to about 10 nM, about 900 pM to about 5 nM, about 900 pM to about 2 nM, about 900 pM to about 1 nM, about 900 pM to about 950 pM, about 1 nM to about 250 nM, about 1 nM to about 245 nM, about 1 nM to about 240 nM, about 1 nM to about 235 nM, about 1 nM to about 230 nM, about 1 nM to about 225 nM, about 1 nM to about 220 nM, about 1 nM to about 215 nM, about 1 nM to about 210 nM, about 1 nM to about 205 nM, about 1 nM to about 200 nM, about 1 nM to about 195 nM, about 1 nM to about 190 nM, about 1 nM to about 185 nM, about 1 nM to about 180 nM, about 1 nM to about 175 nM, about 1 nM to about 170 nM, about 1 nM to about 165 nM, about 1 nM to about 160 nM, about 1 nM to about 155 nM, about 1 nM to about 150 nM, about 1 nM to about 145 nM, about 1 nM to about 140 nM, about 1 nM to about 135 nM, about 1 nM to about 130 nM, about 1 nM to about 125 nM, about 1 nM to about 120 nM, about 1 nM to about 115 nM, about 1 nM to about 110 nM, about 1 nM to about 105 nM, about 1 nM to about 100 nM, about 1 nM to about 95 nM, about 1 nM to about 90 nM, about 1 nM to about 85 nM, about 1 nM to about 80 nM, about 1 nM to about 75 nM, about 1 nM to about 70 nM, about 1 nM to about 65 nM, about 1 nM to about 60 nM, about 1 nM to about 55 nM, about 1 nM to about 50 nM, about 1 nM to about 45 nM, about 1 nM to about 40 nM, about 1 nM to about 35 nM, about 1 nM to about 30 nM, about 1 nM to about 25 nM, about 1 nM to about 20 nM, about 1 nM to about 15 nM, about 1 nM to about 10 nM, about 1 nM to about 5 nM, about 2 nM to about 250 nM, about 2 nM to about 245 nM, about 2 nM to about 240 nM, about 2 nM to about 235 nM, about 2 nM to about 230 nM, about 2 nM to about 225 nM, about 2 nM to about 220 nM, about 2 nM to about 215 nM, about 2 nM to about 210 nM, about 2 nM to about 205 nM, about 2 nM to about 200 nM, about 2 nM to about 195 nM, about 2 nM to about 190 nM, about 2 nM to about 185 nM, about 2 nM to about 180 nM, about 2 nM to about 175 nM, about 2 nM to about 170 nM, about 2 nM to about 165 nM, about 2 nM to about 160 nM, about 2 nM to about 155 nM, about 2 nM to about 150 nM, about 2 nM to about 145 nM, about 2 nM to about 140 nM, about 2 nM to about 135 nM, about 2 nM to about 130 nM, about 2 nM to about 125 nM, about 2 nM to about 120 nM, about 2 nM to about 115 nM, about 2 nM to about 110 nM, about 2 nM to about 105 nM, about 2 nM to about 100 nM, about 2 nM to about 95 nM, about 2 nM to about 90 nM, about 2 nM to about 85 nM, about 2 nM to about 80 nM, about 2 nM to about 75 nM, about 2 nM to about 70 nM, about 2 nM to about 65 nM, about 2 nM to about 60 nM, about 2 nM to about 55 nM, about 2 nM to about 50 nM, about 2 nM to about 45 nM, about 2 nM to about 40 nM, about 2 nM to about 35 nM, about 2 nM to about 30 nM, about 2 nM to about 25 nM, about 2 nM to about 20 nM, about 2 nM to about 15 nM, about 2 nM to about 10 nM, about 2 nM to about 5 nM, about 4 nM to about 250 nM, about 4 nM to about 245 nM, about 4 nM to about 240 nM, about 4 nM to about 235 nM, about 4 nM to about 230 nM, about 4 nM to about 225 nM, about 4 nM to about 220 nM, about 4 nM to about 215 nM, about 4 nM to about 210 nM, about 4 nM to about 205 nM, about 4 nM to about 200 nM, about 4 nM to about 195 nM, about 4 nM to about 190 nM, about 4 nM to about 185 nM, about 4 nM to about 180 nM, about 4 nM to about 175 nM, about 4 nM to about 170 nM, about 4 nM to about 165 nM, about 4 nM to about 160 nM, about 4 nM to about 155 nM, about 4 nM to about 150 nM, about 4 nM to about 145 nM, about 4 nM to about 140 nM, about 4 nM to about 135 nM, about 4 nM to about 130 nM, about 4 nM to about 125 nM, about 4 nM to about 120 nM, about 4 nM to about 115 nM, about 4 nM to about 110 nM, about 4 nM to about 105 nM, about 4 nM to about 100 nM, about 4 nM to about 95 nM, about 4 nM to about 90 nM, about 4 nM to about 85 nM, about 4 nM to about 80 nM, about 4 nM to about 75 nM, about 4 nM to about 70 nM, about 4 nM to about 65 nM, about 4 nM to about 60 nM, about 4 nM to about 55 nM, about 4 nM to about 50 nM, about 4 nM to about 45 nM, about 4 nM to about 40 nM, about 4 nM to about 35 nM, about 4 nM to about 30 nM, about 4 nM to about 25 nM, about 4 nM to about 20 nM, about 4 nM to about 15 nM, about 4 nM to about 10 nM, about 4 nM to about 5 nM, about 5 nM to about 250 nM, about 5 nM to about 245 nM, about 5 nM to about 240 nM, about 5 nM to about 235 nM, about 5 nM to about 230 nM, about 5 nM to about 225 nM, about 5 nM to about 220 nM, about 5 nM to about 215 nM, about 5 nM to about 210 nM, about 5 nM to about 205 nM, about 5 nM to about 200 nM, about 5 nM to about 195 nM, about 5 nM to about 190 nM, about 5 nM to about 185 nM, about 5 nM to about 180 nM, about 5 nM to about 175 nM, about 5 nM to about 170 nM, about 5 nM to about 165 nM, about 5 nM to about 160 nM, about 5 nM to about 155 nM, about 5 nM to about 150 nM, about 5 nM to about 145 nM, about 5 nM to about 140 nM, about 5 nM to about 135 nM, about 5 nM to about 130 nM, about 5 nM to about 125 nM, about 5 nM to about 120 nM, about 5 nM to about 115 nM, about 5 nM to about 110 nM, about 5 nM to about 105 nM, about 5 nM to about 100 nM, about 5 nM to about 95 nM, about 5 nM to about 90 nM, about 5 nM to about 85 nM, about 5 nM to about 80 nM, about 5 nM to about 75 nM, about 5 nM to about 70 nM, about 5 nM to about 65 nM, about 5 nM to about 60 nM, about 5 nM to about 55 nM, about 5 nM to about 50 nM, about 5 nM to about 45 nM, about 5 nM to about 40 nM, about 5 nM to about 35 nM, about 5 nM to about 30 nM, about 5 nM to about 25 nM, about 5 nM to about 20 nM, about 5 nM to about 15 nM, about 5 nM to about 10 nM, about 10 nM to about 250 nM, about 10 nM to about 245 nM, about 10 nM to about 240 nM, about 10 nM to about 235 nM, about 10 nM to about 230 nM, about 10 nM to about 225 nM, about 10 nM to about 220 nM, about 10 nM to about 215 nM, about 10 nM to about 210 nM. about 10 nM to about 205 nM, about 10 nM to about 200 nM, about 10 nM to about 195 nM, about 10 nM to about 190 nM, about 10 nM to about 185 nM, about 10 nM to about 180 nM, about 10 nM to about 175 nM, about 10 nM to about 170 nM, about 10 nM to about 165 nM, about 10 nM to about 160 nM, about 10 nM to about 155 nM, about 10 nM to about 150 nM, about 10 nM to about 145 nM, about 10 nM to about 140 nM, about 10 nM to about 135 nM, about 10 nM to about 130 nM, about 10 nM to about 125 nM, about 10 nM to about 120 nM, about 10 nM to about 115 nM, about 10 nM to about 110 nM, about 10 nM to about 105 nM, about 10 nM to about 100 nM, about 10 nM to about 95 nM, about 10 nM to about 90 nM, about 10 nM to about 85 nM, about 10 nM to about 80 nM, about 10 nM to about 75 nM, about 10 nM to about 70 nM, about 10 nM to about 65 nM, about 10 nM to about 60 nM, about 10 nM to about 55 nM, about 10 nM to about 50 nM, about 10 nM to about 45 nM, about 10 nM to about 40 nM, about 10 nM to about 35 nM, about 10 nM to about 30 nM, about 10 nM to about 25 nM, about 10 nM to about 20 nM, about 10 nM to about 15 nM, about 15 nM to about 250 nM, about 15 nM to about 245 nM, about 15 nM to about 240 nM, about 15 nM to about 235 nM, about 15 nM to about 230 nM, about 15 nM to about 225 nM, about 15 nM to about 220 nM, about 15 nM to about 215 nM, about 15 nM to about 210 nM, about 15 nM to about 205 nM, about 15 nM to about 200 nM, about 15 nM to about 195 nM, about 15 nM to about 190 nM, about 15 nM to about 185 nM, about 15 nM to about 180 nM, about 15 nM to about 175 nM, about 15 nM to about 170 nM, about 15 nM to about 165 nM, about 15 nM to about 160 nM, about 15 nM to about 155 nM, about 15 nM to about 150 nM, about 15 nM to about 145 nM, about 15 nM to about 140 nM, about 15 nM to about 135 nM, about 15 nM to about 130 nM, about 15 nM to about 125 nM, about 15 nM to about 120 nM, about 15 nM to about 115 nM, about 15 nM to about 110 nM, about 15 nM to about 105 nM, about 15 nM to about 100 nM, about 15 nM to about 95 nM, about 15 nM to about 90 nM, about 15 nM to about 85 nM, about 15 nM to about 80 nM, about 15 nM to about 75 nM, about 15 nM to about 70 nM, about 15 nM to about 65 nM, about 15 nM to about 60 nM, about 15 nM to about 55 nM, about 15 nM to about 50 nM, about 15 nM to about 45 nM, about 15 nM to about 40 nM, about 15 nM to about 35 nM, about 15 nM to about 30 nM, about 15 nM to about 25 nM, about 15 nM to about 20 nM, about 20 nM to about 250 nM, about 20 nM to about 245 nM, about 20 nM to about 240 nM, about 20 nM to about 235 nM, about 20 nM to about 230 nM, about 20 nM to about 225 nM, about 20 nM to about 220 nM, about 20 nM to about 215 nM, about 20 nM to about 210 nM, about 20 nM to about 205 nM, about 20 nM to about 200 nM, about 20 nM to about 195 nM, about 20 nM to about 190 nM, about 20 nM to about 185 nM, about 20 nM to about 180 nM, about 20 nM to about 175 nM, about 20 nM to about 170 nM, about 20 nM to about 165 nM, about 20 nM to about 160 nM, about 20 nM to about 155 nM, about 20 nM to about 150 nM, about 20 nM to about 145 nM, about 20 nM to about 140 nM, about 20 nM to about 135 nM, about 20 nM to about 130 nM, about 20 nM to about 125 nM, about 20 nM to about 120 nM, about 20 nM to about 115 nM, about 20 nM to about 110 nM, about 20 nM to about 105 nM, about 20 nM to about 100 nM, about 20 nM to about 95 nM, about 20 nM to about 90 nM, about 20 nM to about 85 nM, about 20 nM to about 80 nM, about 20 nM to about 75 nM, about 20 nM to about 70 nM, about 20 nM to about 65 nM, about 20 nM to about 60 nM, about 20 nM to about 55 nM, about 20 nM to about 50 nM, about 20 nM to about 45 nM, about 20 nM to about 40 nM, about 20 nM to about 35 nM, about 20 nM to about 30 nM, about 20 nM to about 25 Nm, about 25 nM to about 250 nM, about 25 nM to about 245 nM, about 25 nM to about 240 nM, about 25 nM to about 235 nM, about 25 nM to about 230 nM, about 25 nM to about 225 nM, about 25 nM to about 220 nM, about 25 nM to about 215 nM, about 25 nM to about 210 nM, about 25 nM to about 205 nM, about 25 nM to about 200 nM, about 25 nM to about 195 nM, about 25 nM to about 190 nM, about 25 nM to about 185 nM, about 25 nM to about 180 nM, about 25 nM to about 175 nM, about 25 nM to about 170 nM, about 25 nM to about 165 nM, about 25 nM to about 160 nM, about 25 nM to about 155 nM, about 25 nM to about 150 nM, about 25 nM to about 145 nM, about 25 nM to about 140 nM, about 25 nM to about 135 nM, about 25 nM to about 130 nM, about 25 nM to about 125 nM, about 25 nM to about 120 nM, about 25 nM to about 115 nM, about 25 nM to about 110 nM, about 25 nM to about 105 nM, about 25 nM to about 100 nM, about 25 nM to about 95 nM, about 25 nM to about 90 nM, about 25 nM to about 85 nM, about 25 nM to about 80 nM, about 25 nM to about 75 nM, about 25 nM to about 70 nM, about 25 nM to about 65 nM, about 25 nM to about 60 nM, about 25 nM to about 55 nM, about 25 nM to about 50 nM, about 25 nM to about 45 nM, about 25 nM to about 40 nM, about 25 nM to about 35 nM, about 25 nM to about 30 nM, about 30 nM to about 250 nM, about 30 nM to about 245 nM, about 30 nM to about 240 nM, about 30 nM to about 235 nM, about 30 nM to about 230 nM, about 30 nM to about 225 nM, about 30 nM to about 220 nM, about 30 nM to about 215 nM, about 30 nM to about 210 nM, about 30 nM to about 205 nM, about 30 nM to about 200 nM, about 30 nM to about 195 nM, about 30 nM to about 190 nM, about 30 nM to about 185 nM, about 30 nM to about 180 nM, about 30 nM to about 175 nM, about 30 nM to about 170 nM, about 30 nM to about 165 nM, about 30 nM to about 160 nM, about 30 nM to about 155 nM, about 30 nM to about 150 nM, about 30 nM to about 145 nM, about 30 nM to about 140 nM, about 30 nM to about 135 nM, about 30 nM to about 130 nM, about 30 nM to about 125 nM, about 30 nM to about 120 nM, about 30 nM to about 115 nM, about 30 nM to about 110 nM, about 30 nM to about 105 nM, about 30 nM to about 100 nM, about 30 nM to about 95 nM, about 30 nM to about 90 nM, about 30 nM to about 85 nM, about 30 nM to about 80 nM, about 30 nM to about 75 nM, about 30 nM to about 70 nM, about 30 nM to about 65 nM, about 30 nM to about 60 nM, about 30 nM to about 55 nM, about 30 nM to about 50 nM, about 30 nM to about 45 nM, about 30 nM to about 40 nM, about 30 nM to about 35 nM, about 35 nM to about 250 nM, about 35 nM to about 245 nM, about 35 nM to about 240 nM, about 35 nM to about 235 nM, about 35 nM to about 230 nM, about 35 nM to about 225 nM, about 35 nM to about 220 nM, about 35 nM to about 215 nM, about 35 nM to about 210 nM, about 35 nM to about 205 nM, about 35 nM to about 200 nM, about 35 nM to about 195 nM, about 35 nM to about 190 nM, about 35 nM to about 185 nM, about 35 nM to about 180 nM, about 35 nM to about 175 nM, about 35 nM to about 170 nM, about 35 nM to about 165 nM, about 35 nM to about 160 nM, about 35 nM to about 155 nM, about 35 nM to about 150 nM, about 35 nM to about 145 nM, about 35 nM to about 140 nM, about 35 nM to about 135 nM, about 35 nM to about 130 nM, about 35 nM to about 125 nM, about 35 nM to about 120 nM, about 35 nM to about 115 nM, about 35 nM to about 110 nM, about 35 nM to about 105 nM, about 35 nM to about 100 nM, about 35 nM to about 95 nM, about 35 nM to about 90 nM, about 35 nM to about 85 nM, about 35 nM to about 80 nM, about 35 nM to about 75 nM, about 35 nM to about 70 nM, about 35 nM to about 65 nM, about 35 nM to about 60 nM, about 35 nM to about 55 nM, about 35 nM to about 50 nM, about 35 nM to about 45 nM, about 35 nM to about 40 nM, about 40 nM to about 250 nM, about 40 nM to about 245 nM, about 40 nM to about 240 nM, about 40 nM to about 235 nM, about 40 nM to about 230 nM, about 40 nM to about 225 nM, about 40 nM to about 220 nM, about 40 nM to about 215 nM, about 40 nM to about 210 nM, about 40 nM to about 205 nM, about 40 nM to about 200 nM, about 40 nM to about 195 nM, about 40 nM to about 190 nM, about 40 nM to about 185 nM, about 40 nM to about 180 nM, about 40 nM to about 175 nM, about 40 nM to about 170 nM, about 40 nM to about 165 nM, about 40 nM to about 160 nM, about 40 nM to about 155 nM, about 40 nM to about 150 nM, about 40 nM to about 145 nM, about 40 nM to about 140 nM, about 40 nM to about 135 nM, about 40 nM to about 130 nM, about 40 nM to about 125 nM, about 40 nM to about 120 nM, about 40 nM to about 115 nM, about 40 nM to about 110 nM, about 40 nM to about 105 nM, about 40 nM to about 100 nM, about 40 nM to about 95 nM, about 40 nM to about 90 nM, about 40 nM to about 85 nM, about 40 nM to about 80 nM, about 40 nM to about 75 nM, about 40 nM to about 70 nM, about 40 nM to about 65 nM, about 40 nM to about 60 nM, about 40 nM to about 55 nM, about 40 nM to about 50 nM, about 40 nM to about 45 nM, about 45 nM to about 250 nM, about 45 nM to about 245 nM, about 45 nM to about 240 nM, about 45 nM to about 235 nM, about 45 nM to about 230 nM, about 45 nM to about 225 nM, about 45 nM to about 220 nM, about 45 nM to about 215 nM, about 45 nM to about 210 nM, about 45 nM to about 205 nM, about 45 nM to about 200 nM, about 45 nM to about 195 nM, about 45 nM to about 190 nM, about 45 nM to about 185 nM, about 45 nM to about 180 nM, about 45 nM to about 175 nM, about 45 nM to about 170 nM, about 45 nM to about 165 nM, about 45 nM to about 160 nM, about 45 nM to about 155 nM, about 45 nM to about 150 nM, about 45 nM to about 145 nM, about 45 nM to about 140 nM, about 45 nM to about 135 nM, about 45 nM to about 130 nM, about 45 nM to about 125 nM, about 45 nM to about 120 nM, about 45 nM to about 115 nM, about 45 nM to about 110 nM, about 45 nM to about 105 nM, about 45 nM to about 100 nM, about 45 nM to about 95 nM, about 45 nM to about 90 nM, about 45 nM to about 85 nM, about 45 nM to about 80 nM, about 45 nM to about 75 nM, about 45 nM to about 70 nM, about 45 nM to about 65 nM, about 45 nM to about 60 nM, about 45 nM to about 55 nM, about 45 nM to about 50 nM, about 50 nM to about 250 nM, about 50 nM to about 245 nM, about 50 nM to about 240 nM, about 50 nM to about 235 nM, about 50 nM to about 230 nM, about 50 nM to about 225 nM, about 50 nM to about 220 nM, about 50 nM to about 215 nM, about 50 nM to about 210 nM, about 50 nM to about 205 nM, about 50 nM to about 200 nM, about 50 nM to about 195 nM, about 50 nM to about 190 nM, about 50 nM to about 185 nM, about 50 nM to about 180 nM, about 50 nM to about 175 nM, about 50 nM to about 170 nM, about 50 nM to about 165 nM, about 50 nM to about 160 nM, about 50 nM to about 155 nM, about 50 nM to about 150 nM, about 50 nM to about 145 nM, about 50 nM to about 140 nM, about 50 nM to about 135 nM, about 50 nM to about 130 nM, about 50 nM to about 125 nM, about 50 nM to about 120 nM, about 50 nM to about 115 nM, about 50 nM to about 110 nM, about 50 nM to about 105 nM, about 50 nM to about 100 nM, about 50 nM to about 95 nM, about 50 nM to about 90 nM, about 50 nM to about 85 nM, about 50 nM to about 80 nM, about 50 nM to about 75 nM, about 50 nM to about 70 nM, about 50 nM to about 65 nM, about 50 nM to about 60 nM, about 50 nM to about 55 nM, about 55 nM to about 250 nM, about 55 nM to about 245 nM, about 55 nM to about 240 nM, about 55 nM to about 235 nM, about 55 nM to about 230 nM, about 55 nM to about 225 nM, about 55 nM to about 220 nM, about 55 nM to about 215 nM, about 55 nM to about 210 nM, about 55 nM to about 205 nM, about 55 nM to about 200 nM, about 55 nM to about 195 nM, about 55 nM to about 190 nM, about 55 nM to about 185 nM, about 55 nM to about 180 nM, about 55 nM to about 175 nM, about 55 nM to about 170 nM, about 55 nM to about 165 nM, about 55 nM to about 160 nM, about 55 nM to about 155 nM, about 55 nM to about 150 nM, about 55 nM to about 145 nM, about 55 nM to about 140 nM, about 55 nM to about 135 nM, about 55 nM to about 130 nM, about 55 nM to about 125 nM, about 55 nM to about 120 nM, about 55 nM to about 115 nM, about 55 nM to about 110 nM, about 55 nM to about 105 nM, about 55 nM to about 100 nM, about 55 nM to about 95 nM, about 55 nM to about 90 nM, about 55 nM to about 85 nM, about 55 nM to about 80 nM, about 55 nM to about 75 nM, about 55 nM to about 70 nM, about 55 nM to about 65 nM, about 55 nM to about 60 nM, about 60 nM to about 250 nM, about 60 nM to about 245 nM, about 60 nM to about 240 nM, about 60 nM to about 235 nM, about 60 nM to about 230 nM, about 60 nM to about 225 nM, about 60 nM to about 220 nM, about 60 nM to about 215 nM, about 60 nM to about 210 nM, about 60 nM to about 205 nM, about 60 nM to about 200 nM, about 60 nM to about 195 nM, about 60 nM to about 190 nM, about 60 nM to about 185 nM, about 60 nM to about 180 nM, about 60 nM to about 175 nM, about 60 nM to about 170 nM, about 60 nM to about 165 nM, about 60 nM to about 160 nM, about 60 nM to about 155 nM, about 60 nM to about 150 nM, about 60 nM to about 145 nM, about 60 nM to about 140 nM, about 60 nM to about 135 nM, about 60 nM to about 130 nM, about 60 nM to about 125 nM, about 60 nM to about 120 nM, about 60 nM to about 115 nM, about 60 nM to about 110 nM, about 60 nM to about 105 nM, about 60 nM to about 100 nM, about 60 nM to about 95 nM, about 60 nM to about 90 nM, about 60 nM to about 85 nM, about 60 nM to about 80 nM, about 60 nM to about 75 nM, about 60 nM to about 70 nM, about 60 nM to about 65 nM, about 65 nM to about 250 nM, about 65 nM to about 245 nM, about 65 nM to about 240 nM, about 65 nM to about 235 nM, about 65 nM to about 230 nM, about 65 nM to about 225 nM, about 65 nM to about 220 nM, about 65 nM to about 215 nM, about 65 nM to about 210 nM, about 65 nM to about 205 nM, about 65 nM to about 200 nM, about 65 nM to about 195 nM, about 65 nM to about 190 nM, about 65 nM to about 185 nM, about 65 nM to about 180 nM, about 65 nM to about 175 nM, about 65 nM to about 170 nM, about 65 nM to about 165 nM, about 65 nM to about 160 nM, about 65 nM to about 155 nM, about 65 nM to about 150 nM, about 65 nM to about 145 nM, about 65 nM to about 140 nM, about 65 nM to about 135 nM, about 65 nM to about 130 nM, about 65 nM to about 125 nM, about 65 nM to about 120 nM, about 65 nM to about 115 nM, about 65 nM to about 110 nM, about 65 nM to about 105 nM, about 65 nM to about 100 nM, about 65 nM to about 95 nM, about 65 nM to about 90 nM, about 65 nM to about 85 nM, about 65 nM to about 80 nM, about 65 nM to about 75 nM, about 65 nM to about 70 nM, about 70 nM to about 250 nM, about 70 nM to about 245 nM, about 70 nM to about 240 nM, about 70 nM to about 235 nM, about 70 nM to about 230 nM, about 70 nM to about 225 nM, about 70 nM to about 220 nM, about 70 nM to about 215 nM, about 70 nM to about 210 nM, about 70 nM to about 205 nM, about 70 nM to about 200 nM, about 70 nM to about 195 nM, about 70 nM to about 190 nM, about 70 nM to about 185 nM, about 70 nM to about 180 nM, about 70 nM to about 175 nM, about 70 nM to about 170 nM, about 70 nM to about 165 nM, about 70 nM to about 160 nM, about 70 nM to about 155 nM, about 70 nM to about 150 nM, about 70 nM to about 145 nM, about 70 nM to about 140 nM, about 70 nM to about 135 nM, about 70 nM to about 130 nM, about 70 nM to about 125 nM, about 70 nM to about 120 nM, about 70 nM to about 115 nM, about 70 nM to about 110 nM, about 70 nM to about 105 nM, about 70 nM to about 100 nM, about 70 nM to about 95 nM, about 70 nM to about 90 nM, about 70 nM to about 85 nM, about 70 nM to about 80 nM, about 70 nM to about 75 nM, about 75 nM to about 250 nM, about 75 nM to about 245 nM, about 75 nM to about 240 nM, about 75 nM to about 235 nM, about 75 nM to about 230 nM, about 75 nM to about 225 nM, about 75 nM to about 220 nM, about 75 nM to about 215 nM, about 75 nM to about 210 nM, about 75 nM to about 205 nM, about 75 nM to about 200 nM, about 75 nM to about 195 nM, about 75 nM to about 190 nM, about 75 nM to about 185 nM, about 75 nM to about 180 nM, about 75 nM to about 175 nM, about 75 nM to about 170 nM, about 75 nM to about 165 nM, about 75 nM to about 160 nM, about 75 nM to about 155 nM, about 75 nM to about 150 nM, about 75 nM to about 145 nM, about 75 nM to about 140 nM, about 75 nM to about 135 nM, about 75 nM to about 130 nM, about 75 nM to about 125 nM, about 75 nM to about 120 nM, about 75 nM to about 115 nM, about 75 nM to about 110 nM, about 75 nM to about 105 nM, about 75 nM to about 100 nM, about 75 nM to about 95 nM, about 75 nM to about 90 nM, about 75 nM to about 85 nM, about 75 nM to about 80 nM, about 80 nM to about 250 nM, about 80 nM to about 245 nM, about 80 nM to about 240 nM, about 80 nM to about 235 nM, about 80 nM to about 230 nM, about 80 nM to about 225 nM, about 80 nM to about 220 nM, about 80 nM to about 215 nM, about 80 nM to about 210 nM, about 80 nM to about 205 nM, about 80 nM to about 200 nM, about 80 nM to about 195 nM, about 80 nM to about 190 nM, about 80 nM to about 185 nM, about 80 nM to about 180 nM, about 80 nM to about 175 nM, about 80 nM to about 170 nM, about 80 nM to about 165 nM, about 80 nM to about 160 nM, about 80 nM to about 155 nM, about 80 nM to about 150 nM, about 80 nM to about 145 nM, about 80 nM to about 140 nM, about 80 nM to about 135 nM, about 80 nM to about 130 nM, about 80 nM to about 125 nM, about 80 nM to about 120 nM, about 80 nM to about 115 nM, about 80 nM to about 110 nM, about 80 nM to about 105 nM, about 80 nM to about 100 nM, about 80 nM to about 95 nM, about 80 nM to about 90 nM, about 80 nM to about 85 nM, about 85 nM to about 250 nM, about 85 nM to about 245 nM, about 85 nM to about 240 nM, about 85 nM to about 235 nM, about 85 nM to about 230 nM, about 85 nM to about 225 nM, about 85 nM to about 220 nM, about 85 nM to about 215 nM, about 85 nM to about 210 nM, about 85 nM to about 205 nM, about 85 nM to about 200 nM, about 85 nM to about 195 nM, about 85 nM to about 190 nM, about 85 nM to about 185 nM, about 85 nM to about 180 nM, about 85 nM to about 175 nM, about 85 nM to about 170 nM, about 85 nM to about 165 nM, about 85 nM to about 160 nM, about 85 nM to about 155 nM, about 85 nM to about 150 nM, about 85 nM to about 145 nM, about 85 nM to about 140 nM, about 85 nM to about 135 nM, about 85 nM to about 130 nM, about 85 nM to about 125 nM, about 85 nM to about 120 nM, about 85 nM to about 115 nM, about 85 nM to about 110 nM, about 85 nM to about 105 nM, about 85 nM to about 100 nM, about 85 nM to about 95 nM, about 85 nM to about 90 nM, about 90 nM to about 250 nM, about 90 nM to about 245 nM, about 90 nM to about 240 nM, about 90 nM to about 235 nM, about 90 nM to about 230 nM, about 90 nM to about 225 nM, about 90 nM to about 220 nM, about 90 nM to about 215 nM, about 90 nM to about 210 nM, about 90 nM to about 205 nM, about 90 nM to about 200 nM, about 90 nM to about 195 nM, about 90 nM to about 190 nM, about 90 nM to about 185 nM, about 90 nM to about 180 nM, about 90 nM to about 175 nM, about 90 nM to about 170 nM, about 90 nM to about 165 nM, about 90 nM to about 160 nM, about 90 nM to about 155 nM, about 90 nM to about 150 nM, about 90 nM to about 145 nM, about 90 nM to about 140 nM, about 90 nM to about 135 nM, about 90 nM to about 130 nM, about 90 nM to about 125 nM, about 90 nM to about 120 nM, about 90 nM to about 115 nM, about 90 nM to about 110 nM, about 90 nM to about 105 nM, about 90 nM to about 100 nM, about 90 nM to about 95 nM, about 95 nM to about 250 nM, about 95 nM to about 245 nM, about 95 nM to about 240 nM, about 95 nM to about 235 nM, about 95 nM to about 230 nM, about 95 nM to about 225 nM, about 95 nM to about 220 nM, about 95 nM to about 215 nM, about 95 nM to about 210 nM, about 95 nM to about 205 nM, about 95 nM to about 200 nM, about 95 nM to about 195 nM, about 95 nM to about 190 nM, about 95 nM to about 185 nM, about 95 nM to about 180 nM, about 95 nM to about 175 nM, about 95 nM to about 170 nM, about 95 nM to about 165 nM, about 95 nM to about 160 nM, about 95 nM to about 155 nM, about 95 nM to about 150 nM, about 95 nM to about 145 nM, about 95 nM to about 140 nM, about 95 nM to about 135 nM, about 95 nM to about 130 nM, about 95 nM to about 125 nM, about 95 nM to about 120 nM, about 95 nM to about 115 nM, about 95 nM to about 110 nM, about 95 nM to about 105 nM, about 95 nM to about 100 nM, about 100 nM to about 250 nM, about 100 nM to about 245 nM, about 100 nM to about 240 nM, about 100 nM to about 235 nM, about 100 nM to about 230 nM, about 100 nM to about 225 nM, about 100 nM to about 220 nM, about 100 nM to about 215 nM, about 100 nM to about 210 nM, about 100 nM to about 205 nM, about 100 nM to about 200 nM, about 100 nM to about 195 nM, about 100 nM to about 190 nM, about 100 nM to about 185 nM, about 100 nM to about 180 nM, about 100 nM to about 175 nM, about 100 nM to about 170 nM, about 100 nM to about 165 nM, about 100 nM to about 160 nM, about 100 nM to about 155 nM, about 100 nM to about 150 nM, about 100 nM to about 145 nM, about 100 nM to about 140 nM, about 100 nM to about 135 nM, about 100 nM to about 130 nM, about 100 nM to about 125 nM, about 100 nM to about 120 nM, about 100 nM to about 115 nM, about 100 nM to about 110 nM, about 100 nM to about 105 nM, about 105 nM to about 250 nM, about 105 nM to about 245 nM, about 105 nM to about 240 nM, about 105 nM to about 235 nM, about 105 nM to about 230 nM, about 105 nM to about 225 nM, about 105 nM to about 220 nM, about 105 nM to about 215 nM, about 105 nM to about 210 nM, about 105 nM to about 205 nM, about 105 nM to about 200 nM, about 105 nM to about 195 nM, about 105 nM to about 190 nM, about 105 nM to about 185 nM, about 105 nM to about 180 nM, about 105 nM to about 175 nM, about 105 nM to about 170 nM, about 105 nM to about 165 nM, about 105 nM to about 160 nM, about 105 nM to about 155 nM, about 105 nM to about 150 nM, about 105 nM to about 145 nM, about 105 nM to about 140 nM, about 105 nM to about 135 nM, about 105 nM to about 130 nM, about 105 nM to about 125 nM, about 105 nM to about 120 nM, about 105 nM to about 115 nM, about 105 nM to about 110 nM, about 110 nM to about 250 nM, about 110 nM to about 245 nM, about 110 nM to about 240 nM, about 110 nM to about 235 nM, about 110 nM to about 230 nM, about 110 nM to about 225 nM, about 110 nM to about 220 nM, about 110 nM to about 215 nM, about 110 nM to about 210 nM, about 110 nM to about 205 nM, about 110 nM to about 200 nM, about 110 nM to about 195 nM, about 110 nM to about 190 nM, about 110 nM to about 185 nM, about 110 nM to about 180 nM, about 110 nM to about 175 nM, about 110 nM to about 170 nM, about 110 nM to about 165 nM, about 110 nM to about 160 nM, about 110 nM to about 155 nM, about 110 nM to about 150 nM, about 110 nM to about 145 nM, about 110 nM to about 140 nM, about 110 nM to about 135 nM, about 110 nM to about 130 nM, about 110 nM to about 125 nM, about 110 nM to about 120 nM, about 110 nM to about 115 nM, about 115 nM to about 250 nM, about 115 nM to about 245 nM, about 115 nM to about 240 nM, about 115 nM to about 235 nM, about 115 nM to about 230 nM, about 115 nM to about 225 nM, about 115 nM to about 220 nM, about 115 nM to about 215 nM, about 115 nM to about 210 nM, about 115 nM to about 205 nM, about 115 nM to about 200 nM, about 115 nM to about 195 nM, about 115 nM to about 190 nM, about 115 nM to about 185 nM, about 115 nM to about 180 nM, about 115 nM to about 175 nM, about 115 nM to about 170 nM, about 115 nM to about 165 nM, about 115 nM to about 160 nM, about 115 nM to about 155 nM, about 115 nM to about 150 nM, about 115 nM to about 145 nM, about 115 nM to about 140 nM, about 115 nM to about 135 nM, about 115 nM to about 130 nM, about 115 nM to about 125 nM, about 115 nM to about 120 nM, about 120 nM to about 250 nM, about 120 nM to about 245 nM, about 120 nM to about 240 nM, about 120 nM to about 235 nM, about 120 nM to about 230 nM, about 120 nM to about 225 nM, about 120 nM to about 220 nM, about 120 nM to about 215 nM, about 120 nM to about 210 nM, about 120 nM to about 205 nM, about 120 nM to about 200 nM, about 120 nM to about 195 nM, about 120 nM to about 190 nM, about 120 nM to about 185 nM, about 120 nM to about 180 nM, about 120 nM to about 175 nM, about 120 nM to about 170 nM, about 120 nM to about 165 nM, about 120 nM to about 160 nM, about 120 nM to about 155 nM, about 120 nM to about 150 nM, about 120 nM to about 145 nM, about 120 nM to about 140 nM, about 120 nM to about 135 nM, about 120 nM to about 130 nM, about 120 nM to about 125 nM, about 125 nM to about 250 nM, about 125 nM to about 245 nM, about 125 nM to about 240 nM, about 125 nM to about 235 nM, about 125 nM to about 230 nM, about 125 nM to about 225 nM, about 125 nM to about 220 nM, about 125 nM to about 215 nM, about 125 nM to about 210 nM, about 125 nM to about 205 nM, about 125 nM to about 200 nM, about 125 nM to about 195 nM, about 125 nM to about 190 nM, about 125 nM to about 185 nM, about 125 nM to about 180 nM, about 125 nM to about 175 nM, about 125 nM to about 170 nM, about 125 nM to about 165 nM, about 125 nM to about 160 nM, about 125 nM to about 155 nM, about 125 nM to about 150 nM, about 125 nM to about 145 nM, about 125 nM to about 140 nM, about 125 nM to about 135 nM, about 125 nM to about 130 nM, about 130 nM to about 250 nM, about 130 nM to about 245 nM, about 130 nM to about 240 nM, about 130 nM to about 235 nM, about 130 nM to about 230 nM, about 130 nM to about 225 nM, about 130 nM to about 220 nM, about 130 nM to about 215 nM, about 130 nM to about 210 nM, about 130 nM to about 205 nM, about 130 nM to about 200 nM, about 130 nM to about 195 nM, about 130 nM to about 190 nM, about 130 nM to about 185 nM, about 130 nM to about 180 nM, about 130 nM to about 175 nM, about 130 nM to about 170 nM, about 130 nM to about 165 nM, about 130 nM to about 160 nM, about 130 nM to about 155 nM, about 130 nM to about 150 nM, about 130 nM to about 145 nM, about 130 nM to about 140 nM, about 130 nM to about 135 nM, about 135 nM to about 250 nM, about 135 nM to about 245 nM, about 135 nM to about 240 nM, about 135 nM to about 235 nM, about 135 nM to about 230 nM, about 135 nM to about 225 nM, about 135 nM to about 220 nM, about 135 nM to about 215 nM, about 135 nM to about 210 nM, about 135 nM to about 205 nM, about 135 nM to about 200 nM, about 135 nM to about 195 nM, about 135 nM to about 190 nM, about 135 nM to about 185 nM, about 135 nM to about 180 nM, about 135 nM to about 175 nM, about 135 nM to about 170 nM, about 135 nM to about 165 nM, about 135 nM to about 160 nM, about 135 nM to about 155 nM, about 135 nM to about 150 nM, about 135 nM to about 145 nM, about 135 nM to about 140 nM, about 140 nM to about 250 nM, about 140 nM to about 245 nM, about 140 nM to about 240 nM, about 140 nM to about 235 nM, about 140 nM to about 230 nM, about 140 nM to about 225 nM, about 140 nM to about 220 nM, about 140 nM to about 215 nM, about 140 nM to about 210 nM, about 140 nM to about 205 nM, about 140 nM to about 200 nM, about 140 nM to about 195 nM, about 140 nM to about 190 nM, about 140 nM to about 185 nM, about 140 nM to about 180 nM, about 140 nM to about 175 nM, about 140 nM to about 170 nM, about 140 nM to about 165 nM, about 140 nM to about 160 nM, about 140 nM to about 155 nM, about 140 nM to about 150 nM, about 140 nM to about 145 nM, about 145 nM to about 250 nM, about 145 nM to about 245 nM, about 145 nM to about 240 nM, about 145 nM to about 235 nM, about 145 nM to about 230 nM, about 145 nM to about 225 nM, about 145 nM to about 220 nM, about 145 nM to about 215 nM, about 145 nM to about 210 nM, about 145 nM to about 205 nM, about 145 nM to about 200 nM, about 145 nM to about 195 nM, about 145 nM to about 190 nM, about 145 nM to about 185 nM, about 145 nM to about 180 nM, about 145 nM to about 175 nM, about 145 nM to about 170 nM, about 145 nM to about 165 nM, about 145 nM to about 160 nM, about 145 nM to about 155 nM, about 145 nM to about 150 nM, about 150 nM to about 250 nM, about 150 nM to about 245 nM, about 150 nM to about 240 nM, about 150 nM to about 235 nM, about 150 nM to about 230 nM, about 150 nM to about 225 nM, about 150 nM to about 220 nM, about 150 nM to about 215 nM, about 1 0 nM to about 210 nM, about 150 nM to about 205 nM, about 150 nM to about 200 nM, about 150 nM to about 195 nM, about 150 nM to about 190 nM, about 150 nM to about 185 nM, about 150 nM to about 180 nM, about 150 nM to about 175 nM, about 150 nM to about 170 nM, about 150 nM to about 165 nM_: about 150 nM to about 160 nM, about 150 nM to about 155 nM, about 155 nM to about 250 nM, about 155 nM to about 245 nM, about 155 nM to about 240 nM, about 155 nM to about 235 nM, about 155 nM to about 230 nM, about 155 nM to about 225 nM, about 155 nM to about 220 nM, about 155 nM to about 215 nM, about 155 nM to about 210 nM, about 155 nM to about 205 nM, about 155 nM to about 200 nM, about 155 nM to about 195 nM, about 155 nM to about 190 nM, about 155 nM to about 185 nM, about 155 nM to about 180 nM, about 155 nM to about 175 nM, about 155 nM to about 170 nM, about 155 nM to about 165 nM, about 155 nM to about 160 nM, about 160 nM to about 250 nM, about 160 nM to about 245 nM, about 160 nM to about 240 nM, about 160 nM to about 235 nM, about 160 nM to about 230 nM, about 160 nM to about 225 nM, about 160 nM to about 220 nM, about 160 nM to about 215 nM, about 160 nM to about 210 nM, about 160 nM to about 205 nM, about 160 nM to about 200 nM, about 160 nM to about 195 nM, about 160 nM to about 190 nM, about 160 nM to about 185 nM, about 160 nM to about 180 nM, about 160 nM to about 175 nM, about 160 nM to about 170 nM, about 160 nM to about 165 nM, about 165 nM to about 250 nM, about 165 nM to about 245 nM, about 165 nM to about 240 nM, about 165 nM to about 235 nM, about 165 nM to about 230 nM, about 165 nM to about 225 nM, about 165 nM to about 220 nM, about 165 nM to about 215 nM, about 165 nM to about 210 nM, about 165 nM to about 205 nM, about 165 nM to about 200 nM, about 165 nM to about 195 nM, about 165 nM to about 190 nM, about 165 nM to about 185 nM, about 165 nM to about 180 nM, about 165 nM to about 175 nM, about 165 nM to about 170 nM, about 170 nM to about 250 nM, about 170 nM to about 245 nM, about 170 nM to about 240 nM, about 170 nM to about 235 nM, about 170 nM to about 230 nM, about 170 nM to about 225 nM, about 170 nM to about 220 nM, about 170 nM to about 215 nM, about 170 nM to about 210 nM, about 170 nM to about 205 nM, about 170 nM to about 200 nM, about 170 nM to about 195 nM, about 170 nM to about 190 nM, about 170 nM to about 185 nM, about 170 nM to about 180 nM, about 170 nM to about 175 nM, about 175 nM to about 250 nM, about 175 nM to about 245 nM, about 175 nM to about 240 nM, about 175 nM to about 235 nM, about 175 nM to about 230 nM, about 175 nM to about 225 nM, about 175 nM to about 220 nM, about 175 nM to about 215 nM, about 175 nM to about 210 nM, about 175 nM to about 205 nM, about 175 nM to about 200 nM, about 175 nM to about 195 nM, about 175 nM to about 190 nM, about 175 nM to about 185 nM, about 175 nM to about 180 nM, about 180 nM to about 250 nM, about 180 nM to about 245 nM, about 180 nM to about 240 nM, about 180 nM to about 235 nM, about 180 nM to about 230 nM, about 180 nM to about 225 nM, about 180 nM to about 220 nM, about 180 nM to about 215 nM, about 180 nM to about 210 nM, about 180 nM to about 205 nM, about 180 nM to about 200 nM, about 180 nM to about 195 nM, about 180 nM to about 190 nM, about 180 nM to about 185 nM, about 185 nM to about 250 nM, about 185 nM to about 245 nM, about 185 nM to about 240 nM, about 185 nM to about 235 nM, about 185 nM to about 230 nM, about 185 nM to about 225 nM, about 185 nM to about 220 nM, about 185 nM to about 215 nM, about 185 nM to about 210 nM, about 185 nM to about 205 nM, about 185 nM to about 200 nM, about 185 nM to about 195 nM, about 185 nM to about 190 nM, about 190 nM to about 250 nM, about 190 nM to about 245 nM, about 190 nM to about 240 nM, about 190 nM to about 235 nM, about 190 nM to about 230 nM, about 190 nM to about 225 nM, about 190 nM to about 220 nM, about 190 nM to about 215 nM, about 190 nM to about 210 nM, about 190 nM to about 205 nM, about 190 nM to about 200 nM, about 190 nM to about 195 nM, about 195 nM to about 250 nM, about 195 nM to about 245 nM, about 195 nM to about 240 nM, about 195 nM to about 235 nM, about 195 nM to about 230 nM, about 195 nM to about 225 nM, about 195 nM to about 220 nM, about 195 nM to about 215 nM, about 195 nM to about 210 nM, about 195 nM to about 205 nM, about 195 nM to about 200 nM, about 200 nM to about 250 nM, about 200 nM to about 245 nM, about 200 nM to about 240 nM, about 200 nM to about 235 nM, about 200 nM to about 230 nM, about 200 nM to about 225 nM, about 200 nM to about 220 nM, about 200 nM to about 215 nM, about 200 nM to about 210 nM, about 200 nM to about 205 nM, about 205 nM to about 250 nM, about 205 nM to about 245 nM, about 205 nM to about 240 nM, about 205 nM to about 235 nM, about 205 nM to about 230 nM, about 205 nM to about 225 nM, about 205 nM to about 220 nM, about 205 nM to about 215 nM, about 205 nM to about 210 nM, about 210 nM to about 250 nM, about 210 nM to about 245 nM, about 210 nM to about 240 nM, about 210 nM to about 235 nM, about 210 nM to about 230 nM, about 210 nM to about 225 nM, about 210 nM to about 220 nM, about 210 nM to about 215 nM, about 215 nM to about 250 nM, about 215 nM to about 245 nM, about 215 nM to about 240 nM, about 215 nM to about 235 nM, about 215 nM to about 230 nM, about 215 nM to about 225 nM, about 215 nM to about 220 nM, about 220 nM to about 250 nM, about 220 nM to about 245 nM, about 220 nM to about 240 nM, about 220 nM to about 235 nM, about 220 nM to about 230 nM, about 220 nM to about 225 nM, about 225 nM to about 250 nM, about 225 nM to about 245 nM, about 225 nM to about 240 nM, about 225 nM to about 235 nM, about 225 nM to about 230 nM, about 230 nM to about 250 nM, about 230 nM to about 245 nM, about 230 nM to about 240 nM, about 230 nM to about 235 nM, about 235 nM to about 250 nM_: about 235 nM to about 245 nM, about 235 nM to about 240 nM, about 240 nM to about 250 nM, about 240 nM to about 245 nM, and about 240 nM to about 250 nM).

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the KD of the first antigen-binding domain at a neutral pH (e.g., any of the neutral pHs described herein) and/or an acidic pH (e.g., any of the acidic pHs described herein) is between about 250 nM to about lmM (e.g., about 250 nM to about 900 μΜ, about 250 nM to about 800 μΜ, about 250 nM to about 700 μΜ, about 250 nM to about 600 μΜ, about 250 nM to about 500 μΜ, about 250 nM to about 400 μΜ, about 250 nM to about 300 μΜ, about 250 nM to about 200 μΜ, about 250 nM to about 100 μΜ, about 250 nM to about 90 μΜ, about 250 nM to about 80 μΜ, about 250 nM to about 70 μΜ, about 250 nM to about 60 μΜ, about 250 nM to about 50 uM, about 250 nM to about 40 μΜ, about 250 nM to about 30 μΜ, about 250 nM to about 20 uM, about 250 nM to about 10 μΜ, about 250 nM to about 5 μΜ, about 250 nM to about 4 μΜ, about 250 nM to about 2 μΜ, about 250 nM to about 1 μΜ, about 250 nM to about 900 nM, about 250 nM to about 800 nM, about 250 nM to about 700 nM, about 250 nM to about 600 nM, about 250 nM to about 500 nM, about 250 nM to about 400 nM, about 250 nM to about 300 nM, about 300 nM to about 900 μΜ, about 300 nM to about 800 μΜ, about 300 nM to about 700 μΜ, about 300 nM to about 600 uM, about 300 nM to about 500 μΜ, about 300 nM to about 400 μΜ, about 300 nM to about 300 μΜ, about 300 nM to about 200 μΜ, about 300 nM to about 100 μΜ, about 300 nM to about 90 μΜ, about 300 nM to about 80 μΜ, about 300 nM to about 70 μΜ, about 300 nM to about 60 μΜ, about 300 nM to about 50 μΜ, about 300 nM to about 40 μΜ, about 300 nM to about 30 μΜ, about 300 nM to about 20 μΜ, about 300 nM to about 10 μΜ, about 300 nM to about 5 μΜ, about 300 nM to about 4 μΜ, about 300 nM to about 2 μΜ, about 300 nM to about 1 μΜ, about 300 nM to about 900 nM, about 300 nM to about 800 nM, about 300 nM to about 700 nM, about 300 nM to about 600 nM, about 300 nM to about 500 nM, about 300 nM to about 400 nM, about 400 nM to about 900 μΜ, about 400 nM to about 800 μΜ, about 400 nM to about 700 μΜ, about 400 nM to about 600 μΜ, about 400 nM to about 500 uM, about 400 nM to about 400 μΜ, about 400 nM to about 300 μΜ, about 400 nM to about 200 μΜ, about 400 nM to about 100 μΜ, about 400 nM to about 90 μΜ, about 400 nM to about 80 μΜ, about 400 nM to about 70 μΜ, about 400 nM to about 60 μΜ, about 400 nM to about 50 μΜ, about 400 nM to about 40 μΜ, about 400 nM to about 30 μΜ, about 400 nM to about 20 μΜ, about 400 nM to about 10 μΜ, about 400 nM to about 5 μΜ, about 400 nM to about 4 μΜ, about 400 nM to about 2 μΜ, about 400 nM to about 1 μΜ, about 400 nM to about 900 nM, about 400 nM to about 800 nM, about 400 nM to about 700 nM, about 400 nM to about 600 nM_; about 400 nM to about 500 nM, about 500 nM to about 900 μΜ, about 500 nM to about 800 μΜ, about 500 nM to about 700 μΜ, about 500 nM to about 600 μΜ, about 500 nM to about 500 μΜ, about 500 nM to about 400 μΜ, about 500 nM to about 300 μΜ, about 500 nM to about 200 μΜ, about 500 nM to about 100 μΜ, about 500 nM to about 90 μΜ_; about 500 nM to about 80 μΜ, about 500 nM to about 70 μΜ, about 500 nM to about 60 μΜ, about 500 nM to about 50 μΜ, about 500 nM to about 40 μΜ, about 500 nM to about 30 μΜ, about 500 nM to about 20 μΜ, about 500 nM to about 10 μΜ, about 500 nM to about 5 μΜ, about 500 nM to about 4 μΜ, about 500 nM to about 2 μΜ, about 500 nM to about 1 μΜ, about 500 nM to about 900 nM, about 500 nM to about 800 nM, about 500 nM to about 700 nM, about 500 nM to about 600 nM, about 1 μΜ to about 1 mM, about 1 μΜ to about 900 μΜ, about 1 μΜ to about 800 μΜ, about 1 μΜ to about 700 μΜ, about 1 μΜ to about 600 μΜ, about 1 μΜ to about 500 μΜ, about 1 μΜ to about 400 μΜ, about 1 μΜ to about 300 μΜ, about 1 μΜ to about 200 μΜ, about 1 μΜ to about 100 μΜ, about 1 μΜ to about 90 μΜ, about 1 μΜ to about 80 μΜ, about 1 μΜ to about 70 μΜ, about 1 μΜ to about 60 μΜ, about

1 μΜ to about 50 μΜ, about 1 μΜ to about 40 μΜ, about 1 μΜ to about 30 μΜ, about 1 μΜ to about 20 μΜ, about 1 μΜ to about 10 μΜ, about 1 μΜ to about 5 μΜ, about 1 μΜ to about

4 μΜ, about 1 μΜ to about 3 μΜ, about 1 μΜ to about 2 μΜ, about 2 μΜ to about 1 mM, about 2 μΜ to about 900 μΜ, about 2 μΜ to about 800 μΜ, about 2 μΜ to about 700 μΜ, about 2 μΜ to about 600 μΜ, about 2 μΜ to about 500 μΜ, about 2 μΜ to about 400 μΜ, about 2 μΜ to about 300 μΜ, about 2 μΜ to about 200 μΜ, about 2 μΜ to about 100 μΜ, about 2 μΜ to about 90 μΜ, about 2 μΜ to about 80 μΜ, about 2 μΜ to about 70 μΜ, about

2 μΜ to about 60 μΜ, about 2 μΜ to about 50 μΜ, about 2 μΜ to about 40 μΜ, about 2 μΜ to about 30 μΜ, about 2 μΜ to about 20 μΜ, about 2 μΜ to about 10 μΜ, about 2 μΜ to about 5 μΜ, about 2 μΜ to about 4 μΜ, about 2 μΜ to about 3 μΜ, about 5 μΜ to about 1 mM, about 5 μΜ to about 900 μΜ, about 5 μΜ to about 800 μΜ, about 5 μΜ to about 700 μΜ, about 5 μΜ to about 600 μΜ, about 5 μΜ to about 500 μΜ, about 5 μΜ to about 400 μΜ, about 5 μΜ to about 300 μΜ, about 5 μΜ to about 200 μΜ, about 5 μΜ to about 100 μΜ, about 5 μΜ to about 90 μΜ, about 5 μΜ to about 80 μΜ, about 5 μΜ to about 70 μΜ, about 5 μΜ to about 60 μΜ, about 5 μΜ to about 50 μΜ, about 5 μΜ to about 40 μΜ, about

5 μΜ to about 30 μΜ, about 5 μΜ to about 20 μΜ, about 5 μΜ to about 10 μΜ, about 10 μΜ to about 1 mM, about 10 μΜ to about 900 μΜ, about 10 μΜ to about 800 μΜ, about 10 μΜ to about 700 μΜ, about 10 μΜ to about 600 μΜ, about 10 μΜ to about 500 μΜ, about 10 μΜ to about 400 μΜ, about 10 μΜ to about 300 μΜ, about 10 μΜ to about 200 μΜ, about 10 uM to about 100 μΜ, about 10 μΜ to about 90 μΜ, about 10 μΜ to about 80 μΜ, about 10 μΜ to about 70 μΜ, about 10 μΜ to about 60 μΜ, about 10 μΜ to about 50 μΜ, about 10 μΜ to about 40 μΜ, about 10 μΜ to about 30 μΜ, about 10 μΜ to about 20 μΜ, about 20 μΜ to about 1 mM, about 20 μΜ to about 900 μΜ, about 20 μΜ to about 800 μΜ, about 20 μΜ to about 700 μΜ, about 20 μΜ to about 600 μΜ, about 20 μΜ to about 500 μΜ, about 20 μΜ to about 400 μΜ, about 20 μΜ to about 300 μΜ, about 20 μΜ to about 200 μΜ, about 20 μΜ to about 100 μΜ, about 20 μΜ to about 90 μΜ, about 20 μΜ to about 80 μΜ, about 20 μΜ to about 70 μΜ, about 20 μΜ to about 60 μΜ, about 20 μΜ to about 50 μΜ, about 20 μΜ to about 40 μΜ, about 20 μΜ to about 30 μΜ, about 30 μΜ to about 1 mM, about 30 μΜ to about 900 μΜ, about 30 μΜ to about 800 μΜ, about 30 μΜ to about 700 μΜ, about 30 μΜ to about 600 μΜ, about 30 μΜ to about 500 μΜ, about 30 μΜ to about 400 μΜ, about 30 μΜ to about 300 μΜ, about 30 μΜ to about 200 μΜ, about 30 μΜ to about 100 μΜ, about 30 μΜ to about 90 μΜ, about 30 μΜ to about 80 μΜ, about 30 μΜ to about 70 μΜ, about 30 μΜ to about 60 μΜ, about 30 μΜ to about 50 μΜ, about 30 μΜ to about 40 μΜ, about 40 μΜ to about 1 mM, about 40 μΜ to about 900 μΜ, about 40 μΜ to about 800 μΜ, about 40 μΜ to about 700 μΜ, about 40 μΜ to about 600 μΜ, about 40 μΜ to about 500 μΜ, about 40 μΜ to about 400 μΜ, about 40 μΜ to about 300 μΜ, about 40 μΜ to about 200 μΜ, about 40 μΜ to about 100 μΜ, about 40 μΜ to about 90 μΜ, about 40 μΜ to about 80 μΜ, about 40 μΜ to about 70 μΜ, about 40 μΜ to about 60 μΜ, about 40 μΜ to about 50 μΜ, about 50 μΜ to about 1 mM, about 50 μΜ to about 900 μΜ, about 50 μΜ to about 800 μΜ, about 50 μΜ to about 700 μΜ, about 50 μΜ to about 600 μΜ, about 50 μΜ to about 500 μΜ, about 50 μΜ to about 400 μΜ, about 50 μΜ to about 300 μΜ, about 50 μΜ to about 200 μΜ, about 50 μΜ to about 100 μΜ, about 50 μΜ to about 90 μΜ, about 50 μΜ to about 80 μΜ, about 50 μΜ to about 70 μΜ, about 50 μΜ to about 60 μΜ, about 60 μΜ to about 1 mM, about 60 μΜ to about 900 μΜ, about 60 μΜ to about 800 μΜ, about 60 μΜ to about 700 μΜ, about 60 μΜ to about 600 μΜ, about 60 μΜ to about 500 μΜ, about 60 μΜ to about 400 μΜ, about 60 μΜ to about 300 μΜ, about 60 μΜ to about 200 μΜ, about 60 μΜ to about 100 μΜ, about 60 μΜ to about 90 μΜ, about 60 μΜ to about 80 μΜ, about 60 μΜ to about 70 μΜ, about 70 μΜ to about 1 mM, about 70 μΜ to about 900 μΜ, about 70 μΜ to about 800 μΜ, about 70 μΜ to about 700 μΜ, about 70 μΜ to about 600 μΜ, about 70 μΜ to about 500 μΜ, about 70 μΜ to about 400 μΜ, about 70 μΜ to about 300 μΜ, about 70 μΜ to about 200 μΜ, about 70 μΜ to about 100 μΜ, about 70 μΜ to about 90 μΜ, about 70 μΜ to about 80 μΜ, about 80 μΜ to about 1 mM, about 80 μΜ to about 900 μΜ, about 80 μΜ to about 800 μΜ, about 80 μΜ to about 700 μΜ, about 80 μΜ to about 600 μΜ, about 80 μΜ to about 500 μΜ, about 80 μΜ to about 400 μΜ, about 80 μΜ to about 300 μΜ, about 80 μΜ to about 200 μΜ, about 80 μΜ to about 100 μΜ, about 80 μΜ to about 90 μΜ, about 90 μΜ to about 1 mM, about 90 μΜ to about 900 μΜ, about 90 μΜ to about 800 μΜ, about 90 μΜ to about 700 μΜ, about 90 μΜ to about 600 μΜ, about 90 μΜ to about 500 μΜ, about 90 μΜ to about 400 μΜ, about 90 μΜ to about 300 μΜ, about 90 μΜ to about 200 μΜ, about 90 μΜ to about 100 μΜ, about 100 μΜ to about 1 mM, about 100 μΜ to about 900 μΜ, about 100 μΜ to about 800 μΜ, about 100 μΜ to about 700 μΜ, about 100 μΜ to about 600 μΜ, about 100 μΜ to about 500 μΜ, about 100 μΜ to about 400 μΜ, about 100 μΜ to about 300 μΜ, about 100 μΜ to about 200 μΜ, about 200 μΜ to about 1 mM, about 200 μΜ to about 900 μΜ, about 200 μΜ to about 800 μΜ, about 200 μΜ to about 700 μΜ, about 200 μΜ to about 600 μΜ, about 200 μΜ to about 500 μΜ, about 200 μΜ to about 400 μΜ, about 200 μΜ to about 300 μΜ, about 300 μΜ to about 1 mM, about 300 μΜ to about 900 μΜ, about 300 μΜ to about 800 μΜ, about 300 μΜ to about 700 μΜ, about 300 μΜ to about 600 μΜ, about 300 μΜ to about 500 μΜ, about 300 μΜ to about 400 μΜ, about 400 μΜ to about 1 mM, about 400 μΜ to about 900 μΜ, about 400 μΜ to about 800 μΜ, about 400 μΜ to about 700 μΜ, about 400 μΜ to about 600 μΜ, about 400 μΜ to about 500 μΜ, about 500 μΜ to about 1 mM, about 500 μΜ to about 900 μΜ, about 500 μΜ to about 800 μΜ, about 500 μΜ to about 700 μΜ, about 500 μΜ to about 600 μΜ, about 600 μΜ to about 1 mM, about 600 μΜ to about 900 μΜ, about 600 μΜ to about 800 μΜ, about 600 μΜ to about 700 μΜ, about 700 μΜ to about 1 mM, about 700 μΜ to about 900 μΜ, about 700 μΜ to about 800 μΜ, about 800 μΜ to about 1 mM, about 800 μΜ to about 900 μΜ, or about 900 μΜ to about 1 mM).

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the KD of the first antigen-binding domain for the identifying antigen at an acidic pH (e.g., any of the acidic pHs described herein) and/or at a neutral pH (e.g., any of the neutral pHs described herein) can be between about 1 nM to about 10 nM (e.g., about 1 nM to about 9 nM, about 1 nM to about 8 nM, about 1 nM to about 7 nM, about 1 nM to about 6 nM, about 1 nM to about 5 nM, about 1 nM to about 4 nM, about 1 nM to about 3 nM, about 1 nM to about 2 nM, about 2 nM to about 10 nM, about 2 nM to about 9 nM, about 2 nM to about 8 nM, about 2 nM to about 7 nM, about 2 nM to about 6 nM, about 2 nM to about 5 nM, about 2 nM to about 4 nM, about 2 nM to about 3 nM, about 3 nM to about 10 nM, about 3 nM to about 9 nM, about 3 nM to about 8 nM, about 3 nM to about 7 nM, about 3 nM to about 6 nM, about 3 nM to about 5 nM, about 3 nM to about 4 nM, about 4 nM to about 10 nM, about 4 nM to about 9 nM, about 4 nM to about 8 nM, about 4 nM to about 7 nM, about 4 nM to about 6 nM, about 4 nM to about 5 nM, about 5 nM to about 10 nM, about 5 nM to about 9 nM, about 5 nM to about 8 nM, about 5 nM to about 7 nM, about 5 nM to about 6 nM, about 6 nM to about 10 nM, about 6 nM to about 9 nM, about 6 nM to about 8 nM, about 6 nM to about 7 nM, about 7 nM to about 10 nM, about 7 nM to about 9 nM, about 7 nM to about 8 nM, about 8 nM to about 10 nM, about 8 nM to about 9 nM, and about 9 nM to about 10 nM).

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the first antigen-binding domain has a KD for the identifying antigen that is increased at an acidic pH (e.g., any of the acidic pHs described herein) as compared to the KD of the first antigen-binding domain for the identifying antigen at a neutral pH (e.g., any of the neutral pHs described herein). In some embodiments of any of the multi-specific antigen- binding protein constructs described herein, the first antigen-binding domain has a KD for the identifying antigen at an acidic pH (e.g., any of the acidic pHs described herein) that is at least 10% increased (e.g., at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%) as compared to the KD of the first antigen-binding domain at a neutral pH (e.g., any of the neutral pHs described herein).

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the first antigen-binding domain has a KD for the identifying antigen at an acidic pH (e.g., any of the acidic pHs described herein) that is at least 1-fold greater (e.g., at least 1.5-fold, at least 2-fold, at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, at least 5.5-fold, at least 6-fold, at least 6.5-fold, at least 7- fold, at least 7.5-fold, at least 8-fold, at least 8.5-fold, at least 9-fold, at least 9.5-fold, at least 10-fold, at least 10.5 -fold, at least 11 -fold, at least 11.5 -fold, at least 12-fold, at least 12.5- fold, at least 13-fold, at least 13.5-fold, at least 14-fold, at least 14.5-fold, at least 15-fold, at least 15.5-fold, at least 16-fold, at least 16.5-fold, at least 17-fold, at least 17.5-fold, at least 18-fold, at least 18.5-fold, at least 19-fold, at least 19.5-fold, or at least 20-fold) than the KD of the first antigen-binding domain at a neutral pH (e.g., any of the neutral pHs described herein). In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the dissociation rate of the first antigen-binding domain for the identifying antigen at an acidic pH (e.g., any of the acidic pHs described herein) is at least 10% (e.g., at least 15% , at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%) increased as compared to the dissociation rate of the first antigen-binding domain for the identifying antigen at a neutral pH (e.g., any of the neutral pHs described herein).

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the dissociation rate of the first antigen-binding domain for the identifying antigen at an acidic pH (e.g., any of the acidic pHs described herein) is at least 2-fold (e.g., at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, at least 5.5-fold, at least 6-fold, at least 6.5-fold, at least 7-fold, at least 7.5-fold, at least 8- fold, at least 8.5-fold, at least 9-fold, at least 9.5-fold, at least 10-fold, at least 10.5-fold, at least 11.0-fold, at least 11.5-fold, at least 12.0-fold, at least 12.5-fold, at least 13.0-fold, at least 13.5-fold, at least 14.0-fold, at least 14.5-fold, or at least 15.0-fold) increased as compared to the dissociation rate of the first antigen-binding domain for the identifying antigen at a neutral pH (e.g., any of the neutral pHs described herein). Second Antigen-Binding Domain

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the second antigen-binding domain is capable of specifically binding to an epitope of a polypeptide complex, wherein the polypeptide complex includes i) a poly peptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2πι) poly peptide, wherein: (a) the dissociation rate of the second antigen- binding domain at an acidic pH (e.g., any of the acidic pHs described herein) is slower than the dissociation rate at a neutral pH (e.g., any of the neutral pHs described herein); or (b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH (e.g., any of the acidic pHs described herein) is less than the KD at a neutral pH (e.g., any of the neutral pHs described herein); and the second antigen-binding domain includes at least one paratope that includes at least one (e.g., 1, 2, 3, 4, or 5) histidine residue.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the second antigen-binding domain is capable of specifically binding to an epitope of a polypeptide complex (PC), wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2πι) polypeptide, wherein the multi-specific ABPC has increased (e.g., at least a 1% increase, at least a 2% increase, at least a 4% increase, at least a 6% increase, at least a 8% increase, at least a 10% increase, at least a 12% increase, at least a 14% increase, at least a 16% increase, at least a 18% increase, at least a 20% increase, at least a 25% increase, at least a 30% increase, at least a 35% increase, at least a 40% increase, at least a 45% increase, at least a 50% increase, at least a 55% increase, at least a 60% increase, at least a 65% increase, at least a 70% increase, at least a 75% increase, at least a 80% increase, at least a 85% increase, at least a 90% increase, at least a 95% increase, at least a 100% increase, at least a 110% increase, at least a 120% increase, at least a 130% increase, at least a 140% increase, at least a 150% increase, at least a 160% increase, at least a 170% increase, at least a 180% increase, at least a 190% increase, at least a 200% increase, at least a 210% increase, at a least a 220% increase, at least a 230% increase, at least a 240% increase, at least a 250% increase, at least a 260% increase, at least a 270% increase, at least a 280% increase, at least at a 290% increase, or at least a 300% increase) endosomal recycling in a mammalian cell that presents the PC on its surface or in a cellular compartment as compared to a control ABPC (e.g., any of the control ABPCs described herein).

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the second antigen-binding domain is capable of specifically binding to an epitope of a polypeptide complex (PC), wherein the polypeptide complex includes i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2πι) polypeptide, wherein the multi-specific ABPC has reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 32% reduced, at least 34% reduced, at least 36% reduced, at least 38% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) toxin liberation and/or reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 32% reduced, at least 34% reduced, at least 36% reduced, at least 38% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) cell killing potency in a mammalian cell presenting the PC complex on its surface or a cell with the PC complex present in a cellular compartment as compared to a control ABPC (e.g., any of the control ABPCs described herein).

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the second antigen-binding domain is capable of specifically binding an epitope of a beta 2-microglobulin (β2πι) polypeptide, wherein: (a) the dissociation rate of the second antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH (e.g., any of the neutral pHs described herein); or (b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH (e.g., any of the acidic pHs described herein) is less than the KD at a neutral pH; and the second antigen-binding domain includes at least one paratope that includes at least one (e.g., 1, 2, 3, 4, or 5) histidine residue.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the PC can further include a peptide of about 8-12 amino acids in length that is bound to the PC. In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the PC can further include a peptide of about 8-12 amino acids in length that is associated with the PC (e.g., non-covalently bound to the PC).

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the second antigen-binding domain is capable of specifically binding to an epitope expressed on the surface of human cells and an epitope that is expressed on the surface of a cell from an Old World Monkey (e.g., any of the Old World Monkeys described herein).

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the second antigen-binding domain specifically binds to an epitope that includes at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) amino acid of a polypeptide encoded by an HLA gene selected from the group of HLA-A, HLA-B, and HLA- C, and at least one (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) amino acid of a β2ιη polypeptide.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the epitope of the PC is an at least partially monomorphic epitope.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the second antigen-binding domain specifically binds to an epitope of the β2πι polypeptide when the β2πι polypeptide is bound to a polypeptide encoded by an HLA gene selected from the group of HLA-A, HLA-B, and HLA-C.

Some embodiments of the multi-specific antigen-binding protein constructs described herein can bind to an epitope of a polypeptide complex (PC) (e.g., any of the polypeptide complexes described herein) or an epitope of a beta 2-microglobulin (β2πι) poly peptide at an acidic pH (e.g., any of the acidic pHs described herein) or at neutral pH (e.g., any of the neutral pHs described herein) with a dissociation equilibrium constant (KD) of less than 1 x 10^"3 M, less than 1 x 10 M, less than 1 x 10^"5 M, less than 1 x 10^"6 M, less than 1 x 10^"7 M, less than 1 x 10^"8 M, less than 1 x 10^"9 M, less than 1 x 10^"10 M, less than 1 x 10^"11 M, less than 1 x 10⁴² M, or less than 1 x 10⁴³ M.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain at an acidic pH (e.g., any of the acidic pHs described herein) is between about 1 pM to about 250 nM (e.g., about 1 pM to about 240 nM, about 1 pM to about 230 nM, about 1 pM to about 220 nM, about 1 pM to about 210 nM, about 1 pM to about 200 nM, about 1 pM to about 190 nM, about 1 pM to about 180 nM, about 1 pM to about 170 nM, about 1 pM to about 160 nM, about 1 pM to about 150 nM, about 1 pM to about 140 nM, about 1 pM to about 130 nM, about 1 pM to about 120 nM, about 1 pM to about 110 nM, about 1 pM to about 100 nM, about 1 pM to about 95 nM, about 1 pM to about 90 nM, about 1 pM to about 85 nM, about 1 pM to about 80 nM, about 1 pM to about 75 nM, about 1 pM to about 70 nM, about 1 pM to about 65 nM, about 1 pM to about 60 nM, about 1 pM to about 55 nM, about 1 pM to about 50 nM, about 1 pM to about 45 nM, about 1 pM to about 40 nM, about 1 pM to about 35 nM, about 1 pM to about 30 nM, about 1 pM to about 25 nM, about 1 pM to about 20 nM, about 1 pM to about 15 nM, about 1 pM to about 10 nM, about 1 pM to about 5 nM, about 1 pM to about 2 nM, about 1 pM to about 1 nM, about 1 pM to about 950 pM, about 1 pM to about 900 pM, about

1 pM to about 850 pM, about 1 pM to about 800 pM, about 1 pM to about 750 pM, about 1 pM to about 700 pM, about 1 pM to about 650 pM, about 1 pM to about 600 pM, about 1 pM to about 550 pM, about 1 pM to about 500 pM, about 1 pM to about 450 pM, about 1 pM to about 400 pM, about 1 pM to about 350 pM, about 1 pM to about 300 pM, about 1 pM to about 250 pM, about 1 pM to about 200 pM, about 1 pM to about 150 pM, about 1 pM to about 100 pM, about 1 pM to about 90 pM, about 1 pM to about 80 pM, about 1 pM to about 70 pM, about 1 pM to about 60 pM, about 1 pM to about 50 pM, about 1 pM to about 40 pM, about 1 pM to about 30 pM, about 1 pM to about 20 pM, about 1 pM to about 10 pM, about 1 pM to about 5 pM, about 1 pM to about 4 pM, about 1 pM to about 3 pM, about 1 pM to about 2 pM, about 2 pM to about 250 nM, about 2 pM to about 240 nM, about 2 pM to about 230 nM, about 2 pM to about 220 nM, about 2 pM to about 210 nM, about 2 pM to about 200 nM, about 2 pM to about 190 nM, about 2 pM to about 180 nM, about 2 pM to about 170 nM, about 2 pM to about 160 nM, about 2 pM to about 150 nM, about 2 pM to about 140 nM, about 2 pM to about 130 nM, about 2 pM to about 120 nM, about 2 pM to about 110 nM, about 2 pM to about 100 nM, about 2 pM to about 95 nM, about 2 pM to about 90 nM, about

2 pM to about 85 nM, about 2 pM to about 80 nM, about 2 pM to about 75 nM, about 2 pM to about 70 nM, about 2 pM to about 65 nM, about 2 pM to about 60 nM, about 2 pM to about 55 nM, about 2 pM to about 50 nM, about 2 pM to about 45 nM, about 2 pM to about 40 nM, about 2 pM to about 35 nM, about 2 pM to about 30 nM, about 2 pM to about 25 nM, about 2 pM to about 20 nM, about 2 pM to about 15 nM, about 2 pM to about 10 nM, about 2 pM to about 5 nM, about 2 pM to about 2 nM, about 2 pM to about 1 nM, about 2 pM to about 950 pM, about 2 pM to about 900 pM, about 2 pM to about 850 pM, about 2 pM to about 800 pM, about 2 pM to about 750 pM, about 2 pM to about 700 pM, about 2 pM to about 650 pM, about 2 pM to about 600 pM, about 2 pM to about 550 pM, about 2 pM to about 500 pM, about 2 pM to about 450 pM, about 2 pM to about 400 pM, about 2 pM to about 350 pM, about 2 pM to about 300 pM, about 2 pM to about 250 pM, about 2 pM to about 200 pM, about 2 pM to about 150 pM, about 2 pM to about 100 pM, about 2 pM to about 90 pM, about 2 pM to about 80 pM, about 2 pM to about 70 pM, about 2 pM to about 60 pM, about 2 pM to about 50 pM, about 2 pM to about 40 pM, about 2 pM to about 30 pM, about 2 pM to about 20 pM, about 2 pM to about 10 pM, about 2 pM to about 5 pM, about 2 pM to about 4 pM, about 2 pM to about 3 pM, about 5 pM to about 250 nM, about 5 pM to about 240 nM, about 5 pM to about 230 nM, about 5 pM to about 220 nM, about 5 pM to about 210 nM, about 5 pM to about 200 nM, about 5 pM to about 190 nM, about 5 pM to about 180 nM, about 5 pM to about 170 nM, about 5 pM to about 160 nM, about 5 pM to about 150 nM, about 5 pM to about 140 nM, about 5 pM to about 130 nM, about 5 pM to about 120 nM, about 5 pM to about 110 nM, about 5 pM to about 100 nM, about 5 pM to about 95 nM, about 5 pM to about 90 nM, about 5 pM to about 85 nM, about 5 pM to about 80 nM, about 5 pM to about 75 nM, about 5 pM to about 70 nM, about 5 pM to about 65 nM, about 5 pM to about 60 nM, about 5 pM to about 55 nM, about 5 pM to about 50 nM, about 5 pM to about 45 nM, about 5 pM to about 40 nM, about 5 pM to about 35 nM, about 5 pM to about 30 nM, about 5 pM to about 25 nM, about 5 pM to about 20 nM, about 5 pM to about 15 nM, about 5 pM to about 10 nM, about 5 pM to about 5 nM, about 5 pM to about 2 nM, about 5 pM to about 1 nM, about 5 pM to about 950 pM, about 5 pM to about 900 pM, about 5 pM to about 850 pM, about 5 pM to about 800 pM, about 5 pM to about 750 pM, about 5 pM to about 700 pM, about 5 pM to about 650 pM, about 5 pM to about 600 pM, about 5 pM to about 550 pM, about 5 pM to about 500 pM. about 5 pM to about 450 pM, about 5 pM to about 400 pM, about 5 pM to about 350 pM, about 5 pM to about 300 pM, about 5 pM to about 250 pM, about 5 pM to about 200 pM, about 5 pM to about 150 pM, about 5 pM to about 100 pM, about 5 pM to about 90 pM, about 5 pM to about 80 pM, about 5 pM to about 70 pM, about 5 pM to about 60 pM, about 5 pM to about 50 pM, about 5 pM to about 40 pM, about 5 pM to about 30 pM, about 5 pM to about 20 pM, about 5 pM to about 10 pM, about 10 pM to about 250 nM, about 10 pM to about 240 nM, about 10 pM to about 230 nM, about 10 pM to about 220 nM, about 10 pM to about 210 nM, about 10 pM to about 200 nM, about 10 pM to about 190 nM, about 10 pM to about 180 nM, about 10 pM to about 170 nM, about 10 pM to about 160 nM, about 10 pM to about 150 nM, about 10 pM to about 140 nM, about 10 pM to about 130 nM, about 10 pM to about 120 nM, about 10 pM to about 110 nM, about 10 pM to about 100 nM, about 10 pM to about 95 nM, about 10 pM to about 90 nM, about 10 pM to about 85 nM, about 10 pM to about 80 nM, about 10 pM to about 75 nM, about 10 pM to about 70 nM, about 10 pM to about 65 nM, about 10 pM to about 60 nM, about 10 pM to about 55 nM, about 10 pM to about 50 nM, about 10 pM to about 45 nM, about 10 pM to about 40 nM, about 10 pM to about 35 nM, about 10 pM to about 30 nM, about 10 pM to about 25 nM, about 10 pM to about 20 nM, about 10 pM to about 15 nM, about 10 pM to about 10 nM, about 10 pM to about 5 nM, about 10 pM to about 2 nM, about 10 pM to about 1 nM, about 10 pM to about 950 pM, about 10 pM to about 900 pM, about 10 pM to about 850 pM_: about 10 pM to about 800 pM, about 10 pM to about 750 pM, about 10 pM to about 700 pM_; about 10 pM to about 650 pM, about 10 pM to about 600 pM, about 10 pM to about 550 pM, about 10 pM to about 500 pM, about 10 pM to about 450 pM, about 10 pM to about 400 pM, about 10 pM to about 350 pM, about 10 pM to about 300 pM, about 10 pM to about 250 pM_; about 10 pM to about 200 pM, about 10 pM to about 150 pM, about 10 pM to about 100 pM_; about 10 pM to about 90 pM, about 10 pM to about 80 pM, about 10 pM to about 70 pM, about 10 pM to about 60 pM, about 10 pM to about 50 pM, about 10 pM to about 40 pM, about 10 pM to about 30 pM, about 10 pM to about 20 pM, about 15 pM to about 250 nM, about 15 pM to about 240 nM, about 15 pM to about 230 nM, about 15 pM to about 220 nM, about 15 pM to about 210 nM, about 15 pM to about 200 nM, about 15 pM to about 190 nM, about 15 pM to about 180 nM, about 15 pM to about 170 nM, about 15 pM to about 160 nM, about 15 pM to about 150 nM, about 15 pM to about 140 nM, about 15 pM to about 130 nM, about 15 pM to about 120 nM, about 15 pM to about 110 nM, about 15 pM to about 100 nM, about 15 pM to about 95 nM, about 15 pM to about 90 nM, about 15 pM to about 85 nM, about 15 pM to about 80 nM, about 15 pM to about 75 nM, about 15 pM to about 70 nM, about 15 pM to about 65 nM, about 15 pM to about 60 nM, about 15 pM to about 55 nM, about 15 pM to about 50 nM, about 15 pM to about 45 nM, about 15 pM to about 40 nM, about 15 pM to about 35 nM, about 15 pM to about 30 nM, about 15 pM to about 25 nM, about 15 pM to about 20 nM, about 15 pM to about 1 nM, about 15 pM to about 10 nM, about 15 pM to about 5 nM, about 15 pM to about 2 nM, about 15 pM to about 1 nM, about 15 pM to about 950 pM, about 15 pM to about 900 pM, about 15 pM to about 850 pM, about 15 pM to about 800 pM, about 15 pM to about 750 pM, about 15 pM to about 700 pM, about 15 pM to about 650 pM, about 15 pM to about 600 pM, about 15 pM to about 550 pM, about 15 pM to about 500 pM, about 15 pM to about 450 pM, about 15 pM to about 400 pM, about 15 pM to about 350 pM, about 15 pM to about 300 pM, about 15 pM to about 250 pM, about 15 pM to about 200 pM, about 15 pM to about 150 pM, about 15 pM to about 100 pM, about 15 pM to about 90 pM, about 15 pM to about 80 pM, about 15 pM to about 70 pM, about 15 pM to about 60 pM, about 15 pM to about 50 pM, about 15 pM to about 40 pM, about 15 pM to about 30 pM, about 15 pM to about 20 pM, about 20 pM to about 250 nM, about 20 pM to about 240 nM, about 20 pM to about 230 nM, about 20 pM to about 220 nM, about 20 pM to about 210 nM, about 20 pM to about 200 nM, about 20 pM to about 190 nM, about 20 pM to about 180 nM, about 20 pM to about 170 nM, about 20 pM to about 160 nM, about 20 pM to about 150 nM, about 20 pM to about 140 nM, about 20 pM to about 130 nM, about 20 pM to about 120 nM, about 20 pM to about 110 nM, about 20 pM to about 100 nM, about 20 pM to about 95 nM, about 20 pM to about 90 nM, about 20 pM to about 85 nM, about 20 pM to about 80 nM, about 20 pM to about 75 nM, about 20 pM to about 70 nM, about 20 pM to about 65 nM, about 20 pM to about 60 nM, about 20 pM to about 55 nM, about 20 pM to about 50 nM, about 20 pM to about 45 nM, about 20 pM to about 40 nM, about 20 pM to about 35 nM, about 20 pM to about 30 nM, about 20 pM to about 25 nM, about 20 pM to about 20 nM, about 20 pM to about 15 nM, about 20 pM to about 10 nM, about 20 pM to about 5 nM, about 20 pM to about 2 nM, about 20 pM to about 1 nM, about 20 pM to about 950 pM, about 20 pM to about 900 pM, about 20 pM to about 850 pM, about 20 pM to about 800 pM, about 20 pM to about 750 pM, about 20 pM to about 700 pM, about 20 pM to about 650 pM, about 20 pM to about 600 pM, about 20 pM to about 550 pM, about 20 pM to about 500 pM, about 20 pM to about 450 pM, about 20 pM to about 400 pM, about 20 pM to about 350 pM, about 20 pM to about 300 pM, about 20 pM to about 250 pM, about 20 pM to about 20 pM, about 200 pM to about 150 pM, about 20 pM to about 100 pM, about 20 pM to about 90 pM, about 20 pM to about 80 pM, about 20 pM to about 70 pM, about 20 pM to about 60 pM, about 20 pM to about 50 pM, about 20 pM to about 40 pM, about 20 pM to about 30 pM, about 30 pM to about 250 nM, about 30 pM to about 240 nM, about 30 pM to about 230 nM, about 30 pM to about 220 nM, about 30 pM to about 210 nM, about 30 pM to about 200 nM, about 30 pM to about 190 nM, about 30 pM to about 180 nM, about 30 pM to about 170 nM, about 30 pM to about 160 nM, about 30 pM to about 150 nM, about 30 pM to about 140 nM, about 30 pM to about 130 nM, about 30 pM to about 120 nM, about 30 pM to about 110 nM, about 30 pM to about 100 nM, about 30 pM to about 95 nM, about 30 pM to about 90 nM, about 30 pM to about 85 nM, about 30 pM to about 80 nM, about 30 pM to about 75 nM, about 30 pM to about 70 nM, about 30 pM to about 65 nM, about 30 pM to about 60 nM, about 30 pM to about 55 nM, about 30 pM to about 50 nM, about 30 pM to about 45 nM, about 30 pM to about 40 nM, about 30 pM to about 35 nM, about 30 pM to about 30 nM, about 30 pM to about 25 nM, about 30 pM to about 20 nM, about 30 pM to about 15 nM, about 30 pM to about 10 nM, about 30 pM to about 5 nM, about 30 pM to about 2 nM, about 30 pM to about 1 nM, about 30 pM to about 950 pM, about 30 pM to about 900 pM, about 30 pM to about 850 pM, about 30 pM to about 800 pM, about 30 pM to about 750 pM, about 30 pM to about 700 pM, about 30 pM to about 650 pM, about 30 pM to about 600 pM, about 30 pM to about 550 pM, about 30 pM to about 500 pM, about 30 pM to about 450 pM, about 30 pM to about 400 pM, about 30 pM to about 350 pM, about 30 pM to about 300 pM, about 30 pM to about 250 pM, about 30 pM to about 200 pM, about 30 pM to about 150 pM, about 30 pM to about 100 pM, about 30 pM to about 90 pM, about 30 pM to about 80 pM, about 30 pM to about 70 pM, about 30 pM to about 60 pM, about 30 pM to about 50 pM, about 30 pM to about 40 pM, about 40 pM to about 250 nM, about 40 pM to about 240 nM, about 40 pM to about 230 nM, about 40 pM to about 220 nM, about 40 pM to about 210 nM, about 40 pM to about 200 nM, about 40 pM to about 190 nM, about 40 pM to about 180 nM, about 40 pM to about 170 nM, about 40 pM to about 160 nM, about 40 pM to about 150 nM, about 40 pM to about 140 nM, about 40 pM to about 130 nM, about 40 pM to about 120 nM, about 40 pM to about 110 nM, about 40 pM to about 100 nM, about 40 pM to about 95 nM, about 40 pM to about 90 nM, about 40 pM to about 85 nM, about 40 pM to about 80 nM, about 40 pM to about 75 nM, about 40 pM to about 70 nM, about 40 pM to about 65 nM, about 40 pM to about 60 nM, about 40 pM to about 55 nM, about 40 pM to about 50 nM, about 40 pM to about 45 nM, about 40 pM to about 40 nM, about 40 pM to about 35 nM, about 40 pM to about 30 nM, about 40 pM to about 25 nM, about 40 pM to about 30 nM, about 40 pM to about 15 nM, about 40 pM to about 10 nM, about 40 pM to about 5 nM, about 40 pM to about 2 nM, about 40 pM to about 1 nM, about 40 pM to about 950 pM, about 40 pM to about 900 pM, about 40 pM to about 850 pM, about 40 pM to about 800 pM, about 40 pM to about 750 pM, about 40 pM to about 700 pM, about 40 pM to about 650 pM, about 40 pM to about 600 pM, about 40 pM to about 550 pM, about 40 pM to about 500 pM, about 40 pM to about 450 pM, about 40 pM to about 400 pM, about 40 pM to about 350 pM, about 40 pM to about 300 pM, about 40 pM to about 250 pM, about 40 pM to about 200 pM, about 40 pM to about 150 pM, about 40 pM to about 100 pM, about 40 pM to about 90 pM, about 40 pM to about 80 pM, about 40 pM to about 70 pM, about 40 pM to about 60 pM, about 40 pM to about 50 pM, about 50 pM to about 250 nM, about 50 pM to about 240 nM, about 50 pM to about 230 nM, about 50 pM to about 220 nM, about 50 pM to about 210 nM, about 50 pM to about 200 nM, about 50 pM to about 190 nM, about 50 pM to about 180 nM, about 50 pM to about 170 nM, about 50 pM to about 160 nM, about 50 pM to about 150 nM, about 50 pM to about 140 nM, about 50 pM to about 130 nM, about 50 pM to about 120 nM, about 50 pM to about 110 nM, about 50 pM to about 100 nM, about 50 pM to about 95 nM, about 50 pM to about 90 nM, about 50 pM to about 85 nM, about 50 pM to about 80 nM, about 50 pM to about 75 nM, about 50 pM to about 70 nM, about 50 pM to about 65 nM, about 50 pM to about 60 nM, about 50 pM to about 55 nM, about 50 pM to about 50 nM, about 50 pM to about 45 nM, about 50 pM to about 40 nM, about 50 pM to about 35 nM, about 50 pM to about 30 nM, about 50 pM to about 25 nM, about 50 pM to about 30 nM, about 50 pM to about 15 nM, about 50 pM to about 10 nM, about 50 pM to about 5 nM, about 50 pM to about 2 nM, about 50 pM to about 1 nM, about 50 pM to about 950 pM, about 50 pM to about 900 pM, about 50 pM to about 850 pM, about 50 pM to about 800 pM, about 50 pM to about 750 pM, about 50 pM to about 700 pM, about 50 pM to about 650 pM, about 50 pM to about 600 pM, about 50 pM to about 550 pM, about 50 pM to about 500 pM, about 50 pM to about 450 pM, about 50 pM to about 400 pM, about 50 pM to about 350 pM, about 50 pM to about 300 pM, about 50 pM to about 250 pM, about 50 pM to about 200 pM, about 50 pM to about 150 pM, about 50 pM to about 100 pM, about 50 pM to about 90 pM, about 50 pM to about 80 pM, about 50 pM to about 70 pM, about 50 pM to about 60 pM, about 60 pM to about 250 nM, about 60 pM to about 240 nM, about 60 pM to about 230 nM, about 60 pM to about 220 nM, about 60 pM to about 210 nM, about 60 pM to about 200 nM, about 60 pM to about 190 nM, about 60 pM to about 180 nM, about 60 pM to about 170 nM, about 60 pM to about 160 nM, about 60 pM to about 150 nM, about 60 pM to about 140 nM, about 60 pM to about 130 nM, about 60 pM to about 120 nM, about 60 pM to about 110 nM, about 60 pM to about 100 nM, about 60 pM to about 95 nM, about 60 pM to about 90 nM, about 60 pM to about 85 nM, about 60 pM to about 80 nM, about 60 pM to about 75 nM, about 60 pM to about 70 nM, about 60 pM to about 65 nM, about 60 pM to about 60 nM, about 60 pM to about 55 nM, about 60 pM to about 50 nM, about 60 pM to about 45 nM, about 60 pM to about 40 nM, about 60 pM to about 35 nM, about 60 pM to about 30 nM, about 60 pM to about 25 nM, about 60 pM to about 20 nM, about 60 pM to about 15 nM, about 60 pM to about 10 nM, about 60 pM to about 5 nM, about 60 pM to about 2 nM, about 60 pM to about 1 nM, about 60 pM to about 950 pM, about 60 pM to about 900 pM, about 60 pM to about 850 pM, about 60 pM to about 800 pM, about 60 pM to about 750 pM, about 60 pM to about 700 pM, about 60 pM to about 650 pM, about 60 pM to about 600 pM, about 60 pM to about 550 pM, about 60 pM to about 500 pM, about 60 pM to about 450 pM, about 60 pM to about 400 pM, about 60 pM to about 350 pM, about 60 pM to about 300 pM, about 60 pM to about 250 pM, about 60 pM to about 200 pM, about 60 pM to about 150 pM, about 60 pM to about 100 pM, about 60 pM to about 90 pM, about 60 pM to about 80 pM, about 60 pM to about 70 pM, about 70 pM to about 250 nM, about 70 pM to about 240 nM, about 70 pM to about 230 nM, about 70 pM to about 220 nM, about 70 pM to about 210 nM, about 70 pM to about 200 nM, about 70 pM to about 190 nM, about 70 pM to about 180 nM, about 70 pM to about 170 nM, about 70 pM to about 160 nM, about 70 pM to about 150 nM, about 70 pM to about 140 nM, about 70 pM to about 130 nM, about 70 pM to about 120 nM, about 70 pM to about 110 nM, about 70 pM to about 100 nM, about 70 pM to about 95 nM, about 70 pM to about 90 nM, about 70 pM to about 85 nM, about 70 pM to about 80 nM, about 70 pM to about 75 nM, about 70 pM to about 70 nM, about 70 pM to about 65 nM, about 70 pM to about 60 nM, about 70 pM to about 55 nM, about 70 pM to about 50 nM, about 70 pM to about 45 nM, about 70 pM to about 40 nM, about 70 pM to about 35 nM, about 70 pM to about 30 nM, about 70 pM to about 25 nM, about 70 pM to about 20 nM, about 70 pM to about 15 nM, about 70 pM to about 10 nM, about 70 pM to about 5 nM, about 70 pM to about 2 nM, about 70 pM to about 1 nM, about 70 pM to about 950 pM, about 70 pM to about 900 pM, about 70 pM to about 850 pM, about 70 pM to about 800 pM, about 70 pM to about 750 pM, about 70 pM to about 700 pM, about 70 pM to about 650 pM, about 70 pM to about 600 pM, about 70 pM to about 550 pM, about 70 pM to about 500 pM, about 70 pM to about 450 pM, about 70 pM to about 400 pM, about 70 pM to about 350 pM, about 70 pM to about 300 pM, about 70 pM to about 250 pM, about 70 pM to about 200 pM, about 70 pM to about 150 pM, about 70 pM to about 100 pM, about 70 pM to about 90 pM, about 70 pM to about 80 pM, about 80 pM to about 250 nM, about 80 pM to about 240 nM, about 80 pM to about 230 nM, about 80 pM to about 220 nM, about 80 pM to about 210 nM, about 80 pM to about 200 nM, about 80 pM to about 190 nM, about 80 pM to about 180 nM, about 80 pM to about 170 nM, about 80 pM to about 160 nM, about 80 pM to about 150 nM, about 80 pM to about 140 nM, about 80 pM to about 130 nM, about 80 pM to about 120 nM, about 80 pM to about 110 nM, about 80 pM to about 100 nM, about 80 pM to about 95 nM, about 80 pM to about 90 nM, about 80 pM to about 85 nM, about 80 pM to about 80 nM, about 80 pM to about 75 nM, about 80 pM to about 70 nM, about 80 pM to about 65 nM, about 80 pM to about 60 nM, about 80 pM to about 55 nM, about 80 pM to about 50 nM, about 80 pM to about 45 nM, about 80 pM to about 40 nM, about 80 pM to about 35 nM, about 80 pM to about 30 nM, about 80 pM to about 25 nM, about 80 pM to about 20 nM, about 80 pM to about 15 nM, about 80 pM to about 10 nM, about 80 pM to about 5 nM, about 80 pM to about 2 nM, about 80 pM to about 1 nM, about 80 pM to about 950 pM, about 80 pM to about 900 pM, about 80 pM to about 850 pM, about 80 pM to about 800 pM, about 80 pM to about 750 pM, about 80 pM to about 700 pM, about 80 pM to about 650 pM, about 80 pM to about 600 pM, about 80 pM to about 550 pM, about 80 pM to about 500 pM, about 80 pM to about 450 pM, about 80 pM to about 400 pM, about 80 pM to about 350 pM, about 80 pM to about 300 pM, about 80 pM to about 250 pM, about 80 pM to about 200 pM, about 80 pM to about 150 pM, about 80 pM to about 100 pM, about 80 pM to about 90 pM, about 90 pM to about 250 nM, about 90 pM to about 240 nM, about 90 pM to about 230 nM, about 90 pM to about 220 nM, about 90 pM to about 210 nM, about 90 pM to about 200 nM, about 90 pM to about 190 nM, about 90 pM to about 180 nM, about 90 pM to about 170 nM, about 90 pM to about 160 nM, about 90 pM to about 150 nM, about 90 pM to about 140 nM, about 90 pM to about 130 nM, about 90 pM to about 120 nM, about 90 pM to about 110 nM, about 90 pM to about 100 nM, about 90 pM to about 95 nM, about 90 pM to about 90 nM, about 90 pM to about 85 nM, about 90 pM to about 80 nM, about 90 pM to about 75 nM, about 90 pM to about 70 nM, about 90 pM to about 65 nM, about 90 pM to about 60 nM, about 90 pM to about 55 nM, about 90 pM to about 50 nM, about 90 pM to about 45 nM, about 90 pM to about 40 nM, about 90 pM to about 35 nM, about 90 pM to about 30 nM, about 90 pM to about 25 nM, about 90 pM to about 30 nM, about 90 pM to about 15 nM, about 90 pM to about 10 nM, about 90 pM to about 5 nM, about 90 pM to about 2 nM, about 90 pM to about 1 nM, about 90 pM to about 950 pM, about 90 pM to about 900 pM, about 90 pM to about 850 pM, about 90 pM to about 800 pM, about 90 pM to about 750 pM, about 90 pM to about 700 pM, about 90 pM to about 650 pM, about 90 pM to about 600 pM, about 90 pM to about 550 pM, about 90 pM to about 500 pM, about 90 pM to about 450 pM, about 90 pM to about 400 pM, about 90 pM to about 350 pM, about 90 pM to about 300 pM, about 90 pM to about 250 pM, about 90 pM to about 200 pM, about 90 pM to about 150 pM, about 90 pM to about 100 pM, about 100 pM to about 30 nM, about 100 pM to about 25 nM, about 100 pM to about 250 nM, about 100 pM to about 240 nM, about 100 pM to about 230 nM, about 100 pM to about 220 nM, about 100 pM to about 210 nM, about 100 pM to about 200 nM, about 100 pM to about 190 nM, about 100 pM to about 180 nM, about 100 pM to about 170 nM, about 100 pM to about 160 nM, about 100 pM to about 150 nM, about 100 pM to about 140 nM, about 100 pM to about 130 nM, about 100 pM to about 120 nM, about 100 pM to about 110 nM, about 100 pM to about 100 nM, about 100 pM to about 95 nM, about 100 pM to about 90 nM, about 100 pM to about 85 nM, about 100 pM to about 80 nM, about 100 pM to about 75 nM, about 100 pM to about 70 nM, about 100 pM to about 65 nM, about 100 pM to about 60 nM, about 100 pM to about 55 nM, about 100 pM to about 50 nM, about 100 pM to about 45 nM, about 100 pM to about 40 nM, about 100 pM to about 35 nM, about 100 pM to about 30 nM, about 100 pM to about 15 nM, about 100 pM to about 10 nM, about 100 pM to about 5 nM, about 100 pM to about 2 nM, about 100 pM to about 1 nM, about 100 pM to about 950 pM, about 100 pM to about 900 pM, about 100 pM to about 850 pM, about 100 pM to about 800 pM, about 100 pM to about 750 pM, about 100 pM to about 700 pM, about 100 pM to about 650 pM, about 100 pM to about 600 pM, about 100 pM to about 550 pM, about 100 pM to about 500 pM, about 100 pM to about 450 pM, about 100 pM to about 400 pM, about 100 pM to about 350 pM, about 100 pM to about 300 pM, about 100 pM to about 250 pM_; about 100 pM to about 200 pM, about 100 pM to about 150 pM, about 150 pM to about 250 nM, about 150 pM to about 240 nM, about 150 pM to about 230 nM, about 150 pM to about 220 nM, about 150 pM to about 210 nM, about 150 pM to about 200 nM, about 150 pM to about 190 nM, about 150 pM to about 180 nM, about 150 pM to about 170 nM, about 150 pM to about 160 nM, about 150 pM to about 150 nM, about 150 pM to about 140 nM, about 150 pM to about 130 nM, about 150 pM to about 120 nM, about 150 pM to about 110 nM, about 150 pM to about 100 nM, about 150 pM to about 95 nM, about 150 pM to about 90 nM, about 150 pM to about 85 nM, about 150 pM to about 80 nM, about 150 pM to about 75 nM, about 150 pM to about 70 nM, about 150 pM to about 65 nM, about 150 pM to about 60 nM, about 150 pM to about 55 nM, about 150 pM to about 50 nM, about 150 pM to about 45 nM, about 150 pM to about 40 nM, about 150 pM to about 35 nM, about 150 pM to about 30 nM, about 150 pM to about 25 nM, about 150 pM to about 30 nM, about 150 pM to about 15 nM, about 150 pM to about 10 nM, about 150 pM to about 5 nM, about 150 pM to about 2 nM, about 150 pM to about 1 nM, about 1 0 pM to about 950 pM, about 150 pM to about 900 pM, about 150 pM to about 850 pM, about 150 pM to about 800 pM, about 150 pM to about 750 pM, about 150 pM to about 700 pM, about 150 pM to about 650 pM, about 150 pM to about 600 pM, about 150 pM to about 550 pM, about 150 pM to about 500 pM, about 150 pM to about 450 pM, about 150 pM to about 400 pM, about 150 pM to about 350 pM, about 150 pM to about 300 pM, about 150 pM to about 250 pM, about 150 pM to about 200 pM, about 200 pM to about 250 nM, about 200 pM to about 240 nM, about 200 pM to about 230 nM, about 200 pM to about 220 nM, about 200 pM to about 210 nM, about 200 pM to about 200 nM, about 200 pM to about 190 nM, about 200 pM to about 180 nM, about 200 pM to about 170 nM, about 200 pM to about 160 nM, about 200 pM to about 150 nM, about 200 pM to about 140 nM, about 200 pM to about 130 nM, about 200 pM to about 120 nM, about 200 pM to about 110 nM, about 200 pM to about 100 nM, about 200 pM to about 95 nM, about 200 pM to about 90 nM, about 200 pM to about 85 nM, about 200 pM to about 80 nM, about 200 pM to about 75 nM, about 200 pM to about 70 nM, about 200 pM to about 65 nM, about 200 pM to about 60 nM, about 200 pM to about 55 nM, about 200 pM to about 50 nM, about 200 pM to about 45 nM, about 200 pM to about 40 nM, about 200 pM to about 35 nM, about 200 pM to about 30 nM, about 200 pM to about 25 nM, about 200 pM to about 30 nM, about 200 pM to about 15 nM, about 200 pM to about 10 nM, about 200 pM to about 5 nM, about 200 pM to about 2 nM, about 200 pM to about 1 nM, about 200 pM to about 950 pM, about 200 pM to about 900 pM, about 200 pM to about 850 pM, about 200 pM to about 800 pM, about 200 pM to about 750 pM, about 200 pM to about 700 pM, about 200 pM to about 650 pM, about 200 pM to about 600 pM, about 200 pM to about 550 pM, about 200 pM to about 500 pM, about 200 pM to about 450 pM, about 200 pM to about 400 pM, about 200 pM to about 350 pM, about 200 pM to about 300 pM, about 200 pM to about 250 pM, about 300 pM to about 30 nM, about 300 pM to about 25 nM, about 300 pM to about 250 nM, about 300 pM to about 240 nM, about 300 pM to about 230 nM, about 300 pM to about 220 nM, about 300 pM to about 210 nM, about 300 pM to about 200 nM, about 300 pM to about 190 nM, about 300 pM to about 180 nM, about 300 pM to about 170 nM, about 300 pM to about 160 nM, about 300 pM to about 150 nM, about 300 pM to about 140 nM, about 300 pM to about 130 nM, about 300 pM to about 120 nM, about 300 pM to about 110 nM, about 300 pM to about 100 nM, about 300 pM to about 95 nM, about 300 pM to about 90 nM, about 300 pM to about 85 nM, about 300 pM to about 80 nM, about 300 pM to about 75 nM, about 300 pM to about 70 nM, about 300 pM to about 65 nM, about 300 pM to about 60 nM, about 300 pM to about 55 nM, about 300 pM to about 50 nM, about 300 pM to about 45 nM, about 300 pM to about 40 nM, about 300 pM to about 35 nM, about 300 pM to about 30 nM, about 300 pM to about 15 nM, about 300 pM to about 10 nM, about 300 pM to about 5 nM, about 300 pM to about 2 nM, about 300 pM to about 1 nM, about 300 pM to about 950 pM, about 300 pM to about 900 pM, about 300 pM to about 850 pM, about 300 pM to about 800 pM, about 300 pM to about 750 pM, about 300 pM to about 700 pM, about 300 pM to about 650 pM, about 300 pM to about 600 pM, about 300 pM to about 550 pM, about 300 pM to about 500 pM, about 300 pM to about 450 pM, about 300 pM to about 400 pM, about 300 pM to about 350 pM, about 400 pM to about 250 nM, about 400 pM to about 240 nM, about 400 pM to about 230 nM, about 400 pM to about 220 nM, about 400 pM to about 210 nM, about 400 pM to about 200 nM, about 400 pM to about 190 nM, about 400 pM to about 180 nM, about 400 pM to about 170 nM, about 400 pM to about 160 nM, about 400 pM to about 150 nM, about 400 pM to about 140 nM, about 400 pM to about 130 nM, about 400 pM to about 120 nM, about 400 pM to about 110 nM, about 400 pM to about 100 nM, about 400 pM to about 95 nM, about 400 pM to about 90 nM, about 400 pM to about 85 nM, about 400 pM to about 80 nM, about 400 pM to about 75 nM, about 400 pM to about 70 nM, about 400 pM to about 65 nM, about 400 pM to about 60 nM, about 400 pM to about 55 nM, about 400 pM to about 50 nM, about 400 pM to about 45 nM, about 400 pM to about 40 nM, about 400 pM to about 35 nM, about 400 pM to about 30 nM, about 400 pM to about 25 nM, about 400 pM to about 20 nM, about 400 pM to about 15 nM, about 400 pM to about 10 nM, about 400 pM to about 5 nM, about 400 pM to about 2 nM, about 400 pM to about 1 nM, about 400 pM to about 950 pM, about 400 pM to about 900 pM, about 400 pM to about 850 pM, about 400 pM to about 800 pM, about 400 pM to about 750 pM, about 400 pM to about 700 pM, about 400 pM to about 650 pM, about 400 pM to about 600 pM, about 400 pM to about 550 pM, about 400 pM to about 500 pM, about 500 pM to about 250 nM, about 500 pM to about 240 nM, about 500 pM to about 230 nM, about 500 pM to about 220 nM, about 500 pM to about 210 nM, about 500 pM to about 200 nM, about 500 pM to about 190 nM, about 500 pM to about 180 nM, about 500 pM to about 170 nM, about 500 pM to about 160 nM, about 500 pM to about 150 nM, about 500 pM to about 140 nM, about 500 pM to about 130 nM, about 500 pM to about 120 nM, about 500 pM to about 110 nM, about 500 pM to about 100 nM, about 500 pM to about 95 nM, about 500 pM to about 90 nM, about 500 pM to about 85 nM, about 500 pM to about 80 nM, about 500 pM to about 75 nM, about 500 pM to about 70 nM, about 500 pM to about 65 nM, about 500 pM to about 60 nM, about 500 pM to about 55 nM, about 500 pM to about 50 nM, about 500 pM to about 45 nM, about 500 pM to about 40 nM, about 500 pM to about 35 nM, about 500 pM to about 30 nM, about 500 pM to about 25 nM, about 500 pM to about 20 nM, about 500 pM to about 15 nM, about 500 pM to about 10 nM, about 500 pM to about 5 nM, about 500 pM to about 2 nM, about 500 pM to about 1 nM, about 500 pM to about 950 pM, about 500 pM to about 900 pM, about 500 pM to about 850 pM, about 500 pM to about 800 pM, about 500 pM to about 750 pM, about 500 pM to about 700 pM, about 500 pM to about 650 pM, about 500 pM to about 600 pM, about 500 pM to about 550 pM, about 600 pM to about 250 nM, about 600 pM to about 240 nM, about 600 pM to about 230 nM, about 600 pM to about 220 nM, about 600 pM to about 210 nM, about 600 pM to about 200 nM, about 600 pM to about 190 nM, about 600 pM to about 180 nM, about 600 pM to about 170 nM, about 600 pM to about 160 nM, about 600 pM to about 150 nM, about 600 pM to about 140 nM, about 600 pM to about 130 nM, about 600 pM to about 120 nM, about 600 pM to about 110 nM, about 600 pM to about 100 nM, about 600 pM to about 95 nM, about 600 pM to about 90 nM, about 600 pM to about 85 nM, about 600 pM to about 80 nM, about 600 pM to about 75 nM, about 600 pM to about 70 nM, about 600 pM to about 65 nM, about 600 pM to about 60 nM, about 600 pM to about 55 nM, about 600 pM to about 50 nM_: about 600 pM to about 45 nM, about 600 pM to about 40 nM, about 600 pM to about 35 nM, about 600 pM to about 30 nM, about 600 pM to about 25 nM, about 600 pM to about 20 nM, about 600 pM to about 15 nM, about 600 pM to about 10 nM, about 600 pM to about 5 nM, about 600 pM to about 2 nM, about 600 pM to about 1 nM, about 600 pM to about 950 pM, about 600 pM to about 900 pM, about 600 pM to about 850 pM, about 600 pM to about 800 pM, about 600 pM to about 750 pM, about 600 pM to about 700 pM, about 600 pM to about 650 pM, about 700 pM to about 250 nM, about 700 pM to about 240 nM, about 700 pM to about 230 nM, about 700 pM to about 220 nM, about 700 pM to about 210 nM, about 700 pM to about 200 nM, about 700 pM to about 190 nM, about 700 pM to about 180 nM, about 700 pM to about 170 nM, about 700 pM to about 160 nM, about 700 pM to about 150 nM, about 700 pM to about 140 nM, about 700 pM to about 130 nM, about 700 pM to about 120 nM, about 700 pM to about 110 nM, about 700 pM to about 100 nM, about 700 pM to about 95 nM, about 700 pM to about 90 nM, about 700 pM to about 85 nM, about 700 pM to about 80 nM, about 700 pM to about 75 nM, about 700 pM to about 70 nM, about 700 pM to about 65 nM, about 700 pM to about 60 nM, about 700 pM to about 55 nM, about 700 pM to about 50 nM, about 700 pM to about 45 nM, about 700 pM to about 40 nM, about 700 pM to about 35 nM, about 700 pM to about 30 nM, about 700 pM to about 25 nM, about 700 pM to about 20 nM, about 700 pM to about 15 nM, about 700 pM to about 10 nM, about 700 pM to about 5 nM, about 700 pM to about 2 nM, about 700 pM to about 1 nM, about 700 pM to about 950 pM, about 700 pM to about 900 pM, about 700 pM to about 850 pM, about 700 pM to about 800 pM, about 700 pM to about 750 pM, about 800 pM to about 250 nM, about 800 pM to about 240 nM, about 800 pM to about 230 nM, about 800 pM to about 220 nM, about 800 pM to about 210 nM, about 800 pM to about 200 nM, about 800 pM to about 190 nM, about 800 pM to about 180 nM, about 800 pM to about 170 nM, about 800 pM to about 160 nM, about 800 pM to about 150 nM, about 800 pM to about 140 nM, about 800 pM to about 130 nM, about 800 pM to about 120 nM, about 800 pM to about 110 nM, about 800 pM to about 100 nM, about 800 pM to about 95 nM, about 800 pM to about 90 nM, about 800 pM to about 85 nM, about 800 pM to about 80 nM, about 800 pM to about 75 nM, about 800 pM to about 70 nM, about 800 pM to about 65 nM, about 800 pM to about 60 nM, about 800 pM to about 55 nM, about 800 pM to about 50 nM, about 800 pM to about 45 nM, about 800 pM to about 40 nM, about 800 pM to about 35 nM, about 800 pM to about 30 nM, about 800 pM to about 25 nM, about 800 pM to about 20 nM, about 800 pM to about 15 nM, about 800 pM to about 10 nM, about 800 pM to about 5 nM, about 800 pM to about 2 nM, about 800 pM to about 1 nM, about 800 pM to about 950 pM, about 800 pM to about 900 pM, about 800 pM to about 850 pM, about 900 pM to about 250 nM, about 900 pM to about 240 nM, about 900 pM to about 230 nM, about 900 pM to about 220 nM, about 900 pM to about 210 nM, about 900 pM to about 200 nM, about 900 pM to about 190 nM, about 900 pM to about 180 nM, about 900 pM to about 170 nM, about 900 pM to about 160 nM, about 900 pM to about 150 nM, about 900 pM to about 140 nM, about 900 pM to about 130 nM, about 900 pM to about 120 nM, about 900 pM to about 110 nM, about 900 pM to about 100 nM, about 900 pM to about 95 nM, about 900 pM to about 90 nM, about 900 pM to about 85 nM, about 900 pM to about 80 nM, about 900 pM to about 75 nM, about 900 pM to about 70 nM, about 900 pM to about 65 nM, about 900 pM to about 60 nM, about 900 pM to about 55 nM, about 900 pM to about 50 nM, about 900 pM to about 45 nM, about 900 pM to about 40 nM, about 900 pM to about 35 nM, about 900 pM to about 30 nM, about 900 pM to about 25 nM, about 900 pM to about 20 nM, about 900 pM to about 15 nM, about 900 pM to about 10 nM, about 900 pM to about 5 nM, about 900 pM to about 2 nM, about 900 pM to about 1 nM, about 900 pM to about 950 pM, about 1 nM to about 250 nM, about 1 nM to about 240 nM, about 1 nM to about 230 nM, about 1 nM to about 220 nM, about 1 nM to about 210 nM, about 1 nM to about 200 nM, about 1 nM to about 190 nM, about 1 nM to about 180 nM, about 1 nM to about 170 nM, about 1 nM to about 160 nM, about 1 nM to about 150 nM, about 1 nM to about 140 nM, about 1 nM to about 130 nM, about 1 nM to about 120 nM, about 1 nM to about 110 nM, about 1 nM to about 100 nM, about 1 nM to about 95 nM, about 1 nM to about 90 nM, about 1 nM to about 85 nM, about 1 nM to about 80 nM, about 1 nM to about 75 nM, about 1 nM to about 70 nM, about 1 nM to about 65 nM, about 1 nM to about 60 nM, about 1 nM to about 55 nM, about 1 nM to about 50 nM, about 1 nM to about 45 nM, about 1 nM to about 40 nM, about 1 nM to about 35 nM, about 1 nM to about 30 nM, about 1 nM to about 25 nM, about 1 nM to about 20 nM, about 1 nM to about 15 nM, about 1 nM to about 10 nM, about 1 nM to about 5 nM, about 2 nM to about 250 nM, about 2 nM to about 240 nM, about 2 nM to about 230 nM, about 2 nM to about 220 nM, about 2 nM to about 210 nM, about 2 nM to about 200 nM, about 2 nM to about 190 nM, about 2 nM to about 180 nM, about 2 nM to about 170 nM, about 2 nM to about 160 nM, about 2 nM to about 150 nM, about 2 nM to about 140 nM, about 2 nM to about 130 nM, about 2 nM to about 120 nM, about 2 nM to about 110 nM, about 2 nM to about 100 nM, about 2 nM to about 95 nM, about 2 nM to about 90 nM, about 2 nM to about 85 nM, about 2 nM to about 80 nM, about 2 nM to about 75 nM, about 2 nM to about 70 nM, about 2 nM to about 65 nM, about 2 nM to about 60 nM, about 2 nM to about 55 nM, about 2 nM to about 50 nM, about 2 nM to about 45 nM, about 2 nM to about 40 nM, about 2 nM to about 35 nM, about 2 nM to about 30 nM, about 2 nM to about 25 nM, about 2 nM to about 20 nM, about 2 nM to about 15 nM, about 2 nM to about 10 nM, about 2 nM to about 5 nM, about 4 nM to about 250 nM, about 4 nM to about 240 nM, about 4 nM to about 230 nM, about 4 nM to about 220 nM, about 4 nM to about 210 nM, about 4 nM to about 200 nM, about 4 nM to about 190 nM, about 4 nM to about 180 nM, about 4 nM to about 170 nM, about 4 nM to about 160 nM, about 4 nM to about 150 nM, about 4 nM to about 140 nM, about 4 nM to about 130 nM, about 4 nM to about 120 nM, about 4 nM to about 110 nM, about 4 nM to about 100 nM, about 4 nM to about 95 nM, about 4 nM to about 90 nM, about 4 nM to about 85 nM, about 4 nM to about 80 nM, about 4 nM to about 75 nM, about 4 nM to about 70 nM, about 4 nM to about 65 nM, about 4 nM to about 60 nM, about 4 nM to about 55 nM, about 4 nM to about 50 nM, about 4 nM to about 45 nM, about 4 nM to about 40 nM, about 4 nM to about 35 nM, about 4 nM to about 30 nM, about 4 nM to about 25 nM, about 4 nM to about 20 nM, about 4 nM to about 15 nM, about 4 nM to about 10 nM, about 4 nM to about 5 nM, about 5 nM to about 250 nM, about 5 nM to about 240 nM, about 5 nM to about 230 nM, about 5 nM to about 220 nM, about 5 nM to about 210 nM, about 5 nM to about 200 nM, about 5 nM to about 190 nM, about 5 nM to about 180 nM, about 5 nM to about 170 nM, about 5 nM to about 160 nM, about 5 nM to about 150 nM, about 5 nM to about 140 nM, about 5 nM to about 130 nM, about 5 nM to about 120 nM, about 5 nM to about 110 nM, about 5 nM to about 100 nM, about 5 nM to about 95 nM, about 5 nM to about 90 nM, about 5 nM to about 85 nM, about 5 nM to about 80 nM, about 5 nM to about 75 nM, about 5 nM to about 70 nM, about 5 nM to about 65 nM, about 5 nM to about 60 nM, about 5 nM to about 55 nM, about 5 nM to about 50 nM, about 5 nM to about 45 nM, about 5 nM to about 40 nM, about 5 nM to about 35 nM, about 5 nM to about 30 nM, about 5 nM to about 25 nM, about 5 nM to about 20 nM, about 5 nM to about 15 nM, about 5 nM to about 10 nM, about 10 nM to about 250 nM, about 10 nM to about 240 nM, about 10 nM to about 230 nM, about 10 nM to about 220 nM, about 10 nM to about 210 nM, about 10 nM to about 200 nM, about 10 nM to about 190 nM, about 10 nM to about 180 nM, about 10 nM to about 170 nM, about 10 nM to about 160 nM, about 10 nM to about 150 nM, about 10 nM to about 140 nM, about 10 nM to about 130 nM, about 10 nM to about 120 nM, about 10 nM to about 110 nM, about 10 nM to about 100 nM, about 10 nM to about 95 nM, about 10 nM to about 90 nM, about 10 nM to about 85 nM, about 10 nM to about 80 nM, about 10 nM to about 75 nM, about 10 nM to about 70 nM, about 10 nM to about 65 nM, about 10 nM to about 60 nM, about 10 nM to about 55 nM, about 10 nM to about 50 nM, about 10 nM to about 45 nM, about 10 nM to about 40 nM, about 10 nM to about 35 nM, about 10 nM to about 30 nM, about 10 nM to about 25 nM, about 10 nM to about 20 nM, about 10 nM to about 15 nM, about 15 nM to about 250 nM, about 15 nM to about 240 nM, about 15 nM to about 230 nM, about 15 nM to about 220 nM, about 15 nM to about 210 nM, about 15 nM to about 200 nM, about 15 nM to about 190 nM, about 15 nM to about 180 nM, about 15 nM to about 170 nM, about 15 nM to about 160 nM, about 15 nM to about 150 nM, about 15 nM to about 140 nM, about 15 nM to about 130 nM, about 15 nM to about 120 nM, about 15 nM to about 110 nM, about 15 nM to about 100 nM, about 15 nM to about 95 nM, about 15 nM to about 90 nM, about 15 nM to about 85 nM, about 15 nM to about 80 nM, about 15 nM to about 75 nM, about 15 nM to about 70 nM, about 15 nM to about 65 nM, about 15 nM to about 60 nM, about 15 nM to about 55 nM, about 15 nM to about 50 nM, about 15 nM to about 45 nM, about 15 nM to about 40 nM, about 15 nM to about 35 nM, about 15 nM to about 30 nM, about 15 nM to about 25 nM, about 15 nM to about 20 nM, about 20 nM to about 250 nM, about 20 nM to about 240 nM, about 20 nM to about 230 nM, about 20 nM to about 220 nM, about 20 nM to about 210 nM, about 20 nM to about 200 nM, about 20 nM to about 190 nM, about 20 nM to about 180 nM, about 20 nM to about 170 nM, about 20 nM to about 160 nM, about 20 nM to about 150 nM, about 20 nM to about 140 nM, about 20 nM to about 130 nM, about 20 nM to about 120 nM, about 20 nM to about 110 nM, about 20 nM to about 100 nM, about 20 nM to about 95 nM, about 20 nM to about 90 nM, about 20 nM to about 85 nM, about 20 nM to about 80 nM, about 20 nM to about 75 nM, about 20 nM to about 70 nM, about 20 nM to about 65 nM, about 20 nM to about 60 nM, about 20 nM to about 55 nM, about 20 nM to about 50 nM, about 20 nM to about 45 nM, about 20 nM to about 40 nM, about 20 nM to about 35 nM, about 20 nM to about 30 nM, about 20 nM to about 25 nM, about 25 nM to about 250 nM, about 25 nM to about 240 nM, about 25 nM to about 230 nM, about 25 nM to about 220 nM, about 25 nM to about 210 nM, about 25 nM to about 200 nM, about 25 nM to about 190 nM, about 25 nM to about 180 nM, about 25 nM to about 170 nM, about 25 nM to about 160 nM, about 25 nM to about 150 nM, about 25 nM to about 140 nM, about 25 nM to about 130 nM, about 25 nM to about 120 nM, about 25 nM to about 110 nM, about 25 nM to about 100 nM, about 25 nM to about 95 nM, about 25 nM to about 90 nM, about 25 nM to about 85 nM, about 25 nM to about 80 nM, about 25 nM to about 75 nM, about 25 nM to about 70 nM, about 25 nM to about 65 nM, about 25 nM to about 60 nM, about 25 nM to about 55 nM, about 25 nM to about 50 nM, about 25 nM to about 45 nM, about 25 nM to about 40 nM, about 25 nM to about 35 nM, about 25 nM to about 30 nM, about 25 nM to about 250 nM, about 25 nM to about 240 nM, about 25 nM to about 230 nM, about 25 nM to about 220 nM, about 25 nM to about 210 nM, about 25 nM to about 200 nM, about 25 nM to about 190 nM, about 25 nM to about 180 nM, about 25 nM to about 170 nM, about 25 nM to about 160 nM, about 25 nM to about 150 nM, about 25 nM to about 140 nM, about 25 nM to about 130 nM, about 25 nM to about 120 nM, about 25 nM to about 110 nM, about 25 nM to about 100 nM, about 25 nM to about 95 nM, about 25 nM to about 90 nM, about 25 nM to about 85 nM, about 25 nM to about 80 nM, about 25 nM to about 75 nM, about 25 nM to about 70 nM, about 25 nM to about 65 nM, about 25 nM to about 60 nM, about 25 nM to about 55 nM, about 25 nM to about 50 nM, about 25 nM to about 45 nM, about 25 nM to about 40 nM, about 25 nM to about 35 nM, about 30 nM to about 250 nM, about 30 nM to about 240 nM, about 30 nM to about 230 nM, about 30 nM to about 220 nM, about 30 nM to about 210 nM, about 30 nM to about 200 nM, about 30 nM to about 190 nM, about 30 nM to about 180 nM, about 30 nM to about 170 nM, about 30 nM to about 160 nM, about 30 nM to about 150 nM, about 30 nM to about 140 nM, about 30 nM to about 130 nM, about 30 nM to about 120 nM, about 30 nM to about 110 nM, about 30 nM to about 100 nM, about 30 nM to about 95 nM, about 30 nM to about 90 nM, about 30 nM to about 85 nM, about 30 nM to about 80 nM, about 30 nM to about 75 nM, about 30 nM to about 70 nM, about 30 nM to about 65 nM, about 30 nM to about 60 nM, about 30 nM to about 55 nM, about 30 nM to about 50 nM, about 30 nM to about 45 nM, about 30 nM to about 40 nM, about 30 nM to about 35 nM, about 30 nM to about 250 nM, about 30 nM to about 240 nM, about 30 nM to about 230 nM, about 30 nM to about 220 nM, about 30 nM to about 210 nM, about 30 nM to about 200 nM, about 30 nM to about 190 nM, about 30 nM to about 180 nM, about 30 nM to about 170 nM, about 30 nM to about 160 nM, about 30 nM to about 150 nM, about 30 nM to about 140 nM, about 30 nM to about 130 nM, about 30 nM to about 120 nM, about 30 nM to about 110 nM, about 30 nM to about 100 nM, about 30 nM to about 95 nM, about 30 nM to about 90 nM, about 30 nM to about 85 nM, about 30 nM to about 80 nM, about 30 nM to about 75 nM, about 30 nM to about 70 nM, about 30 nM to about 65 nM, about 30 nM to about 60 nM, about 30 nM to about 55 nM, about 30 nM to about 50 nM, about 30 nM to about 45 nM, about 30 nM to about 40 nM, about 30 nM to about 35 nM, about 40 nM to about 250 nM, about 40 nM to about 240 nM, about 40 nM to about 230 nM, about 40 nM to about 220 nM, about 40 nM to about 210 nM, about 40 nM to about 200 nM. about 40 nM to about 190 nM, about 40 nM to about 180 nM, about 40 nM to about 170 nM, about 40 nM to about 160 nM, about 40 nM to about 150 nM, about 40 nM to about 140 nM, about 40 nM to about 130 nM, about 40 nM to about 120 nM, about 40 nM to about 110 nM, about 40 nM to about 100 nM, about 40 nM to about 95 nM, about 40 nM to about 90 nM, about 40 nM to about 85 nM, about 40 nM to about 80 nM, about 40 nM to about 75 nM, about 40 nM to about 70 nM, about 40 nM to about 65 nM, about 40 nM to about 60 nM, about 40 nM to about 55 nM, about 40 nM to about 50 nM, about 40 nM to about 45 nM, about 50 nM to about 250 nM, about 50 nM to about 240 nM, about 50 nM to about 230 nM, about 50 nM to about 220 nM, about 50 nM to about 210 nM, about 50 nM to about 200 nM, about 50 nM to about 190 nM, about 50 nM to about 180 nM, about 50 nM to about 170 nM, about 50 nM to about 160 nM, about 50 nM to about 150 nM, about 50 nM to about 140 nM, about 50 nM to about 130 nM, about 50 nM to about 120 nM, about 50 nM to about 110 nM, about 50 nM to about 100 nM, about 50 nM to about 95 nM, about 50 nM to about 90 nM, about 50 nM to about 85 nM, about 50 nM to about 80 nM, about 50 nM to about 75 nM, about 50 nM to about 70 nM, about 50 nM to about 65 nM, about 50 nM to about 60 nM, about 50 nM to about 55 nM, about 60 nM to about 250 nM, about 60 nM to about 240 nM, about 60 nM to about 230 nM, about 60 nM to about 220 nM, about 60 nM to about 210 nM, about 60 nM to about 200 nM, about 60 nM to about 190 nM, about 60 nM to about 180 nM, about 60 nM to about 170 nM, about 60 nM to about 160 nM, about 60 nM to about 150 nM, about 60 nM to about 140 nM, about 60 nM to about 130 nM, about 60 nM to about 120 nM, about 60 nM to about 110 nM, about 60 nM to about 100 nM, about 60 nM to about 95 nM, about 60 nM to about 90 nM, about 60 nM to about 85 nM, about 60 nM to about 80 nM, about 60 nM to about 75 nM, about 60 nM to about 70 nM, about 60 nM to about 65 nM, about 70 nM to about 250 nM, about 70 nM to about 240 nM, about 70 nM to about 230 nM, about 70 nM to about 220 nM, about 70 nM to about 210 nM, about 70 nM to about 200 nM, about 70 nM to about 190 nM, about 70 nM to about 180 nM, about 70 nM to about 170 nM, about 70 nM to about 160 nM, about 70 nM to about 150 nM, about 70 nM to about 140 nM, about 70 nM to about 130 nM, about 70 nM to about 120 nM, about 70 nM to about 110 nM, about 70 nM to about 100 nM, about 70 nM to about 95 nM, about 70 nM to about 90 nM, about 70 nM to about 85 nM, about 70 nM to about 80 nM, about 70 nM to about 75 nM, about 80 nM to about 250 nM, about 80 nM to about 240 nM, about 80 nM to about 230 nM, about 80 nM to about 220 nM, about 80 nM to about 210 nM, about 80 nM to about 200 nM, about 80 nM to about 190 nM, about 80 nM to about 180 nM, about 80 nM to about 170 nM. about 80 nM to about 160 nM, about 80 nM to about 150 nM, about 80 nM to about 140 nM, about 80 nM to about 130 nM, about 80 nM to about 120 nM, about 80 nM to about 110 nM, about 80 nM to about 100 nM, about 80 nM to about 95 nM, about 80 nM to about 90 nM, about 80 nM to about 85 nM, about 90 nM to about 250 nM, about 90 nM to about 240 nM, about 90 nM to about 230 nM, about 90 nM to about 220 nM, about 90 nM to about 210 nM, about 90 nM to about 200 nM, about 90 nM to about 190 nM, about 90 nM to about 180 nM, about 90 nM to about 170 nM, about 90 nM to about 160 nM, about 90 nM to about 150 nM, about 90 nM to about 140 nM, about 90 nM to about 130 nM, about 90 nM to about 120 nM, about 90 nM to about 110 nM, about 90 nM to about 100 nM, about 90 nM to about 95 nM, about 100 nM to about 250 nM, about 100 nM to about 240 nM, about 100 nM to about 230 nM, about 100 nM to about 220 nM, about 100 nM to about 210 nM, about 100 nM to about 200 nM, about 100 nM to about 190 nM, about 100 nM to about 180 nM, about 100 nM to about 170 nM, about 100 nM to about 160 nM, about 100 nM to about 150 nM, about 100 nM to about 140 nM, about 100 nM to about 130 nM, about 100 nM to about 120 nM, about 100 nM to about 110 nM, about 110 nM to about 250 nM, about 110 nM to about 240 nM, about 110 nM to about 230 nM, about 110 nM to about 220 nM, about 110 nM to about 210 nM, about 110 nM to about 200 nM, about 110 nM to about 190 nM, about 110 nM to about 180 nM, about 110 nM to about 170 nM, about 110 nM to about 160 nM, about 110 nM to about 150 nM, about 110 nM to about 140 nM, about 110 nM to about 130 nM, about 110 nM to about 120 nM, about 120 nM to about 250 nM, about 120 nM to about 240 nM, about 120 nM to about 230 nM, about 120 nM to about 220 nM, about 120 nM to about 210 nM, about 120 nM to about 200 nM, about 120 nM to about 190 nM, about 120 nM to about 180 nM, about 120 nM to about 170 nM, about 120 nM to about 160 nM, about 120 nM to about 150 nM, about 120 nM to about 140 nM, about 120 nM to about 130 nM, about 130 nM to about 250 nM, about 130 nM to about 240 nM, about 130 nM to about 230 nM, about 130 nM to about 220 nM, about 130 nM to about 210 nM, about 130 nM to about 200 nM, about 130 nM to about 190 nM, about 130 nM to about 180 nM, about 130 nM to about 170 nM, about 130 nM to about 160 nM, about 130 nM to about 150 nM, about 130 nM to about 140 nM, about 140 nM to about 250 nM, about 140 nM to about 240 nM, about 140 nM to about 230 nM, about 140 nM to about 220 nM, about 140 nM to about 210 nM, about 140 nM to about 200 nM, about 140 nM to about 190 nM, about 140 nM to about 180 nM, about 140 nM to about 170 nM, about 140 nM to about 160 nM, about 140 nM to about 150 nM, about 150 nM to about 250 nM, about 150 nM to about 240 nM, about 150 nM to about 230 nM, about 150 nM to about 220 nM, about 150 nM to about 210 nM, about 150 nM to about 200 nM, about 150 nM to about 190 nM, about 150 nM to about 180 nM, about 150 nM to about 170 nM, about 150 nM to about 160 nM, about 160 nM to about 250 nM, about 160 nM to about 240 nM, about 160 nM to about 230 nM, about 160 nM to about 220 nM, about 160 nM to about 210 nM, about 160 nM to about 200 nM, about 160 nM to about 190 nM, about 160 nM to about 180 nM, about 160 nM to about 170 nM, about 170 nM to about 250 nM, about 170 nM to about 240 nM, about 170 nM to about 230 nM, about 170 nM to about 220 nM, about 170 nM to about 210 nM, about 170 nM to about 200 nM, about 170 nM to about 190 nM, about 170 nM to about 180 nM, about 180 nM to about 250 nM, about 180 nM to about 240 nM, about 180 nM to about 230 nM, about 180 nM to about 220 nM, about 180 nM to about 210 nM, about 180 nM to about 200 nM, about 180 nM to about 190 nM, about 190 nM to about 250 nM, about 190 nM to about 240 nM, about 190 nM to about 230 nM, about 190 nM to about 220 nM, about 190 nM to about 210 nM, about 190 nM to about 200 nM, about 200 nM to about 250 nM, about 200 nM to about 240 nM, about 200 nM to about 230 nM, about 200 nM to about 220 nM, about 200 nM to about 210 nM, about 210 nM to about 250 nM, about 210 nM to about 240 nM, about 210 nM to about 230 nM, about 210 nM to about 220 nM, about 220 nM to about 250 nM, about 220 nM to about 240 nM, about 220 nM to about 230 nM, about 230 nM to about 250 nM, about 230 nM to about 240 nM, or about 240 nM to about 250 nM). In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain at a neutral pH (e.g., any of the neutral pHs described herein) is between about 1 nM to about 30 nM (e.g., about 1 nM to about 30 nM, about 1 nM to about 25 nM, about 1 nM to about 20 nM, about 1 nM to about 15 nM, about 1 nM to about 10 nM, about 1 nM to about 5 nM, about 2 nM to about 30 nM, about 2 nM to about 25 nM, about 2 nM to about 20 nM, about 2 nM to about 15 nM, about 2 nM to about 10 nM, about 2 nM to about 5 nM, about 4 nM to about 30 nM, about 4 nM to about 25 nM, about 4 nM to about 20 nM, about 4 nM to about 15 nM, about 4 nM to about 10 nM, about 4 nM to about 5 nM, about 5 nM to about 30 nM, about 5 nM to about 25 nM, about 5 nM to about 20 nM, about 5 nM to about 15 nM, about 5 nM to about 10 nM, about 10 nM to about 30 nM, about 10 nM to about 25 nM, about 10 nM to about 20 nM, about 10 nM to about 15 nM, about 15 nM to about 30 nM, about 15 nM to about 25 nM, about 15 nM to about 20 nM, about 20 nM to about 30 nM, or about 20 nM to about 25 nM). In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain at a neutral pH (e.g.. any of the neutral pHs described herein) can be between about 1 nM to about 1 mM (e.g., about 1 nM to about 900 μΜ, about 1 nM to about 800 μΜ, about 1 nM to about 700 μΜ, about 1 nM to about 600 μΜ, about 1 nM to about 500 μΜ, about 1 nM to about 400 μΜ, about 1 nM to about 300 μΜ, about 1 nM to about 200 μΜ, about 1 nM to about 100 μΜ, about 1 nM to about 90 μΜ, about 1 nM to about 80 μΜ, about 1 nM to about 70 μΜ, about 1 nM to about 60 μΜ, about 1 nM to about 50 μΜ, about 1 nM to about 40 μΜ, about 1 nM to about 30 μΜ, about 1 nM to about 20 μΜ, about 1 nM to about 10 μΜ, about 1 nM to about 5 μΜ, about 1 nM to about 4 μΜ, about 1 nM to about 2 μΜ, about 1 nM to about 1 μΜ, about 1 nM to about 900 nM, about 1 nM to about 800 nM, about 1 nM to about 700 nM, about 1 nM to about 600 nM, about 1 nM to about 500 nM, about 1 nM to about 400 nM, about 1 nM to about 300 nM, about 1 nM to about 200 nM, about 1 nM to about 100 nM, about 1 nM to about 90 nM, about 1 nM to about 80 nM, about 1 nM to about 70 nM, about 1 nM to about 60 nM, about 1 nM to about 50 nM, about 1 nM to about 40 nM, about 1 nM to about 30 nM, about 2 nM to about 1 mM, about 2 nM to about 900 μΜ, about 2 nM to about 800 μΜ, about 2 nM to about 700 μΜ, about 2 nM to about 600 μΜ, about 2 nM to about 500 μΜ, about 2 nM to about 400 μΜ, about 2 nM to about 300 μΜ, about 2 nM to about 200 μΜ, about 2 nM to about 100 μΜ, about 2 nM to about 90 μΜ, about 2 nM to about 80 μΜ, about 2 nM to about 70 μΜ, about 2 nM to about 60 μΜ, about 2 nM to about 50 μΜ, about 2 nM to about 40 μΜ, about 2 nM to about 30 μΜ, about 2 nM to about 20 μΜ, about 2 nM to about 10 μΜ, about 2 nM to about 5 μΜ, about 2 nM to about 4 μΜ, about 2 nM to about 2 μΜ, about 2 nM to about 1 μΜ, about 2 nM to about 900 nM, about 2 nM to about 800 nM, about 2 nM to about 700 nM, about 2 nM to about 600 nM, about 2 nM to about 500 nM, about 2 nM to about 400 nM, about 2 nM to about 300 nM, about 2 nM to about 200 nM, about 2 nM to about 100 nM, about 2 nM to about 90 nM, about 2 nM to about 80 nM, about 2 nM to about 70 nM, about 2 nM to about 60 nM, about 2 nM to about 50 nM, about 2 nM to about 40 nM, about 2 nM to about 30 nM, about 5 nM to about 1 mM, about 5 nM to about 900 μΜ, about 5 nM to about 800 μΜ, about 5 nM to about 700 μΜ, about 5 nM to about 600 μΜ, about 5 nM to about 500 μΜ, about 5 nM to about 400 μΜ, about 5 nM to about 300 μΜ, about 5 nM to about 200 μΜ, about 5 nM to about 100 μΜ, about 5 nM to about 90 μΜ, about 5 nM to about 80 μΜ, about 5 nM to about 70 μΜ, about 5 nM to about 60 μΜ, about 5 nM to about 50 μΜ, about 5 nM to about 40 μΜ, about 5 nM to about 30 μΜ, about 5 nM to about 20 μΜ, about 5 nM to about 10 μΜ, about 5 nM to about 5 uM, about 5 nM to about 4 μΜ, about 5 nM to about 2 μΜ, about 5 nM to about 1 μΜ, about 5 nM to about 900 nM, about 5 nM to about 800 nM, about 5 nM to about 700 nM, about 5 nM to about 600 nM, about 5 nM to about 500 nM, about 5 nM to about 400 nM, about 5 nM to about 300 nM, about 5 nM to about 200 nM, about 5 nM to about 100 nM, about 5 nM to about 90 nM, about 5 nM to about 80 nM, about 5 nM to about 70 nM, about 5 nM to about 60 nM, about 5 nM to about 50 nM, about 5 nM to about 40 nM, about 5 nM to about 30 nM, about 10 nM to about 1 mM, about 10 nM to about 900 μΜ, about 10 nM to about 800 μΜ, about 10 nM to about 700 μΜ, about 10 nM to about 600 μΜ, about 10 nM to about 500 μΜ, about 10 nM to about 400 μΜ, about 10 nM to about 300 μΜ, about 10 nM to about 200 μΜ, about 10 nM to about 100 μΜ, about 10 nM to about 90 μΜ, about 10 nM to about 80 μΜ, about 10 nM to about 70 μΜ, about 10 nM to about 60 μΜ, about 10 nM to about 50 μΜ, about 10 nM to about 40 μΜ, about 10 nM to about 30 μΜ, about 10 nM to about 20 μΜ, about 10 nM to about 10 μΜ, about 10 nM to about 5 μΜ, about 10 nM to about 4 μΜ, about 10 nM to about 2 μΜ, about 10 nM to about 1 μΜ, about 10 nM to about 900 nM, about 10 nM to about 800 nM, about 10 nM to about 700 nM, about 10 nM to about 600 nM, about 10 nM to about 500 nM, about 10 nM to about 400 nM, about 10 nM to about 300 nM, about 10 nM to about 200 nM, about 10 nM to about 100 nM, about 10 nM to about 90 nM, about 10 nM to about 80 nM, about 10 nM to about 70 nM, about 10 nM to about 60 nM, about 10 nM to about 50 nM, about 10 nM to about 40 nM, about 10 nM to about 30 nM, about 20 nM to about 1 mM, about 20 nM to about 900 μΜ, about 20 nM to about 800 μΜ, about 20 nM to about 700 μΜ, about 20 nM to about 600 μΜ, about 20 nM to about 500 μΜ, about 20 nM to about 400 μΜ, about 20 nM to about 300 μΜ, about 20 nM to about 200 μΜ, about 20 nM to about 100 μΜ, about 20 nM to about 90 μΜ, about 20 nM to about 80 μΜ, about 20 nM to about 70 μΜ, about 20 nM to about 60 μΜ, about 20 nM to about 50 μΜ, about 20 nM to about 40 μΜ, about 20 nM to about 30 μΜ, about 20 nM to about 20 μΜ, about 20 nM to about 10 μΜ, about 20 nM to about 5 μΜ, about 20 nM to about 4 μΜ, about 20 nM to about 2 μΜ, about 20 nM to about 1 μΜ, about 20 nM to about 900 nM, about 20 nM to about 800 nM, about 20 nM to about 700 nM, about 20 nM to about 600 nM, about 20 nM to about 500 nM, about 20 nM to about 400 nM, about 20 nM to about 300 nM, about 20 nM to about 200 nM, about 20 nM to about 100 nM, about 20 nM to about 90 nM, about 20 nM to about 80 nM, about 20 nM to about 70 nM, about 20 nM to about 60 nM, about 20 nM to about 50 nM, about 20 nM to about 40 nM, about 20 nM to about 30 nM; about 1 μΜ to about 1 mM, about 1 μΜ to about 900 uM, about 1 μΜ to about 800 uM, about 1 μΜ to about 700 uM, about 1 μΜ to about 600 μΜ, about 1 μΜ to about 500 μΜ, about 1 μΜ to about 400 uM, about 1 μΜ to about 300 μΜ, about 1 μΜ to about 200 μΜ, about 1 μΜ to about 100 uM, about 1 μΜ to about 90 μΜ, about 1 μΜ to about 80 uM, about 1 μΜ to about 70 uM, about 1 μΜ to about 60 uM, about 1 μΜ to about 50 uM, about 1 μΜ to about 40 μΜ, about 1 μΜ to about 30 μΜ, about 1 μΜ to about 20 μΜ, about 1 μΜ to about 10 μΜ, about 1 μΜ to about 5 μΜ_; about 1 μΜ to about 4 μΜ, about 1 μΜ to about 3 μΜ, about 1 μΜ to about 2 μΜ, about 2 μΜ to about 1 mM, about 2 μΜ to about 900 μΜ, about 2 μΜ to about 800 μΜ, about 2 μΜ to about 700 uM, about 2 μΜ to about 600 μΜ, about 2 μΜ to about 500 μΜ, about 2 μΜ to about 400 μΜ, about 2 μΜ to about 300 μΜ, about 2 μΜ to about 200 uM, about 2 μΜ to about 100 μΜ, about 2 μΜ to about 90 μΜ, about 2 μΜ to about 80 μΜ, about 2 μΜ to about 70 μΜ, about 2 μΜ to about 60 μΜ, about 2 μΜ to about 50 μΜ, about 2 μΜ to about 40 μΜ, about 2 μΜ to about 30 μΜ, about 2 μΜ to about 20 uM, about 2 μΜ to about 10 uM, about 2 μΜ to about 5 uM, about 2 μΜ to about 4 μΜ, about 2 μΜ to about 3 μΜ, about 5 μΜ to about 1 mM, about 5 uM to about 900 μΜ, about 5 μΜ to about 800 μΜ, about 5 μΜ to about 700 μΜ, about 5 μΜ to about 600 μΜ, about 5 μΜ to about 500 μΜ, about 5 μΜ to about 400 μΜ, about 5 μΜ to about 300 μΜ, about 5 μΜ to about 200 uM, about 5 μΜ to about 100 μΜ, about 5 μΜ to about 90 μΜ, about 5 μΜ to about 80 μΜ, about 5 μΜ to about 70 uM, about 5 μΜ to about 60 μΜ, about 5 μΜ to about 50 μΜ, about 5 μΜ to about 40 μΜ, about 5 μΜ to about 30 μΜ, about 5 μΜ to about 20 μΜ, about 5 μΜ to about 10 uM, about 10 μΜ to about 1 mM, about 10 μΜ to about 900 μΜ, about 10 μΜ to about 800 μΜ, about 10 μΜ to about 700 uM, about 10 μΜ to about 600 uM, about 10 μΜ to about 500 μΜ, about 10 μΜ to about 400 uM, about 10 μΜ to about 300 uM, about 10 μΜ to about 200 μΜ, about 10 μΜ to about 100 uM, about 10 μΜ to about 90 μΜ, about 10 μΜ to about 80 uM, about 10 μΜ to about 70 μΜ, about 10 μΜ to about 60 uM, about 10 μΜ to about 50 μΜ, about 10 μΜ to about 40 μΜ, about 10 μΜ to about 30 uM, about 10 μΜ to about 20 μΜ, about 20 μΜ to about 1 mM, about 20 μΜ to about 900 μΜ, about 20 μΜ to about 800 μΜ, about 20 μΜ to about 700 uM, about 20 μΜ to about 600 μΜ, about 20 μΜ to about 500 μΜ, about 20 μΜ to about 400 μΜ, about 20 μΜ to about 300 μΜ, about 20 μΜ to about 200 μ , about 20 μΜ to about 100 uM, about 20 μΜ to about 90 μΜ, about 20 μΜ to about 80 μΜ, about 20 μΜ to about 70 uM, about 20 μΜ to about 60 uM, about 20 μΜ to about 50 μΜ, about 20 μΜ to about 40 uM, about 20 μΜ to about 30 uM, about 30 μΜ to about 1 mM, about 30 μΜ to about 900 μΜ, about 30 μΜ to about 800 μΜ, about 30 μΜ to about 700 μΜ, about 30 μΜ to about 600 μΜ, about 30 μΜ to about 500 μΜ, about 30 μΜ to about 400 μΜ, about 30 μΜ to about 300 μΜ, about 30 μΜ to about 200 μΜ, about 30 μΜ to about 100 μΜ, about 30 μΜ to about 90 μΜ, about 30 μΜ to about 80 μΜ, about 30 μΜ to about 70 μΜ, about 30 μΜ to about 60 μΜ, about 30 μΜ to about 50 μΜ, about 30 μΜ to about 40 μΜ, about 40 μΜ to about 1 mM, about 40 μΜ to about 900 μΜ, about 40 μΜ to about 800 μΜ, about 40 μΜ to about 700 μΜ, about 40 μΜ to about 600 μΜ, about 40 μΜ to about 500 μΜ, about 40 μΜ to about 400 μΜ, about 40 μΜ to about 300 μΜ, about 40 μΜ to about 200 μΜ, about 40 μΜ to about 100 μΜ, about 40 μΜ to about 90 μΜ, about 40 μΜ to about 80 μΜ, about 40 μΜ to about 70 μΜ, about 40 μΜ to about 60 μΜ, about 40 μΜ to about 50 uM, about 50 μΜ to about 1 mM, about 50 μΜ to about 900 μΜ, about 50 μΜ to about 800 μΜ, about 50 μΜ to about 700 μΜ, about 50 μΜ to about 600 μΜ, about 50 μΜ to about 500 μΜ, about 50 μΜ to about 400 μΜ, about 50 μΜ to about 300 μΜ, about 50 μΜ to about 200 μΜ, about 50 μΜ to about 100 μΜ, about 50 μΜ to about 90 μΜ, about 50 μΜ to about 80 μΜ, about 50 μΜ to about 70 μΜ, about 50 μΜ to about 60 μΜ, about 60 μΜ to about 1 mM, about 60 μΜ to about 900 μΜ, about 60 μΜ to about 800 μΜ, about 60 μΜ to about 700 μΜ. about 60 μΜ to about 600 μΜ, about 60 μΜ to about 500 μΜ, about 60 μΜ to about 400 μΜ. about 60 μΜ to about 300 μΜ, about 60 μΜ to about 200 μΜ, about 60 μΜ to about 100 μΜ, about 60 μΜ to about 90 μΜ, about 60 μΜ to about 80 μΜ, about 60 μΜ to about 70 μΜ, about 70 μΜ to about 1 mM, about 70 μΜ to about 900 μΜ, about 70 μΜ to about 800 μΜ, about 70 μΜ to about 700 μΜ, about 70 μΜ to about 600 μΜ, about 70 μΜ to about 500 uM, about 70 μΜ to about 400 μΜ, about 70 μΜ to about 300 μΜ, about 70 μΜ to about 200 μΜ, about 70 μΜ to about 100 μΜ, about 70 μΜ to about 90 μΜ, about 70 μΜ to about 80 μΜ, about 80 μΜ to about 1 mM, about 80 μΜ to about 900 μΜ, about 80 μΜ to about 800 μΜ, about 80 μΜ to about 700 μΜ, about 80 μΜ to about 600 μΜ, about 80 μΜ to about 500 μΜ, about 80 μΜ to about 400 μΜ, about 80 μΜ to about 300 μΜ, about 80 μΜ to about 200 μΜ, about 80 μΜ to about 100 μΜ, about 80 μΜ to about 90 μΜ, about 90 μΜ to about 1 mM, about 90 μΜ to about 900 μΜ, about 90 μΜ to about 800 μΜ, about 90 μΜ to about 700 μΜ, about 90 μΜ to about 600 μΜ, about 90 μΜ to about 500 μΜ, about 90 μΜ to about 400 μΜ, about 90 μΜ to about 300 μΜ, about 90 μΜ to about 200 μΜ, about 90 μΜ to about 100 μ , about 100 μΜ to about 1 mM, about 100 μΜ to about 900 μΜ, about 100 μΜ to about 800 μΜ, about 100 μΜ to about 700 μΜ, about 100 μΜ to about 600 μΜ, about 100 μΜ to about 500 μΜ, about 100 μΜ to about 400 μΜ, about 100 μΜ to about 300 μΜ, about 100 μΜ to about 200 μΜ, about 200 μΜ to about 1 mM, about 200 μΜ to about 900 μΜ, about 200 μΜ to about 800 μΜ, about 200 μΜ to about 700 μΜ, about 200 μΜ to about 600 μΜ, about 200 μΜ to about 500 μΜ, about 200 μΜ to about 400 μΜ, about 200 μΜ to about 300 μΜ, about 300 μΜ to about 1 mM, about 300 μΜ to about 900 μΜ, about 300 μΜ to about 800 μΜ, about 300 μΜ to about 700 μΜ, about 300 μΜ to about 600 μΜ, about 300 μΜ to about 500 μΜ, about 300 μΜ to about 400 μΜ, about 400 μΜ to about 1 mM, about 400 μΜ to about 900 μΜ, about 400 μΜ to about 800 μΜ, about 400 μΜ to about 700 μΜ, about 400 μΜ to about 600 μΜ, about 400 μΜ to about 500 μΜ, about 500 μΜ to about 1 mM, about 500 μΜ to about 900 μΜ, about 500 μΜ to about 800 μΜ, about 500 μΜ to about 700 μΜ, about 500 μΜ to about 600 μΜ, about 600 μΜ to about 1 mM, about 600 μΜ to about 900 μΜ, about 600 μΜ to about 800 μΜ, about 600 μΜ to about 700 μΜ, about 700 μΜ to about 1 mM, about 700 μΜ to about 900 μΜ, about 700 μΜ to about 800 μΜ, about 800 μΜ to about 1 mM, about 800 μΜ to about 900 μΜ, or about 900 μΜ to about 1 mM).

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain for an HLA-A variant polypeptide-beta 2-microglobulin (β2πι) polypeptide complex at an acidic pH (e.g., any of the acidic pHs described herein) is at least 10% (e.g., at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 150%, at least 200%, at least 250%, or at least 300%) increased as compared to the KD of the second antigen-binding domain for the polypeptide encoded by the HLA-A gene-beta 2-microglobulin (β2ηι) polypeptide complex, and wherein the HLA-A variant polypeptide is identical to the polypeptide encoded by the HLA-A gene except at one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) residues which both: (i) are located in the HLA-A epitope bound by the second antigen-binding domain, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-A gene.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain for an HLA-B variant polypeptide-beta 2-microglobulin (β2ηι) polypeptide complex at an acidic pH (e.g., any of the acidic pHs described herein) is at least 10% (e.g., at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 150%, at least 200%, at least 250%, or at least 300%) increased as compared to the KD of the second antigen-binding domain for the polypeptide encoded by the HLA-B gene-beta 2-microglobulin (β2πι) polypeptide complex, and wherein the HLA-B variant polypeptide is identical to the polypeptide encoded by the HLA-B gene except at one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) residues which both: (i) are located in the HLA-B epitope bound by the second antigen-binding domain, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-B gene.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain for an HLA-C variant polypeptide-beta 2-microglobulin (β2ηι) polypeptide complex at an acidic pH (e.g., any of the acidic pHs described herein) is at least 10% (e.g., at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 150%, at least 200%, at least 250%, or at least 300%) increased as compared to the KD of the second antigen-binding domain for the poly peptide product of the HLA-C gene-beta 2-microglobulin (β2πι) polypeptide complex, and wherein the HLA-C variant polypeptide is identical to the polypeptide encoded by the HLA-C gene except at one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) residues which both: (i) are located in the HLA-C epitope bound by the second antigen-binding domain, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-C gene.

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the dissociation rate of the second antigen-binding domain at an acidic pH (e.g., any of the acidic pHs described herein) is at least 10% (e.g., at least 15% , at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) slower than the dissociation rate of the second antigen-binding domain at a neutral pH (e.g., any of the neutral pHs described herein).

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the dissociation rate of the second antigen-binding domain at an acidic pH (e.g., any of the acidic pHs described herein) is at least 1-fold (e.g., at least 1.5-fold, at least 2-fold slower, at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5- fold, at least 5-fold, at least 5.5-fold, at least 6-fold, at least 6.5-fold, at least 7-fold, at least 7.5-fold, at least 8-fold, at least 8.5-fold, at least 9-fold, at least 9.5-fold, at least 10-fold, at least 10.5-fold, at least 11-fold, at least 11.5-fold, at least 12-fold, at least 12.5-fold, at least 13-fold, at least 13.5-fold, at least 14-fold, at least 14.5-fold, at least 15-fold, at least 15.5- fold, at least 16-fold, at least 16.5-fold, at least 17-fold, at least 17.5-fold, at least 18-fold, at least 18.5-fold, at least 19-fold, at least 19.5-fold, or at least 20-fold) slower than the dissociation rate of the second antigen-binding domain at a neutral pH (e.g., any of the neutral pHs described herein).

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain at an acidic pH (e.g., any of the acidic pHs described herein) can be 10% (e.g., at least 15% , at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) less than the KD of the second antigen-binding domain at a neutral pH (e.g., any of the neutral pHs described herein).

In some embodiments of any of the multi-specific antigen-binding protein constructs described herein, the KD of the second antigen-binding domain at an acidic pH (e.g., any of the acidic pHs described herein) is at least 1-fold (e.g., at least 1.5-fold, at least 2-fold, at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, at least 5.5-fold, at least 6-fold, at least 6.5-fold, at least 7-fold, at least 7.5-fold, at least 8- fold, at least 8.5-fold, at least 9-fold, at least 9.5-fold, at least 10-fold, at least 10.5-fold, at least 11-fold, at least 11.5-fold, at least 12-fold, at least 12.5-fold, at least 13-fold, at least 13.5-fold, at least 14-fold, at least 14.5-fold, at least 15-fold, at least 15.5-fold, at least 16- fold, at least 16.5-fold, at least 17-fold, at least 17.5-fold, at least 18-fold, at least 18.5-fold, at least 19-fold, at least 19.5-fold, or at least 20-fold) less than the KD of the second antigen- binding domain at a neutral pH (e.g., any of the neutral pHs described herein).

A variety of different methods known in the art can be used to determine the KD values of any of the multi-specific antigen-binding protein constructs described herein (e.g., an electrophoretic mobility shift assay, a filter binding assay, surface plasmon resonance, and a biomolecular binding kinetics assay, etc.).

In some embodiments of any of the multi-specific antigen-binding protein constructs, the second antigen-binding domain can include a set of three or six CDRs selected from the group consisting of: (1) a light chain CDRl of SEQ ID NO: 448, a light chain CDR2 of SEQ ID NO: 449, a light chain CDR3 of SEQ ID NO: 450, a heavy chain CDRl of SEQ ID NO: 454, a heavy chain CDR2 of SEQ ID NO: 455, and a heavy chain CDR3 of SEQ ID NO: 456;

(2) a light chain CDRl of SEQ ID NO: 448, a light chain CDR2 of SEQ ID NO: 449, a light chain CDR3 of SEQ ID NO: 450, a heavy chain CDRl of SEQ ID NO: 458, a heavy chain CDR2 of SEQ ID NO: 459. and a heavy chain CDR3 of SEQ ID NO: 460;

(3) a light chain CDRl of SEQ ID NO: 448, a light chain CDR2 of SEQ ID NO: 449, a light chain CDR3 of SEQ ID NO: 450, a heavy chain CDRl of SEQ ID NO: 462, a heavy chain CDR2 of SEQ ID NO: 463, and a heavy chain CDR3 of SEQ ID NO: 464;

(4) a light chain CDRl of SEQ ID NO: 448, a light chain CDR2 of SEQ ID NO: 449, a light chain CDR3 of SEQ ID NO: 450, a heavy chain CDRl of SEQ ID NO: 466, a heavy chain CDR2 of SEQ ID NO: 467. and a heavy chain CDR3 of SEQ ID NO: 468;

(6) a heavy chain CDRl of SEQ ID NO: 480, a heavy chain CDR2 of SEQ ID NO:

481, and a heavy chain CDR3 of SEQ ID NO: 482;

(8) a a heavy chain CDRl of SEQ ID NO: 486, a heavy chain CDR2 of SEQ ID NO: 487. and a heavy chain CDR3 of SEQ ID NO: 488;

(9) a heavy chain CDRl of SEQ ID NO: 497. a heavy chain CDR2 of SEQ ID NO: 498, and a heavy chain CDR3 of SEQ ID NO: 499;

(11) a heavy chain CDRl of SEQ ID NO: 509, a heavy chain CDR2 of SEQ ID NO:

510, and a heavy chain CDR3 of SEQ ID NO: 511;

(14) a heavy chain CDRl of SEQ ID NO: 523, a heavy chain CDR2 of SEQ ID NO: 524, and a heavy chain CDR3 of SEQ ID NO: 525; and (15) a heavy chain CDR1 of SEQ ID NO: 529, a heavy chain CDR2 of SEQ ID NO: 530, and a heavy chain CDR3 of SEQ ID NO: 531.

In some embodiments of any of the multi-specific antigen-binding protein constructs, the second antigen-binding domain can include a heavy chain variable domain, or a light chain variable domain and a heavy chain variable domain selected from the group consisting of:

(1) a light chain variable domain of SEQ ID NO: 452 and a heavy chain variable domain of SEQ ID NO: 453;

(5) a heavy chain variable domain of SEQ ID NO: 473;

(6) a heavy chain variable domain of SEQ ID NO: 474;

(7) a heavy chain variable domain of SEQ ID NO: 475;

(8) a heavy chain variable domain of SEQ ID NO: 476;

(9) a heavy chain variable domain of SEQ ID NO: 492;

(10) a heavy chain variable domain of SEQ ID NO: 494;

(11) a heavy chain variable domain of SEQ ID NO: 496;

(12) a heavy chain variable domain of SEQ ID NO: 512;

(13) a heavy chain variable domain of SEQ ID NO: 513;

(14) a heavy chain variable domain of SEQ ID NO: 514; and

(15) a heavy chain variable domain of SEQ ID NO: 516.

Additional Exemplary Aspects for Both Antigen-Binding Protein Constructs and Multi- Specific Antigen-Binding Protein Constructs

In some embodiments of any of the antigen-binding protein constructs described herein or any of the multi-specific ABPC described herein, the HLA-A gene is selected from the group of: a A*24:02 gene, a A*24: 144 gene, a A*02:01 gene, a A*02:09 gene, a A*02:43N gene, a A*02:66 gene, a A*02:75 gene, a A*02:83N gene, a A*02:89 gene, a A*02:97 gene, a A*02: 132 gene, a A*02: 134 gene, a A*02: 140 gene, a A*02:241 gene, a A*02:252 gene, a A*02:256 gene, a A*02:266 gene, a A*02:291 gene, a A*02:294 gene, a A* 02 : 305N gene, a A* 11 : 01 gene, a A* 11 : 102 gene, a A* 11 : 2 IN gene, a A* 11 : 69N gene, a A*ll:86 gene, a A*01:01 gene, a A*01:04N gene, a A*01:22N gene, a A*01:32 gene, a A*01:37 gene, a A*01:45 gene, a A*01:56N gene, a A*01:81 gene, a A*01:87N gene, a A*33:03 gene, a A*33:15 gene, a A*33:25 gene, a A*33:31 gene, aA*33:39 gene, a A*33:44 gene, a A*34:01 gene, a A*03:01 gene, a A*03:20 gene, a A*03:21N gene, a A*03:26 gene, a A* 03: 37 gene, a A*03:45 gene, a A*03:78 gene, aA*03:112 gene, a A*03:118 gene, aA*24:07 gene, aA*23:01 gene, a A*23:07N gene, a A*23:17 gene, a A*23:18 gene, a A*23:20 gene, a A*02:07 gene, a A* 02:15N gene, a A* 02: 265 gene, a A*02:03 gene, a A*02:253 gene, a A* 02: 264 gene, a A*31:01 gene, a A*31:14N gene, a A*31:23 gene, a A*31:46 gene, a A*31:48 gene, a A*26:01 gene, aA*26:24 gene, a A*26:26 gene, a A*26:56 gene, a A*29:01 gene, a A*02:06 gene, a A*02:126 gene, a A*30:01 gene, a A*30:24 gene, a A*30:02 gene, a A*30:33 gene, aA*68:01 gene, a A*68:l IN gene, a A*68:33 gene, a A*68:02 gene, a A*29:02 gene, a A*29:26 gene, a A*74:01 gene, a A*74:02 gene, a A*02:ll gene, a A*02:69 gene, aA*32:01 gene, a A*02:02 gene, a A*34:02 gene, a A*36:01 gene, a A*33:01 gene, a A*ll:02 gene, a A*ll:77 gene, a A*26:03 gene, a A*02:05 gene, a A*02:179 gene, a A*25:01 gene, a A*25:07 gene, a A* 24: 03 gene, aA*24:33 gene, a A*26:02 gene, aA*68:03 gene, a A*03:02 gene, a A*66:01 gene, a A*66:08 gene, a A*30:04 gene, a A*02:17 gene, a A*66:02 gene, a A*24: 10 gene, a A*02:04 gene, a A*24: 17 gene, a A*80:01 gene, a A*69:01 gene, a A*24:20 gene, a A*01:02 gene, a A*68:05 gene, aA*02:10 gene, a A*30:10 gene, a A*34:05 gene, a A*02:131 gene, a A*02:16 gene, a A* 02: 104 gene, a A*02:22 gene, a A*02:20 gene, a A*01:03 gene, a A*66:03 gene, a A*ll:04 gene, a A*24:25 gene, a A*24:23 gene, and a A*02:60 gene. Exemplary sequences for these HLA-A genes are provided in the Sequence Appendix at the end of this application.

In some embodiments of any of the antigen-binding protein constructs described herein or any of the multi-specific antigen-binding protein constructs described herein, the HLA-B gene is selected from the group of: aB*40:01 gene, aB*40:55 gene, aB*40:141 gene, aB*40:150gene, aB*40:151 gene, aB*15:02 gene, aB*15:214 gene, aB*46:01 gene, a B*46: 15N gene, a B*46:24 gene, a B*07:02 gene, a B*07:44 gene, a B*07:49N gene, a B*07:58 gene, aB*07:59 gene, aB*07:61 gene, aB*07:120 gene, aB*07:128 gene, a B*07:129 gene, aB*07:130 gene, aB*53:01 gene, aB*38:02 gene, aB*38:18 gene, a B*08:01 gene, aB*08:19N gene, aB*52:01 gene, a B*52:07 gene, aB*35:01 gene, a B*35:40N gene, aB*35:42 gene, aB*35:57 gene, aB*35:94 gene, aB*35:134Ngene, a B*35:161 gene, aB*44:02 gene, aB*44:27 gene, a B*44:66 gene, aB*44:118 gene, a B*51:01 gene, aB*51:llN gene, aB*51:30 gene, aB*51:32 gene, aB*51:48 gene, a B*51:51 gene, aB*40:06 gene, aB*44:03 gene, aB*58:01 gene, aB*58:ll gene, a B * 58 : 3 IN gene, a B * 15 : 01 gene, a B* 15 : 102 gene, a B * 15 : 104 gene, a B * 15 : 140 gene, a B*15:146 gene, a B* 15:201 gene, aB*35:05 gene, aB*07:05 gene, a 6*07:06 gene, a B*15:35 gene, aB*40:02 gene, aB*40:56 gene, aBⁱ40:97 gene, aB*40:144N gene, a B*54:01 gene, aB*54:17 gene, aB*18:01 gene, aB*18:17N gene, aB*18:53 gene, a B*35:03 gene, aB*35:70 gene, aB*57:01 gene, aB*57:29 gene, aB*57:37 gene, aB*15:03 gene, aB*15:103 gene, aB*13:01 gene, aB*27:05 gene, aB*27:13 gene, aB*42:01 gene, a B*15:25 gene, aB*45:01 gene, aB*45:07 gene, aB*45:13 gene, aB*14:02 gene, aB*58:02 gene, aB*49:01 gene, aB*15:10 gene, aB*38:01 gene, aB*48:01 gene, aB*48:09 gene, a B*57:03 gene, a B*37:01 gene, a B*37:23 gene, a B*39:01 gene, a B*39:46 gene, a B*39:59 gene, a B*35:02 gene, aB*15:21 gene, aB*39:05 gene, a B* 13:02 gene, a B* 13:38 gene, a B*50:01 gene, aB*39:06 gene, aB*55:02 gene, aB*41:01 gene, aB*27:06 gene, aB*15:13 gene, a B*59:01 gene, aB*35:12 gene, aB*55:01 gene, a B* 15: 12 gene, a B*15:19 gene, a B*15:16gene, aB*81:01 gene, aB*81:02 gene, aB*81:03 gene, aB*51:06 gene, aB*27:04 gene, aB*27:68 gene, aB*27:69 gene, aB*35:43 gene, aB*35:67 gene, aB*35:79 gene, a B*15:ll gene, aB*35:08 gene, aB*15:18 gene, aB*15:198 gene, a B* 15: 17 gene, a B*51:02gene, aB*14:01 gene, aB*39:10 gene, aB*56:04 gene, aB*15:27 gene, aB*35:17 gene, aB*15:15 gene, aB*15:07 gene, aB*67:01 gene, aB*78:01 gene, aB*56:01 gene, a B*56:24 gene, aB*41:02 gene, aB*40:05 gene, aB*42:02 gene, aB*40:03 gene, aB*40:10 gene, aB*57:02 gene, aB*15:30 gene, aB*27:02 gene, aB*18:02 gene, aB*39:02 gene, a B*39:08 gene, aB*27:07 gene, aB*48:03 gene, aB*51:08 gene, aB*39:09 gene, aB*15:05 gene, a B*27:03 gene, a B*35:04 gene, a B*40:04 gene, a B*44:05 gene, a B*40:08 gene, a B*15:08 gene, aB*\5:04 gene, aB^!|:48:04 gene, aB*39:ll gene, aB*35:14 gene, aB*47:01 gene, a B*82:01 gene, aB*73:01 gene, aB*14:03 gene, aB*35:20 gene, a B*15:29 gene, a B*50:02 gene, aB*57:04 gene, aB*48:02 gene, aB*15:40 gene, aB*15:06 gene, aB*51:05 gene, a B*40:ll gene, aB*56:03 gene, aB*51:07 gene, aBⁱ39:04 gene, a B*44:10 gene, a B*39:15 gene, aB*15:38 gene, aB*15:32 gene, aB*51:09 gene, aB*39:24 gene, aB*15:39 gene, aB*40:12 gene, aB*40:27 gene, aB*35:10 gene, aB*35:ll gene, aB*15:09 gene, a B*47:03 gene, and a B*48:07 gene. Exemplary sequences for these HLA-B genes are provided in the Sequence Appendix at the end of this application. In some embodiments of any of the antigen-binding protein constructs described herein or any of the multi-specific ABPC described herein, the HLA-C gene is selected from the group of: a C*07:02 gene, a C*07:50 gene, a C*07:66 gene, a C*07:74 gene, a C*07: 159 gene, a C*07: 160 gene, a C*07: 167 gene, a C*04:01 gene, a C*04:09N gene, a C*04:28 gene, a C*04:30 gene, a C*04:41 gene, a C*04:79 gene, a C*04:82 gene, a C*04:84 gene, a C*01 :02 gene, a C*01 :25 gene, a C*01:44 gene, a C*08:01 gene, a C*08:20 gene, a C*08:22 gene, a C*08:24 gene, a C*07:01 gene, a C*07:06 gene, a C*07: 18 gene, a C*07:52 gene, a C*07: 153 gene, a C*07: 166 gene, a C*03:03 gene, a C*03:20N gene, a C*03:62 gene, a C*06:02 gene, a C*06:46N gene, a C*06:55 gene, a C*03:04 gene, a C*03: 100 gene, a C*03: 101 gene, a C* 03: 105 gene, a C*03: 106 gene, a C*15:02 gene, a C*15: 13 gene, a

C*15:47 gene, a C*12:02 gene, a C*16:01 gene, a C*05:01 gene, a C*05:03 gene, a C*05:37 gene, a C*05:53 gene, a C*12:03 gene, a C*12:23 gene, a C*02:02 gene, a C*02: 10 gene, a C*02:29 gene, a C*03:02 gene, a C*14:02 gene, a C* 14:23 gene, a C*14:31 gene, a C*15:05 gene, a C*15:29 gene, a C*17:01 gene, a C*17:02 gene, a C* 17:03 gene, a C*14:03 gene, a C*04:03 gene, a C*08:02 gene, a C*18:01 gene, a C* 18:02 gene, a C*16:02 gene, a C*07:04 gene, a C*07: l 1 gene, a C*03:05 gene, a C*12:04 gene, a C*08:03 gene, a C*08:40 gene, a C*04:06 gene, a C*16:04 gene, a C*08:04 gene, a C*03:06 gene, a C* 04: 04 gene, a C*07:26 gene, a C*15:09 gene, a C*01 :03 gene, a C*01:24 gene, a C* 15:04 gene, and a C*04:07 gene. Exemplary sequences for these HLA-C genes are provided in the Sequence Appendix at the end of this application. In some embodiments of any of the ABPCs described herein or any of the multi-specific ABPC described herein, the epitope of the PC is an at least partially monomorphic epitope.

In some embodiments, any of the antigen-binding protein constructs or multi-speciic antigen-binding protein constructs provided herein have at least a 1% (e.g., at least a 2%, at least a 3%, at least a 4%, at least a 5%, at least a 6%, at least a 8%, at least a 10%, at least a 12%, at least a 15%, at least a 20%, at least a 25%, at least a 30%, at least a 35%, at least a 40%, at least a 45%, at least a 50%, at least a 55%, at least a 60%, at least a 65%, at least a 70%, at least a 75%, at least a 80%, at least a 85%, at least a 90%, at least a 95%, at least a 100%, at least a 105%, at least a 110%, at least a 115%, at least a 120%, at least a 125%, at least a 130%, at least a 135%, at least a 140%, at least a 145%, at least a 150%, at least a 155%, at least a 160%, at least a 165%, at least a 170%, at least a 175%, at least a 180%, at least a 185%, at least a 190%, at least a 195%, at least a 200%, at least a 205%, at least a 210%, at least a 215%, at least a 220%, at least a 225%, at least a 230%, at least a 235%, at least a 240%, at least a 245%, at least a 250%, at least a 255%, at least a 260%, at least a 265%, at least a 270%, at least a 275%, at least a 280%, at least a 285%, at least a 290%, at least a 295%, at least a 300%, at least a 305%, at least a 310%, at least a 315%, at least a 320%, at least a 325%, at least a 330%, at least a 335%, at least a 340%, at least a 345%, at least a 350%, at least a 355%, at least a 360%, at least a 365%, at least a 370%, at least a 375%, at least a 380%, at least a 385%, at least a 390%, at least a 395%, or at least a 400%) increase in half-life in a subject as compared to the half-life of a control ABPC (e.g., any of the control ABPCs described herein) in a similar subject. In some embodiments, the antigen- binding protein construct or multi-speciic antigen-binding protein construct has about a 1% increase to about a 400% increase (e.g., about a 1% increase to about a 380% increase, about a 1 % increase to about a 360% increase, about a 1% increase to about a 340% increase, about a 1 % increase to about a 320% increase, about a 1% increase to about a 300% increase, about a 1 % increase to about a 280% increase, about a 1% increase to about a 260% increase, about a 1 % increase to about a 240% increase, about a 1% increase to about a 220% increase, about a 1 % increase to about a 200% increase, about a 1 % increase to about a 180% increase, about a 1 % increase to about a 160% increase, about a 1% increase to about 140% increase, about a 1% increase to about a 120% increase, about a 1% increase to about a 100% increase, about a

1% increase to about a 95°/o increase, about a 1% increase to about a 90% increase, about a

1% increase to about a 85°/o increase, about a 1% increase to about a 80% increase, about a

1% increase to about a 75°/ Ό increase, about a 1% increase to about a 70% increase, about a

1% increase to about a 65°/ 'o increase, about a 1% increase to about a 60% increase, about a

1% increase to about a 55°/ 'o increase, about a 1% increase to about a 50% increase, about a

1% increase to about a 45°/ ^xo increase, about a 1% increase to about a 40% increase, about a

1% increase to about a 35°/o increase, about a 1% increase to about a 30% increase, about a

1% increase to about a 25°/ 'o increase, about a 1% increase to about a 20% increase, about a

1% increase to about a 18°/ 'o increase, about a 1% increase to about a 16% increase, about a

1% increase to about a 14°/ ⁷o increase, about a 1% increase to about a 12% increase, about a

1% increase to about a 10°/ 'o increase, about a 1% increase to about a 8% increase, about a 1 increase to about a 6% increase, about a 1 % increase to about a 5% increase, about a 1% increase to about a 4% increase, about a 1 % increase to about a 3% increase, about a 2% increase to about a 400% increase, about a 2% increase to about a 380% increase, about a 2% increase to about a 360% increase, about a 2% increase to about a 340% increase, about a 2% increase to about a 320% increase, about a 2% increase to about a 300% increase, about a 2% increase to about a 280% increase, about a 2% increase to about a 260% increase, about a 2% increase to about a 240% increase, about a 2% increase to about a 220% increase, about a 2% increase to about a 200% increase, about a 2% increase to about a 180% increase, about a 2% increase to about a 160% increase, about a 2% increase to about 140% increase, about a 2% increase to about a 120% increase, about a 2% increase to about a 100% increase, about a 2% increase to about a 95% increase, about a 2% increase to about a 90% increase, about a 2% increase to about a 85% increase, about a 2% increase to about a 80% increase, about a 2% increase to about a 75% increase, about a 2% increase to about a 70% increase, about a 2% increase to about a 65% increase, about a 2% increase to about a 60% increase, about a 2% increase to about a 55% increase, about a 2% increase to about a 50% increase, about a 2% increase to about a 45% increase, about a 2% increase to about a 40% increase, about a 2% increase to about a 35% increase, about a 2% increase to about a 30% increase, about a 2% increase to about a 25% increase, about a 2% increase to about a 20% increase, about a 2% increase to about a 18% increase, about a 2% increase to about a 16% increase, about a 2% increase to about a 14% increase, about a 2% increase to about a 12% increase, about a 2% increase to about a 10% increase, about a 2% increase to about a 8% increase, about a 2% increase to about a 6% increase, about a 2% increase to about a 5% increase, about a 2% increase to about a 4% increase, about a 3% increase to about a 400% increase, about a 3% increase to about a 380% increase, about a 3% increase to about a 360% increase, about a 3% increase to about a 340% increase, about a 3% increase to about a 320% increase, about a 3% increase to about a 300% increase, about a 3% increase to about a 280% increase, about a 3% increase to about a 260% increase, about a 3% increase to about a 240% increase, about a 3% increase to about a 220% increase, about a 3% increase to about a 200% increase, about a 3% increase to about a 180% increase, about a 3% increase to about a 160% increase, about a 3% increase to about 140% increase, about a 3% increase to about a 120% increase, about a 3% increase to about a 100% increase, about a 3% increase to about a 95% increase, about a 3% increase to about a 90% increase, about a 3% increase to about a 85% increase, about a 3% increase to about a 80% increase, about a 3% increase to about a 75% increase, about a 3% increase to about a 70% increase, about a 3% increase to about a 65% increase, about a 3% increase to about a 60% increase, about a 3% increase to about a 55% increase, about a 3% increase to about a 50% increase, about a 3% increase to about a 45% increase, about a 3% increase to about a 40% increase, about a 3% increase to about a 35% increase, about a 3% increase to about a 30% increase, about a 3% increase to about a 25% increase, about a 3% increase to about a 20% increase, about a 3% increase to about a 18% increase, about a 3% increase to about a 16% increase, about a 3% increase to about a 14% increase, about a 3% increase to about a 12% increase, about a 3% increase to about a 10% increase, about a 3% increase to about a 8% increase, about a 3% increase to about a 6% increase, about a 3% increase to about a 5% increase, about a 4% increase to about a 400% increase, about a 4% increase to about a 380% increase, about a 4% increase to about a 360% increase, about a 4% increase to about a 340% increase, about a 4% increase to about a 320% increase, about a 4% increase to about a 300% increase, about a 4% increase to about a 280% increase, about a 4% increase to about a 260% increase, about a 4% increase to about a 240% increase, about a 4% increase to about a 220% increase, about a 4% increase to about a 200% increase, about a 4% increase to about a 180% increase, about a 4% increase to about a 160% increase, about a 4% increase to about 140% increase, about a 4% increase to about a 120% increase, about a 4% increase to about a 100% increase, about a 4% increase to about a 95% increase, about a 4% increase to about a 90% increase, about a 4°/ ⁷o increase to about a 85% increase, about a 4% increase to about a 80% increase, about a 4°/ ii increase to about a 75% increase, about a 4% increase to about a 70% increase, about a 4°/ ii increase to about a 65% increase, about a 4% increase to about a 60% increase, about a 4°/ i increase to about a 55% increase, about a 4% increase to about a 50% increase, about a 4°/o increase to about a 45% increase, about a 4% increase to about a 40% increase, about a 4°/o increase to about a 35% increase, about a 4% increase to about a 30% increase, about a 4°/ 'o increase to about a 25% increase, about a 4% increase to about a 20% increase, about a 4°/o increase to about a 18% increase, about a 4% increase to about a 16% increase, about a 4°/o increase to about a 14% increase, about a 4% increase to about a 12% increase, about a 4°/ Ό increase to about a 10% increase, about a 4% increase to about a 8% increase, about a 4% increase to about a 6% increase, about a 5% increase to about a 400% increase, about a 5% increase to about a 380% increase, about a 5% increase to about a 360% increase, about a 5% increase to about a 340% increase, about a 5% increase to about a 320% increase, about a 5% increase to about a 300% increase, about a 5% increase to about a 280% increase, about a 5% increase to about a 260% increase, about a 5% increase to about a 240% increase, about a 5% increase to about a 220% increase, about a 5% increase to about a 200% increase, about a 5% increase to about a 180% increase, about a 5% increase to about a 160% increase, about a 5% increase to about 140% increase, about a 5% increase to about a 120% increase, about a 5% increase to about a 100% increase, about a 5% increase to about a 95% increase, about a 5% increase to about a 90% increase, about a 5°/ ^xo increase to about a 85°/ ^xo increase, about a 5°/ ^xo increase to about a 80% increase, about a

5°/o increase to about a 75°/o increase, about a 5°/o increase to about a 70% increase, about a

5°/o increase to about a 65°/o increase, about a 5°/o increase to about a 60% increase, about a

5°/o increase to about a 55°/o increase, about a 5°/o increase to about a 50% increase, about a

5°/ ^xo increase to about a 45°/ ⁷o increase, about a 5°/ ⁷o increase to about a 40% increase, about a

5°/o increase to about a 35°/o increase, about a 5°/o increase to about a 30% increase, about a

5°/o increase to about a 25°/0 increase, about a 5°/o increase to about a 20% increase, about a

5°/o increase to about a 18°/o increase, about a 5°/o increase to about a 16% increase, about a

5°/o increase to about a 14°/ ⁷o increase, about a 5°/ ⁷o increase to about a 12% increase, about a

5°/o increase to about a 10°/ ⁷o increase, about a 5°/ ⁷o increase to about a 8% increase, about a

10% increase to about a 400% increase, about a 10% increase to about a 380% increase, about a 10% increase to about a 360% increase, about a 10% increase to about a 340% increase, about a 10% increase to about a 320% increase, about a 10% increase to about a 300% increase, about a 10% increase to about a 280% increase, about a 10% increase to about a 260% increase, about a 10% increase to about a 240% increase, about a 10% increase to about a 220% increase, about a 10% increase to about a 200% increase, about a 10% increase to about a 180% increase, about a 10% increase to about a 160% increase, about a 10% increase to about 140% increase, about a 10% increase to about a 120% increase, about a 10% increase to about a 100% increase, about a 10% increase to about a 95% increase, about a 10°/ Ό increase to about a 90°/ Ό increase, about a 10% increase to about a 85% increase, about a 10°/o increase to about a 80°/o increase, about a 10% increase to about a 75% increase, about a 10°/ Ό increase to about a 70°/o increase, about a 10% increase to about a 65% increase, about a 10°/ ^xo increase to about a 60°/ Ό increase, about a 10% increase to about a 55% increase, about a 10°/o increase to about a 50°/o increase, about a 10% increase to about a 45% increase, about a 10°/0 increase to about a 40°/o increase, about a 10% increase to about a 35% increase, about a 10°/o increase to about a 30°/o increase, about a 10% increase to about a 25% increase, about a 10°/ ⁷o increase to about a 20°/ ⁷o increase, about a 10% increase to about a 18% increase, about a 10°/o increase to about a 16°/o increase, about a 10% increase to about a 14% increase, about a 10°/o increase to about a 12°/o increase, about a 12% increase to about a 400°/o increase, about a 12% increase to about a 380% increase, about a 12% increase to about a 360% increase, about a 12% increase to about a 340% increase, about a 12% increase to about a 320% increase, about a 12% increase to about a 300% increase, about a 12% increase to about a 280% increase, about a 12% increase to about a 260% increase, about a 12% increase to about a 240% increase, about a 12% increase to about a 220% increase, about a 12% increase to about a 200% increase, about a 12% increase to about a 180% increase, about a 12% increase to about a 160% increase, about a 12% increase to about 140% increase, about a 12% increase to about a 120% increase, about a 12% increase to about a 100% increase, about a 12% increase to about a 95% increase, about a 12% increase to about a 90% increase, about a 12% increase to about a 85% increase, about a 12% increase to about a 80% increase, about a 12% increase to about a 75% increase, about a 12% increase to about a 70% increase, about a 12% increase to about a 65% increase, about a 12% increase to about a 60% increase, about a 12% increase to about a 55% increase, about a 12% increase to about a 50% increase, about a 12% increase to about a 45% increase, about a 12% increase to about a 40% increase, about a 12% increase to about a 35% increase, about a 12% increase to about a 30% increase, about a 12% increase to about a 25% increase, about a 12% increase to about a 20% increase, about a 12% increase to about a 18% increase, about a 12% increase to about a 16% increase, about a 12% increase to about a 14% increase, about a 14% increase to about a 400% increase, about a 14% increase to about a 380% increase, about a 14% increase to about a 360% increase, about a 14% increase to about a 340% increase, about a 14% increase to about a 320% increase, about a 14% increase to about a 300% increase, about a 14% increase to about a 280% increase, about a 14% increase to about a 260% increase, about a 14% increase to about a 240% increase, about a 14% increase to about a 220% increase, about a 14% increase to about a 200% increase, about a 14% increase to about a 180% increase, about a 14% increase to about a 160% increase, about a 14% increase to about 140% increase, about a 14% increase to about a 120% increase, about a 14% increase to about a 100% increase, about a 14% increase to about a 95% increase, about a 14% increase to about a 90% increase, about a 14°/ Ό increase to about a 85% increase, about a 14% increase to about a 80% increase, about a 14°/ i increase to about a 75% increase, about a 14% increase to about a 70% increase, about a 14°/ i increase to about a 65% increase, about a 14% increase to about a 60% increase, about a 14°/ ⁷o increase to about a 55% increase, about a 14% increase to about a 50% increase, about a 14°/ i increase to about a 45% increase, about a 14% increase to about a 40% increase, about a 14°/ <a increase to about a 35% increase, about a 14% increase to about a 30% increase, about a 14°/o increase to about a 25% increase, about a 14% increase to about a 20% increase, about a 14°/ 'o increase to about a 18% increase, about a 14% increase to about a 16% increase, about a 16°/ ⁷o increase to about a 400% increase, about a 16% increase to about a 380% increase, about a 16% increase to about a 360% increase, about a 16% increase to about a 340% increase, about a 16% increase to about a 320% increase, about a 16% increase to about a 300% increase, about a 16% increase to about a 280% increase, about a 16% increase to about a 260% increase, about a 16% increase to about a 240% increase, about a 16% increase to about a 220% increase, about a 16% increase to about a 200% increase, about a 16% increase to about a 180% increase, about a 16% increase to about a 160% increase, about a 16% increase to about 140% increase, about a 16% increase to about a 120% increase, about a 16% increase to about a 100% increase, about a

16°/ Ό increase to about a 95°/ Ό increase, about a 16°/ increase to about a 90% increase, about a

16°/ 'o increase to about a 85°/ 6 increase, about a 16°/ ^f ₀ increase to about a 80% increase, about a

16°/ i increase to about a 75°/ 6 increase, about a 16°/ Ό increase to about a 70% increase, about a

16°/o increase to about a 65°/o increase, about a 16°/ Ό increase to about a 60% increase, about a

16°/ Ό increase to about a 55°/ Ό increase, about a 16°/ Ό increase to about a 50% increase, about a

16°/o increase to about a 45°/o increase, about a 16°/ ^f ₀ increase to about a 40% increase, about a

16°/ ⁷o increase to about a 35°/ ⁷o increase, about a 16°/ increase to about a 30% increase, about a

16°/o increase to about a 25°/o increase, about a 16°/o increase to about a 20% increase, about a

16°/o increase to about a 18°/ i) increase, about a 18°/ ⁷o increase to about a 400°/ο increase, about a 18% increase to about a 380% increase, about a 18% increase to about a 360% increase, about a 18% increase to about a 340% increase, about a 18% increase to about a 320% increase, about a 18% increase to about a 300% increase, about a 18% increase to about a 280% increase, about a 18% increase to about a 260% increase, about a 18% increase to about a 240% increase, about a 18% increase to about a 220% increase, about a 18% increase to about a 200% increase, about a 18% increase to about a 180% increase, about a 18% increase to about a 160% increase, about a 18% increase to about 140% increase, about a

18% increase to about a 120% increase, about a 18% increase to about a 100% increase, about a 11 i% increase to about a 95% increase, about a 1 ! 1% increase to about a 90°/o increase, about a 11 i% increase to about a 85% increase, about a 1 ! i% increase to about a 80°/ 'o increase, about a I S 1% increase to about a 75% increase, about a I S 1% increase to about a 70°/ ⁷o increase, about a I S 1% increase to about a 65% increase, about a I S 1% increase to about a 60°/ 'o increase, about a I S Wo increase to about a 55% increase, about a I S i% increase to about a 50°/ Ό increase, about a I S i% increase to about a 45% increase, about a 1 ! 1% increase to about a 40°/ 'o increase, about a I S i% increase to about a 35% increase, about a 1 ! 1% increase to about a 30°/ Ό increase, about a I S i% increase to about a 25% increase, about a 1 ! 1% increase to about a 20°/ Ό increase, about a 20% increase to about a 400% increase, about a 20% increase to about a 380% increase, about a 20% increase to about a 360% increase, about a 20% increase to about a 340% increase, about a 20% increase to about a 320% increase, about a 20% increase to about a 300% increase, about a 20% increase to about a 280% increase, about a 20% increase to about a 260% increase, about a 20% increase to about a 240% increase, about a 20% increase to about a 220% increase, about a 20% increase to about a 200% increase, about a 20% increase to about a 180% increase, about a 20% increase to about a 160% increase, about a 20% increase to about 140% increase, about a 20% increase to about a 120% increase, about a 20% increase to about a 100% increase, about a 20% increase to about a 95% increase, about a 20% increase to about a 90% increase, about a 20% increase to about a 85% increase, about a 20% increase to about a 80% increase, about a 20% increase to about a 75% increase, about a 20% increase to about a 70% increase, about a 20% increase to about a 65% increase, about a 20% increase to about a 60% increase, about a 20% increase to about a 55% increase, about a 20% increase to about a 50% increase, about a 20% increase to about a 45% increase, about a 20% increase to about a 40% increase, about a 20% increase to about a 35% increase, about a 20% increase to about a 30% increase, about a 20% increase to about a 25% increase, about a 25% increase to about a 400% increase, about a 25% increase to about a 380% increase, about a 25% increase to about a 360% increase, about a 25% increase to about a 340% increase, about a 25% increase to about a 320% increase, about a 25% increase to about a 300% increase, about a 25% increase to about a 280% increase, about a 25% increase to about a 260% increase, about a 25% increase to about a 240% increase, about a 25% increase to about a 220% increase, about a 25% increase to about a 200% increase, about a 25% increase to about a 180% increase, about a 25% increase to about a 160% increase, about a 25% increase to about 140% increase, about a 25% increase to about a 120% increase, about a 25% increase to about a 100% increase, about a 25% increase to about a 95% increase, about a 25% increase to about a 90% increase, about a 25% increase to about a 85% increase, about a 25% increase to about a 80% increase, about a 25% increase to about a 75% increase, about a 25% increase to about a 70% increase, about a 25% increase to about a 65% increase, about a 25% increase to about a 60% increase, about a 25% increase to about a 55% increase, about a 25% increase to about a 50% increase, about a 25% increase to about a 45% increase, about a 25% increase to about a 40% increase, about a 25% increase to about a 35% increase, about a 25% increase to about a 30% increase, about a 30% increase to about a 400% increase, about a 30% increase to about a 380% increase, about a 30% increase to about a 360% increase, about a 30% increase to about a 340% increase, about a 30% increase to about a 320% increase, about a 30% increase to about a 300% increase, about a 30% increase to about a 280% increase, about a 30% increase to about a 260% increase, about a 30% increase to about a 240% increase, about a 30% increase to about a 220% increase, about a 30% increase to about a 200% increase, about a 30% increase to about a 180% increase, about a 30% increase to about a 160% increase, about a 30% increase to about 140% increase, about a 30% increase to about a 120% increase, about a 30% increase to about a 100% increase, about a 30% increase to about a 95% increase, about a 30% increase to about a 90% increase, about a 30% increase to about a 85% increase, about a 30% increase to about a 80% increase, about a 30% increase to about a 75% increase, about a 30% increase to about a 70% increase, about a 30% increase to about a 65% increase, about a 30% increase to about a 60% increase, about a 30% increase to about a 55% increase, about a 30% increase to about a 50% increase, about a 30% increase to about a 45% increase, about a 30% increase to about a 40% increase, about a 30% increase to about a 35% increase, about a 35% increase to about a 400% increase, about a 35% increase to about a 380% increase, about a 35% increase to about a 360% increase, about a 35% increase to about a 340% increase, about a 35% increase to about a 320% increase, about a 35% increase to about a 300% increase, about a 35% increase to about a 280% increase, about a 35% increase to about a 260% increase, about a 35% increase to about a 240% increase, about a 35% increase to about a 220% increase, about a 35% increase to about a 200% increase, about a 35% increase to about a 180% increase, about a 35% increase to about a 160% increase, about a 35% increase to about 140% increase, about a 35% increase to about a 120% increase, about a 35% increase to about a 100% increase, about a 35% increase to about a 95% increase, about a 35% increase to about a 90% increase, about a 35% increase to about a 85% increase, about a 35% increase to about a 80% increase, about a 35% increase to about a 75% increase, about a 35% increase to about a 70% increase, about a 35% increase to about a 65% increase, about a 35% increase to about a 60% increase, about a 35% increase to about a 55% increase, about a 35% increase to about a 50% increase, about a 35% increase to about a 45% increase, about a 35% increase to about a 40% increase, about a 40% increase to about a 400% increase, about a 40% increase to about a 380% increase, about a 40% increase to about a 360% increase, about a 40% increase to about a 340% increase, about a 40% increase to about a 320% increase, about a 40% increase to about a 300% increase, about a 40% increase to about a 280% increase, about a 40% increase to about a 260% increase, about a 40% increase to about a 240% increase, about a 40% increase to about a 220% increase, about a 40% increase to about a 200% increase, about a 40% increase to about a 180% increase, about a 40% increase to about a 160% increase, about a 40% increase to about 140% increase, about a 40% increase to about a 120% increase, about a 40% increase to about a 100% increase, about a 40% increase to about a 95% increase, about a 40% increase to about a 90% increase, about a 40% increase to about a 85% increase, about a 40% increase to about a 80% increase, about a 40% increase to about a 75% increase, about a 40% increase to about a 70% increase, about a 40% increase to about a 65% increase, about a 40% increase to about a 60% increase, about a 40% increase to about a 55% increase, about a 40% increase to about a 50% increase, about a 40% increase to about a 45% increase, about a 45% increase to about a 400% increase, about a 45% increase to about a 380% increase, about a 45% increase to about a 360% increase, about a 45% increase to about a 340% increase, about a 45% increase to about a 320% increase, about a 45% increase to about a 300% increase, about a 45% increase to about a 280% increase, about a 45% increase to about a 260% increase, about a 45% increase to about a 240% increase, about a 45% increase to about a 220% increase, about a 45% increase to about a 200% increase, about a 45% increase to about a 180% increase, about a 45% increase to about a 160% increase, about a 45% increase to about 140% increase, about a 45% increase to about a 120% increase, about a 45% increase to about a 100% increase, about a 45% increase to about a 95% increase, about a 45% increase to about a 90% increase, about a 45% increase to about a 85% increase, about a 45% increase to about a 80% increase, about a 45% increase to about a 75% increase, about a 45% increase to about a 70% increase, about a 45% increase to about a 65% increase, about a 45% increase to about a 60% increase, about a 45% increase to about a 55% increase, about a 45% increase to about a 50% increase, about a 50% increase to about a 400% increase, about a 50% increase to about a 380% increase, about a 50% increase to about a 360% increase, about a 50% increase to about a 340% increase, about a 50% increase to about a 320% increase, about a 50% increase to about a 300% increase, about a 50% increase to about a 280% increase, about a 50% increase to about a 260% increase, about a 50% increase to about a 240% increase, about a 50% increase to about a 220% increase, about a 50% increase to about a 200% increase, about a 50% increase to about a 180% increase, about a 50% increase to about a 160% increase, about a 50% increase to about 140% increase, about a 50% increase to about a 120% increase, about a 50% increase to about a 100% increase, about a 50% increase to about a 95% increase, about a 50% increase to about a 90% increase, about a 50% increase to about a 85% increase, about a 50% increase to about a 80% increase, about a 50% increase to about a 75% increase, about a 50% increase to about a 70% increase, about a 50% increase to about a 65% increase, about a 50% increase to about a 60% increase, about a 50% increase to about a 55% increase, about a 55% increase to about a 400% increase, about a 55% increase to about a 380% increase, about a 55% increase to about a 360% increase, about a 55% increase to about a 340% increase, about a 55% increase to about a 320% increase, about a 55% increase to about a 300% increase, about a 55% increase to about a 280% increase, about a 55% increase to about a 260% increase, about a 55% increase to about a 240% increase, about a 55% increase to about a 220% increase, about a 55% increase to about a 200% increase, about a 55% increase to about a 180% increase, about a 55% increase to about a 160% increase, about a 55% increase to about 140% increase, about a 55% increase to about a 120% increase, about a 55% increase to about a 100% increase, about a 55% increase to about a 95% increase, about a 55% increase to about a 90% increase, about a 55% increase to about a 85% increase, about a 55% increase to about a 80% increase, about a 55% increase to about a 75% increase, about a 55% increase to about a 70% increase, about a 55% increase to about a 65% increase, about a 55% increase to about a 60% increase, about a 60% increase to about a 400% increase, about a 60% increase to about a 380% increase, about a 60% increase to about a 360% increase, about a 60% increase to about a 340% increase, about a 60% increase to about a 320% increase, about a 60% increase to about a 300% increase, about a 60% increase to about a 280% increase, about a 60% increase to about a 260% increase, about a 60% increase to about a 240% increase, about a 60% increase to about a 220% increase, about a 60% increase to about a 200% increase, about a 60% increase to about a 180% increase, about a 60% increase to about a 160% increase, about a 60% increase to about 140% increase, about a 60% increase to about a 120% increase, about a 60% increase to about a 100% increase, about a 60% increase to about a 95% increase, about a 60% increase to about a 90% increase, about a 60% increase to about a 85% increase, about a 60% increase to about a 80% increase, about a 60% increase to about a 75% increase, about a 60% increase to about a 70% increase, about a 60% increase to about a 65% increase, about a 65% increase to about a 400% increase, about a 65% increase to about a 380% increase, about a 65% increase to about a 360% increase, about a 65% increase to about a 340% increase, about a 65% increase to about a 320% increase, about a 65% increase to about a 300% increase, about a 65% increase to about a 280% increase, about a 65% increase to about a 260% increase, about a 65% increase to about a 240% increase, about a 65% increase to about a 220% increase, about a 65% increase to about a 200% increase, about a 65% increase to about a 180% increase, about a 65% increase to about a 160% increase, about a 65% increase to about 140% increase, about a 65% increase to about a 120% increase, about a 65% increase to about a 100% increase, about a 65% increase to about a 95% increase, about a 65% increase to about a 90% increase, about a 65% increase to about a 85% increase, about a 65% increase to about a 80% increase, about a 65% increase to about a 75% increase, about a 65% increase to about a 70% increase, about a 70% increase to about a 400% increase, about a 70% increase to about a 380% increase, about a 70% increase to about a 360% increase, about a 70% increase to about a 340% increase, about a 70% increase to about a 320% increase, about a 70% increase to about a 300% increase, about a 70% increase to about a 280% increase, about a 70% increase to about a 260% increase, about a 70% increase to about a 240% increase, about a 70% increase to about a 220% increase, about a 70% increase to about a 200% increase, about a 70% increase to about a 180% increase, about a 70% increase to about a 160% increase, about a 70% increase to about 140% increase, about a 70% increase to about a 120% increase, about a 70% increase to about a 100% increase, about a 70% increase to about a 95% increase, about a 70% increase to about a 90% increase, about a 70% increase to about a 85% increase, about a 70% increase to about a 80% increase, about a 70% increase to about a 75% increase, about a 75% increase to about a 400% increase, about a 75% increase to about a 380% increase, about a 75% increase to about a 360% increase, about a 75% increase to about a 340% increase, about a 75% increase to about a 320% increase, about a 75% increase to about a 300% increase, about a 75% increase to about a 280% increase, about a 75% increase to about a 260% increase, about a 75% increase to about a 240% increase, about a 75% increase to about a 220% increase, about a 75% increase to about a 200% increase, about a 75% increase to about a 180% increase, about a 75% increase to about a 160% increase, about a 75% increase to about 140% increase, about a 75% increase to about a 120% increase, about a 75% increase to about a 100% increase, about a 75% increase to about a 95% increase, about a 75% increase to about a 90% increase, about a 75% increase to about a 85% increase, about a 75% increase to about a 80% increase, about a 80% increase to about a 400% increase, about a 80% increase to about a 380% increase, about a 80% increase to about a 360% increase, about a 80% increase to about a 340% increase, about a 80% increase to about a 320% increase, about a 80% increase to about a 300% increase, about a 80% increase to about a 280% increase, about a 80% increase to about a 260% increase, about a 80% increase to about a 240% increase, about a 80% increase to about a 220% increase, about a 80% increase to about a 200% increase, about a 80% increase to about a 180% increase, about a 80% increase to about a 160% increase, about a 80% increase to about 140% increase, about a 80% increase to about a 120% increase, about a 80% increase to about a 100% increase, about a 80% increase to about a 95% increase, about a 80% increase to about a 90% increase, about a 80% increase to about a 85% increase, about a 85% increase to about a 400% increase, about a 85% increase to about a 380% increase, about a 85% increase to about a 360% increase, about a 85% increase to about a 340% increase, about a 85% increase to about a 320% increase, about a 85% increase to about a 300% increase, about a 85% increase to about a 280% increase, about a 85% increase to about a 260% increase, about a 85% increase to about a 240% increase, about a 85% increase to about a 220% increase, about a 85% increase to about a 200% increase, about a 85% increase to about a 180% increase, about a 85% increase to about a 160% increase, about a 85% increase to about 140% increase, about a 85% increase to about a 120% increase, about a 85% increase to about a 100% increase, about a 85% increase to about a 95% increase, about a 85% increase to about a 90% increase, about a 90% increase to about a 400% increase, about a 90% increase to about a 380% increase, about a 90% increase to about a 360% increase, about a 90% increase to about a 340% increase, about a 90% increase to about a 320% increase, about a 90% increase to about a 300% increase, about a 90% increase to about a 280% increase, about a 90% increase to about a 260% increase, about a 90% increase to about a 240% increase, about a 90% increase to about a 220% increase, about a 90% increase to about a 200% increase, about a 90% increase to about a 180% increase, about a 90% increase to about a 160% increase, about a 90% increase to about 140% increase, about a 90% increase to about a 120% increase, about a 90% increase to about a 100% increase, about a 90% increase to about a 95% increase, about a 95% increase to about a 400% increase, about a 95% increase to about a 380% increase, about a 95% increase to about a 360% increase, about a 95% increase to about a 340% increase, about a 95% increase to about a 320% increase, about a 95% increase to about a 300% increase, about a 95% increase to about a 280% increase, about a 95% increase to about a 260% increase, about a 95% increase to about a 240% increase, about a 95% increase to about a 220% increase, about a 95% increase to about a 200% increase, about a 95% increase to about a 180% increase, about a 95% increase to about a 160% increase, about a 95% increase to about 140% increase, about a 95% increase to about a 120% increase, about a 95% increase to about a 100% increase, about a 100% increase to about a 400% increase, about a 100% increase to about a 380% increase, about a 100% increase to about a 360% increase, about a 100% increase to about a 340% increase, about a 100% increase to about a 320% increase, about a 100% increase to about a 300% increase, about a 100% increase to about a 280% increase, about a 100% increase to about a 260% increase, about a 100% increase to about a 240% increase, about a 100% increase to about a 220% increase, about a 100% increase to about a 200% increase, about a 100% increase to about a 180% increase, about a 100% increase to about a 160% increase, about a 100% increase to about 140% increase, about a 100% increase to about a 120% increase, about a 120% increase to about a 400% increase, about a 120% increase to about a 380% increase, about a 120% increase to about a 360% increase, about a 120% increase to about a 340% increase, about a 120% increase to about a 320% increase, about a 120% increase to about a 300% increase, about a 120% increase to about a 280% increase, about a 120% increase to about a 260% increase, about a 120% increase to about a 240% increase, about a 120% increase to about a 220% increase, about a 120% increase to about a 200% increase, about a 120% increase to about a 180% increase, about a 120% increase to about a 160% increase, about a 120% increase to about 140% increase, about a 140% increase to about a 400% increase, about a 140% increase to about a 380% increase, about a 140% increase to about a 360% increase, about a 140% increase to about a 340% increase, about a 140% increase to about a 320% increase, about a 140% increase to about a 300% increase, about a 140% increase to about a 280% increase, about a 140% increase to about a 260% increase, about a 140% increase to about a 240% increase, about a 140% increase to about a 220% increase, about a 140% increase to about a 200% increase, about a 140% increase to about a 180% increase, about a 140% increase to about a 160% increase, about a 160% increase to about a 400% increase, about a 160% increase to about a 380% increase, about a 160% increase to about a 360% increase, about a 160% increase to about a 340% increase, about a 160% increase to about a 320% increase, about a 160% increase to about a 300% increase, about a 160% increase to about a 280% increase, about a 160% increase to about a 260% increase, about a 160% increase to about a 240% increase, about a 160% increase to about a 220% increase, about a 160% increase to about a 200% increase, about a 160% increase to about a 180% increase, about a 180% increase to about a 400% increase, about a 180% increase to about a 380% increase, about a 180% increase to about a 360% increase, about a 180% increase to about a 340% increase, about a 180% increase to about a 320% increase, about a 180% increase to about a 300% increase, about a 180% increase to about a 280% increase, about a 180% increase to about a 260% increase, about a 180% increase to about a 240% increase, about a 180% increase to about a 220% increase, about a 180% increase to about a 200% increase, about a 200% increase to about a 400% increase, about a 200% increase to about a 380% increase, about a 200% increase to about a 360% increase, about a 200% increase to about a 340% increase, about a 200% increase to about a 320% increase, about a 200% increase to about a 300% increase, about a 200% increase to about a 280% increase, about a 200% increase to about a 260% increase, about a 200% increase to about a 240% increase, about a 200% increase to about a 220% increase, about a 220% increase to about a 400% increase, about a 220% increase to about a 380% increase, about a 220% increase to about a 360% increase, about a 220% increase to about a 340% increase, about a 220% increase to about a 320% increase, about a 220% increase to about a 300% increase, about a 220% increase to about a 280% increase, about a 220% increase to about a 260% increase, about a 220% increase to about a 240% increase, about a 240% increase to about a 400% increase, about a 240% increase to about a 380% increase, about a 240% increase to about a 360% increase, about a 240% increase to about a 340% increase, about a 240% increase to about a 320% increase, about a 240% increase to about a 300% increase, about a 240% increase to about a 280% increase, about a 240% increase to about a 260% increase, about a 260% increase to about a 400% increase, about a 260% increase to about a 380% increase, about a 260% increase to about a 360% increase, about a 260% increase to about a 340% increase, about a 260% increase to about a 320% increase, about a 260% increase to about a 300% increase, about a 260% increase to about a 280% increase, about a 280% increase to about a 400% increase, about a 280% increase to about a 380% increase, about a 280% increase to about a 360% increase, about a 280% increase to about a 340% increase, about a 280% increase to about a 320% increase, about a 280% increase to about a 300% increase, about a 300% increase to about a 400% increase, about a 300% increase to about a 380% increase, about a 300% increase to about a 360% increase, about a 300% increase to about a 340% increase, about a 300% increase to about a 320% increase, about a 320% increase to about a 400% increase, about a 320% increase to about a 380% increase, about a 320% increase to about a 360% increase, about a 320% increase to about a 340% increase, about a 340% increase to about a 400% increase, about a 340% increase to about a 380% increase, about a 340% increase to about a 360% increase, about a 360% increase to about a 400% increase, about a 360% increase to about a 380% increase, or about a 380% increase to about a 400% increase) in half-life in a subject (e.g., a human) as compared to the half-life of a control ABPC (e.g., any of the control ABPCs described herein) in a similar subject.

In some embodiments of any of the antigen-binding protein constructs or multi- specific antigen-binding protein constructs described herein, the half-life of the antigen- binding protein construct or multi-specific ABPC in a subject (e.g., a human) is increased about 0.5-fold to about 4-fold (e.g., about 0.5-fold to about 3.5-fold, about 0.5-fold to about 3-fold, about 0.5-fold to about 2.5-fold, about 0.5-fold to about 2-fold, about 0.5-fold to about 1.5-fold, about 0.5-fold to about 1-fold, about 1-fold to about 4-fold, about 1-fold to about 3.5-fold, about 1-fold to about 3-fold, about 1-fold to about 2.5-fold, about 1-fold to about 2- fold, about 1.5 -fold to about 4-fold, about 1.5 -fold to about 3.5 -fold, about 1.5 -fold to about

3- fold, about 1.5-fold to about 2.5-fold, about 1.5-fold to about 2-fold, about 2-fold to about

4- fold, about 2-fold to about 3.5-fold, about 2-fold to about 3-fold, about 2-fold to about 2.5- fold, about 2.5-fold to about 4-fold, about 2.5-fold to about 3.5-fold, about 2.5-fold to about 3-fold, about 3-fold to about 4-fold, about 3-fold to about 3.5-fold, or about 3.5-fold to about 4-fold) as compared to the half-life of a control ABPC (e.g., any of the control ABPCs described herein) in a similar subject.

Conjugation

Any of the antigen-binding protein constructs or multi-specific antigen-binding protein constructs provided herein can be conjugated to a drug (e.g., a chemotherapeutic drug, a small molecule), a toxin, or a radioisotope. Non-limiting examples of drugs, toxins, and radioisotopes (e.g., known to be useful for the treatment of cancer) are known in the art.

In some embodiments, at least one protein of any of the ABPCs described herein or any of the multi-specific ABPCs can be conjugated to the toxin, the radioisotope, or the drug via a cleavable linker. In some embodiments, the cleavable linker includes a protease cleavage site. In some embodiments, the cleavable linker is cleaved on the ABPC or the multi-specific ABPC once it is transported to the lysosome by a mammalian target cell. In some embodiments, the cleavable linker is cleaved on the ABPC or the multi-specific ABPC once it is transported to the lysosome or late endosome by the mammalian target cell. In some embodiments, cleavage of the linker functionally activates the drug or toxin.

In some embodiments, at least one protein of any of the ABPCs described herein or any of the multi-specific ABPCs can be conjugated to the toxin, the radioisotope, or the drug via a non-cleavable linker. In some embodiments, the conjugated toxin, radioisotope, or drug is released during lysosomal and/or late endosomal degradation of the ABPC or the multi- specific ABPC. Non-limiting examples of linkers include: hydrazone linkers, peptide linkers, disulfide linkers, and thioether linkers. See, e.g., Carter et al., Cancer J. 14(3): 154-169, 2008; Sanderson et al., Clin. Cancer Res. 11(2 Ptl):843-852, 2005; Chan et d., Acc. Chem. Res. 41(1):98-107, 2008; Oflazoglu et al, Clin. Cancer Res. 14(19): 6171-6180, 2008; and Lu et al., Int. J. Mol. Sci. 17(4): 561, 2016. Non-limiting examples of cleavable linkers include LEAGCKNFFPR/SFTS CGSLE (SEQ ID NO: 423), CRRRRRR/EAEAC (SEQ ID NO: 424), VSQTSKLT/RAETVFPDV (SEQ ID NO: 425), EDVVCC/SMSY (SEQ ID NO: 426), GGIEGR/GS (SEQ ID NO: 427), RXR/KR (SEQ ID NO: 428), TRHRQPR/GWEQL (SEQ ID NO: 429), RRRRRRR/R/R (SEQ ID NO: 430), TRHRQPR/GWE (SEQ ID NO: 431), and AGNRVRR/SVG (SEQ ID NO: 432). Additional non-limiting examples of cleavable linkers are described in Chen et &\., Adv. DrugDeliv. Rev. 65(10): 1357-1369, 2013.

In some examples, the linker can be a non-cleavable linker. Examples of non- cleavable linkers include: (GGGGS)N (SEQ ID NO: 433), where N can be 1-10;

KESGSVSSEQLAQFRSLD (SEQ ID NO: 434); EGKSSGSGSESKST (SEQ ID NO: 435); GGGGGGGG (SEQ ID NO: 436); GGGGGG (SEQ ID NO: 437); GSAGSAAGSGEF (SEQ ID NO: 438); (GGGGS)₄ (SEQ ID NO: 439); (GGGGS)₃ (SEQ ID NO: 440); GGGGS (SEQ ID NO: 441); (EAAAK)N (SEQ ID NO: 442), where N can be 1-10; A(EAAAK)N (SEQ ID NO: 443), where N is 2-5; and (Ala-Pro)? (SEQ ID NO: 444). Additional examples of non- cleavable linkers are described in Chen et si., Adv. Drug. Deliv. Rev. 65(10): 1357-1369, 2013.

In some embodiments, any of the ABPCs described herein or any of the multi-specific ABPCs described herein is cytotoxic or cytostatic to the mammalian target cell. Expression of an Antigen-Binding Protein Construct or a Multi-Specific Antigen- Binding Protein Construct in a Cell

Also provided herein are methods of generating a recombinant cell that expresses an ABPC (e.g., any of the ABPCs described herein) or a multi-specific ABPC (e.g., any of the multi-specific ABPCs described herein) that include: introducing into a cell a nucleic acid encoding the ABPC or the multi-specific ABPC to produce a recombinant cell; and culturing the recombinant cell under conditions sufficient for the expression of the ABPC or the multi- specific ABPC. In some embodiments, the introducing step includes introducing into a cell an expression vector including a nucleic acid encoding the ABPC or the multi-specific ABPC to produce a recombinant cell.

Any of the ABPCs described herein or any of the multi-specific ABPCs described herein can be produced by any cell, e.g., a eukaryotic cell or a prokaryotic cell. As used herein, the term "eukaryotic cell" refers to a cell having a distinct, membrane-bound nucleus. Such cells may include, for example, mammalian (e.g., rodent, non-human primate, or human), insect, fungal, or plant cells. In some embodiments, the eukaryotic cell is a yeast cell, such as Saccharomyces cerevisiae. In some embodiments, the eukaryotic cell is a higher eukaryote, such as mammalian, avian, plant, or insect cells. As used herein, the term

"prokaryotic cell" refers to a cell that does not have a distinct, membrane-bound nucleus. In some embodiments, the prokaryotic cell is a bacterial cell.

Methods of culturing cells are well known in the art. Cells can be maintained in vitro under conditions that favor proliferation, differentiation, and growth. Briefly, cells can be cultured by contacting a cell (e.g., any cell) with a cell culture medium that includes the necessary growth factors and supplements to support cell viability and growth.

Methods of introducing nucleic acids and expression vectors into a cell (e.g., a eukaryotic cell) are known in the art. Non-limiting examples of methods that can be used to introduce a nucleic acid into a cell include lipofection, transfection, electroporation, microinjection, calcium phosphate transfection, dendrimer-based transfection, cationic polymer transfection, cell squeezing, sonoporation, optical transfection, impalection, hydrodynamic delivery, magnetofection, viral transduction (e.g., adenoviral and lentiviral transduction), and nanoparticle transfection.

Provided herein are methods that further include isolation of the ABPCs or the multi- specific ABPCs from a cell (e.g., a eukaryotic cell) using techniques well-known in the art (e.g., ammonium sulfate precipitation, polyethylene glycol precipitation, ion-exchange chromatography (anion or cation), chromatography based on hydrophobic interaction, metal- affinity chromatography, ligand-affinity chromatography, and size exclusion

chromatography). Methods of Treatment

Provided herein are methods of treating a cancer characterized by having a population of cancer cells that have at least one (e.g., 1, 2, 3, 4, 5, or 6) of the following: (a) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHCl or MHCl complex presentation on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHCl in a cellular compartment as compared to a non-cancerous cell; (b) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide present on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of TAP in the endoplasmic reticulum as compared to a non-cancerous cell; and/or a genetic lesion (e.g., gene deletion) in a TAP gene, as compared to a non-cancerous cell; (c) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of β2ηι polypeptide, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide present on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion (e.g., gene deletion) in a β2ηι gene and/or a HLA gene selected from the group of: HLA- A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the ABPCs described herein or any of the multi-specific ABPCs described herein, or any of the ABPCs described herein or any of the multi-specific ABPCs described herein to a subject identified as having a cancer characterized by having the population of cancer cells.

Provided herein are methods of treating a cancer characterized by having a population of cancer cells that (i) have an identifying antigen (e.g., any of the identify ing antigens described herein or known in the art) present on their surface, and (ii) have at least one (e.g., 1, 2, 3, 4, 5, or 6) of the following: (a) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a poly peptide encoded by a HLA- A, HLA-B, or HLA-C gene, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHC1 or MHC1 complex presentation on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHC1 in a cellular compartment as compared to a non-cancerous cell; (b) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ιη polypeptide present on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of TAP in the endoplasmic reticulum as compared to a non-cancerous cell; and/or a genetic lesion (e.g., gene deletion) in a TAP gene, as compared to a non-cancerous cell; (c) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of β2πι polypeptide, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide present on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion (e.g., gene deletion) in a β2ηι gene and/or a HLA gene selected from the group of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the multi- specific ABPCs described herein or any of the multi-specific ABPCs described herein, to a subject identified as having a cancer characterized by having the population of cancer cells.

Also provided herein are methods of reducing the volume of a tumor in a subject, wherein the tumor is characterized by having a population of cancer cells that have at least one (e.g., 1, 2, 3, 4, 5, or 6) of the following: (a) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHCl or MHCl complex presentation on their surface, and-Or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHCl in a cellular compartment as compared to a non-cancerous cell; (b) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of TAP in the endoplasmic reticulum as compared to a non-cancerous cell; and/or a genetic lesion (e.g., gene deletion) in a TAP gene, as compared to a non-cancerous cell;(c) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of β2ιη polypeptide, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide present on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ηι gene and/or a HLA gene selected from the group of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the ABPCs described herein or any of the multi-specific ABPCs described herein, or any of the ABPCs described herein or any of the multi-specific ABPCs described herein, to a subject identified as having a cancer characterized by having the population of cancer cells. In some embodiments of any of the methods described herein, the volume of at least one (e.g., 1, 2, 3, 4, or 5) tumor (e.g., solid tumor) or tumor location (e.g., a site of metastasis) is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 8%, at least 10%, at least 12%, at least 14%, at least 16%, at least 18%, at least 20%, at least 22%, at least 24%, at least 26%, at least 28%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) reduced as compared to the size of the at least one tumor (e.g., solid tumor) before administration of the ABPC or multi-specific ABPC

Also provided herein are methods of reducing the volume of a tumor in a subject, wherein the tumor is characterized by having a population of cancer cells that (i) have an identifying antigen (e.g., any of the identifying antigens described herein or known in the art) present on their surface, and (ii) have at least one (e.g., 1, 2, 3, 4, 5, or 6) of the following: (a) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHCl or MHCl complex presentation on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHCl in a cellular compartment as compared to a non-cancerous cell; (b) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of TAP in the endoplasmic reticulum as compared to a non-cancerous cell; and/or a genetic lesion (e.g., gene deletion) in a TAP gene, as compared to a non-cancerous cell;(c) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of β2ηι polypeptide, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide present on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ιτι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ιη gene and/or a HLA gene selected from the group of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include:

administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the multi-specific ABPCs described herein, or any of the multi-specific ABPCs described herein, to a subject identified as having a cancer characterized by having the population of cancer cells. In some embodiments of any of the methods described herein, the volume of at least one (e.g., 1, 2, 3, 4, or 5) tumor (e.g., solid tumor) or tumor location (e.g., a site of metastasis) is reduced by at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 8%, at least 10%, at least 12%, at least 14%, at least 16%, at least 18%, at least 20%, at least 22%, at least 24%, at least 26%, at least 28%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) reduced as compared to the size of the at least one tumor (e.g., solid tumor) before administration of the multi-specific ABPC.

Also provided herein are methods of inducing cell death in a cancer cell in a subject, wherein the cancer cell has at least one (e.g., 1, 2, 3, 4, 5, or 6) of the following: (a) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHC1 or MHC1 complex presentation on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHC1 in a cellular compartment as compared to a non-cancerous cell; (b) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of TAP in the endoplasmic reticulum as compared to a non-cancerous cell; and/or a genetic lesion (e.g., gene deletion) in a TAP gene, as compared to a non-cancerous cell; (c) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of β2πι polypeptide, a reduced (e.g., at least 1 % reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ιη polypeptide present on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ιη polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2πι gene and/or a HLA gene selected from the group of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the ABPCs described herein or any of the multi-specific ABPCs described herein, or any of the ABPCs described herein or any of the multi-specific ABPCs described herein, to a subject identified as having a cancer characterized as having the population of cancer cells.

Also provided herein are methods of inducing cell death in a cancer cell in a subject, wherein the cancer cell (i) has an identifying antigen (e.g., any of the identifying antigens described herein or known in the art), and (ii) has at least one (e.g., 1, 2, 3, 4, 5, or 6) of the following: (a) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHCl or MHCl complex presentation on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHCl in a cellular compartment as compared to a non-cancerous cell; (b) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of TAP in the endoplasmic reticulum as compared to a non-cancerous cell; and/or a genetic lesion (e.g., gene deletion) in a TAP gene, as compared to a non-cancerous cell; (c) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of β2ηι polypeptide, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide present on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2πι gene and/or a HLA gene selected from the group of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include:

administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the multi-specific ABPCs described herein, or any of the multi-specific ABPCs described herein, to a subject identified as having a cancer characterized as having the population of cancer cells.

In some embodiments, the cell death that is induced is necrosis. In some

embodiments, the cell death that is induced is apoptosis. In some embodiments of any of the methods described herein, the cancer is a primary tumor.

Provided herein are methods of decreasing the risk of developing a metastasis or decreasing the risk of developing an additional metastasis in a subject having a cancer, wherein the cancer is characterized by having a population of cancer cells that have at least one (e.g., 1, 2, 3, 4, 5, or 6) of the following: (a) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHC1 or MHC1 complex presentation on their surface, and'or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHC1 in a cellular compartment as compared to a non-cancerous cell; (b) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of TAP in the endoplasmic reticulum as compared to a non-cancerous cell; and/or a genetic lesion (e.g., gene deletion) in a TAP gene, as compared to a non-cancerous cell; (c) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of β2ιη polypeptide, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide present on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (c) a genetic lesion in a β2πι gene and/or a HLA gene selected from the group of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the ABPCs described herein or any of the multi-specific ABPCs described herein, or any of the ABPCs described herein or any of the multi-specific ABPCs described herein, to a subject identified as having a cancer characterized as having the population of cancer cells. In some embodiments, the risk of developing a metastasis or the risk of developing an additional metastasis is decreased by at least 1%, by at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 8%, at least 10%, at least 12%, at least 14%, at least 16%, at least 18%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% in the subject as compared to the risk of a subject having a similar cancer, but administered no treatment or a treatment that does not include the administration of any of the ABPCs or any of the multi-specific ABPCs described herein.

Provided herein are methods of decreasing the risk of developing a metastasis or decreasing the risk of developing an additional metastasis in a subject having a cancer, wherein the cancer is characterized by having a population of cancer cells that (ι) have an identifying antigen (e.g., any of the identifying antigens described herein or known in the art) present on their surface, and (ii) have at least one (e.g., 1, 2, 3, 4, 5, or 6) of the following: (a) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHCl or MHCl complex presentation on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHCl in a cellular compartment as compared to a non-cancerous cell; (b) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of TAP in the endoplasmic reticulum as compared to a non-cancerous cell; and/or a genetic lesion (e.g., gene deletion) in a TAP gene, as compared to a non-cancerous cell; (c) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of β2ηι polypeptide, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ιη polypeptide present on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (c) a genetic lesion in a β2ιη gene and/or a HLA gene selected from the group of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include:

administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the multi-specific ABPCs described herein, or any of the multi-specific ABPCs described herein, to a subject identified as having a cancer characterized as having the population of cancer cells. In some embodiments, the risk of developing a metastasis or the risk of developing an additional metastasis is decreased by at least 1%, by at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, at least 8%, at least 10%, at least 12%, at least 14%, at least 16%, at least 18%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% in the subject as compared to the risk of a subject having a similar cancer, but administered no treatment or a treatment that does not include the administration of any of the multi-specific ABPCs described herein.

Provided herein are methods of increasing the level of a ABPC or a multi-specific ABPC in a cellular compartment of a cancer cell in a subject as compared to the level of the ABPC or the multi-specific ABPC, respectively, in the cellular compartment of a noncancerous cell, wherein the cancer cell has at least one (e.g., 1, 2, 3, 4, 5, or 6) of the following: (a) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHCl or MHCl complex presentation on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHCl in a cellular compartment as compared to a non-cancerous cell; (b) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of TAP in the endoplasmic reticulum as compared to a non-cancerous cell; and/or a genetic lesion (e.g., gene deletion) in a TAP gene, as compared to a non-cancerous cell; (c) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of β2ηι polypeptide, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide present on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ιη gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the ABPCs described herein or any of the multi-specific ABPCs described herein, or any of the pharmaceutical compositions that include any of the ABPCs described herein or any of the multi-specific ABPCs described herein, respectively, to a subject identified as having a cancer characterized by having a population of the cancer cells. In some embodiments, these methods can result in at least a 1% increase (e.g., at least a 2% increase, at least a 3% increase, at least a 4% increase, at least a 5% increase, at least a 6% increase, at least a 7% increase, at least a 8% increase, at least a 10% increase, at least a 12% increase, at least a 14% increase, at least a 16% increase, at least a 18% increase, at least a 20% increase, at least a 22% increase, at least a 24% increase, at least a 26% increase, at least a 28% increase, at least a 30% increase, at least a 35% increase, at least a 40% increase, at least a 45% increase, at least a 50% increase, at least a 55% increase, at least a 60% increase, at least a 65% increase, at least a 70% increase, at least a 75% increase, at least a 80% increase, at least a 85% increase, at least a 90% increase, at least a 95% increase, at least a 100% increase, at least a 110% increase, at least a 120% increase, at least a 130% increase, at least a 140% increase, at least a 150% increase, at least a 160% increase, at least a 170% increase, at least a 180% increase, at least a 190% increase, at least a 200% increase, at least a 210% increase, at least a 220% increase, at least a 230% increase, at least a 240% increase, at least a 250% increase, at least a 260% increase, at least a 270% increase, at least a 280% increase, at least a 290% increase, or at least a 300% increase) in the level of the ABPC or the multi-specific ABPC in the cellular compartment of the cancer cell, respectively, in a subject as compared to the level of the ABPC or the multi-specific ABPC, respectively, in the cellular compartment of a non-cancerous cell.

Provided herein are methods of increasing the level of a multi-specific ABPC in a cellular compartment of a cancer cell in a subject as compared to the level of the multi- specific ABPC in the cellular compartment of a non-cancerous cell, wherein the cancer cell (i) has an identifying antigen (e.g., any of the identifying antigens described herein or known in the art) present on their surface, and (ii) has at least one (e.g., 1, 2, 3, 4, 5, or 6) of the following: (a) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHCl or MHCl complex presentation on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHCl in a cellular compartment as compared to a non-cancerous cell; (b) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of TAP in the endoplasmic reticulum as compared to a non-cancerous cell; and/or a genetic lesion (e.g., gene deletion) in a TAP gene, as compared to a non-cancerous cell; (c) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of β2ηι polypeptide, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide present on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ηι gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the multi-specific ABPCs described herein, or any of the multi-specific ABPCs described herein, to a subject identified as having a cancer

characterized by having a population of the cancer cells. In some embodiments, these methods can result in at least a 1% increase (e.g., at least a 2% increase, at least a 3% increase, at least a 4% increase, at least a 5% increase, at least a 6% increase, at least a 7% increase, at least a 8% increase, at least a 10% increase, at least a 12% increase, at least a 14% increase, at least a 16% increase, at least a 18% increase, at least a 20% increase, at least a 22% increase, at least a 24% increase, at least a 26% increase, at least a 28% increase, at least a 30% increase, at least a 35% increase, at least a 40% increase, at least a 45% increase, at least a 50% increase, at least a 55% increase, at least a 60% increase, at least a 65% increase, at least a 70% increase, at least a 75% increase, at least a 80% increase, at least a 85% increase, at least a 90% increase, at least a 95% increase, at least a 100% increase, at least a 110% increase, at least a 120% increase, at least a 130% increase, at least a 140% increase, at least a 150% increase, at least a 160% increase, at least a 170% increase, at least a 180% increase, at least a 190% increase, at least a 200% increase, at least a 210% increase, at least a 220% increase, at least a 230% increase, at least a 240% increase, at least a 250% increase, at least a 260% increase, at least a 270% increase, at least a 280% increase, at least a 290% increase, or at least a 300% increase) in the level of the multi-specific ABPC in the cellular compartment of the cancer cell in a subject as compared to the level of the multi- specific ABPC in the cellular compartment of a non-cancerous cell.

Also provided herein are methods of decreasing the level of a ABPC or a multi- specific ABPC in a cellular compartment of a non-cancerous cell in a subject as compared to the level of the ABPC or the multi-specific ABPC, respectively, in the cellular compartment of a cancerous cell in the subject, wherein the cancer cell has at least one (e.g., 1, 2, 3, 4, 5, or 6) of the following: (a) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHC1 or MHC1 complex presentation on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHC1 in a cellular compartment as compared to a non-cancerous cell; (b) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of TAP in the endoplasmic reticulum as compared to a non-cancerous cell; and/or a genetic lesion (e.g., gene deletion) in a TAP gene, as compared to a non-cancerous cell; (c) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of β2πι polypeptide, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide present on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2πι gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the ABPCs described herein or any of the multi-specific ABPCs described herein, or any of the pharmaceutical compositions that include any of the ABPCs or any of the multi-specific ABPCs described herein, respectively, to a subject identified as having a cancer characterized by having a population of the cancer cells. In some embodiments, these methods can result in at least a 1% decrease (e.g., at least a 2% decrease, at least a 3% decrease, at least a 4% decrease, at least a 5% decrease, at least a 6% decrease, at least a 7% decrease, at least a 8% decrease, at least a 10% decrease, at least a 12% decrease, at least a 14% decrease, at least a 16% decrease, at least a 18% decrease, at least a 20% decrease, at least a 22% decrease, at least a 24% decrease, at least a 26% decrease, at least a 28% decrease, at least a 30% decrease, at least a 35% decrease, at least a 40% decrease, at least a 45% decrease, at least a 50% decrease, at least a 55% decrease, at least a 60% decrease, at least a 65% decrease, at least a 70% decrease, at least a 75% decrease, at least a 80% decrease, at least a 85% decrease, at least a 90% decrease, at least a 95% decrease, or at least a 99% decrease) in the level of the ABPC or multi-specific ABPC in a cellular compartment of a non-cancerous cell in a subject as compared to the level of the ABPC or multi-specific ABPC in the cellular compartment of a cancerous cell in the subject.

Also provided herein are methods of decreasing the level of a multi-specific ABPC in a cellular compartment of a non-cancerous cell in a subject as compared to the level of the multi-specific ABPC in the cellular compartment of a cancerous cell in the subject, wherein the cancer cell (i) has an identifying antigen (e.g., any of the identifying antigens described herein or known in the art) present on their surface, and (ii) has at least one (e.g., 1, 2, 3, 4, 5, or 6) of the following: (a) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a poly peptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHC1 or MHC1 complex presentation on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of MHC1 in a cellular compartment as compared to a non-cancerous cell; (b) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of TAP in the endoplasmic reticulum as compared to a non-cancerous cell; and/or a genetic lesion (e.g., gene deletion) in a TAP gene, as compared to a non-cancerous cell; (c) a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of expression of β2ιη polypeptide, a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide present on their surface, and/or a reduced (e.g., at least 1% reduced, at least 2% reduced, at least 4% reduced, at least 6% reduced, at least 8% reduced, at least 10% reduced, at least 12% reduced, at least 14% reduced, at least 16% reduced, at least 18% reduced, at least 20% reduced, at least 22% reduced, at least 24% reduced, at least 26% reduced, at least 28% reduced, at least 30% reduced, at least 35% reduced, at least 40% reduced, at least 45% reduced, at least 50% reduced, at least 55% reduced, at least 60% reduced, at least 65% reduced, at least 70% reduced, at least 75% reduced, at least 80% reduced, at least 85% reduced, at least 90% reduced, at least 95% reduced, or at least 99% reduced) level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ηι gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, that include: administering a therapeutically effective amount of any of the pharmaceutical compositions that include any of the multi-specific ABPCs described herein or any of the multi-specific ABPCs described herein, to a subject identified as having a cancer characterized by having a population of the cancer cells. In some embodiments, these methods can result in at least a 1% decrease (e.g., at least a 2% decrease, at least a 3% decrease, at least a 4% decrease, at least a 5% decrease, at least a 6% decrease, at least a 7% decrease, at least a 8% decrease, at least a 10% decrease, at least a 12% decrease, at least a 14% decrease, at least a 16% decrease, at least a 18% decrease, at least a 20% decrease, at least a 22% decrease, at least a 24% decrease, at least a 26% decrease, at least a 28% decrease, at least a 30% decrease, at least a 35% decrease, at least a 40% decrease, at least a 45% decrease, at least a 50% decrease, at least a 55% decrease, at least a 60% decrease, at least a 65% decrease, at least a 70% decrease, at least a 75% decrease, at least a 80% decrease, at least a 85% decrease, at least a 90% decrease, at least a 95% decrease, or at least a 99% decrease) in the level of the multi-specific ABPC in a cellular compartment of a non-cancerous cell in a subject as compared to the level of the multi- specific ABPC in the cellular compartment of a cancerous cell in the subject.

Also provided herein are methods of decreasing target-mediated drug disposition (TMDD) in a mammalian cell (e.g., a human cell), the method comprising contacting a mammalian cell with any of the antigen-binding protein constructs or any of the multi- specific antigen-binding protein constructs described herein under physiological conditions (e.g., as compared to a similar mammalian cell contacted with a control ABPC under physiological conditions).

The term "target-mediated drug disposition" or "TMDD" means the binding of an antigen-binding protein construct or a multi-specific antigen-binding protein construct with an affinity that results in one or both of a) a decrease in the level of the antigen-binding protein construct or the multi-specific antigen-binding protein construct, respectively, in the extracellular space that is not pericellular to the cell (e.g., in a liquid culture medium) or b) internalization into cells, degredation, modification, and/or elimination of the antigen-binding protein construct or multi-specific antigen-binding protein construct (e.g., cellular uptake resulting in the release of a toxin or radioisotope from the ABPC or multi-specific ABPC via lysosomal degredation of a cleavable or non-cleavable linker). Methods of determining consumption, degredation, and/or modification of ABPCs or multi-specific ABPCs are known to the art and described herein.

In some embodiments of any of the methods described herein, the cancer is a non-T- cell-infiltrating tumor. In some embodiments of any of the methods described herein, the cancer is a T-cell-infiltrating tumor. In some embodiments of any of the methods described herein, the cellular compartment is part of the endosomal/lysosomal pathway. In some embodiments of any of the methods described herein, the cellular compartment is an endosome.

The term "subject" refers to any mammal. In some embodiments, the subject or

"subject suitable for treatment" may be a canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), ovine, bovine, porcine, caprine, primate, e.g., a simian (e.g., a monkey (e.g., marmoset baboon), or an ape (e.g., a gorilla, chimpanzee, orangutan, or gibbon) or a human; or rodent (e.g., a mouse, a guinea pig, a hamster, or a rat). In some embodiments, the subject or "subject suitable for treatment" may be a non-human mammal, especially mammals that are conventionally used as models for demonstrating therapeutic efficacy in humans (e.g., murine, lapine, porcine, canine or primate animals) may be employed.

As used herein, treating includes reducing the number, frequency, or severity of one or more (e.g., two, three, four, or five) signs or symptoms of a cancer in a patient having a cancer (e.g., any of the cancers described herein). For example, treatment can reducing cancer progression, reduce the severity of a cancer, or reduce the risk of re-occurrence of a cancer in a subject having the cancer. Non-limiting examples of cancer include: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, basal cell carcinoma, brain tumor, bile duct cancer, bladder cancer, bone cancer, breast cancer, bronchial tumor, Burkitt Lymphoma, carcinoma of unknown primary origin, cardiac tumor, cervical cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasm, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma, embryonal tumor, endometrial cancer, ependymoma, esophageal cancer,

esthesioneuroblastoma, fibrous histiocytoma, Ewing sarcoma, eye cancer, germ cell tumor, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic disease, glioma, head and neck cancer, hairy cell leukemia, hepatocellular cancer, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous neck cancer with occult primary, midline tract carcinoma involving NUT gene, mouth cancer, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome,

myelodysplastic/myeloproliferative neoplasm, nasal cavit and para-nasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytomas, pituitary tumor, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell cancer, renal pelvis and ureter cancer,

retinoblastoma, rhabdoid tumor, salivary gland cancer, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, spinal cord tumor, stomach cancer, T-cell lymphoma, teratoid tumor, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, vaginal cancer, vulvar cancer, and Wilms' tumor. Additional examples of cancer are known in the art.

In some embodiments of any of the methods described herein, the cancer is a solid cancer (e.g., breast cancer, prostate cancer, or non-small cell lung cancer). Compositions and Kits

Also provided herein are compositions (e.g., pharmaceutical compositions) that include at least one of any of the ABPCs described herein or at least one of any of the multi- specific ABPCs described herein. In some embodiments, the compositions (e.g., pharmaceutical compositions) that include any of the ABPCs described herein or any of the multi-specific ABPCs described herein can be disposed in a sterile vial or a pre-loaded syringe.

In some embodiments, the compositions (e.g., pharmaceutical compositions) that include any of the ABPCs described herein or any of the multi-specific ABPCs described herein are formulated for different routes of administration (e.g., intravenous, subcutaneous, intramuscular, or lntratumoral). In some embodiments, the compositions (e.g.,

pharmaceutical compositions) that include any of the ABPCs described herein or any of the multi-specific ABPCs described herein can include a pharmaceutically acceptable carrier (e.g., phosphate buffered saline). Single or multiple administrations of any of the pharmaceutical compositions described herein can be given to a subject depending on, for example: the dosage and frequency as required and tolerated by the patient. A dosage of the pharmaceutical composition including any of the ABPCs described herein or any of the multi-specific ABPCs described herein should provide a sufficient quantity of the ABPC or the multi-specific ABPC to effectively treat or ameliorate conditions, diseases, or symptoms.

Also provided herein are methods of treating a subject having a cancer (e.g., any of the cancers described herein) that include administering a therapeutically effective amount of at least one of any of the compositions that include any of the ABPCs described herein or any of the multi-specific ABPCs described herein, or pharmaceutical compositions that include any of the ABPCs described herein or any of the multi-specific ABPCs described herein.

Also provided herein are kits that include any of the ABPCs described herein or any of the multi-specific ABPC described herein, any of the compositions that include any of the ABPCs or any of the multi-specific ABPCs described herein, or any of the pharmaceutical compositions that include any of the ABPCs or any of the multi-specific ABPCs described herein. In some embodiments, the kits can include instructions for performing any of the methods described herein. In some embodiments, the kits can include at least one dose of any of the compositions (e.g., pharmaceutical compositions) described herein. In some embodiments, the kits can provide a syringe for administering any of the pharmaceutical compositions described herein. The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

EXAMPLES

As used in these examples, fully conformed MHC1 (hereafter, fcMHCl) means

MHC1 or MHC1 complex, as defined herein; non fully conformed MHC (hereafter.

nfcMHCl) means a peptide encoded by a HLA-A gene, a HLA-B gene, a HLA-C gene, a HLA-E gene, a HLA-F gene, a HLA-K gene, or a HLA-L gene, or a variant thereof that is not bound to a polypeptide encoded by a 2-microglobulin gene or a variant thereof.

Example 1. Generation of fully conformed MHC1 (fcMHCl)-specific binders and engineering of pH binding dependence

Antigen-binding domains against fcMHCl with enhanced recycling to the cell surface versus binding proteins specific to nfcMHCl are generated using two methods. In the first approach, published monoclonal antibodies against monomorphic epitopes of fcMHCl are used as a starting template for introduction of additional mutations that allow engineering of pH-dependent binding to MHO and recycling to the cell surface via the endosome. The second approach involves discovery of de novo fcMHCl binding proteins via antibody display methods from naive libraries or libraries with defined CDR compositions and screening under conditions designed for selection of pH dependent binding proteins. In either case, histidine residues play an important role in engineering pH dependent binding proteins.

Histidine residues are at least partially protonated at a pH below 6.5 owing to its pKa of 6.0. Therefore, if a histidine side chain in an antigen-binding domain participates in an electrostatic binding interaction with its antigen it will start to turn positively charged at a pH at or below 6.5. This could either weaken or enhance the binding affinity of the interaction at a pH below 6.5, based on the corresponding charge of and interactions with the antigen epitope. Thus, systematic introduction of histi dines into antibody complementarity determining regions (CDRs) in an antibody or other binder library (e.g., an scFv library) can be used to identify substitutions that will affect an antigen-binding domain's interaction with an antigen at lower pH values. The first approach therefore involves histidine-scanning of variable region sequences of published monoclonal antibodies to identify pH dependent variants. Multiple monomorphic MHC1 binding monoclonal antibodies have been described in the literature and can be used as a template for engineering pH-dependent binding (Brodsky, F. M. & Parham, P. (1982) J. Immunol. 128, 129-135; Parham et al. (1982) J. Immunol. Methods 53, 133-173). Briefly, for a subset of the antibody sequences, CDRs in each chain are identified using the methods described by Kabat et al (Kabat et al. (1992) Sequences of Proteins of Immunological Interest (DIANE publishing). To generate pH-sensitive heavy chain and light chain sequence variants, individual amino acid residues within both the heavy and light chain CDRs are systematically substituted with a histidine, one at a time. Antibody variants with only one histidine mutation in either a heavy or a light chain CDR are generated by co-transfection of Expi293 cells with a) one heavy chain or light chain sequence variant, and b) the corresponding wild type light chain or heavy chain, respectively, using methods known to the art. After allowing for a period of protein expression, cell culture supematants are collected, quantified, and the pH dependence of the variant is evaluated using biolayer interferometry (BLI) or other methods known to the art. Briefly, cell culture supematants are normalized to an antibody expression level of 50 μg/mL, and captured on an anti-human Fc sensor (Forte Bio). A baseline is established using IX kinetics buffer (Forte Bio), and the sensor is associated with 100 nM of fcMHCl in IX PBS at pH 7.4 for 300 sec to generate an association curve. In the dissociation phase, the antibody-antigen complex on the sensor is exposed to IX PBS at either pH 5.5 or pH 7.4 for 300-500 sec. Association and dissociation phase curves are examined for the wild type antibody and each corresponding antibody variant at pH 5.5 and pH 7.4 to inform on two criteria: a) enhanced dissociation (e.g., higher koff values) at pH 7.4 due to histidine substitution compared to wild type, and b) reduced dissociation at pH 5.5 (i.e., lower k₀ff values) compared to pH 7.4 in the antibody variant itself and with the wild type. Variants that show either enhanced dissociation at pH 7.4 or reduced dissociation at pH 5.5 or both are selected for further analysis. These variants are expressed at a larger scale and purified using protein A affinity chromatography. Binding kinetics (k_on and k₀fr) of the purified wild type and variant antibodies is measured at pH 5.5 and pH 7.4 using Biacore (GE Healthcare). The ratio of the antibody's rate of dissociation (koff at pH 7.4 and k₀ff at pH 5.5) is also used as a quantitative assessment of pH dependent binding. Antibodies with a ratio >2.0 are selected for further assessment of combinatorial substitutions. Favorable histidine amino acid positions can also be combined to enhance pH dependence; such combinatorial variants are generated and tested/analyzed for differential pH sensitivity using the methods and protocols described above, or others known to the art. Antibody variants that have the highest pH sensitivity ratio are selected as candidates for further analysis (hereafter referred to as "pH-engineered binder variants").

The second method for selection of pH dependent binder variants involves either screening libraries to identify de novo pH dependent fcMHC l binding variants or variants that could serve as templates for engineering pH dependent binding as described above. Two types of libraries can be used for these selections: naive phage/yeast display antibody libraries (Fab, scFv, VHH or VL) or phage/yeast display libraries where CDRs have been mutated to express a subset of amino acid residues. Libraries are screened against soluble recombinant fcMHCl domains using methods known to the art with positive selection for variants that bind weakly at pH 7.4 compared to pH 5.5 and negative selection against nfcMHCl. Three rounds of selections are performed with one round against the cyno fcMHCl to select cross-reactive binders. The final round of binders are screened using ELISA for binding to human fcMHCl and cyno fcMHCl or via mean fluorescence intensity in flow cytometric analysis. If murine cross-reactivity is desired, the final selection round can instead be performed on murine fcMHCl protein. Selected binding proteins are subcloned into mammalian expression vectors and expressed as either full IgG proteins or Fc fusions in Expi293 cells. BLI analysis is performed as described above for selection of pH engineered binder variants and confirmed using Biacore. To confirm the specificity of the binders, binding to nfcMHCl was also tested using BLI to confirm that the binders are specific to fcMHCl.

Example 2. In vitro demonstration of enhanced antibody recycling mediated by interaction with fcMHCl, and enhanced antibody retention by fcMHC- cells

As discussed herein, pH-sensitive fcMHCl binder variants exhibit the desirable property of poor MHCl binding at neutral pH (e.g., pH 7.4), but enhanced binding at lower pH (e.g., pH 6.0), which enhances their recycling from endosomes under physiological conditions while simultaneously preventing widespread binding to MHCl on the cell surface, thereby improving their pharmacokinetic properties.

To demonstrate that pH-sensitive fcMHCl antigen-binding protein construct binds cell surface MHCl poorly at neutral pH, a cell surface binding assay is performed. A panel of human cells that are fcMHCl + and/or MHCl+and FcRn- is assembled. Methods of identifying and quantifying gene expression (e.g., MHCl complex genes or FcRn) for a given cell line are known to the art, and include, e.g., consulting the Cancer Cell Line Encyclopedia (CCLE; portals.broadinstitute.org/ccle website) to ascertain the expression level and/or mutation status of a given gene in a tumor cell line), rtPCR, microarray or RNA-Seq analysis, or cell staining with antibodies known in the art (e.g. W6/32 for MHC, MAB8639 R&D Systems Monoclonal Mouse IgG2B Clone # 937508 for FcRn). Cells are seeded at approximately 5-10,000 per well in 150 μΐ of pH 7.4 culture medium and incubated at 37°C for 5 minutes at several doses with one of the following antibodies: an antibody specific for human fully conformed HLA A/B/C (e.g., W6/32), the pH-sensitive fcMHCl antigen-binding protein construct, a non-pH selective antibody variant of pH-sensitive fcMHCl antigen- binding protein construct (hereafter, non-pH-sensitive fcMHCl antigen-binding protein construct) (e.g. the parent molecule of the pH-sensitive fcMHCl antigen-binding protein construct), , and a pH-sensitive fcMHCl antigen-binding protein construct-matched human isotype negative control mAb. Prior to the onset of the experiment, the binding properties of all antibodies are validated using methods known to the art. Following the 5 minute incubation, cells are fixed with 4% formaldehyde (20 min at room temperature) and incubated with an appropriate fluorophore-labeled secondary antibody (e.g., goat anti-mouse for W6/32, etc.) for 60 minutes. Unbound reagents are washed with a series of PBS images, and the cell panels are imaged using confocal microscopy. Upon analysis of the images, significant fluorescence can be observed on the surface of cells bound with W6/32, non-pH- sensitive fcMHCl antigen-binding protein construct, but little surface binding is observed for pH-sensitive fcMHCl antigen-binding protein construct and the isotype negative control. To isolate the effect of pH on surface binding, the same experiment is repeated twice, with the primary antibody incubation taking place at sequentially lower pH (e.g., pH 6.5 and 5.5). Analysis of the resulting confocal microscopy images shows significant fluorescence on the surface of cells bound with all niAbs tested, excepting the isotype negative control, and that this fluorescence increases for pH-sensitive fcMHCl antigen-binding protein construct as the pH decreases (the pH at which fluorescence is maximal from now on referred to as pH_opt_uptake). Taken together, the results show that the pH engineering process has rendered pH-sensitive fcMHCl antigen-binding protein construct pH-sensitive in its binding properties to fcMHCl, that it is only capable of significant binding at lower pH, and that its binding properties improve as the pH becomes lower.

To demonstrate that the pH dependent binding properties of pH-sensitive fcMHCl antigen-binding protein construct lead to enhanced release of the antibody into the extracellular environment following cellular uptake, an internalization assay is performed using methods known to the art (e.g., Mahmutefendic et al., Int. J. Biochem. Cell Bio., 2011). Briefly, as above, a panel of human cells that express MHCl highly and that are also FcRn- is assembled using methods known to the art. To facilitate antibody uptake via nonspecific mechanisms such as, e.g., pinocytosis, cells are plated, washed three times with PBS, and incubated at 37 degrees C for 60 minutes in media at a pH of about pH_opt_uptake, and in a separate experiment at pH7.4, with added concentrations of 2 micrograms per milliliter of pH-sensitive fcMHCl antigen-binding protein construct and non-pH-sensitive fcMHCl antigen-binding protein construct. In a subset of cells, validation of antibody internalization and endosomal localization is performed using methods known to the art; e.g., cells are fixed in 4% formaldehyde as described above, permeabilized using TWEEN 20 or other methods known to the art (https://www.ncbi.nlm.nih.gov/pubmed/20012820), additionally stained with an endosomal marker, e.g., a fluorescent RAB11 antibody (RAB11 Antibody, Alexa Fluor 488, 3H18L5, ABfinity™ Rabbit Monoclonal), stained with an appropriate fluorescently labeled anti-human secondary antibody, and imaged using confocal fluorescence microscopy, as described above. Having validated endosomal uptake, in a separate experiment the first incubation is repeated and after this first incubation, cells are divided into two groups, one of which is treated with buffered media at pH = 6.0, the other of which is treated with buffered media at pH = 7.4. Cells are incubated for 30 minutes, and the media from all cells is removed and analyzed for antibody concentration using ELISA or other methods known to the art. Upon analysis of the data, it is revealed that for cells treated with pH-sensitive fcMHCl antigen-binding protein construct, the pH = 7.4 media contains significantly more antibody per unit volume than the pH = 6.0 media, and this media antibody concentration pH7.4/pH6.0 ratio, as compared to the media antibody concentration pH7.4/pH6.0 ratio for the non-pH-sensitive fcMHCl antigen-binding protein construct is greater. Taken together, the data demonstrate that the antibodies are taken up about equally well by both cells at pH of around pH_opt_uptake, but pH-sensitive fcMHCl antigen-binding protein construct' s pH- sensitive properties mediate enhanced release of the antibody from the target that it has bound at lower, endosomal pH, to the extracellular environment at pH = 7.4.

To demonstrate that pH-sensitive fcMHCl antigen-binding protein construct exhibits enhanced levels in intracellular compartments of fcMHC l - cancer cells as compared to fcMHCl + healthy cells, a variation of the above-described experiment is performed. Two cell panels are assembled, one comprised of fcMHCl + cells (intended to model tumor cells) and one comprised of fcMHCl- (intended to model normal cells). Methods for identifying the fcMHCl expression status of a cell are known to the art and described herein. To facilitate antibody uptake via nonspecific mechanisms such as, e.g., pinocytosis, cells are plated, washed three times with PBS, and incubated at 37 degrees C for 60 minutes in media at a pH of about pH opt uptake, and in a separate experiment at pH7.4, with added concentrations of 2 micrograms per milliliter with pH-sensitive fcMHCl antigen-binding protein construct. Following incubation, cells are washed three times with PBS, fixed and permeabilized as described above, and stained with a panel of appropriately selected antibodies targeting late endosomal markers as well as lysosomes (e.g., RAB7, and LAMP1; Cell Signaling Technology, Endosomal Marker Antibody Sampler Kit #12666; AbCam, Anti- LAMP2 antibody [GL2A7], ab 13524). After primary antibody staining, cells are stained with an appropriate mixture of fluorescently labeled secondary antibodies (e.g., anti-human and anti-rabbit), imaged using confocal fluorescence microscopy, and regions of co- localization of signal from pH-sensitive fcMHCl antigen-binding protein construct and endosomal markers are visualized and quantified. Upon analysis of the data, it is revealed that there is increased co-localization of pH-sensitive fcMHCl antigen-binding construct signal in fcMHCl- cells as compared to fcMHCl+ cells with late endosomal and lysosomal markers, thereby demonstrating selective retention of the construct in intracellular compartments of fcMHCl - cells (a model system representative of many cancer cells). Example 3. In vitro demonstration of enhanced antibody recycling mediated by interaction with fcMHCl, and enhanced antibody retention by fcMHC- cells

As discussed herein, pH-sensitive fcMHCl binder variants exhibit the desirable property of poor MHC1 binding at neutral pH (e.g., pH 7.4), but enhanced binding at lower pH (e.g., pH 6.0), which enhances their recycling from endosomes under physiological conditions while simultaneously preventing widespread binding to MHC1 on the cell surface, thereby improving their pharmacokinetic properties.

To demonstrate that pH-sensitive fcMHCl antigen-binding protein construct binds cell surface MHO poorly at neutral pH, a cell surface binding assay is performed. A panel of human cells that are fcMHCl+, EGFR+, and FcRn- is assembled. Methods of identifying and quantifying gene expression (e.g., MHC1 complex genes or FcRn) for a given cell line are known to the art, and include, e.g., consulting the Cancer Cell Line Encyclopedia (CCLE; portals.broadinstitute.org/ccle website) to ascertain the expression level and/or mutation status of a given gene in a tumor cell line), rtPCR, microarray or RNA-Seq analysis, or cell staining with antibodies known in the art (e.g. W6/32 for MHC, MAB8639 R&D Systems Monoclonal Mouse IgG2B Clone # 937508 for FcRn, ab30 or cetuximab for EGFR). Cells are seeded at approximately 5-10,000 per well in 150 μΐ of pH 7.4 culture medium and incubated at 37°C for 5 minutes at several doses with one of the following antibodies: an antibody specific for human fully conformed HLA A/B/C (e.g., W6/32), the pH-sensitive fcMHCl antigen-binding protein construct, a non-pH selective antibody variant of pH- sensitive fcMHCl antigen-binding protein construct (hereafter, non-pH-sensitive fcMHCl antigen-binding protein construct) (e.g. the parent molecule of the pH-sensitive fcMHCl antigen-binding protein construct), an anti-EGFR mAb (e.g., ab30 or cetuximab), and a pH- sensitive fcMHC 1 antigen-binding protein construct-matched human isotype negative control mAb. Prior to the onset of the experiment, the binding properties of all antibodies are validated using methods known to the art. Following the 5 minute incubation, cells are fixed with 4% formaldehyde (20 min at room temperature) and incubated with an appropriate fluorophore-labeled secondary antibody (e.g., goat anti-mouse for W6/32, etc.) for 60 minutes. Unbound reagents are washed with a series of PBS images, and the cell panels are imaged using confocal microscopy. Upon analysis of the images, significant fluorescence can be observed on the surface of cells bound with W6/32, non-pH-sensitive fcMHCl antigen-binding protein construct, and ab30, but little surface binding is observed for pH- sensitive fcMHCl antigen-binding protein construct and the isotype negative control. To isolate the effect of pH on surface binding, the same experiment is repeated twice, with the primary antibody incubation taking place at sequentially lower pH (e.g., pH 6.5 and 5.5). Analysis of the resulting confocal microscopy images shows significant fluorescence on the surface of cells bound with all mAbs tested, excepting the isotype negative control, and that this fluorescence increases for pH-sensitive fcMHCl antigen-binding protein construct as the pH decreases (the pH at which surface fluorescence is maximal from now on referred to as pH_opt_surface). Taken together, the results show that the pH engineering process has rendered pH-sensitive fcMHCl antigen-binding protein construct pH-sensitive in its binding properties to fcMHCl, that it is only capable of significant binding at lower pH, and that its binding properties improve as the pH becomes lower.

To demonstrate that the pH dependent binding properties of pH-sensitive fcMHC 1 antigen-binding protein construct lead to enhanced release of the antibody into the extracellular environment following cellular uptake, an internalization assay is performed using methods known to the art (e.g., Mahmutefendic et al., Int. J. Biochem. Cell Bio., 2011). Briefly, as above, a panel of human cells that express MHCl highly and that are also FcRn- is assembled using methods known to the art. To facilitate antibody uptake via nonspecific mechanisms such as, e.g., pinocytosis, cells are plated, washed three times with PBS, and incubated at 37 degrees C for 60 minutes in media at a pH of about pH_opt_surface, and in a separate experiment at pH7.4, with added concentrations of 2 micrograms per milliliter of pH-sensitive fcMHCl antigen-binding protein construct and non-pH-sensitive fcMHCl antigen-binding protein construct. In a subset of cells, validation of antibody internalization and endosomal localization is performed using methods known to the art; e.g., cells are fixed in 4% formaldehyde as described above, permeabilized using TWEEN 20 or other methods known to the art (https://www.ncbi.nlm.nih.gov/pubmed/20012820), additionally stained with an endosomal marker, e.g., a fluorescent RAB5 antibody (Anti-Rab5 antibody - Abeam, abl8211), stained with an appropriate fluorescently labeled anti-human secondary antibody, and imaged using confocal fluorescence microscopy, as described above. Having validated endosomal uptake, in a separate experiment the first incubation is repeated and after this first incubation, cells are divided into two groups, one of which is treated with buffered media at pH = 6.0, the other of which is treated with buffered media at pH = 7.4. Cells are incubated for 30 minutes, and the media from all cells is removed and analyzed for antibody concentration using ELISA or other methods known to the art. Upon analysis of the data, it is revealed that for cells treated with pH-sensitive fcMHCl antigen-binding protein construct, the pH = 7.4 media contains significantly more antibody per unit volume than the pH = 6.0 media, and this media antibody concentration pH7.4/pH6.0 ratio, as compared to the media antibody concentration pH7.4/pH6.0 ratio for the non-pH-sensitive fcMHCl antigen-binding protein construct is greater. Taken together, the data demonstrate that the antibodies are taken up about equally well by both cells at pH of around pH opt surface, but pH-sensitive fcMHCl antigen-binding protein construct' s pH-sensitive properties mediate enhanced release of the antibody from the target that it has bound at lower, endosomal pH, to the extracellular environment at pH = 7.4.

To demonstrate that pH-sensitive fcMHCl antigen-binding protein construct exhibits enhanced levels in intracellular compartments of fcMHC l - cancer cells as compared to fcMHCl + healthy cells, a variation of the above-described experiment is performed. Two cell panels are assembled, one comprised of fcMHCl + cells (intended to model tumor cells) and one comprised of fcMHCl- (intended to model normal cells). Methods for identifying the fcMHCl expression status of a cell are known to the art and described herein. To facilitate antibody uptake via nonspecific mechanisms such as, e.g., pinocytosis, cells are plated, washed three times with PBS, and incubated at 37 degrees C for 60 minutes in media at a pH of about pH opt surface, and in a separate experiment at pH7.4, with added concentrations of 2 micrograms per milliliter with pH-sensitive fcMHCl antigen-binding protein construct. Following incubation, cells are washed three times with PBS, fixed and permeabilized as described above, and stained with a panel of appropriately selected antibodies targeting late endosomal markers as well as lysosomes (e.g., RAB7, and LAMPl; Cell Signaling Technology, Endosomal Marker Antibody Sampler Kit #12666; AbCam, Anti- LAMP2 antibody [GL2A7], ab 13524). After primary antibody staining, cells are stained with an appropriate mixture of fluorescently labeled secondary antibodies (e.g., anti-human and anti-rabbit), imaged using confocal fluorescence microscopy, and regions of co- localization of signal from pH-sensitive fcMHCl antigen-binding protein construct and endosomal markers are visualized and quantified. Upon analysis of the data, it is revealed that there is increased co-localization of pH-sensitive fcMHCl antigen-binding construct signal in fcMHCl- cells as compared to fcMHCl+ cells with late endosomal and lysosomal markers, thereby demonstrating selective retention of the construct in intracellular compartments of fcMHCl - cells (a model system representative of many cancer cells).

Example 4. Conjugation of fcMHC-binding Fabs and fcMHC-binding monoclonal antibodies to cytotoxic drugs

Generation of Antigen-Binding Protein Construct Conjugates:

An antigen-binding protein construct conjugate (ADC) is made comprising the fcMHCl antigen-binding Fab (hereafter, fcMHCl -Fab) described above linked to monomethyl auristatin E (MMAE) via a valine-citrulline (vc) linker (hereafter, fcMHC-Fab- DC). Conjugation of the antigen-binding protein construct with vcMMAE begins with a partial reduction of the fcMHCl -Fab antigen-binding protein construct followed by reaction with Val-Cit-MMAE (vcMMAE). The fcMHCl-Fab antigen-binding protein construct (20 mg/mL) is partially reduced by addition of TCEP (molar equivalents of TCEP:mAb is 2.1) followed by incubation at 0° C. overnight. The reduction reaction is then warmed to 20° C. To conjugate all of the thiols, vcMMAE is added to a final vcMMAE: reduced Cys molar ratio of 1.15. The conjugation reaction is carried out in the presence of 10% v/v of DMSO and allowed to proceed at 20° C for 60 minutes. After the conjugation reaction, excess free N(acetyl)-Cysteine (2 equivalents vs. vcMMAE charge) is added to quench unreacted vcMMAE to produce the Cys-Val-Cit- MMAE adduct. The Cys quenching reaction is allowed to proceed at 20° C. for

approximately 30 minutes. The Cys-quenched reaction mixture is purified as per below. The above conjugation method can also be used to conjugate mcMMAF to an antigen-binding protein construct.

The fcMHCl -Fab-DCs (antigen-binding protein construct conjugates) are purified using a batch purification method. The reaction mixture is treated with the appropriate amount of water washed Bu-HIC resin (ToyoPearl; Tosoh Biosciences), i.e., seven weights of resin is added to the mixture. The resin/reaction mixture is stirred for the appropriate time, and monitored by analytical hydrophobic interaction chromatography for removal of drug conjugate products, filtered through a coarse polypropylene filter, and washed by two bed volumes of a buffer (0.28 M sodium chloride, 7 mM potassium phosphate, pH 7). The combined filtrate and rinses are combined and analyzed for product profile by HIC HPLC. The combined filtrate and rinses are buffer exchanged by ultrafiltration/diafiltration (UF/DF) to 15 mM histidine, pH 6 with 10 diavolumes 15 nM histidine buffer.

In addition to the fcMHCl -Fab-DCs described above, protocols similar to those described above are used to create ADCs comprising monoclonal antibodies specific for fcMHCl (hereafter, fcMHCl x fcMHC l -ADCs), using pH-sensitive fcMHCl antigen- binding protein construct as starting material instead of fcMHCl -Fab.

Example 5. Creation of a cell-surface targeting oncology binder ADC (EGFR/MHC) and demonstration of selective toxicity in fcMHCl (-) cells

Creation of EGFR-binding proteins:

Anti-EGFR antibody sequences can be obtained from sources known to the art

(EP2251357; U.S. Patent No. 9,493,568; and U.S. Patent Application Publication No.

2015/0337043), or generated de novo. For construction of a multispecific antigen-specific binding protein to EGFR and fcMHCl, de novo EGFR binding antibody sequences are obtained by immunization. Many methods for generation of antibodies by immunization are known in the art (see the following papers and their references: Burns R, Meth. Mol. Biol.

508:27-35, 2009; Parker et al, J Biol. Chem. 259(15):9906-12, 1984; Osaki et al., Monoclon.

Antib. Immunodiagn. Immunother. 34(6): 418-422, 2015; Bates et al, Biotechniques

40(2): 199-208, 2006; Hrabovska et al, PLoS One 5(9): el2892, 2010). Purified EGFR ectodomain or EGFR ectodomain fused to the human IgGl Fc region is used as the immunogen and blood samples are collected each week to monitor antibody titers. Spleen, lymph nodes or PBMCs are isolated when a high antibody titer is obtained, and RNA is extracted and reverse transcribed to cDNA using methods known to the art. Heavy and light chain antibody sequences are amplified from cDNA using methods known to one of ordinary skill in the art. Heavy and light chains are assembled as Fab fragments and subcloned into yeast display vectors (Van Deventer and Wittrup (2014) Methods Mol. Biol. 1131 : 151-181). Display vectors are transformed into competent yeast cells to generate combinatorial antibody libraries. Libraries are subjected to screening with cyno and human EGFR to select cross-reactive antibodies. Antibody fragments are subcloned into an IgG scaffold and expressed as bivalent IgG antibodies (i.e., with two antibody fragments per IgG) in Expi293 cells. Antibody fragments are also separately expressed as independent, monovalent Fabs. Purified IgG antibodies and Fab molecules are tested in functional assays for two criteria: a) ligand competition with other EGFR ligands (e.g. EGF, or anti-EGFR antibodies), and b) the internalization rate of the monovalent Fab molecule into EGFR expressing cells. Assays for determining the internalization rate of a molecule present on the surface of a cell are known to the art. See, e.g., Wiley et al. (1991) J Biol. Chem. 266: 11083-11094; and Sorkin and Duex (2010) Curr. Protoc. Cell Biol. Chapter, Unit-15.14; Vainshtein et al. (2015) Pharm Res. 32: 286-299. Antigen-binding domains are selected on the basis that they a) successfully compete with other EGFR ligands, and b) are internalized at an acceptable rate; the antigen-binding domains that exhibit the best performance in both of these categories are selected for further analysis. Ligand competition assays are well-described throughout the art (see, e.g., Wells et al. (1980) Biochim Biophys Acta 632: 464-469; de Jong et al. (2005) J. Chromatogr B Analyt Technol Biomed Life Sri 829(1-2): 1-25). The EGFR antigen-binding domain that individually exhibit the best overall performance properties (e.g., competition with other EGFR ligands, and internalization at the highest rate amongst candidates) is selected for further development. The molecule selected for further development is humanized using methods known in the art (see the following papers and their references: Safardi et al., Biotechnol. Genet. Eng. Rev. 29: 175-86, 2013; Almagro et al, Front. Biosci. 13: 1619-33 , 2008), and the resulting humanized molecules are tested using the same assays above to confirm their suitability for further development. Assembly of a bispecific antigen-binding protein construct:

An EGFR x fcMHCl bispecific antigen-binding protein construct is assembled using the EGFR and fcMHCl antigen binding arms selected as described in the above paragraph and in Example 1, respectively. Heavy and light chain constructs with engineered mutations for heavy and light chain pairing (Spiess et al., "Alternative molecular formats and therapeutic applications of bispecific antibodies," 2015) are synthesized for both arms.

Antigen-binding protein constructs are produced by co-expression of corresponding heavy and light chain plasmids in Expi293 cells. Cell culture supernatants are harvested and subjected to Protein A purification. Heterodimeric antigen-binding protein constructs are separated from homodimeric species via additional purification steps such as ion exchange chromatography, hydrophobic interaction chromatography, and mixed mode

chromatography. The purified EGFR x fcMHCl bispecific antigen-binding protein constructs are characterized via mass spectrometry to confirm the purity and absence of homodimeric species and size exclusion chromatography to confirm the presence of monomeric antigen-binding protein construct species. Binding to all antigens is confirmed via Biacore analysis. Functional characterization of antigen-binding protein constructs is performed by using cell based assays for each antigen as described in the above examples. Binding to fcMHCl is confirmed using Biacore, EGFR downregulation and internalization is quantified using Western blotting and ligand competition assays known to the art. EGFR internalization is studied using internalization assays described herein and others known to one of ordinary skill in the art.

Generation of bispecific antigen-binding protein construct conjugates:

An antigen-binding protein construct conjugate (ADC) is made comprising the EGFR x fcMHCl bispecific antigen-binding protein construct described above linked to monomethyl auristatin E (MMAE) via a valine-citrulline (vc) linker (hereafter, EGFR x fcMHCl-ADC). Conjugation of the antigen-binding protein construct with vcMMAE begins with a partial reduction of the EGFR x fcMHCl bispecific antigen-binding protein construct followed by reaction with Val-Cit-MMAE (vcMMAE). The EGFR x fcMHCl bispecific antigen-binding protein construct (20 mg/mL) is partially reduced by addition of TCEP (molar equivalents of TCEP:mAb is 2.1) followed by incubation at 0° C. overnight. The reduction reaction is then warmed to 20° C. To conjugate all of the thiols, vcMMAE is added to a final vcMMAE: reduced Cys molar ratio of 1.15. The conjugation reaction is carried out in the presence of 10% v/v of DMSO and allowed to proceed at 20° C for 60 minutes.

After the conjugation reaction, excess free N(acetyl)-Cysteine (2 equivalents vs. vcMMAE charge) is added to quench unreacted vcMMAE to produce the Cys-Val-Cit- MMAE adduct. The Cys quenching reaction is allowed to proceed at 20° C. for

The EGFR x fcMHCl-ADC bispecific antigen-binding protein construct is purified using a batch purification method. The reaction mixture is treated with the appropriate amount of water washed Bu-HIC resin (ToyoPearl; Tosoh Biosciences), i.e., seven weights of resin is added to the mixture. The resin/reaction mixture is stirred for the appropriate time, and monitored by analytical hydrophobic interaction chromatography for removal of drug conjugate products, filtered through a coarse polypropylene filter, and washed by two bed volumes of a buffer (0.28 M sodium chloride, 7 mM potassium phosphate, pH 7). The combined filtrate and rinses are combined and analyzed for product profile by HIC HPLC. The combined filtrate and rinses are buffer exchanged by ultrafiltration/diafiltration (UF/DF) to 15 mM histidine, pH 6 with 10 diavolumes 15 nM histidine buffer. Demonstration of Increased Endosomal Recycling in MHC+ cells

To demonstrate that the pH dependent binding properties of EGFR x fcMHCl-ADCs leads to enhanced endosomal recycling following cellular uptake, an internalization assay is performed using methods known to the art (e.g., Mahmutefendic et al, Int. J. Biochem. Cell Bio. , 2011). Briefly, as above, a panel of human cells that present fcMHCl and/or MHC1 highly and that are also EGFR+ and FcRn- is assembled using methods known to the art and/or described herein. To facilitate antibody uptake, cells are plated, washed three times with PBS, and incubated at 37 degrees C for 60 minutes in media at several different pHs between 6.0 and 7.4, with added concentrations of 2 micrograms per milliliter of EGFR x fcMHCl-ADC as well as a non-pH sensitive EGFR x fcMHCl-ADC made using a non-pH sensitive fcMHC, e.g., the non-pH-sensitive fcMHCl antigen-binding protein construct described herein (hereafter, non-pH sensitive EGFR x fcMHCl -ADC). Validation of antibody internalization and endosomal localization is performed using methods known to the art; e.g., cells are fixed in 4% formaldehy de as described above, permeabilized using TWEEN 20 or other methods known to the art (www.ncbi.nlm.nih.gov/pubmed/20012820), additionally stained with an endosomal marker, e.g., a RAB5 antibody (Anti-Rab5 antibody - Abeam, abl8211), stained with an appropriate set of fluorescently labeled secondary antibodies, and imaged using confocal fluorescence microscopy, as described above.

Because the fcMHC antigen binding domains on the two EGFR x fcMHCl -ADCs used herein differ in their binding properties as a function of pH, it is necessary to determine a pH at which their cellular uptake is the most comparable; the confocal imaging results are therefore quantitatively analyzed and the optimum pH at which uptake across constructs is the most comparable is determined (hereafter, OpH). If necessary, the doses of antibodies used are varied until approximately equal endosomal uptake is achieved when administered to cells at the OpH.

Having validated endosomal uptake and determined optimal dosing as well as OpH, in a separate experiment the first incubation is repeated, this time using the optimal doses at OpH, and after this first incubation, cells are divided into two groups, one of which is treated with buffered media at pH = 6.0, the other of which is treated with buffered media at pH = 7.4. Cells are incubated for 30 minutes, and the media from all cells is removed and analyzed for antibody concentration using ELISA or other methods known to the art and as described herein, e.g., Example 3. Upon analysis of the data, it is revealed that for cells treated with pH-sensitive EGFR x fcMHCl -ADC, the pH = 7.4 media contains significantly more antibody per unit volume than the pH = 6.0 media, and the media antibody concentration pH7.4/pH6.0 ratio, as compared to the media antibody concentration pH7.4/pH6.0 ratio for the non-pH sensitive EGFR x fcMHCl-ADC, is greater. Taken together, the data demonstrate that the antibodies are taken up about equally well by both cells at OpH, but the EGFR x fcMHCl- ADC's pH-sensitive properties mediate enhanced recycling of the antibody from the lower-pH environment of the endosomes to the more neutral extracellular environment, where pH is approximately 7.4.

Cytotoxicity Assays and Demonstration of Differential Toxin Release:

The cytotoxic activity of EGFR x fcMHCl -ADC bispecific antigen-binding protein constructs are separately evaluated on a panel of EGFR+/fcMHCl- cells (intended to model tumor cells) and a cell panel that is EGFR+/fcMHCl+ (intended to model normal cells). For purposes of validation, prior to use, all cell lines are tested for expression of MHCl complex, fcMHCl complex, and/or EGFR using one or more methods known to the art, e.g., qPCR, flow cytometry, mRNA RPKM, antibody staining using a suitable antibody that binds MHCl complex and/or MHCl complex known (e.g., Abeam ab23755, W6/32) followed by visualization of the stain using fluorescence microscopy, iinmimohistochemistry, flow cytometry, ELISA, or other methods known to the art (e.g., other methods described herein). Cell lines are grouped on the basis of their EGFR status and their fcMHCl and/or MHCl status. The tested cell lines include SW480, HCTl 16, HT-29, and CHO cells transfected with EGFR and/or an HLA-A gene, an HLA-B gene, an HLA-C gene, a beta-2-microglobulin gene, or a combination thereof. To evaluate the cytotoxicity of compounds, cells are seeded at approximately 5-10,000 per well in 150 microliters of culture medium, then treated with graded doses of compounds in quadruplicates at the initiation of the assay. Cytotoxicity assays are carried out for 96 hours after addition of test compounds. Fifty microliters of resazurin dye are added to each well during the last 4 to 6 hours of the incubation to assess viable cells at the end of culture. Dye reduction is determined by fluorescence spectrometry using the excitation and emission wavelengths of 535 nm and 590 nm, respectively. For analysis, the extent of resazurin reduction by the treated cells is compared to that of untreated control cells, and percent cytotoxicity is determined. Upon analysis of the data, it is determined that EGFR x fcMHCl-ADC bispecific antigen-binding protein constructs are substantially cytotoxic to EGFR+/MHC1- cells, but less toxic to EGFR+/MHC1+ cells.

To demonstrate that the increased endosomal recycling of EGFR x fcMHCl-ADCs in cells that contain higher levels of MHCl and/or fcMHCl on their surface and/or in their cellular compartments results in decreased toxin liberation as compared to cells with lowers level of MHCl and/or fcMHCl, the concentration of liberated toxin in both ty pes of cells is quantified using methods known to the art (e.g., Bessire et al. , Bioconjuage Chem., 2016, 27(7), 1645-1654; Erickson et al., Mol. Cancer Ther., 2012, 11(5).). As an example, tritiated mc-MMAF (hereafter, [³H]mc-MMAF) is prepared using methods known to the art, e.g., via reacting an MMAF ring precursor brominated at a phenylalanine ring with tritium gas. The tritiated product is conjugated to EGFR x fcMHCl using methods described herein or others known to the art, thereby creating EGFR x fcMHCl -[³H]mc-MMAF-ADCs. The EGFR x fcMHCl-[³H]mc-MMAF-ADCs are incubated with human liver S9 fraction, which contains a high concentration of lytic lysosomal enzymes, and time point samples are collected. The samples are diluted 1 : 1 with 20 mM TCEP and analysed via LC/'MS/MS using methods known to the art (Bessire et al. , Bioconjuage Chem., 2016, 27(7), 1645-1654), thereby creating a standard set of identifiable ly sosomal degradation products for EGFR x fcMHCl - [³H]mc-MMAF-ADCs (i.e., a positive control for when toxin liberation has occurred). To compare toxin liberation between EGFR+/MHC1- and EGFR+/MHC1+ cells, cell lines of both types, identified using methods described herein, are plated in culture flasks and grown to a density of approximately 10⁷ cells per flask. To facilitate binding of the EGFR x fcMHCl-[³H]mc-MMAF-ADCs to surface EGFR and subsequent uptake and antibody catabolism, cells are incubated with various concentrations of EGFR x fcMHCl -[³H]mc- MMAF-ADCs (e.g., 30 nmol/L) for 2-3 hours on ice (media pH = 7.4), the media is washed and removed and replaced with fresh media (pH = 7.4), and cells are further incubated for various periods of time (e.g., 2-24 hours) to allow for antibody catabolism. Following this final incubation, cells are washed, harvested, lysed, and analyzed using LC/MS/MS using methods similar or identical to those descried above. Upon analysis of the data, it is revealed that the mass spectra of EGFR+/MHC1- cell extracts display an abundance of peaks corresponding to the EGFR x fcMHCl-[³H]mc-MMAF-ADCs lysosomal degradation products described above, whereas the same peaks are absent or significantly reduced in size (when analyzed using an identical protocol) for EGFR+/MHC1+ cells. Taken together, the data demonstrate that EGFR x fcMHCl-ADCs are subject to decreased toxin liberation in cells that contain higher levels of MHCl and/or fcMHCl on their surface or cellular compartments.

To demonstrate that the cytotoxicity -blocking effects of EGFR x fcMHCl-ADC bispecific antigen-binding protein constructs are attenuated when the antibody is blocked from engagement of endogenous endosomal fcMHCl complexes, a binding competition assay is performed in a cell culture system similar to that described above, e.g., an

EGFR+/fcMHC 1 + cell line, treated with EGFR x fcMHCl -ADC bispecific antigen-binding protein constructs. Concentrations from 1 pg/mL to lOOmg/mL of a competitive ligand (e.g., recombinant extracellular domain of fcMHCl complex or a competitive peptide or other reagent that binds to the paratope for MHCl complex collectively, known hereafter as fcMHCl Recombinant Reagent) are added to the cultures of MHC l - cell lines used in the experiment described above, to be taken up via non-specific endocytosis mechanisms (e.g., pinocytosis), either independently or as part of a bound antibody complex. The cytotoxicity assay described above is repeated, and it is observed that the cell death of EGFR+/fcMHCl+ cell lines is increased in a dose-dependent manner in the presence of the MHCl Recombinant Reagent due to competitive blocking of the interaction of EGFR x fcMHC l -ADC with fcMHCl in endosomes. To demonstrate that the cytotoxicity of EGFR x fcMHCl-ADC bispecific antigen-binding protein constructs is enhanced by EGFR-mediated internalization relative to a non-specific binder, an EGFR ligand competition assay is performed. As above, concentrations from 1 pg/mL to lOOmg/mL recombinant EGF protein or peptide or other reagent that binds to the paratope for EGFR on EGFR x fcMHC 1-ADC bispecific antigen-binding protein constructs are added to the cultures of EGFR+ cell lines used in the experiment described above. The cytotoxicity assays described above are repeated, and it is observed that cytotoxicity of EGFR+ cell lines is decreased in the presence of the EGFR recombinant reagent in a dose- dependent manner.

Example 6. Demonstration of enhanced cytotoxicity in the absence of fcMHCl using both fcMHC -Fab-DCs and fcMHCl x fcMHCl-ADCs

The cy totoxic activity of both fcMHC-Fab-DCs and fcMHCl x fcMHCl -ADCs (antigen-binding protein construct conjugates) are separately evaluated on a panel of MHC1+ and MHCl - cell lines, selected using the methods described herein, and cells expressing transgenic MHCl, e.g., CHO cells transfected with the genes required for functional fcMHCl, as described herein. For purposes of validation, prior to use, all cell lines are tested for expression of MHCl complex using methods known to the art, e.g., qPCR, flow cytometry, mRNA RPKM, and antibody staining using anti-MHCl complex antibodies known to the art (such as Novus Biologicals NB500-305 MHC 1 Antibody (MEM-E/08) IgGl Mouse) followed by visualization of the stain using fluorescence microscopy,

immunohistochemistry, flow cytometry, ELISA, or other methods known to the art. To evaluate the cytotoxicity of compounds, cells are seeded at approximately 5-10,000 per well in 150 microliters of culture medium, then treated with graded doses of compounds in quadruplicates at the initiation of the assay. Cytotoxicity assays are carried out for 96 hours after addition of test compounds. Fifty microliters of resazurin dye are added to each well during the last 4 to 6 hours of the incubation to assess viable cells at the end of culture. Dye reduction is determined by fluorescence spectrometry using the excitation and emission wavelengths of 535 nm and 590 nm, respectively. For analysis, the extent of resazurin reduction by the treated cells is compared to that of untreated control cells, and percent cytotoxicity is determined. Upon analy sis of the data, it is determined that both fcMHC-Fab- DCs and fcMHCl x fcMHCl-ADCs are substantially cytotoxic to MHCl- cells, but less toxic to MHC1+ cells. As described herein, a surprising aspect of the invention is its ability to facilitate enhanced recycling of ABPC by a pH-dependent interaction with membrane-bound fcMHCl in the lower pH environment of endosomes, thereby reducing toxicity when fcMHC l is present. To demonstrate that the cytotoxicity -blocking effects of both fcMHC-Fab-DCs and fcMHCl x fcMHCl -ADCs are attenuated when the antibody is blocked from engagement of endogenous endosomal fcMHCl complexes, a binding competition assay is performed. Concentrations from 1 pg/mL to lOOmg/mL of a competitive ligand (e.g., recombinant extracellular domain of fcMHCl complex or a competitive peptide or other reagent that binds to the paratope for MHC1 complex collectively, known hereafter as fcMHCl Recombinant Reagent) are added to the cultures of MHC1+ cell lines used in the experiment described above, to be taken up via non-specific endocytosis mechanisms (e.g., pinocytosis), either independently or as part of a bound antibody complex. The cy totoxicity assay described above is repeated, and it is observed that lysis of MHC1+ cell lines is increased in a dose- dependent manner in the presence of the MHC1 Recombinant Reagent due to competitive blocking of the interaction of fcMHC-Fab-DCs and fcMHC 1 x fcMHC 1 -ADCs with fcMHCl in endosomes.

The efficacy of both fcMHC-Fab-DCs and fcMHCl x fcMHCl-ADCs conjugates (antigen-binding protein construct conjugate) is additionally measured by a cell proliferation assay employing the following protocol (Promega Corp. Technical Bulletin TB288; Mendoza et al, Cancer Res. 62:5485-5488, 2002):

1. An aliquot of 100 microliters of cell culture containing about 104 cells (e.g., SKBR-3, BT474, MCF7 or MDA-MB-468) in medium is deposited in each well of a 96-well, opaque- walled plate.

2. Control wells are prepared containing medium and without cells.

3. ICE- ADC is added to the experimental wells and incubated for 1-5 days.

4. The plates are equilibrated to room temperature for approximately 30 minutes.

5. A volume of CellTiter-Glo Reagent equal to the volume of cell culture medium present in each well is added.

6. The contents are mixed for 2 minutes on an orbital shaker to induce cell lysis.

7. The plate is incubated at room temperature for 10 minutes to stabilize the luminescence signal.

8. Luminescence is recorded and reported in graphs as RLU = relative luminescence units. Example 7. Demonstration of half-life extension for fcMHC binders

One of the expected aspects of the MHC1 -binding ABPCs described by the invention is their ability to facilitate an enhanced serum half-life relative to other, similar ABPCs that lack the pH sensitivity and antigen specificity towards the MHC1 antigens described herein. To demonstrate these properties, a series of animal studies in both mice and monkeys is performed using pH-sensitive fcMHCl antigen-binding protein construct and non-pH- sensitive fcMHCl antigen-binding protein construct using methods known to the art (e.g., http://www.tandfonline.com/doi/pdf/10.1080/19420862.2016.1167294). Briefly, a single intravenous bolus (e.g., 5 mg/'kg) of either pH-sensitive fcMHCl antigen-binding protein construct or non-pH-sensitive fcMHCl antigen-binding protein construct is administered via tail vein to two groups of HLA transgenic mice. The strain of mice is selected from transgenic strains known to the art on the basis that they express all necessary genes required for the formation of fcMHCl or an fcMHCl equivalent (e.g., an HLA-beta-2- microglobulin protein fusion) on at least a subset of their cells (e.g.,

http://www.jimmunol.Org/content/198/l/516). Blood samples are collected via retro-orbital bleeds from each group at each of the following time points: 15m, 30m, lh, 8h, 24h, and 3d, 7d, lOd, 14d, 17d, 2 Id, and 28d. Samples are processed to collect serum, and antibody concentrations are quantified using ELISA or other methods known to the art (e.g., PAC assay or MAC assay; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499303/pdfmabs-4- 623.pdf) Antibody concentrations of pH-sensitive fcMHCl antigen-binding protein construct and non-pH-sensitive fcMHCl antigen-binding protein construct are plotted as a function of time. Upon analysis of the data, it is observed that pH-sensitive fcMHCl antigen-binding protein construct has a significantly longer serum half-life and overall superior

pharmacokinetic properties relative to non-pH-sensitive fcMHCl antigen-binding protein construct, thereby demonstrating the ability of pH-sensitive fcMHCl antigen-binding protein construct's pH sensitivity to facilitate an enhanced serum half-life relative to other, similar binders (e.g., non-pH-sensitive fcMHCl antigen-binding protein construct) that target the same epitope but that lack pH-sensitive fcMHCl antigen-binding protein construct's pH sensitivity.

A similar experiment is performed on monkeys (e.g., cynomolgus monkeys). An equal number of male and female monkeys (e.g., n = 1-2 each) are administered a bolus of either pH-sensitive fcMHCl antigen-binding protein construct or non-pH-sensitive fcMHCl antigen-binding protein construct at a dose of, e.g., 100 mg/kg via saphenous vein injection. Blood samples are collected via the peripheral vein or femoral vein at intervals similar to those described above, and analyzed for the presence of either pH-sensitive fcMHCl antigen- binding protein construct or non-pH-sensitive fcMHCl antigen-binding protein construct using methods known to the art (e.g., ELISA). Upon analysis of the data, it is observed that pH-sensitive fcMHC 1 antigen-binding protein construct has a significantly longer serum half- life and overall superior pharmacokinetic properties relative to pH-sensitive fcMHCl antigen-binding protein construct, thereby demonstrating the ability of pH-sensitive fcMHCl antigen-binding protein construct' s pH sensitivity to facilitate an enhanced serum half-life relative to other, similar binders (e.g., non-pH-sensitive fcMHCl antigen-binding protein construct) that target the same epitope but that lack pH-sensitive fcMHC 1 antigen-binding protein construct's pH sensitivity.

Example 8. Creation of a soluble target-binding bispecific antibody and demonstration of efficacy To demonstrate the ability of the invention to bind a soluble target, a bispecific antibody that binds both sclerostin and fcMHCl is constructed using methods known to one of ordinary skill in the art. Briefly, a sclerostin x fcMHCl antigen-binding protein construct is assembled using light chain/heavy chain pairs from a known, human sclerostin binder and pH-sensitive fcMHCl antigen-binding protein construct, respectively. Heavy and light chain constructs with engineered mutations for heavy and light chain pairing (Spiess et al.,

"Alternative molecular formats and therapeutic applications of bispecific antibodies," 2015) are synthesized for both arms. Antigen-binding protein constructs are produced by co- expression of corresponding heavy and light chain plasmids in Expi293 cells. Cell culture supernatants are harvested and subjected to Protein A purification. Heterodimeric antigen- binding protein constructs are separated from homodimeric species via additional purification steps such as ion exchange chromatography, hydrophobic interaction chromatography , and mixed mode chromatography. The purified sclerostin x fcMHCl multispecific antibodies are characterized via mass spectrometry to confirm the purity and absence of homodimeric species and size exclusion chromatography to confirm the presence of monomeric antigen- binding protein construct species. Binding to all antigens is confirmed via Biacore analysis. Other methods of bispecific antibody production are known to the art and could also be used to create sclerostin x fcMHCl multispecific antibodies described herein (e.g., http://www.nature om/nprot/j^'oumal/V9/nlO/abs/nprot.2014.169.htm^ as would be apparent to one of ordinary skill in the art.

The sclerostin x fcMHC 1 antigen-binding protein constructs are purified using a batch purification method. The reaction mixture is treated with the appropriate amount of water washed Bu-HIC resin (ToyoPearl; Tosoh Biosciences), i.e., seven weights of resin is added to the mixture. The resin/reaction mixture is stirred for the appropriate time, and monitored by analytical hydrophobic interaction chromatography for removal of drug conjugate products, filtered through a coarse polypropylene filter, and washed by two bed volumes of a buffer (0.28 M sodium chloride, 7 mM potassium phosphate, pH 7). The combined filtrate and rinses are combined and analyzed for product profile by HIC HPLC. The combined filtrate and rinses are buffer exchanged by ultrafiltration/diafiltration (UF/DF) to 15 mM histidine, pH 6 with 10 diavolumes 15 nM histidine buffer.

Functional in vitro characterization of sclerostin target binding as well as antigen- binding protein constructs is performed by using the assays and cell assays described in the examples below.

A FLAG®-sclerostin fusion protein is prepared according to protocols provided by the manufacturer (Sigma Aldrich, St. Louis, Mo.) and as described in U.S. Pat. No.

6,395,511. Each well of a 96 well microtiter plate is coated with anti-FLAG® monoclonal antibody (Sigma Aldrich) and then blocked with 10% BSA in PBS. The fusion protein (20 ng) is added to 100 μΐ PBS/0.2% BSA and adsorbed onto the 96-well plate for 60 minutes at room temperature. This protein solution is removed and the wells are washed to remove unbound fusion protein. A bone morphogenic protein (BMP), proteins to which sclerostin is known in the art to bind (Winkler et al, EMBO J., 22(23): 6267-6276), e.g., BMP -4, BMP-5, BMP-6, or BMP-7, is diluted in PBS/0.2% BSA and added to each well at concentrations ranging from 10 pM to 500 nM. After an incubation for 2 hours at room temperature, the binding solution is removed and the plate is washed three times with 200 μΐ volumes of PBS/0.2% BSA. Binding of the BMP to sclerostin is detected using polyclonal antiserum or monoclonal antibody specific for the BMP and an appropriate enzyme-conjugated second step reagent according to standard ELISA techniques (see, e.g., Ausubel et al, Current Protocols in Mol Biol. Vol 2 11.2.1-11.2.22 (1998)). Specific binding is calculated by subtracting non-specific binding from total binding and analyzed using the LIGAND program (Munson and Podbard, Anal Bwchem. 107:220-39 (1980)). The above experiment is repeated, this time in the presence of the sclerostin x fcMHCl antigen-binding protein construct. An ELISA is performed essentially as described herein except that the BMP concentration is held fixed at its KD (determined, for example, by BIAcore analysis). In addition, sclerostin x fcMHCl antigen-binding protein construct is added to the wells to a concentration of 1 μΜ. The antigen-binding protein construct is incubated for 2 hours at room temperature with the BMP and sclerostin, the solution is removed, and the bound BMP is quantified as described. It is observed that the antigen- binding protein construct inhibits 40% of the BMP binding observed in the absence of antibody, and is therefore considered an antagonist of this interaction. Sclerostin x fcMHCl antigen-binding protein construct is further evaluated as a potential inhibitor of the

BMP/sclerostin binding interaction by performing titration studies to determine the sclerostin x fcMHCl antigen-binding protein construct' s inhibition constants and their effect on TGF- beta binding-protein binding affinity. Comparable specificity control assays may also be conducted to establish the selectivity profile for the sclerostin x fcMHCl antigen-binding protein construct using assays dependent on the BMP ligand action (e.g., a BMP/BMP receptor competition study).

The sclerostin x fcMHCl antigen-binding protein construct' s ability to interfere with sclerostin-mediated signaling by binding of sclerostin is tested using the cell assays described below. Other assays are known to the art and could be used as well, e.g., Li etal, J. Biol. Chem., 2005, 280(20): 19883-7, Thouverey and Caverzasio, Bonekey Rep, 2015, 4:757.

Determining Effects of Sclerostin Protein on Human Mesenchymal Cells (hMSC or hMSC cells): hMSC cells are plated in 96-well tissue culture dishes at a density of 10,000 cells/cm2 in Osteoblast-Inducing medium. Partially purified preparations of baculovirus- expressed sclerostin protein are prepared in sterile PBS using NAP-5 columns prior to use, or purchased from the sources described herein. Human sclerostin protein (0 to 30 μg/ml) or an equal volume of Sf9 conditioned media (Control) is added to cultures of hMSC cells at various times after plating (1 day, 8 days, 15 days, or 21 days). The effects of sclerostin on osteoblastic differentiation are assessed by measuring alkaline phosphatase activity (ALP, determined in cell layers using DEAA buffer (Pierce) containing 0.5% NP-40 and 10 mM p- nitrophenylphosphate), synthesis of collagen type I (Prolagen C ELISA), and calcium deposition for mineralization (colorimetric assay of acid lysates of cell layers, Sigma). The experiment demonstrates that sclerostin decreases alkaline phosphatase activity, type 1 collagen synthesis, and mineralization in hMSC cells in a dose-dependent manner, whereas control treatment does not.

After establishing a baseline response in the absence of sclerostin x fcMHCl antigen- binding protein constructs, the experiment is repeated, and this time various concentrations of sclerostin x fcMHCl antigen-binding protein construct is added to perform a dose-response study of the ability of sclerostin x fcMHCl antigen-binding protein construct to block sclerostin binding to its biological targets, and thereby inhibit the sclerostin-mediated decrease in alkaline phosphatase activity and mineralization in hMSC cells. Upon analysis of the data, it is observed that sclerostin x fcMHCl antigen-binding protein construct significantly reduces the effects of sclerostin exposure in hMSCs in a dose-depedent manner (e.g., decreased alkaline phosphatase activity, type 1 collagen synthesis, and cellular mineralization), thereby demonstrating the efficacy of the sclerostin x fcMHCl antigen- binding protein construct.

To demonstrate that sclerostin x fcMHCl antigen-binding protein constructs exhibit enhanced recycling from endosomes, experiments are performed analogously to those described in Example 2. Briefly, as above, a panel of human cells that are

MHCl+/fcMHCl+ is assembled using methods known to the art and as described herein. To facilitate antibody uptake via nonspecific mechanisms such as, e.g., pinocytosis, cells are plated, washed three times with PBS, and incubated at 37 degrees C for 60 minutes in media at a pH of about pH opt uptake, and in a separate experiment at pH7.4, with added concentrations of 2 micrograms per milliliter with sclerostin x fcMHCl antigen-binding protein construct and a non-pH engineered antibody that also binds sclerostin, hereafter referred to as "non-pH sensitive sclerostin antibody." In a subset of cells, validation of antibody internalization and endosomal localization is performed using methods known to the art; e.g., cells are fixed in 4% formaldehy de as described above, permeabilized using TWEEN 20 or other methods known to the art

(https://www.ncbi.nlm.nih.gov/pubmed/20012820), additionally stained with an endosomal marker, e.g., a fluorescent RAB5 antibody (Cell Signaling Technolgies Rab5 (C8B1) Rabbit mAb #3547), stained with an appropriate fluorescently labeled anti-human secondary antibody, and imaged using confocal fluorescence microscopy, as described above.

Following endosomal uptake validation and the second incubation, cells are divided into two groups, one of which is treated with buffered media at pH = 6.0, the other of which is treated with buffered media at pH = 7.4. Cells are incubated for 30 minutes, and the media from all cells is removed and analyzed for antibody concentration using ELISA or other methods known to the art and as described herein, e.g., Example 6. Upon analysis of the data, it is revealed that for cells treated with sclerostin x fcMHCl antigen-binding protein construct, the pH = 7.4 media contains significantly more antibody per unit volume than the pH = 6.0 media, and the ratio of media antibody concentration pH7.4/pH6.0 is greater as compared to cells treated with non-pH sensitive sclerostin antibody and its media antibody concentration pH7/4/pH6.0 ratio. Taken together, the data demonstrate that the sclerostin x fcMHCl antigen-binding protein construct' s pH-sensitive properties mediate enhanced release of the antibody from the target that it has bound at lower, endosomal pH, to the extracellular environment at pH = 7.4, i.e., enhanced endosomal recycling.

Generation ofbispecific sclerostin x fcMHCl antigen-binding protein construct drug conjugates:

Recent evidence in the art suggests that sclerostin binding and activity may contribute to bone disease in cancer patients, and possibly bone metastases (e.g., Gkotzamanidou et al., Expert Opin. Ther. Targets., 2012, 16(8):761-9; Garcia-Fontana et al., Bone , Volume 50 , S181); therefore, therapeutic agents that combine the therapeutic properties of a sclerostin binding protein construct with the selective anti-tumor properties of an antibody drug conjugate or a cytotoxic or cytostatic drug are useful and desirable (e.g., a bispecific sclerostin x fcMHCl antigen-binding protein construct conjugated to a cytotoxic drug, e.g., MMAE, that is selectively liberated in cancer cells). An antigen-binding protein construct conjugate (ADC) is made comprising the bispecific sclerostin x fcMHCl antigen-binding protein construct described above linked to monomethyl auristatin E (MMAE) via a valine- citrulhne (vc) linker (hereafter, sclerostin x fcMHCl -ADC). Conjugation of the antigen- binding protein construct with vcMMAE begins with a partial reduction of the sclerostin x fcMHCl bispecific antigen-binding protein construct followed by reaction with Val-Cit- MMAE (vcMMAE). The sclerostin x fcMHCl bispecific antigen-binding protein construct (20 mg/mL) is partially reduced by addition of TCEP (molar equivalents of TCEP:mAb is 2.1) followed by incubation at 0° C. overnight. The reduction reaction is then warmed to 20° C. To conjugate all of the thiols, vcMMAE is added to a final vcMMAE:reduced Cys molar ratio of 1.15. The conjugation reaction is carried out in the presence of 10% v/v of DMSO and allowed to proceed at 20° C for 60 minutes. After the conjugation reaction, excess free N(acetyl)-Cysteine (2 equivalents vs. vcMMAE charge) is added to quench unreacted vcMMAE to produce the Cys-Val-Cit- MMAE adduct. The Cys quenching reaction is allowed to proceed at 20° C. for

The sclerostin x fcMHC l-ADC bispecific antigen-binding protein construct is purified using a batch purification method. The reaction mixture is treated with the appropriate amount of water washed Bu-HIC resin (ToyoPearl; Tosoh Biosciences), i.e., seven weights of resin is added to the mixture. The resin/reaction mixture is stirred for the appropriate time, and monitored by analytical hydrophobic interaction chromatography for removal of drug conjugate products, filtered through a coarse polypropylene filter, and washed by two bed volumes of a buffer (0.28 M sodium chloride, 7 mM potassium phosphate, pH 7). The combined filtrate and rinses are combined and analyzed for product profile by HIC HPLC. The combined filtrate and rinses are buffer exchanged by

ultrafiltration/diafiltration (UF/DF) to 15 mM histidine, pH 6 with 10 diavolumes 15 nM histidine buffer.

Demonstration of Increased Endosomal Recycling in MHC 1+ cells

To demonstrate that the pH dependent binding properties of sclerostin x fcMHCl -

ADCs leads to enhanced endosomal recycling following cellular uptake, an internalization assay is performed using methods known to the art (e.g., Mahmutefendic et al., Int. J.

Biochem. Cell Bio. , 2011). Briefly, as above, a panel of human cells that present fcMHCl and/or MHC1 highly and that are also FcRn- is assembled using methods known to the art and/or described herein. To facilitate non-specific antibody uptake, cells are plated, washed three times with PBS, and incubated at 37 degrees C for 60 minutes in media at several different pHs between 6.0 and 7.4, with added concentrations of 2 micrograms per milliliter of sclerostin x fcMHCl -ADC as well as a non-pH sensitive sclerostin x fcMHCl -ADC made using a non-pH sensitive fcMHC, e.g., the non-pH-sensitive fcMHCl antigen-binding protein construct described herein (hereafter, non-pH sensitive sclerostin x fcMHCl -ADC).

Validation of antibody internalization and endosomal localization is performed using methods known to the art; e.g., cells are fixed in 4% formaldehyde as described above, permeabilized using TWEEN 20 or other methods known to the art (https://www.ncbi.nlm.nih.gov/pubmed/20012820), additionally stained with an endosomal marker, e.g., a RAB5 antibody (Anti-Rab5 antibody - Abeam, abl 8211), stained with an appropriate set of fluorescently labeled secondary antibodies, and imaged using confocal fluorescence microscopy, as described above. Because the fcMHC antigen binding domains on the two sclerostin x fcMHCl-ADCs used herein differ in their binding properties as a function of pH, it is necessary to determine a pH at which their cellular uptake is the most comparable; the confocal imaging results are therefore quantitatively analyzed and the optimum pH at which uptake across constructs is the most comparable is determined

(hereafter, OpH). If necessary, the doses of antibodies used are varied until approximately equal endosomal uptake is achieved when administered to cells at the OpH.

Having validated endosomal uptake and determined optimal dosing as well as OpH, in a separate experiment the first incubation is repeated, this time using the optimal doses at OpH, and after this first incubation, cells are divided into two groups, one of which is treated with buffered media at pH = 6.0, the other of which is treated with buffered media at pH = 7.4. Cells are incubated for 30 minutes, and the media from all cells is removed and analyzed for antibody concentration using ELISA or other methods known to the art and as described herein. Upon analysis of the data, it is revealed that for cells treated with pH-sensitive sclerostin x fcMHCl-ADC, the pH = 7.4 media contains significantly more antibody per unit volume than the pH = 6.0 media, and the media antibody concentration pH7.4/pH6.0 ratio, as compared to the media antibody concentration pH7.4/pH6.0 ratio for the non-pH sensitive sclerostin x fcMHCl-ADC, is greater. Taken together, the data demonstrate that the antibodies are taken up about equally well by both cells at OpH, but the sclerostin x fcMHCl -ADC's pH-sensitive properties mediate enhanced recycling of the antibody from the lower-pH environment of the endosomes to the more neutral extracellular environment, where pH is approximately 7.4.

Example 9. Creation of a soluble target-binding bispecific antibody and testing of both efficacy and increased half-life using a bispecific binding format

To demonstrate the ability of the invention to bind a soluble target and facilitate improved half-life when bound to said soluble target, a bispecific antibody that binds both sclerostin and fcMHCl is constructed using methods known to one of ordinary skill in the art.

Briefly, a sclerostin x fcMHCl antigen-binding protein construct is assembled using light chain/heavy chain pairs from a known, human sclerostin binder and pH-sensitive fcMHCl antigen-binding protein construct, respectively. Heavy and light chain constructs with engineered mutations for heavy and light chain pairing (Spiess et al, "Alternative molecular formats and therapeutic applications of bispecific antibodies," 2015) are synthesized for both arms. Antigen-binding protein constructs are produced by co-expression of corresponding heavy and light chain plasmids in Expi293 cells. Cell culture supernatants are harvested and subjected to Protein A purification. Heterodimeric antigen-binding protein constructs are separated from homodimeric species via additional purification steps such as ion exchange chromatography, hydrophobic interaction chromatography, and mixed mode

chromatography. The purified sclerostin x fcMHCl multispecific antibodies are

characterized via mass spectrometry to confirm the purity and absence of homodimeric species and size exclusion chromatography to confirm the presence of monomeric antigen- binding protein construct species. Binding to all antigens is confirmed via Biacore analysis. Other methods of bispecific antibody production are known to the art and could also be used to create sclerostin x fcMHCl multispecific antibodies described herein (e.g.,

http://www.nature.com/nprot/joumal/v9/nl0/abs/nprot.2014.169.html) as would be apparent to one of ordinary skill in the art.

6,395,511. Each well of a 96 well microtiter plate is coated with anti-FLAG® monoclonal antibody (Sigma Aldrich) and then blocked with 10% BSA in PBS. The fusion protein (20 ng) is added to 100 μΐ PBS/0.2% BSA and adsorbed onto the 96-well plate for 60 minutes at room temperature. This protein solution is removed and the wells are washed to remove unbound fusion protein. A bone morphogenic protein (BMP), proteins to which sclerostin is known in the art to bind (Winkler et al, EMBO J., 22(23): 6267-6276), e.g., BMP -4, BMP-5, BMP-6, or BMP-7, is diluted in PBS/0.2% BSA and added to each well at concentrations ranging from 10 pM to 500 nM. After an incubation for 2 hours at room temperature, the binding solution is removed and the plate is washed three times with 200 μΐ volumes of PBS/0.2% BSA. Binding of the BMP to sclerostin is detected using polyclonal antiserum or monoclonal antibody specific for the BMP and an appropriate enzyme-conjugated second step reagent according to standard ELISA techniques (see, e.g., Ausubel et al, Current Protocols in Mol Biol. Vol 2 11.2.1-11.2.22 (1998)). Specific binding is calculated by subtracting non-specific binding from total binding and analyzed using the LIGAND program (Munson and Podbard, Anal. Biochem. 107:220-39 (1980)).

The above experiment is repeated, this time in the presence of the sclerostin x fcMHCl antigen-binding protein construct. An ELISA is performed essentially as described herein except that the BMP concentration is held fixed at its KD (determined, for example, by BIAcore analysis). In addition, sclerostin x fcMHCl antigen-binding protein construct is added to the wells to a concentration of 1 μΜ. The antigen-binding protein construct is incubated for 2 hours at room temperature with the BMP and sclerostin, the solution is removed, and the bound BMP is quantified as described. It is observed that the antigen- binding protein construct inhibits 40% of the BMP binding observed in the absence of antibody, and is therefore considered an antagonist of this interaction. Sclerostin x fcMHCl antigen-binding protein construct is further evaluated as a potential inhibitor of the

The sclerostin x fcMHC 1 antigen-binding protein construct' s ability to interfere with sclerostin-mediated signaling by binding of sclerostin is tested using the cell assays described below. Other assays are known to the art and could be used as well, e.g., Li et al, J. Biol. Chem, 2005, 280(20): 19883-7, Thouverey and Caverzasio, Bonekey Rep., 2015, 4:757. Determining Effects of Sclerostin Protein on Human Mesenchymal Cells (hMSC or hMSC cells): hMSC cells are plated in 96-well tissue culture dishes at a density of 10,000 cells/cm2 in Osteoblast-Inducing medium. Partially purified preparations of baculovirus- expressed sclerostin protein are prepared in sterile PBS using NAP-5 columns prior to use, or purchased from the sources described herein. Human sclerostin protein (0 to 30 μg/ml) or an equal volume of Sf conditioned media (Control) is added to cultures of hMSC cells at various times after plating (1 day, 8 days, 15 days, or 21 days). The effects of sclerostin on osteoblastic differentiation are assessed by measuring alkaline phosphatase activity (ALP, determined in cell layers using DEAA buffer (Pierce) containing 0.5% NP-40 and 10 raM p- nitrophenylphosphate), synthesis of collagen type I (Prolagen C ELISA), and calcium deposition for mineralization (colorimetric assay of acid lysates of cell layers, Sigma). The experiment demonstrates that sclerostin decreases alkaline phosphatase activity, type 1 collagen synthesis, and mineralization in hMSC cells in a dose-dependent manner, whereas control treatment does not.

MHCl+/fcMHCl+ is assembled using methods known to the art and as described herein. To facilitate antibody uptake via nonspecific mechanisms such as, e.g., pinocytosis, cells are plated, washed three times with PBS, and incubated at 37 degrees C for 60 minutes in media at a pH of about pH opt uptake, and in a separate experiment at pH7.4, with added concentrations of 2 micrograms per milliliter with sclerostin x fcMHCl antigen-binding protein construct and a non-pH engineered antibody that also binds sclerostin, hereafter referred to as "non-pH sensitive sclerostin antibody." In a subset of cells, validation of antibody internalization and endosomal localization is performed using methods known to the art; e.g., cells are fixed in 4% formaldehyde as described above, permeabilized using TWEEN 20 or other methods known to the art

Following endosomal uptake validation and the second incubation, cells are divided into two groups, one of which is treated with buffered media at pH = 6.0, the other of which is treated with buffered media at pH = 7.4. Cells are incubated for 30 minutes, and the media from all cells is removed and analyzed for antibody concentration using ELISA or other methods known to the art and as described herein, e.g., Example 6. Upon analysis of the data, it is revealed that for cells treated with sclerostin x fcMHCl antigen-binding protein construct, the pH = 7.4 media contains significantly more antibody per unit volume than the pH = 6.0 media, and the ratio of media antibody concentration pH7.4/pH6.0 is greater as compared to cells treated with non-pH sensitive sclerostin antibody and its media antibody concentration pH7/4/pH6.0 ratio. Taken together, the data demonstrate that the sclerostin x fcMHCl antigen-binding protein construct' s pH-sensitiv e properties mediate enhanced release of the antibody from the target that it has bound at lower, endosomal pH, to the extracellular environment at pH = 7.4, i.e., enhanced endosomal recycling.

Generation ofbispecific sclerostin x fcMHCl antigen-binding protein construct drug conjugates

Recent evidence in the art suggests that sclerostin binding and activity may contribute to bone disease in cancer patients, and possibly bone metastases (e.g., Gkotzamanidou et al., Expert Opin. Ther. Targets., 2012, 16(8):761-9; Garcia-Fontana et al., Bone , Volume 50 , S181); therefore, therapeutic agents that combine the therapeutic properties of a sclerostin binding protein construct with the selective anti-tumor properties of an antibody drug conjugate or a cytotoxic or cytostatic drug are useful and desirable (e.g., a bispecific sclerostin x fcMHCl antigen-binding protein construct conjugated to a cytotoxic drug, e.g., MMAE, that is selectively liberated in cancer cells). An antigen-binding protein construct conjugate (ADC) is made comprising the bispecific sclerostin x fcMHCl antigen-binding protein construct described above linked to monomethyl auristatin E (MMAE) via a valine- citrulline (vc) linker (hereafter, sclerostin x fcMHCl -ADC). Conjugation of the antigen- binding protein construct with vcMMAE begins with a partial reduction of the sclerostin x fcMHCl bispecific antigen-binding protein construct followed by reaction with Val-Cit- MMAE (vcMMAE). The sclerostin x fcMHCl bispecific antigen-binding protein construct (20 mg/mL) is partially reduced by addition of TCEP (molar equivalents of TCEP:mAb is 2.1) followed by incubation at 0° C. ovemight. The reduction reaction is then warmed to 20° C. To conjugate all of the thiols, vcMMAE is added to a final vcMMAE:reduced Cys molar ratio of 1.15. The conjugation reaction is carried out in the presence of 10% v/v of DMSO and allowed to proceed at 20° C for 60 minutes.

The sclerostin x fcMHC l -ADC bispecific antigen-binding protein construct is purified using a batch purification method. The reaction mixture is treated with the appropriate amount of water washed Bu-HIC resin (ToyoPearl; Tosoh Biosciences), i.e., seven weights of resin is added to the mixture. The resin/reaction mixture is stirred for the appropriate time, and monitored by analytical hydrophobic interaction chromatography for removal of drug conjugate products, filtered through a coarse polypropylene filter, and washed by two bed volumes of a buffer (0.28 M sodium chloride, 7 mM potassium phosphate, pH 7). The combined filtrate and rinses are combined and analyzed for product profile by HIC HPLC The combined filtrate and rinses are buffer exchanged by

ultrafiltration/diafiltration (UF/DF) to 15 mM histidine, pH 6 with 10 diavolumes 15 nM histidine buffer. Demonstration of Increased Endosomal Recycling in MHC1 + cells

To demonstrate that the pH dependent binding properties of sclerostin x fcMHCl - ADCs leads to enhanced endosomal recycling following cellular uptake, an internalization assay is performed using methods known to the art (e.g., Mahmutefendic et al., Int. J. Biochem. Cell Bio. , 2011). Briefly, as above, a panel of human cells that present fcMHCl and/or MHC1 highly and that are also FcRn- is assembled using methods known to the art and/or described herein. To facilitate non-specific antibody uptake, cells are plated, washed three times with PBS, and incubated at 37 degrees C for 60 minutes in media at several different pHs between 6.0 and 7.4, with added concentrations of 2 micrograms per milliliter of sclerostin x fcMHCl -ADC as well as a non-pH sensitive sclerostin x fcMHCl -ADC made using a non-pH sensitive fcMHC, e.g., the non-pH-sensitive fcMHCl antigen-binding protein construct described herein (hereafter, non-pH sensitive sclerostin x fcMHCl -ADC).

Validation of antibody internalization and endosomal localization is performed using methods known to the art; e.g., cells are fixed in 4% formaldehyde as described above, permeabilized using TWEEN 20 or other methods known to the art

(https://www.ncbi.nlm.nih.gov/pubmed/20012820), additionally stained with an endosomal marker, e.g., a RAB5 antibody (Anti-Rab5 antibody - Abeam, abl 8211), stained with an appropriate set of fluorescently labeled secondary antibodies, and imaged using confocal fluorescence microscopy, as described above. Because the fcMHC antigen binding domains on the two sclerostin x fcMHCl -ADCs used herein differ in their binding properties as a function of pH, it is necessary to determine a pH at which their cellular uptake is the most comparable; the confocal imaging results are therefore quantitatively analyzed and the optimum pH at which uptake across constructs is the most comparable is determined (hereafter, OpH). If necessary, the doses of antibodies used are varied until approximately equal endosomal uptake is achieved when administered to cells at the OpH.

Having validated endosomal uptake and determined optimal dosing as well as OpH, in a separate experiment the first incubation is repeated, this time using the optimal doses at OpH, and after this first incubation, cells are divided into two groups, one of which is treated with buffered media at pH = 6.0, the other of which is treated with buffered media at pH = 7.4. Cells are incubated for 30 minutes, and the media from all cells is removed and analyzed for antibody concentration using ELISA or other methods known to the art and as described herein. Upon analysis of the data, it is revealed that for cells treated with pH-sensitive sclerostin x fcMHCl -ADC, the pH = 7.4 media contains significantly more antibody per unit volume than the pH = 6.0 media, and the media antibody concentration pH7.4/pH6.0 ratio, as compared to the media antibody concentration pH7.4/pH6.0 ratio for the non-pH sensitive sclerostin x fcMHCl -ADC, is greater. Taken together, the data demonstrate that the antibodies are taken up about equally well by both cells at OpH, but the sclerostin x fcMHCl -ADC's pH-sensitive properties mediate enhanced recycling of the antibody from the lower-pH environment of the endosomes to the more neutral extracellular environment, where pH is approximately 7.4.

Example 10: Cytotoxicity Assays and Testing of Differential Toxin Release for

Bispecific ABPC

To demonstrate that sclerostin x fcMHCl -ADC bispecific antigen-binding protein constructs are selectively cytotoxic to cancer cells but not normal cells, the cytotoxic activity of sclerostin x fcMHCl -ADC bispecific antigen-binding protein constructs is separately evaluated on a panel of fcMHCl - cells (intended to model tumor cells) and a cell panel that is fcMHCl+ (intended to model normal cells). For purposes of validation, prior to use, all cell lines are tested for expression of MHCl complex and/or fcMHCl complex, using one or more methods known to the art, e.g., qPCR, flow cytometry, mRNA RPKM, antibody- staining using a suitable antibody that binds MHCl complex and/or fcMHCl complex known (e.g., Abeam ab23755, W6/32) followed by visualization of the stain using fluorescence microscopy, immunohistochemistry, flow cytometry, ELISA, or other methods known to the art (e.g., other methods described herein). Cell lines are grouped on the basis of their fcMHCl and/or MHCl status. The tested cell lines include, e.g., CHO cells transfected with an HLA-A gene, an HLA-B gene, an HLA-C gene, a beta-2-microglobulin gene, or a combination thereof. To evaluate the cytotoxicity of compounds, cells are seeded at approximately 5-10,000 per well in 150 microliters of culture medium, then treated with graded doses of compounds in quadruplicates at the initiation of the assay. Cytotoxicity assays are carried out for 96 hours after addition of test compounds. Fifty microliters of resazurin dye are added to each well during the last 4 to 6 hours of the incubation to assess viable cells at the end of culture. Dye reduction is determined by fluorescence spectrometry using the excitation and emission wavelengths of 535 nm and 590 nm, respectively. For analysis, the extent of resazurin reduction by the treated cells is compared to that of untreated control cells, and percent cytotoxicity is determined. Upon analysis of the data, it is determined that sclerostin x fcMHCl -ADC bispecific antigen-binding protein constructs are substantially cytotoxic to MHCl- cells, but less toxic to MHC1+ cells.

To demonstrate that the increased endosomal recycling of sclerostin x fcMHCl -ADCs in cells that contain higher levels of MHCl and/or fcMHCl on their surface and/or in their cellular compartments results in decreased toxin liberation as compared to cells with lowers level of MHC1 and/or fcMHCl, the concentration of liberated toxin in both ty pes of cells is quantified using methods known to the art (e.g., Bessire et al. , Bioconjuage Chem., 2016, 27(7), 1645-1654; Erickson et al., Mol. Cancer Ther., 2012, 11(5).). As an example, tritiated mc-MMAF (hereafter, [³H]mc-MMAF) is prepared using methods known to the art, e.g., via reacting an MMAF ring precursor brominated at a phenylalanine ring with tritium gas. The tritiated product is conjugated to sclerostin x fcMHCl using methods described herein or others known to the art, thereby creating sclerostin x fcMHC l-[³H]mc-MMAF-ADCs. The sclerostin x fcMHCl-[³H]mc-MMAF-ADCs are incubated with human liver S9 fraction, which contains a high concentration of lytic lysosomal enzymes, and time point samples are collected. The samples are diluted 1 : 1 with 20 mM TCEP and analysed via LC/MS/MS using methods known to the art (Bessire et al , Bioconjuage Chem., 2016, 27(7), 1645-1654), thereby creating a standard set of identifiable lysosomal degradation products for sclerostin x fcMHCl-[³H]mc-MMAF-ADCs (i.e., a positive control for when toxin liberation has occurred). To compare toxin liberation between MHC1- and MHC1+ cells, cell lines of both types, identified using methods described herein, are plated in culture flasks and grown to a density of approximately 10⁷ cells per flask. To facilitate antibody uptake of the sclerostin x fcMHCl-[³H]mc-MMAF-ADCs) via nonspecific mechanisms such as, e.g., pinocytosis, cells are plated, washed three times with PBS, and incubated at 37 degrees C for 60 minutes in media at a OpH, and in a separate experiment at pH7.4, with added concentrations of 2 micrograms per milliliter of sclerostin x fcMHCl-[ H]mc-MMAF-ADCs. Cells are then further incubated for various periods of time (e.g., 2-24 hours) to allow for antibody catabolism. Following this final incubation, cells are washed, harvested, lysed, and analyzed using LC/MS/MS using methods similar or identical to those descried above. Upon analysis of the data, it is revealed that the mass spectra of MHC1- cell extracts display an abundance of peaks corresponding to the sclerostin x fcMHCl-[³H] mc-MMAF- ADCs lysosomal degradation products described above, whereas the same peaks are absent or significantly reduced in size (when analyzed using an identical protocol) for MHC1+ cells. Taken together, the data demonstrate that sclerostin x fcMHCl -ADCs are subject to decreased toxin liberation in cells that contain higher levels of MHC1 and/or fcMHCl on their surface or cellular compartments.

To demonstrate that the cytotoxi city-blocking effects of sclerostin x fcMHCl -ADC bispecific antigen-binding protein constructs are attenuated when the antibody is blocked from engagement of endogenous endosomal fcMHCl complexes, a binding competition assay is performed in a cell culture system similar to that described above, e.g., a fcMHCl+ cell line, treated with sclerostin x fcMHC l -ADC bispecific antigen-binding protein constructs. Concentrations from 1 pg/mL to lOOmg/mL of a competitive ligand (e.g., recombinant extracellular domain of fcMHCl complex or a competitive peptide or other reagent that binds to the paratope for MHCl complex collectively, known hereafter as fcMHCl Recombinant Reagent) are added to the cultures of MHC l - cell lines used in the experiment described above, to be taken up via non-specific endocytosis mechanisms (e.g., pinocytosis), either independently or as part of a bound antibody complex. The cytotoxicity assay described above is repeated, and it is observed that the cell death of fcMHCl+ cell lines is increased in a dose-dependent manner in the presence of the MHC 1 Recombinant Reagent due to competitive blocking of the interaction of sclerostin x fcMHCl -ADC with fcMHCl in endosomes.

Example 11. Generation of fully conformed MHCl (fcMHCl)-specific antigen-binding domains and engineering of pH binding dependence

Please note that CDR sequences referenced in these examples 11, 12, and 13 are all Kabat (Kabat et al. (1992) Sequences of Proteins of ^'Immunological Interest (DIANE publishing)), except for some CDRH1 sequences, which are extended from the Kabat CDRH1 (SEQ ID NOs: 445, 454, 458, 462, 466, 477, 480, 483, 486, 477, 483, 486, 497, 500, 503, 506, 509, 517, 520, 523, 526, and 529). Please also note that all heavy and light chain as well as CDR sequences of all constructs referenced in these examples 11, 12, and 13 are listed in tabular format in FIGURE 23.

Antigen-binding domains against fcMHCl with enhanced recycling to the cell surface versus binding proteins specific to nfcMHCl were generated using two methods. In the first approach, published monoclonal antibodies against monomorphic epitopes of fcMHCl were used as a starting template for introduction of additional mutations that allow engineering of pH-dependent binding to MHCl and recycling to the cell surface via the endosome. The second approach involved discovery of de novo fcMHCl binding proteins via antibody phage display methods from libraries with defined CDR compositions and screening under conditions designed for selection of pH-dependent binding proteins. In either case, histidine residues played an important role in engineering these pH dependent binding proteins.

Histidine residues are at least partially protonated at a pH below 6.5 owing to its pKa of 6.0. Therefore, if a histidine side chain in an antigen-binding domain participates in an electrostatic binding interaction with its antigen, it will start to turn positively charged at a pH at or below 6.5. This could either weaken or enhance the binding affinity of the interaction at a pH below 6.5, based on the corresponding charge of and interactions with the antigen epitope. Thus, systematic introduction of histi dines into antibody complementarity determining regions (CDRs) in an antibody or other antigen-binding domain library (e.g., a VH library) can be used to identify substitutions that will affect an antigen-binding domain's interaction with an antigen at lower pH values. The first approach therefore involved histidine-scanning of variable region sequences of the published monoclonal antibody W6/32 to identify pH dependent variants.

Multiple monomorphic MHC1 binding monoclonal antibodies, including W6/32, have been described in the literature and can be used as a template for engineering pH-dependent binding (Brodsky, F. M. & Parham, P. (1982) J Immunol. 128, 129-135; Parham et al. (1982) J. Immunol. Methods 53, 133-173). Briefly, for a subset of the antibody sequences, CDRs in each chain were identified using the methods described in the art (e.g., Kabat et al. (1992) Sequences of Proteins of Immunological Interest (DIANE publishing); Lefranc et al. (1999) Nucleic Acids Research 27, 209-212). The HI, H2, H3, LI, L2, and L3 CDRs of W6/32 are provided in SEQ ID NOs: 445, 446, 447, 448, 449, and 450, respectively (Congy- Jolivet, N. (2013) J. Immunol.Methods . 390, 41-51). The amino acid sequences of the heavy and light chains of epitope-tagged W6/32 Fab fragment are provided in SEQ ID NO: 451 and SEQ ID NO: 452, respectively. To generate pH-sensitive heavy chain sequence variants, individual amino acid residues within the heavy chain CDRs of epitope-tagged W6/32 Fab fragment were systematically substituted with a histidine, one at a time. In total, 39 epitope- tagged W6/32 Fab fragment variants were generated in this manner. Epitope-tagged W6/32 Fab fragment variants with only one histidine mutation in a heavy chain CDR were generated by co-transfection of Expi293 cells with a) one heavy chain sequence variant, and b) the corresponding light chain, using methods known to the art. As a control, a non-variant, epitope-tagged W6/32 Fab fragment was also generated in the same experiment. After allowing for a period of protein expression, cell culture supernatants were collected, assayed for purity and the relative level of Fab expression using SDS-PAGE using methods known to the art (FIGURE 1). Next, the pH dependence of the epitope-tagged W6/32 Fab fragment and its variants were evaluated by staining of HeLa cells followed by flow cytometry.

Briefly, HeLa cells (ATCC Cat # CCL-2) (passage number less than 25) were harvested and 100,000 cells per well were plated in a U-Bottom 96-well microplate. The cells were washed twice with 200 μΐ, of FACS buffer (lxPBS containing 3% Fetal Bovine Serum) at either pH 5.8 or 7.4 depending on the condition being tested. All further wash and incubation steps were performed at the same pH. Cell culture supernatants were diluted 1 :4 in FACS buffer of the appropriate pH and the final pH was adjusted to pH 5.8 or pH 7.4 depending on the sample. Supernatants were incubated with cells for 1 hour on ice, plates were washed twice, and then incubated with an anti-myc tag mouse secondary mAb conjugated to Alexa Fluor 488 (Cell Signaling Technologies 2279S) for 30 minutes. The plates were washed twice as before, resuspended in FACS buffer of the appropriate pH, and then read on a flow cytometer (Accuri C6, BD Biosciences). Binding was observed as a shift in the FL1 signal versus secondary antibody only control (anti-myc tag secondary antibody, Clone 9B11, Cell Signaling Technology). As shown in FIGURE 2, at least two variants MYT0080 and MYT0094 show pH-dependent binding with stronger binding (i.e., higher mean fluorescence intensity , hereafter referred to as MFI) at pH 5.8 and low or no binding (relatively low MFI) at pH 7.4. Two additional variants, MYT0075 and MYT0098 were also selected for further analysis. As a control, W6/32 Fab (MYT0064) was also tested in this assay and was not found to be pH dependent. This confirmed that both the W6/32 Fab and the secondary antibody used do not exhibit pH-dependent binding and that pH-dependent binding is only introduced via histidine substitution in a CDR. Four epitope-tagged W6/32 Fab fragment variants (MYT0075, MYT0080, MYT0094, and MYT0098), whose heavy chains, and CDRs HI, H2, H3 as in SEQ ID NO: 453-468, and whose light chains and CDRs LI, L2 and L3 as in SEQ ID NO: 452 and SEQ ID NO: 448-450, were selected as candidates for further analysis based on the criteria defined above (hereafter referred to as "pH-engineered antigen- binding domain variants"). To confirm that the broad reactivity of W6/32 for HLA-A, HLA- B, and HLA-C alleles was retained in the epitope-tagged W6/32 Fab fragment variants, we measured the pH-dependent binding of several epitope-tagged W6/32 Fab fragment variants to recombinantly expressed HLA-C antigens at pH 5.8. Briefly, cell culture supernatants of candidate Fab constructs were diluted 1 :4 in FACS buffer (PBS containing 3% Fetal Bovine Serum) pH 5.8 and the final pH was adjusted to pH 5.8. 100 μΐ of the prepared cell culture supernatants was mixed with 5 of the FlowPRA Single Antigen HLA-C beads (One Lambda, FL1HD09 , including HLA-C*01:02, HLA-C*02:02, HLA-C*03:02, HLA-

C*04:01, HLA-C*05:01, HLA-C*06:02 and HLA-C*07;02 antigens) and incubated for 30 min at RT. Beads were washed twice via centrifugation at 9,000xg for 2 minutes and resuspended in 1 mL of FACS buffer pH 5.8. ΙΟΟμί_^ of anti myc-tag mouse mAb-Alexa Fluor 488 (Cell Signaling Technologies, Cat # 2279S) diluted 1 :50 in FACS buffer pH 5.8 was added and the beads were further incubated for 30 minutes. Beads were washed twice, resuspended in ΙΟΟμί FACS buffer pH 5.8, and then read on a flow cytometer (Accuri C6, BD Biosciences). Binding was observed as a shift in the FL1 signal versus secondary antibody only control (anti-myc tag secondary antibody, Clone 9B11, Cell Signaling Technology). W6/32 Fab (MYT0064) and the anti-myc secondary only were included as controls. As shown in FIGURE 3, in addition to the positive control (MYT0064) MYT0080 and MYT0094 show binding to all tested HLA-C alleles above the negative control

(secondary only). This cell binding and recombinant HLA-C data shows that both pH engineered W6/32 Fab fragment variants, MYT0080 and MYT0094, bind HLA-C. This data also suggests that several epitope-tagged W6/32 Fab fragment variants are expected to retain the broad reactivity of W6/32 for multiple HLA alleles and classes (i.e., HLA-A, HLA-B, and HLA-C).

The second method for selection of pH-dependent antigen-binding domains involved screening libraries to identify both de novo pH dependent fcMHCl antigen-binding domains and antigen-binding domains that could serve as templates for engineering pH dependent binding as described above. A VH phage display antibody library where CDRs were constructed to express a subset of amino acid residues, including histidine, was constructed and used for screening using methods known in the art (Igawa T. (2014) Biochim Biophys Acta 1844 (11): 1943-1950; Adams J. (2014) Curr Opm Struct Biol 24 : 1-9; Lerner R.

(2016) Nat Rev Immunol 16(8): 498-508; Miersch S. (2012) Methods 57 (4): 486-98)). This librar was screened against soluble recombinant fcMHCl domains using methods known to the art with positive selection for variants that bind weakly at pH 7.4 compared to pH 5.8; three rounds of selections were performed (hereafter referred to as a "pH-dependent pH 5.8- enhancing phage panning"). Each round of selection involved generating phage, binding to soluble recombinant fcMHCl domains on beads in a physiologically acceptable buffer at pH 5.8, eluting and then collecting the bound phage in a physiologically acceptable buffer at pH 7.4 ("koff selection"), and, optionally, binding to soluble recombinant fcMHCl domains on beads in a physiologically acceptable buffer at pH 7.4 and collecting the unbound supernatant ("kon selection"). Soluble recombinant fcMHC l domains were generated as Fc fusions. The amino acid sequences for a HLA-A monovalent fcMHCl polypeptide with human Fc domain (MYT0002), a HLA-B monovalent fcMHCl polypeptide with human Fc domain

(MYT0003), and a HLA-A bivalent fcMHCl polypeptide with mouse Fc domain (MYT0051) are provided in SEQ ID NO: 469-472. These soluble recombinant fcMHCl domains were generated by co-transfection of mammalian cells with a) one Fc-fcMHCl fusion gene and b) for the human Fc versions only, one Fc fragment gene, using methods known in the art. After allowing for a period of protein expression, cell culture supernatants were collected, purified by Protein A and cation exchange chromatography using methods known in the art, quantified for yield, assayed for purity using SDS-PAGE and size exclusion chromatography using methods known in the art (FIGURE 4), and validated for binding to fcMHCl antibodies BB7.1 (anti-HLA-B7 specific antibody, Biolegend, Cat# 372402), BB7.2 (anti-HLA-A2 specific antibody, Biolegend, Cat# 343302), and BBM. l (anti-beta2m specific antibody, Thermo Fisher Scientific, Cat# MAI -26040) using biolayer interferometry via Octet (FIGURE 5). Briefly, 50 nM of purified MYT0002 or MYT0003 in PBST (PBS + 0.05% Tween-20) pH 7.4 was immobilized on anti -human Fc biosensors (Forte Bio, Cat #18- 5060) and tested with 50 nM of BB7.1, BB7.2, or BBM.l antibodies in PBST pH 7.4. The binding response is shown in FIGURE 5. MYT0002 shows binding to BB7.2 and BBM.1, while MYT0003 shows binding to BB7.1 and BBM.1. To validate the successful expression and well-behaved biophysical state of the soluble recombinant fcMHCl domain-Fc fusions, purified proteins were also characterized using size-exclusion chromatography using methods known in the art (FIGURE 4). Because these antigens were well-expressed, at high purity, and validated to bind known fcMHCl antibodies in Octet, we concluded that they were a valid substrate for selection and validation of pH-dependent fcMHCl antigen-binding domains specific to HLA-A and HLA-B alleles, respectively.

Using methods known in the art, a first pH-dependent pH 5.8-enhancing phage panning for pH-dependent fcMHCl antigen-binding domains was performed using

MYT0002 (HLA-A monovalent fcMHCl polypeptide with human Fc domain) as the soluble recombinant fcMHCl domain, utilizing a k_on selection step and then a k₀ff selection step as described herein. At least four VH antigen-binding domains were discovered to be enriched during the screen. The protein sequences of these four VH antigen-binding domains, TAM0039, TAM0121, TAM0146, and TAM0165, are provided in SEQ ID NO:473-476 and their CDRs in SEQ ID NO: 477-488. Phage ELISA was performed for the antigen-binding domains to test their pH-dependent binding to MYT0002 and demonstrated strongly pH- dependent binding for all four antigen-binding domains (FIGURE 6). Briefly, 50 μίΛ βΙΙ of biotinylated MYT0002 and human Fc were immobilized on a streptavidin precoated 96 well plate (Maxisorp, Thermo Scientific) for 1 hour and blocked with 300 μΕ/well of 5% nonfat dry milk in PBS for 1-2 hours at RT. After washing three times with either PBS pH 5.8 or pH 7.4, 50 μΐ of punfied phage particles expressing TAM0039, TAM0121, TAM0146, and TAMO 165 at pH 5.8 were incubated with MYT0002, human Fc, or streptavidin at pH 5.8 for 1 hour at RT. 50 μΐ of the samples above were also incubated with MYT0002 at pH 7.4 for 1 hour at RT. The plate was washed three times with either PBS pH 5.8 or pH 7.4 and secondary incubation with 50 μΐ, of an anti-M13-HRP phage detection antibody (Sino Biological, Cat #119 3-MM05T-H) in 3% milk PBS pH 5.8 or pH 7.4 was performed. The plate was developed using 50 μ]_, of TMB per well (Thermo Fisher Scientific, Cat# 34028) after performing three final washes with PBS at either pH 5.8 or 7.4. The reaction was stopped using 50 ΐ, of 2N sulfuric acid and OD450 was measured using SpectraMax M2 plate reader (Molecular Devices). The raw OD450 values at pH 5.8 and pH 7.4 are shown in FIGURE 6. Subsequently, soluble TAM0039, TAM0146, and TAM0165 VH domains were generated by transformation of ss320 E. coli cells (Lucigen, Cat # 60512) using methods known in the art. Transformed cells were grown to logarithmic phase and induced with IPTG using methods known to the art. After allowing for a period of protein expression.

periplasmic extracts were collected, purified by Ni-NTA affinity chromatography using methods known in the art, quantified for yield, and validated for pH-dependent binding to MYT0002 (HLA-A monovalent fcMHCl polypeptide with human Fc domain), MYT0003 (HLA-B monovalent fcMHCl polypeptide with human Fc domain), and human Fc domain control using Octet. Briefly, 50 nM MYT0002, MYT0003, or human Fc was immobilized on an anti-human Fc sensor (Forte Bio, Cat# 18-5060) for 120 sec. Sensors were incubated in PBS, pH 5.8 or 7.4 for 120 sec to establish a baseline. The association step consisted of a 300 sec incubation with 50 μg/mL of purified TAM0039, TAM0146, or TAM0165 VH domains for 300 sec followed by dissociation in the same buffer for 600 or 300 sec. Binding responses for each construct at both pH values are shown in FIGURE 7A (MYT0002) and Figure 7B (MYT0003). All antigen-binding domains were well expressed, but surprisingly, only TAMO 146 and TAMO 165 showed clear pH-dependent binding to MYT0002 using Octet. None of the antigen-binding domains showed strong binding to MYT0003, revealing low to no cross-reactivity to this HLA-B fcMHCl domain.

Next, three of the VH domains (TAM0039, TAM0146, and TAM0165), were converted to bivalent human VH-Fc fusion format (MYT0061, MYT0062, and MYT0063, respectively). The protein sequences of MYT0061, MYT0062, and MYT0063 are provided in SEQ ID NO:489-491 and their CDRs in SEQ ID NO: 477-479 and 483-488. MYT0061, MYT0062, and MYT0063 were generated by transfection of Expi293 cells with a plasmid encoding the fusion of the corresponding VH domain with human IgGl-Fc using methods known to the art. After allowing for a period of protein expression, cell culture supernatants were collected, purified by protein A chromatography using methods known in the art, quantified for yield, assayed for purity using SDS-PAGE using methods known in the art (FIGURE 8A), and validated for pH-dependent binding to MYT0051 using Octet (FIGURE 8B). Briefly, 50 nM MYT0061, MYT0062, or MYT0063 was immobilized on an anti-human Fc sensor (Forte Bio, Cat# 18-5060) for 120 sec. Sensors were incubated in PBS 5.8 or 7.4 for 120 sec to establish a baseline. The association step consisted of a 300 sec incubation with 50 nM of MYT0051 at either pH 5.8 or pH 7.4 for 300 sec followed by dissociation in the same buffer for 300 sec . Binding responses for each construct at both pH values are shown in FIGURE 8B. All three VH-Fc fusions were well expressed, at high purity, and showed pH- dependent binding to MYT0051 with stronger binding at pH 5.8 and no binding at pH 7.4. In combination with the earlier phage ELISA and Octet data, this demonstrated that TAM0039, TAMO 146, and TAMO 165 VH domains retain pH-sensitive binding to fcMHCl across multiple formats (e.g., as isolated VH domains and as VH-Fc fusions).

Next, we tested whether our VH-Fc fusions were specific for fcMHCl domains over nfcMHCl domains. HC-10 and HCA2 are antibodies known in the art to be specific for nfcMHCl domains, whereas W6/32 is known to the art to be specific for fcMHCl, and fcMHCl on the surface of cells can be transformed into nfcMHCl by removal of its beta 2- microglobulin subunit using an acid treatment on cells (e.g. Perosa, F. et al. (2003) J.

Immunol. 171, 1918-1926; Seitz, C. et al. (1998) Mol. Immunol. 35, 819-827; Chandran, P. A. et al. (2017) Front. Immunol. 8, 96; Stam, N. J. et al. (1990) Int. Immunol. 2, 113-125; Parham, P. et al. (1979) J. Immunol. 123, 342-349). We tested the specificity of MYT0061, MYT0062, and MYT0063 for fcMHC 1 over nfcMHC 1 by quantitative staining of live cells before (fcMHCl +) and after (fcMHCl - nfcMHC l +) an acid treatment followed by flow cytometry, using HC-10 (Origene, Cat#: AM33035PU-N), HCA2 (Ongene, Cat #:

AM33034PU-N) as controls for nfcMHCl -specific antibodies, and W6/32 (Biolegend, Cat # 311402) as a control for a fcMHCl -specific antibody. A human isotype control antibody was also used as a control (BioXcell, Cat # BE0297). Briefly, l.OxlO⁵ THP-1 (ATCC Cat # ΤΓΒ- 202), H526 (ATCC Cat # CRL-5811), and H1693 (ATCC Cat # CRL-5887) cells were added to a 96-well plate. Cells were washed in FACS buffer and resuspended in either PBS pH 2.7 or pH 5.8 for 1 mm followed by a wash with assay buffer (PBS with 2% FBS pH 5.8). All samples were resuspended in assay buffer plus anti-HLA constructs or control antibodies (clones HC-10, HCA2, W6 32, and human isotype control) followed by incubation at 4° C for 45 min. Cells were washed with assay buffer and then stained with rat anti-human Fc- Alexa Fluor 488 (clone M1310G05, Biolegend) at 4° C for 45 min. Samples were washed in assay buffer, fixed in 1% PFA and read using a flow cytometer (Accuri C6, BD Biosciences). The data is shown in FIGURE 9. All three anti-HLA constructs (MYT0061, MYT0062, and MYT0063) show reduced binding to acid treated cells, HC-10 and HCA2 showed increased binding to acid treated cells with low pre-existing (i.e., on non-acid-treated cells) levels of nfcMHCl (e.g., H1693 and H526) consistent with their known specificity for nfcMHCl, and W6/32 showed decreased binding to acid-treated cells consistent with its known specificity for fcMHCl. This demonstrated that MYT0061, MYT0062, and MYT0063 were all specific for fcMHCl over nfcMHCl. Positive staining of H1693 cells with MYT0061, MYT0062, and MYT0063 before an acid strip also demonstrated that MYT0061, MYT0062, and MYT0063 were cross-reactive with another HLA allele besides HLA-A*02:01 (e.g., MYT0002), because the HLA genotype of H1693 cells was HLA-A*03:01 homozygous, HLA-B*44:02/HLA-B*07:02, HLA-C*07:04 homozygous, and H1693 cells are HLA- A*02:01- (TRON Cell Line Portal, http://celllines.tron-mainz.de/ accessed Oct 7, 2018), and therefore the epitopes of MYT0061, MYT0062, and MYT0063 were at least partially monomorphic.

A second pH-dependent pH 5.8-enhancing phage panning for pH-dependent fcMHC 1 antigen-binding domains was performed using MYT0002 (HLA-A monovalent fcMHCl polypeptide with human Fc domain) as the soluble recombinant fcMHCl domain, utilizing only a koff selection step as described herein. At least five antigen-binding domains were discovered to be enriched during the screen. The protein sequences of these antigen-binding domains (TAM0389, TAM0400, TAM0401, TAM0424, and TAM0461) are provided in SEQ ID NO:492-496 and their CDRs in SEQ ID NO:497-511. Phage ELISA was performed for the antigen-binding domains to test their pH-dependent binding to MYT0002 and demonstrated strongly pH-dependent binding with low or no cross-reactivity to streptavidin or Fc domain for 3 out of 5 antigen-binding domains (FIGURE 10). Briefly, 50 μίΛνβΙΙ of biotinvlated MYT0002 and human Fc were immobilized on a streptavidin pre-coated 96 well plate (Maxisorp, Thermo Scientific) for 1 hour and blocked with 300 ίΛνβΙΙ of 5% nonfat dry milk in PBS for 1-2 hours at RT. After washing three times with either PBS at pH 5.8 or pH 7.4, 50 of phage supernatant from individual clones normalized to pH 5.8 or pH 7.4 was incubated with MYT0002, human Fc, and streptavidin to test pH-dependent binding. The plate was washed three times with either PBS at pH 5.8 or pH 7.4 and secondary incubation with 50 of an anti-M13-HRP phage detection antibody (Sino Biological, Cat #11973- MM05T-H) in 3% milk PBS at pH 5.8 or pH 7.4 was performed. The plate was developed using 50 of TMB per well (Thermo Fisher Scientific, Cat# 34028) after performing three final washes with PBS at either pH 5.8 or 7.4. The reaction was stopped using 50 μΐ of 2N sulfuric acid and OD450 was measured using SpectraMax M2 plate reader (Molecular Devices). The raw OD450 values at pH 5.8 and pH 7.4 are shown in FIGURE 10. We also noticed that TAM0039, TAM0121, and TAM0165 were enriched in the panning, which validated the reproducibility of our panning protocols to generate HLA-A specific pH- dependent antigen-binding domains against MYT0002.

A third pH-dependent pH 5.8-enhancing phage panning for pH-dependent fcMHCl antigen-binding domains was performed using MYT0003 (HLA-B monovalent fcMHCl polypeptide with human Fc domain) as the soluble recombinant fcMHCl domain, utilizing only a k₀ff selection step as described herein. At least five antigen-binding domains were discovered to be enriched during the screen. The protein sequences of these five antigen- binding domains (TAM0570, TAM0623, TAM0672, TAM0692 and TAM0728) are provided in SEQ ID NO:512-516 and their CDRs in SEQ ID NO:517-531. Phage ELISA was performed for the antigen-binding domains to test their pH-dependent binding to MYT0003 and demonstrated strongly pH-dependent binding with low or no cross-reactivity to streptavidin or Fc domain for 4 out of 5 antigen-binding domains (FIGURE 11). Briefly, a clear flat-bottomed Nunc Maxisorp plate was coated overnight with 100 of 5 μg/mL of Streptavidin (Pierce Streptavidin 21122) in lx PBS pH 7.4 at 4°C. The next morning the plates were washed twice with lx PBS pH 7.4 and coated with either 100 μί of ^g/mL biotinylated MYT0003 or 100 μΐ, of ^g/mL biotinylated human-Fc for 30 minutes at room temperature. The plates were washed twice with lx PBS pH 7.4 and then blocked for 1 hour at room temperature with 3% non-fat dry milk in lxPBS pH 7.4. Following blocking, then plates were washed twice and the wash buffer was kept at either lx PBS pH 5.8 or 7.4, depending on the binding condition being tested. Phage supernatant was adjusted to pH 5.8 or 7.4 and 100 μ]_, was added to the appropriate plates (biotinylated MYT0003, biotinylated h- Fc, streptavidin only) and incubated at room temperature for one hour. The plates were washed three times and then secondary anti-M13 HRP conjugate was added (Sino Biological 11973-MM05T-H) and incubated at room temperature protected from light for one hour. The plates were washed three times and 100 μί of TMB (Thermo Scientific 34028) was added and allowed to develop at room temperature. The reaction was stopped using 100 μΐ_^ of 2N sulfuric Acid and the OD450 was measured. Binding was measured as fold over background as shown in FIGURE 11. This successful panning validated the repeatability of our panning protocols to generate pH-dependent antigen-binding domains against arbitrary fcMHCl classes (e.g. HLA-B in addition to HLA-A).

Example 12. In vitro demonstration of enhanced antibody recycling mediated by interaction with fcMHCl, and enhanced antibody retention by fcMHC- cells

As discussed herein, non-pH-sensitive fcMHCl antigen-binding domains (e.g.,

W6/32) exhibited internalization and recycling back to the cell surface. Also as discussed herein, pH-sensitive fcMHCl antigen-binding domain variants exhibited the desirable property of poor MHC1 binding at neutral pH (e.g., pH 7.4), but enhanced binding at lower pH (e.g., pH 5.8). Because of this pH-sensitive binding property, and the recycling of non- pH-sensitive fcMHCl antigen-binding domains demonstrated herein, and the low pH of the endolysosomal system which is known to the art (Huotari J. and Helenius A. (2011) EMBO J. 30, 3481-3500), pH-sensitive fcMHC l antigen-binding domain variants a) were prevented from widespread binding to MHC1 on the cell surface at pH 7.4, and b) showed enhanced release from fcMHCl found on the surface cells at pH 7.4 after binding to fcMHC at a lower pH, such as, for example, after being recycled back to the cell surface from the acidic environment of the endolysosomal system, and c) are expected to show enhanced

internalization and recycling from the endolysosomal system under physiological conditions. Because of these demonstrated and expected properties, it is expected that pH-sensitive fcMHCl antigen-binding domain variants will have improved pharmacokinetic properties in vivo (e.g., extend their half life).

A panel of fcMHCl+ human cells (NK cells from primary human PBMCs and HeLa cells), and fcMHCl- (NCI-H82, ATCC Cat # HTB-175) and NCI-H69 cells, ATCC Cat # HTB-119) was assembled. The HLA genotype of the NK cells from primary human PBMCs was not tested. The HLA genotype of HeLa cells was HLA-A* 68: 02 homozygous, HLA- B*15:03/HLA-B* 15, HLA-C* 12:03 homozygous; the HLA genotype of NCI-H82 cells was HLA-A*01 :01/HLA-A*02, HLA-B*08:01/HLA-B*44: 18, HLA-C*07/Unknown; and the HLA genotype of NCI-H69 cells was HLA-A*23:01/HLA-A*02, HLA-B*58:05/HLA-B*42, HLA-C*14:02/HLA-C*07 (TRON Cell Line Portal, http://celllines.tron-mainz.de/ accessed Oct 7, 2018). fcMHCl expression and MYT0061, MYT0062, and MYT0063 cross-reactivity to the fcMHCl alleles present on these cells was confirmed in this panel of cell lines by quantitative staining of live cells followed by flow cytometry at pH 5.8. Briefly, cells were seeded in a 96-well plate at 5.0 x 10⁵ cells/well in pH 5.8 staining buffer (PBS 2% FBS). Constructs were labeled with PE (Buccuite™ Rapid PE Antibody Labeling Kit, AAT

Bioquest) and added at 500 nM and incubated at 4° C for 45 min. In separate wells, Quantum Simply Cellular anti-Mouse IgG beads (Bangs Laboratories) were incubated with constructs or anti-HLA-PE (clone W6/32, Biolegend) at 4°C for 45 min. PBMCs were isolated from buffy coat (Research Blood Components) by density gradient centrifugation followed by RBC lysis (Ammonium Chloride, StemCell Technologies). Primary NK cells were identified from PBMC by NKp46+ (Biolegend, 331938) CD3- (Biolegend, 317344) CD14- (Biolegend, 325628) CD19- (Biolegend, 363018) HLA-DR- (Biolegend, 307636) antibody staining. All samples were read by flow cytometry (BD LSRII, BD Biosciences). The results of this experiment are shown in FIGURE 12. Because this experiment was quantitative as to the number of molecules bound, and because W6/32 is known to the art to bind to a

monomorphic epitope (Hilton, H. G. and Parham P. (2013) Tissue Antigens 81, 212-220), we could conclude that the MYT0061, MYT0062, and MYT0063 constructs consistently bound approximately 50-100% of the fcMHCl expressed on fcMHCl + HeLa and NK cells as determined by quantitative assessment of W6/32 binding, and that NCI-H82 and NCI-H69 cells were functionally fcMHCl-, with very low levels, if any, of fcMHCl expressed as detected by W6/32, MYT0061, MYT0062, and MYT0063. This quantitative staining pattern of MYT0061, MYT0062, and MYT0063 having approximately 50-100% of the MFI level as compared to W6/32 across multiple cell lines also suggested that MYT0061, MYT0062, and MYT0063 were highly specific for fcMHCl, as detected by W6/32. Furthermore, the positive and quantitative 50-100% staining of fcMHCl of MYT0061, MYT0062, and

MYT0063 as compared to W6/32 on HeLa cells, which do not encode for a HLA-A*02 allele in their genome, was further evidence that MYT0061, MYT0062, and MYT0063 were cross- reactive with another HLA allele besides HLA-A*02:01 (i.e. MYT0002), and therefore, their epitope is at least partially monomorphic. As a control, we also ran an experiment to confirm the non-pH-dependence of W6/32. Briefly, 1.0xl0E5 HeLa cells were seeded in a 96 well plate in FACS buffer (PBS FBS 2%) at either pH 5.8 or 7.4. W6/32 was serially diluted in FACS buffer at either pH 5.8 or 7.4 from 600 nM down to 80 pM final concentration. Cells and antibody were incubated at 4°C for 2 hours followed by a wash with sample's respective pH FACS buffer and then 1% PFA fixation. Samples were read by flow cytometry (Accuri C6, BD Biosciences). The dose response curve of W6/32 at pH 5.8 and pH 7.4 is shown in FIGURE 13. This experiment showed that W6/32 bound cells with the approximately the same Kd at pH 5.8 and pH 7.4. An isotype control was used to confirm that binding represented specific binding of the antibodies to fcMHCl and not FcRn or other Fc receptors via the Fc domain.

To demonstrate that the pH-sensitive fcMHCl antigen-binding VH domains bind cell surface fcMHCl in a pH-selective manner and poorly at neutral pH, a cell surface binding assay utilizing quantitative staining of live cells followed by flow cytometry was performed at pH 7.4, and pH 5.8 as a control. Briefly, HeLa or THP-1 cells were seeded in a 96-well plate at l .OxlO⁵ cells/well followed by wash and resuspension in either pH 7.4 or pH 5.8 assay buffer (PBS 2% FBS). Constructs or an IgGl isotype control were added to cells at 500 nM and incubated at 4°C for 45 min. All conditions were washed and resuspended in their respective assay buffer followed by 1:50 secondary antibody (rat anti -human Fc-AF488, Biolegend) for 45 min at 4° C. All conditions were washed and resuspended in their respective assay buffer and read by flow cytometry (Accuri C6, BD Biosciences). The results are shown in FIGURE 14. In contrast to the pH sensitivity we observed, W6/32 was shown to be a non-pH-sensitive fcMHCl antibody with appreciable binding of cell surface fcMHCl at pH 7.4 (FIGURE 13), as discussed previously. This result demonstrated that W6/32 binds appreciably to cell surface fcMHCl at pH 7.4 and that its binding is not pH-sensitive. Taken together with the results in FIGURE 8B, the results from FIGURE 14 showed that the pH- dependent pH 5.8-enhancing phage panning: a) rendered the pH-sensitive fcMHCl antigen- binding VH domains contained in MYT0061, MYT0062, and MYT0063 to be cross-reactive to multiple alleles of fcMHCl (because HeLa is HLA-A*02-, whereas THP-1 is HLA- A* 02+), and b) rendered the pH-sensitive fcMHCl antigen-binding VH domains contained in MYT0061, MYT0062, and MYT0063 to be pH-sensitive in their binding to multiple alleles of fcMHCl (because HeLa is HLA-A*02-, whereas THP-1 is HLA-A*02+). The results additionally demonstrate: a) that those pH-sensitive fcMHCl antigen-binding VH domains contained in MYT0061, MYT0062, and MYT0063 were only capable of significant binding at lower pH and not at neutral pH (e.g., pH 5.8 and 7.4, respectively), and b) that their binding properties improved as the pH became lower. This is important because fcMHCl is known to the art to be widely expressed in the body (e.g. Daar, A. S. et al. (1984)

Transplantation 38, 287-92), and it is also known to the art that the interstitial fluid of most tissues is at neutral pH (e.g. Burton, R. F. (2001) Physiological and Biochemical Zoology: Ecological and Evolutionary Approaches 74, 607-615). Therefore, the lack of significant binding at neutral pH of MYT0061, MYT0062, and MYT0063 as compared to W6/32 suggested that MYT0061, MYT0062, and MYT0063 are expected to have significantly improved pharmacokinetics (e.g., longer half life) in animals as compared to non-pH- sensitive antigen-binding domains, such as W6/32, due to less binding of fcMHCl on the surface of cells at neutral pH. This also suggested that MYT0061, MYT0062, and MYT0063 are expected to have significantly less target-mediated drug disposition than non-pH- dependent antigen-binding domains, as mediated by internalization of fcMHCl into cells on the surface of cells at neutral pH. This expected lower level of target-mediated drug disposition is another reason why it was expected that MYT0061, MYT0062, and MYT0063 will have improved pharmacokinetics (e.g., longer half life) in animals, and an extended half life versus non-pH-dependent fcMHCl antigen-binding domains. It was also expected that this lower level of target-mediated drug disposition for MYT0061, MYT0062, and MYT0063 on normal fcMHCl + cells at neutral pH versus non-pH-sensitive antigen-binding domains will result in less toxicity in an animal and in normal fcMHCl+ tissues in an animal administered a drug- or toxin- conjugated antibody-drug conjugate (ADC) based on

MYT0061, MYT0062, or MYT0063.

To demonstrate that the pH-dependent binding properties of pH-sensitive fcMHCl antigen-binding VH domains lead to enhanced release of the antibody into the extracellular environment at neutral pH following cellular internalization and recycling, a surface release assay was performed on fcMHCl+ HeLa cells using methods known to the art (e.g., as generally described in Gera N. (2012) PLoS ONE 7(11): e48928). Briefly, HeLa cells (passage number less than 25) were harvested and 50,000 cells per well were plated in a U- Bottomed 96-well microplate. Three conditions were tested; binding and secondary staining at pH 5.8, binding and secondary staining at pH 7.4, and binding at pH 5.8 followed by release at pH 7.4 for 30 minutes and secondary staining at pH 5.8. The cells were washed two times with 200 μΐ of F ACS buffer (lxPBS containing 3% Fetal Bovine Serum) at either pH 5.8 or 7.4 depending on the condition being tested. The purified protein samples were diluted into FACS buffer of the appropriate pH and added to the HeLa cells and allowed to bind for one hour on ice. After incubation with the primary antibodies the pH 5.8 and pH 7.4 conditions were washed twice as before, and then 100 of secondary rat anti -human Fc AF488 (BioLegend 410706) diluted 1 :50 or anti Myc-Tag mouse mAb-AF488 (Cell Signaling Technologies 2279S) diluted 1 :50 was added in FACS buffer of the appropriate pH, and incubated for 30 minutes on ice. The pH 7.4 release condition was washed twice with FACS buffer pH 7.4 and then resuspended in 100 of FACS buffer pH 7.4 and incubated on ice for 30 minutes, followed by secondary staining in FACS buffer pH 5.8 as described for the other conditions. The plates were washed twice as before and resuspended in 1% paraformaldehyde in the appropriate FACS buffer to fix them for flow cytometry analysis. All conditions were read on a flow cytometer (Accuri C6, BD Biosciences). Binding was observed as a shift in the FLl signal (as a mean fluorescence intensity) versus secondary alone as shown in FIGURE 15. This showed that MYT0061, MYT0062, and MYT0063 released from fcMHCl found on the surface cells at neutral pH after binding to fcMHC at a lower pH, such as, for example, after being recycled back to the cell surface from the acidic environment of the endolysosomal system. In contrast, a Fab of W6/32 (MYT0064), a non- pH-sensitive antibody, was not able to release from fcMHCl on the cell surface at neutral pH, such as for example, after being recycled back to the cell surface from the acidic environment of the endolysosomal system.

Next, W6/32 was shown to bind and internalize at pH 7.4, then recycle back to the cell surface. Briefly, HeLa cells were seeded in a 96-well plate 1.0x10^s cells/well. Purified W6/32 (Biolegend, 311402) was added at 166 nM and incubated overnight at 37° C in pH 7.4 assay buffer (PBS 2% FBS). All conditions were washed in pH 7.4 assay buffer and either resuspended in 0.1 M glycine, pH 2.7, for 1 min room temperature to strip antibodies from cell surface or resuspended back into pH 7.4 assay buffer. All conditions were washed 2x in pH 7.4 assay buffer and placed back at 37° C for indicated time points. At each time point cells were transferred to a pre-chilled 96-well plate at 4°C Secondary antibody (goat anti- mouse Fc-AF488 clone Poly4053) was added 1 :50 and incubated at 4°C for 45 mm. All conditions were washed with pH 7.4 assay buffer and fixed in pH 7.4 PBS 1% PFA. Samples were read by flow cytometry (Accuri C6, BD Biosciences). The results are shown in FIGURE 16. This demonstrated that W6/32, a non-pH-dependent fcMHC antigen-binding domain, appreciably internalized at pH 7.4 and then recycled back to the cell surface.

Taken as a whole, the results obtained in this example suggested that pH-sensitive fcMHCl antigen-binding domains like MYT0061, MYT0062, and MYT0063 had and have the following unique properties as compared to non-pH-sensitive fcMHCl control antigen- binding domains, such as W6/32 or non-binding isotype controls: a) the pH-sensitive fcMHCl antigen-binding domains did not bind cell surface fcMHCl at neutral pH to an appreciable extent, which suggests that the pH-sensitive fcMHCl antigen-binding domains are expected to have improved pharmacokinetics (e.g., longer half life) in animals versus non-pH-sensitive fcMHCl control antigen-binding domains, which did bind cell surface fcMHCl at neutral pH to an appreciable extent, and b) because the pH-sensitive fcMHCl antigen-binding domains did not appreciably bind cell surface fcMHCl at neutral pH, the pH- sensitive fcMHCl antigen-binding domains are expected not to have appreciable target- mediated drug disposition mediated by internalization of fcMHCl on cells at neutral pH, whereas non-pH-sensitive fcMHCl control antigen-binding domains are expected to show significant target-mediated drug disposition mediated by internalization of fcMHCl at neutral pH, and c) because of this expected reduction in target-mediated drug disposition at neutral pH, the pH-sensitive fcMHCl antigen-binding domains are expected to have increased half- life as compared to non-pH-sensitive fcMHCl control antigen-binding domains, and d) because of this expected reduced target-mediated drug disposition at neutral pH, the pH- sensitive fcMHCl antigen-binding domains are expected to have reduced toxicity to normal fcMHCl+ cells at neutral pH in an animal when conjugated to a drug or toxin as in an ADC as compared to non-pH-sensitive fcMHCl control antigen-binding domain when conjugated to a drug or toxin as in an ADC, and e) because the non-pH-sensitive fcMHCl antigen- binding domains recycled back to the cell surface when internalized into a cell, and it is known to the art that internalized fcMHCl is located in the endolysosomal system (Adiko AC et al. (2015) Front. Immunol. 6, 335), and it is known in the art that the lumen of the endolysosomal system is at an acidic pH (Huotari J. and Helenius A. (2011) EMBO J. 30, 3481-3500), it is expected that pH-sensitive fcMHCl antigen-binding domains will be recycled back to the cell surface when internalized into a cell, and f) the pH-sensitive fcMHCl antigen-binding domains released from the cell surface at neutral pH, whereas while a non-pH-dependent fcMHCl control antigen-binding domain did recycle, it did not release from the cell surface at neutral pH, and g) because of this expected recycling and observed release, and the fact that it is known to the art that antibodies are cleared from the body by phagocytosis in normal tissues by cells such as endothelial cells and immune cells (Pyzik M. et al. (2015) J Immunol. 194, 4595-4603), almost all of which are fcMHCl+ (Akilesh S. et al. (2007) J Immunol. 179, 4580-4588; Jin Y. et al. (2002) J Immunol. 168, 5415-5423; Greene J. M. et al. (2011) BMC Immunol. 12, 39), the pH-sensitive fcMHCl antigen-binding domains are expected to have an improved half life in vivo (increased half life) as compared to a non-binding isotype control or a non-pH-dependent fcMHCl control antigen-binding domain, and h) because of this expected recycling and observed release, and the fact that it is known in the art that many ADC drugs and toxins are released after being internalized (Rock B.M. et al. (2015) Drug Metabolism and Disposition 43, 1341-1344); Widdison W.C. et al. (2015) Bioconjugate Chem. 26, 2261-2278), when the pH-sensitive fcMHCl antigen-binding domains are conjugated to a drug or toxin as in an ADC, the resulting pH-sensitive fcMHCl antigen-binding domain- ADCs are expected to have reduced toxicity to normal tissues and an animal comprising fcMHCl + cells at normal pH, as compared to a non-binding isotype control -ADC or a non-pH-dependent fcMHC l control antigen-binding domain-ADC, and i) because this expected recycling and observed release is expected to be fcMHCl -dependent, when the pH-sensitive fcMHCl antigen-binding domains are conjugated to a drug or toxin as in an ADC, they are expected to retain toxicity to tumor tissues comprising fcMHCl - cells as compared to a non-binding isotype control-ADC

Example 13. Creation of a soluble target-binding bispecific antibody and demonstration of efficacy, internalization, recycling, and release from the surface at neutral pH

To demonstrate the ability of the invention in the form of a bispecific antibody comprising a) a pH-dependent fcMHCl antigen-binding domain as generated and characterized in Example 11 and Example 12, and b) an additional binding domain to a second target, the second target being either soluble or presented on the surface of a cell or in a cellular compartment, that additional binding domain being either pH-dependent or non- pH-dependent in its binding to the second target, to bind to the second target while the molecule as a whole is conferred all of the properties of the pH-dependent fcMHCl antigen- binding domain alone as described in Example 11 and Example 12 (e.g., pH-dependent binding, release at neutral pH etc... ), a series of bispecific antibodies that contain a pH- dependent fcMHCl antigen-binding domain and an antigen-binding domain to a second target were constructed using methods known in the art. pH-dependent anti-IL6R, pH- dependent anti-TNFa, anti-EGFR, anti-RANKL, anti-CEA, and anti-SOST antigen-binding domain sequences were obtained from sources known to the art (US 2013/0011866A1, WO2016/000813,US 2012/0077731 Al, WO2005/044858, US 2017/0253652 Al, WO 2015/044386A1 and WO 2010/130830 A2), and their sequences are provided in SEQ ID NO: 532-541 and their CDRs in SEQ ID NO:542-571. A series of thirteen bispecific constructs were generated in different formats, combining pH-dependent fcMHCl antigen-binding domains and the second antigen-binding domains referenced above in different valencies and orientations, with and without an Fc domain: Fab-VH-Fc, KiH VH-Fc, KiH VH-tandem VH- Fc, tandem VH-Fc, and tandem VH as shown in FIGURE 17. The protein sequences of the relevant tandem VH, heavy, and light chains of these thirteen constructs are provided in SEQ ID NOs: 533, 535, and 572-586, and their CDRs in SEQ ID: 483-488, and 542-571. In some of these constructs, heavy chain constructs with engineered mutations for heavy chain pairing (Spiess et al., "Alternative molecular formats and therapeutic applications of bispecific antibodies," 2015) were synthesized for both arms. These thirteen constructs were generated by co-transfection of mammalian cells with the relevant tandem VH, heavy chain, and light chain constructs for each construct using methods known to the art. After allowing for a period of protein expression, cell culture supernatants were collected, purified by protein A chromatography and, additionally for the KiH constructs, cation exchange chromatography using methods known in the art, quantified for yield, assayed for purity using SDS-PAGE using methods known in the art (FIGURE 18), and validated for binding to fcMHCl in a pH- dependent manner and the relevant second antigen (if applicable, in a pH-dependent manner) using Octet (FIGURE 19 A, B, and C). Briefly, 50 nM of bispecific antibodies MYT0045- 0049 or MYT0052-0055 were captured on an anti-human Fc biosensor (Forte Bio, 18-5060) for 120 sec. Baseline was established in PBST at pH 5.8 or pH 7.4 for 120 seconds and the sensors were associated with either 50 nM HLA-A-mFc (MYT0051) or the relevant target antigen 100 nM IL6R (Sino Biological Cat #10398-H08H), 250 nM TNFa (Sino Biological, Cat # 10602-HNAE), 50 nM EGFR (Sino Biological, Cat # 10001-H08H), 100 nM RANKL (R&D systems, Cat # 390-TN), or 50 nM CEA ( R&D systems, Cat # 4128-CM) in pH 5.8 or pH 7.4 for 300 seconds. The dissociation step was also carried out in the respective for 300 seconds. As shown in FIGURE 19A and 19B, all bispecific antibodies show pH-dependent binding to MYT0051 and also show binding to their respective second antigen. As expected, MYT0045 and MYT0046 show pH-dependent binding to IL6R and TNF alpha, respectively (i.e., lower binding response at pH 5.8 and higher binding response at pH 7.4), as the binding domains for IL6R and TNF alpha, respectively, are known in the art to be pH-sensitive. Note that binding of MYT0048 and MYT0053 to RANKL and CEA respectively was only tested at pH 7.4. Surprisingly, MYT0054 showed relatively lower binding to EGFR than MYT0055, but maintained binding to MYT0051 at both pH 5.8 and pH 7.4 suggesting that the orientation of anti-EGFR vs anti-HLA VH domain in MYT0055 was preferred. Tandem VH constructs MYT0056-0059 were also tested for binding to HLA-A-hFc (MYT0002).

MYT0002 was captured on anti-human Fc biosensors (Forte Bio, Cat # 18-5060) for 120 seconds. Baseline was established in PBST at pH 5.8 or pH 7.4 for 120 seconds and the sensors were associated with 500 nM of MYT0056, MYT0057, MYT0058, or MYT0059 in either pH 5.8 or pH 7.4. The dissociation step was also carried out in the respective for 300 seconds. As shown in FIGURE 19C, all bispecific antibodies show pH-dependent binding to MYT0002. To confirm binding to the second antigen, two different sensor types were used. For MYT0057 and MYT0058 the second antigen, i.e., 50 nM EGFR-Fc (R&D systems, Cat # 344-ER-050) or 50 nM IL6R-Fc (Sino Biological, Cat# 10398-H02H) were captured on anti- human Fc sensor (Forte Bio, Cat# 18-5060) for 120 seconds. For MYT0059, an anti-penta-his sensor (Forte Bio, Cat # 18-5120) was used to capture 100 nM of MYT0059 via the his tag for 120 seconds. For both sensor types, baseline was established in PBST at pH 5.8 or pH 7.4 for 120 seconds and the sensors were associated with 500 nM MYT0057 or MYT0058 in either pH 5.8 or pH 7.4 or 100 nM of soluble sclerostin (R&D systems, Cat # 1406-ST-025). The dissociation step was also carried out in the respective buffer for 300 seconds. As shown in Figure 19C, bispecific antibodies show binding to their respective second target antigen. Binding of MYT0056 to RANKL was not measured, however the anti-RANKL VH domain present in MYT0056 was previously tested (as a VH domain in MYT0048) for binding to RANKL. Because all thirteen constructs were well-expressed, at high purity, and validated to bind their targets with the expected presence or absence of pH-dependence in Octet, we concluded that they had retained the biophysical binding characteristics of the individual antigen-binding domains to fcMHCl and the second target when integrated into a bispecific construct format, across the five formats we generated.

To further validate the successful expression and well-behaved biophysical state of the KiH constructs used in experiments in this example, purified proteins were characterized using size exclusion chromatography using methods known to the art as shown in FIGURE 22. Five of five constructs tested (MYT0045, MYT0046, MYT0047, MYT0048, and MYT0049) showed excellent behavior on SEC, with a 98%+ concentration of monomer species observed.

To demonstrate that these thirteen constructs (hereafter referred to as "the fcMHCl bispecific constructs") exhibit all the same properties of the fcMHCl antigen-binding domain alone as described in Example 11 and Example 12 as conferred onto them by virtue of containing these same fcMHCl antigen-binding domains, including a) pH-dependent fcMHCl -dependent binding to cells, and b) an experimental confirmation of the expected enhanced internalization and recycling due to the presence of the fcMHCl antigen-binding domain, and c) enhanced release from fcMHCl on the surface of cells, a series of experiments were performed analogous to those described in Example 11 and Example 12.

To demonstrate that the cell binding data shown in FIGURE 15 and the internalization and recycling data shown in FIGURE 21 (all discussed further below) was not driven by the fcMHCl -binding bispecific construct' s binding to the second target, we quantitatively analyzed the cell lines used in our experiments for the presence of the second target (i.e., IL6R, EGFR, and CEA) on the surface of these cell lines, for those second targets that are known in the art to be membrane proteins. Cell lines were evaluated for cell-surface expression of these second targets by quantitative staining of live cells followed by flow cytometry, including the cell lines used in FIGURE 15 and FIGURE 21. Briefly, 5.0xl0E5 H526, H82, HeLa, and H69 cells were added to a 96-well plate is FACS buffer (PBS 1% PBS pH 7.4), and anti-EGFR-PE (BD Biosciences, 555997), anti-IL-6R-PE (Biolegend, 352804), or purified anti-CEA (Biolegend, 847002) were added to the cells and incubated for at 4° C for 45 min. The cells were then washed in FACS buffer and goat anti-mouse-AF488 (Biolegend, 405319) was added to the CEA sample followed by incubation at 4° C for 45 min. The samples washed in FACS buffer and fixed in 1% PFA. The samples were read on flow cytometer (Accuri, BD Biosciences). The staining data are shown in FIGURE 20.

Fluorescence intensity histograms showed low to no expression of these antigens on cells versus isotype control, further suggesting that the data and behavior of the fcMHCl bispecific constructs in FIGURE 15 and FIGURE 21 was fcMHCl -dependent and not second-target- dependent.

To demonstrate that the fcMHCl bispecific constructs bind cell surface fcMHCl poorly at neutral pH, a cell surface binding assay utilizing quantitative staining of live HeLa cells followed by flow cytometry was performed at pH 7.4, and pH 5.8 as a control. Briefly, HeLa cells (passage number less than 25) were harvested and 50,000 cells per well were plated in a U-Bottomed 96-well microplate. The cells were washed two times with 200 of FACS buffer (lxPBS containing 3% Fetal Bovine Serum) at either pH 5.8 or 7.4 depending on the condition being tested. The purified protein samples were diluted into FACS buffer of the appropriate pH and added to the HeLa cells and allowed to bind for one hour on ice. After incubation with the primary antibodies, the pH 5.8 and pH 7.4 conditions were washed twice as before and then 100 of secondary rat anti-human Fc AF488 (BioLegend 410706) diluted 1 :50 or anti Myc-Tag mouse mAb-AF488 (Cell Signaling Technologies 2279S) diluted 1 :50 was added in FACS buffer of the appropriate pH, and incubated for 30 minutes on ice. The plates were washed twice as before and resuspended in 1% paraformaldehyde in the appropriate FACS buffer to fix them for flow cytometry analysis. All conditions were read on a flow cytometer (Accuri C6, BD Biosciences). Binding was observed as a shift in the FL1 signal versus secondary alone as shown in FIGURE 15. MYT0064 (myc tagged- W6/32 Fab) was included as a control and did not show any pH-dependent cell surface binding. However, all bispecific constructs showed significantly reduced binding at pH 7.4 compared to pH 5.8. In contrast, as shown in a previous experiment, W6/32 was shown to be a non-pH-sensitive fcMHCl antibody with appreciable binding of cell surface fcMHCl at pH 7.4. Taken together with the results in Figure 19, the results showed that the pH-dependent pH 5.8-enhancing phage panning: a) rendered pH-sensitive fcMHCl antigen-binding VH domains contained in the fcMHCl bispecific constructs to be pH-sensitive in their binding properties to fcMHCl, and b) that the fcMHCl bispecific constructs were only capable of significant binding at lower pH and not at neutral pH (e.g., pH 5.8 and 7.4, respectively), and c) that the fcMHCl bispecific constructs' binding properties improved as the pH became lower. This is important because fcMHC l is known to the art to be widely expressed in animal bodies (e.g., Daar, A. S. et al. (1984) Transplantation 38, 287-92), and it is also known to the art that the interstitial fluid of most tissues in an animal is at neutral pH (e.g. Burton, R. F. (2001) Physiological and Biochemical Zoology: Ecological and Evolutionary Approaches 74, 607-615). Therefore, the lack of significant binding at neutral pH of the fcMHCl bispecific constructs as compared to W6/32 suggests that the fcMHCl bispecific constructs are expected to have significantly improved pharmacokinetics (and therefore, longer half life) in animals as compared to non-pH-sensitive antigen-binding domains, such as W6/32, due to less binding of fcMHCl on the surface of cells at neutral pH. This also suggests that the fcMHCl bispecific constructs are expected to have significantly less target- mediated drug disposition than non-pH-dependent antigen-binding domains, as mediated by internalization of fcMHCl into cells on the surface of cells at neutral pH. This expected decreased level of target-mediated drug disposition is another reason why the fcMHCl bispecific constructs are expected to have improved pharmacokinetics (e.g., longer half life) in animals, and an extended half life versus non-pH-dependent fcMHCl antigen-binding domains. This expected lower level of TMDD for the fcMHCl bispecific constructs on normal fcMHCl + cells at neutral pH versus non-pH-sensitive antigen-binding domains also suggests that the fcMHCl bispecific constructs, when conjugated to a toxin or drug (e.g., an ADC) will have less toxicity in normal fcMHCl+ tissues and animals. To demonstrate that the pH-dependent binding properties of the fcMHCl bispecific constructs lead to enhanced release of the antibody into the extracellular environment following recycling to the cell surface, a surface release assay was performed using methods known in the art (e.g., as generally described in Gera N. (2012) PLoS ONE 7(11): e48928) on fcMHCl+ HeLa cells. Briefly, HeLa cells (passage number less than 25) were harvested and 50,000 cells per well were plated in a U-Bottomed 96-well microplate. Three conditions were tested; binding and secondary staining at pH 5.8, binding and secondary staining at pH 7.4, and binding at pH 5.8 followed by release at pH 7.4 for 30 minutes and secondary staining at pH 5.8. The cells were washed two times with 200 \\L of FACS buffer (lxPBS containing 3% Fetal Bovine Serum) at either pH 5.8 or 7.4 depending on the condition being tested. The purified protein samples were diluted into FACS buffer of the appropriate pH and added to the HeLa cells and allowed to bind for one hour on ice. After incubation with the primary antibodies the pH 5.8 and pH 7.4 conditions were washed twice as before and then 100 ih of secondary rat anti-human Fc AF488 (BioLegend 410706) diluted 1 :50 or anti Myc-Tag mouse mAb-AF488 (Cell Signaling Technologies 2279S) diluted 1 : 50 was added in FACS buffer of the appropriate pH, and incubated for 30 minutes on ice. The pH 7.4 release condition was washed twice with FACS buffer pH 7.4 and then resuspended in 100 iL of FACS buffer pH 7.4 and incubated on ice for 30 minutes, followed by secondary staining in FACS buffer pH 5.8 as described for the other conditions. The plates were washed twice as before and resuspended in 1% paraformaldehyde in the appropriate FACS buffer to fix them for flow cytometry analysis. All conditions were read on a flow cytometer (Accuri C6, BD Biosciences). Binding was observed as a shift in the FL1 signal (as a mean fluorescence intensity ) versus secondary alone. As shown in FIGURE 15, eight of nine bispecific molecules tested (MYT0045, MYT0046, MYT0047, MYT0048, MYT0049, MYT0053, MYT0054, and MYT0055, but not MYT0052) show lower signal after a 30 min incubation in pH 7.4 buffer, demonstrating that higher pH leads to release of the antibodies from the cell surface. Surprisingly, MYT0052 did not show release from cell surface at pH 7.4. This showed that all, except one, of the fcMHCl bispecific constructs were able to release from fcMHCl found on the surface cells at neutral pH after binding to fcMHC at a lower pH, such as, for example, after being recycled back to the cell surface from the acidic environment of the endolysosomal system. In contrast, MYT0064 (W6/32 Fab), a non-pH-sensitive antibody, was not able to release from fcMHCl on the cell surface at neutral pH, such as for example, after being recycled back to the cell surface from the acidic environment of the endolysosomal system.

Next, an internalization and recycling assay was performed for the fcMHCl bispecific constructs on fcMHCl + HeLa cells and fcMHCl - NCI-H82 cells. Since it was now understood that, after binding at at lower pH (e.g., in an endolysosomal compartment), the fcMHCl bispecific constructs were able to quickly release from the surface of cells at pH greater than or equal to pH 7.4, we used this pH 7.4 condition to remove surface-bound antibody in the protocol for our recycling assay using methods known to the art (e.g., as generally described in Mahmutefendic et al, Int. J. Biochem. Cell Bio., 2011). Briefly, HeLa and H82 cells were seeded in a 96-well plate l .OxlO⁵ cells/well. Constructs and control antibodies were added at 500 nM and incubated overnight at 37° C in pH 5.8 assay buffer (PBS 2% FBS). All conditions were washed in pH 5.8 assay buffer and either resuspended in PBS pH 8.0 for 1 min room temperature to strip antibodies from cell surface or resuspended back into pH 5.8 assay buffer. All conditions were washed 2x in pH 5.8 assay buffer and placed back at 37° C for the indicated time points. At each time point cells were transferred to a pre-chilled 96-well plate at 4° C. Secondary antibody rat anti-human Fc-AF488 clone M1310G05 or goat anti-mouse Fc-AF488 clone Poly 4053, was added 1 :50 and incubated at 4° C for 45 min. All conditions were washed with pH 5.8 assay buffer and fixed in pH 5.8 PBS 1% PFA. Samples were read by flow cytometry (Accuri C6, BD Biosciences).

Recycling was calculated in all samples as the difference in MFI signal between the 1 hour and 0 minute timepoints. The results are shown in FIGURE 21. Upon analysis of the data, it was revealed that for fcMHCl + HeLa cells treated with the fcMHCl bispecific constructs, the amount of antibody internalized and then recycled back to the cell surface was higher than the IgGl non-binding isotype control for six of seven bispecific constructs tested (MYT0047, MYT0049, MYT0052, MYT0053, MYT0054, and MYT0055, but not

MYT0048). Additionally, the lack of internalization and recycling in fcMHCl - NCI-H82 cells demonstrated that the recycling of the fcMHCl bispecific constructs was fcMHCl- dependent. Taken together, the data for the fcMHCl bispecific constructs in the surface release assay and the internalization and recycling assay suggested that the fcMHCl bispecific constructs were able to internalize, recycle, then release into the media at neutral pH in a fcMHCl -dependent manner, at much higher levels than a isotype control. The observed difference between fcMHCl bispecific constructs and the IgGl non-binding isotype control also ruled out isotype-driven involvement of Fc receptors such as FcRn playing a significant role in this internalization, recycling, and release.

In a similar experiment, as discussed previously, W6 32 was shown to bind and internalize, this time at pH 7.4, then recycle back to the cell surface (Figure 16). This demonstrated that W6/32, a non-pH-dependent fcMHC antigen-binding domain, appreciably internalized at pH 7.4 and then recycled back to the cell surface.

Taken as a whole, the results obtained from these experiments suggested that pH- sensitive fcMHCl antigen-binding domain-containing constructs, such as the majority of the tested fcMHCl bispecific constructs described herein, had and have the following unique properties as compared to non-pH-sensitive fcMHCl antigen-binding domain-containing control constructs such as W6/32, or non-binding isotype controls: a) the fcMHCl bispecific constructs did not bind cell surface fcMHCl at neutral pH to an appreciable extent, which indicates that the bispecific constructs are likely to have improved pharmacokinetics (e.g., longer half life) in animals versus non-pH-sensitive fcMHCl antigen-binding domain- containing control constructs, which did bind cell surface fcMHCl at neutral pH to an appreciable extent, and b) because the fcMHCl bispecific constructs did not appreciably bind cell surface fcMHCl at neutral pH, the fcMHCl bispecific constructs are expected not to have appreciable target-mediated drug disposition mediated by internalization of fcMHCl on cells at neutral pH, whereas non-pH-sensitive fcMHCl antigen-binding domain-containing control constructs are expected to show significant target-mediated drug disposition mediated by internalization of fcMHCl at neutral pH, and c) because of this expected reduction in target- mediated drug disposition at neutral pH, the fcMHCl bispecific constructs are expected to have increased half-life as compared to non-pH-sensitive fcMHCl antigen- binding domain-containing control constructs, and d) because of this expected reduction in target- mediated drug disposition at neutral pH, the fcMHCl bispecific constructs are expected to have reduced toxicity to normal fcMHCl + cells at neutral pH in an animal when conjugated to a drug or toxin as in an ADC as compared to non-pH-sensitive fcMHCl antigen-binding domain-containing control constructs when conjugated to a drug or toxin as in an ADC, and e) when internalized into a cell, the fcMHCl bispecific constructs recycled back to the cell surface in a fcMHC 1 -dependent manner and under similar conditions released from the cell surface at neutral pH, whereas a non-binding isotype control did not recycle, and a non-pH-dependent fcMHC l antigen-binding domain-containing control construct did recycle but did not release from the cell surface at neutral pH, and f) because of this recycling and release, and the fact that it is known to the art that antibodies are cleared from the body by phagocytosis in normal tissues by cells such as endothelial cells and immune cells (Pyzik M. et al. (2015) J Immunol. 194, 4595-4603), almost all of which are fcMHCl+ (Akilesh S. et al. (2007) J Immunol. 179, 4580-4588; Jin Y. et al. (2002) J Immunol. 168, 5415-5423; Greene J. M. et al. (2011) BMC Immunol. 12, 39), the fcMHCl bispecific constructs are expected to have an improved half life in vivo (increased half life) as compared to a non-binding isotype control or a non-pH-dependent fcMHCl antigen-binding domain-containing control construct, and g) because of this recycling and release, and the fact that it is known to the art that many ADC drugs and toxins are released after being internalized (Rock B.M. et al. (2015) Drug Metabolism and Disposition 43, 1341-1344); Widdison W.C. et al. (2015) Bioconjugate Chem. 26, 2261-2278), when the fcMHCl bispecific constructs are conjugated to a drug or toxin as in an ADC, the resulting fcMHCl bispecific construct-ADCs are expected to have reduced toxicity to normal tissues and animals comprising fcMHC l+ cells at normal pH as compared to a non-binding isotype control -ADC or a non-pH-dependent fcMHC l antigen-binding domain-containing control construct- ADC, and h) because this recycling and release is fcMHCl -dependent, when the fcMHCl bispecific constructs are conjugated to a drug or toxin as in an ADC, they are expected to retain toxicity to tumor tissues comprising fcMHCl- cells as compared to a non- binding isotype control- ADC.

OTHER EMBODIMENTS

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Exemplary Embodiments- Part A

Embodiment 1 A. A pharmaceutical composition comprising an effective amount of a multi-specific antigen-binding protein construct (ABPC) comprising: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, wherein:

the second antigen-binding domain is capable of specifically binding to an epitope of a polypeptide complex, wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ιη) polypeptide, wherein:

(b) the dissociation constant (Kx>) of the second antigen-binding domain at an acidic pH is less than the KD at a neutral pH; and

the second antigen-binding domain comprises at least one paratope that comprises at least one histidine residue. Embodiment 2A. A pharmaceutical composition comprising an effective amount of a multi-specific antigen-binding protein construct (ABPC) comprising: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, wherein:

the second antigen-binding domain capable of specifically binding to an epitope of a polypeptide complex (PC), wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2ιη) poly peptide,

wherein the multi-specific ABPC has increased endosomal recycling in a mammalian cell that presents the PC on its surface or in a cellular compartment as compared to a control ABPC. Embodiment 3A. A pharmaceutical composition comprising an effective amount of a multi-specific antigen-binding protein construct (ABPC) comprising: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, wherein:

the second antigen-binding domain is capable of specifically binding an epitope of a beta 2-microglobulin (β2ιη) polypeptide, wherein:

the second antigen-binding domain comprises at least one paratope that comprises at least one histidine residue.

Embodiment 4A. A pharmaceutical composition comprising an effective amount of a multi-specific antigen-binding protein construct (ABPC) comprising:

(a) a first antigen-binding domain capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell;

(b) a second antigen-binding domain capable of specifically binding to an epitope of a polypeptide complex (PC), wherein the polypeptide complex comprises (i) a polypeptide encoded by an HLA gene selected from HLA- A, HLA-B, and HLA-C, and (ii) a beta 2- microglobulin (β2ιη) polypeptide; and

(c) a conjugated toxin, radioisotope, or drug,

wherein the multi-specific ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC complex on its surface or in a cellular compartment as compared to a control ABPC.

Embodiment 5 A. The pharmaceutical composition of any one of embodiments 1 A, 2A, and 4A, wherein the second antigen-binding domain specifically binds to an epitope that comprises at least one amino acid of the polypeptide encoded by the HLA gene selected from the group consisting of HLA- A, HLA-B, and HLA-C, and at least one amino acid of the β2ηι polypeptide. Embodiments 6A. The pharmaceutical composition of any one of embodiments 1A, 2A, 3A, 4A. and 5 A, wherein the epitope of the PC is an at least partially monomorphic epitope.

Embodiment 7 A. The pharmaceutical composition of any one of embodiments 1 A, 2A, and 4A, wherein the second antigen-binding domain specifically binds to an epitope of a polypeptide encoded by the HLA gene selected from HLA-A, HLA-B, and HLA-C, when the polypeptide encoded by the HLA gene is bound to the β2ιη polypeptide.

Embodiment 8A. The pharmaceutical composition of embodiment 3A, wherein the second antigen-binding domain specifically binds to an epitope of the β2ιη polypeptide when the β2πι polypeptide is bound to a polypeptide encoded by an HLA gene selected from the group consisting of HLA-A, HLA-B, and HLA-C.

Embodiment 9 A. The pharmaceutical composition of any one of embodiments 1 A, 2A, 4A, 5 A. 6A, and 7A, wherein the KD of the second antigen-binding domain for an HLA- A variant polypeptide-beta 2-microglobulin (β2ηι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the second antigen-binding domain for the polypeptide encoded by the HLA-A gene-beta 2-microglobulin (β2ιη) polypeptide complex, and wherein the HLA-A variant polypeptide is identical to the polypeptide encoded by the HLA-A gene except at one or more residues which both: (i) are located in the HLA-A epitope bound by the second antigen-binding domain, wherein the epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-A gene.

Embodiment 10A. The pharmaceutical composition of any one of embodiments 1A. 2A, 4A, 5 A. 6A, and 7A, wherein the KD of the second antigen-binding domain for an HLA- B variant polypeptide-beta 2-microglobulin (β2ιη) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the second antigen-binding domain for the polypeptide encoded by the HLA-B gene-beta 2-microglobulin (β2ιη) polypeptide complex, and wherein the HLA-B variant polypeptide is identical to the polypeptide encoded by the HLA-B gene except at one or more residues which both: (i) are located in the HLA-B epitope bound by the second antigen-binding domain, wherein the epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-B gene.

Embodiment 11 A. The pharmaceutical composition of any one of embodiments 1 A. 2A, 4A, 5 A. 6A, and 7A, wherein the KD of the second antigen-binding domain for an HLA- C variant polypeptide-beta 2-microglobulin (β2ηι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the second antigen-binding domain for the polypeptide product of the HLA-C gene-beta 2-microglobulin (β2ιη) polypeptide complex, and wherein the HLA-C variant polypeptide is identical to the polypeptide encoded by the HLA-C gene except at one or more residues which both: (i) are located in the HLA-C epitope bound by the second antigen-binding domain, wherein the epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-C gene. Embodiment 12 A. The pharmaceutical composition of any one of embodiments 1A,

2A, 4A, 5 A. 6A, 7A, and 9A, wherein the HLA-A gene is selected from the group consisting of: a A*24:02 gene, a A*24: 144 gene, a A*02:01 gene, a A*02:09 gene, a A*02:43N gene, a A*02:66 gene, a A*02:75 gene, a A*02:83N gene, a A*02: 89 gene, a A^Hi02:97 gene, a A*02: 132 gene, a A*02: 134 gene, a A*02: 140 gene, a A* 02: 241 gene, a A*02:252 gene, a A*02:256 gene, a A*02:266 gene, a A*02:291 gene, a A*02:294 gene, a A*02:305N gene, a A* 11 :01 gene, a A* l 1 : 102 gene, a A*11 :21N gene, a A*11 :69N gene, a A* 11 :86 gene, a A*01 :01 gene, a A*01 :04N gene, a A*01 :22N gene, a A*01:32 gene, a A*01 :37 gene, a A*01 :45 gene, a A*01 :56N gene_: a A*01 :81 gene, a A*01:87N gene, a A*33:03 gene, a A*33: 15 gene, a A*33:25 gene, a A*33:31 gene, a A*33:39 gene, a A*33:44 gene, a A*34:01 gene, a A*03:01 gene, a A*03:20 gene, a A*03:21N gene, a A*03:26 gene, a A*03:37 gene, a A*03:45 gene, a A*03:78 gene, a A*03: 112 gene, a A*03: 118 gene, a A*24:07 gene, a A*23:01 gene, a A*23:07N gene, a A*23: 17 gene, a A*23: 18 gene, a A*23:20 gene, a A* 02: 07 gene, a A*02: 15N gene, a A*02:265 gene, a A* 02: 03 gene, a A*02:253 gene, a A*02:264 gene, a A*31 :01 gene, a A*31 : 14N gene, a A*31 :23 gene, a A*31 :46 gene, a A*31 :48 gene, a A*26:01 gene, a A*26:24 gene, a A*26:26 gene, a A*26:56 gene, a A*29:01 gene, a A*02:06 gene, a A*02: 126 gene, a A*30:01 gene, a A*30:24 gene, a A*30:02 gene, a A*30:33 gene, a A*68:01 gene, a A*68: l lN gene, a A*68:33 gene, a A*68:02 gene, a A*29:02 gene, a A*29:26 gene, a A*74:01 gene, a A*7402 gene, aA*0211 gene, a A*02:69 gene, a A*32:01 gene, a A*02:02 gene, a A*34 02 gene, aA*36 01 gene, a A*33:01 gene, a A*ll:02 gene, a A*ll:77 gene, a A*26: 03 gene, aA*0205 gene, a A*02:179 gene, a A*25:01 gene, a A*25:07 gene, a A*24: 03 gene, aA*2433 gene, a A*26:02 gene, a A*68:03 gene, a A*03:02 gene, a A*6601 gene, aA*6608 gene, a A*30:04 gene, a A*02:17 gene, a A*66:02 gene, a A*24: 10 gene, aA*0204 gene, a A*24:17 gene, a A*80:01 gene, a A*69:01 gene, a A*24: 20 gene, aA*01 02 gene, a A*68:05 gene, a A*02: 10 gene, a A*30: 10 gene, a A*3405 gene, aA*02131 gene, a A* 02: 16 gene, a A* 02: 104 gene, a A* 02: 22 gene, a A*02: 20 gene, aA*01 03 gene, a A*66:03 gene, a A*ll:04 gene, a A*24:25 gene, a A*24: 23 gene, and a A*02:60 gene.

Embodiment 13 A. The pharmaceutical composition of any one of embodiments 1A, 2A, 4A, 5 A, 6A, 7 A, and 10A, wherein the HLA-B gene is selected from the group consisting of: aB*40:01 gene, aB*40:55 gene, aB*40:141 gene, aB*40:150gene, aB*40:151 gene, a B*15:02 gene, aB*15:214 gene, aB*46:01 gene, aB*46:15N gene, aB*46:24 gene, a B*07:02 gene, a B*07:44 gene, a B*07:49N gene, a B*07:58 gene, a B*07:59 gene, a B*07:61 gene, aB*07:120 gene, aB*07:128 gene, aB*07:129 gene, a B*07: 130 gene, a B*53:01 gene, aB*38:02 gene, aB*38:18 gene, aB*08:01 gene, a B* 08:19N gene, a B*52:01 gene, aB*52:07 gene, aB*35:01 gene, aB*35:40N gene, aB*35:42 gene, a B*35:57 gene, aB*35:94 gene, aB*35:134N gene, aB*35:161 gene, a B* 44: 02 gene, a B*44:27 gene, aB*44:66 gene, aB*44:118 gene, aB*51:01 gene, aB*51:llN gene, a B*51:30gene, aB*51:32 gene, aB*51:48 gene, aB*51:51 gene, aB*40:06 gene, aB*44:03 gene, aB*58:01 gene, aB*58:ll gene, aB*58:31N gene, a B* 15:01 gene, aB*15:102 gene, aB*15:104 gene, aB*15:140 gene, aB*15:146 gene, aB*15:201 gene, aB*35:05 gene, a B*07:05 gene, aB*07:06 gene, aB*15:35 gene, aB*40:02 gene, aB*40:56 gene, aB*40:97 gene, aB*40:144Ngene, aB*54:01 gene, aB*54:17 gene, aB*18:01 gene, aB*18:17N gene, a B* 18:53 gene, aB*35:03 gene, aB*35:70 gene, aB*57:01 gene, a B*57:29 gene, a B*57:37 gene, aB*15:03 gene, aB*15:103 gene, aB*13:01 gene, aB*27:05 gene, a B*27:13 gene, aB*42:01 gene, aB*15:25 gene, aBⁱ45:01 gene, aB*45:07 gene, aB*45:13 gene, aB*14:02 gene, aB*58:02 gene, aB*49:01 gene, aB*15:10 gene, aB*38:01 gene, a B*48:01 gene, aB*48:09 gene, aB*57:03 gene, aB*37:01 gene, aB*37:23 gene, aB*39:01 gene, aB*39:46 gene, aB*39:59 gene, aB*35:02 gene, a B* 15:21 gene, aB*39:05 gene, a B*13:02 gene, aB*13:38 gene, aB*50:01 gene, aB*39:06 gene, aB*55:02 gene, aB*41:01 gene, a B*27:06 gene, aB*15:13 gene, aB*59:01 gene, aB*35:12 gene, a B*55:01 gene, a B*15:12gene, aB*15:19 gene, aB*15:16 gene, aB*81:01 gene, aB*81:02 gene, aB*81:03 gene, a B*51:06 gene, aB*27:04 gene, aB*27:68 gene, aB*27:69 gene, a B*35:43 gene, a B*35:67 gene, aB*35:79 gene, aB*15:ll gene, aB*35:08 gene, aB*15:18 gene, a B*15:198 gene, aB*15:17 gene, aB*51:02 gene, aB*14:01 gene, aB*39:10 gene, a

B*56:04 gene, aB*15:27 gene, aB*35:17 gene, aB*15:15 gene, aB*15:07 gene, aB*67:01 gene, a 6*78:01 gene, aB*56:01 gene, aB*56:24 gene, a B*41:02 gene, aB*40:05 gene, a B*42:02 gene, aB*40:03 gene, aB*40:10 gene, aB*57:02 gene, aB*15:30 gene, aB*27:02 gene, aB*18:02 gene, aB*39:02 gene, aB*39:08 gene, aB*27:07 gene, aB*48:03 gene, a B*51:08 gene, aB*39:09 gene, aB*15:05 gene, aB*27:03 gene, aB*35:04 gene, aB*40:04 gene, aB*44:05 gene, aB*40:08 gene, aB*15:08 gene, aB*15:04 gene, aB*48:04 gene, a B*39:ll gene, aB*35:14 gene, aB*47:01 gene, aB*82:01 gene, aB*73:01 gene, aB*14:03 gene, a B*35:20 gene, a B*15:29 gene, a B*50:02 gene, a B*57:04 gene, a B*48:02 gene, a B*15:40 gene, aB*15:06 gene, aB*51:05 gene, aB*40:ll gene, aB*56:03 gene, aB*51:07 gene, a B*39:04 gene, aB*44:10 gene, aB*39:15 gene, a B* 15:38 gene, a B* 15:32 gene, a B*51:09 gene, aB*39:24 gene, aB*15:39 gene, aB*40:12 gene, aB*40:27 gene, aB*35:10 gene, a B*35:ll gene, aB*15:09 gene, aB*47:03 gene, and aB*48:07 gene.

Embodiment 14 A. The pharmaceutical composition of any one of embodiments 1A, 2A, 4A, 5 A, 6A, 7 A, and 11 A, wherein the HLA-C gene is selected from the group consisting of: a C*07:02 gene, a C*07:50 gene, a C*07:66 gene, a C*07:74 gene, a C*07:159 gene, a C*07:160 gene, a C*07:167 gene, a C*04:01 gene, a C*04:09N gene, a C*04:28 gene, a C*04:30 gene, aC*04:41 gene, aC*04:79 gene, aC*04:82 gene, aC*04:84 gene, aC*01:02 gene, a C*01 :25 gene, a C*01:44 gene, a C*08:01 gene, a C*08:20 gene, a C*08:22 gene, a C*08:24 gene, aC*07:01 gene, aC*07:06 gene, aC*07:18 gene, aC*07:52 gene, a C*07:153 gene, a C*07:166 gene, a C*03:03 gene, a C*03:20N gene, a C*03:62 gene, a C*06:02 gene, a C*06:46N gene, a C*06:55 gene, a C*03:04 gene, a C*03:100 gene, a C*03:101 gene, a C* 03: 105 gene, a C*03:106 gene, aC*15:02 gene, a C*15:13 gene, a C*15:47 gene, aC*12:02 gene, aC*16:01 gene, a 0*05:01 gene, aC*05:03 gene, aC*05:37 gene, a C*05:53 gene, a C*12:03 gene, a C*12:23 gene, a C*02:02 gene, a C*02:10 gene, a C*02:29 gene, aC*03:02 gene, aC*14:02 gene, aC*14:23 gene, aC*14:31 gene, aC*15:05 gene, a C*15:29 gene, a C*17:01 gene, a C*17:02 gene, a C*17:03 gene, a C*14:03 gene, a C*04:03 gene, aC*08:02 gene, aC*18:01 gene, aC*18:02 gene, aC*16:02 gene, aC*07:04 gene, a C*07: l 1 gene, a C*03:05 gene, a C*12:04 gene, a C*08:03 gene, a C*08:40 gene, a C*04:06 gene, a C*16:04 gene, a C*08:04 gene, a C*03:06 gene, a C*04:04 gene, a C*07:26 gene, a C*15:09 gene, a C*01 :03 gene, a C*01:24 gene, a C* 15:04 gene, and a C*04:07 gene.

Embodiment 15 A. The pharmaceutical composition of any one of embodiments 1A. 2A, 4A, 5 A, 6A, 7 A, 9A, 10A, 11A, 12A, 13 A, and 14A, wherein the PC further comprises a peptide of about 8-12 amino acids in length that is bound to the PC.

Embodiment 16 A. The pharmaceutical composition of any one of embodiments 1A. 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, and 15A, wherein the first antigen-binding domain and, if present, the second antigen-binding domain is capable of specifically binding to an epitope expressed on the surface or in a cellular compartment of human cells and an epitope that is expressed on the surface or in a cellular compartment of a cell from an Old World Monkey.

Embodiment 17 A. The pharmaceutical composition of any one of embodiments 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, and 16A, wherein the dissociation rate of the second antigen-binding domain at an acidic pH is at least 10% slower than the dissociation rate of the second antigen-binding domain at a neutral pH.

Embodiment 18 A. The pharmaceutical composition of any one of embodiments 1A. 2A, 3A, 4A_; 5A, 6A, 7A, 8A, 9A, 10A_; 11A, 12A, 13A, 14A, 15A, and 16A, wherein the dissociation rate of the second antigen-binding domain at an acidic pH is at least 3-fold slower than the dissociation rate of the second antigen-binding domain at a neutral pH.

Embodiment 19 A. The pharmaceutical composition of any one of embodiments 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, and 16A, wherein the dissociation rate of the second antigen-binding domain at an acidic pH is at least 10-fold slower than the dissociation rate of the second antigen-binding domain at a neutral pH.

Embodiment 20 A. The pharmaceutical composition of any one of embodiments 1 A.

2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, and 19A, wherein the KD of the second antigen-binding domain at an acidic pH is at least 10% less than the KD of the second antigen-binding domain at a neutral pH.

Embodiment 21 A. The pharmaceutical composition of any one of embodiments 1 A. 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A₅ 1 1A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, and 19A, wherein the KD of the second antigen-binding domain at an acidic pH is at least 3-fold less than the KD of the second antigen-binding domain at a neutral pH.

Embodiment 22 A. The pharmaceutical composition of any one of embodiments 1 A, 2A, 3A, 4A_: 5A, 6A, 7A, 8A, 9A, 10A, 1 1A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, and 19A, wherein the KD of the second antigen-binding domain at an acidic pH is at least 10-fold less than the KD of the second antigen-binding domain at a neutral pH.

Embodiment 23 A. The pharmaceutical composition of any one of embodiments 1 A. 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 1 1 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21 A, and 22A, wherein the identifying antigen is a protein, a carbohydrate, or a lipid, or a combination thereof.

Embodiment 24 A. The pharmaceutical composition of any one of embodiments 1 A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 1 1A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, and 23 A, wherein the identifying antigen is an antigen that is expressed on a surface of a cancer cell and the first target mammalian cell is the cancer cell.

Embodiment 25 A. The pharmaceutical composition of any one of embodiments 1 A. 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 1 1 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23 A, and 24A, wherein the identifying antigen is an epithelial-derived growth factor receptor (EGFR) antigen.

Embodiment 26 A. The pharmaceutical composition of any one of embodiments 1 A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 1 1 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23 A, 24A, and 25 A, wherein the antigen-binding protein construct is cytotoxic or cytostatic to the mammalian target cell. Embodiment 27 A. The pharmaceutical composition of any one of embodiments 1 A. 2A, 3A, 4A_; 5 A, 6A, 7 A, 8A, 9 A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23 A, 24A, 25A, and 26A, wherein the multi-specific ABPC comprises a single polypeptide.

Embodiment 28A. The pharmaceutical composition of embodiment 27A, wherein the first antigen-binding domain and the second antigen-binding domain are each independently selected from the group consisting of: a VHH domain, a VNAR domain, and a scFv. Embodiment 29A. The pharmaceutical composition of embodiment 27A, wherein the multi-specific ABPC is a BiTe, a (scFv)2, a nanobody, a nanobody-HS A, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH-CL-scFv, a HSAbody, scDiabody-HAS, or a tandem-scFv. Embodiment 3 OA. The pharmaceutical composition of any one of embodiments 1A.

2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23 A, 24A, 25A, and 26A, wherein the multi-specific ABPC comprises two or more polypeptides. Embodiment 31 A. The pharmaceutical composition of embodiment 3 OA, wherein the antigen-binding protein construct is selected from the group of an antibody, a VHH-scAb, a VHH-Fab, a Dual scFab, a F(ab')₂, a diabody, a crossMab, a DAF (two-in-one), a DAF (four- in-one), a DutaMab, a DT-IgG, a knobs-in-holes common light chain, a knobs-in-holes assembly, a charge pair, a Fab-arm exchange, a SEEDbody, a LUZ-Y, a Fcab, a κλ-body, an orthogonal Fab, a DVD-IgG, a IgG(H)-scFv, a scFv-(H)IgG IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG- 2scFv, scFv4-Ig, Zybody, DVI-IgG, Diabody-CH3, a triple body, a miniantibody, a minibody, a TriBi minibody, scFv-CH3 KIH, Fab-scFv, a F(ab')2-scFv2, a scFv-K H, a Fab- scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a Diabody-Fc, a tandem scFv-Fc, an

Intrabody, a dock and lock, an ImmTAC, an IgG-IgG conjugate, a Cov-X-Body, and a scFvl- PEG-scFv2. Embodiment 32A. The pharmaceutical composition of any one of embodiments 1A. 2A, 3A, 4A_; 5 A, 6A, 7 A, 8A, 9 A, 10A, 1 1A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21 A, 22A, 23 A, 24A, 25A, 26A, 27A, 28A, 29A, 30A, and 31 A, wherein at least one protein of the multi-specific ABPC is conjugated to the toxin, the radioisotope, or the drug via a cleavable linker.

Embodiment 33A. The pharmaceutical composition of any one of embodiments 1A. 2A, 3A, 4A_: 5A, 6A, 7A, 8A, 9A, 10A, 1 1A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21 A, 22A, 23 A, 24A, 25A, 26A, 27A, 28A, 29A, 30A, and 31 A, wherein at least one protein of the multi-specific ABPC is conjugated to the toxin, the radioisotope, or the drug via a non-cleavable linker.

Embodiments 34 A. The pharmaceutical composition of any one of embodiments 1A, 2A, and 3A, wherein the multi-specific ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC on its surface or in a cellular compartment as compared to a control ABPC.

Embodiment 35A. The pharmaceutical composition of any one of embodiments 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 1 1A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23A, 24A, 25 A, 26A, 27A, 28A, 29A, 30A, 31A, 32A, 33A, 34A, wherein the first antigen-binding domain has a KD that is increased at an acidic pH as compared to the KD of the first antigen-binding domain at a neutral pH.

Embodiment 36 A. The pharmaceutical composition of embodiment 35 A, wherein the first antigen-binding domain has a KD at an acidic pH that is at least 10% increased as compared to the KD of the first antigen-binding domain at a neutral pH.

Embodiment 37 A. The pharmaceutical composition of embodiment 35 A, wherein the first antigen-binding domain has a KD at an acidic pH that is at least 3-fold greater than the KD of the first antigen-binding domain at a neutral pH.

Embodiment 38 A. The pharmaceutical composition of embodiment 37 A, wherein the first antigen-binding domain has a KD at an acidic pH that is at least 10-fold greater than the KD of the first antigen-binding domain at a neutral pH. Embodiment 39A. A kit comprising at least one dose of the pharmaceutical compositions of any one of embodiments 1A, 2A, 3 A, 4A, 5 A, 6A, 7 A, 8A, 9 A. 10A, 11 A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23 A, 24A, 25 A, 26A, 27A, 28A, 29A, 30A, 31A, 32A, 33A, 34A, 35A, 36A, 37A, and 38A.

Embodiment 40A. A multi-specific antigen-binding protein construct (ABPC) comprising: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, wherein:

the second antigen-binding domain is capable of specifically binding to an epitope of a polypeptide complex, wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2ηι) poly peptide, wherein:

Embodiment 41 A. A multi-specific antigen-binding protein construct (ABPC) comprising: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, wherein:

the second antigen-binding domain capable of specifically binding an epitope of a polypeptide complex (PC), wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2ηι) poly peptide,

wherein the multi-specific ABPC has increased endosomal recycling in a mammalian cell that presents the PC on its surface or in a cellular compartment as compared to a control ABPC. Embodiment 42A. A multi-specific antigen-binding protein construct (ABPC) comprising: a first antigen-binding domain, a second antigen-binding domain, and a conjugated toxin, radioisotope, or drug, wherein:

Embodiment 43 A. A multi-specific antigen-binding protein construct (ABPC) comprising:

(a) a first antigen-binding domain is capable of specifically binding to an identifying antigen present on a surface of a mammalian target cell;

(b) a second antigen-binding domain capable of specifically binding to an epitope of a polypeptide complex (PC), wherein the polypeptide complex comprises (i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and (ii) a beta 2- microglobulin (β2ιη) polypeptide; and

(c) a conjugated toxin, radioisotope, or drug,

Embodiment 44 A. The multi-specific ABPC of any one of embodiments 40A, 41 A, and 43A, wherein the second antigen-binding domain specifically binds to an epitope that comprises at least one amino acid of the polypeptide product of the HLA gene selected from the group consisting of HLA-A, HLA-B, and HLA-C, and at least one amino acid of the β2ηι polypeptide. Embodiment 45 A. The multi-specific ABPC of any one of embodiments 40A, 41 A, 42A, 43A, and 44A, wherein the epitope of the PC is an at least partially monomorphic epitope.

Embodiment 46A. The multi-specific ABPC of any one of embodiments 40A, 41 A, and 43A, wherein the second antigen-binding domain specifically binds to an epitope of a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, when the polypeptide encoded by the HLA gene is bound to the 2m polypeptide.

Embodiment 47A. The multi-specific ABPC of embodiment 42A, wherein the second antigen-binding domain specifically binds to an epitope of the β2ηι polypeptide when the β2πι polypeptide is bound to a polypeptide encoded by an HLA gene selected from the group consisting of HLA-A, HLA-B, and HLA-C.

Embodiment 48 A. The multi-specific ABPC of any one of embodiments 40A, 41 A, 43 A, 44A, 45 A, and 46A. wherein the KD of the second antigen-binding domain for an HLA- A variant polypeptide-beta 2-microglobulin (β2ηι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the second antigen-binding domain for the polypeptide encoded by the HLA-A gene-beta 2-microglobulin (β2ιη) polypeptide complex, and wherein the HLA-A variant polypeptide is identical to the polypeptide encoded by the HLA-A gene except at one or more residues which both: (i) are located in the HLA-A epitope bound by the second antigen-binding domain, wherein the epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-A gene.

Embodiment 49A. The multi-specific ABPC of any one of embodiments 40A, 41 A, 43 A, 44A, 45 A, and 46A. wherein the KD of the second antigen-binding domain for an HLA- B variant polypeptide-beta 2-microglobulin (β2ιη) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the second antigen-binding domain for the polypeptide encoded by the HLA-B gene-beta 2-microglobulin (β2ηι) polypeptide complex, and wherein the HLA-B variant polypeptide is identical to the polypeptide encoded by the HLA-B gene except at one or more residues which both: (i) are located in the HLA-B epitope bound by the second antigen-binding domain, wherein the epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-B gene.

Embodiment 50A. The multi-specific ABPC of any one of embodiments 40A, 41A, 43 A, 44A, 45 A, and 46A. wherein the KD of the second antigen-binding domain for an HLA- C variant polypeptide-beta 2-microglobulin (β2ηι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the second antigen-binding domain for the polypeptide product of the HLA-C gene-beta 2-microglobulin (β2πι) polypeptide complex, and wherein the HLA-C variant polypeptide is identical to the polypeptide encoded by the HLA-C gene except at one or more residues which both: (i) are located in the HLA-C epitope bound by the second antigen-binding domain, wherein the epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-C gene. Embodiment 51 A. The multi-specific ABPC of any one of embodiments 40A, 41 A,

43 A, 44A, 45 A, 46A, and 48A, wherein the HLA-A gene is selected from the group consisting of: a A*24:02 gene, a A*24: 144 gene, a A*02:01 gene, a A*02:09 gene, a A*02:43N gene, a A*02:66 gene, a A*02:75 gene, a A*02:83N gene, a A*02:89 gene, a A*02:97 gene, a A*02: 132 gene, a A*02: 134 gene, a A*02: 140 gene, a A*02:241 gene, a A*02:252 gene, a A*02:256 gene, a A*02:266 gene, a A*02:291 gene, a A*02:294 gene, a A* 02 : 305N gene, a A* 11 : 01 gene, a A* 11 : 102 gene, a A* 11 : 2 IN gene, a A* 11 : 69N gene, a A* l l :86 gene, a A*01 :01 gene, a A*01 :04N gene, a A*01:22N gene, a A*01 :32 gene, a A*01 :37 gene, a A*01 :45 gene, a A*01 :56N gene, a A*01: 81 gene, a A*01 :87N gene, a A*33:03 gene, a A*33: 15 gene, a A*33:25 gene, a A*33:31 gene, a A*33:39 gene, a A*33:44 gene, a A*34:01 gene, a A*03:01 gene, a A*03:20 gene, a A*03:21N gene, a A*03:26 gene, a A*03:37 gene, a A*03:45 gene, a A*03:78 gene, a A*03: 112 gene, a A*03: 118 gene, a A*24:07 gene, a A*23:01 gene, a A*23:07N gene, a A*23: 17 gene, a A*23: 18 gene, a A* 23: 20 gene, a A*02:07 gene, a A* 02: 15N gene, a A* 02: 265 gene, a A*02:03 gene, a A*02:253 gene, a A* 02: 264 gene, a A*31 :01 gene, a A*31 : 14N gene, a A*31 :23 gene, a A*31 :46 gene, a A*31 :48 gene, a A*26:01 gene, a A*26:24 gene, a A*26:26 gene, a A*26:56 gene, a A*29:01 gene, a A*02:06 gene, a A*02: 126 gene, a A*30:01 gene, a A*30:24 gene, a A*30:02 gene, a A*30:33 gene, a A*68:01 gene, a A*68: l IN gene, a A*68:33 gene, a A*68:02 gene, a A*29:02 gene, a A*29:26 gene, a A*7401 gene, aA*7402 gene, aA*0211 gene, a A*02:69 gene, a A*32:01 gene, a A*02: 02 gene, aA*34 02 gene, aA*36 01 gene, a A*33:01 gene, a A*ll:02 gene, a A*ll 77 gene, a A*26 03 gene, aA*0205 gene, a A*02:179 gene, a A*25:01 gene, a A*25: 07 gene, a A*2403 gene, aA*2433 gene, a A*26:02 gene, a A*68:03 gene, a A*03: 02 gene, aA*6601 gene, aA*6608 gene, a A*30:04 gene, a A*02:17 gene, a A*6602 gene, a A*2410 gene, aA*0204 gene, a A*24:17 gene, a A*80:01 gene, a A*6901 gene, a A*2420 gene, aA*01 02 gene, a A*68:05 gene, a A*02:10 gene, a A*30: 10 gene, aA*3405 gene, aA*02131 gene, aA*02:16 gene, a A*02:104 gene, a A*02: 22 gene, a A*02: 20 gene, aA*01 03 gene, a A*66:03 gene, a A* 11:04 gene, a A*24: 25 gene, a A*2423 gene, and a A*02:60 gene.

Embodiment 52A. The multi-specific ABPC of any one of embodiments 40A, 41 A, 43 A, 44A, 45 A, 46 A, and 49A, wherein the HLA-B gene is selected from the group consisting of: aB*40:01 gene, aB*40:55 gene, aB*40:141 gene, aB*40:150 gene, a B*40:151 gene, aB*15:02 gene, aB*15:214 gene, aB*46:01 gene, aB*46:15N gene, a B*46:24 gene, a B*07:02 gene, a B*07:44 gene, a B*07:49N gene, a B*07:58 gene, a B*07:59 gene, a B*07:61 gene, a B*07: 120 gene, a B*07: 128 gene, a 6*07: 129 gene, a B*07:130 gene, aB*53:01 gene, aB*38:02 gene, aB*38:18 gene, aB*08:01 gene, a B*08:19N gene, aB*52:01 gene, aB*52:07 gene, aB*35:01 gene, aB*35:40Ngene, a B*35:42gene, aB*35:57 gene, aB*35:94 gene, aB*35:134N gene, aB*35:161 gene, a B*44:02 gene, aB*44:27 gene, aB*44:66 gene, aB*44:118 gene, aB*51:01 gene, a B*51:11N gene, aB*51:30 gene, aB*51:32 gene, aB*51:48 gene, aB*51:51 gene, a B*40:06 gene, aB*44:03 gene, aB*58:01 gene, aB*58:ll gene, aB*58:31N gene, a B*15:01 gene, aB*15:102 gene, aB*15:104 gene, a B* 15: 140 gene, aB*15:146 gene, a B*15:201 gene, aB*35:05 gene, aB*07:05 gene, aB*07:06 gene, aB*15:35 gene, a B*40:02 gene, a B*40:56 gene, a B*40:97 gene, a B*40: 144N gene, a B*54:01 gene, a B*54:17 gene, aB*18:01 gene, aB*18:17N gene, aB*18:53 gene, aB*35:03 gene, a B*35:70 gene, aB*57:01 gene, aB*57:29 gene, aBⁱ57:37 gene, a B* 15:03 gene, a B*15:103 gene, aB*13:01 gene, aB*27:05 gene, aB*27:13 gene, aB*42:01 gene, a B*15:25 gene, aB*45:01 gene, aB*45:07 gene, aB*45:13 gene, a B* 14: 02 gene, aB*58:02 gene, aB*49:01 gene, aB*15:10 gene, aB*38:01 gene, aB*48:01 gene, aB*48:09 gene, a B*57:03 gene, a B*37:01 gene, a B*37:23 gene, a B*39:01 gene, a B*39:46 gene, a B*39:59 gene, a B*35:02 gene, aB*15:21 gene, aB*39:05 gene, a B* 13:02 gene, a B* 13:38 gene, a B*50:01 gene, aB*39:06 gene, aB*55:02 gene, aB*41:01 gene, aB*27:06 gene, aB*15:13 gene, a B*59:01 gene, aB*35:12 gene, aB*55:01 gene, a B* 15: 12 gene, a B*15:19 gene, a B*15:16gene, aB*81:01 gene, aB*81:02 gene, aB*81:03 gene, aB*51:06 gene, aB*27:04 gene, a B*27:68 gene, aB*27:69 gene, aB*35:43 gene, aB*35:67 gene, a B*35:79 gene, a B*15:ll gene, aB*35:08 gene, aB*15:18 gene, aB*15:198 gene, aB*15:17 gene, a

B*51:02 gene, aB*14:01 gene, aB*39:10 gene, aBⁱ56:04 gene, aB*15:27 gene, aB*35:17 gene, aB*15:15 gene, aB*15:07 gene, aB*67:01 gene, aB*78:01 gene, aB*56:01 gene, a B*56:24 gene, aB*41:02 gene, aB*40:05 gene, aB*42:02 gene, aB*40:03 gene, aB*40:10 gene, aB*57:02 gene, aB*15:30 gene, aB*27:02 gene, a B* 18:02 gene, aB*39:02 gene, a B*39:08 gene, aB*27:07 gene, aB*48:03 gene, aB*51:08 gene, aB*39:09 gene, aB*15:05 gene, a B*27:03 gene, a B*35:04 gene, a B*40:04 gene, a B*44:05 gene, a B*40:08 gene, a B*15:08 gene, aB*15:04 gene, aB*48:04 gene, aB*39:ll gene, aB*35:14 gene, aB*47:01 gene, a B*82:01 gene, aB*73:01 gene, aB*14:03 gene, aB*35:20 gene, a B*15:29 gene, a B*50:02 gene, aB*57:04 gene, aB*48:02 gene, aB*15:40 gene, aB*15:06 gene, aB*51:05 gene, aB*40:ll gene, aB*56:03 gene, aB*51:07 gene, aB*39:04 gene, aB*44:10 gene, a B*39:15 gene, aB*15:38 gene, aB*15:32 gene, aB*51:09 gene, aB*39:24 gene, aB*15:39 gene, a B*40:12 gene, aB*40:27 gene, aB*35:10 gene, aB*35:ll gene, a B* 15:09 gene, a B*47:03 gene, and a B*48:07 gene. Embodiment 53A. The multi-specific ABPC of any one of embodiments 40A, 41A,

43 A, 44A, 45 A, 46 A, and 50A, wherein the HLA-C gene is selected from the group consisting of: a C*07:02 gene, a C*07:50 gene, a C*07:66 gene, a C*07:74 gene, a

C*07:159 gene, a C*07:160 gene, a C*07:167 gene, a C*04:01 gene, a C*04:09N gene, a C*04:28 gene, aC*04:30gene, aC*04:41 gene, aC*04:79 gene, aC*04:82 gene, a C*04:84 gene, a C*01 :02 gene, a C*01:25 gene, a C*01:44 gene, a C*08:01 gene, a C*08:20 gene, a C*08:22 gene, a C*08:24 gene, aC*07:01 gene, aC*07:06 gene, aC*07:18 gene, aC*07:52 gene, a C*07:153 gene, a C*07: 166 gene, a C*03:03 gene, a C*03:20N gene, a C*03:62 gene, a C*06:02 gene, a C*06:46N gene, a C*06:55 gene, a C*03:04 gene, a C*03:100 gene, aC*03:101 gene, aC*03:105 gene, aC*03:106 gene, aC*15:02 gene, a C*15:13 gene, a C*15:47 gene, aC*12:02gene, aC*16:01 gene, aC*05:01 gene, aC*05:03 gene, a C*05:37 gene, a C*05:53 gene, a C*12:03 gene, a C*12:23 gene, a C*02:02 gene, a C*02:10 gene, a C*02:29 gene, aC*03:02 gene, aC*14:02 gene, aC*14:23 gene, aC*14:31 gene, aC*15:05 gene, a C*15:29 gene, a C*17:01 gene, a C*17:02 gene, a C*17:03 gene, a C*14:03 gene, a C*04:03 gene, a C*08:02 gene, a C*18:01 gene, a C* 18:02 gene, a C* 16:02 gene, a C*07:04 gene, a C*07: l 1 gene, a C*03:05 gene, a C*12:04 gene, a C*08:03 gene, a C*08:40 gene, a C*04:06 gene, a C*16:04 gene, a C*08:04 gene, a C*03:06 gene, a C*04:04 gene, a C*07:26 gene, a C*15:09 gene, a C*01 :03 gene, a C*01:24 gene, a C* 15:04 gene, and a C*04:07 gene.

Embodiment 54A. The multi-specific ABPC of any one of embodiments 40A, 41 A, 43 A, 44A, 45 A, 46A, 48A, 49A, 50A, 51 A, 52A, and 53A, wherein the PC further comprises a peptide of about 8-12 amino acids in length that is bound to the PC.

Embodiment 55A. The multi-specific ABPC of any one of embodiments 40A, 41A, 42A, 43A, 44A, 45 A, 46 A, 47A, 48A, 49A, 50A, 51 A, 52A, 53 A, and 54A, wherein the first antigen-binding domain and, if present, the second antigen-binding domain is capable of binding specifically to an epitope expressed on the surface or in a cellular compartment of human cells and an epitope that is expressed on the surface or in a cellular compartment of a cell from an Old World Monkey.

Embodiment 56A. The multi-specific ABPC of any one of embodiments 40A, 41A, 42A, 43A, 44A, 45 A, 46 A, 47A, 48A, 49A, 50A, 51 A, 52A, 53 A, 54A, and 55A, wherein the dissociation rate of the second antigen-binding domain at an acidic pH is at least 10% slower than the dissociation rate of the second antigen-binding domain at a neutral pH.

Embodiment 57A. The multi-specific ABPC of any one of embodiments 40A, 41A, 42A, 43A, 44A, 45 A, 46 A, 47A, 48A, 49A, 50A, 51 A, 52A, 53 A, 54A, and 55A, wherein the dissociation rate of the second antigen-binding domain at an acidic pH is at least 3-fold slower than the dissociation rate of the second antigen-binding domain at a neutral pH.

Embodiment 58 A. The multi-specific ABPC of any one of embodiments 40A, 41 A, 42A, 43A, 44A, 45 A, 46 A, 47A, 48A, 49A, 50A, 51 A, 52A, 53 A, 54A, and 55A, wherein the dissociation rate of the second antigen-binding domain at an acidic pH is at least 10-fold slower than the dissociation rate of the second antigen-binding domain at a neutral pH. Embodiment 59A. The multi-specific ABPC of any one of embodiments 40A, 41A, 42A, 43A, 44A, 45 A, 46A, 47A, 48A, 49A, 50A, 51 A, 52A, 53 A, 54A, 55A, 56A, 57A, and 58A, wherein the KD of the second antigen-binding domain at an acidic pH is at least 10% less than the KD of the second antigen-binding domain at a neutral pH.

Embodiment 60A. The multi-specific ABPC of any one of embodiments 40A, 41 A, 42A, 43A, 44A, 45 A, 46A, 47A, 48A, 49A, 50A, 51 A, 52A, 53 A, 54A, 55A, 56A, 57A, 58A, and 59A, wherein the KD of the second antigen-binding domain at an acidic pH is at least 3- fold less than the KD of the second antigen-binding domain at a neutral pH.

Embodiment 61 A. The multi-specific ABPC of any one of embodiments 40A, 41 A, 42A, 43A, 44A, 45 A, 46A, 47A, 48A, 49A, 50A, 51 A, 52A, 53 A, 54A, 55A, 56A, 57A, 58A, and 59A, wherein the KD of the second antigen-binding domain at an acidic pH is at least 10- fold less than the KD of the second antigen-binding domain at a neutral pH.

Embodiment 62A. The multi-specific ABPC of any one of embodiments 40A, 41 A, 42A, 43A, 44A, 45 A, 46A, 47A, 48A, 49A, 50A, 51 A, 52A, 53 A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, and 61 A, wherein the identifying antigen is a protein, a carbohydrate, or a lipid, or a combination thereof.

Embodiment 63 A. The multi-specific ABPC of any one of embodiments 40A, 41 A, 42A, 43A, 44A, 45 A, 46A, 47A, 48A, 49A, 50A, 51 A, 52A, 53 A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61 A, and 62A_; wherein the identifying antigen is an antigen that is presented on a surface of a cancer cell and the target mammalian cell is the cancer cell.

Embodiment 64 A. The multi-specific ABPC of any one of embodiments 40A, 41 A, 42A, 43A, 44A, 45 A, 46A, 47A, 48A, 49A, 50A, 51 A, 52A, 53 A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61 A, 62A, and 63A, wherein the identifying antigen is an epithelial-derived growth factor receptor (EGFR) antigen.

Embodiment 65 A. The multi-specific ABPC of any one of embodiments 40A, 41 A, 42A, 43A, 44A, 45 A, 46A, 47A, 48A, 49A, 50A, 51 A, 52A, 53 A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61 A, 62A, 63 A, and 64A, wherein the antigen-binding protein construct is cytotoxic or cytostatic to the mammalian target cell.

Embodiment 66A. The multi-specific ABPC of any one of embodiments 40A, 41 A, 42A, 43A, 44A, 45 A, 46A, 47A, 48A, 49A, 50A, 51 A, 52A, 53 A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61 A, 62A, 63A, 64A, and 65A, wherein the multi-specific ABPC comprises a single polypeptide.

Embodiment 67A. The multi-specific ABPC of embodiment 66A, wherein the first antigen-binding domain and the second antigen-binding domain are each independently selected from the group consisting of: a VHH domain, a VNAR domain, and a scFv.

Embodiment 68A. The multi-specific ABPC of embodiment 66A, wherein the ABPC is a BiTe, a (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH-CL-scFv, a HSAbody, scDiabody -HAS, or a tandem-scFv.

Embodiment 69A. The multi-specific ABPC of any one of embodiments 40A, 41 A, 42A, 43A, 44A, 45 A, 46A, 47A, 48A, 49A, 50A, 51 A, 52A, 53 A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61 A, 62A, 63A, 64A, and 65A, wherein the multi-specific ABPC comprises two or more polypeptides.

Embodiment 70A. The multi-specific ABPC of embodiment 69 A, wherein the antigen-binding protein construct is selected from the group of an antibody, a VHH-scAb, a VHH-Fab, a Dual scFab, a F(ab')2, a diabody, a crossMab, a DAF (two-in-one), a DAF (four- in-one), a DutaMab, a DT-IgG, a knobs-in-holes common light chain, a knobs-in-holes assembly, a charge pair, a Fab-arm exchange, a SEEDbody, a LUZ-Y, a Fcab, a κλ-body, an orthogonal Fab, a DVD-IgG, a IgG(H)-scFv, a scFv-(H)IgG IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG- 2scFv, scFv4-Ig, Zybody, DVI-IgG, Diabody-CH3, a triple body, a miniantibody, a minibody, a TriBi minibody, scFv-CH3 KIH, Fab-scFv, a F(ab')2-scFv2, a scFv-KIH, a Fab- scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a Diabody-Fc, a tandem scFv-Fc, an

Intrabody, a dock and lock, an ImmTAC, an IgG-IgG conjugate, a Cov-X-Body, and a scFvl- PEG-scFv2. Embodiment 71 A. The multi-specific ABPC of any one of embodiments 40A, 41 A, 42A, 43A, 44A, 45 A, 46A, 47A, 48A, 49A, 50A, 51 A, 52A, 53 A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61 A, 62A, 63 A, 64A, 65 A, 66A, 67A, 68A, 69A, and 70A, wherein at least one protein of the multi-specific ABPC is conjugated to the toxin, the radioisotope, or the drug via a cleavable linker.

Embodiment 72A. The multi-specific ABPC of any one of embodiments 40A, 41 A, 42A, 43A, 44A, 45 A, 46A, 47A, 48A, 49A, 50A, 51 A, 52A, 53 A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61 A, 62A, 63 A, 64A, 65 A, 66A, 67A, 68A, 69A, and 70A, wherein at least one protein of the multi-specific ABPC is conjugated to the toxin, the radioisotope, or the drug via a non-cleavable linker.

Embodiment 73 A. The multi-specific ABPC of any one of embodiments 40A, 41 A, and 42A, wherein the multi-specific ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC on its surface or in a cellular compartment as compared to a control ABPC.

Embodiment 74A. The multi-specific ABPC of any one of embodiments 40A, 41 A, 42A, 43A, 44A, 45 A, 46A, 47A, 48A, 49A, 50A, 51 A, 52A, 53 A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61A, 62A, 63A, 64A, 65A, 66A, 67A, 68A, 69A, 70A, 71A, 72A, amd 73A, wherein the first antigen-binding domain has a KD that is increased at an acidic pH as compared to the KD of the first antigen-binding domain at a neutral pH.

Embodiment 75A. The multi-specific ABPC of embodiment 74A, wherein the first antigen-binding domain has a KD at an acidic pH that is at least 10% increased as compared to the KD of the first antigen-binding domain at a neutral pH.

Embodiment 76A. The multi-specific ABPC of embodiment 74A, wherein the first antigen-binding domain has a KD at an acidic pH that is at least 3-fold greater than the KD of the first antigen-binding domain at a neutral pH.

Embodiment 77A. The multi-specific ABPC of embodiment 74A, wherein the first antigen-binding domain has a KD at an acidic pH that is at least 10-fold greater than the KD of the first antigen-binding domain at a neutral pH. Embodiment 78A. A kit comprising a multi-specific ABPC of any one of

embodiments 40A, 41A, 42A, 43A, 44A, 45A, 46A, 47 A, 48A, 49A, 50A, 51A, 52A, 53A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61A, 62A, 63A, 64A, 65 A, 66A, 67 A, 68A, 69A, 70A, 71A, 72A, 73 A, 74A, 75 A, 76A, and 77A.

Embodiment 79A. A method of treating a cancer characterized by having a population of cancer cells that (i) have the identifying antigen present on their surface, and (ii) have at least one of the following:

(a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced level of MHC1 presentation on their surface, and/or a reduced level of MHC1 in a cellular compartment as compared to a non-cancerous cell;

(b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced level of TAP in the endoplasmic reticulum of a cell and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell;

(c) a reduced level of expression of β2ηι polypeptide, a reduced level of β2ηι polypeptide present on their surface, and/or a reduced level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and

(d) a genetic lesion in a β2ιη gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, the method comprising:

administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23A, 24A, 25A, 26A, 27A, 28A, 29A, 30A, 31A, 32A, 33A, 34A, 35A, 36A, 37A, and 38A or the multi-specific ABPC of any one of embodiments 40A, 41A, 42A, 43A, 44A, 45A, 46A, 47 A, 48A, 49A, 50A, 51A, 52A, 53A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61A, 62A, 63A, 64A, 65 A, 66A, 67 A, 68A, 69A, 70A, 71A, 72A, 73 A, 74A, 75 A, 76A, and 77A to a subject identified as having a cancer characterized by having the population of cancer cells Embodiment 80A. A method of reducing the volume of a tumor in a subject, wherein the tumor is characterized by having a population of cancer cells that (i) have the identifying antigen present on their surface, and (ii) have at least one of the following: (a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced level of MHC1 presentation on their surface, and/or a reduced level of MHC1 in a cellular compartment as compared to a non-cancerous cell;

(b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced lev el of TAP in the endoplasmic reticulum of a cell and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell;

(c) a reduced level of expression of β2πι polypeptide, a reduced level of β2ηι polypeptide present on their surface, and/or a reduced level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and

administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23A, 24A, 25A, 26A, 27A, 28A, 29A, 30A, 31A, 32A, 33A, 34A, 35A, 36A, 37A, and 38A or the multi-specific ABPC of any one of embodiments 40A, 41A, 42A, 43A, 44A, 45A, 46A, 47 A, 48A, 49A, 50A, 51A, 52A, 53A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61A, 62A, 63A, 64A, 65 A, 66A, 67 A, 68A, 69A, 70A, 71A, 72A, 73 A, 74A, 75 A, 76A, and 77A to a subject identified as having a cancer characterized by having the population of cancer cells

Embodiment 81 A. A method of inducing cell death in a cancer cell in a subject, wherein the cancer cell (i) has the identifying antigen present on its surface, and (li) have at least one of the following:

(a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA-B, or

HLA-C gene, a reduced level of MHC1 presentation on their surface, and/or a reduced level of MHC1 in a cellular compartment as compared to a non-cancerous cell;

(c) a reduced level of expression of β2ηι polypeptide, a reduced level of β2ηι polypeptide present on their surface, and/or a reduced level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ηι gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, the method comprising:

administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23A, 24A, 25A, 26A, 27A, 28A, 29A, 30A, 31A, 32A, 33A, 34A, 35A, 36A, 37A, and 38A or the multi-specific ABPC of any one of embodiments 40A, 41A, 42A, 43A, 44A, 45A, 46A, 47 A, 48A, 49A, 50A, 51A, 52A, 53A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61A, 62A, 63A, 64A, 65 A, 66A, 67 A, 68A, 69A, 70A, 71A, 72A, 73 A, 74A, 75 A, 76A, and 77A to a subject identified as having a cancer characterized by having the population of cancer cells.

Embodiment 82A. The method of any one of embodiments 79A, 80A, and 81A, wherein the cancer is a primary tumor.

Embodiment 83A. The method of any one of embodiments 79A, 80A, and 81A, wherein the cancer is a metastasis.

Embodment 84A. The method of any one of embodiments 79A, 80A, and 81 A, wherein the cancer is a non-T-cell-infiltrating tumor.

Embodiment 85A. The method of any one of embodiments 79A, 80A, and 81A, wherein the cancer is a T-cell-infiltrating tumor. Embodiment 86A. A method of decreasing the risk of developing a metastasis or decreasing the risk of developing an additional metastasis in a subject having a cancer, wherein the cancer is characterized by having a population of cancer cells that (ι) have the identifying antigen present on their surface, and (ii) have at least one of the following:

(b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced lev el of TAP in the endoplasmic reticulum of a cell and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell; (c) a reduced level of expression of β2ηι polypeptide, a reduced level of β2ηι polypeptide present on their surface, and/or a reduced level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and

Embodiment 87A. A method of increasing the level of a multi-specific ABPC in a cellular compartment of a cancer cell in a subject as compared to the level of the multi- specific ABPC in the cellular compartment of a non-cancerous cell, wherein the cancer cell (i) has the identifying antigen present on its surface, and (ii) has at least one of the following:

administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23A, 24A, 25A, 26A, 27A, 28A, 29A, 30A, 31A, 32A, 33A, 34A, 35A, 36A, 37A, and 38A or the multi-specific ABPC of any one of embodiments 40A, 41A, 42A, 43A, 44A, 45A, 46A, 47 A, 48A, 49A, 50A, 51A, 52A, 53A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61A, 62A, 63A, 64A, 65 A, 66A, 67 A, 68A, 69A, 70A, 71A, 72A, 73 A, 74A, 75 A, 76A, and 77A to a subject identified as having a cancer characterized by having a population of the cancer cells.

Embodiment 88A. A method of decreasing the level of a multi-specific ABPC in a cellular compartment of a non-cancerous cell in a subject as compared to the level of the multi-specific ABPC in the cellular compartment of a cancerous cell in the subject, wherein the cancer cell (i) has the identifying antigen present on its surface, and (ii) has at least one of the following:

administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 1A, 2A, 3A, 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A, 23A, 24A, 25A, 26A, 27A, 28A, 29A, 30A, 31A, 32A, 33A, 34A, 35A, 36A, 37A, and 38A or the multi-specific ABPC of any one of embodiments 40A, 41A, 42A, 43A, 44A, 45A, 46A, 47 A, 48A, 49A, 50A, 51A, 52A, 53A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61A, 62A, 63A, 64A, 65 A, 66A, 67 A, 68A, 69A, 70A, 71A, 72A, 73 A, 74A, 75 A, 76A, and 77A to a subject identified as having a cancer characterized by having a population of the cancer cells. Embodiment 89A. The method of any one of embodiments 86A, 87A, and 88A, wherein the cancer is a non-T-cell-infiltrating tumor.

Embodiment 90A. The method of any one of embodiments 86A, 87A, and 88A, wherein the cancer is a T-cell infiltrating tumor.

Embodiment 91A. The method of any one of embodiments 79A, 80A, 81A, 82A, 83A, 84A, 85 A, 86A, 87A, 88A, 89A, and 90A, wherein the cellular compartment is part of the endosomal/lysosomal pathway.

Embodiment 92A. The method of any one of embodiments 79A, 80A, 81 A, 82A, 83A, 84A, 85 A, 86A, 87A, 88A, 89A, and 90A, wherein the cellular compartment is an endosome.

Exemplary Embodiments- Part B

Embodiment IB. A pharmaceutical composition comprising an effective amount of an antigen-binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex, wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ιη) polypeptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain, wherein:

the first antigen-binding domain comprises at least one paratope that comprises at least one histidine residue.

Embodiment 2B. A pharmaceutical composition comprising an effective amount of an antigen-binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex (PC), wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2πι) polypeptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain, wherein:

the ABPC has increased endosomal recycling in a mammalian cell that presents the PC on its surface or in a cellular compartment as compared to a control ABPC.

Embodiment 3B. A pharmaceutical composition comprising an effective amount of an antigen-binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding to an epitope of a beta 2-microglobulin (β2ιη) polypeptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and an additional antigen-binding domain, wherein:

Embodiment 4B. A pharmaceutical composition comprising an effective amount of an antigen-binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding to an epitope of a polypeptide complex (PC), wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2πι) polypeptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain,

wherein:

the ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC complex on its surface or in a cellular compartment as compared to a control ABPC.

Embodiment 5B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, and 4B, wherein the ABPC further comprises a second antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex, wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2πι) polypeptide, wherein:

(b) the dissociation constant (KD) of the second antigen-binding domain at an acidic pH is less than the KD at a neutral pH, and

wherein the second antigen-binding domain comprises at least one paratope that comprises at least one histidine residue. Embodiment 6B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, and 4B, wherein the ABPC further comprises a second antigen-binding domain that is capable of specifically binding an epitope of a beta 2-microglobulin (β2πι) polypeptide, wherein:

(a) the dissociation rate of the second antigen-binding domain at an acidic pH is slower than the disassociation rate at a neutral pH; or

wherein the second antigen-binding domain comprises at least one paratope that comprises at least one histidine residue.

Embodiment 7B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, and 6B, wherein the additional antigen-binding domain is capable of specifically binding to a soluble antigen or an antigen that is presented on the surface or in a cellular compartment of a target cell, or an antigen that is pericellular to a target cell.

Embodiment 8B. The pharmaceutical composition of any one of embodiments IB, 2B, 4B, 5B, and 7B, wherein the first antigen-bindmg domain and the second antigen-binding domain, if present, specifically bind(s) an epitope that comprises at least one amino acid of the polypeptide encoded by the HLA gene selected from the group consisting of HLA-A, HLA-B, and HLA-C, and at least one amino acid of the β2πι polypeptide.

Embodiment 9B. The pharmaceutical composition of any one of embodiments IB, 2B, 4B, 5B, and 7B, wherein the first antigen-binding domain and the second antigen-binding domain, if present, specifically bind(s) an epitope of the polypeptide encoded by the HLA gene selected from HLA-A, HLA-B, and HLA-C, when the polypeptide encoded by the HLA gene is bound to the β2ηι peptide.

Embodiments 10B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, and 9B, wherein the epitope of the PC is an at least partially monomorphic epitope. Embodiment 1 IB. The pharmaceutical composition of embodiment 3B or 6B, wherein the second antigen-binding domain specifically binds an epitope of the β2ιη polypeptide, when the β2πι polypeptide is bound to a polypeptide encoded by an HLA gene selected from the group consisting of HLA-A, HLA-B, and HLA-C.

Embodiment 12B. The pharmaceutical composition of any one of embodiments IB, 2B, 4B, 5B, 7B, 8B, 9B, and 10B, wherein the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-A variant polypeptide-beta 2- microglobulin (β2ηι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-A gene-beta 2-microglobulin (β2ιη) polypeptide complex,

wherein the HLA-A variant polypeptide is identical to the polypeptide encoded by the HLA-A gene except at one or more residues which both: (i) are located in the HLA-A epitope bound by the first antigen-binding domain or the second antigen-binding domain, respectively, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-A gene.

Embodiment 13B. The pharmaceutical composition of any one of embodiments IB, 2B, 4B, 5B, 7B, 8B, 9B, and 10B, wherein the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-B variant polypeptide-beta 2- microglobulin (β2ιη) poly peptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-B gene-beta 2-microglobulin (β2ιη) polypeptide complex,

wherein the HLA-B variant polypeptide is identical to the polypeptide encoded by the HLA-B gene except at one or more residues which both: (i) are located in the HLA-B epitope bound by the first antigen-binding domain or the second antigen-binding domain, respectively, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-B gene.

Embodiment 14B. The pharmaceutical composition of any one of embodiments IB, 2B, 4B, 5B, 7B, 8B, 9B, and 10B, wherein the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-C variant polypeptide-beta 2- microglobulin (β2ιτι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-C gene-beta 2-microglobulin (β2ιη) polypeptide complex,

wherein the HLA-C variant polypeptide is identical to the polypeptide encoded by the HLA-C gene except at one or more residues which both: (i) are located in the HLA-C epitope bound by the first antigen-binding domain or the second antigen-binding domain, respectively, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-C gene.

Embodiment 15B. The pharmaceutical composition of any one of embodiments IB, 2B, 4B, 5B, 7B, 8B, 9B, 10B, and 12B, wherein the HLA-A gene is selected from the group consisting of: a A*24:02 gene, a A*24: 144 gene, a A*02:01 gene, a A*02:09 gene, a A*02:43N gene, a A*02:66 gene, a A*02:75 gene, a A*02:83N gene, a A*02:89 gene, a A*02:97 gene, a A*02: 132 gene, a A*02: 134 gene, a A*02: 140 gene, a A*02:241 gene, a A*02:252 gene, a A*02:256 gene, a A*02:266 gene, a A*02:291 gene, a A*02:294 gene, a A* 02 : 305N gene, a A* 11 : 01 gene, a A* 11 : 102 gene, a A* 11 : 2 IN gene, a A* 11 : 69N gene, a A* l l :86 gene, a A*01 :01 gene, a A*01 :04N gene, a A*01:22N gene, a A*01 :32 gene, a A*01 :37 gene, a A*01 :45 gene, a A*01 :56N gene, a A*01: 81 gene, a A*01 :87N gene, a A*33:03 gene, a A*33: 15 gene, a A*33:25 gene, a A*33:31 gene, a A*33:39 gene, a A*33:44 gene, a A*34:01 gene, a A*03:01 gene, a A*03:20 gene, a A*03:21N gene, a A*03:26 gene, a A*03:37 gene, a A*03:45 gene, a A*03:78 gene, a A*03: 112 gene, a A*03: 118 gene, a A*24:07 gene, a A*23:01 gene, a A*23:07N gene, a A*23: 17 gene, a A*23: 18 gene, a A*23:20 gene, a A*02:07 gene, a A*02: 15N gene, a A*02:265 gene, a A*02:03 gene, a A*02:253 gene, a A* 02: 264 gene, a A*31 :01 gene, a A*31 : 14N gene, a A*31 :23 gene, a A*31 :46 gene, a A*31 :48 gene, a A*26:01 gene, a A*26:24 gene, a A*26:26 gene, a A*26:56 gene, a A*29:01 gene, a A*02:06 gene, a A*02: 126 gene, a A*30:01 gene, a A*30:24 gene, a A*30:02 gene, a A*30:33 gene, a A*68:01 gene, a A*68: l IN gene, a A*68:33 gene, a A*68:02 gene, a A*29:02 gene, a A*29:26 gene, a A*74:01 gene, a A*74:02 gene, a A*02: l l gene, a A*02:69 gene, a A*32:01 gene, a A*02:02 gene, a A*34:02 gene, a A*36:01 gene, a A*33:01 gene, a A*l l :02 gene, a A* l l :77 gene, a A*26:03 gene, a A*02:05 gene, a A*02: 179 gene, a A*25:01 gene, a A*25:07 gene, a A*24:03 gene, aA*24:33 gene, a A*26:02 gene, aA*68:03 gene, a A*03:02 gene, a A*66:01 gene, a A*66:08 gene, a A*30:04 gene, a A*02:17 gene, a A*66:02 gene, a A*24: 10 gene, a A*02:04 gene, a A*24: 17 gene, a A*80:01 gene, a A*69:01 gene, a A*24:20 gene, a A*01:02 gene, a A*68:05 gene, aA*02:10 gene, a A*30:10 gene, a A*34:05 gene, a A*02:131 gene, a A*02:16 gene, a A* 02: 104 gene, a A*02:22 gene, a A* 02: 20 gene, a A*01:03 gene, a A*66:03 gene, a A*ll:04 gene, a A*24:25 gene, a A*24:23 gene, and a A*02:60 gene.

Embodiment 16B. The pharmaceutical composition of any one of embodiments IB, 2B, 4B, 5B, 7B, 8B, 9B, 10B, and 13B, wherein the HLA-B gene is selected from the group consisting of: aB*40:01 gene, aB*40:55 gene, aB*40:141 gene, aB*40:150 gene, a B*40:151 gene, aB*15:02 gene, aB*15:214 gene, aB*46:01 gene, aB*46:15N gene, a B*46:24 gene, a B*07:02 gene, a B*07:44 gene, a B*07:49N gene, a B*07:58 gene, a B*07:59 gene, a B*07:61 gene, a B*07: 120 gene, a B*07: 128 gene, a B*07: 129 gene, a B*07:130 gene, aB*53:01 gene, aB*38:02 gene, aB*38:18 gene, aB*08:01 gene, a B*08:19N gene, aB*52:01 gene, aB*52:07 gene, aB*35:01 gene, aB*35:40Ngene, a B*35:42 gene, aB*35:57 gene, aB*35:94 gene, aBⁱ35:134N gene, aB*35:161 gene, a B*44:02 gene, aB*44:27 gene, aB*44:66 gene, aBⁱ44:118 gene, aB*51:01 gene, a B*51:11N gene, aB*51:30 gene, aB*51:32 gene, aB*51:48 gene, aB*51:51 gene, a B*40:06 gene, aB*44:03 gene, aB*58:01 gene, aB*58:ll gene, aB*58:31N gene, a B*15:01 gene, aB*15:102 gene, aB*15:104 gene, a B* 15: 140 gene, a B* 15: 146 gene, a B*15:201 gene, aB*35:05 gene, aB*07:05 gene, aB*07:06 gene, aB*15:35 gene, a B*40:02 gene, a B*40:56 gene, a B*40:97 gene, a B*40: 144N gene, a B*54:01 gene, a B*54:17 gene, aB*18:01 gene, aB*18:17N gene, aB*18:53 gene, aB*35:03 gene, a B*35:70 gene, aB*57:01 gene, aB*57:29 gene, aB*57:37 gene, a B* 15:03 gene, a B*15:103 gene, aB*13:01 gene, aB*27:05 gene, aB*27:13 gene, aB*42:01 gene, a B*15:25 gene, aB*45:01 gene, aB*45:07 gene, aB*45:13 gene, aB*14:02 gene, aB*58:02 gene, aB*49:01 gene, aB*15:10 gene, aB*38:01 gene, aBⁱ48:01 gene, aB*48:09 gene, a B*57:03 gene, a B*37:01 gene, a B*37:23 gene, a Β^φ39:01 gene, a B*39:46 gene, a B*39:59 gene, aB*35:02 gene, aB*15:21 gene, aB*39:05 gene, a B* 13:02 gene, aB*13:38 gene, a B*50:01 gene, aB*39:06 gene, aB*55:02 gene, aB*41:01 gene, aB*27:06 gene, aB*15:13 gene, aB*59:01 gene, aB*35:12 gene, aB*55:01 gene, a B* 15: 12 gene, aB*15:19 gene, a B*15:16gene, aB*81:01 gene, aB*81:02 gene, aB*81:03 gene, aB*51:06 gene, aB*27:04 gene, a B*27:68 gene, aB*27:69 gene, aB*35:43 gene, aB*35:67 gene, a B*35:79 gene, a B*15:ll gene, aB*35:08 gene, aB*15:18 gene, aB*15:198 gene, aB*15:17 gene, a B*51:02 gene, aB*14:01 gene, aB*39:10 gene, aB*56:04 gene, aB*15:27 gene, aB*35:17 gene, aB*15:15 gene, aB*15:07 gene, aB*67:01 gene, aB*78:01 gene, aB*56:01 gene, a B*56:24 gene, aB*41:02 gene, aB*40:05 gene, aB*42:02 gene, aB*40:03 gene, aB*40:10 gene, aB*57:02 gene, aB*15:30 gene, aB*27:02 gene, aB*18:02 gene, aB*39:02 gene, a B*39:08 gene, aB*27:07 gene, aB*48:03 gene, aB*51:08 gene, aB*39:09 gene, aB*15:05 gene, a B*27:03 gene, a B*35:04 gene, a B*40:04 gene, a B*44:05 gene, a B*40:08 gene, a B*15:08 gene, aB*15:04 gene, aB*48:04 gene, aB*39:ll gene, aB*35:14 gene, aB*47:01 gene, aB*82:01 gene, aB*73:01 gene, aB*14:03 gene, aB*35:20 gene, aB*15:29 gene, a B*50:02 gene, aB*57:04 gene, aB*48:02 gene, aB*15:40 gene, aB*15:06 gene, aB*51:05 gene, a B*40:ll gene, aB*56:03 gene, aB*51:07 gene, aB*39:04 gene, a B*44:10 gene, a B*39:15 gene, aB*15:38 gene, aB*15:32 gene, aB*51:09 gene, aB*39:24 gene, aB*15:39 gene, a B*40:12 gene, aB*40:27 gene, aB*35:10 gene, aB*35:ll gene, a B* 15:09 gene, a B*47:03 gene, and a B*48:07 gene.

Embodiment 17B. The pharmaceutical composition of any one of embodiments IB, 2B, 4B, 5B, 7B, 8B, 9B, 10B, and 14B, wherein the HLA-C gene is selected from the group consisting of: a C*07:02 gene, a C*07:50 gene, a C*07:66 gene, a C*07:74 gene, a

C*07:159 gene, a C*07:160 gene, a C*07:167 gene, a C*04:01 gene, a C*04:09N gene, a C*04:28 gene, aC*04:30gene, aC*04:41 gene, aC*04:79 gene, aC*04:82 gene, aC*04:84 gene, a C*01 :02 gene, a C*01:25 gene, a C*01:44 gene, a C*08:01 gene, a C*08:20 gene, a C*08:22 gene, a C*08:24 gene, aC*07:01 gene, aC*07:06 gene, aC*07:18 gene, aC*07:52 gene, a C*07:153 gene, a C*07: 166 gene, a C*03:03 gene, a C*03:20N gene, a C*03:62 gene, a C*06:02 gene, a C*06:46N gene, a C*06:55 gene, a C*03:04 gene, a C*03:100 gene, aC*03:101 gene, aC*03:105 gene, aC*03:106 gene, aC*15:02 gene, a C*15:13 gene, a C*15:47 gene, aC*12:02 gene, aC*16:01 gene, aC*05:01 gene, aC*05:03 gene, aC*05:37 gene, a 0*05:53 gene, a C*12:03 gene, a C*12:23 gene, a 0*02:02 gene, a C*02:10 gene, a C*02:29 gene, aC*03:02 gene, aC*14:02 gene, a 0*14:23 gene, aC*14:31 gene, aC*15:05 gene, a C*15:29 gene, a C*17:01 gene, a C*17:02 gene, a C*17:03 gene, a C*14:03 gene, a C*04:03 gene, aC*08:02 gene, aC*18:01 gene, aC*18:02 gene, aC*16:02 gene, aC*07:04 gene, a C*07:l 1 gene, a C*03:05 gene, a C*12:04 gene, a C*08:03 gene, a C*08:40 gene, a C*04:06 gene, aC*16:04 gene, aC*08:04 gene, aC*03:06 gene, aC*04:04 gene, a C*07:26 gene, a C*15:09 gene, a C*01 :03 gene, a C*01 :24 gene, a C* 15:04 gene, and a C*04:07 gene.

Embodiment 18B. The pharmaceutical composition of any one of embodiments IB, 2B, 4B, 5B, 7B, 8B, 9B, 10B, 12B, 13B, 14B, 15B, 16B, and 17B, wherein the PC further comprises a peptide of about 8-12 amino acids in length that is bound to the PC.

Embodiment 19B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, and 18B, wherein the first antigen-binding domain, and, if present, the second antigen-binding domain or the additional antigen-binding domain is/are capable of specifically binding to an epitope present on the surface or in a cellular compartment of human cells and an epitope that is present on the surface or in a cellular compartment of cells from an Old World Monkey. Embodiment 20B. The pharmaceutical composition of any one of embodiments IB,

2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, and 19B, wherein the dissociation rate of the first antigen-binding domain and the second antigen- binding domain, if present, at an acidic pH is/are at least 10% slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 21B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, and 19B, wherein the dissociation rate of the first antigen-binding domain and the second antigen- binding domain, if present, at an acidic pH is at least 3 -fold slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 22B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, and 19B, wherein the dissociation rate of the first antigen-binding domain and the second antigen- binding domain, if present, at an acidic pH is at least 10-fold slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 23B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, and 22B, wherein the D of the first antigen-binding domain and the second antigen- binding domain, if present, at an acidic pH is at least 10% less than the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 24B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, and 22B, wherein the KD of the first antigen-binding domain and the second antigen- binding domain, if present, at an acidic pH is at least 3-fold less than the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 25B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, and 22B, wherein the KD of the first antigen-binding domain and the second antigen- binding domain, if present, at an acidic pH is at least 10-fold less than the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 26B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, and 25B, wherein the ABPC is cytotoxic or cytostatic to a cancer cell.

Embodiment 27B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, and 26B, wherein the ABPC comprises a single polypeptide.

Embodiment 28B. The pharmaceutical composition of embodiment 27B, wherein the first antigen-binding domain and the second antigen-binding domain, if present, are each independently selected from the group consisting of: a VHH domain, a VNAR domain, and a scFv. Embodiment 29B. The pharmaceutical composition of embodiment 27B, wherein the ABPC is a BiTe, a (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH-CL-scFv, a HSAbody, scDiabody -HAS, or a tandem-scFv.

Embodiment 30B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, and 26B, wherein the ABPC comprises two or more polypeptides. Embodiment 3 IB. The pharmaceutical composition of embodiment 30B, wherein the

ABPC is selected from the group of an antibody, a VHH-scAb, a VHH-Fab, a Dual scFab, a F(ab')2, a diabody, a crossMab, a DAF (two-in-one), a DAF (four-in-one), a DutaMab, a DT- IgG, a knobs-in-holes common light chain, a knobs-in-holes assembly, a charge pair, a Fab- arm exchange, a SEEDbody, a LUZ-Y, a Fcab, a κλ-body, an orthogonal Fab, a DVD-lgG, a IgG(H)-scFv, a scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, Diabody-CH3, a triple body, a miniantibody, a minibody, a TriBi minibody, scFv-CH3 KIH, Fab-scFv, a F(ab')2-scFv2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a Diabody-Fc, a tandem scFv-Fc, an Intrabody, a dock and lock, an ImmTAC, an IgG-IgG conjugate, a Cov-X-Body, and a scFvl-PEG-scFv2.

Embodiment 32B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, and 31B, wherein at least one protein of the ABPC is conjugated to the toxin, the radioisotope, or the drug via a cleavable linker.

Embodiment 33B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, and 3 IB, wherein at least one protein of the ABPC is conjugated to the toxin, the radioisotope, or the drug via a non-cleavable linker.

Embodiment 34B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, 3 IB, 32B, and 33B, wherein the ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC on its surface or in a cellular compartment as compared to a control ABPC. Embodiment 35B. The pharmaceutical composition of any one of embodiments IB,

2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, 3 IB, 32B, 33B, and 34B, wherein the additional antigen-binding domain has a KD that is increased at an acidic pH as compared to the KD of the additional antigen-binding domain at a neutral pH.

Embodiment 36B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, 3 IB, 32B, 33B, and 34B, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 10% increased as compared to the KD of the additional antigen-binding domain at a neutral pH.

Embodiment 37B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, 3 IB, 32B, 33B, and 34B, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 3-fold greater than the KD of the additional antigen-binding domain at a neutral pH.

Embodiment 38B. The pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, 3 IB, 32B, 33B, and 34B, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 10-fold greater than the KD of the additional antigen-binding domain at a neutral pH.

Embodiment 39B. A kit comprising at least one dose of the pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, 31B, 32B, 33B, 34B, 35B, 36B, 37B, and 38B. Embodiment 40B. An antigen-binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex (PC), wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2πι) poly peptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain, wherein:

wherein:

Embodiment 4 IB. An antigen-binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex (PC), wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2ηι) polypeptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain,

wherein:

Embodiment 42B. An antigen-binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding to an epitope of 2-microglobulin (β2ιη) polypeptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain,

wherein: (a) the dissociation rate of the first antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or

Embodiment 43B. An antigen-binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding to an epitope of polypeptide complex (PC), wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2πι) poly peptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain,

wherein:

Embodiment 44B. The ABPC of any one of embodiments 40B, 41B, 42B, and 43B, wherein the ABPC further comprises a second antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex, wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2πι) polypeptide, wherein:

wherein the second antigen-binding domain comprises at least one paratope that comprises at least one histidine residue. Embodiment 45B. The ABPC of any one of embodiments 40B, 41B, 42B, and 43B, wherein the ABPC further comprises a second antigen-binding domain that is capable of specifically binding an epitope of a beta 2-microglobulin (β2πι) polypeptide,

wherein:

(b) the dissociation constant (Kx>) of the second antigen-binding domain at an acidic pH is less than the KD at a neutral pH, and

Embodiment 46B. The ABPC of any one of embodiments 40B, 41B, 42B, and 43B, wherein the additional antigen-binding domain is capable of specifically binding to a soluble antigen or an antigen that is presented on the surface or in a cellular compartment of a target cell, or an antigen that is pericellular to a target cell.

Embodiment 47B. The ABPC of any one of embodiments 40B, 41B, 42B, and 43B, wherein the first antigen-binding domain and the second antigen-binding domain, if present, specifically bind(s) an epitope that comprises at least one amino acid of the polypeptide encoded by the HLA gene selected from the group consisting of HLA-A, HLA-B, and HLA- C, and at least one amino acid of the β2πι polypeptide.

Embodiment 48B. The ABPC of any one of embodiments 40B, 41B, 42B, and 43B, wherein the first antigen-binding domain and the second antigen-binding domain, if present, specifically bind(s) an epitope of the polypeptide encoded by the HLA gene selected from HLA-A, HLA-B, and HLA-C, when the polypeptide encoded by the HLA gene is bound to the β2ηι peptide.

Embodiment 49B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, and 48B, wherein the epitope of the PC is an at least partially monomorphic epitope. Embodiment 50B. The ABPC of any one of embodiments 42B, 44B, and 45B, wherein the second antigen-binding domain specifically binds an epitope of the β2ιη polypeptide, when the β2πι polypeptide is bound to a polypeptide encoded by an HLA gene selected from the group consisting of HLA-A, HLA-B, and HLA-C.

Embodiment 5 IB. The ABPC of any one of embodiments 40B, 41B, 43B, 44B, 46B, 47B, 48B, and 49B, wherein the KD of the first antigen-binding domain and the second antigen-binding domain, if present, for an HLA-A variant polypeptide-beta 2-microglobulin (β2ηι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-A gene-beta 2-microglobulin (β2ηι) polypeptide complex,

Embodiment 52B. The ABPC of any one of embodiments 40B, 41B, 43B, 44B, 46B, 47B, 48B, and 49B, wherein the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-B variant polypeptide-beta 2-microglobulin (β2ιη) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-B gene-beta 2-microglobulin (β2πι) polypeptide complex,

Embodiment 53B. The ABPC of any one of embodiments 40B, 41B, 43B, 44B, 46B, 47B, 48B, and 49B, wherein the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-C variant polypeptide-beta 2-microglobulin (β2ιη) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-C gene-beta 2-microglobulin (β2πι) polypeptide complex,

Embodiment 54B. The ABPC of any one of embodiments 40B, 41B, 43B, 44B, 46B, 47B, 48B, 49B, and 5 IB, wherein the HLA-A gene is selected from the group consisting of: a A*24:02 gene, a A*24: 144 gene, a A*02:01 gene, a A*02:09 gene, a A*02:43N gene, a A*02:66 gene, a A*02:75 gene, a A*02:83N gene, a A*02: 89 gene, a A*02:97 gene, a A*02: 132 gene, a A*02: 134 gene, a A*02: 140 gene, a A* 02: 241 gene, a A*02:252 gene, a A*02:256 gene, a A*02:266 gene, a A*02:291 gene, a A*02:294 gene, a A*02:305N gene, a A* 11 :01 gene, a A* l 1 : 102 gene, a A*11 :21N gene, a A*11 :69N gene, a A* 11 :86 gene, a A*01 :01 gene, a A*01 :04N gene, a A*01 :22N gene, a A*01:32 gene, a A*01 :37 gene, a A*01 :45 gene, a A*01 :56N gene, a A*01 :81 gene, a A*01:87N gene, a A*33:03 gene, a A*33: 15 gene, a A*33:25 gene, a A*33:31 gene, a A*33:39 gene, a A*33:44 gene, a A*34:01 gene, a A*03:01 gene, a A*03:20 gene, a A*03:21N gene, a A*03:26 gene, a A*03:37 gene, a A*03:45 gene, a A*03:78 gene, a A*03: 112 gene, a A*03: 118 gene, a A*24:07 gene, a A*23:01 gene, a A*23:07N gene, a A*23: 17 gene, a A*23: 18 gene, a A*23:20 gene, a A*02:07 gene, a A* 02: 15N gene, a A*02:265 gene, a A*02:03 gene, a A*02:253 gene, a A*02:264 gene, a A*31 :01 gene, a A*31 : 14N gene, a A*31 :23 gene, a A*31 :46 gene, a A*31 :48 gene, a A*26:01 gene, a A*26:24 gene, a A*26:26 gene, a A*26:56 gene, a A*29:01 gene, a A*02:06 gene, a A*02: 126 gene, a A*30:01 gene, a A*30:24 gene, a A* 30: 02 gene, a A*30:33 gene, a A*68:01 gene, a A*68: l lN gene, a A*68:33 gene, a A*68:02 gene, a A*29:02 gene, a A*29:26 gene, a A*74:01 gene, a A*74:02 gene, a A*02: 11 gene, a A*02:69 gene, a A*32:01 gene, a A*02:02 gene, a A*34:02 gene, a A*36:01 gene, a A*33:01 gene, a A*l 1:02 gene, a A*l l :77 gene, a A*26:03 gene, a A*02:05 gene, a A*02: 179 gene, a A*25:01 gene, a A*25:07 gene, a A*24:03 gene, a A*24:33 gene, a A*26:02 gene, a A*68:03 gene, aA*03:02 gene, a A*66:01 gene, a A*66:08 gene, a A*30:04 gene, a A*02:17 gene, aA*66:02 gene, a A*24:10 gene, a A*02:04 gene, a A*24:17 gene, a A*80:01 gene, aA*69:01 gene, a A*24:20 gene, a A*01:02 gene, a A*68:05 gene, a A*02:10 gene, a A*30:10 gene, a A*34:05 gene, a A*02:131 gene, a A* 02: 16 gene, a A* 02: 104 gene, a A* 02: 22 gene, a A*02:20 gene, a A*01:03 gene, a A*66:03 gene, a A*l 1:04 gene, aA*24:25 gene, a A*24:23 gene, and a A*02:60 gene.

Embodiment 55B. The ABPC of any one of embodiments 40B, 41B, 43B, 44B, 46B, 47B, 48B, 49B, and 52B, wherein the HLA-B gene is selected from the group consisting of: aB*40:01 gene, aB*40:55 gene, aB*40:141 gene, aB*40:150 gene, aB*40:151 gene, a B*15:02 gene, aB*15:214 gene, aB*46:01 gene, aB*46:15N gene, aB*46:24 gene, a B*07:02 gene, a B*07:44 gene, a B*07:49N gene, a B*07:58 gene, a B*07:59 gene, a B*07:61 gene, aB*07:120 gene, aB*07:128 gene, aB*07:129 gene, a B*07: 130 gene, a B*53:01 gene, aB*38:02 gene, aB*38:18gene, aB*08:01 gene, aB*08:19N gene, a B*52:01 gene, aB*52:07 gene, aB*35:01 gene, aB*35:40N gene, aB*35:42 gene, a B*35:57 gene, aB*35:94 gene, aB*35:134N gene, aB*35:161 gene, a B* 44: 02 gene, a B*44:27 gene, aB*44:66 gene, aB*44:118 gene, aB*51:01 gene, aB*51:llN gene, a B*51:30gene, aB*51:32 gene, aB*51:48 gene, aB*51:51 gene, aB*40:06 gene, aB*44:03 gene, aB*58:01 gene, aB*58:ll gene, aB*58:31N gene, a B* 15:01 gene, aB*15:102 gene, aB*15:104 gene, aB*15:140 gene, aB*15:146 gene, aB*15:201 gene, aB*35:05 gene, a B*07:05 gene, aB*07:06 gene, aB*15:35 gene, aB*40:02 gene, aB*40:56 gene, aB*40:97 gene, aB*40:144Ngene, aB*54:01 gene, aB*54:17 gene, aB*18:01 gene, aB*18:17N gene, a B* 18:53 gene, aB*35:03 gene, aB*35:70 gene, aB*57:01 gene, a B*57:29 gene, a B*57:37 gene, aB*15:03 gene, aB*15:103 gene, aB*13:01 gene, aB*27:05 gene, a

B*27:13 gene, aB*42:01 gene, aB*15:25 gene, aB*45:01 gene, aB*45:07 gene, aB*45:13 gene, aB*14:02 gene, aB*58:02 gene, aB*49:01 gene, aB*15:10 gene, aB*38:01 gene, a B*48:01 gene, aB*48:09 gene, aB*57:03 gene, aBⁱ37:01 gene, aB*37:23 gene, aB*39:01 gene, a B*39:46 gene, aB*39:59 gene, aB*35:02 gene, a B* 15:21 gene, a B*39:05 gene, a B*13:02gene, aB*13:38 gene, aB*50:01 gene, aB*39:06 gene, aB*55:02 gene, aB*41:01 gene, aB*27:06 gene, aB*15:13 gene, aB*59:01 gene, aB*35:12 gene, aB*55:01 gene, a B*15:12gene, aB*15:19 gene, aB*15:16 gene, aB*81:01 gene, aB*81:02 gene, aB*81:03 gene, a B*51:06 gene, aB*27:04 gene, aB*27:68 gene, aB*27:69 gene, a B*35:43 gene, a B*35:67 gene, aB*35:79 gene, aB*15:ll gene, aB*35:08 gene, aB*15:18 gene, a B*15:198 gene, aB*15:17 gene, aB*51:02 gene, aB*14:01 gene, aB*39:10 gene, a B*56:04 gene, aB*15:27 gene, aB*35:17 gene, aB*15:15 gene, aB*15:07 gene, aB*67:01 gene, aB*78:01 gene, aB*56:01 gene, aB*56:24 gene, aB*41:02 gene, aB*40:05 gene, a B*42:02 gene, aB*40:03 gene, aB*40:10 gene, aB*57:02 gene, a B* 15:30 gene, aB*27:02 gene, a B* 18:02 gene, aB*39:02 gene, aB*39:08 gene, aBⁱ27:07 gene, aB*48:03 gene, a B*51:08 gene, aB*39:09 gene, aB*15:05 gene, aBⁱ27:03 gene, aB*35:04 gene, aB*40:04 gene, aB*44:05 gene, aB*40:08 gene, aB*15:08 gene, aB*15:04 gene, aB*48:04 gene, a B*39:ll gene, aB*35:14 gene, aB*47:01 gene, aB*82:01 gene, aB*73:01 gene, aB*14:03 gene, aB*35:20 gene, aB*15:29 gene, aB*50:02 gene, aB*57:04 gene, aB*48:02 gene, a B*15:40 gene, aB*15:06 gene, aB*51:05 gene, aB*40:ll gene, aB*56:03 gene, aB*51:07 gene, a B*39:04 gene, aB*44:10 gene, aB*39:15 gene, a B* 15:38 gene, a B* 15:32 gene, a B*51:09 gene, aB*39:24 gene, aB*15:39 gene, aB*40:12 gene, aB*40:27 gene, aB*35:10 gene, a B*35:ll gene, aB*15:09 gene, aB*47:03 gene, and aB*48:07 gene.

Embodiment 56B. The ABPC of any one of embodiments 40B, 41B, 43B, 44B, 46B, 47B, 48B, 49B, and 53B, wherein the HLA-C gene is selected from the group consisting of: a C*07:02 gene, a C*07:50 gene, a C*07:66 gene, a C*07:74 gene, a C*07:159 gene, a C*07:160 gene, a C*07: 167 gene, a C*04:01 gene, a C*04:09N gene, a C*04:28 gene, a C*04:30gene, aC*04:41 gene, aC*04:79 gene, aC*04:82 gene, aC*04:84 gene, aC*01:02 gene, a C*01 :25 gene, a C*01:44 gene, a C*08:01 gene, a C*08:20 gene, a C*08:22 gene, a C*08:24 gene, aC*07:01 gene, aC*07:06 gene, aC*07:18 gene, aC*07:52 gene, a C*07:153 gene, a C*07:166 gene, a C*03:03 gene, a C*03:20N gene, a C*03:62 gene, a C*06:02 gene, a C*06:46N gene, a C*06:55 gene, a C*03:04 gene, a C*03:100 gene, a C*03:101 gene, a C* 03: 105 gene, a C*03:106 gene, aC*15:02 gene, aC*15:13 gene, a

C*15:47 gene, aC*12:02 gene, aC*16:01 gene, aC*05:01 gene, aC*05:03 gene, aC*05:37 gene, a C*05:53 gene, a C*12:03 gene, a C*12:23 gene, a C*02:02 gene, a C*02:10 gene, a C*02:29 gene, aC*03:02 gene, aC*14:02 gene, a 0*14:23 gene, aC*14:31 gene, aC*15:05 gene, a C*15:29 gene, a 0*17:01 gene, a C*17:02 gene, a C*17:03 gene, a C*14:03 gene, a C*04:03 gene, aC*08:02gene, aC*18:01 gene, aC*18:02 gene, aC*16:02 gene, aC*07:04 gene, a C*07:l 1 gene, a C*03:05 gene, a C*12:04 gene, a C*08:03 gene, a C*08:40 gene, a C*04:06 gene, a C*16:04 gene, a C*08:04 gene, a C*03:06 gene, a C*04:04 gene, a C*07:26 gene, a C*15:09 gene, a C*01 :03 gene, a C*01:24 gene, a C* 15:04 gene, and a C*04:07 gene.

Embodiment 57B. The ABPC of any one of embodiments 40B, 41B, 43B, 44B, 46B, 47B, 48B, 49B, 5 IB, 52B, 53B, 54B, 55B, and 56B, wherein the PC further comprises a peptide of about 8-12 amino acids in length that is bound to the PC.

Embodiment 58B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B 55B, 56B, and 57B, wherein the first antigen-binding domain, and, if present, the second antigen-binding domain or the additional antigen-binding domain is/are capable of specifically binding to an epitope present on the surface or in a cellular compartment of human cells and an epitope that is present on the surface or in a cellular compartment of cells from an Old World Monkey. Embodiment 59B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B,

45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B 55B, 56B, 57B, and 58B, wherein the dissociation rate of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is/are at least 10% slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 60B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B 55B, 56B, 57B, and 58B, wherein the dissociation rate of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 3-fold slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 61B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B 55B, 56B, 57B, and 58B, wherein the dissociation rate of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 10-fold slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 62B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B,

45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B 55B, 56B, 57B, 58B, 59B, 60B, and 61B, wherein the KD of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 10% less than the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH. Embodiment 63B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B,

45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B 55B, 56B, 57B, 58B, 59B, 60B, and 61B, wherein the KD of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 3-fold less than the KD of the first antigen- binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 64B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B 55B, 56B, 57B, 58B, 59B, 60B, and 61B, wherein the KD of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 10-fold less than the KD of the first antigen- binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 65B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, and 64B, wherein the ABPC is less cytotoxic or cytostatic to a cancer cell.

Embodiment 66B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, and 65B, wherein the ABPC comprises a single polypeptide. Embodiment 67B. The ABPC of embodiment 66B, wherein the first antigen-binding domain and the second antigen-binding domain, if present, are each independently selected from the group consisting of: a VHH domain, a VNAR domain, and a scFv.

Embodiment 68B. The ABPC of embodiment 66B, wherein the ABPC is a BiTe, a (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH-CL-scFv, a HSAbody, scDiabody -HAS, or a tandem-scFv. Embodiment 69B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, and 65B, wherein the ABPC comprises two or more polypeptides.

Embodiment 70B. The ABPC of embodiment 69B, wherein the ABPC is selected from the group of an antibody, a VHH-scAb, a VHH-Fab, a Dual scFab, a F(ab')2, a diabody, a crossMab, a DAF (two-in-one), a DAF (four-in-one), a DutaMab, a DT-IgG, a knobs-in- holes common light chain, a knobs-in-holes assembly, a charge pair, a Fab-arm exchange, a SEEDbody, a LUZ-Y, a Fcab, a κλ-body , an orthogonal Fab, a DVD-IgG, a IgG(H)-scFv, a scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, Diabody- CH3, a triple body, a miniantibody, a minibody, a TriBi minibody, scFv-CH3 KIH, Fab-scFv, a F(ab')2-scFv2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a Diabody -Fc, a tandem scFv-Fc, an Intrabody, a dock and lock, an ImmTAC, an IgG-IgG conjugate, a Cov-X-Body, and a scFvl-PEG-scFv2.

Embodiment 71B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, and 70B, wherein at least one protein of the ABPC is conjugated to a toxin, a radioisotope, or a drug via a cleavable linker.

Embodiment 72B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, and 70B, wherein at least one protein of the ABPC is conjugated to a toxin, a radioisotope, or a drug via a non-cleavable linker.

Embodiment 73B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 7 IB, and 72B, wherein the ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC on its surface or in a cellular compartment as compared to a control ABPC.

Embodiment 74B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, and 73B, wherein the additional antigen-binding domain has a Kxi that is increased at an acidic pH as compared to the KD of the additional antigen-binding domain at a neutral pH. Embodiment 75B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B,

45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, and 73B, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 10% increased as compared to the KD of the additional antigen-binding domain at a neutral pH.

Embodiment 76B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 51B, 52B, 53B, 54B 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, and 73B, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 3-fold greater than the KD of the additional antigen-binding domain at a neutral pH.

Embodiment 77B. The ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, and 73B, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 10-fold greater than the KD of the additional antigen-binding domain at a neutral pH.

Embodiment 78B. A kit comprising an ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, 73B, 74B, 75B, 76B, and 77B.

Embodiment 79B. A method of treating a cancer characterized by having a population of cancer cells that have at least one of the following:

HLA-C gene, a reduced level of MHCl presentation on their surface, and/or a reduced level of MHCl in a cellular compartment as compared to a non-cancerous cell; (b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced lev el of TAP in the endoplasmic reticulum of a cell and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell;

(c) a reduced level of expression of β2ηι polypeptide, a reduced level of β2πι polypeptide present on their surface, and/or a reduced level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and

administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, 31B, 32B, 33B, 34B, 35B, 36B, 37B, and 38B or the ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B, 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, 73B, 74B, 75B, 76B, and 77B to a subject identified as having a cancer characterized by having the population of cancer cells

Embodiment 80B. A method of reducing the volume of a tumor in a subject, wherein the tumor is characterized by having a population of cancer cells that have at least one of the following:

(d) a genetic lesion in a β2ηι gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, the method comprising: administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, 31B, 32B, 33B, 34B, 35B, 36B, 37B, and 38B or the ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B, 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, 73B, 74B, 75B, 76B, and 77B to a subject identified as having a cancer characterized by having the population of cancer cells Embodiment 8 IB. A method of inducing cell death in a cancer cell in a subject, wherein the cancer cell has at least one of the following:

(d) a genetic lesion in a β2ηι gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, the method comprising:

administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 1 IB, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, 31B, 32B, 33B, 34B, 35B, 36B, 37B, and 38B or the ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B, 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, 73B, 74B, 75B, 76B, and 77B to a subject identified as having a cancer characterized by having the population of cancer cells. Embodiment 82B. The method of any one of embodiments 79B, 80B, and 8 IB, wherein the cancer is a primary tumor.

Embodiment 83B. The method of any one of embodiments 79B, 80B, and 8 IB, wherein the cancer is a metastasis.

Embodiment 84B. The method of any one of embodiments 79B, 80B, and 8 IB, wherein the cancer is a non-T-cell-infiltrating tumor. Embodiment 85B. The method of any one of embodiments 79B, 80B, and 8 IB, wherein the cancer is a T-cell infiltrating tumor.

Embodiment 86B. A method of decreasing the risk of developing a metastasis or decreasing the risk of developing an additional metastasis in a subject having a cancer, wherein the cancer is characterized by having a population of cancer cells that have at least one of the following:

administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 1 IB, 12B, 13B, 14B,

15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, 31B,

32B, 33B, 34B, 35B, 36B, 37B, and 38B or the ABPC of any one of embodiments 40B, 41B,

42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B, 55B, 56B, 57B, 58B,

59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, 73B, 74B, 75B, 76B, and 77B to a subject identified as having a cancer characterized by havi

population of cancer cells.

Embodiment 87B. A method of increasing the level of an ABPC in a cellular compartment of a cancer cell in a subject as compared to the level of the ABPC in the cellular compartment of a non-cancerous cell, wherein the cancer cell has at least one of the following:

(b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced level of TAP in a cellular compartment and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell;

(c) a reduced level of expression of β2ηι polypeptide, a reduced level of β2ιη polypeptide present on their surface, and/or a reduced level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and

administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments IB, 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B, 24B, 25B, 26B, 27B, 28B, 29B, 30B, 31B, 32B, 33B, 34B, 35B, 36B, 37B, and 38B or the ABPC of any one of embodiments 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 5 IB, 52B, 53B, 54B, 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B, 66B, 67B, 68B, 69B, 70B, 71B, 72B, 73B, 74B, 75B, 76B, and 77B to a subject identified as having a cancer characterized by having a population of the cancer cells.

Embodiment 88B. A method of decreasing the level of an ABPC in a cellular compartment of a non-cancerous cell in a subject as compared to the level of the ABPC in the cellular compartment of a cancerous cell in the subject, wherein the cancer cell has at least one of the following: (a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced level of MHC1 presentation on their surface, and/or a reduced level of MHC1 in a cellular compartment as compared to a non-cancerous cell;

Embodiment 89B. The method of any one of embodiments 86B, 87B, and 88B, wherein the cancer is a non-T-cell-infiltrating tumor. Embodiment 90B. The method of any one of embodiments 86B, 87B, and 88B, wherein the cancer is a T-cell infiltrating tumor.

Embodiment 9 IB. The method of any one of embodiments 79B, 80B, 8 IB, 82B, 83B, 84B, 85B, 86B, 87B, 88B, 89B, and 90B, wherein the cellular compartment is part of the endosomal/lysosomal pathway.

Embodiment 92B. The method of any one of embodiments 79B, 80B, 8 IB, 82B, 83B, 84B, 85B, 86B, 87B, 88B, 89B, and 90B, wherein the cellular compartment is an endosome. Exemplary Embodiments- Part C

Embodiment 1C. A pharmaceutical composition comprising an effective amount of an antigen-binding protein construct (ABPC) comprising:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain, wherein:

(b) the dissociation constant ( D) of the first antigen-binding domain at an acidic pH is less than the KD at a neutral pH; and

the first antigen-binding domain comprises at least one paratope that comprises at least one histidine residue, and the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC in vivo.

Embodiment 2C. A pharmaceutical composition comprising an effective amount of an antigen-binding protein construct (ABPC) comprising:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain, wherein:

the ABPC has increased endosomal recycling in a mammalian cell that presents the PC on its surface or in a cellular compartment as compared to a control ABPC; and

the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC in vivo.

Embodiment 3C. A pharmaceutical composition comprising an effective amount of an antigen-binding protein construct (ABPC) comprising: a first antigen-binding domain that is capable of specifically binding to an epitope of a beta 2-microglobulin (β2ιη) polypeptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain, wherein:

the first antigen-binding domain comprises at least one paratope that comprises at least one histidine residue; and

Embodiment 4C. A pharmaceutical composition comprising an effective amount of an antigen-binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding to an epitope of a polypeptide complex (PC), wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2πι) poly peptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain,

wherein:

the ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC complex on its surface or in a cellular compartment as compared to a control ABPC; and

Embodiment 5C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, and 4C, wherein the ABPC further comprises a second antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex, wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2πι) polypeptide, wherein: (a) the dissociation rate of the second antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or

Embodiment 6C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, and 4C, wherein the ABPC further comprises a second antigen-binding domain that is capable of specifically binding an epitope of a beta 2-microglobulin (β2πι) polypeptide, wherein:

Embodiment 7C . The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, and 6C, wherein the additional antigen-binding domain is capable of specifically binding to a soluble antigen or an antigen that is presented on the surface or in a cellular compartment of a target cell, or an antigen that is pericellular to a target cell.

Embodiment 8C. The pharmaceutical composition of any one of embodiments 1C, 2C, 4C, 5C, and 7C, wherein the first antigen-binding domain and the second antigen-binding domain, if present, specifically bind(s) an epitope that comprises at least one amino acid of the polypeptide encoded by the HLA gene selected from the group consisting of HLA-A, HLA-B, and HLA-C, and at least one amino acid of the β2ιη polypeptide. Embodiment 9C. The pharmaceutical composition of any one of embodiments 1C,

2C, 4C, 5C, and 7C, wherein the first antigen-binding domain and the second antigen-binding domain, if present, specifically bind(s) an epitope of the polypeptide encoded by the HLA gene selected from HLA-A, HLA-B, and HLA-C, when the polypeptide encoded by the HLA gene is bound to the β2ηι peptide.

Embodiment IOC. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, and 9C, wherein the epitope of the PC is an at least partially monomorphic epitope.

Embodiment 11C. The pharmaceutical composition of embodiment 3C or 6C, wherein the second antigen-binding domain specifically binds an epitope of the β2ηι polypeptide, when the β2ηι polypeptide is bound to a polypeptide encoded by an HLA gene selected from the group consisting of HLA-A, HLA-B, and HLA-C.

Embodiment 12C. The pharmaceutical composition of any one of embodiments 1C, 2C, 4C, 5C, 7C, 8C, 9C, and IOC, wherein the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-A variant polypeptide-beta 2- microglobulin (β2πι) poly peptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-A gene-beta 2-microglobulin (β2ιη) polypeptide complex,

wherein the HLA-A variant polypeptide is identical to the polypeptide encoded by the

HLA-A gene except at one or more residues which both: (i) are located in the HLA-A epitope bound by the first antigen-binding domain or the second antigen-binding domain, respectively, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-A gene.

Embodiment 13C. The pharmaceutical composition of any one of embodiments 1C, 2C, 4C, 5C, 7C, 8C, 9C, and IOC, wherein the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-B variant polypeptide-beta 2- microglobulin (β2ιη) poly peptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-B gene-beta 2-microglobulin (β2ιη) polypeptide complex, wherein the HLA-B variant polypeptide is identical to the polypeptide encoded by the HLA-B gene except at one or more residues which both: (i) are located in the HLA-B epitope bound by the first antigen-binding domain or the second antigen-binding domain, respectively, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-B gene.

Embodiment 14C. The pharmaceutical composition of any one of embodiments 1C, 2C, 4C, 5C, 7C, 8C, 9C, and IOC, wherein the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-C variant polypeptide-beta 2- microglobulin (β2ηι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-C gene-beta 2-microglobulin (P2m) polypeptide complex,

wherein the HLA-C variant polypeptide is identical to the polypeptide encoded by the HLA-C gene except at one or more residues which both: (i) are located in the HLA-C epitope bound by the first antigen-binding domain or the second antigen-binding domain, respectively, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-C gene. Embodiment 15C. The pharmaceutical composition of any one of embodiments 1C,

2C, 4C, 5C, 7C, 8C, 9C, IOC, and 12C, wherein the HLA-A gene is selected from the group consisting of: a A*24:02 gene, a A*24: 144 gene, a A*02:01 gene, a A*02:09 gene, a A*02:43N gene, a A*02:66 gene, a A*02:75 gene, a A*02:83N gene, a A*02:89 gene, a A*02:97 gene, a A*02: 132 gene, a A*02: 134 gene, a A*02: 140 gene, a A*02:241 gene, a A*02:252 gene, a A*02:256 gene, a A*02:266 gene, a A*02:291 gene, a A*02:294 gene, a A* 02 : 305N gene, a A* 11 : 01 gene, a A* 11 : 102 gene, a A* 11 : 2 IN gene, a A* 11 : 69N gene, a A* l l :86 gene, a A*01 :01 gene, a A*01 :04N gene, a A*01:22N gene, a A*01 :32 gene, a A*01 :37 gene, a A*01 :45 gene, a A*01 :56N gene, a A*01: 81 gene, a A*01 :87N gene, a A*33:03 gene, a A*33: 15 gene, a A*33:25 gene, a A*33:31 gene, a A*33:39 gene, a A*33:44 gene, a A*34:01 gene, a A*03:01 gene, a A*03:20 gene, a A*03:21N gene, a A*03:26 gene, a A*03:37 gene, a A*03:45 gene, a A*03:78 gene, a A*03: 112 gene, a A*03: 118 gene, a A*24:07 gene, a A*23:01 gene, a A*23:07N gene, a A*23: 17 gene, a A*23: 18 gene, a A*23:20 gene, a A*02:07 gene, a A* 02: 15N gene, a A* 02: 265 gene, a A*02:03 gene, a A*02:253 gene, a A* 02: 264 gene, a A*31:01 gene, a A*31:14N gene, a A*31:23 gene, a A*31:46 gene, a A*31:48 gene, a A*26:01 gene, a A*26:24 gene, a A*26:26 gene, a A*26:56 gene, a A*29:01 gene, a A*02:06 gene, a A*02: 126 gene, a A*30:01 gene, a A*30:24 gene, a A*30:02 gene, a A*30:33 gene, aA*68:01 gene, a A*68:l IN gene, a A*68:33 gene, a A*68:02 gene, a A*29:02 gene, a A*29:26 gene, a A*74:01 gene, a A*74:02 gene, a A*02. l gene, a A*02:69gene, a A*32:01 gene, a A*02:02 gene, a A*34:02 gene, a A*36:01 gene, a A*33:01 gene, a A*ll:02 gene, a A*ll:77 gene, a A*26:03 gene, a A*02:05 gene, a A*02:179 gene, a A*25:01 gene, a A*25:07 gene, a A*24:03 gene, aA*24:33 gene, a A*26:02 gene, aA*68:03 gene, a A*03:02 gene, a A*66:01 gene, a A*66:08 gene, a A*30:04gene, aA*02:17 gene, a A*66:02 gene, a A*24:10 gene, a A*02:04 gene, a A*24:17 gene, aA*80:01 gene, a A*69:01 gene, a A*24:20 gene, a A*01:02 gene, a A*68:05 gene, aA*02:10 gene, a A*30:10 gene, a A*34:05 gene, a A*02:131 gene, a A*02:16 gene, a A* 02: 104 gene, a A*02:22 gene, a A*02:20 gene, a A*01:03 gene, a A*66:03 gene, a A*ll:04 gene, a A*24:25 gene, a A*24:23 gene, and a A*02:60 gene.

Embodiment 16C. The pharmaceutical composition of any one of embodiments 1C, 2C, 4C, 5C, 7C, 8C.9C, IOC, and 13C, wherein the HLA-B gene is selected from the group consisting of: aB*40:01 gene, aB*40:55 gene, aB*40:141 gene, aB*40:150 gene, a B*40:151 gene, a B* 15:02 gene, aB*15:214 gene, aB*46:01 gene, aB*46:15N gene, a B*46:24 gene, a B*07:02 gene, a B*07:44 gene, a B*07:49N gene, a B*07:58 gene, a B*07:59 gene, a B*07:61 gene, a B*07: 120 gene, a B*07: 128 gene, a B*07: 129 gene, a B*07:130 gene, a B*53:01 gene, a B*38:02 gene, a B*38:18 gene, a B*08:01 gene, a B*08:19N gene, aB*52:01 gene, aB*52:07 gene, aB*35:01 gene, aB*35:40Ngene, a B*35:42 gene, aB*35:57 gene, aB*35:94 gene, aB*35:134N gene, aB*35:161 gene, a B*44:02 gene, a B*44:27 gene, a B*44:66 gene, a B*44: 118 gene, a B*51:01 gene, a B*51:11N gene, a B*51:30 gene, a B*51:32 gene, aB*51:48 gene, aB*51:51 gene, a B*40:06 gene, aB*44:03 gene, aB*58:01 gene, aB*58:ll gene, aB*58:31N gene, a 6*15:01 gene, a B * 15 : 102 gene, a B* 15 : 104 gene, a B* 15 : 140 gene, a B* 15 : 146 gene, a B* 15:201 gene, a B*35:05 gene, a B*07:05 gene, a B*07:06 gene, a B*15:35 gene, a B*40:02 gene, a B*40:56 gene, a B*40:97 gene, a B*40: 144N gene, a B*54:01 gene, a B*54:17 gene, aB*18:01 gene, aB*18:17N gene, aB*18:53 gene, aB*35:03 gene, a B*35:70 gene, a B*57:01 gene, aB*57:29 gene, aB*57:37 gene, a B* 15:03 gene, a B*15:103 gene, aB*13:01 gene, aB*27:05 gene, aB*27:13 gene, aB*42:01 gene, a B*15:25 gene, aB*45:01 gene, aB*45:07 gene, aB*45:13 gene, aB*14:02 gene, aB*58:02 gene, aB*49:01 gene, aB*15:10 gene, aB*38:01 gene, aB*48:01 gene, aB*48:09 gene, a B*57:03 gene, aB*37:01 gene, aB*37:23 gene, aB*39:01 gene, aB*39:46 gene, aB*39:59 gene, a B*35:02 gene, aB*15:21 gene, aB*39:05 gene, a B* 13:02 gene, a B* 13:38 gene, a B*50:01 gene, aB*39:06 gene, aB*55:02 gene, aBⁱ41:01 gene, aB*27:06 gene, aB*15:13 gene, aB*59:01 gene, aB*35:12 gene, aB*55:01 gene, a B* 15: 12 gene, aB*15:19 gene, a B*15:16gene, aB*81:01 gene, aB*81:02 gene, aB*81:03 gene, aB*51:06 gene, aB*27:04 gene, aB*27:68 gene, aB*27:69 gene, aB*35:43 gene, aB*35:67 gene, aB*35:79 gene, a B*15:ll gene, aB*35:08 gene, aB*15:18 gene, aB*15:198 gene, a B* 15: 17 gene, a

B*51:02 gene, aB*14:01 gene, aB*39:10 gene, aB*56:04 gene, aB*15:27 gene, aB*35:17 gene, aB*15:15 gene, aB*15:07 gene, aB*67:01 gene, aB*78:01 gene, aB*56:01 gene, a B*56:24 gene, aB*41:02 gene, aB*40:05 gene, aB*42:02 gene, aB*40:03 gene, aB*40:10 gene, aB*57:02 gene, aB*15:30 gene, aB*27:02 gene, aB*18:02 gene, aB*39:02 gene, a B*39:08 gene, aB*27:07 gene, aB*48:03 gene, aB*51:08 gene, aB*39:09 gene, aB*15:05 gene, a B*27:03 gene, a B*35:04 gene, a B*40:04 gene, a B*44:05 gene, a B*40:08 gene, a B*15:08 gene, aB*15:04 gene, aB*48:04 gene, aBⁱ39:ll gene, aB*35:14 gene, aB*47:01 gene, aB*82:01 gene, aB*73:01 gene, aB*14:03 gene, aB*35:20 gene, aB*15:29 gene, a B*50:02 gene, aB*57:04 gene, aB*48:02 gene, aB*15:40 gene, aB*15:06 gene, aB*51:05 gene, aB*40:ll gene, aB*56:03 gene, aB*51:07 gene, aB*39:04 gene, aB*44:10 gene, a B*39:15 gene, aB*15:38 gene, aB*15:32 gene, aB*51:09 gene, aB*39:24 gene, aB*15:39 gene, aB*40:12 gene, aB*40:27 gene, aB*35:10 gene, aB*35:ll gene, aB*15:09 gene, a B*47:03 gene, and a B*48:07 gene. Embodiment 17C. The pharmaceutical composition of any one of embodiments 1C,

2C, 4C, 5C, 7C, 8C, 9C, IOC, and 14C, wherein the HLA-C gene is selected from the group consisting of: a C*07:02 gene, a C*07:50 gene, a C*07:66 gene, a C*07:74 gene, a

C*07:159 gene, a C*07:160 gene, a C*07:167 gene, a 0*04:01 gene, a C*04:09N gene, a C*04:28 gene, aC*04:30gene, aC*04:41 gene, a 0*04:79 gene, aC*04:82 gene, aC*04:84 gene, a C*01 :02 gene, a C*01:25 gene, a C*01:44 gene, a C*08:01 gene, a C*08:20 gene, a C*08:22 gene, a C*08:24 gene, aC*07:01 gene, aC*07:06 gene, aC*07:18 gene, aC*07:52 gene, a C*07:153 gene, a C*07: 166 gene, a C*03:03 gene, a C*03:20N gene, a C*03:62 gene, a C*06:02 gene, a C*06:46N gene, a C*06:55 gene, a C*03:04 gene, a C*03:100 gene, a C*03: 101 gene, a C*03: 105 gene, a C*03: 106 gene, a C*15:02 gene, a C*15: 13 gene, a C*15:47 gene, a C*12:02 gene, a C*16:01 gene, a C*05:01 gene, a C*05:03 gene, a C*05:37 gene, a C*05:53 gene, a C*12:03 gene, a C*12:23 gene, a C*02:02 gene, a C*02: 10 gene, a C*02:29 gene, a C*03:02 gene, a C*14:02 gene, a C* 14:23 gene, a C* 14:31 gene, a C*15:05 gene, a C*15:29 gene, a C*17:01 gene, a C*17:02 gene, a C* 17:03 gene, a C*14:03 gene, a C*04:03 gene, a C*08:02 gene, a C*18:01 gene, a 0* 18:02 gene, a C* 16: 02 gene, a C*07:04 gene, a C*07: l l gene, a C*03:05 gene, a C*12:04 gene, a C*08:03 gene, a C*08:40 gene, a C*04:06 gene, a C*16:04 gene, a C*08:04 gene, a C*03:06 gene, a C*04:04 gene, a C*07:26 gene, a C*15:09 gene, a C*01 :03 gene, a C*01:24 gene, a C* 15:04 gene, and a C*04:07 gene.

Embodiment 18C. The pharmaceutical composition of any one of embodiments 1C, 2C, 4C, 5C, 7C, 8C, 9C, IOC, 12C, 13C, 14C, 15C, 16C, and 17C, wherein the PC further comprises a peptide of about 8-12 amino acids in length that is bound to the PC.

Embodiment 19C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 11C, 12C, 13C, 14C, 15C, 16C, 17C, and 18C, wherein the first antigen-binding domain, and, if present, the second antigen-binding domain or the additional antigen-binding domain is/are capable of specifically binding to an epitope present on the surface or in a cellular compartment of human cells and an epitope that is present on the surface or in a cellular compartment of cells from an Old World Monkey.

Embodiment 20C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 11C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, and 19C, wherein the dissociation rate of the first antigen-binding domain and the second antigen- binding domain, if present, at an acidic pH is/are at least 10% slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH. Embodiment 21C. The pharmaceutical composition of any one of embodiments 1C,

2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 11C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, and 19C, wherein the dissociation rate of the first antigen-binding domain and the second antigen- binding domain, if present, at an acidic pH is at least 3-fold slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 22C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 1 1C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, and 19C, wherein the dissociation rate of the first antigen-binding domain and the second antigen- binding domain, if present, at an acidic pH is at least 10-fold slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 23C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 1 1C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, and 22C, wherein the D of the first antigen-binding domain and the second antigen- binding domain, if present, at an acidic pH is at least 10% less than the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 24C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 1 1C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, and 22C, wherein the KD of the first antigen-binding domain and the second antigen- binding domain, if present, at an acidic pH is at least 3-fold less than the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 25C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 1 1C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, and 22C, wherein the KD of the first antigen-binding domain and the second antigen- binding domain, if present, at an acidic pH is at least 10-fold less than the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 26C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 1 1C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, and 25C, wherein the ABPC is cytotoxic or cytostatic to a cancer cell. Embodiment 27C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 11C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, and 26C, wherein the ABPC comprises a single polypeptide. Embodiment 28C. The pharmaceutical composition of embodiment 27C, wherein the first antigen-binding domain and the second antigen-binding domain, if present, are each independently selected from the group consisting of: a VHH domain, a VNAR domain, and a scFv. Embodiment 29C. The pharmaceutical composition of embodiment 27C, wherein the

ABPC is a BiTe, a (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH-CL-scFv, a HSAbody, scDiabody -HAS, or a tandem-scFv.

Embodiment 30C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 11C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, and 26C, wherein the ABPC comprises two or more polypeptides.

Embodiment 31 C. The pharmaceutical composition of embodiment 30C, wherein the ABPC is selected from the group of an antibody, a VHH-scAb, a VHH-Fab, a Dual scFab, a F(ab')2, a diabody, a crossMab, a DAF (two-in-one), a DAF (four-in-one), a DutaMab, a DT- IgG, a knobs-in-holes common light chain, a knobs-in-holes assembly, a charge pair, a Fab- arm exchange, a SEEDbody, a LUZ-Y, a Fcab, a κλ-body, an orthogonal Fab, a DVD-IgG, a IgG(H)-scFv, a scFv-(H)IgG, IgG(L)-scFv scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, Diabody-CH3, a triple body, a miniantibody, a minibody, a TriBi mmibody, scFv-CH3 KIH, Fab-scFv, a F(ab')2-scFv2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a Diabody-Fc, a tandem scFv-Fc, an Intrabody, a dock and lock, an ImmTAC, an IgG-IgG conjugate, a Cov-X-Body, and a scFvl-PEG-scFv2. Embodiment 32C. The pharmaceutical composition of any one of embodiments 1C,

2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 11C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, and 31 C, wherein at least one protein of the ABPC is conjugated to the toxin, the radioisotope, or the drug via a cleavable linker. Embodiment 33C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 1 1C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, and 31 C, wherein at least one protein of the ABPC is conjugated to the toxin, the radioisotope, or the drug via a non-cleavable linker.

Embodiment 34C. The pharmaceutical composition of any one of embodiments 1C, 2C, and 3C, wherein the ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC on its surface or in a cellular compartment as compared to a control ABPC.

Embodiment 35C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 1 1C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, 31C, 32C, 33C, and 34C, wherein the additional antigen-binding domain has a KD that is increased at an acidic pH as compared to the KD of the additional antigen-binding domain at a neutral pH.

Embodiment 36C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 1 1C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, 31C, 32C, 33C, and 34C, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 10% increased as compared to the KD of the additional antigen-binding domain at a neutral pH. Embodiment 37C. The pharmaceutical composition of any one of embodiments 1C,

2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 1 1C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, 31C, 32C, 33C, and 34C, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 3-fold greater than the KD of the additional antigen-binding domain at a neutral pH.

Embodiment 38C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 1 1C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, 31C, 32C, 33C, and 34C, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 10-fold greater than the KD of the additional antigen-binding domain at a neutral pH.

Embodiment 39C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 11C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, 31C, 32C, 33C, 34C, 35C, 36C, 37C, and 38C, wherein the half-life of the ABPC in vivo is increased about 10% to about 400% as compared to the half-life of a control ABPC in vivo. Embodiment 40C. The pharmaceutical composition of any one of embodiments 1C,

2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 11C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, 31C, 32C, 33C, 34C, 35C, 36C, 37C, and 38C, wherein the half-life of the ABPC in vivo is increased about 0.5-fold to about 4-fold as compared to the half-life of a control ABPC in vivo.

Embodiment 41C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 11C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, 31C, 32C, 33C, 34C, 35C, 36C, 37C, and 38C, wherein the half-life of the ABPC in vivo is increased about 1-fold to about 4-fold as compared to the half-life of a control ABPC in vivo.

Embodiment 42C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 11C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, 31C, 32C, 33C, 34C, 35C, 36C, 37C, and 38C, wherein the half-life of the ABPC in vivo is increased about 1.5-fold to about 4-fold as compared to the half-life of a control ABPC in vivo.

Embodiment 43C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 11C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, 31C, 32C, 33C, 34C, 35C, 36C, 37C, and 38C, wherein the half-life of the ABPC in vivo is increased about 2-fold to about 4-fold as compared to the half-life of a control ABPC in vivo. Embodiment 44C. The pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 11C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, 31C, 32C, 33C, 34C, 35C, 36C, 37C, and 38C, wherein the half-life of the ABPC in vivo is increased about 2.5-fold to about 4-fold as compared to the half-life of a control ABPC in vivo.

Embodiment 45C. A kit comprising at least one dose of the pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 11C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, 31C, 32C, 33C, 34C, 35C, 36C, 37C, 38C, 39C, 40C, 41C, 42C, 43C, and 44C.

Embodiment 46C. An antigen-binding protein construct (ABPC) comprising:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain, wherein:

wherein:

Embodiment 47C. An antigen-binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex (PC), wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2πι) polypeptide; and one or both of: a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain,

wherein:

Embodiment 48C. An antigen-binding protein construct (ABPC) comprising:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain,

wherein:

Embodiment 49C. An antigen-binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding to an epitope of a polypeptide complex (PC), wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2ηι) polypeptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain,

wherein: the ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC complex on its surface or in a cellular compartment as compared to a control ABPC; and

Embodiment 50C. The ABPC of any one of embodiments 46C, 47C, 48C, and 49C, wherein the ABPC further comprises a second antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex, wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2πι) polypeptide, wherein:

Embodiment 51 C. The ABPC of any one of embodiments 46C, 47C, 48C, and 49C, wherein the ABPC further comprises a second antigen-binding domain that is capable of specifically binding an epitope of a beta 2-microglobulin (β2πι) polypeptide,

wherein:

wherein the second antigen-binding domain comprises at least one paratope that comprises at least one histidine residue. Embodiment 52C. The ABPC of any one of embodiments 46C, 47C, 48C, and 49C, wherein the additional antigen-binding domain is capable of specifically binding to a soluble antigen or an antigen that is presented on the surface or in a cellular compartment of a target cell, or an antigen that is pericellular to a target cell. Embodiment 53C. The ABPC of any one of embodiments 46C, 47C, 48C, and 49C, wherein the first antigen-binding domain and the second antigen-binding domain, if present, specifically bind(s) an epitope that comprises at least one amino acid of the polypeptide encoded by the HLA gene selected from the group consisting of HLA-A, HLA-B. and HLA- C, and at least one amino acid of the β2πι polypeptide.

Embodiment 54C. The ABPC of any one of embodiments 46C, 47C, 48C, and 49C, wherein the first antigen-binding domain and the second antigen-binding domain, if present, specifically bind(s) an epitope of the polypeptide encoded by the HLA gene selected from HLA-A, HLA-B, and HLA-C, when the polypeptide encoded by the HLA gene is bound to the β2πι peptide.

Embodiment 55C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, and 54C, wherein the epitope of the PC is an at least partially monomorphic epitope.

Embodiment 56C. The ABPC of any one of embodiments 48C, 50C, and 51C, wherein the second antigen-binding domain specifically binds an epitope of the β2ιη polypeptide, when the β2ηι polypeptide is bound to a polypeptide encoded by an HLA gene selected from the group consisting of HLA-A, HLA-B, and HLA-C.

Embodiment 57C. The ABPC of any one of embodiments 46C, 47C, 49C, 50C, 52C, 53C, 54C, and 55C, wherein the KD of the first antigen-binding domain and the second antigen-binding domain, if present, for an HLA-A variant poly peptide-beta 2-microglobulin (β2ιη) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-A gene-beta 2-microglobulin (β2ηι) polypeptide complex,

Embodiment 58C. The ABPC of any one of embodiments 46C, 47C, 49C, 50C, 52C, 53C, 54C, and 55C, wherein the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-B variant polypeptide-beta 2-microglobulin (β2ηι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-B gene-beta 2-microglobulin (β2ηι) polypeptide complex,

Embodiment 59C. The ABPC of any one of embodiments 46C, 47C, 49C, 50C, 52C, 53C, 54C, and 55C, wherein the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-C variant polypeptide-beta 2-microglobulin (β2ιη) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-C gene-beta 2-microglobulin (β2ιη) polypeptide complex,

wherein the HLA-C variant polypeptide is identical to the polypeptide encoded by the HLA-C gene except at one or more residues which both: (i) are located in the HLA-C epitope bound by the first antigen-binding domain or the second antigen-binding domain, respectively, wherein this epitope is at least partially monomorphic and (ii) are glutamic acid or aspartic acid in the polypeptide encoded by the HLA-C gene. Embodiment 60C. The ABPC of any one of embodiments 46C, 47C, 49C, 50C, 52C,

53C, 54C, 55C, and 57C, wherein the HLA-A gene is selected from the group consisting of: a A*24:02 gene, a A*24: 144 gene, a A*02:01 gene, a A*02:09 gene, a A*02:43N gene, a A*02:66 gene, a A*02:75 gene, a A*02:83N gene, a A*02: 89 gene, a A*02:97 gene, a A*02:132 gene, a A*02:134 gene, a A*02:140 gene, a A* 02: 241 gene, a A*02:252 gene, a A*02:256 gene, a A*02:266 gene, a A*02:291 gene, a A*02:294 gene, a A*02:305N gene, a A* 11:01 gene, a A*l 1:102 gene, a A*11:21N gene, a A*11:69N gene, a A* 11:86 gene, a A*01:01 gene, a A*01:04Ngene, a A*01:22N gene, a A*01:32 gene, a A*01:37 gene, a A*01:45 gene, a A*01:56Ngene, aA*01:81 gene, a A*01:87N gene, a A*33:03 gene, a A*33:15 gene, a A*33:25 gene, a A*33:31 gene, a A*33:39 gene, a A*33:44 gene, a A*34:01 gene, a A*03:01 gene, a A*03:20 gene, a A*03:21N gene, a A* 03: 26 gene, a A*03:37 gene, a A*03:45 gene, a A*03:78 gene, a A*03:112 gene, a A*03:118 gene, a A*24:07 gene, a A*23:01 gene, a A*23:07N gene, a A*23:17 gene, a A* 23: 18 gene, a A*23:20gene, a A*02:07 gene, a A* 02:15N gene, aA*02:265 gene, a A*02:03 gene, a A*02:253 gene, aA*02:264 gene, a A*31:01 gene, a A*31:14N gene, a A*31:23 gene, a A*31:46 gene, a A*31:48 gene, a A*26:01 gene, a A*26:24 gene, a A*26:26 gene, a A*26:56 gene, a A*29:01 gene, a A*02:06 gene, a A*02:126 gene, a A*30:01 gene, a A*30:24 gene, a A*30:02 gene, a A*30:33 gene, a A*68:01 gene, aA*68:llN gene, a A*68:33 gene, a A*68:02 gene, a A*29:02 gene, a A*29:26 gene, a A*74:01 gene, a A*74:02 gene, a A*02:ll gene, a A*02:69 gene, a A*32:01 gene, aA*02:02 gene, a A*34:02 gene, a A*36:01 gene, a A*33:01 gene, a A*l 1:02 gene, a A*ll:77 gene, a A*26:03 gene, a A*02:05 gene, a A*02:179 gene, a A*25:01 gene, a A*25:07 gene, a A*24:03 gene, a A*24:33 gene, a A*26:02 gene, a A*68:03 gene, aA*03:02 gene, a A*66:01 gene, a A*66:08 gene, a A*30:04 gene, a A*02:17 gene, aA*66:02 gene, a A*24:10 gene, a A*02:04 gene, a A*24:17 gene, a A*80:01 gene, aA*69:01 gene, a A*24:20 gene, a A*01:02 gene, a A*68:05 gene, a A*02:10 gene, a A*30:10 gene, a A*34:05 gene, a A*02:131 gene, a A* 02: 16 gene, a A* 02: 104 gene, a A* 02: 22 gene, a A*02:20 gene, a A*01:03 gene, a A*66:03 gene, a A*l 1:04 gene, aA*24:25 gene, a A*24:23 gene, and a A*02:60 gene.

Embodiment 61C. The ABPC of any one of embodiments 46C, 47C, 49C, 50C, 52C, 53C, 54C, 55C, and 58C, wherein the HLA-B gene is selected from the group consisting of: a 6*40:01 gene, aB*40:55 gene, aB*40:141 gene, aB*40:150 gene, aB*40:151 gene, a B*15:02 gene, aB*15:214 gene, aB*46:01 gene, aB*46:15N gene, a B*46:24 gene, a B*07:02 gene, a B*07:44 gene, a B*07:49N gene, a B*07:58 gene, a B*07:59 gene, a B*07:61 gene, aB*07:120 gene, aB*07:128 gene, aB*07:129 gene, a B*07: 130 gene, a B*53:01 gene, aB*38:02 gene, aB*38:18 gene, aB*08:01 gene, aB*08:19N gene, a B*52:01 gene, aB*52:07 gene, aB*35:01 gene, aB*35:40N gene, aB*35:42 gene, a B*35:57 gene, aB*35:94 gene, aB*35:134N gene, aB*35:161 gene, aB*44:02 gene, a B*44:27 gene, aB*44:66 gene, a B*44: 118 gene, aB*51:01 gene, aB*51:llN gene, a B*51:30gene, aB*51:32 gene, aB*51:48 gene, aB*51:51 gene, aB*40:06 gene, aB*44:03 gene, aB*58:01 gene, aB*58:ll gene, aB*58:31N gene, aB*15:01 gene, a B*15: 102 gene, a 6*15: 104 gene, a 6*15: 140 gene, aB*15:146 gene, aB*15:201 gene, aB*35:05 gene, a B*07:05 gene, aB*07:06 gene, aB*15:35 gene, aBⁱ40:02 gene, aB*40:56 gene, aB*40:97 gene, aB*40:144Ngene, aB*54:01 gene, aB*54:17 gene, aB*18:01 gene, aB*18:17N gene, aB*18:53 gene, aB*35:03 gene, aB*35:70 gene, aB*57:01 gene, aB*57:29 gene, a B*57:37 gene, aB*15:03 gene, aB*15:103 gene, aB*13:01 gene, aB*27:05 gene, a

B*27:13 gene, aB*42:01 gene, aB*15:25 gene, aB*45:01 gene, aB*45:07 gene, aB*45:13 gene, aB*14:02 gene, aB*58:02 gene, aB*49:01 gene, aB*15:10 gene, aB*38:01 gene, a B*48:01 gene, aB*48:09 gene, aB*57:03 gene, aB*37:01 gene, aB*37:23 gene, aB*39:01 gene, a B*39:46 gene, aB*39:59 gene, aB*35:02 gene, a B* 15:21 gene, a B*39:05 gene, a B*13:02gene, aB*13:38gene, aB*50:01 gene, aB*39:06 gene, aB*55:02 gene, aB*41:01 gene, a B*27:06 gene, aB*15:13 gene, aB*59:01 gene, aB*35:12 gene, a B*55:01 gene, a B*15:12gene, aB*15:19 gene, aB*15:16 gene, aB*81:01 gene, aB*81:02 gene, aB*81:03 gene, aB*51:06 gene, aB*27:04 gene, aB*27:68 gene, aBⁱ27:69 gene, aB*35:43 gene, a B*35:67 gene, aB*35:79 gene, aB*15:ll gene, aB*35:08 gene, aB*15:18 gene, a B*15:198 gene, a B* 15: 17 gene, aB*51:02 gene, aB*14:01 gene, aB*39:10gene, a

B*56:04 gene, aB*15:27 gene, aB*35:17 gene, aB*15:15 gene, aB*15:07 gene, aB*67:01 gene, aB*78:01 gene, aB*56:01 gene, aB*56:24 gene, aB*41:02 gene, aB*40:05 gene, a B*42:02 gene, aB*40:03 gene, aB*40:10 gene, aB*57:02 gene, aB*15:30 gene, aB*27:02 gene, aB*18:02 gene, aB*39:02 gene, aB*39:08 gene, aB*27:07 gene, aB*48:03 gene, a B*51:08 gene, aB*39:09 gene, aB*15:05 gene, aB*27:03 gene, aB*35:04 gene, aB*40:04 gene, aB*44:05 gene, aB*40:08 gene, aB*15:08 gene, aB*15:04 gene, aB*48:04 gene, a B*39:ll gene, aB*35:14 gene, aB*47:01 gene, aB*82:01 gene, aB*73:01 gene, aB*14:03 gene, a B*35:20 gene, a B*15:29 gene, a B*50:02 gene, a B*57:04 gene, a B*48:02 gene, a B*15:40 gene, aB*15:06 gene, aB*51:05 gene, aBⁱ40:ll gene, aB*56:03 gene, aB*51:07 gene, aB*39:04 gene, aB*44:10 gene, aB*39:15 gene, a B* 15:38 gene, aB*15:32 gene, a B*51:09 gene, aB*39:24 gene, aB*15:39 gene, aB*40:12 gene, aB*40:27 gene, aB*35:10 gene, aB*35:ll gene, aB*15:09 gene, aB*47:03 gene, and aB*48:07 gene. Embodiment 62C. The ABPC of any one of embodiments 46C, 47C, 49C, 50C, 52C, 53C, 54C, 55C, and 59C, wherein the HLA-C gene is selected from the group consisting of: a C*07:02 gene, a C*07:50 gene, a C*07:66 gene, a C*07:74 gene, a C*07: 159 gene, a C*07:160 gene, a C*07:167 gene, a C*04:01 gene, a C*04:09N gene, a C*04:28 gene, a C*04:30 gene, aC*04:41 gene, aC*04:79 gene, aC*04:82 gene, aC*04:84 gene, aC*01:02 gene, a C*01 :25 gene, a C*01:44 gene, a C*08:01 gene, a C*08:20 gene, a C*08:22 gene, a C*08:24 gene, aC*07:01 gene, aC*07:06 gene, aC*07:18 gene, aC*07:52 gene, a C*07:153 gene, a C*07:166 gene, a C*03:03 gene, a C*03:20N gene, a C*03:62 gene, a C*06:02 gene, a C*06:46N gene, a C*06:55 gene, a C*03:04 gene, a C*03:100 gene, a C*03:101 gene, a C* 03: 105 gene, a C*03:106 gene, aC*15:02 gene, aC*15:13 gene, a

C*15:47 gene, aC*12:02 gene, aC*16:01 gene, aC*05:01 gene, aC*05:03 gene, aC*05:37 gene, a C*05:53 gene, a C*12:03 gene, a C*12:23 gene, a C*02:02 gene, a C*02:10 gene, a C*02:29 gene, aC*03:02 gene, aC*14:02 gene, aC*14:23 gene, aC*14:31 gene, aC*15:05 gene, a C*15:29 gene, a C*17:01 gene, a C*17:02 gene, a C*17:03 gene, a C*14:03 gene, a C*04:03 gene, aC*08:02gene, aC*18:01 gene, aC*18:02 gene, aC*16:02 gene, aC*07:04 gene, a C*07:l 1 gene, a C*03:05 gene, a C*12:04 gene, a C*08:03 gene, a C*08:40 gene, a C*04:06 gene, aC*16:04 gene, aC*08:04 gene, a 0*03:06 gene, a C* 04: 04 gene, a C*07:26 gene, aC*15:09 gene, aC*01:03 gene, aC*01:24 gene, aC*15:04 gene, andaC*04:07 gene.

Embodiment 63C. The ABPC of any one of embodiments 46C, 47C, 49C, 50C, 52C, 53C, 54C, 55C, 57C, 58C, 59C, 60C, 61C, and 62C, wherein the PC further comprises a peptide of about 8-12 amino acids in length that is bound to the PC. Embodiment 64C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C,

51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, and 63C, wherein the first antigen-binding domain, and, if present, the second antigen-binding domain or the additional antigen-binding domain is/are capable of specifically binding to an epitope present on the surface or in a cellular compartment of human cells and an epitope that is present on the surface or in a cellular compartment of cells from an Old World Monkey.

Embodiment 65C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C,

51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, and 64C, wherein the dissociation rate of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is/are at least 10% slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 66C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, and 64C, wherein the dissociation rate of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 3-fold slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH. Embodiment 67C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C,

51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, and 64C, wherein the dissociation rate of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 10-fold slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 68C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, and 67C, wherein the KD of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 10% less than the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 69C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, and 67C, wherein the KD of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 3-fold less than the KD of the first antigen- binding domain or the second antigen-binding domain, respectively, at a neutral pH.

Embodiment 70C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, and 67C, wherein the KD of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 10-fold less than the KD of the first antigen- binding domain or the second antigen-binding domain, respectively, at a neutral pH. Embodiment 71C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, and 70C, wherein the ABPC is less cytotoxic or cytostatic to a cancer cell. Embodiment 72C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C,

51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, and 71 C, wherein the ABPC comprises a single polypeptide.

Embodiment 73. The ABPC of embodiment 72C, wherein the first antigen-binding domain and the second antigen-binding domain, if present, are each independently selected from the group consisting of: a VHH domain, a VNAR domain, and a scFv.

Embodiment 74C. The ABPC of embodiment 72C, wherein the ABPC is a BiTe, a (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH-CL-scFv, a HS Abody, scDiabody -HAS, or a tandem-scFv.

Embodiment 75C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, and 70C, wherein the ABPC comprises two or more polypeptides.

Embodiment 76C. The ABPC of embodiment 75C, wherein the ABPC is selected from the group of an antibody, a VHH-scAb, a VHH-Fab, a Dual scFab, a F(ab')2, a diabody, a crossMab, a DAF (two-in-one), a DAF (four-in-one), a DutaMab, a DT-IgG, a knobs-in- holes common light chain, a knobs-in-holes assembly, a charge pair, a Fab-arm exchange, a SEEDbody, a LUZ-Y, a Fcab, a κλ-body , an orthogonal Fab, a DVD-IgG, a IgG(H)-scFv, a scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, Diabody- CH3, a triple body, a miniantibody, a minibody, a TriBi minibody, scFv-CH3 KIH, Fab-scFv, a F(ab')2-scFv2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody -Fc, a Diabody -Fc, a tandem scFv-Fc, an Intrabody, a dock and lock, an ImmTAC, an IgG-IgG conjugate, a Cov-X-Body, and a scFvl-PEG-scFv2. Embodiment 77C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, and 76C, wherein at least one protein of the ABPC is conjugated to a toxin, a radioisotope, or a drug via a cleavable linker.

Embodiment 78C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, and 76C, wherein at least one protein of the ABPC is conjugated to a toxin, a radioisotope, or a drug via a non-cleavable linker.

Embodiment 79C. The ABPC of any one of embodiments 46C, 47C, and 48C, wherein the ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC on its surface or in a cellular compartment as compared to a control ABPC.

Embodiment 80C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, 76C, 77C, 78C, and 79C, wherein the additional antigen-binding domain has a Kx> that is increased at an acidic pH as compared to the KD of the additional antigen-binding domain at a neutral pH.

Embodiment 81C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, 76C, 77C, 78C, and 79C, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 10% increased as compared to the KD of the additional antigen-binding domain at a neutral pH.

Embodiment 82C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, 76C, 77C, 78C, and 79C, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 3-fold greater than the KD of the additional antigen-binding domain at a neutral pH. Embodiment 83C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, 76C, 77C, 78C, and 79C, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 10-fold greater than the KD of the additional antigen-binding domain at a neutral pH.

Embodiment 84C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, 76C, 77C, 78C, 79C, 80C, 81C, 82C, and 83C, wherein the half-life of the ABPC in vivo is increased about 10% to about 400% as compared to the half-life of a control ABPC in vivo.

Embodiment 85C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, 76C, 77C, 78C, 79C, 80C, 81C, 82C, and 83C, wherein the half-life of the ABPC in vivo is increased about 0.5-fold to about 4-fold as compared to the half-life of a control ABPC in vivo.

Embodiment 86C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, 76C, 77C, 78C, 79C, 80C, 81C, 82C, and 83C, wherein the half-life of the ABPC in vivo is increased about 1-fold to about 4-fold as compared to the half-life of a control ABPC in vivo. Embodiment 87C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C,

51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, 76C, 77C, 78C, 79C, 80C, 81C, 82C, and 83C, wherein the half-life of the ABPC in vivo is increased about 1.5-fold to about 4-fold as compared to the half-life of a control ABPC in vivo.

Embodiment 88C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, 76C, 77C, 78C, 79C, 80C, 81C, 82C, and 83C, wherein the half-life of the ABPC in vivo is increased about 2-fold to about 4-fold as compared to the half-life of a control ABPC in vivo.

Embodiment 89C. The ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, 76C, 77C, 78C, 79C, 80C, 81C, 82C, and 83C, wherein the half-life of the ABPC in vivo is increased about 2.5-fold to about 4-fold as compared to the half-life of a control ABPC in vivo. Embodiment 90C. A kit comprising an ABPC of any one of embodiments 46C, 47C,

48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, 76C, 77C, 78C, 79C, 80C, 81C, 82C, 83C, 84C, 85C, 86C, 87C, 88C, and 89C. Embodiment 91 C. A method of treating a cancer characterized by having a population of cancer cells that have at least one of the following:

administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 11C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, 31C, 32C, 33C, 34C, 35C, 36C, 37C, 38C, 39C, 40C, 41C, 42C, 43C, and 44C or the ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, 76C, 77C, 78C, 79C, 80C, 81C, 82C, 83C, 84C, 85C, 86C, 87C, 88C, and 89C to a subject identified as having a cancer characterized by having the population of cancer cells Embodiment 92C. A method of reducing the volume of a tumor in a subject, wherein the tumor is characterized by having a population of cancer cells that have at least one of the following:

administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 11C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, 31C, 32C, 33C, 34C, 35C, 36C, 37C, 38C, 39C, 40C, 41C, 42C, 43C, and 44C or the ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, 76C, 77C, 78C, 79C, 80C, 81C, 82C, 83C, 84C, 85C, 86C, 87C, 88C, and 89C to a subject identified as having a cancer characterized by having the population of cancer cells

Embodiment 93C. A method of inducing cell death in a cancer cell in a subject, wherein the cancer cell has at least one of the following:

(a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced level of MHC1 presentation on their surface, and/or a reduced level of MHC1 in a cellular compartment as compared to a non-cancerous cell; (b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced lev el of TAP in the endoplasmic reticulum of a cell and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell;

administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, l lC, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, 31C, 32C, 33C, 34C, 35C, 36C, 37C, 38C, 39C, 40C, 41C, 42C, 43C, and 44C or the ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, 76C, 77C, 78C, 79C, 80C, 81C, 82C, 83C, 84C, 85C, 86C, 87C, 88C, and 89C to a subject identified as having a cancer characterized by having the population of cancer cells.

Embodiment 94C. The method of any one of embodiments 91 C, 92C, and 93C, wherein the cancer is a primary tumor.

Embodiment 95C. The method of any one of embodiments 91 C, 92C, and 93C, wherein the cancer is a metastasis.

Embodiment 96C. The method of any one of embodiments 91 C, 92C, and 93C, wherein the cancer is a non-T-cell-infiltrating tumor.

Embodiment 97C. The method of any one of embodiments 91 C, 92C, and 93C, wherein the cancer is a T-cell infiltrating tumor.

Embodiment 98C. A method of decreasing the risk of developing a metastasis or decreasing the risk of developing an additional metastasis in a subject having a cancer, wherein the cancer is characterized by having a population of cancer cells that have at least one of the following: (a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced level of MHC1 presentation on their surface, and/or a reduced level of MHC1 in a cellular compartment as compared to a non-cancerous cell;

administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 11C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, 31C, 32C, 33C, 34C, 35C, 36C, 37C, 38C, 39C, 40C, 41C, 42C, 43C, and 44C or the ABPC of any one of embodiments 46C 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, 76C, 77C, 78C, 79C, 80C, 81C, 82C, 83C, 84C, 85C, 86C, 87C, 88C, and 89C to a subject identified as having a cancer characterized by having the population of cancer cells.

Embodiment 99C. A method of increasing the level of an ABPC in a cellular compartment of a cancer cell in a subject as compared to the level of the ABPC in the cellular compartment of a non-cancerous cell, wherein the cancer cell has at least one of the following:

(b) a reduced level of expression of a polypeptide encoded by a transporter associated with antigen processing (TAP), a reduced level of TAP in a cellular compartment and/or a genetic lesion in a TAP gene as compared to a non-cancerous cell; (c) a reduced level of expression of β2ηι polypeptide, a reduced level of β2ηι polypeptide present on their surface, and/or a reduced level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and

administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, 11C, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, 31C, 32C, 33C, 34C, 35C, 36C, 37C, 38C, 39C, 40C, 41C, 42C, 43C, and 44C or the ABPC of any one of embodiments 46C 47C, 48C, 49C, 50C, 51C 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, 76C, 77C, 78C, 79C, 80C, 81C, 82C, 83C, 84C, 85C, 86C, 87C, 88C, and 89C to a subject identified as having a cancer characterized by having a population of the cancer cells.

Embodiment lOOC. A method of decreasing the level of an ABPC in a cellular compartment of a non-cancerous cell in a subject as compared to the level of the ABPC in the cellular compartment of a cancerous cell in the subject, wherein the cancer cell has at least one of the following:

administering a therapeutically effective amount of the pharmaceutical composition of any one of embodiments 1C, 2C, 3C, 4C, 5C, 6C, 7C, 8C, 9C, IOC, l lC, 12C, 13C, 14C, 15C, 16C, 17C, 18C, 19C, 20C, 21C, 22C, 23C, 24C, 25C, 26C, 27C, 28C, 29C, 30C, 31C, 32C, 33C, 34C, 35C, 36C, 37C, 38C, 39C, 40C, 41C, 42C, 43C, and 44C or the ABPC of any one of embodiments 46C, 47C, 48C, 49C, 50C, 51C, 52C, 53C, 54C, 55C, 56C, 57C, 58C, 59C, 60C, 61C, 62C, 63C, 64C, 65C, 66C, 67C, 68C, 69C, 70C, 71C, 72C, 73C, 74C, 75C, 76C, 77C, 78C, 79C, 80C, 81C, 82C, 83C, 84C, 85C, 86C, 87C, 88C, and 89C to a subject identified as having a cancer characterized by having a population of the cancer cells.

Embodiment 101C. The method of any one of embodiments 98C, 99C, and lOOC, wherein the cancer is a non-T-cell-infiltrating tumor.

Embodiment 102C. The method of any one of embodiments 98C, 99C, and lOOC, wherein the cancer is a T-cell infiltrating tumor.

Embodiment 103C. The method of any one of embodiments 91C, 92C, 93C, 94C, 95C, 96C, 97C, 98C, 99C, lOOC, 101C, and 102C, wherein the cellular compartment is part of the endosomal/lysosomal pathway.

Embodiment 104C. The method of any one of embodiments 91C, 92C, 93C, 94C, 95C, 96C, 97C, 98C, 99C, lOOC, 101C, and 102C, wherein the cellular compartment is an endosome.

SEQUENCE APPENDIX (All sequences shown below are human.)

HLA-A*24:02 as exemplified by A*24:02:01 :01 ID=HLA:HLA00050 (SEQ ID NO: 1) HLA-A*24: 144 as exemplified by A*24: 144 ID=HLA:HLA05249 (SEQ ID NO: 2) HLA-A*02:01 as exemplified by A*02:01 :01 :01 ID=HLA:HLA00005 (SEQ ID NO: 3) HLA-A*02:09 as exemplified by A*02:09 ID=HLA:HLA00014 (SEQ ID NO: 4) HLA-A*02:43N as exemplified by A*02:43N ID=HLA:HLA01218 (SEQ ID NO: 5) HLA-A*02:66 as exemplified by A*02:66 ID=HLA:HLA01781 (SEQ ID NO: 6) HLA-A*02:75 as exemplified by A*02:75 ID=HLA:HLA02051 (SEQ ID NO: 7) HLA-A*02:83N as exemplified by A*02:83N ID=HLA:HLA02202 (SEQ ID NO: 8) HLA-A*02:89 as exemplified by A*02:89 ID=HLA:HLA02351 (SEQ ID NO: 9) HLA-A*02:97 as exemplified by A*02:97:01 ID=HLA:HLA02509 (SEQ ID NO: 10) HLA-A*02: 132 as exemplified by A*02: 132 ID=HLA:HLA03118 (SEQ ID NO: 11) HLA-A*02: 134 as exemplified by A*02: 134 ID=HLA:HLA03144 (SEQ ID NO: 12) HLA-A*02: 140 as exemplified by A*02: 140 ID=HLA:HLA03241 (SEQ ID NO: 13) HLA-A*02:241 as exemplified by A*02:241 ID=HLA:HLA04890 (SEQ ID NO: 14) HLA-A*02:252 as exemplified by A*02:252 ID=HLA:HLA05229 (SEQ ID NO: 15) HLA-A*02:256 as exemplified by A*02:256 ID=HLA:HLA05244 (SEQ ID NO: 16) HLA-A*02:266 as exemplified by A*02:266 ID=HLA:HLA05408 (SEQ ID NO: 17) HLA-A*02:291 as exemplified by A*02:291 ID=HLA:HLA06077 (SEQ ID NO: 18) HLA-A*02:294 as exemplified by A*02:294 ID=HLA:HLA06081 (SEQ ID NO: 19) HLA-A*02:305N as exemplified by A*02:305N ID=HLA:HLA06373 (SEQ ID NO: 20) HLA-A*11 :01 as exemplified by A*l l :01 :01 :01 ID=HLA:HLA00043 (SEQ ID NO: 21) HLA-A* 11 : 102 as exemplified by A* 11 : 102 ID=HLA:HLA06527 (SEQ ID NO: 22) HLA-A*11 :21N as exemplified by A* 11 :21N ID=HLA:HLA02052 (SEQ ID NO: 23) HLA-A*11 :69N as exemplified by A* 11 :69N ID=HLA:HLA05529 (SEQ ID NO: 24) HLA-A*11 :86 as exemplified by A* l l :86 ID=HLA:HLA06027 (SEQ ID NO: 25) HLA-A*01 :01 as exemplified by A*01 :01 :01 :01 ID=HLA:HLA00001 (SEQ ID NO: 26) HLA-A*01 :04N as exemplified by A*01 :04N ID=HLA:HLA00004 (SEQ ID NO: 27) HLA-A*01 :22N as exemplified by A*01 :22N ID=HLA:HLA02878 (SEQ ID NO: 28) HLA-A*01 :32 as exemplified by A*01 :32 ID=HLA:HLA03522 (SEQ ID NO: 29)

HLA-A*01 :37 as exemplified by A*01 :37 ID=HLA:HLA03831 (SEQ ID NO: 30)

HLA-A*01 :45 as exemplified by A*01 :45 ID=HLA:HLA04137 (SEQ ID NO: 31)

HLA-A*01 :56N as exemplified by A*01 :56N ID=HLA:HLA05224 (SEQ ID NO: 32) HLA-A*01 :81 as exemplified by A*01 :81 ID=HLA:HLA05908 (SEQ ID NO: 33) HLA-A*01 :87N as exemplified by A*01 :87N ID=HLA:HLA06531 (SEQ ID NO: 34) HLA-A*33:03 as exemplified by A*33:03:01 ID=HLA:HLA00106 (SEQ ID NO: 35) HLA-A*33: 15 as exemplified by A*33: 15 ID=HLA:HLA03246 (SEQ ID NO: 36) HLA-A*33:25 as exemplified by A*33:25 ID=HLA:HLA03915 (SEQ ID NO: 37) HLA-A*33:31 as exemplified by A*33:31 ID=HLA:HLA05367 (SEQ ID NO: 38) HLA-A*33:39 as exemplified by A*33:39 ID=HLA:HLA06055 (SEQ ID NO: 39) HLA-A*33:44 as exemplified by A*33:44 ID=HLA:HLA06372 (SEQ ID NO: 40) HLA-A*34:01 as exemplified by A*34:01 :01 ID=HLA:HLA00108 (SEQ ID NO: 41) HLA-A*03:01 as exemplified by A*03:01 :01 :01 ID=HLA:HLA00037 (SEQ ID NO: 42) HLA-A*03:20 as exemplified by A*03:20 ID=HLA:HLA02325 (SEQ ID NO: 43) HLA-A*03:21N as exemplified by A*03:21N ID=HLA:HLA02369 (SEQ ID NO: 44) HLA-A*03:26 as exemplified by A*03:26 ID=HLA:HLA02761 (SEQ ID NO: 45) HLA-A*03:37 as exemplified by A*03:37 ID=HLA:HLA03120 (SEQ ID NO: 46) HLA-A*03:45 as exemplified by A*03:45 ID=HLA:HLA03548 (SEQ ID NO: 47) HLA-A*03:78 as exemplified by A*03:78 ID=HLA:HLA05233 (SEQ ID NO: 48) HLA-A*03: 1 12 as exemplified by A*03: l 12 ID=HLA:HLA05832 (SEQ ID NO: 49) HLA-A*03: 1 18 as exemplified by A*03: l 18 ID=HLA:HLA06370 (SEQ ID NO: 50) HLA-A*24:07 as exemplified by A*24:07:01 ID=HLA:HLA00057 (SEQ ID NO: 51) HLA-A*23:01 as exemplified by A*23:01 :01 :01 ID=HLA:HLA00048 (SEQ ID NO: 52) HLA-A*23:07N as exemplified by A*23:07N ID=HLA:HLA01470 (SEQ ID NO: 53) HLA-A*23: 17 as exemplified by A*23: 17 ID=HLA:HLA03165 (SEQ ID NO: 54) HLA-A*23.18 as exemplified by A*23: 18 ID=HLA:HLA03170 (SEQ ID NO: 55) HLA-A*23:20 as exemplified by A*23:20 ID=HLA:HLA03597 (SEQ ID NO: 56) HLA-A*02:07 as exemplified by A*02:07:01 ID=HLA:HLA00012 (SEQ ID NO: 57) HLA-A*02: 15N as exemplified by A*02: 15N ID=HLA:HLA00020 (SEQ ID NO: 58) HLA-A*02:265 as exemplified by A*02:265 ID=HLA:HLA05422 (SEQ ID NO: 59) HLA-A*02:03 as exemplified by A*02:03:01 ID=HLA:HLA00008 (SEQ ID NO: 60) HLA-A*02:253 as exemplified by A*02:253 ID=HLA:HLA05231 (SEQ ID NO: 61) HLA-A*02:264 as exemplified by A*02:264 ID=HLA:HLA05420 (SEQ ID NO: 62) HLA-A*31 :01 as exemplified by A*31 :01 :02:01 ID=HLA:HLA00097 (SEQ ID NO: 63) HLA-A*31 : 14N as exemplified by A*31 : 14N ID=HLA:HLA02651 (SEQ ID NO: 64) HLA-A*31 :23 as exemplified by A*31 :23 ID=HLA:HLA03417 (SEQ ID NO: 65) HLA-A*31 :46 as exemplified by A*31 :46 ID=HLA:HLA05799 (SEQ ID NO: 66) HLA-A*31 :48 as exemplified by A*31 :48 ID=HLA:HLA06122 (SEQ ID NO: 67) HLA-A*26:01 as exemplified by A*26:01 :01 :01 ID=HLA:HLA00073 (SEQ ID NO: 68) HLA-A*26:24 as exemplified by A*26:24 ID=HLA:HLA02076 (SEQ ID NO: 69) HLA-A*26:26 as exemplified by A*26:26 ID=HLA:HLA02159 (SEQ ID NO: 70) HLA-A*26:56 as exemplified by A*26:56 ID=HLA:HLA05911 (SEQ ID NO: 71) HLA-A*29:01 as exemplified by A*29:01 :01 :01 ID=HLA:HLA00085 (SEQ ID NO: 72) HLA-A*02:06 as exemplified by A*02:06:01 :01 ID=HLA:HLA00011 (SEQ ID NO: 73) HLA-A*02: 126 as exemplified by A*02: 126 ID=HLA:HLA02964 (SEQ ID NO: 74) HLA-A*30:01 as exemplified by A*30:01 :01 ID=HLA:HLA00089 (SEQ ID NO: 75) HLA-A*30:24 as exemplified by A*30:24 ID=HLA:HLA03097 (SEQ ID NO: 76) HLA-A*30:02 as exemplified by A*30:02:01 :01 ID=HLA:HLA00090 (SEQ ID NO: 77) HLA-A*30:33 as exemplified by A*30:33 ID=HLA:HLA04637 (SEQ ID NO: 78) HLA-A*68:01 as exemplified by A*68:01 :01 :01 ID=HLA:HLA00115 (SEQ ID NO: 79) HLA-A*68: 11N as exemplified by A*68: 11N ID=HLA:HLA00973 (SEQ ID NO: 80)

HLA- ■A*68: :33 as exemplified by A* 68: :33 ID=HLA:HLA02531 (SEQ ID NO: 81)

HLA- -A*68: :02 as exemplified by A*68: :02 :01 :01 ID=HLA:HLA00117 (SEQ ID NO: 82)

HLA- -A*29: :02 as exemplified by A*29: :02 :01 :01 ID=HLA:HLA00086 (SEQ ID NO: 83)

HLA- -A*29: :26 as exemplified by A*29: :26 ID =HLA:HLA05903 (SEQ ID NO: 84)

HLA- -A*74: :01 as exemplified by A*74: :01 :01 ID=HLA:HLA00127 (SEQ ID NO: 85)

HLA- -A*74: :02 as exemplified by A*74: :02 :01 :01 ID=HLA:HLA00128 (SEQ ID NO: 86)

HLA- -A*02: : 11 as exemplified by A*02: : 11 :01 ID=HLA:HLA00016 (SEQ ID NO: 87)

HLA- -A*02: :69 as exemplified by A*02: :69 ID =HLA:HLA01903 (SEQ ID NO: 88)

HLA- -A*32: :01 as exemplified by A*32: :01 :01 :01 ID=HLA:HLA00101 (SEQ ID NO: 89)

HLA- ■A*02: :02 as exemplified by A*02: :02 :01 :01 ID=HLA:HLA00007 (SEQ ID NO: 90)

HLA- ■A*34: :02 as exemplified by A*34: :02 :01 ID=HLA:HLA00109 (SEQ ID NO: 91)

HLA- -A*36: :01 as exemplified by A*36: :01 ID =HLA:HLA00110 (SEQ ID NO: 92)

HLA- -A*33: :01 as exemplified by A*33: :01 :01 :01 ID=HLA:HLA00104 (SEQ ID NO: 93)

HLA- ^■A*l l : :02 as exemplified by A* 11 : :02 :01 ID=HLA:HLA00044 (SEQ ID NO: 94)

HLA- ^■A*l l : :77 as exemplified by A* 11 : :77 ID =HLA:HLA05798 (SEQ ID NO: 95)

HLA- -A*26: :03 as exemplified by A*26: :03 :01 ID=HLA:HLA00075 (SEQ ID NO: 96)

HLA- -A*02: :05 as exemplified by A*02: :05 :01 :01 ID=HLA:HLA00010 (SEQ ID NO: 97)

HLA-A*02: 179 as exemplified by A*02: 179 ID=HLA:HLA03833 (SEQ ID NO: 98) HLA-A*25:01 as exemplified by A*25:01 :01 :01 ID=HLA:HLA00071 (SEQ ID NO: 99) HLA-A*25:07 as exemplified by A*25:07 ID=HLA:HLA03523 (SEQ ID NO: 100) HLA-A*24:03 as exemplified by A*24:03:01 :01 ID=HLA:HLA00053 (SEQ ID NO: 101) HLA-A*24:33 as exemplified by A*24:33 ID=HLA:HLA01491 (SEQ ID NO: 102) HLA-A*26:02 as exemplified by A*26:02:01 ID=HLA:HLA00074 (SEQ ID NO: 103) HLA-A*68:03 as exemplified by A*68:03:01 ID=HLA:HLA00118 (SEQ ID NO: 104) HLA-A*03:02 as exemplified by A*03:02:01 ID=HLA:HLA00040 (SEQ ID NO: 105) HLA-A*66:01 as exemplified by A*66:01 :01 :01 ID=HLA:HLA00112 (SEQ ID NO: 106) HLA-A*66:08 as exemplified by A*66:08 ID=HLA:HLA03416 (SEQ ID NO: 107) HLA-A*30:04 as exemplified by A*30:04:01 ID=HLA:HLA00092 (SEQ ID NO: 108) HLA-A*02: 17 as exemplified by A*02: 17:01 ID=HLA:HLA00022 (SEQ ID NO: 109) HLA-A*66:02 as exemplified by A*66:02 ID=HLA:HLA00113 (SEQ ID NO: 1 10) HLA-A*24: 10 as exemplified by A*24: 10:01 ID=HLA:HLA00060 (SEQ ID NO: 111) HLA-A*02:04 as exemplified by A*02:04 ID=HLA:HLA00009 (SEQ ID NO: 112) HLA-A*24: 17 as exemplified by A*24: 17 ID=HLA:HLA00067 (SEQ ID NO: 113)

HLA-A*80:01 as exemplified by A*80:01 :01 :01 ID=HLA:HLA00130 (SEQ ID NO: 114) HLA-A*69:01 as exemplified by A*69:01 :01 :01 ID=HLA:HLA00126 (SEQ ID NO: 115) HLA-A*24:20 as exemplified by A*24:2O:Ol :01 ID=HLA:HLA00070 (SEQ ID NO: 116) HLA-A*01 :02 as exemplified by A*01 :02 ID=HLA:HLA00002 (SEQ ID NO: 117) HLA-A*68:05 as exemplified by A*68:05 ID=HLA:HLA00121 (SEQ ID NO: 118) HLA-A*02: 10 as exemplified by A*02: 10 ID=HLA:HLA00015 (SEQ ID NO: 119) HLA-A*30: 10 as exemplified by A*30: 10 ID=HLA:HLA01411 (SEQ ID NO: 120) HLA-A*34:05 as exemplified by A*34:05 ID=HLA:HLA01675 (SEQ ID NO: 121) HLA-A*02: 131 as exemplified by A*02: 131 ID=HLA:HLA03096 (SEQ ID NO: 122) HLA-A*02: 16 as exemplified by A*02: 16 ID=HLA:HLA00021 (SEQ ID NO: 123) HLA-A*02: 104 as exemplified by A*02: 104 ID=HLA:HLA02668 (SEQ ID NO: 124) HLA-A*02:22 as exemplified by A*02:22:01 :01 ID=HLA:HLA00028 (SEQ ID NO: 125) HLA-A*02:20 as exemplified by A*02:20:01 ID=HLA:HLA00026 (SEQ ID NO: 126) HLA-A*01 :03 as exemplified by A*01 :03:01 :01 ID=HLA:HLA00003 (SEQ ID NO: 127) HLA-A*66:03 as exemplified by A*66:03 ID=HLA:HLA00114 (SEQ ID NO: 128) HLA-A*11 :04 as exemplified by A* l l :04 ID=HLA:HLA00046 (SEQ ID NO: 129) HLA-A*24:25 as exemplified by A*24:25 ID=HLA:HLA01189 (SEQ ID NO: 130) HLA-A*24:23 as exemplified by A*24:23 ID=HLA:HLA01041 (SEQ ID NO: 131) HLA-A*02:60 as exemplified by A*02:60:01 ID=HLA:HLA01665 (SEQ ID NO: 132) HLA-B*40:01 as exemplified by B*40:01 :01 ID=HLA:HLA00291 (SEQ ID NO: 133) HLA-B*40:55 as exemplified by B*40:55 ID=HLA:HLA01993 (SEQ ID NO: 134) HLA-B*40: 141 as exemplified by B*40: 141 ID=HLA:HLA05282 (SEQ ID NO: 135) HLA-B*40: 150 as exemplified by B*40: 150 ID=HLA:HLA05803 (SEQ ID NO: 136) HLA-B*40: 151 as exemplified by B*40: 151 ID=HLA:HLA05805 (SEQ ID NO: 137) HLA-B* 15:02 as exemplified by B* 15:02:01 ID=HLA:HLA00165 (SEQ ID NO: 138) HLA-B* 15:214 as exemplified by B*15:214 ID=HLA:HLA06032 (SEQ ID NO: 139) HLA-B*46:01 as exemplified by B*46:01 :01 ID=HLA:HLA00331 (SEQ ID NO: 140) HLA-B*46: 15N as exemplified by B*46: 15N ID=HLA:HLA03357 (SEQ ID NO: 141) HLA-B*46:24 as exemplified by B*46:24 ID=HLA:HLA05412 (SEQ ID NO: 142) HLA-B*07:02 as exemplified by B*07:02:01 :01 ID=HLA:HLA00132 (SEQ ID NO: 143) HLA-B*07:44 as exemplified by B*07:44N ID=HLA:HLA02350 (SEQ ID NO. 144) HLA-B*07:49N as exemplified by B*07:49N ID=HLA:HLA02519 (SEQ ID NO: 145) HLA-B*07:58 as exemplified by B*07:58 ID=HLA:HLA02978 (SEQ ID NO: 146) HLA-B*07:59 as exemplified by B*07:59 ID=HLA:HLA02991 (SEQ ID NO: 147) HLA-B*07:61 as exemplified by B*07:61 ID=HLA:HLA03166 (SEQ ID NO: 148) HLA-B*07: 120 as exemplified by B*07: 120 ID=HLA:HLA06131 (SEQ ID NO: 149) HLA-B*07: 128 as exemplified by B*07: 128 ID=HLA:HLA06586 (SEQ ID NO: 150) HLA-B*07: 129 as exemplified by B*07: 129 ID=HLA:HLA06658 (SEQ ID NO: 151) HLA-B*07: 130 as exemplified by B*07: 130 ID=HLA:HLA06659 (SEQ ID NO: 152) HLA-B*53:01 as exemplified by B*53:01 :01 ID=HLA:HLA00364 (SEQ ID NO: 153) HLA-B*38:02 as exemplified by B*38:02:01 ID=HLA:HLA00268 (SEQ ID NO: 154) HLA-B*38: 18 as exemplified by B*38: 18 ID=HLA:HLA03590 (SEQ ID NO: 155) HLA-B*08:01 as exemplified by B*08:01 :01 :01 ID=HLA:HLA00146 (SEQ ID NO: 156) HLA-B*08: 19N as exemplified by B*08: 19N ID=HLA:HLA01717 (SEQ ID NO: 157)

HLA-B*52:01 as exemplified by B*52:01 :01 :01 ID=HLA:HLA00362 (SEQ ID NO: 158) HLA-B*52:07 as exemplified by B*52:07 ID=HLA:HLA02196 (SEQ ID NO: 159) HLA-B*35:01 as exemplified by B*35:01 :01 :01 ID=HLA:HLA00237 (SEQ ID NO: 160) HLA-B*35:40N as exemplified by B*35:40N ID=HLA:HLA01550 (SEQ ID NO: 161) HLA-B*35:42 as exemplified by B*35:42:01 ID=HLA:HLA01578 (SEQ ID NO: 162) HLA-B*35:57 as exemplified by B*35:57 ID=HLA:HLA02091 (SEQ ID NO: 163) HLA-B*35:94 as exemplified by B*35:94 ID=HLA:HLA03343 (SEQ ID NO: 164) HLA-B*35: 134N as exemplified by B*35: 134N ID=HLA:HLA04874 (SEQ ID NO: 165) HLA-B*35: 161 as exemplified by B*35: 161 ID=HLA:HLA06376 (SEQ ID NO: 166) HLA-B*44:02 as exemplified by B*44:02:01 :01 ID=HLA:HLA00318 (SEQ ID NO: 167) HLA-B*44:27 as exemplified by B*44:27:01 ID=HLA:HLA01489 (SEQ ID NO: 168) HLA-B*44:66 as exemplified by B*44:66 ID=HLA:HLA03601 (SEQ ID NO: 169) HLA-B*44: 118 as exemplified by B*44: 118 ID=HLA:HLA06156 (SEQ ID NO: 170) HLA-B*51 :01 as exemplified by B*51 :01 :01 :01 ID=HLA:HLA00344 (SEQ ID NO: 171) HLA-B*51 : 1 IN as exemplified by B*51 : 11N ID=HLA:HLA00356 (SEQ ID NO: 172) HLA-B*51 :30 as exemplified by B*51 :30 ID=HLA:HLA01621 (SEQ ID NO: 173) HLA-B*51 :32 as exemplified by B*51 :32 ID=HLA:HLA01657 (SEQ ID NO: 174) HLA-B*51 :48 as exemplified by B*51 :48 ID=HLA:HLA02885 (SEQ ID NO: 175) HLA-B*51 :51 as exemplified by B*51 :51 ID=HLA:HLA03123 (SEQ ID NO: 176) HLA-B*40:06 as exemplified by B*40:06:01 :01 ID=HLA:HLA00297 (SEQ ID NO: 177) HLA-B*44:03 as exemplified by B* 44:03:01 :01 ID=HLA:HLA00319 (SEQ ID NO: 178) HLA-B*58:01 as exemplified by B*58:01 :01 :01 ID=HLA:HLA00386 (SEQ ID NO: 179) HLA-B*58: 11 as exemplified by B*58: 11 ID=HLA:HLA02201 (SEQ ID NO: 180) HLA-B*58:31N as exemplified by B*58:31N ID=HLA:HLA05742 (SEQ ID NO: 181) HLA-B* 15:01 as exemplified by B* 15:01 :01 :01 ID=HLA:HLA00162 (SEQ ID NO: 182) HLA-B* 15: 102 as exemplified by B* 15: 102 ID=HLA.HLA02184 (SEQ ID NO: 183) HLA-B* 15: 104 as exemplified by B* 15: 104 ID=HLA:HLA02244 (SEQ ID NO: 184) HLA-B* 15: 140 as exemplified by B*15: 140 ID=HLA:HLA03202 (SEQ ID NO: 185) HLA-B* 15: 146 as exemplified by B*15: 146 ID=HLA:HLA03287 (SEQ ID NO: 186) HLA-B* 15:201 as exemplified by B* 15:201 ID=HLA:HLA05380 (SEQ ID NO: 187) HLA-B*35.05 as exemplified by B*35:05:01 :01 ID=HLA:HLA00241 (SEQ ID NO: 188) HLA-B*07:05 as exemplified by B*07:05:01 :01 ID=HLA:HLA00137 (SEQ ID NO: 189) HLA-B*07:06 as exemplified by B*07:06:01 ID=HLA:HLA00138 (SEQ ID NO: 190) HLA-B* 15:35 as exemplified by B* 15:35 ID=HLA:HLA00198 (SEQ ID NO: 191) HLA-B*40:02 as exemplified by B*40:02:01 :01 ID=HLA:HLA00293 (SEQ ID NO: 192) HLA-B*40:56 as exemplified by B*40:56 ID=HLA:HLA01994 (SEQ ID NO: 193) HLA-B*40:97 as exemplified by B*40:97 ID=HLA:HLA03746 (SEQ ID NO: 194) HLA-B*40: 144N as exemplified by B*40: 144N ID=HLA:HLA05286 (SEQ ID NO: 195) HLA-B*54:01 as exemplified by B*54:01 :01 ID=HLA:HLA00367 (SEQ ID NO: 196) HLA-B*54: 17 as exemplified by B*54: 17 ID=HLA:HLA03508 (SEQ ID NO: 197) HLA-B* 18:01 as exemplified by B* 18:01 :01 :01 ID=HLA:HLA00213 (SEQ ID NO: 198) HLA-B* 18: 17N as exemplified by B* 18: 17N ID=HLA:HLA01532 (SEQ ID NO: 199) HLA-B* 18:53 as exemplified by B*18:53 ID=HLA:HLA06063 (SEQ ID NO: 200) HLA-B*35:03 as exemplified by B*35:03:01 :01 ID=HLA:HLA00239 (SEQ ID NO: 201) HLA-B*35:70 as exemplified by B*35:70 ID=HLA:HLA02734 (SEQ ID NO: 202) HLA-B*57:01 as exemplified by B*57:01 :01 ID=HLA:HLA00381 (SEQ ID NO: 203) HLA-B*57:29 as exemplified by B*57:29 ID=HLA:HLA04576 (SEQ ID NO: 204) HLA-B*57:37 as exemplified by B*57:37 ID=HLA:HLA05876 (SEQ ID NO: 205) HLA-B* 15:03 as exemplified by B* 15:03:01 :01 ID=HLA:HLA00166 (SEQ ID NO: 206) HLA-B* 15: 103 as exemplified by B*15: 103 ID=HLA:HLA02236 (SEQ ID NO: 207) HLA-B* 13:01 as exemplified by B* 13:01 :01 :01 ID=HLA:HLA00152 (SEQ ID NO: 208) HLA-B*27:05 as exemplified by B*27:05:02:01 ID=HLA:HLA00225 (SEQ ID NO: 209) HLA-B*27: 13 as exemplified by B*27: 13 ID=HLA:HLA00234 (SEQ ID NO: 210) HLA-B*42:01 as exemplified by B*42:01 :01 ID=HLA:HLA00315 (SEQ ID NO: 211) HLA-B* 15:25 as exemplified by B* 15:25:01 ID=HLA:HLA00188 (SEQ ID NO: 212) HLA-B*45:01 as exemplified by B*45:01 :01 ID=HLA:HLA00329 (SEQ ID NO: 213) HLA-B*45:07 as exemplified by B*45:07 ID=HLA:HLA01940 (SEQ ID NO: 214) HLA-B*45: 13 as exemplified by B*45: 13 ID=HLA:HLA05825 (SEQ ID NO: 215) HLA-B* 14:02 as exemplified by B* 14:02:01 :01 ID=HLA:HLA00158 (SEQ ID NO: 216) HLA-B*58:02 as exemplified by B*58:02:01 ID=HLA:HLA00387 (SEQ ID NO: 217) HLA-B*49:01 as exemplified by B*49:01 :01 :01 ID=HLA:HLA00340 (SEQ ID NO: 218) HLA-B* 15: 10 as exemplified by B* 15: 10:01 ID=HLA:HLA00173 (SEQ ID NO: 219) HLA-B*38:01 as exemplified by B*38:01 :01 ID=HLA:HLA00267 (SEQ ID NO: 220) HLA-B*48:01 as exemplified by B*48:01 :01 :01 ID=HLA:HLA00335 (SEQ ID NO: 221) HLA-B*48:09 as exemplified by B*48:09 ID=HLA:HLA01981 (SEQ ID NO: 222) HLA-B*57:03 as exemplified by B*57:03:01 :01 ID=HLA:HLA00383 (SEQ ID NO: 223) HLA-B*37:01 as exemplified by B*37:01 :01 ID=HLA:HLA00265 (SEQ ID NO: 224) HLA-B*37:23 as exemplified by B*37:23 ID=HLA:HLA05421 (SEQ ID NO: 225) HLA-B*39:01 as exemplified by B*39:01 :01 :01 ID=HLA:HLA00271 (SEQ ID NO: 226) HLA-B*39:46 as exemplified by B*39:46 ID=HLA:HLA03542 (SEQ ID NO: 227) HLA-B*39:59 as exemplified by B*39:59 ID=HLA:HLA05276 (SEQ ID NO: 228) HLA-B*35:02 as exemplified by B*35:02:01 :01 ID=HLA:HLA00238 (SEQ ID NO: 229) HLA-B*15:21 as exemplified by B*15:21 ID=HLA:HLA00184 (SEQ ID NO: 230) HLA-B*39:05 as exemplified by B*39:05:01 ID=HLA:HLA00278 (SEQ ID NO: 231) HLA-B*13:02 as exemplified by B* 13:02:01 :01 ID=HLA:HLA00153 (SEQ ID NO: 232) HLA-B*13:38 as exemplified by B*13:38 ID=HLA:HLA05118 (SEQ ID NO: 233) HLA-B*50:01 as exemplified by B*50:01:01:01 ID=HLA:HLA00341 (SEQ ID NO: 234) HLA-B*39:06 as exemplified by B*39:06:01 ID=HLA:HLA00279 (SEQ ID NO: 235) HLA-B*55:02 as exemplified by B*55:02:01:01 ID=HLA:HLA00369 (SEQ ID NO: 236) HLA-B*41:01 as exemplified by B*41:01:01 ID=HLA:HLA00312 (SEQ ID NO: 237) HLA-B*27:06 as exemplified by B*27:06 ID=HLA:HLA00227 (SEQ ID NO: 238) HLA-B*15:13 as exemplified by B*15:13:01 ID=HLA:HLA00176 (SEQ ID NO: 239) HLA-B*59:01 as exemplified by B*59:01:01:01 ID=HLA:HLA00389 (SEQ ID NO: 240) HLA-B*35:12 as exemplified by B*35: 12:01 ID=HLA:HLA00249 (SEQ ID NO: 241) HLA-B*55:01 as exemplified by B*55:01:01 ID=HLA:HLA00368 (SEQ ID NO: 242) HLA-B*15:12 as exemplified by B*15:12 ID=HLA:HLA00175 (SEQ ID NO: 243) HLA-B*15:19 as exemplified by B*15:19 ID=HLA:HLA00182 (SEQ ID NO: 244)

HLA-B*15:16 as exemplified by B*15:16:01:01 ID=HLA:HLA00179 (SEQ ID NO: 245) VGIVAGLAVLAVVVIGAVVATVMCRRKSSGGKGGSYSQAASSDSAQGSDVSLTA HLA-B*81:01 as exemplified by B*81:01 ID=HLA:HLA00398 (SEQ ID NO: 246) HLA-B*81:02 as exemplified by B*81:02 ID=HLA:HLA01809 (SEQ ID NO: 247) HLA-B*81:03 as exemplified by B*81:03 ID=HLA:HLA03049 (SEQ ID NO: 248) HLA-B*51:06 as exemplified by B*51:06:01 ID=HLA:HLA00351 (SEQ ID NO: 249) HLA-B*27:04 as exemplified by B*27:04:01 ID=HLA:HLA00223 (SEQ ID NO: 250) HLA-B*27:68 as exemplified by B*27:68 ID=HLA:HLA05268 (SEQ ID NO: 251) HLA-B*27:69 as exemplified by B*27:69 ID=HLA:HLA05269 (SEQ ID NO: 252) HLA-B*35:43 as exemplified by B*35:43:01 ID=HLA:HLA00185 (SEQ ID NO: 253) HLA-B*35:67 as exemplified by B*35:67 ID=HLA:HLA02489 (SEQ ID NO: 254) HLA-B*35:79 as exemplified by B*35:79 ID=HLA:HLA03008 (SEQ ID NO: 255) HLA-B*15:11 as exemplified by B*15:ll:01 ID=HLA:HLA00174 (SEQ ID NO: 256) HLA-B*35:08 as exemplified by B*35:08:01:01 ID=HLA:HLA00244 (SEQ ID NO: 257) HLA-B*15:18 as exemplified by B*15:18:01:01 ID=HLA:HLA00181 (SEQ ID NO: 258) HLA-B*15:198 as exemplified by B* 15: 198 ID=HLA:HLA05265 (SEQ ID NO: 259) HLA-B*15:17 as exemplified by B*15:17:01:01 ID=HLA:HLA00180 (SEQ ID NO: 260) HLA-B*51:02 as exemplified by B*51:02:01:01 ID=HLA:HLA00346 (SEQ ID NO: 261) HLA-B* 14:01 as exemplified by B* 14:01 :01 :01 ID=HLA:HLA00157 (SEQ ID NO: 262) HLA-B*39: 10 as exemplified by B*39: 10:01 ID=HLA:HLA00284 (SEQ ID NO: 263) HLA-B*56:04 as exemplified by B*56:04 ID=HLA:HLA00379 (SEQ ID NO: 264) HLA-B* 15:27 as exemplified by B* 15:27:01 ID=HLA:HLA00190 (SEQ ID NO: 265) HLA-B*35: 17 as exemplified by B*35: 17:01 ID=HLA:HLA00254 (SEQ ID NO: 266) HLA-B* 15: 15 as exemplified by B* 15: 15 ID=HLA:HLA00178 (SEQ ID NO: 267) HLA-B* 15:07 as exemplified by B* 15:07:01 :01 ID=HLA:HLA00170 (SEQ ID NO: 268) HLA-B*67:01 as exemplified by B*67:01 :01 ID=HLA:HLA00390 (SEQ ID NO: 269) HLA-B*78:01 as exemplified by B*78:01 :01 :01 ID=HLA:HLA00393 (SEQ ID NO: 270) HLA-B*56:01 as exemplified by B*56:01 :01 :01 ID=HLA:HLA00376 (SEQ ID NO: 271) HLA-B*56:24 as exemplified by B*56:24 ID=HLA:HLA03511 (SEQ ID NO: 272) HLA-B*41 :02 as exemplified by B*41 :02:01 ID=HLA:HLA00313 (SEQ ID NO: 273) HLA-B*40:05 as exemplified by B* 40:05:01 :01 ID=HLA:HLA00296 (SEQ ID NO: 274) HLA-B*42:02 as exemplified by B*42:02:01 :01 ID=HLA:HLA00316 (SEQ ID NO: 275) HLA-B*40:03 as exemplified by B*40:03:01 :01 ID=HLA:HLA00294 (SEQ ID NO: 276) HLA-B*40: 10 as exemplified by B*40: 10:01 :01 ID=HLA:HLA00301 (SEQ ID NO: 277) HLA-B*57:02 as exemplified by B*57:02:01 ID=HLA:HLA00382 (SEQ ID NO: 278) HLA-B* 15:30 as exemplified by B* 15:30 ID=HLA:HLA00193 (SEQ ID NO: 279) HLA-B*27:02 as exemplified by B*27:02:01 :01 ID=HLA:HLA00221 (SEQ ID NO: 280) HLA-B* 18:02 as exemplified by B* 18:02 ID=HLA:HLA00214 (SEQ ID NO: 281) HLA-B*39:02 as exemplified by B*39:02:01 ID=HLA:HLA00274 (SEQ ID NO: 282) HLA-B*39:08 as exemplified by B*39:08 ID=HLA:HLA00282 (SEQ ID NO: 283) HLA-B*27:07 as exemplified by B*27:07:01 ID=HLA:HLA00228 (SEQ ID NO: 284) HLA-B*48:03 as exemplified by B*48:03:01 ID=HLA:HLA00337 (SEQ ID NO: 285) HLA-B*51 :08 as exemplified by B*51 :08:01 ID=HLA:HLA00353 (SEQ ID NO: 286) HLA-B*39:09 as exemplified by B*39:09:01 :01 ID=HLA:HLA00283 (SEQ ID NO: 287) HLA-B* 15:05 as exemplified by B* 15:05:01 ID=HLA:HLA00168 (SEQ ID NO: 288) HLA-B*27:03 as exemplified by B*27:03 ID=HLA:HLA00222 (SEQ ID NO: 289) HLA-B*35:04 as exemplified by B*35:04:01 ID=HLA:HLA00240 (SEQ ID NO: 290) HLA-B*40:04 as exemplified by B*40:04 ID=HLA:HLA00295 (SEQ ID NO: 291) HLA-B*44:05 as exemplified by B*44:05:01 ID=HLA:HLA00322 (SEQ ID NO: 292) HLA-B*40:08 as exemplified by B*40:08 ID=HLA:HLA00299 (SEQ ID NO: 293) HLA-B* 15:08 as exemplified by B* 15:08:01 ID=HLA:HLA00171 (SEQ ID NO: 294) HLA-B* 15:04 as exemplified by B* 15:04:01 :01 ID=HLA:HLA00167 (SEQ ID NO: 295) HLA-B*48:04 as exemplified by B*48:04:01 ID=HLA:HLA00338 (SEQ ID NO: 296) HLA-B*39: 1 1 as exemplified by B*39: l l ID=HLA:HLA00285 (SEQ ID NO: 297) HLA-B*35: 14 as exemplified by B*35: 14:01 ID=HLA:HLA00251 (SEQ ID NO: 298) HLA-B*47:01 as exemplified by B*47:01 :01 :01 ID=HLA:HLA00332 (SEQ ID NO: 299) HLA-B*82:01 as exemplified by B*82:01 ID=HLA:HLA00399 (SEQ ID NO: 300) HLA-B*73:01 as exemplified by B*73:01 ID=HLA:HLA00392 (SEQ ID NO: 301) HLA-B* 14:03 as exemplified by B* 14:03 ID=HLA:HLA00159 (SEQ ID NO: 302) HLA-B*35:20 as exemplified by B*35:20:01 ID=HLA:HLA00257 (SEQ ID NO: 303) HLA-B* 15:29 as exemplified by B* 15:29 ID=HLA:HLA00192 (SEQ ID NO: 304) HLA-B*50:02 as exemplified by B*50:02 ID=HLA:HLA00342 (SEQ ID NO: 305) HLA-B*57:04 as exemplified by B*57:04:01 ID=HLA:HLA00384 (SEQ ID NO: 306) HLA-B*48:02 as exemplified by B*48:02:01 ID=HLA:HLA00336 (SEQ ID NO: 307) HLA-B* 15:40 as exemplified by B* 15:40:01 ID=HLA:HLA00203 (SEQ ID NO: 308) HLA-B* 15:06 as exemplified by B* 15:06 ID=HLA:HLA00169 (SEQ ID NO: 309) HLA-B*51 :05 as exemplified by B*51 :05 ID=HLA:HLA00350 (SEQ ID NO: 310) HLA-B*40: 11 as exemplified by B*40: 11 :01 ID=HLA:HLA00302 (SEQ ID NO: 311) HLA-B*56:03 as exemplified by B*56:03 ID=HLA:HLA00378 (SEQ ID NO: 312) HLA-B*51 :07 as exemplified by B*51 :07:01 ID=HLA:HLA00352 (SEQ ID NO: 313) HLA-B*39:04 as exemplified by B*39:04 ID=HLA:HLA00277 (SEQ ID NO: 314) HLA-B*44: 10 as exemplified by B*44: 10 ID=HLA:HLA00327 (SEQ ID NO: 315) HLA-B*39: 15 as exemplified by B*39: 15 ID=HLA:HLA00289 (SEQ ID NO: 316) HLA-B* 15:38 as exemplified by B* 15:38:01 ID=HLA:HLA00201 (SEQ ID NO: 317) HLA-B* 15:32 as exemplified by B* 15:32:01 ID=HLA:HLA00195 (SEQ ID NO: 318) HLA-B*51 :09 as exemplified by B*51 :09:01 ID=HLA:HLA00354 (SEQ ID NO: 319) HLA-B*39:24 as exemplified by B*39:24:01 ID=HLA:HLA01221 (SEQ ID NO: 320) HLA-B* 15:39 as exemplified by B* 15:39:01 ID=HLA:HLA00202 (SEQ ID NO: 321) HLA-B*40: 12 as exemplified by B*40: 12 ID=HLA:HLA00303 (SEQ ID NO: 322) HLA-B*40:27 as exemplified by B*40:27:01 ID=HLA:HLA01129 (SEQ ID NO: 323) HLA-B*35: 10 as exemplified by B*35: 10 ID=HLA:HLA00247 (SEQ ID NO: 324) HLA-B*35: 1 1 as exemplified by B*35: l l :01 ID=HLA:HLA00248 (SEQ ID NO: 325) HLA-B* 15:09 as exemplified by B* 15:09:01 ID=HLA:HLA00172 (SEQ ID NO: 326) HLA-B*47:03 as exemplified by B*47:03 ID=HLA:HLA00334 (SEQ ID NO: 327) HLA-B*48:07 as exemplified by B*48:07 ID=HLA:HLA01069 (SEQ ID NO: 328) HLA-C*07:02 as exemplified by C*07:02:01 :01 ID=HLA:HLA00434 (SEQ ID NO: 329) HLA-C*07:50 as exemplified by C*07:50 ID=HLA:HLA03004 (SEQ ID NO: 330) HLA-C*07:66 as exemplified by C*07:66 ID=HLA:HLA03631 (SEQ ID NO: 33) HLA-C*07:74 as exemplified by C*07:74 ID=HLA:HLA03977 (SEQ ID NO: 332) HLA-C*07: 159 as exemplified by C*07: 159 ID=HLA:HLA05888 (SEQ ID NO: 333) HLA-C*07: 160 as exemplified by C*07: 160 ID=HLA:HLA05889 (SEQ ID NO: 334) HLA-C*07: 167 as exemplified by C*07: 167 ID=HLA:HLA06127 (SEQ ID NO: 335) HLA-C*04:01 as exemplified by C*04:01 :01 :01 ID=HLA:HLA00420 (SEQ ID NO: 336) HLA-C*04:09N as exemplified by C*04:09N ID=HLA:HLA01451 (SEQ ID NO: 337) HLA-C*04:28 as exemplified by C*04:28 ID=HLA:HLA03007 (SEQ ID NO: 338) HLA-C*04:30 as exemplified by C*04:30 ID=HLA:HLA03122 (SEQ ID NO: 339) HLA-C*04:41 as exemplified by C*04:41 ID=HLA:HLA03832 (SEQ ID NO: 340) HLA-C*04:79 as exemplified by C*04:79 ID=HLA:HLA05763 (SEQ ID NO: 341) HLA-C*04:82 as exemplified by C*04:82 ID=HLA:HLA05916 (SEQ ID NO: 342) HLA-C*04:84 as exemplified by C*04:84 ID=HLA:HLA06068 (SEQ ID NO: 343) HLA-C*01 :02 as exemplified by C*01 :02:01 :01 ID=HLA:HLA00401 (SEQ ID NO: 344) HLA-C*01 :25 as exemplified by C*01 :25 ID=HLA:HLA03650 (SEQ ID NO: 345) HLA-C*01 :44 as exemplified by C*01 :44 ID=HLA:HLA05762 (SEQ ID NO: 346) HLA-C*08:01 as exemplified by C*08:01 :01 :01 ID=HLA:HLA00445 (SEQ ID NO: 347) HLA-C*08:20 as exemplified by C*08:20 ID=HLA:HLA03632 (SEQ ID NO: 348) HLA-C*08:22 as exemplified by C*08:22 ID=HLA:HLA03680 (SEQ ID NO: 349) HLA-C*08:24 as exemplified by C*08:24 ID=HLA:HLA03763 (SEQ ID NO: 350) HLA-C*07:01 as exemplified by C*07:01 :01 :01 ID=HLA:HLA00433 (SEQ ID NO: 351) HLA-C*07:06 as exemplified by C*07:06 ID=HLA:HLA00438 (SEQ ID NO: 352) HLA-C*07: 18 as exemplified by C*07: 18 ID=HLA:HLA01672 (SEQ ID NO: 353) HLA-C*07:52 as exemplified by C*07:52 ID=HLA:HLA03135 (SEQ ID NO: 354) HLA-C*07: 153 as exemplified by C*07: 153 ID=HLA:HLA05764 (SEQ ID NO: 355) HLA-C*07: 166 as exemplified by C*07: 166 ID=HLA:HLA06071 (SEQ ID NO: 356) HLA-C*03:03 as exemplified by C*03:03:01 :01 ID=HLA:HLA00411 (SEQ ID NO: 357) HLA-C*03:20N as exemplified by C*03:20N ID=HLA:HLA02346 (SEQ ID NO: 358) HLA-C*03:62 as exemplified by C*03:62 ID=HLA:HLA04134 (SEQ ID NO: 359) HLA-C*06:02 as exemplified by C*06:02:01 :01 ID=HLA:HLA00430 (SEQ ID NO: 360) HLA-C*06:46N as exemplified by C*06:46N ID=HLA:HLA05526 (SEQ ID NO: 361) HLA-C*06:55 as exemplified by C*06:55 ID=HLA:HLA05884 (SEQ ID NO: 362) HLA-C*03:04 as exemplified by C*03:04:01 :01 ID=HLA:HLA00413 (SEQ ID NO: 363) HLA-C*03: 100 as exemplified by C*03: 100 ID=HLA:HLA0 788 (SEQ ID NO: 364) HLA-C*03: 101 as exemplified by C*03: 101 ID=HLA:HLA05870 (SEQ ID NO: 365) HLA-C*03: 105 as exemplified by C*03: 105 ID=HLA:HLA06150 (SEQ ID NO: 366) HLA-C*03 : 106 as exemplified by C*03 : 106 ID=HLA:HLA06167 (SEQ ID NO: 367) HLA-C* 15:02 as exemplified by C* 15:02:01 :01 ID=HLA:HLA00467 (SEQ ID NO: 368) HLA-C* 15: 13 as exemplified by C* 15: 13:01 :01 ID=HLA:HLA02022 (SEQ ID NO: 369) HLA-C* 15:47 as exemplified by C* 15:47 ID=HLA:HLA06073 (SEQ ID NO: 370) HLA-C* 12:02 as exemplified by C* 12:02:01 ID=HLA:HLA00453 (SEQ ID NO: 371) HLA-C* 16:01 as exemplified by C* 16:01 :01 :01 ID=HLA:HLA00475 (SEQ ID NO: 372) HLA-C*05:01 as exemplified by C*05:01 :01 :01 ID=HLA:HLA00427 (SEQ ID NO: 373) HLA-C*05:03 as exemplified by C*05:03 ID=HLA:HLAO 1169 (SEQ ID NO: 374) HLA-C*05:37 as exemplified by C*05:37 ID=HLA.HLA04856 (SEQ ID NO: 375) HLA-C*05:53 as exemplified by C*05:53 ID=HLA:HLA06125 (SEQ ID NO: 376) HLA-C* 12:03 as exemplified by C* 12:03:01 :01 ID=HLA:HLA00455 (SEQ ID NO: 377) HLA-C* 12:23 as exemplified by C* 12:23 ID=HLA:HLA03988 (SEQ ID NO: 378) HLA-C*02:02 as exemplified by C*02:02:01 ID=HLA:HLA00404 (SEQ ID NO: 379) HLA-C*02: 10 as exemplified by C*02: 10:01 :01 ID=HLA:HLA02120 (SEQ ID NO: 380) HLA-C*02:29 as exemplified by C*02:29 ID=HLA:HLA04016 (SEQ ID NO: 381) HLA-C*03:02 as exemplified by C*03:02:01 ID=HLA:HLA00410 (SEQ ID NO: 382) HLA-C* 14:02 as exemplified by C* 14:02:01 :01 ID=HLA:HLA00462 (SEQ ID NO: 383) HLA-C* 14:23 as exemplified by C* 14:23 ID=HLA:HLA05789 (SEQ ID NO: 384) HLA-C* 14:31 as exemplified by C* 14:31 ID=HLA:HLA06529 (SEQ ID NO: 385) HLA-C* 15:05 as exemplified by C* 15:05:01 ID=HLA:HLA00470 (SEQ ID NO: 386) HLA-C* 15:29 as exemplified by C* 15:29 ID=HLA:HLA05113 (SEQ ID NO: 387) HLA-C* 17:01 as exemplified by C* 17:01 :01 :02 ID=HLA:HLA04311 (SEQ ID NO: 388) HLA-C* 17:02 as exemplified by C* 17:02 ID=HLA:HLA00482 (SEQ ID NO: 389) HLA-C* 17:03 as exemplified by C* 17:03:01 :01 ID=HLA:HLA00993 (SEQ ID NO: 390) HLA-C* 14:03 as exemplified by C* 14:03 ID=HLA:HLA00464 (SEQ ID NO: 391) HLA-C*04:03 as exemplified by C*04:03:01 ID=HLA:HLA00423 (SEQ ID NO: 392) HLA-C*08:02 as exemplified by C*08:02:01 :01 ID=HLA:HLA00446 (SEQ ID NO: 393) HLA-C* 18:01 as exemplified by C*18:01 ID=HLA:HLA00483 (SEQ ID NO: 394) HLA-C* 18:02 as exemplified by C* 18:02 ID=HLA:HLA00484 (SEQ ID NO: 395) HLA-C* 16:02 as exemplified by C* 16:02:01 ID=HLA:HLA00476 (SEQ ID NO: 396) HLA-C*07:04 as exemplified by 0*07:04:01 :01 ID=HLA:HLA00436 (SEQ ID NO: 397) HLA-C*07: 1 1 as exemplified by C*07: l l ID=HLA:HLA00443 (SEQ ID NO: 398) HLA-C*03:05 as exemplified by C*03:05 ID=HLA:HLA00415 (SEQ ID NO: 399) HLA-C* 12:04 as exemplified by C* 12:04:02 ID=HLA:HLA00457 (SEQ ID NO: 400) HLA-C*08:03 as exemplified by C*08:03:01 ID=HLA:HLA00447 (SEQ ID NO: 401) HLA-C*08:40 as exemplified by C*08:40 ID=HLA:HLA05785 (SEQ ID NO: 402) HLA-C*04:06 as exemplified by C*04:06 ID=HLA:HLA00426 (SEQ ID NO: 403)

HLA-C* 16:04 as exemplified by C* 16:04:01 :01 ID=HLA:HLA00478 (SEQ ID NO: 404) HLA-C*08:04 as exemplified by C*08:04:01 ID=HLA:HLA00448 (SEQ ID NO: 405) HLA-C*03:06 as exemplified by C*03:06:01 ID=HLA:HLA00416 (SEQ ID NO: 406) HLA-C*04:04 as exemplified by C*04:04:01 :01 ID=HLA:HLA00424 (SEQ ID NO: 407) HLA-C*07:26 as exemplified by C*07:26:01 ID=HLA:HLA01889 (SEQ ID NO: 408) HLA-C* 15:09 as exemplified by C* 15:09 ID=HLA:HLA01124 (SEQ ID NO: 409) HLA-C*01 :03 as exemplified by CO 1 :03 ID=HLA:HLA00402 (SEQ ID NO: 410) HLA-C*01 :24 as exemplified by C*01 :24 ID=HLA:HLA03636 (SEQ ID NO: 411) HLA-C* 15:04 as exemplified by C* 15:04:01 ID=HLA:HLA00469 (SEQ ID NO: 412) HLA-C*04:07 as exemplified by C*04:07 ID=HLA:HLA01078 (SEQ ID NO: 413)

Beta-2-Microglobulin, human, amino acids 21-119, signal sequence removed (Uniprot ID=P61769) (SEQ ID NO: 414) cDNA Human EGFR (SEQ ID NO: 415)

Human EGFR protein sequence (SEQ ID NO: 416)

cDNA Human TPBG (SEQ ID NO: 417)

Human TPBG protein sequence (SEQ ID NO: 418)

cDNA Human GUCY2C (SEQ ID NO: 419)

Human GUCY2C protein sequence (SEQ ID NO: 420)

cDN A Human LY6E (SEQ ID NO : 421 )

Human LY6E protein sequence (SEQ ID NO: 422) Heavy Chain CDR1 of W6/32 (SEQ ID NO: 445)

Heavy Chain CDR2 of W6/32 (SEQ ID NO: 446)

Heavy Chain CDR3 of W6/32 (SEQ ID NO: 447)

Light Chain CDR1 of W6/32 (SEQ ID NO. 448)

Light Chain CDR2 of W6/32 (SEQ ID NO: 449)

Light Chain CDR3 of W6/32 (SEQ ID NO: 450)

Heavy Chain of epitope-tagged W6/32 Fab, which is chimeric (SEQ ID NO: 451)

Light Chain of epitope-tagged W6/32 Fab. which is chimeric (SEQ ID NO: 452)

Heavy chain of MYT0075 (SEQ ID NO: 453)

Heavy chain CDR1 of MYT0075 (SEQ ID NO: 454)

Heavy chain CDR2 of MYT0075 (SEQ ID NO: 455)

Heavy chain CDR3 of MYT0075 (SEQ ID NO: 456)

Heavy chain of MYT0080 (SEQ ID NO: 457)

Heavy chain CDR1 of MYT0080 (SEQ ID NO 458)

Heavy chain CDR2 of MYT0080 (SEQ ID NO: 459)

Heavy chain CDR3 of MYT0080 (SEQ ID NO: 460)

Heavy chain of MYT0094 (SEQ ID NO: 461)

Heavy Chain CDR1 of MYT0094 (SEQ ID NO: 462)

Heavy Chain CDR2 of MYT0094 (SEQ ID NO: 463)

Heavy Chain CDR3 of MYT0094 (SEQ ID NO: 464)

Heavy chain of MYT0098 (SEQ ID NO: 465)

Heavy Chain CDR1 of MYT0098 (SEQ ID NO: 466)

Heavy Chain CDR2 of MYT0098 (SEQ ID NO: 467)

Heavy Chain CDR3 of MYT0098 (SEQ ID NO: 468)

Heavy chain of MYT0002 (SEQ ID NO: 469)

Heavy chain of MYT0003 (SEQ ID NO: 470)

Human Fc with knob mutations (SEQ ID NO: 471)

Heavy chain of MYT0051 (SEQ ID NO: 472)

TAM0039 (SEQ ID NO: 473)

TAM0121 (SEQ ID NO: 474)

TAM0146 (SEQ ID NO: 475)

TAM0165 (SEQ ID NO: 476) TAM0039 CDR1 (SEQ ID NO: 477)

TAM0039 CDR2 (SEQ ID NO: 478)

TAM0039 CDR3 (SEQ ID NO: 479)

TAM0121 CDR1 (SEQ ID NO: 480)

TAM0121 CDR2 (SEQ ID NO: 481)

TAM0121 CDR3 (SEQ ID NO: 482)

TAM0146 CDR1 (SEQ ID NO: 483)

TAM0146 CDR2 (SEQ ID NO: 484)

TAM0146 CDR3 (SEQ ID NO: 485)

TAM0165 CDR1 (SEQ ID NO: 486)

TAM0165 CDR2 (SEQ ID NO: 487)

TAM0165 CDR3 (SEQ ID NO: 488)

MYT0061, bivalent TAM0039 VH-Fc (SEQ ID NO: 489)

MYT0062, bivalent TAM0146 VH-Fc (SEQ ID NO: 490)

MYT0063, bivalent TAM0165 VH-Fc (SEQ ID NO: 491)

TAM0389, MYT0002 antigen-binding VH domain (SEQ ID NO: 492)

TAM0400, MYT0002 antigen-binding VH domain (SEQ ID NO: 493)

TAM0401, MYT0002 antigen-binding VH domain (SEQ ID NO: 494)

TAM0424, MYT0002 antigen-binding VH domain (SEQ ID NO: 495) TAM0461 , MYT0002 antigen-binding VH domain (SEQ ID NO: 496)

TAM0389 CDR1 (SEQ ID NO: 497)

TAM0389 CDR2 (SEQ ID NO: 498)

TAM0389 CDR3 (SEQ ID NO: 499)

TAM0400 CDR1 (SEQ ID NO: 500)

TAM0400 CDR2 (SEQ ID NO: 501)

TAM0400 CDR3 (SEQ ID NO: 502)

TAM0401 CDR1 (SEQ ID NO: 503)

TAM0401 CDR2 (SEQ ID NO: 504)

TAM0401 CDR3 ( SEQ ID NO: 505)

TAM0424 CDR1 (SEQ ID NO: 506)

TAM0424 CDR2 (SEQ ID NO: 507)

TAM0424 CDR3 (SEQ ID NO: 508)

TAM0461 CDR1 (SEQ ID NO: 509) TAM0461 CDR2 (SEQ ID NO: 510)

TAM0461 CDR3 (SEQ ID NO: 511)

TAM0570, MYT0003 antigen-binding VH domain (SEQ ID NO: 512)

TAM0623, MYT0003 antigen-binding VH domain (SEQ ID NO: 513) TAM0672, MYT0003 antigen-binding VH domain (SEQ ID NO: 514)

TAM0692, MYT0003 antigen-binding VH domain (SEQ ID NO: 515)

TAM0728, MYT0003 antigen-binding VH domain (SEQ ID NO: 516)

TAM0570 CDR1 (SEQ ID NO: 517)

TAM0570 CDR2 (SEQ ID NO: 518)

TAM0570 CDR3 (SEQ ID NO: 519)

TAM0623 CDR1 (SEQ ID NO: 520)

TAM0623 CDR2 (SEQ ID NO: 521)

TAM0623 CDR3 (SEQ ID NO: 522)

TAM0672 CDR1 (SEQ ID NO: 523)

TAM0672 CDR2 (SEQ ID NO: 524)

TAM0672 CDR3 (SEQ ID NO: 525)

TAM0692 CDR1 (SEQ ID NO: 526)

TAM0692 CDR2 (SEQ ID NO: 527)

TAM0692 CDR3 (SEQ ID NO: 528)

TAM0728 CDR1 (SEQ ID NO: 529)

TAM0728 CDR2 (SEQ ID NO: 530)

TAM0728 CDR3 (SEQ ID NO: 531)

pH dependent anti-IL6R Fab heavy chain (SEQ ID NO: 532) pH dependent anti-IL6R Fab light chain (SEQ ID NO: 533) pH dependent anti-TNFalpha Fab heavy chain (SEQ ID NO: 534) pH dependent anti-TNFalpha Fab light chain (SEQ ID NO: 535) anti-IL6R VH (SEQ ID NO: 536)

anti-TNFalpha VH (SEQ ID NO: 537)

anti-EGFR VH (SEQ ID NO: 538)

anti-RANKL VH (SEQ ID NO: 539)

anti-CEA VH (SEQ ID NO: 540)

anti-SOST VH (SEQ ID NO: 541)

pH dependent anti-IL6R Fab heavy chain CDR1 (SEQ ID NO: 542) pH dependent anti-IL6R Fab heavy chain CDR2 (SEQ ID NO: 543) pH dependent anti-IL6R Fab heavy chain CDR3 (SEQ ID NO: 544) pH dependent anti-IL6R Fab light chain CDRl (SEQ ID NO: 545) pH dependent anti-IL6R Fab light chain CDR2 (SEQ ID NO: 546) pH dependent anti-IL6R Fab light chain CDR3 (SEQ ID NO: 547) pH dependent anti-TNFalpha Fab heavy chain CDRl (SEQ ID NO: 548) pH dependent anti-TNFalpha Fab heavy chain CDR2 (SEQ ID NO: 549) pH dependent anti-TNFalpha Fab heavy chain CDR3 (SEQ ID NO: 550) pH dependent anti-TNFalpha Fab light chain CDRl (SEQ ID NO: 551) pH dependent anti-TNFalpha Fab light chain CDR2 (SEQ ID NO: 552) pH dependent anti-TNFalpha Fab light chain CDR3 (SEQ ID NO: 553) anti-IL6R VH CDRl (SEQ ID NO: 554)

anti-IL6R VH CDR2 (SEQ ID NO: 555)

anti-IL6R VH CDR3 (SEQ ID NO: 556)

anti-TNFalpha VH CDRl (SEQ ID NO: 557)

anti-TNFalpha VH CDR2 (SEQ ID NO: 558)

anti-TNFalpha VH CDR3 (SEQ ID NO: 559)

anti-EGFR VH CDRl (SEQ ID NO: 560)

anti-EGFR VH CDR2 (SEQ ID NO: 561)

anti-EGFR VH CDR3 (SEQ ID NO: 562)

anti-RANKL VH CDRl (SEQ ID NO: 563)

anti-RANKL VH CDR2 (SEQ ID NO: 564)

anti-RANKL VH CDR3 (SEQ ID NO: 565)

anti-CEA VH CDRl (SEQ ID NO: 566)

anti-CEA VH CDR2 (SEQ ID NO: 567)

anti-CEA VH CDR3 (SEQ ID NO: 568)

anti-SOST VH CDRl (SEQ ID NO: 569)

anti-SOST VH CDR2 (SEQ ID NO. 570)

anti-SOST VH CDR3 (SEQ ID NO: 571)

MYT0045 heavy chain A - Fab-Fc (SEQ ID NO: 572)

MYT0045 heavy chain B - VH-Fc (SEQ ID NO: 573)

MYT0046 heavy chain A - Fab-Fc (SEQ ID NO: 574)

MYT0047 heavy chain A (SEQ ID NO: 575) MYT0048 heavy chain A (SEQ ID NO: 576)

MYT0049 heavy chain A (SEQ ID NO: 577)

MYT0049 heavy chain B (SEQ ID NO: 578)

MYT0052 heavy chain (SEQ ID NO: 579)

MYT0053 heavy chain (SEQ ID NO: 580)

MYT0054 heavy chain (SEQ ID NO: 581)

MYT0055 heavy chain (SEQ ID NO: 582)

MYT0056 heavy chain (SEQ ID NO: 583)

MYT0057 heavy chain (SEQ ID NO: 584)

MYT0058 heavy chain (SEQ ID NO: 585)

MYT0059 heavy chain (SEQ ID NO: 586)

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising an effective amount of an antigen- binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex (PC), wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2ιη) poly peptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain, wherein:

2. The pharmaceutical composition of claim 1, wherein the ABPC has increased endosomal recycling in a mammalian cell that presents the PC on its surface or in a cellular compartment as compared to a control ABPC.

3. The pharmaceutical composition of claim 1 or 2, wherein the ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC complex on its surface or in a cellular compartment as compared to a control ABPC.

4. A pharmaceutical composition comprising an effective amount of an antigen- binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding to an epitope of a beta 2-microglobulin (p2m) polypeptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain, wherein:

(a) the dissociation rate of the first antigen-binding domain at an acidic pH is slower than the dissociation rate at a neutral pH; or (b) the dissociation constant (KD) of the first antigen-binding domain at an acidic pH is less than the KD at a neutral pH;

5. A pharmaceutical composition comprising an effective amount of an antigen- binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding to an epitope of a polypeptide complex (PC), wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2πι) polypeptide; and both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain,

wherein:

6. The pharmaceutical composition of any of claims 1-5, wherein the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC in vivo.

7. The pharmaceutical composition of any one of claims 1-6, wherein the ABPC further comprises a second antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex, wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2πι) polypeptide, wherein:

8. The pharmaceutical composition of any one of claims 1-6, wherein the ABPC further comprises a second antigen-binding domain that is capable of specifically binding an epitope of a beta 2-microglobulin (β2πι) polypeptide,

wherein:

9. The pharmaceutical composition of any one of claims 1-8, wherein the additional antigen-binding domain is capable of specifically binding to a soluble antigen or an antigen that is presented on the surface or in a cellular compartment of a target cell, or an antigen that is pericellular to a target cell.

10. The pharmaceutical composition of any one of claims 1-3, 5, and 7, wherein the first antigen-binding domain and the second antigen-binding domain, if present, specifically bind(s) an epitope that comprises at least one amino acid of the polypeptide encoded by the HLA gene selected from the group consisting of HLA- A, HLA-B, and HLA-C, and at least one amino acid of the β2ιη polypeptide.

11. The pharmaceutical composition of any one of claims 1-3, 5, and 7, wherein the first antigen-binding domain and the second antigen-binding domain, if present, specifically bind(s) an epitope of the polypeptide encoded by the HLA gene selected from HLA- A, HLA- B, and HLA-C, when the polypeptide encoded by the HLA gene is bound to the β2ιη peptide.

12. The pharmaceutical composition of any one of claims 1-11, wherein the epitope of the PC is an at least partially monomorphic epitope.

13. The pharmaceutical composition of claim 4 or 8, wherein the second antigen- binding domain specifically binds an epitope of the β2πι polypeptide, when the β2πι polypeptide is bound to a polypeptide encoded by an HLA gene selected from the group consisting of HLA- A, HL A-B, and HLA-C.

14. The pharmaceutical composition of any one of claims 1-3, 5, 7, and 9-12, wherein the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-A variant polypeptide-beta 2-microglobulin (β2πι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-A gene-beta 2-microglobulin (β2πι) polypeptide complex,

15. The pharmaceutical composition of any one of claims 1-3, 5, 7, and 9-12, wherein the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-B variant polypeptide-beta 2-microglobulin (β2πι) poly peptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-B gene-beta 2-microglobulin (β2ιη) polypeptide complex,

16. The pharmaceutical composition of any one of claims 1-3, 5, 7, and 9-12, wherein the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-C variant polypeptide-beta 2-microglobulin (β2πι) poly peptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-C gene-beta 2-microglobulin (β2ιη) polypeptide complex,

17. The pharmaceutical composition of any one of claims 1-3, 5, 7, 9-12, and 14, wherein the HLA-A gene is selected from the group consisting of: a A*24:02 gene, a A*24:144 gene, a A*02:01 gene, a A*02:09 gene, a A*02:43N gene, a A*02:66 gene, a A*02:75 gene, a A*02:83N gene, a A*02:89 gene, a A*02:97 gene, a A* 02: 132 gene, a A*02:134 gene, a A*02:140 gene, a A*02:241 gene, a A* 02: 252 gene, a A*02:256 gene, a A*02:266 gene, a A*02:291 gene, a A*02:294 gene, a A*02:305N gene, a A*l 1:01 gene, a A*ll:102 gene, a A*11:21N gene, a A*11:69N gene, a A* 11:86 gene, aA*01:01 gene, a A*01:04N gene, a A*01:22N gene, aA*01:32 gene, a A*01:37 gene, a A*01:45 gene, a A*01:56Ngene, a A*01:81 gene, a A*01:87N gene, aA*33:03 gene, a A*33:15 gene, a A*33:25 gene, a A*33:31 gene, a A*33:39 gene, a A*33:44 gene, a A*34:01 gene, a A*03:01 gene, a A* 03: 20 gene, a A*03:21N gene, a A*03:26 gene, a A*03:37 gene, a A*03:45 gene, a A*03:78 gene, a A*03:112 gene, a A*03:118 gene, a A*24:07 gene, a A*23:01 gene, a A*23:07Ngene, a A*23:17 gene, a A*23:18 gene, a A*23:20 gene, a A*02:07 gene, a A*02: 15N gene, a A*02:265 gene, a A*02:03 gene, a A*02:253 gene, a A*02:264 gene, aA*31:01 gene, aA*31:14N gene, a A*31:23 gene, aA*31:46 gene, a A*31:48 gene, a A*26:01 gene, a A*26:24 gene, a A*26:26 gene, a A*26:56 gene, a A*29:01 gene, a A*02:06 gene, a A*02:126 gene, a A*30:01 gene, a A* 30:24 gene, a A*30:02 gene, a A*30:33 gene, a A*68:01 gene, a A*68:11N gene, a A*68:33 gene, a A*68:02 gene, a A*29:02 gene, a A*29:26 gene, a A*74:01 gene, aA*74:02 gene, a A*02:ll gene, a A*02:69 gene, a A*32:01 gene, a A*02:02 gene, a A*34:02 gene, a A*36:01 gene, a A*33:01 gene, a A*ll:02 gene, a A*l 1:77 gene, a A*26:03 gene, a A*02:05 gene, a A*02: 179 gene, aA*25:01 gene, a A*25:07 gene, a A*24:03 gene, a A*24:33 gene, a A*26:02 gene, a A*68:03 gene, a A*03:02 gene, aA*66:01 gene, a A*66:08 gene, a A*30:04 gene, a A*02:17 gene, a A*66:02 gene, a A*24:10 gene, a A*02:04 gene, a A*24:17 gene, a A*80:01 gene, a A*69:01 gene, aA*24:20 gene, a A*01:02 gene, a A* 68: 05 gene, a A*02:10 gene, a A*30:10 gene, a A*34:05 gene, a A*02:131 gene, a A*02:16 gene, aA*02:104 gene, a A*02:22 gene, a A*02:20 gene, a A*01:03 gene, a A*66:03 gene, a A*ll:04 gene, a A*24:25 gene, aA*24:23 gene, and a A*02:60 gene.

18. The pharmaceutical composition of any one of claims 1-3, 5, 7, 9-12, and 15, wherein the HLA-B gene is selected from the group consisting of: a B*40:01 gene, a B*40:55 gene, aB*40:141 gene, aB*40:150gene, aB*40:151 gene, a B* 15:02 gene, a B*15:214 gene, aB*46:01 gene, aB*46:15N gene, aB*46:24 gene, aB*07:02 gene, a B*07:44 gene, a B*07:49N gene, a B*07:58 gene, a B*07:59 gene, a B*07:61 gene, a B*07:120 gene, aB*07:128 gene, aB*07:129 gene, aB*07:130 gene, aB*53:01 gene, a B*38:02 gene, aB*38:18 gene, aB*08:01 gene, aBⁱ08:19N gene, aB*52:01 gene, a B*52:07 gene, aB*35:01 gene, aB*35:40N gene, aB*35:42 gene, aB*35:57 gene, a B*35:94 gene, aB*35:134N gene, aB*35:161 gene, aB*44:02 gene, a B* 44: 27 gene, a B*44:66 gene, a B*44: 118 gene, a B*51:01 gene, a B*51 : 1 IN gene, a B*51:30 gene, a B*51:32gene, aB*51:48 gene, aB*51:51 gene, aB*40:06 gene, aB*44:03 gene, aB*58:01 gene, aB*58:ll gene, aB*58:31Ngene, aB*15:01 gene, aB*15:102 gene, aB*15:104 gene, aB*15:140 gene, aB*15:146 gene, aB*15:201 gene, aB*35:05 gene, aB*07:05 gene, aB*07:06 gene, a B* 15:35 gene, aB*40:02 gene, aB*40:56 gene, aB*40:97 gene, a B*40:144Ngene, aB*54:01 gene, aB*54:17 gene, aB*18:01 gene, a B* 18:17N gene, a B*18:53 gene, aB*35:03 gene, aB*35:70 gene, aB*57:01 gene, aB*57:29 gene, aB*57:37 gene, aB*15:03 gene, aB*15:103 gene, aB*13:01 gene, aB*27:05 gene, aB*27:13 gene, a B*42:01 gene, aB*15:25 gene, aB*45:01 gene, aBⁱ45:07 gene, aB*45:13 gene, aB*14:02 gene, a 6*58:02 gene, aB*49:01 gene, aB*15:10 gene, aB*38:01 gene, aB*48:01 gene, a B*48:09 gene, aB*57:03 gene, aB*37:01 gene, aB*37:23 gene, aB*39:01 gene, aB*39:46 gene, aB*39:59 gene, aB*35:02 gene, aB*15:21 gene, aB*39:05 gene, aB*13:02 gene, a B*13:38 gene, aB*50:01 gene, aB*39:06 gene, aB*55:02 gene, aB*41:01 gene, aB*27:06 gene, a B*15:13 gene, aB*59:01 gene, aB*35:12 gene, aB*55:01 gene, a B*15:12 gene, a B*15:19gene, aB*15:16 gene, aB*81:01 gene, aB*81:02 gene, aB*81:03 gene, aB*51:06 gene, a B*27:04 gene, aB*27:68 gene, aB*27:69 gene, aB*35:43 gene, a B*35:67 gene, a B*35:79 gene, aB*15:ll gene, aB*35:08 gene, aB*15:18 gene, a B* 15: 198 gene, a B*15:17gene, aB*51:02 gene, aB*14:01 gene, aB*39:10 gene, aB*56:04 gene, aB*15:27 gene, aB*35:17 gene, aB*15:15 gene, aB*15:07 gene, aBⁱ67:01 gene, aB*78:01 gene, a B*56:01 gene, aB*56:24 gene, aB*41:02 gene, aBⁱ40:05 gene, aB*42:02 gene, aB*40:03 gene, aB*40:10 gene, aB*57:02 gene, aB*15:30 gene, aB*27:02 gene, aB*18:02 gene, a B*39:02 gene, aB*39:08 gene, aB*27:07 gene, aB*48:03 gene, aB*51:08 gene, aB*39:09 gene, aB*15:05 gene, aB*27:03 gene, aB*35:04 gene, aB*40:04 gene, aB*44:05 gene, a B*40:08 gene, aB*15:08 gene, aB*15:04 gene, aB*48:04 gene, aB*39:ll gene, aB*35:14 gene, aB*47:01 gene, aB*82:01 gene, aB*73:01 gene, aB*14:03 gene, aB*35:20 gene, a B*15:29 gene, aB*50:02 gene, aB*57:04 gene, aB*48:02 gene, aB*15:40 gene, aB*15:06 gene, aB*51:05 gene, aB*40:ll gene, aB*56:03 gene, aB*51:07 gene, aB*39:04 gene, a B*44:10gene, aB*39:15 gene, aB*15:38 gene, aB*15:32 gene, aB*51:09 gene, aB*39:24 gene, a B* 15:39 gene, aB*40:12 gene, aB*40:27 gene, aB*35:10 gene, a B*35:ll gene, a B*15:09 gene, aB*47:03 gene, and aB*48:07 gene.

19. The pharmaceutical composition of any one of claims 1-3, 5, 7, 9-12, and 16, wherein the HLA-C gene is selected from the group consisting of: a C*07:02 gene, a C*07:50 gene, a C*07:66 gene, a C*07:74 gene, a C*07: 159 gene, a C*07: 160 gene, a C*07:167 gene, a C*04:01 gene, a C*04:09N gene, a C*04:28 gene, a C*04:30 gene, a C*04:41 gene, aC*04:79gene, aC*04:82 gene, aC*04:84 gene, aC*01:02 gene, aC*01:25 gene, a C*01 :44 gene, a C*08:01 gene, a C*08:20 gene, a C*08:22 gene, a C*08:24 gene, a C*07:01 gene, a C*07:06 gene, a C*07: 18 gene, a C*07:52 gene, a C*07: 153 gene, a C*07:166 gene, a C*03:03 gene, a C*03:20N gene, a C*03:62 gene, a C*06:02 gene, a C*06:46N gene, a C*06:55 gene, a C*03:04 gene, a C*03:100 gene, a C*03: 101 gene, a C*03:105 gene, a C* 03: 106 gene, a C*15:02 gene, aC*15:13 gene, aC*15:47 gene, a C*12:02 gene, aC*16:01 gene, aC*05:01 gene, a 0*05:03 gene, aC*05:37 gene, aC*05:53 gene, a C*12:03 gene, a C*12:23 gene, a C*02:02 gene, a C*02:10 gene, a C*02:29 gene, a C*03:02 gene, aC*14:02 gene, aC*14:23 gene, aC*14:31 gene, aC*15:05 gene, aC*15:29 gene, a C*17:01 gene, a C*17:02 gene, a C*17:03 gene, a C*14:03 gene, a C*04:03 gene, a C*08:02 gene, aC*18:01 gene, aC*18:02 gene, aC*16:02 gene, aC*07:04 gene, a C*07:ll gene, a C*03:05 gene, a C*12:04 gene, a C*08:03 gene, a C*08:40 gene, a C*04:06 gene, a C*16:04 gene, aC*08:04 gene, aC*03:06 gene, aC*04:04 gene, aC*07:26 gene, aC*15:09 gene, a C*01:03 gene, aC*01:24 gene, a C* 15:04 gene, and aC*04:07 gene.

20. The pharmaceutical composition of any one of claims 1-3, 5, 7, 9-12, and 14-19, wherein the PC further comprises a peptide of about 8-12 amino acids in length that is bound to the PC.

21. The pharmaceutical composition of any one of claims 1-20, wherein the first antigen-binding domain, and, if present, the second antigen-binding domain or the additional antigen-binding domain is/are capable of specifically binding to an epitope present on the surface or in a cellular compartment of human cells and an epitope that is present on the surface or in a cellular compartment of cells from an Old World Monkey.

22. The pharmaceutical composition of any one of claims 1-21, wherein the dissociation rate of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is/are at least 10% slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

23. The pharmaceutical composition of any one of claims 1-21, wherein the dissociation rate of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 3-fold slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

24. The pharmaceutical composition of any one of claims 1-21, wherein the dissociation rate of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 10-fold slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

25. The pharmaceutical composition of any one of claims 1-24, wherein the KD of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 10% less than the KD of the first antigen-binding domain or the second antigen- binding domain, respectively, at a neutral pH.

26. The pharmaceutical composition of any one of claims 1-24, wherein the KD of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 3 -fold less than the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

27. The pharmaceutical composition of any one of claims 1-24, wherein the KD of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 10-fold less than the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

28. The pharmaceutical composition of any one of claims 1-27, wherein the ABPC is cytotoxic or cytostatic to a cancer cell.

29. The pharmaceutical composition of any one of claims 1-28, wherein the ABPC comprises a single polypeptide.

30. The pharmaceutical composition of claim 29, wherein the first antigen-binding domain and the second antigen-binding domain, if present, are each independently selected from the group consisting of: a VHH domain, a VNAR domain, and a scFv.

31. The pharmaceutical composition of claim 29, wherein the ABPC is a BiTe, a (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH-CL-scFv, a HSAbody, scDiabody -HAS, or a tandem-scFv.

32. The pharmaceutical composition of any one of claims 1-28, wherein the ABPC comprises two or more polypeptides.

33. The pharmaceutical composition of claim 32, wherein the ABPC is selected from the group of an antibody, a VHH-scAb, a VHH-Fab, a Dual scFab, a F(ab')2, a diabody, a crossMab, a DAF (two-in-one), a DAF (four-in-one), a DutaMab, a DT-lgG, a knobs-in-holes common light chain, a knobs-in-holes assembly, a charge pair, a Fab-arm exchange, a SEEDbody, a LUZ-Y, a Fcab, a κλ-body, an orthogonal Fab, a DVD-IgG, a IgG(H)-scFv, a scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, Diabody- CH3, a triple body, a miniantibody, a minibody, a TriBi minibody, scFv-CH3 KIH, Fab-scFv, a F(ab')2-scFv2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody -Fc, a Diabody -Fc, a tandem scFv-Fc, an Intrabody, a dock and lock, an ImmTAC, an IgG-IgG conjugate, a Cov-X-Body, and a scFvl-PEG-scFv2.

34. The pharmaceutical composition of any one of claims 1-33, wherein at least one protein of the ABPC is conjugated to the toxin, the radioisotope, or the drug via a cleavable linker.

35. The pharmaceutical composition of any one of claims 1-33, wherein at least one protein of the ABPC is conjugated to the toxin, the radioisotope, or the drug via a non- cleavable linker.

36. The pharmaceutical composition of any one of claims 1-4, wherein the ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC on its surface or in a cellular compartment as compared to a control ABPC.

37. The pharmaceutical composition of any one of claims 1-36, wherein the additional antigen-binding domain has a KD that is increased at an acidic pH as compared to the KD of the additional antigen-binding domain at a neutral pH.

38. The pharmaceutical composition of any one of claims 1-36, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 10% increased as compared to the KD of the additional antigen-binding domain at a neutral pH.

39. The pharmaceutical composition of any one of claims 1-36, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 3-fold greater than the KD of the additional antigen-binding domain at a neutral pH.

40. The pharmaceutical composition of any one of claims 1-36, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 10-fold greater than the KD of the additional antigen-binding domain at a neutral pH.

41. The pharmaceutical composition of any one of claims 1-40, wherein the half-life of the ABPC in vivo is increased about 10% to about 400% as compared to the half-life of a control ABPC in vivo.

42. The pharmaceutical composition of any one of claims 1-40, wherein the half-life of the ABPC in vivo is increased about 0.5-fold to about 4-fold as compared to the half-life of a control ABPC in vivo.

43. The pharmaceutical composition of any one of claims 1-40, wherein the half-life of the ABPC in vivo is increased about 1-fold to about 4-fold as compared to the half-life of a control ABPC in vivo.

44. The pharmaceutical composition of any one of claims 1-40, wherein the half-life of the ABPC in vivo is increased about 1.5-fold to about 4-fold as compared to the half-life of a control ABPC in vivo.

45. The pharmaceutical composition of any one of claims 1-40, wherein the half-life of the ABPC in vivo is increased about 2-fold to about 4-fold as compared to the half-life of a control ABPC in vivo.

46. The pharmaceutical composition of any one of claims 1-40, wherein the half-life of the ABPC in vivo is increased about 2.5-fold to about 4-fold as compared to the half-life of a control ABPC in vivo.

47. A kit comprising at least one dose of the pharmaceutical composition of any one of claims 1-46.

48. An antigen-binding protein construct (ABPC) comprising:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain, wherein:

wherein:

49. The ABPC of claim 48, wherein the ABPC has increased endosomal recycling in a mammalian cell that presents the PC on its surface or in a cellular compartment as compared to a control ABPC.

50. The ABPC of claim 48 or 49, wherein the ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC complex on its surface or in a cellular compartment as compared to a control ABPC.

51. An antigen-binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding to an epitope of a beta 2-microglobulin (β2ηι) polypeptide; and one or both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain,

wherein:

52. An antigen-binding protein construct (ABPC) comprising:

a first antigen-binding domain that is capable of specifically binding to an epitope of a polypeptide complex (PC), wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2- microglobulin (β2πι) poly peptide; and both of:

a conjugated toxin, radioisotope, or drug, and

an additional antigen-binding domain,

wherein:

53. The ABPC of any one of claims 48-52, wherein the half-life of the ABPC in vivo is increased as compared to the half-life of a control ABPC in vivo.

54. The ABPC of any one of claims 48-53, wherein the ABPC further comprises a second antigen-binding domain that is capable of specifically binding an epitope of a polypeptide complex, wherein the polypeptide complex comprises i) a polypeptide encoded by an HLA gene selected from HLA-A, HLA-B, and HLA-C, and ii) a beta 2-microglobulin (β2ιη) polypeptide, wherein:

55. The ABPC of any one of claims 48-53, wherein the ABPC further comprises a second antigen-binding domain that is capable of specifically binding an epitope of a beta 2- microglobulin (β2πι) polypeptide,

wherein:

56. The ABPC of any one of claims 48-53, wherein the additional antigen-binding domain is capable of specifically binding to a soluble antigen or an antigen that is presented on the surface or in a cellular compartment of a target cell, or an antigen that is pericellular to a target cell.

57. The ABPC of any one of claims 48-50, 52, and 54, wherein the first antigen- binding domain and the second antigen-binding domain, if present, specifically bind(s) an epitope that comprises at least one amino acid of the polypeptide encoded by the HLA gene selected from the group consisting of HLA-A, HLA-B, and HLA-C, and at least one amino acid of the β2πι polypeptide.

58. The ABPC of any one of claims 48-50, 52, and 54, wherein the first antigen- binding domain and the second antigen-binding domain, if present, specifically bind(s) an epitope of the polypeptide encoded by the HLA gene selected from HLA-A. HLA-B, and HLA-C, when the polypeptide encoded by the HLA gene is bound to the β2πι peptide.

59. The ABPC of any one of claims 48-58, wherein the epitope of the PC is an at least partially monomorphic epitope.

60. The ABPC of any one of claims 51 and 55, wherein the second antigen-binding domain specifically binds an epitope of the β2ηι polypeptide, when the β2ηι polypeptide is bound to a polypeptide encoded by an HLA gene selected from the group consisting of HLA- A, HLA-B, and HLA-C.

61. The ABPC of any one of claims 48-50, 52, and 54, wherein the KD of the first antigen-binding domain and the second antigen-binding domain, if present, for an HLA-A variant polypeptide-beta 2-microglobulin (β2πι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-A gene-beta 2-microglobulin (β2ηι) polypeptide complex,

62. The ABPC of any one of claims 48-50, 52, and 54, wherein the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-B variant polypeptide-beta 2-microglobulin (β2πι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-B gene-beta 2-microglobulin (β2ηι) polypeptide complex,

63. The ABPC of any one of claims 48-50, 52, and 54, wherein the KD of the first antigen-binding domain, and the second antigen-binding domain, if present, for an HLA-C variant polypeptide-beta 2-microglobulin (β2πι) polypeptide complex at an acidic pH is at least 10% increased as compared to the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, for the polypeptide encoded by the HLA-C gene-beta 2-microglobulin (β2ηι) polypeptide complex,

64. The ABPC of any one of claims 48-50, 52, 54, and 61, wherein the HLA-A gene is selected from the group consisting of: a A*24:02 gene, a A*24: 144 gene, a A*02:01 gene, a A*02:09 gene, a A*02:43N gene, a A*02:66 gene, a A*02:75 gene, a A*02:83N gene, a A*02:89 gene, a A* 02: 97 gene, a A*02: 132 gene, a A*02: 134 gene, a A*02: 140 gene, a A*02:241 gene, a A*02:252 gene, a A*02:256 gene, a A*02:266 gene, a A*02:291 gene, a A*02:294 gene, a A*02:305N gene, a A* l l :01 gene, a A*l l : 102 gene, a A* 11 :2 IN gene, a A* l l :69N gene, a A*l l :86 gene, a A*01 :01 gene, a A*01 :04N gene, a A*01 :22N gene, a A*01 :32 gene, a A*01 :37 gene, a A*01 :45 gene, a A*01:56N gene, a A*01 :81 gene, a A*01 :87N gene, a A*33:03 gene, a A*33: 15 gene, a A*33:25 gene, a A*33:31 gene, a A*33:39 gene, a A*33:44 gene, a A*34:01 gene, a A*03:01 gene, a A*03:20 gene, a A*03:21N gene, a A*03:26 gene, a A*03:37 gene, a A*03:45 gene, a A*03:78 gene, a A*03: 112 gene, a A*03: 118 gene, a A*24:07 gene, a A*23:01 gene, a A*23:07N gene, a A*23: 17 gene, a A* 23: 18 gene, a A*23:20 gene, a A*02:07 gene, a A*02: 15N gene, a A*02:265 gene, a A*02:03 gene, a A*02:253 gene, a A*02:264 gene, a A*31 :01 gene, a A*31 : 14N gene, a A*31 :23 gene, a A*31 :46 gene, a A*31:48 gene, a A*26:01 gene, a A*26:24 gene, a A*26:26 gene, a A*26:56 gene, a A*29:01 gene, a A*02:06 gene, a A*02: 126 gene, a A*30:01 gene, a A*30:24 gene, a A*30:02 gene, a A*30:33 gene, a A*68:01 gene, a A*68: 1 IN gene, a A*68:33 gene, a A*68:02 gene, a A*29:02 gene, a A*29:26 gene, a A*74:01 gene, a A*74:02 gene, a A*02: 11 gene, aA*02:69 gene, a A*32:01 gene, a A*02:02 gene, a A*34:02 gene, a A*36:01 gene, aA*33:01 gene, a A*ll:02 gene, a A*ll:77 gene, a A*26:03 gene, a A*02:05 gene, a A*02:179 gene, a A*25:01 gene, a A*25:07 gene, a A*24:03 gene, a A*24:33 gene, aA*26:02 gene, a A*68:03 gene, a A*03:02 gene, a A*66:01 gene, a A*66:08 gene, aA*30:04 gene, a A*02:17 gene, a A*66:02 gene, a A*24:10 gene, a A*02:04 gene, a A*24:17 gene, a A*80:01 gene, a A*69:01 gene, a A*24:20 gene, a A*01:02 gene, aA*68:05 gene, a A*02:10 gene, a A*30:10 gene, a A*34:05 gene, a A*02:131 gene, a A*02:16 gene, a A*02:104 gene, aA*02:22 gene, aA*02:20 gene, a A*01:03 gene, aA*66:03 gene, a A* 11:04 gene, a A*24:25 gene, a A*24:23 gene, and a A*02:60 gene.

65. The ABPC of any one of claims 48-50, 52, 54, and 62, wherein the HLA-B gene is selected from the group consisting of: a B*40:01 gene, a B*40:55 gene, a B*40: 141 gene, aB*40:150 gene, aB*40:151 gene, aB*15:02 gene, a B* 15:214 gene, a B*46:01 gene, a B*46:15N gene, aB*46:24 gene, aB*07:02 gene, aB*07:44 gene, aB*07:49Ngene, a B*07:58 gene, a B*07:59 gene, a B*07:61 gene, a B*07: 120 gene, a B*07: 128 gene, a B*07:129 gene, aB*07:130 gene, aB*53:01 gene, aB*38:02 gene, a 6*38: 18 gene, a B*08:01 gene, aB*08:19N gene, aB*52:01 gene, a B* 52: 07 gene, aB*35:01 gene, a B*35:40N gene, aB*35:42 gene, aB*35:57 gene, aBⁱ35:94 gene, aB*35:134Ngene, a B*35:161 gene, aB*44:02 gene, aB*44:27 gene, aB*44:66 gene, aB*44:118 gene, a B*51:01 gene, aB*51:llN gene, aB*51:30 gene, aB*51:32 gene, a B*51:48 gene, a B*51:51 gene, aB*40:06 gene, aB*44:03 gene, aB*58:01 gene, aB*58:ll gene, a B * 58 : 3 IN gene, a B * 15 : 01 gene, a B* 15 : 102 gene, a B * 15 : 104 gene, a B * 15 : 140 gene, a B*15:146 gene, a B* 15:201 gene, aB*35:05 gene, aB*07:05 gene, aB*07:06 gene, a B*15:35 gene, aB*40:02 gene, aB*40:56 gene, aB*40:97 gene, aB*40:144N gene, a B*54:01 gene, aB*54:17 gene, a B* 18:01 gene, aB*18:17N gene, aB*18:53 gene, a B*35:03 gene, aB*35:70 gene, aB*57:01 gene, aB*57:29 gene, aB*57:37 gene, aB*15:03 gene, aB*15:103 gene, aB*13:01 gene, aB*27:05 gene, aB*27:13 gene, aB*42:01 gene, a B*15:25 gene, aB*45:01 gene, aB*45:07 gene, aBⁱ45:13 gene, aB*14:02 gene, aB*58:02 gene, aB*49:01 gene, aB*15:10 gene, aB*38:01 gene, aB*48:01 gene, aB*48:09 gene, a B*57:03 gene, a B*37:01 gene, a B*37:23 gene, a B*39:01 gene, a B*39:46 gene, a B*39:59 gene, aB*35:02 gene, aB*15:21 gene, aB*39:05 gene, a B* 13:02 gene, aB*13:38 gene, a B*50:01 gene, aB*39:06 gene, aB*55:02 gene, aB*41:01 gene, aB*27:06 gene, aB*15:13 gene, a B*59:01 gene, aB*35:12 gene, aB*55:01 gene, a B* 15: 12 gene, a B*15:19 gene, a B*15:16gene, aB*81:01 gene, aB*81:02 gene, aB*81:03 gene, aB*51:06 gene, aB*27:04 gene, a B*27:68 gene, aB*27:69 gene, aB*35:43 gene, aB*35:67 gene, a B*35:79 gene, a B* 15 : 11 gene, a B*35 : 08 gene, a B* 15: 18 gene, a B* 15 : 198 gene, a B* 15 : 17 gene, a B*51:02 gene, aB*14:01 gene, aB*39:10 gene, aB*56:04 gene, aB*15:27 gene, aB*35:17 gene, aB*15:15 gene, aB*15:07 gene, aB*67:01 gene, aBⁱ78:01 gene, aB*56:01 gene, a B*56:24 gene, aB*41:02 gene, aB*40:05 gene, aBⁱ42:02 gene, aB*40:03 gene, aB*40:10 gene, aB*57:02 gene, aB*15:30 gene, aB*27:02 gene, aB*18:02 gene, aB*39:02 gene, a B*39:08 gene, aB*27:07 gene, aB*48:03 gene, aB*51:08 gene, aB*39:09 gene, aB*15:05 gene, a B*27:03 gene, a B*35:04 gene, a B*40:04 gene, a B*44:05 gene, a B*40:08 gene, a B*15:08 gene, aB*15:04 gene, aB*48:04 gene, aB*39:ll gene, aB*35:14 gene, aB*47:01 gene, a B*82:01 gene, aB*73:01 gene, aB*14:03 gene, aB*35:20 gene, a B*15:29 gene, a B*50:02 gene, aB*57:04 gene, aB*48:02 gene, aB*15:40 gene, aB*15:06 gene, aB*51:05 gene, a B*40:ll gene, aB*56:03 gene, aB*51:07 gene, aB*39:04 gene, a B*44:10 gene, a B*39:15 gene, aB*15:38gene, aB*15:32 gene, aB*51:09 gene, aB*39:24 gene, aB*15:39 gene, a B*40:12 gene, aB*40:27 gene, aB*35:10 gene, aB*35:ll gene, a B* 15:09 gene, a B*47:03 gene, and a B*48:07 gene.

66. The ABPC of any one of claims 48-50, 52, 54, and 63, wherein the HLA-C gene is selected from the group consisting of: a C*07:02 gene, a C*07:50 gene, a C*07:66 gene, a C*07:74 gene, a C*07: 159 gene, a C*07: 160 gene, a C*07: 167 gene, a C*04:01 gene, a C*04:09N gene, a C*04:28 gene, a C*04:30 gene, a C*04:41 gene, a C*04:79 gene, a C*04:82 gene, aC*04:84 gene, aC*01:02 gene, aC*01:25 gene, aC*01:44 gene, aC*08:01 gene, a C*08:20 gene, a C*08:22 gene, a C*08:24 gene, a C*07:01 gene, a C*07:06 gene, a C*07:18 gene, aC*07:52gene, aC*07:153 gene, aC*07:166 gene, aC*03:03 gene, a C*03:20N gene, a C*03:62 gene, a C*06:02 gene, a C*06:46N gene, a C*06:55 gene, a C*03:04 gene, aC*03:100 gene, a C*03:101 gene, aC*03:105 gene, a C*03:106 gene, a C*15:02 gene, a C*15:13 gene, a C*15:47 gene, a C*12:02 gene, a C*16:01 gene, a C*05:01 gene, a C*05:03 gene, aC*05:37 gene, aC*05:53 gene, a 0*12:03 gene, a C*12:23 gene, a C*02:02 gene, a C*02: 10 gene, a C*02:29 gene, a C*03:02 gene, a C*14:02 gene, a C*14:23 gene, a C*14:31 gene, aC*15:05 gene, aC*15:29 gene, a C* 17:01 gene, a C*17:02 gene, a C*17:03 gene, aC*14:03 gene, aC*04:03 gene, aC*08:02 gene, aC*18:01 gene, aC*18:02 gene, aC*16:02 gene, aC*07:04 gene, aC*07:ll gene, aC*03:05 gene, a C*12:04 gene, a C*08:03 gene, a C*08:40 gene, a C*04:06 gene, a C* 16:04 gene, a C*08: 04 gene, a C*03:06 gene, a C*04:04 gene, a C*07:26 gene, a C* 15:09 gene, a C*01 :03 gene, a C*01 :24 gene, a C* 15:04 gene, and a C*04:07 gene.

67. The ABPC of any one of claims 48-50, 52, 54, and 61 -66, wherein the PC further comprises a peptide of about 8-12 amino acids in length that is bound to the PC.

68. The ABPC of any one of claims 48-67, wherein the first antigen-binding domain, and, if present, the second antigen-binding domain or the additional antigen-binding domain is/are capable of specifically binding to an epitope present on the surface or in a cellular compartment of human cells and an epitope that is present on the surface or in a cellular compartment of cells from an Old World Monkey.

69. The ABPC of any one of claims 48-68, wherein the dissociation rate of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is/are at least 10% slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

70. The ABPC of any one of claims 48-68, wherein the dissociation rate of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 3-fold slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

71. The ABPC of any one of claims 48-68, wherein the dissociation rate of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 10-fold slower than the dissociation rate of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

72. The ABPC of any one of claims 48-71 , wherein the KD of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 10% less than the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

73. The ABPC of any one of claims 48-71 , wherein the KD of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 3-fold less than the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

74. The ABPC of any one of claims 48-71 , wherein the KD of the first antigen-binding domain and the second antigen-binding domain, if present, at an acidic pH is at least 10-fold less than the KD of the first antigen-binding domain or the second antigen-binding domain, respectively, at a neutral pH.

75. The ABPC of any one of claims 48-74, wherein the ABPC is less cytotoxic or cytostatic to a non-cancerous cell.

76. The ABPC of any one of claims 48-75, wherein the ABPC comprises a single polypeptide.

77. The ABPC of claim 76, wherein the first antigen-binding domain and the second antigen-binding domain, if present, are each independently selected from the group consisting of: a VHH domain, a VNAR domain, and a scFv.

78. The ABPC of claim 76, wherein the ABPC is a BiTe, a (scFv)2, a nanobody, a nanobody-HSA, a DART, a TandAb, a scDiabody, a scDiabody-CH3, scFv-CH-CL-scFv, a HSAbody, scDiabody-HAS, or a tandem-scFv.

79. The ABPC of any one of claims 48-74, wherein the ABPC comprises two or more polypeptides.

80. The ABPC of claim 79, wherein the ABPC is selected from the group of an antibody, a VHH-scAb, a VHH-Fab, a Dual scFab, a F(ab')2, a diabody, a crossMab, a DAF (two-in-one), a DAF (four-in-one), a DutaMab, a DT-IgG, a knobs-in-holes common light chain, a knobs-in-holes assembly, a charge pair, a Fab-arm exchange, a SEEDbody, a LUZ- Y, a Fcab, a κλ-body, an orthogonal Fab, a DVD-IgG, a IgG(H)-scFv, a scFv-(H)IgG IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybodv, DVI-IgG, Diabody-CH3, a triple body, a miniantibody, a minibody, a TriBi minibody, scFv-CH3 ICIH, Fab-scFv, a F(ab')2-scFv2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a Diabody-Fc, a tandem scFv-Fc, an Intrabody, a dock and lock, an ImmTAC, an IgG-lgG conjugate, a Cov-X-Body, and a scF l-PEG-scFv2.

81. The ABPC of any one of claims 48-80, wherein at least one protein of the ABPC is conjugated to a toxin, a radioisotope, or a drug via a cleavable linker.

82. The ABPC of any one of claims 48-80, wherein at least one protein of the ABPC is conjugated to a toxin, a radioisotope, or a drug via a non-cleavable linker.

83. The ABPC of any one of claims 48-52 wherein the ABPC has reduced toxin liberation or reduced cell killing potency in a mammalian cell presenting the PC on its surface or in a cellular compartment as compared to a control ABPC.

84. The ABPC of any one of claims 48-83, wherein the additional antigen-binding domain has a KD that is increased at an acidic pH as compared to the KD of the additional antigen-binding domain at a neutral pH.

85. The ABPC of any one of claims 48-83, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 10% increased as compared to the KD of the additional antigen-binding domain at a neutral pH.

86. The ABPC of any one of claims 48-83, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 3-fold greater than the KD of the additional antigen-binding domain at a neutral pH.

87. The ABPC of any one of claims 48-83, wherein the additional antigen-binding domain has a KD at an acidic pH that is at least 10-fold greater than the KD of the additional antigen-binding domain at a neutral pH.

88. The ABPC of any one of claims 48-87, wherein the half-life of the ABPC in vivo is increased about 10% to about 400% as compared to the half-life of a control ABPC in vivo.

89. The ABPC of any one of claims 48-87, wherein the half-life of the ABPC in vivo is increased about 0.5-fold to about 4-fold as compared to the half-life of a control ABPC in vivo.

90. The ABPC of any one of claims 48-87, wherein the half-life of the ABPC in vivo is increased about 1-fold to about 4-fold as compared to the half-life of a control ABPC in vivo.

91. The ABPC of any one of claims 48-87, wherein the half-life of the ABPC in vivo is increased about 1.5-fold to about 4-fold as compared to the half-life of a control ABPC in vivo.

92. The ABPC of any one of claims 48-87, wherein the half-life of the ABPC in vivo is increased about 2-fold to about 4-fold as compared to the half-life of a control ABPC in vivo.

93. The ABPC of any one of claims 48-87, wherein the half-life of the ABPC in vivo is increased about 2.5-fold to about 4-fold as compared to the half-life of a control ABPC in vivo.

94. A kit comprising an ABPC of any one of claims 48-93.

95. A method of treating a cancer characterized by having a population of cancer cells that have at least one of the following:

(a) a reduced level of expression of a polypeptide encoded by a HLA-A, HLA-B, or HLA-C gene, a reduced level of MHCl presentation on their surface, and/or a reduced level of MHCl in a cellular compartment as compared to a non-cancerous cell;

administering a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-46 or the ABPC of any one of claims 48-93 to a subject identified as having a cancer characterized by having the population of cancer cells

96. A method of reducing the volume of a tumor in a subject, wherein the tumor is characterized by having a population of cancer cells that have at least one of the following:

administering a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-46 or the ABPC of any one of claims 48-93 to a subject identified as having a cancer characterized by having the population of cancer cells.

97. A method of inducing cell death in a cancer cell in a subject, wherein the cancer cell has at least one of the following:

98. The method of any one of claims 95-97, wherein the cancer is a primary tumor.

99. The method of any one of claims 95-97, wherein the cancer is a metastasis.

100. The method of any one of claims 95-97, wherein the cancer is a non-T-cell- infiltrating tumor.

101. The method of any one of claims 95-97, wherein the cancer is a T-cell infiltrating tumor.

102. A method of decreasing the risk of developing a metastasis or decreasing the risk of developing an additional metastasis in a subject having a cancer, wherein the cancer is characterized by having a population of cancer cells that have at least one of the following:

(c) a reduced level of expression of β2ηι polypeptide, a reduced level of β2πι polypeptide present on their surface, and/or a reduced level of β2ηι polypeptide in a cellular compartment as compared to a non-cancerous cell; and (d) a genetic lesion in a β2ηι gene and/or a HLA gene selected from the group consisting of: HLA-A, HLA-B, and HLA-C, as compared to a non-cancerous cell, the method comprising:

103. A method of increasing the level of an ABPC in a cellular compartment of a cancer cell in a subject as compared to the level of the ABPC in the cellular compartment of a non-cancerous cell, wherein the cancer cell has at least one of the following:

administering a therapeutically effective amount of the pharmaceutical composition of any one of claims 1-46 or the ABPC of any one of claims 48-93 to a subject identified as having a cancer characterized by having a population of the cancer cells.

104. A method of decreasing the level of an ABPC in a cellular compartment of a non-cancerous cell in a subject as compared to the level of the ABPC in the cellular compartment of a cancerous cell in the subject, wherein the cancer cell has at least one of the following:

105. The method of any one of claims 102-104, wherein the cancer is a non-T-cell- infiltrating tumor.

106. The method of any one of claims 102-104, wherein the cancer is a T-cell infiltrating tumor.

107. The method of any one of claims 95-106, wherein the cellular compartment is part of the endosomal/lysosomal pathway.

108. The method of any one of claims 95-106, wherein the cellular compartment is an endosome.