Bispecific antibodies that bind to MICA / b and CD3

Abstract

Provided herein are anti-CD3 × anti-MICA / B antibodies and methods of using such antibodies for the treatment of cancers.

Description

Attorney Docket: 51096.4019 / WO BISPECIFIC ANTIBODIES THAT BIND TO MICA / B AND CD3 CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 703,846,filed October 04, 2024, and U.S. Provisional Application No.63 / 716,367, filed November 05, 2024, which are hereby incorporated by reference in their entireties. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submittedelectronically in ST.26 XML format and is hereby incorporated by reference in its entirety. Said ST.26 XML format file was created on October 2, 2025, is named 51096_4019-WO_SL.xml and is 850,162 bytes in size. BACKGROUND

[0003] Antibody-based therapeutics have been used successfully to treat a variety of diseases,including cancer. An increasingly prevalent avenue being explored is the engineering of single immunoglobulin molecules that co-engage two different antigens. Such alternate antibody formats that engage two different antigens are often referred to as bispecific antibodies. Because the considerable diversity of the antibody variable region (Fv) makes it possible to produce an Fv that recognizes virtually any molecule, the typical approach to bispecific antibody generation is the introduction of new variable regions into the antibody.

[0004] Bispecific antibodies engineered to concurrently bind T cells and tumor cells, therebyredirecting the cytotoxic activity of T cells towards malignant cells, are an emerging class of solid tumor immunotherapies. One of the challenges solid tumors present to immunotherapies is a hostile immunosuppressive environment. Additional costimulatory signals can enhance T cell cytotoxicity and help T cells overcome the immune suppression. Tumor microenvironment- induced antigens offer a distinct strategy for targeting tumor cells with immunotherapies. MHC class I polypeptide-related sequence A and B (MICA and MICB, referred to as MICA / B) are stress-induced antigens expressed across various malignancies. These antigens, in their membrane-bound form, interact with NKG2D receptor expressed on CD8 T cells and NK cells,Attorney Docket: 51096.4019 / WO and exert an immuno-stimulatory activity. Conversely, the cleavage of MICA / B antigens in the tumor microenvironment prevent NKG2D-mediated tumor recognition and facilitate immune evasion.

[0005] The present disclosure is directed to improved bispecific MICA / B and CD3 antibodiesand the use of such antibodies for use in therapy (e.g., cancer therapy). SUMMARY

[0006] In one aspect, the present disclosure provides a bispecific antibody that binds MICA / Band CD3, comprising: (a) a first monomer, comprising: (i) an anti-CD3 scFv comprising, from N-terminus to C-terminus: (1) a first variable heavy (VH1) domain, an scFv linker, and a first variable light (VL1) domain, or (2) a first variable light (VL1) domain, an scFv linker, and a first variable heavy (VH1) domain; and (ii) a first Fc domain comprising, from N-terminus to C- terminus: a constant domain 2 of a heavy chain (CH2) and a constant domain 3 of a heavy chain (CH3), wherein the C-terminus of the anti-CD3 scFv is covalently attached to the N-terminus of the first Fc domain using a domain linker; (b) a second monomer comprising, from N-terminus to C-terminus: a second variable heavy (VH2) domain, a constant domain 1 of a heavy chain (CH1), a constant domain 2 of a heavy chain (CH2), a constant domain 3 of a heavy chain (CH3), wherein VH2 is a second variable heavy domain and CH2-CH3 is a second Fc domain; and (c) a common light chain comprising, from N-terminus to C-terminus: a second variable light (VL2) domain and a constant domain light chain (CL), wherein the second variable heavy (VH2) domain and the second variable light (VL2) domain form a MICA / B antigen binding domain.

[0007] In some embodiments, the MICA / B antigen binding domain comprises a set of vhCDR1-3 and vlCDR1-3 from a variable heavy domain and variable light domain pair, wherein the set of vhCDR1-3 and vlCDR1-3 is selected from the group consisting of: D99136_2C11 [MICA / B]_H0, D99136_2C11 [MICA / B]_H1, D99136_2C11 [MICA / B]_H2, D94837_1E11_1 [MICA / B]_H0, D94837_1E11_1 [MICA / B]_H1, D94837_1E11_1 [MICA / B]_H2 for the set of vhCDR1-3, and D99136_2C11 [MICA / B]_L0, D99136_2C11 [MICA / B]_L1, D99136_2C11 [MICA / B]_L2, D94837_1E11_1 [MICA / B]_L0, D94837_1E11_1 [MICA / B]_L1, D94837_1E11_1 [MICA / B]_L2 for the set of vlCDR1-3.Attorney Docket: 51096.4019 / WO

[0008] In some embodiments, the MICA / B antigen binding domain comprises a variable heavydomain and variable light domain pair selected from the group consisting of: D99136_2C11 [MICA / B]_H0L0, D99136_2C11 [MICA / B]_H1L1, D99136_2C11 [MICA / B]_H1L2, D99136_2C11 [MICA / B]_H2L1, D99136_2C11 [MICA / B]_H2L2, D94837_1E11_1 [MICA / B]_H0L0, D94837_1E11_1 [MICA / B]_H1L1, D94837_1E11_1 [MICA / B]_H1L2. D94837_1E11_1 [MICA / B]_H2L1, and D94837_1E11_1 [MICA / B]_H2L2, as depicted in Figure 16.

[0009] In some embodiments, the anti-CD3 scFv comprises a first variable heavy VH1 domainand first variable light VL1 domain pair selected from the group consisting of: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.31, as depicted in Figure 15.

[0010] In some embodiments, the first variable light (VL1) domain of the anti-CD3 scFv iscovalently attached to the N-terminus of the first Fc domain using the domain linker. In some embodiments, the first variable heavy (VH1) domain of the anti-CD3 scFv is covalently attached to the N-terminus of the first Fc domain using the domain linker.

[0011] In one aspect, the present disclosure provides a bispecific antibody that binds MICA / Band CD3, comprising: (a) a first monomer, comprising: (i) an anti-MICA / B scFv comprising, from N-terminus to C-terminus: (1) a first variable heavy (VH1) domain, an scFv linker, and a first variable light (VL1) domain, or (2) a first variable light (VL1) domain, an scFv linker, and a first variable heavy (VH1) domain; and (ii) a first Fc domain comprising, from N-terminus to C- terminus: a constant domain 2 of a heavy chain (CH2) and a constant domain 3 of a heavy chain (CH3), wherein the C-terminus of the anti-MICA / B scFv is covalently attached to the N- terminus of the first Fc domain using a domain linker; (b) a second monomer comprising, from N-terminus to C-terminus: a second variable (VH2) domain, a constant domain 1 of a heavy chain (CH1), a constant domain 2 of a heavy chain (CH2), a constant domain 3 of a heavy chain (CH3), wherein CH2-CH3 is a second Fc domain; and (c) a common light chain comprising, from N-terminus to C-terminus: a second variable light (VL2) domain and a constant domain light chain (CL), wherein the second variable heavy (VH2) domain and the second variable light (VL2) domain form a CD3 antigen binding domain.Attorney Docket: 51096.4019 / WO

[0012] In some embodiments, the CD3 antigen binding domain comprises a set of vhCDR1-3and vlCDR1-3 from a variable heavy domain and variable light domain pair selected from the group consisting of: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.31, as depicted in Figure 15. In some embodiments, the CD3 antigen binding domain comprises a variable heavy domain and variable light domain pair selected from the group consisting of: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.31.

[0013] In some embodiments, the anti-MICA / B scFv comprises a set of vhCDR1-3 andvlCDR1-3 from a first variable heavy VH1 domain and first variable light VL1 domain pair, wherein the set of vhCDR1-3 and vlCDR1-3 is selected from the group consisting of: D99136_2C11 [MICA / B]_H0, D99136_2C11 [MICA / B]_H1, D99136_2C11 [MICA / B]_H2, D94837_1E11_1 [MICA / B]_H0, D94837_1E11_1 [MICA / B]_H1, D94837_1E11_1 [MICA / B]_H2 for the set of vhCDR1-3, and D99136_2C11 [MICA / B]_L0, D99136_2C11 [MICA / B]_L1, D99136_2C11 [MICA / B]_L2, D94837_1E11_1 [MICA / B]_L0, D94837_1E11_1 [MICA / B]_L1, D94837_1E11_1 [MICA / B]_L2 for the set of vlCDR1-3, as depicted in Figure 16. In some embodiments, the anti-MICA / B scFv comprises a first variable heavy domain and first variable light domain pair selected from the group consisting of: D99136_2C11 [MICA / B]_H0L0, D99136_2C11 [MICA / B]_H1L1, D99136_2C11 [MICA / B]_H1L2, D99136_2C11 [MICA / B]_H2L1, D99136_2C11 [MICA / B]_H2L2, D94837_1E11_1 [MICA / B]_H0L0, D94837_1E11_1 [MICA / B]_H1L1, D94837_1E11_1 [MICA / B]_H1L2. D94837_1E11_1 [MICA / B]_H2L1, and D94837_1E11_1 [MICA / B]_H2L2.

[0014] In some embodiments, the first variable light (VL1) domain of the anti-MICA / B scFv iscovalently attached to the N-terminus of the first Fc domain using the domain linker. In some embodiments, the first variable heavy (VH1) domain of the anti-MICA / B scFv is covalently attached to the N-terminus of the first Fc domain using the domain linker.

[0015] In some embodiments, the scFv linker is a charged scFv linker.

[0016] In some embodiments, the scFv linker is a charged scFv linker having the amino acidsequence (GKPGS)4(SEQ ID NO: 1).Attorney Docket: 51096.4019 / WO

[0017] In some embodiments, the first and second Fc domains are each variant Fc domains.

[0018] In some embodiments, the first and / or second variant Fc domains comprise one or moreFcγRIIIA (CD16a) binding variant substitutions.

[0019] In some embodiments, the one or more FcγRIIIA (CD16a) binding variant substitutionsare selected from the group consisting of: (i) 236A, (ii) 239D, (iii) 239E, (iv) 243L, (v) 298A, (vi) 299T, (vii) 332E, (viii) 332D, (ix) 239D / 332E, (x) 236A / 332E, (xi) 239D / 332E / 330L, and (xii) 332E / 330L, wherein numbering is according to EU numbering.

[0020] In some embodiments, the first and second variant Fc domains comprise a set ofFcγRIIIA (CD16a) binding variant substitutions selected from the group consisting of: (i) S239D / I332E : S239D / I332E, (ii) S239D : S239D, (iii) I332E : I332E, (iv) WT : S239D / I332E, (v) WT : S239D, (vi) WT : I332E, (vii) S239D / I332E : WT, (viii) S239D : WT, (ix) I332E : WT, (x) S239D / I332E : S239D, (xi) S239D / I332E : I332E, (xii) S239D : S239D / I332E, (xiii) I332E : S239D / I332E, (xiv) S239D : I332E, and (xv) I332E : S239D, wherein numbering is according to EU numbering.

[0021] In some embodiments, the first and / or second variant Fc domains comprise the FcγRIIIA(CD16a) binding variant substitutions of S239D / I332E, wherein numbering is according to EU numbering.

[0022] In some embodiments, the first and second variant Fc domains comprise a set ofheterodimerization variants selected from the group consisting of: (i) S364K / E357Q : L368D / K370S, (ii) S364K : L368D / K370S, (iii) S364K : L368E / K370S, (iv) D401K : T411E / K360E / Q362E, and (v) T366W : T366S / L368A / Y407V, wherein numbering is according to EU numbering.

[0023] In some embodiments, the first and second variant Fc domains further comprise one ormore ablation variants. In some embodiments, the one or more ablation variants are E233P / L234V / L235A / G236del / S267K, wherein numbering is according to EU numbering.

[0024] In some embodiments, the first and / or second variant Fc domain comprises one or morepI variants. In some embodiments, the one or more pI variants are N208D / Q295E / N384D / Q418E / N421D, wherein numbering is according to EU numbering.Attorney Docket: 51096.4019 / WO

[0025] In some embodiments, the first monomer comprises amino acid variantsS364K / E357Q / E233P / L234V / L235A / G236del / S267K, wherein the second monomer comprises amino acid variants L368D / K370S / N208D / Q295E / N384D / Q418E / N421D / E233P / L234V / L235A / G236del / S267K, and wherein numbering is according to EU numbering.

[0026] In some embodiments, the first and second monomers each further comprise amino acidvariants M428L / N434S, M428L / N434A or M252Y / S254T / T256E, wherein numbering is according to EU numbering.

[0027] In some embodiments, any one of the bispecific antibodies is selected from the groupconsisting of: XENP50442, XENP50444, and XENP50445.

[0028] In some embodiments, provided herein is a nucleic acid composition comprising nucleicacids encoding the first and second monomers and the light chain of the antibody described herein. In some embodiments, provided herein is an expression vector comprising any of the nucleic acids described herein. In some embodiments, provided herein is a host cell transformed with any expression vector described herein.

[0029] In another aspect, provided herein is a method of making a bispecific antibodycomprising: (a) culturing the host cell according to any described herein under conditions wherein the bispecific antibody is expressed; and (b) recovering the bispecific antibody.

[0030] In one aspect, provided herein is a bispecific antibody that binds MICA / B and CD3,comprising: (a) a first monomer comprising, from N-terminus to C-terminus: a first variable heavy (VH1) domain, a first constant domain 1 of a heavy chain (CH1), a(n) (optional) hinge domain, the first VH1 domain, the first CH1 domain, a constant domain 2 of a heavy chain (CH2), a constant domain 3 of a heavy chain (CH3), wherein CH2-CH3 is a first Fc domain; (b) a light chain comprising, from N-terminus to C-terminus: a first variable light (VL1) domain and a constant domain light chain (CL), wherein the VH1 and VL1 form MICA / B antigen binding domains; and (c) a second monomer comprising, from N-terminus to C-terminus: an anti-CD3 scFv and a second Fc domain, wherein the scFv is covalently attached to the N-terminus of the second Fc domain using a second linker.Attorney Docket: 51096.4019 / WO

[0031] In some embodiments, the anti-CD3 scFv comprises, from N-terminus to C-terminus: (1)a second variable heavy (VH2) domain, an scFv linker, and a second variable light (VL2) domain, or (2) a second variable light (VL2) domain, an scFv linker, and a second variable heavy (VH2) domain.

[0032] In some embodiments, the anti-CD3 scFv comprises a set of vhCDR1-3 and vlCDR1-3from a variable heavy domain and variable light domain pair selected from the group consisting of: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.31, as depicted in Figure 15. In some embodiments, the anti-CD3 scFv comprises a variable heavy domain and variable light domain pair selected from the group consisting of: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.31, as depicted in Figure 15.

[0033] In some embodiments, each of the MICA / B antigen binding domains comprise a set ofvhCDR1-3 and vlCDR1-3 from a variable heavy domain and variable light domain pair, wherein the set of vhCDR1-3 and vlCDR1-3 is selected from the group consisting of: D99136_2C11 [MICA / B]_H0, D99136_2C11 [MICA / B]_H1, D99136_2C11 [MICA / B]_H2, D94837_1E11_1 [MICA / B]_H0, D94837_1E11_1 [MICA / B]_H1, and D94837_1E11_1 [MICA / B]_H2 for the set of vhCDR1-3, and D99136_2C11 [MICA / B]_L0, D99136_2C11 [MICA / B]_L1, D99136_2C11 [MICA / B]_L2, D94837_1E11_1 [MICA / B]_L0, D94837_1E11_1 [MICA / B]_L1, and D94837_1E11_1 [MICA / B]_L2 for the set of vlCDR1-3, as depicted in Figure 16.

[0034] In some embodiments, each of the MICA / B antigen binding domains comprise a variableheavy domain and variable light domain pair selected from the group consisting of: D99136_2C11 [MICA / B]_H0L0, D99136_2C11 [MICA / B]_H1L1, D99136_2C11 [MICA / B]_H1L2, D99136_2C11 [MICA / B]_H2L1, D99136_2C11 [MICA / B]_H2L2, D94837_1E11_1 [MICA / B]_H0L0, D94837_1E11_1 [MICA / B]_H1L1, D94837_1E11_1 [MICA / B]_H1L2. D94837_1E11_1 [MICA / B]_H2L1, and D94837_1E11_1 [MICA / B]_H2L2, as depicted in Figure 16.

[0035] In one aspect, provided herein is a bispecific antibody, comprising: (a) a first monomercomprising, from N-terminus to C-terminus: a first variable heavy (VH1) domain, a first constantAttorney Docket: 51096.4019 / WO domain 1 of a heavy chain (CH1), a(n) (optional) hinge domain, the first VH1 domain, the first CH1 domain, a constant domain 2 of a heavy chain (CH2), a constant domain 3 of a heavy chain (CH3), wherein CH2-CH3 is a first Fc domain; (b) a light chain comprising, from N-terminus to C-terminus: a first variable light (VL1) domain and a constant domain light chain (CL), wherein the VH1 and VL1 form CD3 antigen binding domains; and (c) a second monomer comprising, from N-terminus to C-terminus: an anti-MICA / B scFv and a second Fc domain, wherein the scFv is covalently attached to the N-terminus of the second Fc domain using a second linker.

[0036] In some embodiments, the anti-MICA / B scFv comprises, from N-terminus to C-terminus:(1) a second variable heavy (VH2) domain, an scFv linker, and a second variable light (VL2) domain, or (2) a second variable light (VL2) domain, an scFv linker, and a second variable heavy (VH2) domain.

[0037] In some embodiments, the anti-MICA / B scFv comprises a set of vhCDR1-3 andvlCDR1-3 from a variable heavy domain and variable light domain pair, wherein the set of vhCDR1-3 and vlCDR1-3 is selected from the group consisting of: D99136_2C11 [MICA / B]_H0, D99136_2C11 [MICA / B]_H1, D99136_2C11 [MICA / B]_H2, D94837_1E11_1 [MICA / B]_H0, D94837_1E11_1 [MICA / B]_H1, and D94837_1E11_1 [MICA / B]_H2 for the set of vhCDR1-3, and D99136_2C11 [MICA / B]_L0, D99136_2C11 [MICA / B]_L1, D99136_2C11 [MICA / B]_L2, D94837_1E11_1 [MICA / B]_L0, D94837_1E11_1 [MICA / B]_L1, and D94837_1E11_1 [MICA / B]_L2 for the set of vlCDR1-3, as depicted in Figure 16.

[0038] In some embodiments, the anti-MICA / B scFv comprises a variable heavy domain andvariable light domain pair selected from the group consisting of: D99136_2C11 [MICA / B]_H0L0, D99136_2C11 [MICA / B]_H1L1, D99136_2C11 [MICA / B]_H1L2, D99136_2C11 [MICA / B]_H2L1, D99136_2C11 [MICA / B]_H2L2, D94837_1E11_1 [MICA / B]_H0L0, D94837_1E11_1 [MICA / B]_H1L1, D94837_1E11_1 [MICA / B]_H1L2. D94837_1E11_1 [MICA / B]_H2L1, and D94837_1E11_1 [MICA / B]_H2L2, as depicted in Figure 16.

[0039] In some embodiments, each of the CD3 antigen binding domains comprise a set ofvhCDR1-3 and vlCDR1-3 from a variable heavy domain and variable light domain pair, wherein the set of vhCDR1-3 and vlCDR1-3 is selected from the group consisting of: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30,Attorney Docket: 51096.4019 / WO L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.31, as depicted in Figure 15.

[0040] In some embodiments, each of the CD3 antigen binding domains comprise a variableheavy domain and variable light domain pair selected from the group consisting of: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.31, as depicted in Figure 15.

[0041] In some embodiments, the scFv linker is a charged scFv linker.

[0042] In some embodiments, the scFv linker is a charged scFv linker having the amino acidsequence (GKPGS)4(SEQ ID NO: 1).

[0043] In some embodiments, the first and second linkers are each domain linkers.

[0044] In some embodiments, the first and second Fc domains are each variant Fc domains.

[0045] In some embodiments, the first and / or second variant Fc domains comprise one or moreFcγRIIIA (CD16a) binding variant substitutions.

[0046] In some embodiments, the one or more FcγRIIIA (CD16a) binding variant substitutionsare selected from the group consisting of: (i) 236A, (ii) 239D, (iii) 239E, (iv) 243L, (v) 298A, (vi) 299T, (vii) 332E, (viii) 332D, (ix) 239D / 332E, (x) 236A / 332E, (xi) 239D / 332E / 330L, and (xii) 332E / 330L, wherein numbering is according to EU numbering.

[0047] In some embodiments, the first and second variant Fc domains comprise a set ofFcγRIIIA (CD16a) binding variant substitutions selected from the group consisting of: (i) S239D / I332E : S239D / I332E, (ii) S239D : S239D, (iii) I332E : I332E, (iv) WT : S239D / I332E, (v) WT : S239D, (vi) WT : I332E, (vii) S239D / I332E : WT, (viii) S239D : WT, (ix) I332E : WT, (x) S239D / I332E : S239D, (xi) S239D / I332E : I332E, (xii) S239D : S239D / I332E, (xiii) I332E : S239D / I332E, (xiv) S239D : I332E, and (xv) I332E : S239D, wherein numbering is according to EU numbering.

[0048] In some embodiments, the first and / or second variant Fc domains comprise the FcγRIIIA(CD16a) binding variant substitutions of S239D / I332E, wherein numbering is according to EU numbering.Attorney Docket: 51096.4019 / WO

[0049] In some embodiments, the first and second variant Fc domains comprise a set ofheterodimerization variants selected from the group consisting of: (i) S364K / E357Q : L368D / K370S, (ii) S364K : L368D / K370S, (iii) S364K : L368E / K370S, (iv) D401K : T411E / K360E / Q362E, and (v) T366W : T366S / L368A / Y407V, wherein numbering is according to EU numbering.

[0050] In some embodiments, the first and second Fc variant domains further comprise one ormore ablation variants. In some embodiments, one or more ablation variants are E233P / L234V / L235A / G236del / S267K, wherein numbering is according to EU numbering.

[0051] In some embodiments, the first and / or second variant Fc domain further comprises one ormore pI variants. In some embodiments, the one or more pI variants are N208D / Q295E / N384D / Q418E / N421D, wherein numbering is according to EU numbering.

[0052] In some embodiments, the first monomer comprises amino acid variantsS364K / E357Q / E233P / L234V / L235A / G236del / S267K, wherein the second monomer comprises amino acid variants L368D / K370S / N208D / Q295E / N384D / Q418E / N421D / E233P / L234V / L235A / G236del / S267K, and wherein numbering is according to EU numbering.

[0053] In some embodiments, the first and second monomers each further comprise amino acidvariants M428L / N434S, M428L / N434A or M252Y / S254T / T256E, wherein numbering is according to EU numbering.

[0054] In some embodiments, any one of the bispecific antibodies is selected from the groupconsisting of: XENP50514, XENP50515, XENP50516, XENP50517, XENP50518, and XENP50519.

[0055] In another aspect, provided herein is a nucleic acid composition comprising nucleic acidsencoding the first and second monomers and the light chain of the antibody described herein. In some embodiments, provided herein is an expression vector comprising any of the nucleic acids described herein. In some embodiments, provided herein is a host cell transformed with an expression vector described herein.

[0056] In another aspect, provided herein is a bispecific antibody comprising: (a) a means forbinding MICA / B; and (b) a means for binding CD3.Attorney Docket: 51096.4019 / WO

[0057] In another aspect, provided herein is a pharmaceutical composition comprising thebispecific antibody according to any of the aspects and embodiments described herein.

[0058] In another aspect, provided herein is a pharmaceutical composition comprising: (a) a firstcomposition comprising a means for binding MICA / B; and (b) a second composition comprising a means for binding CD3.

[0059] In another aspect, provided herein is a pharmaceutical composition comprising: (a) ameans for binding MICA / B; (b) a means for binding CD3; and (c) a pharmaceutically acceptable carrier.

[0060] In another aspect, provided herein is a bispecific antibody according to any of the aspectsor embodiments described herein or a pharmaceutical composition according to any of the aspects or embodiments described herein for use in the treatment of a MICA / B-associated disease and / or a CD3-associated disease in a subject in need thereof.

[0061] In another aspect, provided herein is a bispecific antibody according to any of the aspectsor embodiments described herein or a pharmaceutical composition according to any of the aspects or embodiments described herein for inhibiting or reducing MICA / B-mediated activity and / or CD3-mediated activity in a subject in need thereof.

[0062] In another aspect, provided herein is a bispecific antibody according to any of the aspectsor embodiments described herein or a pharmaceutical composition according to any of the aspects or embodiments described herein for use in the manufacture of a medicament for the treatment of a MICA / B-associated disease and / or CD3-mediated activity in a subject in need thereof.

[0063] In a further embodiment according to any of the aspects or embodiments describedherein, the subject is a human subject.

[0064] In another aspect, provided herein is a kit comprising a bispecific antibody according toany of the aspects or embodiments described herein or a pharmaceutical composition according to any of the aspects or embodiments described herein.

[0065] In another aspect, provided herein is a vessel or delivery device comprising a bispecificantibody according to any of the aspects or embodiments described herein or a pharmaceutical composition according to any of the aspects or embodiments described herein.Attorney Docket: 51096.4019 / WO

[0066] In another aspect, provided herein is a method of treating a cancer in a subject in needthereof, the method comprising administering a bispecific antibody according to any of the aspects or embodiments described herein or a pharmaceutical composition according to any of the aspects or embodiments described herein to the subject.

[0067] In another aspect, provided herein is a method of reducing tumor growth or inhibitingcancer cell proliferation in a subject in need thereof, the method comprising: administering a bispecific antibody according to any of the aspects or embodiments described herein or a pharmaceutical composition according to any of the aspects or embodiments described herein.

[0068] In another aspect, provided herein is a method of treating a MICA / B-associated diseaseand / or a CD3-associated disease in a subject in need thereof, the method comprising administering to the subject a bispecific antibody according to any of the aspects or embodiments described herein or a pharmaceutical composition according to any of the aspects or embodiments described herein.

[0069] In a further embodiment according to any of the aspects or embodiments describedherein, the subject is a human subject. In some further embodiments, the human subject has a cancer, was diagnosed with a cancer, or has at least one symptom associated with a cancer.

[0070] In another aspect, provided herein is the use of a bispecific antibody according to any ofthe aspects or embodiments described herein or a pharmaceutical composition according to any of the aspects or embodiments described herein for treating a MICA / B-associated disease and / or a CD3-associated disease in a subject in need thereof.

[0071] In another aspect, provided herein is the use of a bispecific antibody according to any ofthe aspects or embodiments described herein or a pharmaceutical composition according to any of the aspects or embodiments described herein in the manufacture of a medicament for the treatment of a MICA / B-associated disease and / or CD3-associated disease in a subject in need thereof.

[0072] In another aspect, provided herein is the use of a bispecific antibody according to any ofthe aspects or embodiments described herein or a pharmaceutical composition according to any of the aspects or embodiments described herein in the manufacture of a medicament forAttorney Docket: 51096.4019 / WO inhibiting or reducing MICA / B-mediated activity and / or CD3-mediated activity in a subject in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0073] The novel features of the invention are set forth with particularity in the appended claims.A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “Fig.,” “FIG.,” “Figure,” “Figures,” “Figs.,” and “FIGs.” herein) of which.

[0074] Fig. 1 depicts the sequences for human, mouse, and cynomolgus CD3. Such CD3 areuseful for the development of cross-reactive CD3 antigen binding domains for ease of clinical development.

[0075] Fig. 2 depicts the sequences for human and cynomolgus MICA. Such MICA are usefulfor the development of cross-reactive MICA antigen binding domains for ease of clinical development. The following alleles of MICA are known: MICA*001, MICA*002, MICA*004, MICA*005, MICA*006, MICA*007, MICA*008, MICA*009, MICA*010, MICA*011, MICA*012, MICA*013, MICA*014, MICA*015, MICA*016, MICA*017, MICA*018, MICA*019, MICA*020, MICA*022, MICA*023, MICA*024, MICA*025, MICA*026, MICA*027, MICA*028, MICA*029, MICA*030, MICA*031, MICA*032, MICA*033, MICA*034, MICA*035, MICA*036, MICA*037, MICA*038, MICA*039, MICA*040, MICA*041, MICA*042, MICA*043, MICA*044, MICA*045, MICA*046, MICA*047, MICA*048, MICA*049, MICA*050, MICA*051, MICA*052, MICA*053, MICA*054, MICA*055 and MICA*056.

[0076] Fig. 3 depicts the sequences for human and cynomolgus MICB. Such MICB are usefulfor the development of cross-reactive MICA antigen binding domains for ease of clinical development. The following alleles of MICB are known: MICB*001, MICB*002, MICB*003, MICB*004, MICB*005, MICB*006, MICB*007, MICB*008, MICB*009N, MICB*010, MICB*011, MICB*012, MICB*013, MICB*014, MICB*015, MICB*016, MICB*018, MICB*019, MICB*020, MICB*021N and MICB*022. MICB*009N and MICB*021N are null alleles which are not expressed. The three most common MICB alleles in the human populationAttorney Docket: 51096.4019 / WO could be MICB*005, MICB*004, and MICB*002.

[0077] Figs. 4A-4F depict useful pairs of heterodimerization variant sets (including skew and pIvariants). There are variants for which there are no corresponding “monomer 2” variants. Such variants are pI variants that can be used alone on either monomer of a bispecific antibody (e.g., MICA / B × CD3 bsAb), or included, for example, on the non-scFv side of a format that utilizes an scFv as a component and an appropriate charged scFv linker can be used on the second monomer that utilizes an scFv as the CD3 binding domain. Suitable charged linkers are shown in Fig.7.

[0078] Fig. 5 depicts a list of isosteric variant antibody constant regions and their respectivesubstitutions. pI_(-) indicates lower pI variants, while pI_(+) indicates higher pI variants. These variants can be optionally and independently combined with other variants, including heterodimerization variants, outlined herein.

[0079] Fig. 6 depicts useful ablation variants that ablate FcγR binding (also referred to as“knockouts” or “KO” variants). In some embodiments, such ablation variants are included in the Fc domain of both monomers of the subject antibody described herein. In other embodiments, the ablation variants are only included on only one variant Fc domain.

[0080] Fig. 7 depicts a number of charged scFv linkers that find use in increasing or decreasingthe pI of the subject heterodimeric bispecific antibodies that utilize one or more scFv as a component, as described herein (e.g., MICA / B × CD3 bispecific antibodies (bsAbs)). The (+H) positive linker finds particular use herein, particularly with anti-CD3 VL and VH sequences shown herein. A single prior art scFv linker with a single charge is referenced as “Whitlow,” from Whitlow et al., Protein Engineering 6(8):989-995 (1993). It should be noted that this linker was used for reducing aggregation and enhancing proteolytic stability in scFvs. Such charged scFv linkers can be used in any of the subject antibody formats disclosed herein that include scFvs (e.g., 1 + 1 Fab-scFv-Fc and 2 + 1 Fab2-scFv-Fc formats).

[0081] Fig. 8 depicts a number of exemplary domain linkers. In some embodiments, theselinkers find use linking a single-chain Fv to an Fc chain. In some embodiments, these linkers may be combined in any orientation. For example, a GGGGS linker (SEQ ID NO: 2) may be combined with a “lower half hinge” linker at the N-terminus or at the C-terminus.Attorney Docket: 51096.4019 / WO

[0082] Fig. 9 shows a particularly useful bispecific antibody backbone for the MICA / B × CD3bispecific antibodies (bsAbs) of the invention. Although the backbone is described here in the context of the 1 + 1 Fab-scFv-Fc format, they can be adapted for use in other bispecific antibody formats.

[0083] Fig. 10 depicts various heterodimeric skew variant amino acid substitutions that can beused with the heterodimeric antibodies described herein.

[0084] Figs. 11A-11E show the sequences of several useful heterodimeric MICA / B × CD3 bsAbbackbones based on human IgG1, without the variable domains. Heterodimeric Fc backbone 1 is based on human IgG1 (356E / 358M allotype), and includes the L368D / K370S skew variants and the Q295E / N384D / Q418E / N421D pI variants on a first heterodimeric Fc chain, the S364K / E357Q skew variants on a second heterodimeric Fc chain, and the E233P / L234V / L235A / G236del / S267K ablation variants on both chains. Heterodimeric Fc backbone 2 is based on human IgG1 (356E / 358M allotype), and includes the L368D / K370S skew variants and the Q295E / N384D / Q418E / N421D pI variants on a first heterodimeric Fc chain, the S364K skew variant on a second heterodimeric Fc chain, and the E233P / L234V / L235A / G236del / S267K ablation variants on both chains. Heterodimeric Fc backbone 3 is based on human IgG1 (356E / 358M allotype), and includes the L368E / K370S skew variants and the Q295E / N384D / Q418E / N421D pI variants on a first heterodimeric Fc chain, the S364K skew variant on a second heterodimeric Fc chain, and the E233P / L234V / L235A / G236del / S267K ablation variants on both chains. Heterodimeric Fc backbone 4 is based on human IgG1 (356E / 358M allotype), and includes the K360E / Q362E / T411E skew variants and the Q295E / N384D / Q418E / N421D pI variants on a first heterodimeric Fc chain, the D401K skew variant on a second heterodimeric Fc chain, and the E233P / L234V / L235A / G236del / S267K ablation variants on both chains. Heterodimeric Fc backbone 5 is based on human IgG1 (356D / 358L allotype), and includes the L368D / K370S skew variants and the Q295E / N384D / Q418E / N421D pI variants on a first heterodimeric Fc chain, the S364K / E357Q skew variants on a second heterodimeric Fc chain, and the E233P / L234V / L235A / G236del / S267K ablation variants on both chains. Heterodimeric Fc backbone 6 is based on human IgG1 (356E / 358M allotype), and includes the L368D / K370S skew variants and the Q295E / N384D / Q418E / N421D pI variants on a first heterodimeric Fc chain, the S364K / E357Q skew variants on a second heterodimeric Fc chain, and theAttorney Docket: 51096.4019 / WO E233P / L234V / L235A / G236del / S267K ablation variants and N297A variant that removes glycosylation on both chains. Heterodimeric Fc backbone 7 is based on human IgG1 (356E / 358M allotype), and includes the L368D / K370S skew variants and the Q295E / N384D / Q418E / N421D pI variants on a first heterodimeric Fc chain, the S364K / E357Q skew variants on a second heterodimeric Fc chain, and the E233P / L234V / L235A / G236del / S267K ablation variants and N297S variant that removes glycosylation on both chains. Heterodimeric Fc backbone 8 is based on human IgG4, and includes the L368D / K370S skew variants and the Q295E / N384D / Q418E / N421D pI variants on a first heterodimeric Fc chain, the S364K / E357Q skew variants on a second heterodimeric Fc chain, and the S228P (according to EU numbering, S241P in Kabat) variant that ablates Fab arm exchange (as is known in the art) on both chains. Heterodimeric Fc backbone 9 is based on human IgG2, and includes the L368D / K370S skew variants and the Q295E / N384D / Q418E / N421D pI variants on a first heterodimeric Fc chain, the S364K / E357Q skew variants on a second heterodimeric Fc chain. Heterodimeric Fc backbone 10 is based on human IgG2, and includes the L368D / K370S skew variants and the Q295E / N384D / Q418E / N421D pI variants on a first heterodimeric Fc chain, the S364K / E357Q skew variants on a second heterodimeric Fc chain, and the S267K ablation variant on both chains. Heterodimeric Fc backbone 11 is based on human IgG1 (356E / 358M allotype), and includes the L368D / K370S skew variants and the Q295E / N384D / Q418E / N421D pI variants on a first heterodimeric Fc chain, the S364K / E357Q skew variants on a second heterodimeric Fc chain, and the E233P / L234V / L235A / G236del / S267K ablation variants and M428L / N434S Xtend variants on both chains. Heterodimeric Fc backbone 12 is based on human IgG1 (356E / 358M allotype), and includes the L368D / K370S skew variants on a first heterodimeric Fc chain, the S364K / E357Q skew variants and P217R / P229R / N276K pI variants on a second heterodimeric Fc chain, and the E233P / L234V / L235A / G236del / S267K ablation variants on both chains. Heterodimeric Fc backbone 13 is based on human IgG1 (356E / 358M allotype), and includes the T366W skew variant on a first heterodimeric Fc chain, the T366S / L368A / Y407V skew variants and H435R / Y436F purification variants on a second heterodimeric Fc chain, and the L234A / L235A / D265S ablation variants on both chains. Heterodimeric Fc backbone 14 is based on human IgG1 (356E / 358M allotype), and includes the T366W skew variant on a first heterodimeric Fc chain, the T366S / L368A / Y407V skew variants and H435R / Y436F purificationAttorney Docket: 51096.4019 / WO variants on a second heterodimeric Fc chain, and the L234A / L235A / D265S ablation variants and M252Y / S254T / T256E half-life extension variants on both chains. Heterodimeric Fc backbone 15 is based on human IgG1 (356D / 358L allotype), and includes the L368D / K370S skew variants and the Q295E / N384D / Q418E / N421D pI variants on a first heterodimeric Fc chain, the S364K / E357Q skew variants on a second heterodimeric Fc chain, and the E233P / L234V / L235A / G236del / S267K ablation variants and M428L / N434S Xtend variants on both chains. Heterodimeric Fc backbone 16 is based on human IgG1 (356E / 358M allotype), and includes the L368D / K370S skew variants and the Q295E / N384D / Q418E / N421D pI variants on a first heterodimeric Fc chain, the S364K / E357Q skew variants on a second heterodimeric Fc chain, and the E233P / L234V / L235A / G236del / S267K ablation variants and M428L / N434A Xtend variants on both chains. Heterodimeric Fc backbone 17 is based on human IgG1 (356D / 358L allotype), and includes the L368D / K370S skew variants and the Q295E / N384D / Q418E / N421D pI variants on a first heterodimeric Fc chain, the S364K / E357Q skew variants on a second heterodimeric Fc chain, and the E233P / L234V / L235A / G236del / S267K ablation variants and M428L / N434A Xtend variants on both chains.

[0085] Included within each of these backbones are sequences that are 90, 95, 98 and 99%identical (as defined herein) to the recited sequences, and / or contain from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 additional amino acid substitutions (as compared to the “parent” of the Figure, which, as will be appreciated by those in the art, already contain a number of amino acid modifications as compared to the parental human IgG1 (or IgG2 or IgG4, depending on the backbone). That is, the recited backbones may contain additional amino acid modifications (generally amino acid substitutions) in addition or as an alternative to the skew, pI and ablation variants contained within the backbones of this Figure. Additionally, the backbones depicted herein may include deletion of the C-terminal glycine (G446_) and / or lysine (K447_). The C-terminal glycine and / or lysine deletion may be intentionally engineered to reduce heterogeneity or in the context of certain bispecific formats, such as the mAb-scFv format. Additionally, C-terminal glycine and / or lysine deletion may occur naturally for example during production and storage.

[0086] Fig. 12 depicts sequences for “CH1” that find use in embodiments of MICA / B × CD3bsAbs.Attorney Docket: 51096.4019 / WO

[0087] Fig. 13 depicts sequences for “hinge” that find use in embodiments of MICA / B × CD3bsAbs.

[0088] Fig. 14 depicts the constant domain of the cognate light chains that find use in the subjectMICA / B × CD3 bsAbs that utilize a Fab binding domain.

[0089] Figs. 15A-15F depict the variable heavy and variable light chain sequences forillustrative CD3 binding domains which find use in the MICA / B × CD3 bsAbs of the invention. The CDRs are underlined, the scFv linker is double underlined (in the sequences, the scFv linker is a positively charged scFv (GKPGS)4 linker (SEQ ID NO: 1), although as will be appreciated by those in the art, this linker can be replaced by other linkers, including uncharged or negatively charged linkers, some of which are depicted in Figure 6), and the slashes indicate the border(s) of the variable domains. In addition, the naming convention illustrates the orientation of the scFv from N- to C-terminus. As noted herein and is true for every sequence herein containing CDRs, the exact identification of the CDR locations may be slightly different depending on the numbering used as is shown in Table 2, and thus included herein are not only the CDRs that are underlined but also CDRs included within the VH and VL domains using other numbering systems. Furthermore, as for all the sequences in the Figures, these VH and VL sequences can be used either in a scFv format or in a Fab format.

[0090] Figs. 16A-16S depict the variable heavy and variable light chain sequences for novelMICA / B binding domains which may find use in the invention. As noted herein and is true for every sequence herein containing CDRs, the exact identification of the CDR locations may be slightly different depending on the numbering used as is shown in Table 2, and thus included herein are not only the CDRs that are underlined but also CDRs included within the VH and VL domains using other numbering systems. Furthermore, as for all the sequences in the Figures, these VH and VL sequences can be used either in a scFv format or in a Fab format.

[0091] Figs. 17A-17B depict the variable heavy and variable light chain sequences for additionalMICA / B binding domains which may find use in the invention. As noted herein and is true for every sequence herein containing CDRs, the exact identification of the CDR locations may be slightly different depending on the numbering used as is shown in Table 2, and thus included herein are not only the CDRs that are underlined but also CDRs included within the VH and VL domains using other numbering systems. For instance, CDRs are as defined by the Kabat,Attorney Docket: 51096.4019 / WO Chothia, Kabat + Chothia, AbM, contact, or IMGT definition. Furthermore, as for all the sequences in the Figures, these VH and VL sequences can be used either in a scFv format or in a Fab format.

[0092] Figs. 18A-18N depict bispecific formats of the present invention. Fig. 18A depicts the “1+ 1 Fab-scFv-Fc” format, with a first Fab arm binding a first antigen and a second scFv arm binding second antigen. The 1 + 1 Fab-scFv-Fc format comprises a first monomer comprising a first heavy chain variable region (VH1) covalently attached to the N-terminus of a first heterodimeric Fc backbone (optionally via a linker), a second monomer comprising a single- chain Fv covalently attached to the N-terminus of a second corresponding heterodimeric Fc backbone (optionally via a linker), and a third monomer comprising a light chain variable region covalently to a light chain constant domain, wherein the light chain variable region is complementary to the VH1. Fig.18B depicts the “2 + 1 Fab2-scFv-Fc” format, with a first Fab arm and a second Fab-scFv arm, wherein the Fab binds a first antigen and the scFv binds second antigen. The 2 + 1 Fab2-scFv-Fc format comprises a first monomer comprising a first heavy chain variable region (VH1) covalently attached to the N-terminus of a first heterodimeric Fc backbone (optionally via a linker), a second monomer comprising the VH1 covalently attached (optionally via a linker) to a single-chain Fv covalently attached (optionally via a linker) to the N-terminus of a second corresponding heterodimeric Fc backbone, and a third monomer comprising a light chain variable region covalently to a light chain constant domain, wherein the light chain variable region is complementary to the VH1. Fig.18C depicts the “1 + 1 Common Light Chain” or “1 + 1 CLC” format, with a first Fc comprising a first Fab arm binding a first antigen and a second Fc comprising a second Fab arm binding second antigen. The 1 + 1 CLC format comprises a first monomer comprising VH1-CH1-hinge-CH2-CH3, a second monomer comprising VH2-CH1-hinge-CH2-CH3, and a third monomer comprising VL-CL. The VL pairs with the VH1 to form a binding domain with a first antigen binding specificity; and the VL pairs with the VH2 to form a binding domain with a second antigen binding specificity. Fig.18D depicts the “2 + 1 Common Light Chain” or “2 + 1 CLC” format, with a first Fc comprising 2 Fab arms each binding a first antigen and a second Fc comprising 1 Fab arm binding a second antigen. The 2 + 1 CLC format comprises a first monomer comprising VH1-CH1-hinge-VH1- CH1-hinge-CH2-CH3, a second monomer comprising VH2-CH1-hinge-CH2-CH3, and a third monomer comprising VL-CL. The VL pairs with the first and second VH1 to form bindingAttorney Docket: 51096.4019 / WO domains with a first antigen binding specificity; and the VL pairs with the VH2 to form a binding domain with a second antigen binding specificity. Fig.18E depicts the “2 + 1 mAb- scFv” format, with a first Fc comprising an N-terminal Fab arm binding a first antigen and a second Fc comprising an N-terminal Fab arm binding the first antigen and a C-terminal scFv binding a second antigen. The 2 + 1 mAb-scFv format comprises a first monomer comprising VH1-CH1-hinge-CH2-CH3, a second monomer comprising VH1-CH1-hinge-CH2-CH3-scFv, and a third monomer comprising VL-CL. The VL pairs with the first and second VH1 to form binding domains with binding specificity for the first antigen. Fig.18F depicts the “2 + 1 mAb- scFv” format which comprises a first monomer comprising from N-terminal to C-terminal VH1- CH1-linker-VH2-CH1-hinge-CH2-CH3 wherein CH2-CH3 is a first heterodimeric Fc domain; a second monomer comprising from N-terminal to C-terminal scFv-linker-CH2-CH3 wherein CH2-CH3 is a second heterodimeric Fc domain complementary to the first heterodimeric Fc domain and wherein the scFv has a first antigen specificity; and a third monomer that is a common light chain comprising from N-terminal to C-terminal VL-CL wherein the VL pairs with VH1 and VH2 of the first monomer to form two antigen binding domains each having a specificity for a second antigen binding domain. Additional bispecific formats include: dual scFv (Fig.18G), one-arm scFv-mAb (Fig.18H), scFv-mAb (Fig.18I), bispecific mAb (Fig.18J), one- arm central-scFv (Fig.18K), mAb-Fv (Fig.18L), central-Fv (Fig.18M), and trident (Fig.18N).

[0093] Fig. 19 depicts soluble MICA / B (sMICA / B) binding NKG2D receptor on NK cellsinhibiting signaling. MICA / B bsAbs of the invention may engage cell surface MICA / B and prevent shedding as soluble MICA / B.

[0094] Figs. 20A-20B depict population frequencies of MICA (Fig. 20A) and MICB (Fig. 20B)allelic variants.

[0095] Fig. 21 depicts α3 domain sequence alignment to identify higher frequency MICA andMICB variants. Figure discloses SEQ ID NOS: 748-753, respectively, in order of appearance.

[0096] Fig. 22 depicts epitope binning of novel MICA / B binding domains (as well as severalprior art MICA / B binding domains).

[0097] Fig. 23 depicts MICA surface density inversely correlating with soluble MICA.Therefore, surface MICA was used as a readout for screening novel MICA / B binding domains for their ability to prevent MICA and MICB shedding.Attorney Docket: 51096.4019 / WO

[0098] Fig. 24 depicts MICA*002 surface density versus MICA*008 surface density to screenMICA / B binding domains that are able to prevent shedding of multiple MICA allelic variants.

[0099] Fig. 25 depicts MICB*004 surface density versus MICB*005 surface density to screenMICA / B binding domains that are able to prevent shedding of multiple MICB allelic variants.

[0100] Fig. 26 depicts upregulation of surface MICA*004 under normoxic conditions versushypoxic conditions.

[0101] Fig. 27 depicts lysis of MCF7 target cells (4:1 E:T) by NK cells following 72 hourstreatment with the novel MICA / B binding domains.

[0102] Fig. 28 depicts production of IFNγ by NK cells in co-culture with MCF7 target cells(10:1 E:T) following 24 hours treatment with the novel MICA / B binding domains.

[0103] Fig. 29 depicts blockade of soluble MICA shedding from CHO cells engineered toexpress MICA*004-GFP by novel MICA / B binding domains.

[0104] Fig. 30 depicts binding to MICA*004 over-expressed in A375 cell line by novel MICA / Bbinding domains.

[0105] Fig. 31 depicts surface upregulation of MICA*004 expressed in CHO cell line engineeredto express MICA*004-GFP following treatment with novel MICA / B binding domains under normoxic conditions.

[0106] Fig. 32 depicts surface upregulation of MICA*004 expressed in CHO cell line engineeredto express MICA*004-GFP following treatment with novel MICA / B binding domains under hypoxic conditions.

[0107] Fig. 33 shows pan tumor tissue microarray (TMA) stained with MICA / B antibodiesshowing that breast, testis, esophagus, and stomach show tumor MICA / B expression. Pancreas, skin, lung, and ovary are additional tumor histologies showing tumor MICA / B expression (not shown).

[0108] Fig. 34 depicts MICA / B mAbs mechanisms of action. 1) ADCC, 2) NKG2D agonism,and 3) blockade of MICA and MICB cleavage.

[0109] Figs. 35A-35B depict tumor cell kill (Fig. 35A) and induction of IFNγ secretion (Fig.35B) by NK cells co-cultured with A375-B2M-KO-RP tumor cell line and dose titration ofAttorney Docket: 51096.4019 / WO MICA / B mAb alone, MICA / B mAb with blocking NKG2D mAb, RSV isotype control mAb alone, or RSV mAb with blocking NKG2D mAb.

[0110] Figs. 36A-36B depict blockade of soluble MICA (Fig. 36A) and blockade of solubleMICB (Fig.36B) after incubating CHO engineered to express MICA or MICB with MICA / B mAb, RSV mAb, or batimastat.

[0111] Figs. 37A-37B depict population frequencies of MICA (Fig. 37A) and MICB (Fig. 37B)allelic variants.

[0112] Fig. 38 depicts α3 domain sequence alignment to identify higher frequency MICA andMICB variants. Figure discloses SEQ ID NOS: 748-753, respectively, in order of appearance.

[0113] Fig. 39 depicts correlation between IFNγ AUC and target lysis EC50 of differentMICA / B mAbs.

[0114] Figs. 40A-40B depict induction of IFNγ secretion (Fig. 40A) and target lysis (Fig. 40B)by NK cells co-cultured with MCF7-RFP cells and 1E11-1-based mAb.

[0115] Fig. 41 depicts cartoon illustrating surface MICA (MICB) density, measured via C-terminal GFP intensity, inversely correlates with the membrane MICA (MICB) cleavage.

[0116] Fig. 42 depicts increases in surface MICA*008 versus surface MICB*005 to screenMICA / B binding domains that are able to prevent shedding of MICA and MICB.

[0117] Fig. 43 depicts increases in surface MICA*002 versus surface MICB*004 to screenMICA / B binding domains that are able to prevent shedding of MICA and MICB.

[0118] Fig. 44A depicts MCF7 cell kill by MICA / B × CD3 bsAbs in the 1 + 1 and 2 + 1 formatswith 2C11 MICA / B binding domain. Culture supernatant was collected at 24h for IFNγ (Fig. 44B) and IL2 (Fig.44C) assessment.

[0119] Fig. 45 depicts MCF7 cell kill by MICA / B × CD3 bsAbs in the 2 + 1 (top panel) vs 1 + 1format (bottom panel) and with 1E11 vs.2C11 MICA / B binding domain.

[0120] Fig. 46 depicts induction of IFNγ production by MICA / B × CD3 bsAbs in the presenceof T cells and MCF7 target cells with or without NKG2D blockade. NKG2D blockade leads to some reduction of IFNγ production for 1 + 1 format.

[0121] Fig. 47A depicts MCF7 cell kill by MICA / B × CD3 bsAbs in the presence of CD8 (topAttorney Docket: 51096.4019 / WO panel) or CD4 (bottom panel) T cells with or without NKG2D blockade. NKG2D blockade reduces target lysis by CD8 T cells but not by CD4 T cells.

[0122] Fig. 47B depicts an experiment in which T cells were cocultured with A375-RFP cellline, with or without NKG2D blocking Abs, and IFNγ in the supernatants was measured with MSD. NKG2D blockade reduces IFNγ production.

[0123] Fig. 47C depicts the data shown in Fig. 47B schematically.

[0124] Fig. 48 depicts MCF7 cell kill by MICA / B × CD3 vs. B7H3 × CD3.

[0125] Figs. 49A-49B depict an experiment in which T cells were cocultured with a MICA*004-inducible target cell line (A375 RFP IndEx-2-MICA*004) and a 2 + 1 MICA / B × CD3 TCE. Target cell growth was assessed with Incucyte (Fig.49A). IndEx-2 is a cell-based platform by RoukenBio, designed to express a target antigen over a range of antigen levels. The MICA*004 antigen density on the A375 RFP IndEx-2-MICA*004 cells in each of the four wells is shown (Fig.49B).

[0126] Figs. 50A-50C depict illustrative sequences for MICA / B × CD3 bsAbs in the 1 + 1 Fab-scFv-Fc format.

[0127] Figs. 51A-51F depict illustrative sequences for MICA / B × CD3 bsAbs in the 2 + 1 Fab2-scFv-Fc format. DETAILED DESCRIPTION

[0128] The description is presented to enable one of ordinary skill in the art to make and use theinvention and is provided in the context of a patent application and its requirements. The section headings used herein are for organization purposes only and are not to be construed as limiting the subject matter described. While various embodiments of the invention(s) of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention(s). It should be understood that various alternatives to the embodiments of the invention(s) described herein may be employed in practicing any one of the inventions(s) set forth herein.

[0129] All patents, published patent applications, other publications, and sequences fromAttorney Docket: 51096.4019 / WO GenBank, and other databases referred to herein are incorporated by reference in their entirety with respect to the related technology. I. Overview

[0130] Provided herein are novel anti-CD3 × anti-MICA / B (also referred to as anti-MICA / B ×anti-CD3, αCD3 × αMICA / B, αMICA / B × αCD3, or sometimes just MICA / B × CD3 or CD3 × MICA / B) heterodimeric bispecific antibodies and methods of using such antibodies for the treatment of cancers. In particular, provided herein are anti-CD3, anti-MICA / B bispecific antibodies in a variety of formats. In some embodiments, the bispecific antibody has a format of the 1 + 1 Fab-scFv format as schematically depicted in Figure 18A. In some embodiments, the MICA / A x CD3 bispecific antibody has a format of the 1 + 1 Fab-scFv format as depicted in Figure 50. In some embodiments, the bispecific antibody has a format of the 2 + 1 Fab2-scFv format as schematically depicted in Figure 18B. In some embodiments, the MICA / A x CD3 bispecific antibody has a format of the 1 + 1 Fab-scFv format as depicted in Figure 51. II. Nomenclature

[0131] The antibodies provided herein are listed in several different formats. In some instances,each monomer of a particular antibody is given a unique “XENP” number, although as will be appreciated in the art, a longer sequence might contain a shorter one. For example, a “scFv-Fc” monomer of a 1 + 1 Fab-scFv-Fc format antibody may have a first XENP number, while the scFv domain itself will have a different XENP number. Some molecules have three polypeptides, so the XENP number, with the components, is used as a name. Thus, the molecule XENP50444, which is in 1 + 1 Fab-scFv-Fc format, comprises three sequences a “Fab-Fc Heavy Chain” monomer (“Chain 1”); 2) a “scFv-Fc Heavy Chain” monomer (“Chain 2”); and 3) a “Light Chain” monomer (“Chain 3”) or equivalents, although one of skill in the art would be able to identify these easily through sequence alignment. These XENP numbers are in the sequence listing as well as identifiers, and used in the Figures. In addition, one molecule, comprising the three components, gives rise to multiple sequence identifiers. For example, the listing of the Fab includes, the full heavy chain sequence, the variable heavy domain sequence and the three CDRs of the variable heavy domain sequence, the full light chain sequence, a variable light domain sequence and the three CDRs of the variable light domain sequence. A Fab-scFv-Fc monomerAttorney Docket: 51096.4019 / WO includes a full-length sequence, a variable heavy domain sequence, 3 heavy CDR sequences, and an scFv sequence (include scFv variable heavy domain sequence, scFv variable light domain sequence and scFv linker). Note that some molecules herein with a scFv domain use a single charged scFv linker (+H), although others can be used. In addition, the naming nomenclature of particular antigen binding domains (e.g., CD3 and MICA / B binding domains) use a “Hx.xx_Ly.yy” type of format, with the numbers being unique identifiers to particular variable chain sequences. Thus, an Fv domain of the antigen binding domain is “H1 L1,” which indicates that the variable heavy domain, H1, was combined with the light domain L1. In the case that these sequences are used as scFvs, the designation “H1 L1,” indicates that the variable heavy domain, H1 is combined with the light domain, L1, and is in VH-linker-VLorientation, from N- to C-terminus. This molecule with the identical sequences of the heavy and light variable domains but in the reverse order (VL-linker-VH orientation, from N- to C-terminus) would be designated “L1_H1.1”. Similarly, different constructs may “mix and match” the heavy and light chains as will be evident from the sequence listing and the figures. III. Definitions

[0132] In order that the application may be more completely understood, several definitions areset forth below. Such definitions are meant to encompass grammatical equivalents.

[0133] “MICA and MICB” and “MICA / B” is herein meant NKG2D ligands which can, in someinstances, be upregulated in several human cancers. MICA / B are transmembrane proteins with MHC‐like extracellular domains that, do not associate with beta‐2 microglobulin nor present antigens. The proteins can undergo proteolytic cleavage in a multistep process and thereafter, the soluble MICA / B can bind NKG2D on NK cells. In some cases, the soluble MICA / B is shed in the blood plasma and serum in subjects with cancer. Additional information includes amino acid sequences of “MHC class I polypeptide-related sequence A,” “MIC-A” or “MICA” can be found in, for example, UniProt No. Q29983 (human), GenBank Accession Numbers NP_000238.1 (human), NP_001170990.1 (human), NP_001276081 (human), NP_001276082 (human), and NP_001276082 (human). Additional information includes amino acid sequences of “MHC class I polypeptide-related sequence B,” “MIC-B” or “MICB” can be found in, for example, UniProt No. Q29980 (human), GenBank Accession Numbers NP_001276089 (human), NP_001276090 (human), NP_005922 (human), NP_715641 (mouse), and NP_715642 (mouse). ExemplaryAttorney Docket: 51096.4019 / WO MICA / B sequences are depicted in Figures 2 and 3. Unless otherwise noted, references to MICA / B are to the human MICA / B sequences.

[0134] “CD3” of “cluster of differentiation 3” is herein meant a protein complex and T cell co-receptor. The complex includes a CD3delta (CD3γ) chain, a CD3gamma (CD3δ) chain, and two CD3epsilon (CD3ε) chains. Additional information includes amino acid sequences of CD3delta can be found in, for example, UniProt No. P04234 (human), GenBank Accession Numbers NP_000723.1 (human), and NP_001035741.1 (human). Additional information includes amino acid sequences of CD3epsilon can be found in, for example, UniProt No. P07766 (human) and GenBank Accession Number NP_000724.1 (human). Additional information includes amino acid sequences of CD3gamma can be found in, for example, UniProt No. P09693 (human) and GenBank Accession Number NP_000064.1 (human). Exemplary CD3 sequences are depicted in Figure 1. Unless otherwise noted, references to CD3 are to the human CD3 sequences.

[0135] By “ablation” herein is meant a decrease or removal of activity. Thus, for example,“ablating FcγR binding” means the Fc region amino acid variant has less than 50% starting binding as compared to an Fc region not containing the specific variant, with more than 70-80- 90-95-98% loss of activity being preferred, and in general, with the activity being below the level of detectable binding in a Biacore, SPR or BLI assay.

[0136] By “ADCC” or “antibody dependent cell-mediated cytotoxicity” as used herein is meantthe cell-mediated reaction, wherein nonspecific cytotoxic cells that express FcγRs recognize bound antibody on a target cell and subsequently cause lysis of the target cell. ADCC is correlated with binding to FcγRIIIa; increased binding to FcγRIIIa leads to an increase in ADCC activity.

[0137] By “ADCP” or antibody dependent cell-mediated phagocytosis as used herein is meantthe cell-mediated reaction wherein nonspecific phagocytic cells that express FcγRs recognize bound antibody on a target cell and subsequently cause phagocytosis of the target cell.

[0138] As used herein, the term “antibody” is used generally. Antibodies provided herein cantake on a number of formats as described herein, including traditional antibodies as well as antibody derivatives, fragments, and mimetics, described herein.

[0139] Traditional immunoglobulin (Ig) antibodies are “Y” shaped tetramers. Each tetramer isAttorney Docket: 51096.4019 / WO typically composed of two identical pairs of polypeptide chains, each pair having one “light chain” monomer (typically having a molecular weight of about 25 kDa) and one “heavy chain” monomer (typically having a molecular weight of about 50-70 kDa).

[0140] Other useful antibody formats include, but are not limited to, the “1 + 1 Fab × scFv” (alsoreferred to herein as the “1 + 1 Fab-scFv-Fc” or “bottle-opener” format), “1 + 1 empty × Fab- scFv” (also referred to herein as the “one-armed central-scFv” format), “2 + 1 Fab × Fab-scFv” (also referred to herein as the “2 + 1 Fab2-scFv-Fc” format), “2 + 1 Fab2 × scFv” (also referred to herein as the “2 + 1 stab Fab2-scFv-Fc” format), and “2 + 1 mAb-scFv” (also referred to herein as the “mAb-scFv” format) formats provided herein (see, e.g., Figs.18A-18N). Additional useful antibody formats include, but are not limited to: “mAb-Fv,” “central-Fv,” “1 + 1 common light chain” (CLC), “2 + 1 CLC,” “one-armed scFv-mAb,” “scFv-mAb,” “dual scFv,” “bispecific mAb,” and “trident” format antibodies as depicted in Fig.36 of U.S. Publ. App. No. 2022 / 0289839, hereby incorporated by reference in its entirety and specifically for its disclosure of antibody formats.

[0141] Antibody heavy chains typically include a variable heavy (VH) domain, which includesvhCDR1-3, and an Fc domain, which includes a CH2-CH3 monomer. In some embodiments, antibody heavy chains include a hinge and CH1 domain. Traditional antibody heavy chains are monomers that are organized, from N- to C-terminus: VH-CH1-hinge-CH2-CH3. The CH1- hinge-CH2-CH3 is collectively referred to as the heavy chain “constant domain” or “constant region” of the antibody, of which there are five different categories or “isotypes”: IgA, IgD, IgG, IgE and IgM.

[0142] In some embodiments, the antibodies provided herein include IgG isotype constantdomains, which has several subclasses, including, but not limited to IgG1, IgG2, and IgG4. In the IgG subclass of immunoglobulins, there are several immunoglobulin domains in the heavy chain. By “immunoglobulin (Ig) domain” herein is meant a region of an immunoglobulin having a distinct tertiary structure. Of interest in the present invention are the heavy chain domains, including, the constant heavy (CH) domains and the hinge domains. In the context of IgG antibodies, the IgG isotypes each have three CH regions. Accordingly, “CH” domains in the context of IgG are as follows: “CH1” refers to positions 118-215 according to the EU index as in Kabat. “Hinge” refers to positions 216-230 according to the EU index as in Kabat. “CH2” refersAttorney Docket: 51096.4019 / WO to positions 231-340 according to the EU index as in Kabat, and “CH3” refers to positions 341- 447 according to the EU index as in Kabat. As shown in Table 1, the exact numbering and placement of the heavy chain domains can be different among different numbering systems. As shown herein and described below, the pI variants can be in one or more of the CH regions, as well as the hinge region, discussed below.

[0143] It should be noted that IgG1 has different allotypes with polymorphisms at 356 (D or E)and 358 (L or M). The sequences depicted herein use the 356E / 358M allotype, however the other allotype is included herein. That is, any sequence inclusive of an IgG1 Fc domain included herein can have 356D / 358L replacing the 356E / 358M allotype. It should be understood that therapeutic antibodies can also comprise hybrids of isotypes and / or subclasses. For example, as shown in US Publication 2009 / 0163699, incorporated by reference, the present antibodies, in some embodiments, include human IgG1 / G2 hybrids.

[0144] By “Fc” or “Fc region” or “Fc domain” as used herein is meant the polypeptidecomprising the constant region of an antibody, in some instances, excluding all of the first constant region immunoglobulin domain (e.g., CH1) or a portion thereof, and in some cases, optionally including all or part of the hinge. For IgG, the Fc domain comprises immunoglobulin domains CH2 and CH3 (Cγ2 and Cγ3), and optionally all or a portion of the hinge region between CH1 (Cγ1) and CH2 (Cγ2). Thus, in some cases, the Fc domain includes, from N- to C- terminal, CH2-CH3 and hinge-CH2-CH3. In some embodiments, the Fc domain is that from IgG1, IgG2, or IgG4, with IgG1 hinge-CH2-CH3 and IgG4 hinge-CH2-CH3 finding particular use in many embodiments. Additionally, in the case of human IgG1 Fc domains, the hinge may include a C220S amino acid substitution. Furthermore, in the case of human IgG4 Fc domains, the hinge may include a S228P amino acid substitution. Although the boundaries of the Fc region may vary, the human IgG heavy chain Fc region is usually defined to include residues E216, C226, or A231 to its carboxyl- terminal, wherein the numbering is according to the EU index as in Kabat. In some embodiments, as is more fully described below, amino acid modifications are made to the Fc region, for example to alter binding to one or more FcγR or to the FcRn.

[0145] By “heavy chain constant region” herein is meant the CH1-hinge-CH2-CH3 portion of anantibody (or fragments thereof), excluding the variable heavy domain; in EU numbering of human IgG1 this is amino acids 118-447. By “heavy chain constant region fragment” herein isAttorney Docket: 51096.4019 / WO meant a heavy chain constant region that contains fewer amino acids from either or both of the N- and C-termini but still retains the ability to form a dimer with another heavy chain constant region.

[0146] Another type of domain of the heavy chain is the hinge region. By “hinge” or “hingeregion” or “antibody hinge region” or “hinge domain” herein is meant the flexible polypeptide comprising the amino acids between the first and second constant domains of an antibody. Structurally, the IgG CH1 domain ends at EU position 215, and the IgG CH2 domain begins at residue EU position 231. Thus, for IgG the antibody hinge is herein defined to include positions 216 (E216 in IgG1) to 230 (P230 in IgG1), wherein the numbering is according to the EU index as in Kabat. In some cases, a “hinge fragment” is used, which contains fewer amino acids at either or both of the N- and C-termini of the hinge domain. As noted herein, pI variants can be made in the hinge region as well. Many of the antibodies herein have at least one the cysteines at position 220 according to EU numbering (hinge region) replaced by a serine. Generally, this modification is on the “scFv monomer” side (when 1 + 1 or 2 + 1 formats are used) for most of the sequences depicted herein, although it can also be on the “Fab monomer” side, or both, to reduce disulfide formation. Specifically included within the sequences herein are one or both of these cysteines replaced (C220S).

[0147] As will be appreciated by those in the art, the exact numbering and placement of theheavy chain constant region domains (i.e., CH1, hinge, CH2 and CH3 domains) can be different among different numbering systems. A useful comparison of heavy constant region numbering according to EU and Kabat is as below, see Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85 and Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed., United States Public Health Service, National Institutes of Health, Bethesda, entirely incorporated by reference. Table 1 EU Numbering Kabat NumberingAttorney Docket: 51096.4019 / WO

[0148] The antibody light chain generally comprises two domains: the variable light domain(VL), which includes light chain CDRs vlCDR1-3, and a constant light chain region (often referred to as CL or CK). The antibody light chain is typically organized from N- to C-terminus: VL-CL.

[0149] By “antigen binding domain” or “ABD” herein is meant a set of six ComplementaryDetermining Regions (CDRs) that, when present as part of a polypeptide sequence, specifically binds a target antigen (e.g., CD3 or MICA / B) as discussed herein. As is known in the art, these CDRs are generally present as a first set of variable heavy CDRs (vhCDRs or VHCDRs) and a second set of variable light CDRs (vlCDRs or VLCDRs), each comprising three CDRs: vhCDR1, vhCDR2, vhCDR3 variable heavy CDRs and vlCDR1, vlCDR2 and vlCDR3 vhCDR3 variable light CDRs. The CDRs are present in the variable heavy domain (vhCDR1-3) and variable light domain (vlCDR1-3). The variable heavy domain and variable light domain form an Fv region.

[0150] The present invention provides a large number of different CDR sets. In this case, a “fullCDR set” comprises the three variable light and three variable heavy CDRs, e.g., a vlCDR1, vlCDR2, vlCDR3, vhCDR1, vhCDR2 and vhCDR3. These can be part of a larger variable light or variable heavy domain, respectfully. In addition, as more fully outlined herein, the variable heavy and variable light domains can be on separate polypeptide chains, when a heavy and light chain is used (for example when Fabs are used), or on a single polypeptide chain in the case of scFv sequences.

[0151] As will be appreciated by those in the art, the exact numbering and placement of theCDRs can be different among different numbering systems. However, it should be understood that the disclosure of a variable heavy and / or variable light sequence includes the disclosure of the associated (inherent) CDRs. Accordingly, the disclosure of each variable heavy region is a disclosure of the vhCDRs (e.g., vhCDR1, vhCDR2, and vhCDR3 (sometimes referred to collectively as vhCDR1-3)) and the disclosure of each variable light region is a disclosure of the vlCDRs (e.g., vlCDR1, vlCDR2, and vlCDR3 (sometimes referred to collectively as vlCDR1- 3)). A useful comparison of CDR numbering is as below, see Lafranc et al., Dev. Comp. Immunol.27(1): 55-77 (2003).Attorney Docket: 51096.4019 / WO Table 2 Kabat IMGT Kabat AbM Chothia Contact Xencor +Chothia

[0152] Throughout the present specification, the Kabat numbering system is generally usedwhen referring to a residue in the variable domain (approximately, residues 1-107 of the light chain variable region and residues 1-113 of the heavy chain variable region) and the EU numbering system for Fc regions (e.g., Kabat et al., supra (1991)).

[0153] The CDRs contribute to the formation of the antigen-binding, or more specifically,epitope binding site of the antigen binding domains and antibodies. “Epitope” refers to a determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. Epitopes are groupings of molecules such as amino acids or sugar side chains and usually have specific structural characteristics, as well as specific charge characteristics. A single antigen may have more than one epitope.

[0154] The epitope may comprise amino acid residues directly involved in the binding (alsocalled immunodominant component of the epitope) and other amino acid residues, which are not directly involved in the binding, such as amino acid residues which are effectively blocked by the specifically antigen binding peptide; in other words, the amino acid residue is within the footprint of the specifically antigen binding peptide.

[0155] Epitopes may be either conformational or linear. A conformational epitope is producedby spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. Conformational and non-conformational epitopes may be distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.

[0156] An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acidsin a unique spatial conformation. Antibodies that recognize the same epitope can be verified in aAttorney Docket: 51096.4019 / WO simple immunoassay showing the ability of one antibody to block the binding of another antibody to a target antigen, for example “binning.” As outlined below, the invention not only includes the enumerated antigen binding domains and antibodies herein, but those that compete for binding with the epitopes bound by the enumerated antigen binding domains.

[0157] In some embodiments, the six CDRs of the antigen binding domain are contributed by avariable heavy and a variable light domain. In a “Fab” format, the set of 6 CDRs are contributed by two different polypeptide sequences, the variable heavy domain (vh, VH, or VH; containing the vhCDR1, vhCDR2 and vhCDR3) and the variable light domain (vl, VL, or VL; containing the vlCDR1, vlCDR2 and vlCDR3), with the C-terminus of the vh domain being attached to the N-terminus of the CH1 domain of the heavy chain and the C-terminus of the vl domain being attached to the N-terminus of the constant light domain (and thus forming the light chain). In a scFv format, the vh and vl domains are covalently attached, generally through the use of a linker (a “scFv linker”) as outlined herein, into a single polypeptide sequence, which can be either (starting from the N-terminus) vh-linker-vl or vl-linker-vh, with the former being generally preferred (including optional domain linkers on each side, depending on the format used. In general, the C-terminus of the scFv domain is attached to the N-terminus of all or part of the hinge in the second monomer.

[0158] By “variable region” or “variable domain” as used herein is meant the region of animmunoglobulin that comprises one or more Ig domains substantially encoded by any of the Vκ, Vλ, and / or VHgenes that make up the kappa, lambda, and heavy chain immunoglobulin genetic loci respectively, and contains the CDRs that confer antigen specificity. Thus, a “variable heavy domain” pairs with a “variable light domain” to form an antigen binding domain (“ABD”). In addition, each variable domain comprises three hypervariable regions (“complementary determining regions,” “CDRs”) (vhCDR1, vhCDR2 and vhCDR3 for the variable heavy domain and vlCDR1, vlCDR2 and vlCDR3 for the variable light domain) and four framework (FR) regions, arranged from amino-terminus to carboxy-terminus in the following order: FR1-CDR1- FR2-CDR2-FR3-CDR3-FR4.

[0159] By “Fab” or “Fab region” as used herein is meant the antibody region that comprises theVH, CH1, VL, and CL immunoglobulin domains, generally on two different polypeptide chains (e.g., VH-CH1 on one chain and VL-CLon the other). Fab may refer to this region in isolation, orAttorney Docket: 51096.4019 / WO this region in the context of a bispecific antibody of the invention. In the context of a Fab, the Fab comprises an Fv region in addition to the CH1 and CL domains.

[0160] By “Fv” or “Fv fragment” or “Fv region” as used herein is meant the antibody region thatcomprises the VLand VHdomains. Fv regions can be formatted as both Fabs (as discussed above, generally two different polypeptides that also include the constant regions as outlined above) and single chain Fvs (scFvs), where the vl and vh domains are included in a single peptide, attached generally with a linker as discussed herein.

[0161] By “single chain Fv” or “scFv” herein is meant a variable heavy domain covalentlyattached to a variable light domain, generally using a scFv linker as discussed herein, to form a scFv or scFv domain. A scFv domain can be in either orientation from N- to C-terminus (vh- linker-vl or vl-linker-vh). In the sequences depicted in the sequence listing and in the figures, the order of the vh and vl domain is indicated in the name, e.g., H.X L.Y means N- to C-terminal is vh-linker-vl, and L.Y H.X is vl-linker-vh.

[0162] Some embodiments of the subject antibodies provided herein comprise at least one scFvdomain, which, while not naturally occurring, generally includes a variable heavy domain and a variable light domain, linked together by a scFv linker. As outlined herein, while the scFv domain is generally from N- to C-terminus oriented as VH-scFv linker-VL, this can be reversed for any of the scFv domains (or those constructed using vh and vl sequences from Fabs), to VL- scFv linker-VH, with optional linkers at one or both ends depending on the format.

[0163] By “modification” or “variant” herein is meant an amino acid substitution, insertion,and / or deletion in a polypeptide sequence or an alteration to a moiety chemically linked to a protein. For example, a modification may be an altered carbohydrate or PEG structure attached to a protein. By “amino acid modification” herein is meant an amino acid substitution, insertion, and / or deletion in a polypeptide sequence. For clarity, unless otherwise noted, the amino acid modification is always to an amino acid coded for by DNA, e.g., the 20 amino acids that have codons in DNA and RNA.

[0164] By “amino acid substitution” or “substitution” herein is meant the replacement of anamino acid at a particular position in a parent polypeptide sequence with a different amino acid. In particular, in some embodiments, the substitution is to an amino acid that is not naturally occurring at the particular position, either not naturally occurring within the organism or in anyAttorney Docket: 51096.4019 / WO organism. For example, the substitution E272Y refers to a variant polypeptide, in this case an Fc variant, in which the glutamic acid at position 272 is replaced with tyrosine. For clarity, a protein which has been engineered to change the nucleic acid coding sequence but not change the starting amino acid (for example exchanging CGG (encoding arginine) to CGA (still encoding arginine) to increase host organism expression levels) is not an “amino acid substitution;” that is, despite the creation of a new gene encoding the same protein, if the protein has the same amino acid at the particular position that it started with, it is not an amino acid substitution.

[0165] By “amino acid insertion” or “insertion” as used herein is meant the addition of an aminoacid sequence at a particular position in a parent polypeptide sequence. For example, -233E or 233E designates an insertion of glutamic acid after position 233 and before position 234. Additionally, -233ADE or A233ADE designates an insertion of AlaAspGlu after position 233 and before position 234.

[0166] By “amino acid deletion” or “deletion” as used herein is meant the removal of an aminoacid sequence at a particular position in a parent polypeptide sequence. For example, E233- or E233#, E233(), E233_ or E233del designates a deletion of glutamic acid at position 233. Additionally, EDA233- or EDA233# designates a deletion of the sequence GluAspAla that begins at position 233.

[0167] By “variant protein” or “protein variant,” or “variant” as used herein is meant a proteinthat differs from that of a parent protein by virtue of at least one amino acid modification. The protein variant has at least one amino acid modification compared to the parent protein, yet not so many that the variant protein will not align with the parental protein using an alignment program such as that described below. In general, variant proteins (such as variant Fc domains, etc., outlined herein, are generally at least 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to the parent protein, using the alignment programs described below, such as BLAST.

[0168] “Variant” as used herein also refers to particular amino acid modifications that conferparticular function (e.g., a “heterodimerization variant,” “pI variant,” “ablation variant,” etc.).

[0169] As described below, in some embodiments the parent polypeptide, for example an Fcparent polypeptide, is a human wild-type sequence, such as the heavy constant domain or Fc region from IgG1, IgG2, or IgG4, although human sequences with variants can also serve as “parent polypeptides,” for example the IgG1 / 2 hybrid of US Publication 2006 / 0134105 can beAttorney Docket: 51096.4019 / WO included. The protein variant sequence herein will preferably possess at least about 80% identity with a parent protein sequence, and most preferably at least about 90% identity, more preferably at least about 95-98-99% identity. Accordingly, by “antibody variant” or “variant antibody” as used herein is meant an antibody that differs from a parent antibody by virtue of at least one amino acid modification, “IgG variant” or “variant IgG” as used herein is meant an antibody that differs from a parent IgG (again, in many cases, from a human IgG sequence) by virtue of at least one amino acid modification, and “immunoglobulin variant” or “variant immunoglobulin” as used herein is meant an immunoglobulin sequence that differs from that of a parent immunoglobulin sequence by virtue of at least one amino acid modification. “Fc variant” or “variant Fc” as used herein is meant a protein comprising an amino acid modification in an Fc domain as compared to an Fc domain of human IgG1, IgG2 or IgG4.

[0170] “Fc variant” or “variant Fc” as used herein is meant a protein comprising an amino acidmodification in an Fc domain. The modification can be an addition, deletion, or substitution. The Fc variants are defined according to the amino acid modifications that compose them. Thus, for example, N434S or 434S is an Fc variant with the substitution for serine at position 434 relative to the parent Fc polypeptide, wherein the numbering is according to the EU index. Likewise, M428L / N434S defines an Fc variant with the substitutions M428L and N434S relative to the parent Fc polypeptide. The identity of the WT amino acid may be unspecified, in which case the aforementioned variant is referred to as 428L / 434S. It is noted that the order in which substitutions are provided is arbitrary, that is to say that, for example, 428L / 434S is the same Fc variant as 434S / 428L, and so on. For all positions discussed herein that relate to antibodies or derivatives and fragments thereof (e.g., Fc domains), unless otherwise noted, amino acid position numbering is according to the EU index. The “EU index” or “EU index as in Kabat” or “EU numbering” scheme refers to the numbering of the EU antibody (Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85, hereby entirely incorporated by reference). The modification can be an addition, deletion, or substitution.

[0171] In general, variant Fc domains have at least about 80, 85, 90, 95, 96, 97, 98 or 99 percentidentity to the corresponding parental human IgG Fc domain (using the identity algorithms discussed below, with one embodiment utilizing the BLAST algorithm as is known in the art, using default parameters). Alternatively, the variant Fc domains can have from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acid modificationsAttorney Docket: 51096.4019 / WO as compared to the parental Fc domain. Alternatively, the variant Fc domains can have up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acid modifications as compared to the parental Fc domain. Additionally, as discussed herein, the variant Fc domains described herein still retain the ability to form a dimer with another Fc domain as measured using known techniques as described herein, such as non-denaturing gel electrophoresis.

[0172] By “protein” as used herein is meant at least two covalently attached amino acids, whichincludes proteins, polypeptides, oligopeptides, and peptides. In addition, polypeptides that make up the antibodies of the invention may include synthetic derivatization of one or more side chains or termini, glycosylation, PEGylation, circular permutation, cyclization, linkers to other molecules, fusion to proteins or protein domains, and addition of peptide tags or labels.

[0173] By “residue” as used herein is meant a position in a protein and its associated amino acididentity. For example, Asparagine 297 (also referred to as Asn297 or N297) is a residue at position 297 in the human antibody IgG1.

[0174] By “IgG subclass modification” or “isotype modification” as used herein is meant anamino acid modification that converts one amino acid of one IgG isotype to the corresponding amino acid in a different, aligned IgG isotype. For example, because IgG1 comprises a tyrosine and IgG2 a phenylalanine at EU position 296, a F296Y substitution in IgG2 is considered an IgG subclass modification.

[0175] By “non-naturally occurring modification” as used herein is meant an amino acidmodification that is not isotypic. For example, because none of the human IgGs comprise a serine at position 434, the substitution 434S in IgG1, IgG2, or IgG4 (or hybrids thereof) is considered a non-naturally occurring modification.

[0176] By “amino acid” and “amino acid identity” as used herein is meant one of the 20naturally occurring amino acids that are coded for by DNA and RNA.

[0177] By “effector function” as used herein is meant a biochemical event that results from theinteraction of an antibody Fc region with an Fc receptor or ligand. Effector functions include but are not limited to ADCC, ADCP, and CDC.

[0178] By “IgG Fc ligand” as used herein is meant a molecule, preferably a polypeptide, fromAttorney Docket: 51096.4019 / WO any organism that binds to the Fc region of an IgG antibody to form an Fc / Fc ligand complex. Fc ligands include but are not limited to FcγRIs, FcγRIIs, FcγRIIIs, FcRn, C1q, C3, mannan binding lectin, mannose receptor, staphylococcal protein A, streptococcal protein G, and viral FcγR. Fc ligands also include Fc receptor homologs (FcRH), which are a family of Fc receptors that are homologous to the FcγRs (Davis et al., 2002, Immunological Reviews 190: 123-136, entirely incorporated by reference). Fc ligands may include undiscovered molecules that bind Fc. Particular IgG Fc ligands are FcRn and Fc gamma receptors. By “Fc ligand” as used herein is meant a molecule, preferably a polypeptide, from any organism that binds to the Fc region of an antibody to form an Fc / Fc ligand complex.

[0179] By “Fc gamma receptor,” “FcyR ,” “FcγR,” or “FcgammaR” as used herein is meant anymember of the family of proteins that bind the IgG antibody Fc region and is encoded by an FcγR gene. In humans this family includes but is not limited to FcγRI (CD64), including isoforms FcγRIa, FcγRIb, and FcγRIc; FcγRII (CD32), including isoforms FcγRIIa (including allotypes H131 and R131), FcγRIIb (including FcγRIIb-1 and FcγRIIb-2), and FcγRIIc; and FcγRIII (CD16), including isoforms FcγRIIIa (including allotypes V158 and F158) and FcγRIIIb (including allotypes FcγRIIb-NA1 and FcγRIIb-NA2) (Jefferis et al., 2002, Immunol Lett 82:57- 65, entirely incorporated by reference), as well as any undiscovered human FcγRs or FcγR isoforms or allotypes. An FcγR may be from any organism, including but not limited to humans, mice, rats, rabbits, and monkeys. Mouse FcγRs include but are not limited to FcγRI (CD64), FcγRII (CD32), FcγRIII (CD 16), and FcγRIII-2 (CD16-2), as well as any undiscovered mouse FcγRs or FcγR isoforms or allotypes.

[0180] By “FcRn” or “neonatal Fc Receptor” as used herein is meant a protein that binds the IgGantibody Fc region and is encoded at least in part by an FcRn gene. The FcRn may be from any organism, including but not limited to humans, mice, rats, rabbits, and monkeys. As is known in the art, the functional FcRn protein comprises two polypeptides, often referred to as the heavy chain and light chain. The light chain is beta-2-microglobulin and the heavy chain is encoded by the FcRn gene. Unless otherwise noted herein, FcRn or an FcRn protein refers to the complex of FcRn heavy chain with beta-2-microglobulin. A variety of FcRn variants used to increase binding to the FcRn receptor, and in some cases, to increase serum half-life. An “FcRn variant” is an amino acid modification that contributes to increased binding to the FcRn receptor, and suitable FcRn variants are shown below.Attorney Docket: 51096.4019 / WO

[0181] By “parent polypeptide” as used herein is meant a starting polypeptide that issubsequently modified to generate a variant. The parent polypeptide may be a naturally occurring polypeptide, or a variant or engineered version of a naturally occurring polypeptide. Accordingly, by “parent immunoglobulin” as used herein is meant an unmodified immunoglobulin polypeptide that is modified to generate a variant, and by “parent antibody” as used herein is meant an unmodified antibody that is modified to generate a variant antibody. It should be noted that “parent antibody” includes known commercial, recombinantly produced antibodies as outlined below. In this context, a “parent Fc domain” will be relative to the recited variant; thus, a “variant human IgG1 Fc domain” is compared to the parent Fc domain of human IgG1, a “variant human IgG4 Fc domain” is compared to the parent Fc domain human IgG4, etc.

[0182] By “position” as used herein is meant a location in the sequence of a protein. Positionsmay be numbered sequentially, or according to an established format, for example the EU index for numbering of antibody domains (e.g., a CH1, CH2, CH3 or hinge domain).

[0183] By “target antigen” as used herein is meant the molecule that is bound specifically by theantigen binding domain comprising the variable regions of a given antibody.

[0184] By “strandedness” in the context of the monomers of the heterodimeric antibodies of theinvention herein is meant that, similar to the two strands of DNA that “match,” heterodimerization variants are incorporated into each monomer so as to preserve the ability to “match” to form heterodimers. For example, if some pI variants are engineered into monomer A (e.g., making the pI higher) then steric variants that are “charge pairs” that can be utilized as well do not interfere with the pI variants, e.g., the charge variants that make a pl higher are put on the same “strand” or “monomer” to preserve both functionalities. Similarly, for “skew” variants that come in pairs of a set as more fully outlined below, the skilled artisan will consider pI in deciding into which strand or monomer one set of the pair will go, such that pI separation is maximized using the pI of the skews as well.

[0185] By “target cell” as used herein is meant a cell that expresses a target antigen.

[0186] By “host cell” in the context of producing a bispecific antibody according to theinvention herein is meant a cell that contains the exogeneous nucleic acids encoding the components of the bispecific antibody and is capable of expressing the bispecific antibody under suitable conditions. Suitable host cells are discussed below.Attorney Docket: 51096.4019 / WO

[0187] By “wild-type” or “WT” herein is meant an amino acid sequence or a nucleotidesequence that is found in nature, including allelic variations. A WT protein has an amino acid sequence or a nucleotide sequence that has not been intentionally modified.

[0188] Provided herein are a number of antibody domains (e.g., Fc domains) that have sequenceidentity to human antibody domains. Sequence identity between two similar sequences (e.g., antibody variable domains) can be measured by algorithms such as that of Smith, T.F. & Waterman, M.S. (1981) “Comparison Of Biosequences,” Adv. Appl. Math.2:482 [local homology algorithm]; Needleman, S.B. & Wunsch, CD. (1970) “A General Method Applicable To The Search For Similarities In The Amino Acid Sequence Of Two Proteins,” J. Mol. Biol.48:443 [homology alignment algorithm], Pearson, W.R. & Lipman, D.J. (1988) “Improved Tools For Biological Sequence Comparison,” Proc. Natl. Acad. Sci. (U.S.A.) 85:2444 [search for similarity method]; or Altschul, S.F. et al, (1990) “Basic Local Alignment Search Tool,” J. Mol. Biol.215:403-10 , the “BLAST” algorithm, see https: / / blast.ncbi.nlm.nih.gov / Blast.cgi. When using any of the aforementioned algorithms, the default parameters (for Window length, gap penalty, etc.) are used. In one embodiment, sequence identity is done using the BLAST algorithm, using default parameters.

[0189] The antibodies of the present invention are generally isolated or recombinant. “Isolated,”when used to describe the various polypeptides disclosed herein, means a polypeptide that has been identified and separated and / or recovered from a cell or cell culture from which it was expressed. Ordinarily, an isolated polypeptide will be prepared by at least one purification step. An “isolated antibody,” refers to an antibody which is substantially free of other antibodies having different antigenic specificities. “Recombinant” means the antibodies are generated using recombinant nucleic acid techniques in exogeneous host cells, and they can be isolated as well.

[0190] “Specific binding” or “specifically binds to” or is “specific for” a particular antigen or anepitope means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target.

[0191] Specific binding for a particular antigen or an epitope can be exhibited, for example, byAttorney Docket: 51096.4019 / WO an antibody having a KDfor an antigen or epitope of at least about 10-4M, at least about 10-5M, at least about 10-6M, at least about 10-7M, at least about 10-8M, at least about 10-9M, alternatively at least about 10-10M, at least about 10-11M, at least about 10-12M, or greater, where KDrefers to a dissociation rate of a particular antibody-antigen interaction. Typically, an antibody that specifically binds an antigen will have a KD that is 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for a control molecule relative to the antigen or epitope.

[0192] Also, specific binding for a particular antigen or an epitope can be exhibited, forexample, by an antibody having a KA or Ka for an antigen or epitope of at least 20-, 50-, 100-, 500-, 1000-, 5,000-, 10,000- or more times greater for the epitope relative to a control, where KA or Karefers to an association rate of a particular antibody-antigen interaction. Binding affinity is generally measured using a Biacore, SPR or BLI assay.

[0193] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “an antigen” includes mixtures of antigens; reference to “a pharmaceutically acceptable carrier” includes mixtures of two or more such carriers, and the like. As such, the terms “a” (or “an”), “one or more,” and “at least one” can be used interchangeably herein.

[0194] Furthermore, “and / or” where used herein is to be taken as specific disclosure of each ofthe two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” herein is intended to include “A and B,” “A or B,” “A (alone),” and “B (alone)”.

[0195] As used herein, the term “about” a value (or parameter) refers to, for example, ±1%,±2%, ±3%, ±4%, ±5%, 6%, ±7%, ±8%, ±9%, ±10% and the like of a stated value. When referring to a range of values (or parameters), the term “about” refers to +10% of the upper limit and -10% of the lower limit of a stated range of values. When a range of values is provided, it is to be understood that each intervening value between the upper and lower limit of that range, and any other stated or intervening value in that stated range, is encompassed within the scope of the present disclosure. Where the stated range includes upper and / or lower limits, ranges excluding either of those included limits are also included in the present disclosure. IV. Antigen Binding DomainsAttorney Docket: 51096.4019 / WO

[0196] In another aspect, provided herein are anti-CD3 × anti-MICA / B (also referred to herein as“αCD3 × αMICA / B,” “anti-MICA / B × anti-CD3,” and “αMICA / B × αCD3”) bispecific antibodies. Such antibodies include at least one CD3 binding domain and at least one MICA / B binding domain.

[0197] Note that unless specified herein, the order of the antigen list in the name does not conferstructure. That is to say, for example, an anti-CD3 × anti-MICA / B 1 + 1 Fab-scFv-Fc antibody can have the scFv bind to CD3 or MICA / B, although, in some cases, the order specifies structure as indicated.

[0198] As is more fully outlined herein, these combinations of antigen binding domains (ABDs)can be in a variety of formats, as outlined below, generally in combinations where one ABD is in a Fab format and the other is in an scFv format. Exemplary formats that are used in the bispecific antibodies provided herein include the 1 + 1 Fab × scFv, 1 + 1 empty × Fab-scFv, 2 + 1 Fab × Fab-scFv, 2 + 1 Fab2 × scFv, and 2 + 1 mAb-scFv formats (see, e.g., Figs.18A-18N). Other useful antibody formats include, but are not limited to, “mAb-Fv,” “central-Fv,” “1 + 1 common light chain” (CLC), “2 + 1 CLC,” “one-armed scFv-mAb,” “scFv-mAb,” “dual scFv,” “bispecific mAb,” and “trident” format antibodies as depicted in Fig.36 of U.S. Publ. App. No. 2022 / 0289839, hereby incorporated by reference in its entirety and specifically for its disclosure of antibody formats.

[0199] In addition, generally, one of the ABDs comprises a scFv as outlined herein, in anorientation from N- to C-terminus of VH-scFv linker-VLor VL-scFv linker-VH. One or both of the other ABDs, according to the format, generally is a Fab, comprising a VHdomain on one protein chain (generally as a component of a heavy chain) and a VL on another protein chain (generally as a component of a light chain).

[0200] As will be appreciated by those in the art, any set of 6 CDRs or VH and VL domains canbe in the scFv format or in the Fab format, which is then added to the heavy and light constant domains, where the heavy constant domains comprise variants (including within the CH1 domain, as well as the Fc domain). The scFv sequences contained in the sequence listing utilize a particular charged linker, but as outlined herein, uncharged or other charged linkers can be used, including those depicted in Fig.7 (see, e.g., SEQ ID NOs: 22-49).

[0201] In addition, as discussed above, the numbering used in the sequence listing for theAttorney Docket: 51096.4019 / WO identification of the CDRs is Kabat; however, different numbering can be used, which will change the amino acid sequences of the CDRs as shown in Table 2.

[0202] For all of the variable heavy and light domains listed herein, further variants can bemade. As outlined herein, in some embodiments, the set of 6 CDRs can have 0, 1, 2, 3, 4, or 5 amino acid modifications (with amino acid substitutions finding particular use), as well as changes in the framework regions of the variable heavy and light domains, as long as the frameworks (excluding the CDRs) retain at least about 80%, about 85%, about 90%, about 95%, or about 99% identity to a human germline sequence selected from those listed in Fig.1 of U.S. Pat. No.7,657,380, which Figure and Legend is incorporated by reference in its entirety herein. Thus, for example, the identical CDRs as described herein can be combined with different framework sequences from human germline sequences, as long as the framework regions retain at least about 80%, about 85%, about 90%, about 95%, or about 99% identity to a human germline sequence selected from those listed in Fig.1 of U.S. Pat. No.7,657,380. Alternatively, the CDRs can have amino acid modifications (e.g., from 1, 2, 3, 4, or 5 amino acid modifications in the set of CDRs (that is, the CDRs can be modified as long as the total number of changes in the set of 6 CDRs is less than 6 amino acid modifications, with any combination of CDRs being changed; e.g., there may be one change in vlCDR1, two in vhCDR2, none in vhCDR3, etc.)), as well as having framework region changes, as long as the framework regions retain at least about 80%, about 85%, about 90%, about 95%, or about 99% identity to a human germline sequence selected from those listed in Fig.1 of U.S. Pat. No.7,657,380.

[0203] As discussed herein, the subject heterodimeric antibodies include two ABDs, each ofwhich binds to CD3 or MICA / B. As outlined herein, these heterodimeric antibodies can be bispecific and bivalent (each antigen is bound by a single ABD, for example, in the format depicted in Fig.18), or bispecific and trivalent (one antigen is bound by a single ABD and the other is bound by two ABDs, for example, in the format depicted in Fig.18). A. MICA / B Antigen Binding Domains

[0204] Herein is provided monoclonal and bispecific antibodies (e.g., the anti-CD3 × anti-MICA / B antibodies provided herein), and fusion proteins that contain ABDs that bind to MICA / B. Suitable sets of 6 CDRs (vhCDR1-3 and vlCDR1-3; see, e.g., SEQ ID NOs: 245-247,Attorney Docket: 51096.4019 / WO 253-255, 261-263, 269-271, 277-279, 285-287, 293-295, 301-303, 309-311, 317-319, 325-327, 333-335, 341-343, 349-351, 357-359, 365-367, 373-375, 381-383, 389-391, 397-399, 405-407, 413-415, 421-423, 429-431, 437-439, 445-447, 453-455, 461-463, 469-471, 477-479, 485-487, 493-495, 501-503, 509-511, 517-519, 525-527, 533-535, 541-543, 549-551, 557-559, 565-567, 573-575, 581-583, 589-591, 597-599, 605-607, 613-615, 621-623, 629-631, 637-639, 645-647, 653-655, 661-663, 669-671, 677-679, 653-655, 685-687, 693-695, 701-703, 709-711, and 717- 719 and 249-251, 257-259, 265-267, 273-275, 281-283, 289-291, 297-299, 305-307, 313-315, 321-323, 329-331, 337-339, 345-347, 353-355, 361-363, 369-371, 377-379, 385-387, 393-395, 401-403, 409-411, 417-419, 425-427, 433-435, 441-443, 449-451, 457-459, 465-467, 473-475, 481-483, 489-491, 497-499, 505-507, 513-515, 521-523, 529-531, 537-539, 545-547, 553-555, 561-563, 569-571, 577-579, 585-587, 593-595, 601-603, 609-611, 617-619, 625-627, 633-635, 641-643, 649-651, 657-659, 665-667, 673-675, 681-683, 657-659, 689-691, 697-699, 705-707, 713-715, and 721-723, respectively) and / or VH and VL domains (see, e.g., SEQ ID NOs: 244, 252, 260, 268, 276, 284, 292, 300, 308, 316, 324, 332, 340, 348, 356, 364, 372, 380, 388, 396, 404, 412, 420, 428, 436, 444, 452, 460, 468, 476, 484, 492, 500, 508, 516, 524, 532, 540, 548, 556, 564, 572, 580, 588, 596, 604, 612, 620, 628, 636, 644, 652, 660, 668, 676, 652, 684, 692, 700, 708, and 716 and 248, 256, 264, 272, 280, 288, 296, 304, 312, 320, 328, 336, 344, 352, 360, 368, 376, 384, 392, 400, 408, 416, 424, 432, 440, 448, 456, 464, 472, 480, 488, 496, 504, 512, 520, 528, 536, 544, 552, 560, 568, 576, 584, 592, 600, 608, 616, 624, 632, 640, 648, 656, 664, 672, 680, 656, 688, 696, 704, 712, and 720, respectively) are depicted in Figs.16 and 17. In some embodiments, the heterodimeric antibody is a 1 + 1 Fab × scFv, 1 + 1 empty × Fab-scFv, 2 + 1 Fab × Fab-scFv, 2 + 1 Fab2 × scFv, or 2 + 1 mAb-scFv format antibody (see, e.g., Fig.18).

[0205] In some embodiments, the MICA / B ABD has a set of vhCDRs selected from thevhCDR1, vhCDR2, and vhCDR3 sequences from a VHselected from the group including: (i) D94837_1E11_1 [MICA / B]_H0 (SEQ ID NOS: 245-247), (ii) D94837_1E11_1 [MICA / B]_H1 (SEQ ID NOS: 253-255 and 261-263), (iii) D94837_1E11_1 [MICA / B]_H2 (SEQ ID NOS: 269- 271 and 277-279), (iv) 2E5 [MICA / B]_H0 (SEQ ID NOS: 285-287), (v) 2E5 [MICA / B]_H1 (SEQ ID NOS: 293-295 and 301-303), (vi) 2E5 [MICA / B]_H2 (SEQ ID NOS: 309-311 and 317- 319), (vii) D94852_2E12 [MICA / B]_H0 (SEQ ID NOS: 325-327), (viii) D94852_2E12 [MICA / B]_H1 (SEQ ID NOS: 333-335 and 341-343), (ix) D94852_2E12 [MICA / B]_H2 (SEQ ID NOS: 349-351 and 357-359), (x) D99136_2F7 [MICA / B]_H0 (SEQ ID NOS: 365-367), (xi)Attorney Docket: 51096.4019 / WO D99136_2F7 [MICA / B]_H1 (SEQ ID NOS: 373-375 and 381-383), (xii) D99136_2F7 [MICA / B]_H2 (SEQ ID NOS: 389-391 and 397-399), (xiii) D103388_1C7 [MICA / B]_H0 (SEQ ID NOS: 405-407), (xiv) D103388_1C7 [MICA / B]_H1 (SEQ ID NOS: 413-415 and 421-423), (xv) D103388_1C7 [MICA / B]_H2 (SEQ ID NOS: 429-431 and 437-439), (xvi) D103388_1D7 [MICA / B]_H0 (SEQ ID NOS: 445-447), (xvii) D103388_1D7 [MICA / B]_H1 (SEQ ID NOS: 453-455 and 461-463), (xviii) D103388_1D7 [MICA / B]_H2 (SEQ ID NOS: 469-471 and 477- 479), (xix) D105317_1A2 [MICA / B]_H0 (SEQ ID NOS: 485-487), (xx) D105317_1A2 [MICA / B]_H1 (SEQ ID NOS: 493-495 and 501-503), (xxi) D105317_1A2 [MICA / B]_H2 (SEQ ID NOS: 509-511 and 517-519), (xxii) D99136_2C11 [MICA / B]_H0 (SEQ ID NOS: 525-527), (xxiii) D99136_2C11 [MICA / B]_H1 (SEQ ID NOS: 533-535 and 541-543), (xxiv) D99136_2C11 [MICA / B]_H2 (SEQ ID NOS: 549-551 and 557-559), (xxv) D103388_1B11-2 [MICA / B]_H0 (SEQ ID NOS: 565-567), (xxvi) D105317_1B6 [MICA / B]_H0 (SEQ ID NOS: 573-575), (xxvii) D105317_1C8 [MICA / B]_H0 (SEQ ID NOS: 581-583), (xxviii) D105317_1F6 [MICA / B]_H0 (SEQ ID NOS: 589-591), (xxix) D105317_1F7 [MICA / B]_H0 (SEQ ID NOS: 597-599), (xxx) D94837_1D3 [MICA / B]_H0 (SEQ ID NOS: 605-607), (xxxi) D94837_1D8 [MICA / B]_H0 (SEQ ID NOS: 613-615), (xxxii) D94837_1D9 [MICA / B]_H0 (SEQ ID NOS: 621-623), (xxxiii) D94837_1E1 [MICA / B]_H0 (SEQ ID NOS: 629-631), (xxxiv) D94852_2D4 [MICA / B]_H0 (SEQ ID NOS: 637-639), (xxxv) D94852_2G8 [MICA / B]_H0 (SEQ ID NOS: 645-647), (xxxvi) D88487_2A8 [MICA / B]_H0 (SEQ ID NOS: 653-655), (xxxvii) D94837_3B12 [MICA / B]_H0 (SEQ ID NOS: 661-663), (xxxviii) D99122_1H7 [MICA / B]_H0 (SEQ ID NOS: 669-671), (xxxix) D99136_2E8 [MICA / B]_H0 (SEQ ID NOS: 677-679), (xl) D88487_2A8 [MICA / B]_H0 (SEQ ID NOS: 653-655), (xli) 3F9[MICA / B]_H0 (SEQ ID NOS: 685-687), (xlii) 6E1[MICA / B]_H0 (SEQ ID NOS: 693-695), (xliii) 7C6[MICA / B]_H0 (SEQ ID NOS: 701-703), (xliv) 13A9 [MICA / B]_H0 (SEQ ID NOS: 709-711), and (xlv) 1D5 [MICA / B]_H0 (SEQ ID NOS: 717-719), as shown in Figs.16 and 17. In some embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 245-247 (such as, for example, in D94837_1E11_1 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 253-255 and 261-263 (such as, for example, in D94837_1E11_1 [MICA / B]_H1). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 269-271 and 277-279 (such as, for example, in D94837_1E11_1 [MICA / B]_H2). In other embodiments, the vhCDR1,Attorney Docket: 51096.4019 / WO vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 285 and 287 (such as, for example, in 2E5 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 293-295 and 301-303 (such as, for example, in 2E5 [MICA / B]_H1). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 309-311 and 317-319 (such as, for example, in 2E5 [MICA / B]_H2). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 325-327 (such as, for example, in D94852_2E12 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 333-335 and 341-343 (such as, for example, in D94852_2E12 [MICA / B]_H1). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 349-351 and 357-359 (such as, for example, in D94852_2E12 [MICA / B]_H2). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 365-367 (such as, for example, in D99136_2F7 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 373-375 and 381-383 (such as, for example, in D99136_2F7 [MICA / B]_H1). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 389-391 and 397-399 (such as, for example, in D99136_2F7 [MICA / B]_H2). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 405-407 (such as, for example, in D103388_1C7 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 413-415 and 421-423 (such as, for example, in D103388_1C7 [MICA / B]_H1). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 429-431 and 437-439 (such as, for example, in D103388_1C7 [MICA / B]_H2). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 445-447 (such as, for example, in D103388_1D7 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 453-455 and 461-463 (such as, for example, in D103388_1D7 [MICA / B]_H1). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 469-471 and 477-479 (such as, for example, in D103388_1D7 [MICA / B]_H2). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 485-487 (such as, for example, in D105317_1A2Attorney Docket: 51096.4019 / WO [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 493-495 and 501-503 (such as, for example, in D105317_1A2 [MICA / B]_H1). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 509-511 and 517-519 (such as, for example, in D105317_1A2 [MICA / B]_H2). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 525-527 (such as, for example, in D99136_2C11 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 533-535 and 541-543 (such as, for example, in D99136_2C11 [MICA / B]_H1). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 549-551 and 557-559 (such as, for example, in D99136_2C11 [MICA / B]_H2). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 565 and 567 (such as, for example, in D103388_1B11-2 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 573-575 (such as, for example, in D105317_1B6 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 581-583 (such as, for example, in D105317_1C8 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 589-591 (such as, for example, in D105317_1F6 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 597-599 (such as, for example, in D105317_1F7 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 605-607 (such as, for example, in D94837_1D3 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 613-615 (such as, for example, in D94837_1D8 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 621-623 (such as, for example, in D94837_1D9 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 629-631 (such as, for example, in D94837_1E1 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 637-639 (such as, for example, in D94852_2D4 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of theAttorney Docket: 51096.4019 / WO MICA / B ABD are SEQ ID NOs: 645-647 (such as, for example, in D94852_2G8 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 653-655 (such as, for example, in D88487_2A8 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 661-663 (such as, for example, in D94837_3B12 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 669-671 (such as, for example, in D99122_1H7 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 677-679 (such as, for example, in D99136_2E8 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 653-655 (such as, for example, in D88487_2A8 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 685-687 (such as, for example, in 3F9[MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 693-695 (such as, for example, in 6E1[MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 701-703 (such as, for example, in 7C6[MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 709-711 (such as, for example, in 13A9 [MICA / B]_H0). In other embodiments, the vhCDR1, vhCDR2, and vhCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 717-719 (such as, for example, in 1D5 [MICA / B]_H0).

[0206] In some embodiments, the VH domain of the MICA / B ABD is selected from the groupthe group including: (i) D94837_1E11_1 [MICA / B]_H0 (SEQ ID NO: 244), (ii) D94837_1E11_1 [MICA / B]_H1 (SEQ ID NOS: 252 and 260), (iii) D94837_1E11_1 [MICA / B]_H2 (SEQ ID NOS: 268 and 276), (iv) 2E5 [MICA / B]_H0 (SEQ ID NO: 284), (v) 2E5 [MICA / B]_H1 (SEQ ID NOS: 292 and 300), (vi) 2E5 [MICA / B]_H2 (SEQ ID NOS: 308 and 316), (vii) D94852_2E12 [MICA / B]_H0 (SEQ ID NO: 324), (viii) D94852_2E12 [MICA / B]_H1 (SEQ ID NOS: 332 and 340), (ix) D94852_2E12 [MICA / B]_H2 (SEQ ID NOS: 348 and 356), (x) D99136_2F7 [MICA / B]_H0 (SEQ ID NO: 364), (xi) D99136_2F7 [MICA / B]_H1 (SEQ ID NOS: 372 and 380), (xii) D99136_2F7 [MICA / B]_H2 (SEQ ID NOS: 388 and 396), (xiii) D103388_1C7 [MICA / B]_H0 (SEQ ID NO: 404), (xiv) D103388_1C7 [MICA / B]_H1 (SEQ ID NOS: 412 and 420), (xv) D103388_1C7 [MICA / B]_H2 (SEQ ID NOS:Attorney Docket: 51096.4019 / WO 428 and 436), (xvi) D103388_1D7 [MICA / B]_H0 (SEQ ID NO: 444), (xvii) D103388_1D7 [MICA / B]_H1 (SEQ ID NOS: 452 and 460), (xviii) D103388_1D7 [MICA / B]_H2 (SEQ ID NOS: 468 and 476), (xix) D105317_1A2 [MICA / B]_H0 (SEQ ID NO: 484), (xx) D105317_1A2 [MICA / B]_H1 (SEQ ID NOS: 492 and 500), (xxi) D105317_1A2 [MICA / B]_H2 (SEQ ID NOS: 508 and 516), (xxii) D99136_2C11 [MICA / B]_H0 (SEQ ID NO: 524), (xxiii) D99136_2C11 [MICA / B]_H1 (SEQ ID NOS: 532 and 540), (xxiv) D99136_2C11 [MICA / B]_H2 (SEQ ID NOS: 548 and 556), (xxv) D103388_1B11-2 [MICA / B]_H0 (SEQ ID NO: 564), (xxvi) D105317_1B6 [MICA / B]_H0 (SEQ ID NO: 572), (xxvii) D105317_1C8 [MICA / B]_H0 (SEQ ID NO: 580), (xxviii) D105317_1F6 [MICA / B]_H0 (SEQ ID NO: 588), (xxix) D105317_1F7 [MICA / B]_H0 (SEQ ID NO: 596), (xxx) D94837_1D3 [MICA / B]_H0 (SEQ ID NO: 604), (xxxi) D94837_1D8 [MICA / B]_H0 (SEQ ID NO: 612), (xxxii) D94837_1D9 [MICA / B]_H0 (SEQ ID NO: 620), (xxxiii) D94837_1E1 [MICA / B]_H0 (SEQ ID NO: 628), (xxxiv) D94852_2D4 [MICA / B]_H0 (SEQ ID NO: 636), (xxxv) D94852_2G8 [MICA / B]_H0 (SEQ ID NO: 644), (xxxvi) D88487_2A8 [MICA / B]_H0 (SEQ ID NO: 652), (xxxvii) D94837_3B12 [MICA / B]_H0 (SEQ ID NO: 660), (xxxviii) D99122_1H7 [MICA / B]_H0 (SEQ ID NO: 668), (xxxix) D99136_2E8 [MICA / B]_H0 (SEQ ID NO: 676), (xl) D88487_2A8 [MICA / B]_H0 (SEQ ID NO: 652), (xli) 3F9[MICA / B]_H0 (SEQ ID NO: 684), (xlii) 6E1[MICA / B]_H0 (SEQ ID NO: 692), (xliii) 7C6[MICA / B]_H0 (SEQ ID NO: 700), (xliv) 13A9 [MICA / B]_H0 (SEQ ID NO: 708), and (xlv) 1D5 [MICA / B]_H0 (SEQ ID NO: 716), as shown in Figs.16 and 17.

[0207] In some embodiments, the MICA / B ABD has a set of vlCDRs selected from the vlCDR1,vlCDR2, and vlCDR3 sequences from a VLselected from the group including: (i) D94837_1E11_1 [MICA / B]_L0 (SEQ ID NOS: 249-251), (ii) D94837_1E11_1 [MICA / B]_L1 (SEQ ID NOS: 257-259 and 273-275), (iii) D94837_1E11_1 [MICA / B]_L2 (SEQ ID NOS: 265- 267 and 281-283), (iv) 2E5 [MICA / B]_L0 (SEQ ID NOS: 289-291), (v) 2E5 [MICA / B]_L1 (SEQ ID NOS: 297-299 and 313-315), (vi) 2E5 [MICA / B]_L2 (SEQ ID NOS: 305-307 and 321- 323), (vii) D94852_2E12 [MICA / B]_L0 (SEQ ID NOS: 329-331), (viii) D94852_2E12 [MICA / B]_L1 (SEQ ID NOS: 337-339 and 353-355), (ix) D94852_2E12 [MICA / B]_L2 (SEQ ID NOS: 345-347 and 361-363), (x) D99136_2F7 [MICA / B]_L0 (SEQ ID NOS: 369-371), (xi) D99136_2F7 [MICA / B]_L1 (SEQ ID NOS: 377-379 and 393-395), (xii) D99136_2F7 [MICA / B]_L2 (SEQ ID NOS: 385-387 and 401-403), (xiii) D103388_1C7 [MICA / B]_L0 (SEQ ID NOS: 409-411), (xiv) D103388_1C7 [MICA / B]_L1 (SEQ ID NOS: 417-419 and 433-435),Attorney Docket: 51096.4019 / WO (xv) D103388_1C7 [MICA / B]_L2 (SEQ ID NOS: 425-427 and 441-443), (xvi) D103388_1D7 [MICA / B]_L0 (SEQ ID NOS: 449-451), (xvii) D103388_1D7 [MICA / B]_L1 (SEQ ID NOS: 457-459 and 473-475), (xviii) D103388_1D7 [MICA / B]_L2 (SEQ ID NOS: 465-467 and 481- 483), (xix) D105317_1A2 [MICA / B]_L0 (SEQ ID NOS: 489-491), (xx) D105317_1A2 [MICA / B]_L1 (SEQ ID NOS: 497-499 and 513-515), (xxi) D105317_1A2 [MICA / B]_L2 (SEQ ID NOS: 505-507 and 521-523), (xxii) D99136_2C11 [MICA / B]_L0 (SEQ ID NOS: 529-531), (xxiii) D99136_2C11 [MICA / B]_L1 (SEQ ID NOS: 537-539 and 553-555), (xxiv) D99136_2C11 [MICA / B]_L2 (SEQ ID NOS: 545-547 and 561-563), (xxv) D103388_1B11-2 [MICA / B]_L0 (SEQ ID NOS: 569-571), (xxvi) D105317_1B6 [MICA / B]_L0 (SEQ ID NOS: 577-579), (xxvii) D105317_1C8 [MICA / B]_L0 (SEQ ID NOS: 585-587), (xxviii) D105317_1F6 [MICA / B]_L0 (SEQ ID NOS: 593-595), (xxix) D105317_1F7 [MICA / B]_L0 (SEQ ID NOS: 601-603), (xxx) D94837_1D3 [MICA / B]_L0 (SEQ ID NOS: 609-611), (xxxi) D94837_1D8 [MICA / B]_L0 (SEQ ID NOS: 617-619), (xxxii) D94837_1D9 [MICA / B]_L0 (SEQ ID NOS: 625-627), (xxxiii) D94837_1E1 [MICA / B]_L0 (SEQ ID NOS: 633-635), (xxxiv) D94852_2D4 [MICA / B]_L0 (SEQ ID NOS: 641-643), (xxxv) D94852_2G8 [MICA / B]_L0 (SEQ ID NOS: 649-651), (xxxvi) D88487_2A8 [MICA / B]_L0 (SEQ ID NOS: 657-659), (xxxvii) D94837_3B12 [MICA / B]_L0 (SEQ ID NOS: 665-667), (xxxviii) D99122_1H7 [MICA / B]_L0 (SEQ ID NOS: 673-675), (xxxix) D99136_2E8 [MICA / B]_L0 (SEQ ID NOS: 681-683), (xl) D88487_2A8 [MICA / B]_L0 (SEQ ID NOS: 657-659), (xli) 3F9[MICA / B]_L0 (SEQ ID NOS: 689-691), (xlii) 6E1[MICA / B]_L0 (SEQ ID NOS: 697-699), (xliii) 7C6[MICA / B]_L0 (SEQ ID NOS: 705-707), (xliv) 13A9 [MICA / B]_L0 (SEQ ID NOS: 713-715), and (xlv) 1D5 [MICA / B]_L0 (SEQ ID NOS: 721-723), as shown in Figs.16 and 17. In some embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 249-251 (such as, for example, in D94837_1E11_1 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 257-259 and 273-275 (such as, for example, in D94837_1E11_1 [MICA / B]_L1). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 265-267 and 281-283 (such as, for example, in D94837_1E11_1 [MICA / B]_L2). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 289-291 (such as, for example, in 2E5 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 297-299 and 313-315 (such as, for example, in 2E5Attorney Docket: 51096.4019 / WO [MICA / B]_L1). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 305-307 and 321-323 (such as, for example, in 2E5 [MICA / B]_L2). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 329-331 (such as, for example, in D94852_2E12 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 337-339 and 353-355 (such as, for example, in D94852_2E12 [MICA / B]_L1). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 345-347 and 361-363 (such as, for example, in D94852_2E12 [MICA / B]_L2). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 369-371 (such as, for example, in D99136_2F7 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 377-379 and 393-395 (such as, for example, in D99136_2F7 [MICA / B]_L1). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 385-387 and 401-403 (such as, for example, in D99136_2F7 [MICA / B]_L2). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 409-411 (such as, for example, in D103388_1C7 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 417-419 and 433-435 (such as, for example, in D103388_1C7 [MICA / B]_L1). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 425-427 and 441-443 (such as, for example, in D103388_1C7 [MICA / B]_L2). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 449-451 (such as, for example, in D103388_1D7 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 457-459 and 473-475 (such as, for example, in D103388_1D7 [MICA / B]_L1). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 465-467 and 481-483 (such as, for example, in D103388_1D7 [MICA / B]_L2). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 489-491 (such as, for example, in D105317_1A2 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 497-499 and 513-515 (such as, for example, in D105317_1A2 [MICA / B]_L1). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of theAttorney Docket: 51096.4019 / WO MICA / B ABD are SEQ ID NOs: 505-507 and 521-523 (such as, for example, in D105317_1A2 [MICA / B]_L2). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 529-531 (such as, for example, in D99136_2C11 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 537-539 and 553-555 (such as, for example, in D99136_2C11 [MICA / B]_L1). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 545-547 and 561-563 (such as, for example, in D99136_2C11 [MICA / B]_L2). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 569-571 (such as, for example, in D103388_1B11-2 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 577-579 (such as, for example, in D105317_1B6 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 585-587 (such as, for example, in D105317_1C8 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 593-595 (such as, for example, in D105317_1F6 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 601-603 (such as, for example, in D105317_1F7 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 609-611 (such as, for example, in D94837_1D3 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 617-619 (such as, for example, in D94837_1D8 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 625-627 (such as, for example, in D94837_1D9 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 633-635 (such as, for example, in D94837_1E1 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 641-643 (such as, for example, in D94852_2D4 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 649-651 (such as, for example, in D94852_2G8 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 657-659 (such as, for example, in D88487_2A8Attorney Docket: 51096.4019 / WO [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 665-667 (such as, for example, in D94837_3B12 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 673-675 (such as, for example, in D99122_1H7 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 681-683 (such as, for example, in D99136_2E8 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 657-659 (such as, for example, in D88487_2A8 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 689-691 (such as, for example, in 3F9[MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 697-699 (such as, for example, in 6E1[MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 705-707 (such as, for example, in 7C6[MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 713-715 (such as, for example, in 13A9 [MICA / B]_L0). In other embodiments, the vlCDR1, vlCDR2, and vlCDR3 sequences of the MICA / B ABD are SEQ ID NOs: 721-723 (such as, for example, in 1D5 [MICA / B]_L0).

[0208] In some embodiments, the VL of the MICA / B ABD is selected from the group including:(i) D94837_1E11_1 [MICA / B]_L0 (SEQ ID NO: 248), (ii) D94837_1E11_1 [MICA / B]_L1 (SEQ ID NOS: 256 and 272), (iii) D94837_1E11_1 [MICA / B]_L2 (SEQ ID NOS: 264 and 280), (iv) 2E5 [MICA / B]_L0 (SEQ ID NO: 288), (v) 2E5 [MICA / B]_L1 (SEQ ID NOS: 296 and 312), (vi) 2E5 [MICA / B]_L2 (SEQ ID NOS: 304 and 320), (vii) D94852_2E12 [MICA / B]_L0 (SEQ ID NO: 328), (viii) D94852_2E12 [MICA / B]_L1 (SEQ ID NOS: 336 and 352), (ix) D94852_2E12 [MICA / B]_L2 (SEQ ID NOS: 344 and 360), (x) D99136_2F7 [MICA / B]_L0 (SEQ ID NO: 368), (xi) D99136_2F7 [MICA / B]_L1 (SEQ ID NOS: 376 and 392), (xii) D99136_2F7 [MICA / B]_L2 (SEQ ID NOS: 384 and 400), (xiii) D103388_1C7 [MICA / B]_L0 (SEQ ID NO: 408), (xiv) D103388_1C7 [MICA / B]_L1 (SEQ ID NOS: 416 and 432), (xv) D103388_1C7 [MICA / B]_L2 (SEQ ID NOS: 424 and 440), (xvi) D103388_1D7 [MICA / B]_L0 (SEQ ID NO: 448), (xvii) D103388_1D7 [MICA / B]_L1 (SEQ ID NOS: 456 and 472), (xviii) D103388_1D7 [MICA / B]_L2 (SEQ ID NOS: 464 and 480), (xix) D105317_1A2 [MICA / B]_L0 (SEQ ID NO: 488), (xx) D105317_1A2 [MICA / B]_L1 (SEQ ID NOS: 496 and 512), (xxi)Attorney Docket: 51096.4019 / WO D105317_1A2 [MICA / B]_L2 (SEQ ID NOS: 504 and 520), (xxii) D99136_2C11 [MICA / B]_L0 (SEQ ID NO: 528), (xxiii) D99136_2C11 [MICA / B]_L1 (SEQ ID NOS: 536 and 552), (xxiv) D99136_2C11 [MICA / B]_L2 (SEQ ID NOS: 544 and 560), (xxv) D103388_1B11-2 [MICA / B]_L0 (SEQ ID NO: 568), (xxvi) D105317_1B6 [MICA / B]_L0 (SEQ ID NO: 576), (xxvii) D105317_1C8 [MICA / B]_L0 (SEQ ID NO: 584), (xxviii) D105317_1F6 [MICA / B]_L0 (SEQ ID NO: 592), (xxix) D105317_1F7 [MICA / B]_L0 (SEQ ID NO: 600), (xxx) D94837_1D3 [MICA / B]_L0 (SEQ ID NO: 608), (xxxi) D94837_1D8 [MICA / B]_L0 (SEQ ID NO: 616), (xxxii) D94837_1D9 [MICA / B]_L0 (SEQ ID NO: 624), (xxxiii) D94837_1E1 [MICA / B]_L0 (SEQ ID NO: 632), (xxxiv) D94852_2D4 [MICA / B]_L0 (SEQ ID NO: 640), (xxxv) D94852_2G8 [MICA / B]_L0 (SEQ ID NO: 648), (xxxvi) D88487_2A8 [MICA / B]_L0 (SEQ ID NO: 656), (xxxvii) D94837_3B12 [MICA / B]_L0 (SEQ ID NO: 664), (xxxviii) D99122_1H7 [MICA / B]_L0 (SEQ ID NO: 672), (xxxix) D99136_2E8 [MICA / B]_L0 (SEQ ID NO: 680), (xl) D88487_2A8 [MICA / B]_L0 (SEQ ID NO: 656), (xli) 3F9[MICA / B]_L0 (SEQ ID NO: 688), (xlii) 6E1[MICA / B]_L0 (SEQ ID NO: 696), (xliii) 7C6[MICA / B]_L0 (SEQ ID NO: 704), (xliv) 13A9 [MICA / B]_L0 (SEQ ID NO: 712), and (xlv) 1D5 [MICA / B]_L0 (SEQ ID NO: 720), as shown in Figs.16 and 17.

[0209] Accordingly, included herein are MICA / B ABDs that have a set of 6 CDRs (i.e.,vhCDR1-3 and vlCDR1-3) from VH / VL pairs selected from the group including: (i) SEQ ID NOs: 245-247 for vhCDR1-3 and SEQ ID NOs: 249-251 for vlCDR1-3 of D94837_1E11_1 [MICA / B]_H0_D94837_1E11_1 [MICA / B]_L0, respectively, (ii) SEQ ID NOs: 253-255 for vhCDR1-3 and SEQ ID NOs: 257-259 for vlCDR1-3 of D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L1, respectively, (iii) SEQ ID NOs: 261-263 for vhCDR1-3 and SEQ ID NOs: 265-267 for vlCDR1-3 of D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L2, respectively, (iv) SEQ ID NOs: 269-271 for vhCDR1-3 and SEQ ID NOs: 273-275 for vlCDR1-3 of D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L1, respectively, (v) SEQ ID NOs: 277-279 for vhCDR1-3 and SEQ ID NOs: 281-283 for vlCDR1-3 of D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L2, respectively, (vi) SEQ ID NOs: 285-287 for vhCDR1-3 and SEQ ID NOs: 289-291 for vlCDR1-3 of 2E5 [MICA / B]_H0_2E5 [MICA / B]_L0, respectively, (vii) SEQ ID NOs: 293-295 for vhCDR1-3 and SEQ ID NOs: 297-299 for vlCDR1- 3 of 2E5 [MICA / B]_H1_2E5 [MICA / B]_L1, respectively, (viii) SEQ ID NOs: 301-303 forAttorney Docket: 51096.4019 / WO vhCDR1-3 and SEQ ID NOs: 305-307 for vlCDR1-3 of 2E5 [MICA / B]_H1_2E5 [MICA / B]_L2, respectively, (ix) SEQ ID NOs: 309-311 for vhCDR1-3 and SEQ ID NOs: 313-315 for vlCDR1- 3 of 2E5 [MICA / B]_H2_2E5 [MICA / B]_L1, respectively, (x) SEQ ID NOs: 317-319 for vhCDR1-3 and SEQ ID NOs: 321-323 for vlCDR1-3 of 2E5 [MICA / B]_H2_2E5 [MICA / B]_L2, respectively, (xi) SEQ ID NOs: 325-327 for vhCDR1-3 and SEQ ID NOs: 329-331 for vlCDR1- 3 of D94852_2E12 [MICA / B]_H0_D94852_2E12 [MICA / B]_L0, respectively, (xii) SEQ ID NOs: 333-335 for vhCDR1-3 and SEQ ID NOs: 337-339 for vlCDR1-3 of D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L1, respectively, (xiii) SEQ ID NOs: 341-343 for vhCDR1-3 and SEQ ID NOs: 345-347 for vlCDR1-3 of D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L2, respectively, (xiv) SEQ ID NOs: 349-351 for vhCDR1-3 and SEQ ID NOs: 353-355 for vlCDR1-3 of D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L1, respectively, (xv) SEQ ID NOs: 357-359 for vhCDR1-3 and SEQ ID NOs: 361-363 for vlCDR1-3 of D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L2, respectively, (xvi) SEQ ID NOs: 365-367 for vhCDR1-3 and SEQ ID NOs: 369-371 for vlCDR1-3 of D99136_2F7 [MICA / B]_H0_D99136_2F7 [MICA / B]_L0, respectively, (xvii) SEQ ID NOs: 373-375 for vhCDR1-3 and SEQ ID NOs: 377-379 for vlCDR1-3 of D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L1, respectively, (xviii) SEQ ID NOs: 381-383 for vhCDR1-3 and SEQ ID NOs: 385-387 for vlCDR1-3 of D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L2, respectively, (xix) SEQ ID NOs: 389-391 for vhCDR1-3 and SEQ ID NOs: 393-395 for vlCDR1-3 of D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L1, respectively, (xx) SEQ ID NOs: 397-399 for vhCDR1-3 and SEQ ID NOs: 401-403 for vlCDR1-3 of D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L2, respectively, (xxi) SEQ ID NOs: 405-407 for vhCDR1-3 and SEQ ID NOs: 409-411 for vlCDR1-3 of D103388_1C7 [MICA / B]_H0_D103388_1C7 [MICA / B]_L0, respectively, (xxii) SEQ ID NOs: 413-415 for vhCDR1-3 and SEQ ID NOs: 417-419 for vlCDR1-3 of D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L1, respectively, (xxiii) SEQ ID NOs: 421-423 for vhCDR1-3 and SEQ ID NOs: 425-427 for vlCDR1-3 of D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L2, respectively, (xxiv) SEQ ID NOs: 429-431 for vhCDR1-3 and SEQ ID NOs: 433-435 for vlCDR1-3 of D103388_1C7Attorney Docket: 51096.4019 / WO [MICA / B]_H2_D103388_1C7 [MICA / B]_L1, respectively, (xxv) SEQ ID NOs: 437-439 for vhCDR1-3 and SEQ ID NOs: 441-443 for vlCDR1-3 of D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L2, respectively, (xxvi) SEQ ID NOs: 445-447 for vhCDR1-3 and SEQ ID NOs: 449-451 for vlCDR1-3 of D103388_1D7 [MICA / B]_H0_D103388_1D7 [MICA / B]_L0, respectively, (xxvii) SEQ ID NOs: 453-455 for vhCDR1-3 and SEQ ID NOs: 457-459 for vlCDR1-3 of D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L1, respectively, (xxviii) SEQ ID NOs: 461-463 for vhCDR1-3 and SEQ ID NOs: 465-467 for vlCDR1-3 of D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L2, respectively, (xxix) SEQ ID NOs: 469-471 for vhCDR1-3 and SEQ ID NOs: 473-475 for vlCDR1-3 of D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L1, respectively, (xxx) SEQ ID NOs: 477-479 for vhCDR1-3 and SEQ ID NOs: 481-483 for vlCDR1-3 of D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L2, respectively, (xxxi) SEQ ID NOs: 485-487 for vhCDR1-3 and SEQ ID NOs: 489-491 for vlCDR1-3 of D105317_1A2 [MICA / B]_H0_D105317_1A2 [MICA / B]_L0, respectively, (xxxii) SEQ ID NOs: 493-495 for vhCDR1-3 and SEQ ID NOs: 497-499 for vlCDR1-3 of D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L1, respectively, (xxxiii) SEQ ID NOs: 501-503 for vhCDR1-3 and SEQ ID NOs: 505-507 for vlCDR1-3 of D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L2, respectively, (xxxiv) SEQ ID NOs: 509-511 for vhCDR1-3 and SEQ ID NOs: 513-515 for vlCDR1-3 of D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L1, respectively, (xxxv) SEQ ID NOs: 517-519 for vhCDR1-3 and SEQ ID NOs: 521-523 for vlCDR1-3 of D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L2, respectively, (xxxvi) SEQ ID NOs: 525-527 for vhCDR1-3 and SEQ ID NOs: 529-531 for vlCDR1-3 of D99136_2C11 [MICA / B]_H0_D99136_2C11 [MICA / B]_L0, respectively, (xxxvii) SEQ ID NOs: 533-535 for vhCDR1-3 and SEQ ID NOs: 537-539 for vlCDR1-3 of D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L1, respectively, (xxxviii) SEQ ID NOs: 541-543 for vhCDR1-3 and SEQ ID NOs: 545-547 for vlCDR1-3 of D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L2, respectively, (xxxix) SEQ ID NOs: 549-551 for vhCDR1-3 and SEQ ID NOs: 553-555 for vlCDR1-3 of D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L1, respectively, (xl) SEQ ID NOs: 557-559 forAttorney Docket: 51096.4019 / WO vhCDR1-3 and SEQ ID NOs: 561-563 for vlCDR1-3 of D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L2, respectively, (xli) SEQ ID NOs: 565-567 for vhCDR1-3 and SEQ ID NOs: 569-571 for vlCDR1-3 of D103388_1B11-2 [MICA / B]_H0_D103388_1B11-2 [MICA / B]_L0, respectively, (xlii) SEQ ID NOs: 573-575 for vhCDR1-3 and SEQ ID NOs: 577-579 for vlCDR1-3 of D105317_1B6 [MICA / B]_H0_D105317_1B6 [MICA / B]_L0, respectively, (xliii) SEQ ID NOs: 581-583 for vhCDR1-3 and SEQ ID NOs: 585-587 for vlCDR1-3 of D105317_1C8 [MICA / B]_H0_D105317_1C8 [MICA / B]_L0, respectively, (xliv) SEQ ID NOs: 589-591 for vhCDR1-3 and SEQ ID NOs: 593-595 for vlCDR1-3 of D105317_1F6 [MICA / B]_H0_D105317_1F6 [MICA / B]_L0, respectively, (xlv) SEQ ID NOs: 597-599 for vhCDR1-3 and SEQ ID NOs: 601-603 for vlCDR1-3 of D105317_1F7 [MICA / B]_H0_D105317_1F7 [MICA / B]_L0, respectively, (xlvi) SEQ ID NOs: 605-607 for vhCDR1-3 and SEQ ID NOs: 609-611 for vlCDR1-3 of D94837_1D3 [MICA / B]_H0_D94837_1D3 [MICA / B]_L0, respectively, (xlvii) SEQ ID NOs: 613-615 for vhCDR1-3 and SEQ ID NOs: 617-619 for vlCDR1-3 of D94837_1D8 [MICA / B]_H0_D94837_1D8 [MICA / B]_L0, respectively, (xlviii) SEQ ID NOs: 621-623 for vhCDR1-3 and SEQ ID NOs: 625-627 for vlCDR1-3 of D94837_1D9 [MICA / B]_H0_D94837_1D9 [MICA / B]_L0, respectively, (xlix) SEQ ID NOs: 629-631 for vhCDR1-3 and SEQ ID NOs: 633-635 for vlCDR1-3 of D94837_1E1 [MICA / B]_H0_D94837_1E1 [MICA / B]_L0, respectively, (l) SEQ ID NOs: 637-639 for vhCDR1-3 and SEQ ID NOs: 641-643 for vlCDR1-3 of D94852_2D4 [MICA / B]_H0_D94852_2D4 [MICA / B]_L0, respectively, (li) SEQ ID NOs: 645-647 for vhCDR1-3 and SEQ ID NOs: 649-651 for vlCDR1-3 of D94852_2G8 [MICA / B]_H0_D94852_2G8 [MICA / B]_L0, respectively, (lii) SEQ ID NOs: 653-655 for vhCDR1-3 and SEQ ID NOs: 657-659 for vlCDR1-3 of D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, respectively, (liii) SEQ ID NOs: 661-663 for vhCDR1-3 and SEQ ID NOs: 665-667 for vlCDR1-3 of D94837_3B12 [MICA / B]_H0_D94837_3B12 [MICA / B]_L0, respectively, (liv) SEQ ID NOs: 669-671 for vhCDR1-3 and SEQ ID NOs: 673-675 for vlCDR1-3 of D99122_1H7 [MICA / B]_H0_D99122_1H7 [MICA / B]_L0, respectively, (lv) SEQ ID NOs: 677-679 for vhCDR1-3 and SEQ ID NOs: 681-683 for vlCDR1-3 of D99136_2E8Attorney Docket: 51096.4019 / WO [MICA / B]_H0_D99136_2E8 [MICA / B]_L0, respectively, (lvi) SEQ ID NOs: 653-655 for vhCDR1-3 and SEQ ID NOs: 657-659 for vlCDR1-3 of D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, respectively, (lvii) SEQ ID NOs: 685-687 for vhCDR1-3 and SEQ ID NOs: 689-691 for vlCDR1-3 of 3F9[MICA / B]_H0_3F9[MICA / B]_L0, respectively, (lviii) SEQ ID NOs: 693-695 for vhCDR1-3 and SEQ ID NOs: 697-699 for vlCDR1-3 of 6E1[MICA / B]_H0_6E1[MICA / B]_L0, respectively, (lix) SEQ ID NOs: 701-703 for vhCDR1-3 and SEQ ID NOs: 705-707 for vlCDR1-3 of 7C6[MICA / B]_H0_7C6[MICA / B]_L0, respectively, (lx) SEQ ID NOs: 709-711 for vhCDR1-3 and SEQ ID NOs: 713-715 for vlCDR1-3 of 13A9 [MICA / B]_H0_13A9 [MICA / B]_L0, respectively, and (lxi) SEQ ID NOs: 717-719 for vhCDR1-3 and SEQ ID NOs: 721-723 for vlCDR1-3 of 1D5 [MICA / B]_H0_1D5 [MICA / B]_L0, respectively, as are generally shown in Figs.16 and 17.

[0210] Additionally, included herein are MICA / B ABDs that have VH / VL pairs selected from thegroup including: (i) SEQ ID Nos: 244 and 248 for D94837_1E11_1 [MICA / B]_H0_D94837_1E11_1 [MICA / B]_L0, respectively, (ii) SEQ ID Nos: 252 and 256 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L1, respectively, (iii) SEQ ID Nos: 260 and 264 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L2, respectively, (iv) SEQ ID Nos: 268 and 272 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L1, respectively, (v) SEQ ID Nos: 276 and 280 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L2, respectively, (vi) SEQ ID Nos: 284 and 288 for 2E5 [MICA / B]_H0_2E5 [MICA / B]_L0, respectively, (vii) SEQ ID Nos: 292 and 296 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L1, respectively, (viii) SEQ ID Nos: 300 and 304 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L2, respectively, (ix) SEQ ID Nos: 308 and 312 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L1, respectively, (x) SEQ ID Nos: 316 and 320 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L2, respectively, (xi) SEQ ID Nos: 324 and 328 for D94852_2E12 [MICA / B]_H0_D94852_2E12 [MICA / B]_L0, respectively, (xii) SEQ ID Nos: 332 and 336 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L1, respectively, (xiii) SEQ ID Nos: 340 and 344 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L2, respectively, (xiv) SEQ ID Nos: 348 and 352 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L1, respectively, (xv) SEQ ID Nos: 356 and 360 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L2, respectively, (xvi) SEQ ID Nos: 364 and 368 forAttorney Docket: 51096.4019 / WO D99136_2F7 [MICA / B]_H0_D99136_2F7 [MICA / B]_L0, respectively, (xvii) SEQ ID Nos: 372 and 376 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L1, respectively, (xviii) SEQ ID Nos: 380 and 384 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L2, respectively, (xix) SEQ ID Nos: 388 and 392 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L1, respectively, (xx) SEQ ID Nos: 396 and 400 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L2, respectively, (xxi) SEQ ID Nos: 404 and 408 for D103388_1C7 [MICA / B]_H0_D103388_1C7 [MICA / B]_L0, respectively, (xxii) SEQ ID Nos: 412 and 416 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L1, respectively, (xxiii) SEQ ID Nos: 420 and 424 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L2, respectively, (xxiv) SEQ ID Nos: 428 and 432 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L1, respectively, (xxv) SEQ ID Nos: 436 and 440 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L2, respectively, (xxvi) SEQ ID Nos: 444 and 448 for D103388_1D7 [MICA / B]_H0_D103388_1D7 [MICA / B]_L0, respectively, (xxvii) SEQ ID Nos: 452 and 456 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L1, respectively, (xxviii) SEQ ID Nos: 460 and 464 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L2, respectively, (xxix) SEQ ID Nos: 468 and 472 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L1, respectively, (xxx) SEQ ID Nos: 476 and 480 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L2, respectively, (xxxi) SEQ ID Nos: 484 and 488 for D105317_1A2 [MICA / B]_H0_D105317_1A2 [MICA / B]_L0, respectively, (xxxii) SEQ ID Nos: 492 and 496 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L1, respectively, (xxxiii) SEQ ID Nos: 500 and 504 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L2, respectively, (xxxiv) SEQ ID Nos: 508 and 512 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L1, respectively, (xxxv) SEQ ID Nos: 516 and 520 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L2, respectively, (xxxvi) SEQ ID Nos: 524 and 528 for D99136_2C11 [MICA / B]_H0_D99136_2C11 [MICA / B]_L0, respectively, (xxxvii) SEQ ID Nos: 532 and 536 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L1, respectively, (xxxviii) SEQ ID Nos: 540 and 544 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L2, respectively, (xxxix) SEQ ID Nos: 548 and 552 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L1, respectively, (xl) SEQ ID Nos: 556 and 560 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L2, respectively, (xli) SEQ ID Nos: 564 and 568 for D103388_1B11-2Attorney Docket: 51096.4019 / WO [MICA / B]_H0_D103388_1B11-2 [MICA / B]_L0, respectively, (xlii) SEQ ID Nos: 572 and 576 for D105317_1B6 [MICA / B]_H0_D105317_1B6 [MICA / B]_L0, respectively, (xliii) SEQ ID Nos: 580 and 584 for D105317_1C8 [MICA / B]_H0_D105317_1C8 [MICA / B]_L0, respectively, (xliv) SEQ ID Nos: 588 and 592 for D105317_1F6 [MICA / B]_H0_D105317_1F6 [MICA / B]_L0, respectively, (xlv) SEQ ID Nos: 596 and 600 for D105317_1F7 [MICA / B]_H0_D105317_1F7 [MICA / B]_L0, respectively, (xlvi) SEQ ID Nos: 604 and 608 for D94837_1D3 [MICA / B]_H0_D94837_1D3 [MICA / B]_L0, respectively, (xlvii) SEQ ID Nos: 612 and 616 for D94837_1D8 [MICA / B]_H0_D94837_1D8 [MICA / B]_L0, respectively, (xlviii) SEQ ID Nos: 620 and 624 for D94837_1D9 [MICA / B]_H0_D94837_1D9 [MICA / B]_L0, respectively, (xlix) SEQ ID Nos: 628 and 632 for D94837_1E1 [MICA / B]_H0_D94837_1E1 [MICA / B]_L0, respectively, (l) SEQ ID Nos: 636 and 640 for D94852_2D4 [MICA / B]_H0_D94852_2D4 [MICA / B]_L0, respectively, (li) SEQ ID Nos: 644 and 648 for D94852_2G8 [MICA / B]_H0_D94852_2G8 [MICA / B]_L0, respectively, (lii) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, respectively, (liii) SEQ ID Nos: 660 and 664 for D94837_3B12 [MICA / B]_H0_D94837_3B12 [MICA / B]_L0, respectively, (liv) SEQ ID Nos: 668 and 672 for D99122_1H7 [MICA / B]_H0_D99122_1H7 [MICA / B]_L0, respectively, (lv) SEQ ID Nos: 676 and 680 for D99136_2E8 [MICA / B]_H0_D99136_2E8 [MICA / B]_L0, respectively, (lvi) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, respectively, (lvii) SEQ ID Nos: 684 and 688 for 3F9[MICA / B]_H0_3F9[MICA / B]_L0, respectively, (lviii) SEQ ID Nos: 692 and 696 for 6E1[MICA / B]_H0_6E1[MICA / B]_L0, respectively, (lix) SEQ ID Nos: 700 and 704 for 7C6[MICA / B]_H0_7C6[MICA / B]_L0, respectively, (lx) SEQ ID Nos: 708 and 712 for 13A9 [MICA / B]_H0_13A9 [MICA / B]_L0, respectively, and (lxi) SEQ ID Nos: 716 and 720 for 1D5 [MICA / B]_H0_1D5 [MICA / B]_L0, respectively, as are generally shown in Figs.16 and 17.

[0211] In particular embodiments, the VH / VL pairs used in scFvs are selected from the groupincluding: (i) SEQ ID Nos: 244 and 248 for D94837_1E11_1 [MICA / B]_H0_D94837_1E11_1 [MICA / B]_L0, respectively, (ii) SEQ ID Nos: 252 and 256 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L1, respectively, (iii) SEQ ID Nos: 260 and 264 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L2, respectively, (iv) SEQ ID Nos: 268 and 272 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L1, respectively, (v) SEQ ID Nos: 276 and 280 for D94837_1E11_1Attorney Docket: 51096.4019 / WO [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L2, respectively, (vi) SEQ ID Nos: 284 and 288 for 2E5 [MICA / B]_H0_2E5 [MICA / B]_L0, respectively, (vii) SEQ ID Nos: 292 and 296 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L1, respectively, (viii) SEQ ID Nos: 300 and 304 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L2, respectively, (ix) SEQ ID Nos: 308 and 312 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L1, respectively, (x) SEQ ID Nos: 316 and 320 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L2, respectively, (xi) SEQ ID Nos: 324 and 328 for D94852_2E12 [MICA / B]_H0_D94852_2E12 [MICA / B]_L0, respectively, (xii) SEQ ID Nos: 332 and 336 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L1, respectively, (xiii) SEQ ID Nos: 340 and 344 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L2, respectively, (xiv) SEQ ID Nos: 348 and 352 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L1, respectively, (xv) SEQ ID Nos: 356 and 360 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L2, respectively, (xvi) SEQ ID Nos: 364 and 368 for D99136_2F7 [MICA / B]_H0_D99136_2F7 [MICA / B]_L0, respectively, (xvii) SEQ ID Nos: 372 and 376 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L1, respectively, (xviii) SEQ ID Nos: 380 and 384 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L2, respectively, (xix) SEQ ID Nos: 388 and 392 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L1, respectively, (xx) SEQ ID Nos: 396 and 400 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L2, respectively, (xxi) SEQ ID Nos: 404 and 408 for D103388_1C7 [MICA / B]_H0_D103388_1C7 [MICA / B]_L0, respectively, (xxii) SEQ ID Nos: 412 and 416 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L1, respectively, (xxiii) SEQ ID Nos: 420 and 424 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L2, respectively, (xxiv) SEQ ID Nos: 428 and 432 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L1, respectively, (xxv) SEQ ID Nos: 436 and 440 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L2, respectively, (xxvi) SEQ ID Nos: 444 and 448 for D103388_1D7 [MICA / B]_H0_D103388_1D7 [MICA / B]_L0, respectively, (xxvii) SEQ ID Nos: 452 and 456 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L1, respectively, (xxviii) SEQ ID Nos: 460 and 464 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L2, respectively, (xxix) SEQ ID Nos: 468 and 472 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L1, respectively, (xxx) SEQ ID Nos: 476 and 480 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L2, respectively, (xxxi) SEQ ID Nos: 484 and 488 for D105317_1A2 [MICA / B]_H0_D105317_1A2 [MICA / B]_L0, respectively,Attorney Docket: 51096.4019 / WO (xxxii) SEQ ID Nos: 492 and 496 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L1, respectively, (xxxiii) SEQ ID Nos: 500 and 504 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L2, respectively, (xxxiv) SEQ ID Nos: 508 and 512 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L1, respectively, (xxxv) SEQ ID Nos: 516 and 520 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L2, respectively, (xxxvi) SEQ ID Nos: 524 and 528 for D99136_2C11 [MICA / B]_H0_D99136_2C11 [MICA / B]_L0, respectively, (xxxvii) SEQ ID Nos: 532 and 536 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L1, respectively, (xxxviii) SEQ ID Nos: 540 and 544 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L2, respectively, (xxxix) SEQ ID Nos: 548 and 552 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L1, respectively, (xl) SEQ ID Nos: 556 and 560 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L2, respectively, (xli) SEQ ID Nos: 564 and 568 for D103388_1B11-2 [MICA / B]_H0_D103388_1B11-2 [MICA / B]_L0, respectively, (xlii) SEQ ID Nos: 572 and 576 for D105317_1B6 [MICA / B]_H0_D105317_1B6 [MICA / B]_L0, respectively, (xliii) SEQ ID Nos: 580 and 584 for D105317_1C8 [MICA / B]_H0_D105317_1C8 [MICA / B]_L0, respectively, (xliv) SEQ ID Nos: 588 and 592 for D105317_1F6 [MICA / B]_H0_D105317_1F6 [MICA / B]_L0, respectively, (xlv) SEQ ID Nos: 596 and 600 for D105317_1F7 [MICA / B]_H0_D105317_1F7 [MICA / B]_L0, respectively, (xlvi) SEQ ID Nos: 604 and 608 for D94837_1D3 [MICA / B]_H0_D94837_1D3 [MICA / B]_L0, respectively, (xlvii) SEQ ID Nos: 612 and 616 for D94837_1D8 [MICA / B]_H0_D94837_1D8 [MICA / B]_L0, respectively, (xlviii) SEQ ID Nos: 620 and 624 for D94837_1D9 [MICA / B]_H0_D94837_1D9 [MICA / B]_L0, respectively, (xlix) SEQ ID Nos: 628 and 632 for D94837_1E1 [MICA / B]_H0_D94837_1E1 [MICA / B]_L0, respectively, (l) SEQ ID Nos: 636 and 640 for D94852_2D4 [MICA / B]_H0_D94852_2D4 [MICA / B]_L0, respectively, (li) SEQ ID Nos: 644 and 648 for D94852_2G8 [MICA / B]_H0_D94852_2G8 [MICA / B]_L0, respectively, (lii) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, respectively, (liii) SEQ ID Nos: 660 and 664 for D94837_3B12 [MICA / B]_H0_D94837_3B12 [MICA / B]_L0, respectively, (liv) SEQ ID Nos: 668 and 672 for D99122_1H7 [MICA / B]_H0_D99122_1H7 [MICA / B]_L0, respectively, (lv) SEQ ID Nos: 676 and 680 for D99136_2E8 [MICA / B]_H0_D99136_2E8 [MICA / B]_L0, respectively, (lvi) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, respectively, (lvii) SEQ ID Nos: 684Attorney Docket: 51096.4019 / WO and 688 for 3F9[MICA / B]_H0_3F9[MICA / B]_L0, respectively, (lviii) SEQ ID Nos: 692 and 696 for 6E1[MICA / B]_H0_6E1[MICA / B]_L0, respectively, (lix) SEQ ID Nos: 700 and 704 for 7C6[MICA / B]_H0_7C6[MICA / B]_L0, respectively, (lx) SEQ ID Nos: 708 and 712 for 13A9 [MICA / B]_H0_13A9 [MICA / B]_L0, respectively, and (lxi) SEQ ID Nos: 716 and 720 for 1D5 [MICA / B]_H0_1D5 [MICA / B]_L0, respectively, as are generally shown in Figs.16 and 17.

[0212] In particular embodiments, the VH / VL pairs used in Fabs are selected from the groupincluding: (i) SEQ ID Nos: 244 and 248 for D94837_1E11_1 [MICA / B]_H0_D94837_1E11_1 [MICA / B]_L0, respectively, (ii) SEQ ID Nos: 252 and 256 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L1, respectively, (iii) SEQ ID Nos: 260 and 264 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L2, respectively, (iv) SEQ ID Nos: 268 and 272 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L1, respectively, (v) SEQ ID Nos: 276 and 280 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L2, respectively, (vi) SEQ ID Nos: 284 and 288 for 2E5 [MICA / B]_H0_2E5 [MICA / B]_L0, respectively, (vii) SEQ ID Nos: 292 and 296 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L1, respectively, (viii) SEQ ID Nos: 300 and 304 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L2, respectively, (ix) SEQ ID Nos: 308 and 312 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L1, respectively, (x) SEQ ID Nos: 316 and 320 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L2, respectively, (xi) SEQ ID Nos: 324 and 328 for D94852_2E12 [MICA / B]_H0_D94852_2E12 [MICA / B]_L0, respectively, (xii) SEQ ID Nos: 332 and 336 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L1, respectively, (xiii) SEQ ID Nos: 340 and 344 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L2, respectively, (xiv) SEQ ID Nos: 348 and 352 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L1, respectively, (xv) SEQ ID Nos: 356 and 360 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L2, respectively, (xvi) SEQ ID Nos: 364 and 368 for D99136_2F7 [MICA / B]_H0_D99136_2F7 [MICA / B]_L0, respectively, (xvii) SEQ ID Nos: 372 and 376 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L1, respectively, (xviii) SEQ ID Nos: 380 and 384 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L2, respectively, (xix) SEQ ID Nos: 388 and 392 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L1, respectively, (xx) SEQ ID Nos: 396 and 400 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L2, respectively, (xxi) SEQ ID Nos: 404 and 408 for D103388_1C7 [MICA / B]_H0_D103388_1C7 [MICA / B]_L0, respectively, (xxii) SEQ ID Nos: 412 and 416 forAttorney Docket: 51096.4019 / WO D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L1, respectively, (xxiii) SEQ ID Nos: 420 and 424 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L2, respectively, (xxiv) SEQ ID Nos: 428 and 432 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L1, respectively, (xxv) SEQ ID Nos: 436 and 440 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L2, respectively, (xxvi) SEQ ID Nos: 444 and 448 for D103388_1D7 [MICA / B]_H0_D103388_1D7 [MICA / B]_L0, respectively, (xxvii) SEQ ID Nos: 452 and 456 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L1, respectively, (xxviii) SEQ ID Nos: 460 and 464 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L2, respectively, (xxix) SEQ ID Nos: 468 and 472 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L1, respectively, (xxx) SEQ ID Nos: 476 and 480 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L2, respectively, (xxxi) SEQ ID Nos: 484 and 488 for D105317_1A2 [MICA / B]_H0_D105317_1A2 [MICA / B]_L0, respectively, (xxxii) SEQ ID Nos: 492 and 496 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L1, respectively, (xxxiii) SEQ ID Nos: 500 and 504 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L2, respectively, (xxxiv) SEQ ID Nos: 508 and 512 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L1, respectively, (xxxv) SEQ ID Nos: 516 and 520 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L2, respectively, (xxxvi) SEQ ID Nos: 524 and 528 for D99136_2C11 [MICA / B]_H0_D99136_2C11 [MICA / B]_L0, respectively, (xxxvii) SEQ ID Nos: 532 and 536 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L1, respectively, (xxxviii) SEQ ID Nos: 540 and 544 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L2, respectively, (xxxix) SEQ ID Nos: 548 and 552 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L1, respectively, (xl) SEQ ID Nos: 556 and 560 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L2, respectively, (xli) SEQ ID Nos: 564 and 568 for D103388_1B11-2 [MICA / B]_H0_D103388_1B11-2 [MICA / B]_L0, respectively, (xlii) SEQ ID Nos: 572 and 576 for D105317_1B6 [MICA / B]_H0_D105317_1B6 [MICA / B]_L0, respectively, (xliii) SEQ ID Nos: 580 and 584 for D105317_1C8 [MICA / B]_H0_D105317_1C8 [MICA / B]_L0, respectively, (xliv) SEQ ID Nos: 588 and 592 for D105317_1F6 [MICA / B]_H0_D105317_1F6 [MICA / B]_L0, respectively, (xlv) SEQ ID Nos: 596 and 600 for D105317_1F7 [MICA / B]_H0_D105317_1F7 [MICA / B]_L0, respectively, (xlvi) SEQ ID Nos: 604 and 608 for D94837_1D3 [MICA / B]_H0_D94837_1D3 [MICA / B]_L0, respectively, (xlvii) SEQ ID Nos:Attorney Docket: 51096.4019 / WO 612 and 616 for D94837_1D8 [MICA / B]_H0_D94837_1D8 [MICA / B]_L0, respectively, (xlviii) SEQ ID Nos: 620 and 624 for D94837_1D9 [MICA / B]_H0_D94837_1D9 [MICA / B]_L0, respectively, (xlix) SEQ ID Nos: 628 and 632 for D94837_1E1 [MICA / B]_H0_D94837_1E1 [MICA / B]_L0, respectively, (l) SEQ ID Nos: 636 and 640 for D94852_2D4 [MICA / B]_H0_D94852_2D4 [MICA / B]_L0, respectively, (li) SEQ ID Nos: 644 and 648 for D94852_2G8 [MICA / B]_H0_D94852_2G8 [MICA / B]_L0, respectively, (lii) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, respectively, (liii) SEQ ID Nos: 660 and 664 for D94837_3B12 [MICA / B]_H0_D94837_3B12 [MICA / B]_L0, respectively, (liv) SEQ ID Nos: 668 and 672 for D99122_1H7 [MICA / B]_H0_D99122_1H7 [MICA / B]_L0, respectively, (lv) SEQ ID Nos: 676 and 680 for D99136_2E8 [MICA / B]_H0_D99136_2E8 [MICA / B]_L0, respectively, (lvi) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, respectively, (lvii) SEQ ID Nos: 684 and 688 for 3F9[MICA / B]_H0_3F9[MICA / B]_L0, respectively, (lviii) SEQ ID Nos: 692 and 696 for 6E1[MICA / B]_H0_6E1[MICA / B]_L0, respectively, (lix) SEQ ID Nos: 700 and 704 for 7C6[MICA / B]_H0_7C6[MICA / B]_L0, respectively, (lx) SEQ ID Nos: 708 and 712 for 13A9 [MICA / B]_H0_13A9 [MICA / B]_L0, respectively, and (lxi) SEQ ID Nos: 716 and 720 for 1D5 [MICA / B]_H0_1D5 [MICA / B]_L0, respectively, as are generally shown in Figs.16 and 17.

[0213] As will be appreciated by those in the art, suitable MICA / B binding domains cancomprise a set of 6 CDRs as depicted in the Figures, either as they are underlined or, in the case where a different numbering scheme is used, as described herein and as shown in Table 2, as the CDRs that are identified using other alignments within the VHand VLsequences of those depicted in Figs.16 and 17. Suitable ABDs can also include the entire VH and VL sequences as depicted in these sequences and Figures, used as scFvs or as Fabs. In many of the embodiments herein that contain an Fv to MICA / B, it is the scFv monomer that binds MICA / B. However, in many other embodiments herein that contain an Fv to MICA / B, it is the Fab monomer that binds MICA / B.

[0214] In addition to the parental CDR sets disclosed in the figures and sequence listing thatform an ABD to MICA / B, provided herein are variant MICA / B ABDs having CDRs that include at least one modification of the MICA / B ABD CDRs disclosed herein (see, e.g., Figs.16 and 17). In one embodiment, the MICA / B ABD of the subject heterodimeric antibody includes a set of 6 CDRS with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications as compared to the 6Attorney Docket: 51096.4019 / WO CDRs of a MICA / B binding domain VH / VLpair as described herein, including the figures and sequence listing. In exemplary embodiments, the MICA / B ABD of the subject heterodimeric antibody includes a set of 6 CDRs with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid modifications as compared to the 6 CDRs of one of the following MICA / B binding domain VH / VLpairs: (i) SEQ ID Nos: 244 and 248 for D94837_1E11_1 [MICA / B]_H0_D94837_1E11_1 [MICA / B]_L0, respectively, (ii) SEQ ID Nos: 252 and 256 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L1, respectively, (iii) SEQ ID Nos: 260 and 264 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L2, respectively, (iv) SEQ ID Nos: 268 and 272 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L1, respectively, (v) SEQ ID Nos: 276 and 280 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L2, respectively, (vi) SEQ ID Nos: 284 and 288 for 2E5 [MICA / B]_H0_2E5 [MICA / B]_L0, respectively, (vii) SEQ ID Nos: 292 and 296 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L1, respectively, (viii) SEQ ID Nos: 300 and 304 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L2, respectively, (ix) SEQ ID Nos: 308 and 312 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L1, respectively, (x) SEQ ID Nos: 316 and 320 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L2, respectively, (xi) SEQ ID Nos: 324 and 328 for D94852_2E12 [MICA / B]_H0_D94852_2E12 [MICA / B]_L0, respectively, (xii) SEQ ID Nos: 332 and 336 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L1, respectively, (xiii) SEQ ID Nos: 340 and 344 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L2, respectively, (xiv) SEQ ID Nos: 348 and 352 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L1, respectively, (xv) SEQ ID Nos: 356 and 360 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L2, respectively, (xvi) SEQ ID Nos: 364 and 368 for D99136_2F7 [MICA / B]_H0_D99136_2F7 [MICA / B]_L0, respectively, (xvii) SEQ ID Nos: 372 and 376 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L1, respectively, (xviii) SEQ ID Nos: 380 and 384 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L2, respectively, (xix) SEQ ID Nos: 388 and 392 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L1, respectively, (xx) SEQ ID Nos: 396 and 400 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L2, respectively, (xxi) SEQ ID Nos: 404 and 408 for D103388_1C7 [MICA / B]_H0_D103388_1C7 [MICA / B]_L0, respectively, (xxii) SEQ ID Nos: 412 and 416 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L1, respectively, (xxiii) SEQ ID Nos: 420 and 424 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L2, respectively,Attorney Docket: 51096.4019 / WO (xxiv) SEQ ID Nos: 428 and 432 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L1, respectively, (xxv) SEQ ID Nos: 436 and 440 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L2, respectively, (xxvi) SEQ ID Nos: 444 and 448 for D103388_1D7 [MICA / B]_H0_D103388_1D7 [MICA / B]_L0, respectively, (xxvii) SEQ ID Nos: 452 and 456 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L1, respectively, (xxviii) SEQ ID Nos: 460 and 464 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L2, respectively, (xxix) SEQ ID Nos: 468 and 472 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L1, respectively, (xxx) SEQ ID Nos: 476 and 480 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L2, respectively, (xxxi) SEQ ID Nos: 484 and 488 for D105317_1A2 [MICA / B]_H0_D105317_1A2 [MICA / B]_L0, respectively, (xxxii) SEQ ID Nos: 492 and 496 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L1, respectively, (xxxiii) SEQ ID Nos: 500 and 504 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L2, respectively, (xxxiv) SEQ ID Nos: 508 and 512 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L1, respectively, (xxxv) SEQ ID Nos: 516 and 520 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L2, respectively, (xxxvi) SEQ ID Nos: 524 and 528 for D99136_2C11 [MICA / B]_H0_D99136_2C11 [MICA / B]_L0, respectively, (xxxvii) SEQ ID Nos: 532 and 536 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L1, respectively, (xxxviii) SEQ ID Nos: 540 and 544 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L2, respectively, (xxxix) SEQ ID Nos: 548 and 552 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L1, respectively, (xl) SEQ ID Nos: 556 and 560 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L2, respectively, (xli) SEQ ID Nos: 564 and 568 for D103388_1B11-2 [MICA / B]_H0_D103388_1B11-2 [MICA / B]_L0, respectively, (xlii) SEQ ID Nos: 572 and 576 for D105317_1B6 [MICA / B]_H0_D105317_1B6 [MICA / B]_L0, respectively, (xliii) SEQ ID Nos: 580 and 584 for D105317_1C8 [MICA / B]_H0_D105317_1C8 [MICA / B]_L0, respectively, (xliv) SEQ ID Nos: 588 and 592 for D105317_1F6 [MICA / B]_H0_D105317_1F6 [MICA / B]_L0, respectively, (xlv) SEQ ID Nos: 596 and 600 for D105317_1F7 [MICA / B]_H0_D105317_1F7 [MICA / B]_L0, respectively, (xlvi) SEQ ID Nos: 604 and 608 for D94837_1D3 [MICA / B]_H0_D94837_1D3 [MICA / B]_L0, respectively, (xlvii) SEQ ID Nos: 612 and 616 for D94837_1D8 [MICA / B]_H0_D94837_1D8 [MICA / B]_L0, respectively, (xlviii) SEQ ID Nos: 620 and 624 for D94837_1D9 [MICA / B]_H0_D94837_1D9 [MICA / B]_L0,Attorney Docket: 51096.4019 / WO respectively, (xlix) SEQ ID Nos: 628 and 632 for D94837_1E1 [MICA / B]_H0_D94837_1E1 [MICA / B]_L0, respectively, (l) SEQ ID Nos: 636 and 640 for D94852_2D4 [MICA / B]_H0_D94852_2D4 [MICA / B]_L0, respectively, (li) SEQ ID Nos: 644 and 648 for D94852_2G8 [MICA / B]_H0_D94852_2G8 [MICA / B]_L0, respectively, (lii) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, respectively, (liii) SEQ ID Nos: 660 and 664 for D94837_3B12 [MICA / B]_H0_D94837_3B12 [MICA / B]_L0, respectively, (liv) SEQ ID Nos: 668 and 672 for D99122_1H7 [MICA / B]_H0_D99122_1H7 [MICA / B]_L0, respectively, (lv) SEQ ID Nos: 676 and 680 for D99136_2E8 [MICA / B]_H0_D99136_2E8 [MICA / B]_L0, respectively, (lvi) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, respectively, (lvii) SEQ ID Nos: 684 and 688 for 3F9[MICA / B]_H0_3F9[MICA / B]_L0, respectively, (lviii) SEQ ID Nos: 692 and 696 for 6E1[MICA / B]_H0_6E1[MICA / B]_L0, respectively, (lix) SEQ ID Nos: 700 and 704 for 7C6[MICA / B]_H0_7C6[MICA / B]_L0, respectively, (lx) SEQ ID Nos: 708 and 712 for 13A9 [MICA / B]_H0_13A9 [MICA / B]_L0, respectively, or (lxi) SEQ ID Nos: 716 and 720 for 1D5 [MICA / B]_H0_1D5 [MICA / B]_L0, respectively. In certain embodiments, the MICA / B ABD of the subject antibody is capable of binding to MICA, as measured by at least one of: (i) a Biacore assay, (ii) a surface plasmon resonance (SPR) assay, (iii) a biolayer interferometry (BLI) assay (e.g., an Octet assay), (iv) flow cytometry, or any combination thereof. In particular embodiments, the MICA / B ABD is capable of binding a human MICA antigen (see, e.g., Fig.2; SEQ ID NOs: 12-13 and 15-17). In particular embodiments, the MICA / B ABD is capable of binding the extracellular domain (ECD) of a human MICA antigen (see, e.g., Fig.2; SEQ ID NOs: 12-13 and 15-17). In certain embodiments, the MICA / B ABD of the subject antibody is capable of binding to MICB, as measured by at least one of: (i) a Biacore assay, (ii) a surface plasmon resonance (SPR) assay, (iii) a biolayer interferometry (BLI) assay (e.g., an Octet assay), (iv) flow cytometry, or any combination thereof. In particular embodiments, the MICA / B ABD is capable of binding a human MICB antigen (see, e.g., Fig.3; SEQ ID NO: 18-19 and 21). In particular embodiments, the MICA / B ABD is capable of binding the extracellular domain (ECD) of a human MICB antigen (see, e.g., Fig.3; SEQ ID NO: 18-19 and 21).

[0215] In another exemplary embodiment, the MICA / B ABD of the subject antibody includesthe variable heavy (VH) domain and variable light (VL) domain of any one of the MICA / B binding domain VH / VLpairs described herein, including the figures and sequence listing.Attorney Docket: 51096.4019 / WO

[0216] In some embodiments, the subject antibody includes a MICA / B ABD that includes avariable heavy domain and / or a variable light domain that are variants of a MICA / B ABD VH and / or VL domain disclosed herein. In one embodiment, the variant VH domain and / or variant VL domain has from 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid changes from a VHand / or VLdomain of a MICA / B ABD described herein, including the figures and sequence listing. In exemplary embodiments, the variant VH domain and / or variant VL domain has from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid changes from a VHand / or VLdomain of one of the following MICA / B binding domain VH / VL pairs: (i) SEQ ID Nos: 244 and 248 for D94837_1E11_1 [MICA / B]_H0_D94837_1E11_1 [MICA / B]_L0, respectively, (ii) SEQ ID Nos: 252 and 256 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L1, respectively, (iii) SEQ ID Nos: 260 and 264 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L2, respectively, (iv) SEQ ID Nos: 268 and 272 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L1, respectively, (v) SEQ ID Nos: 276 and 280 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L2, respectively, (vi) SEQ ID Nos: 284 and 288 for 2E5 [MICA / B]_H0_2E5 [MICA / B]_L0, respectively, (vii) SEQ ID Nos: 292 and 296 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L1, respectively, (viii) SEQ ID Nos: 300 and 304 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L2, respectively, (ix) SEQ ID Nos: 308 and 312 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L1, respectively, (x) SEQ ID Nos: 316 and 320 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L2, respectively, (xi) SEQ ID Nos: 324 and 328 for D94852_2E12 [MICA / B]_H0_D94852_2E12 [MICA / B]_L0, respectively, (xii) SEQ ID Nos: 332 and 336 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L1, respectively, (xiii) SEQ ID Nos: 340 and 344 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L2, respectively, (xiv) SEQ ID Nos: 348 and 352 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L1, respectively, (xv) SEQ ID Nos: 356 and 360 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L2, respectively, (xvi) SEQ ID Nos: 364 and 368 for D99136_2F7 [MICA / B]_H0_D99136_2F7 [MICA / B]_L0, respectively, (xvii) SEQ ID Nos: 372 and 376 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L1, respectively, (xviii) SEQ ID Nos: 380 and 384 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L2, respectively, (xix) SEQ ID Nos: 388 and 392 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L1, respectively, (xx) SEQ ID Nos: 396 and 400 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L2, respectively, (xxi) SEQ ID Nos: 404 and 408 for D103388_1C7Attorney Docket: 51096.4019 / WO [MICA / B]_H0_D103388_1C7 [MICA / B]_L0, respectively, (xxii) SEQ ID Nos: 412 and 416 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L1, respectively, (xxiii) SEQ ID Nos: 420 and 424 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L2, respectively, (xxiv) SEQ ID Nos: 428 and 432 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L1, respectively, (xxv) SEQ ID Nos: 436 and 440 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L2, respectively, (xxvi) SEQ ID Nos: 444 and 448 for D103388_1D7 [MICA / B]_H0_D103388_1D7 [MICA / B]_L0, respectively, (xxvii) SEQ ID Nos: 452 and 456 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L1, respectively, (xxviii) SEQ ID Nos: 460 and 464 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L2, respectively, (xxix) SEQ ID Nos: 468 and 472 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L1, respectively, (xxx) SEQ ID Nos: 476 and 480 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L2, respectively, (xxxi) SEQ ID Nos: 484 and 488 for D105317_1A2 [MICA / B]_H0_D105317_1A2 [MICA / B]_L0, respectively, (xxxii) SEQ ID Nos: 492 and 496 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L1, respectively, (xxxiii) SEQ ID Nos: 500 and 504 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L2, respectively, (xxxiv) SEQ ID Nos: 508 and 512 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L1, respectively, (xxxv) SEQ ID Nos: 516 and 520 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L2, respectively, (xxxvi) SEQ ID Nos: 524 and 528 for D99136_2C11 [MICA / B]_H0_D99136_2C11 [MICA / B]_L0, respectively, (xxxvii) SEQ ID Nos: 532 and 536 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L1, respectively, (xxxviii) SEQ ID Nos: 540 and 544 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L2, respectively, (xxxix) SEQ ID Nos: 548 and 552 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L1, respectively, (xl) SEQ ID Nos: 556 and 560 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L2, respectively, (xli) SEQ ID Nos: 564 and 568 for D103388_1B11-2 [MICA / B]_H0_D103388_1B11-2 [MICA / B]_L0, respectively, (xlii) SEQ ID Nos: 572 and 576 for D105317_1B6 [MICA / B]_H0_D105317_1B6 [MICA / B]_L0, respectively, (xliii) SEQ ID Nos: 580 and 584 for D105317_1C8 [MICA / B]_H0_D105317_1C8 [MICA / B]_L0, respectively, (xliv) SEQ ID Nos: 588 and 592 for D105317_1F6 [MICA / B]_H0_D105317_1F6 [MICA / B]_L0, respectively, (xlv) SEQ ID Nos: 596 and 600 for D105317_1F7 [MICA / B]_H0_D105317_1F7 [MICA / B]_L0, respectively, (xlvi) SEQ ID Nos: 604 and 608 forAttorney Docket: 51096.4019 / WO D94837_1D3 [MICA / B]_H0_D94837_1D3 [MICA / B]_L0, respectively, (xlvii) SEQ ID Nos: 612 and 616 for D94837_1D8 [MICA / B]_H0_D94837_1D8 [MICA / B]_L0, respectively, (xlviii) SEQ ID Nos: 620 and 624 for D94837_1D9 [MICA / B]_H0_D94837_1D9 [MICA / B]_L0, respectively, (xlix) SEQ ID Nos: 628 and 632 for D94837_1E1 [MICA / B]_H0_D94837_1E1 [MICA / B]_L0, respectively, (l) SEQ ID Nos: 636 and 640 for D94852_2D4 [MICA / B]_H0_D94852_2D4 [MICA / B]_L0, respectively, (li) SEQ ID Nos: 644 and 648 for D94852_2G8 [MICA / B]_H0_D94852_2G8 [MICA / B]_L0, respectively, (lii) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, respectively, (liii) SEQ ID Nos: 660 and 664 for D94837_3B12 [MICA / B]_H0_D94837_3B12 [MICA / B]_L0, respectively, (liv) SEQ ID Nos: 668 and 672 for D99122_1H7 [MICA / B]_H0_D99122_1H7 [MICA / B]_L0, respectively, (lv) SEQ ID Nos: 676 and 680 for D99136_2E8 [MICA / B]_H0_D99136_2E8 [MICA / B]_L0, respectively, (lvi) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, respectively, (lvii) SEQ ID Nos: 684 and 688 for 3F9[MICA / B]_H0_3F9[MICA / B]_L0, respectively, (lviii) SEQ ID Nos: 692 and 696 for 6E1[MICA / B]_H0_6E1[MICA / B]_L0, respectively, (lix) SEQ ID Nos: 700 and 704 for 7C6[MICA / B]_H0_7C6[MICA / B]_L0, respectively, (lx) SEQ ID Nos: 708 and 712 for 13A9 [MICA / B]_H0_13A9 [MICA / B]_L0, respectively, or (lxi) SEQ ID Nos: 716 and 720 for 1D5 [MICA / B]_H0_1D5 [MICA / B]_L0, respectively. In some embodiments, the changes are in a VH domain depicted in Figs.16 and 17 (see, e.g., SEQ ID NOs: 244, 252, 260, 268, 276, 284, 292, 300, 308, 316, 324, 332, 340, 348, 356, 364, 372, 380, 388, 396, 404, 412, 420, 428, 436, 444, 452, 460, 468, 476, 484, 492, 500, 508, 516, 524, 532, 540, 548, 556, 564, 572, 580, 588, 596, 604, 612, 620, 628, 636, 644, 652, 660, 668, 676, 652, 684, 692, 700, 708, and 716). In some embodiments, the changes are in a VL domain depicted in Figs.16 and 17 (see, e.g., SEQ ID NOs: 248, 256, 264, 272, 280, 288, 296, 304, 312, 320, 328, 336, 344, 352, 360, 368, 376, 384, 392, 400, 408, 416, 424, 432, 440, 448, 456, 464, 472, 480, 488, 496, 504, 512, 520, 528, 536, 544, 552, 560, 568, 576, 584, 592, 600, 608, 616, 624, 632, 640, 648, 656, 664, 672, 680, 656, 688, 696, 704, 712, and 720). In some embodiments, the changes are in a VHand VLdomain depicted in Figs.16 and 17 (see, e.g., SEQ ID NOs: 244, 252, 260, 268, 276, 284, 292, 300, 308, 316, 324, 332, 340, 348, 356, 364, 372, 380, 388, 396, 404, 412, 420, 428, 436, 444, 452, 460, 468, 476, 484, 492, 500, 508, 516, 524, 532, 540, 548, 556, 564, 572, 580, 588, 596, 604, 612, 620, 628, 636, 644, 652, 660, 668, 676, 652, 684, 692, 700, 708, and 716 and 248, 256, 264, 272,Attorney Docket: 51096.4019 / WO 280, 288, 296, 304, 312, 320, 328, 336, 344, 352, 360, 368, 376, 384, 392, 400, 408, 416, 424, 432, 440, 448, 456, 464, 472, 480, 488, 496, 504, 512, 520, 528, 536, 544, 552, 560, 568, 576, 584, 592, 600, 608, 616, 624, 632, 640, 648, 656, 664, 672, 680, 656, 688, 696, 704, 712, and 720). In some embodiments, one or more amino acid changes are in the VHand / or VLframework regions (FR1, FR2, FR3, and / or FR4). In some embodiments, one or more amino acid changes are in one or more CDRs. In certain embodiments, the (variant) MICA / B ABD of the subject antibody is capable of binding to MICA, as measured by at least one of: (i) a Biacore assay, (ii) a SPR assay, (iii) a BLI assay (e.g., an Octet assay), (iv) flow cytometry, or any combination thereof. In particular embodiments, the (variant) MICA / B ABD is capable of binding a human MICA antigen (see, e.g., Fig.2; SEQ ID NOs: 12-13 and 15-17). In particular embodiments, the (variant) MICA / B ABD is capable of binding the ECD of a human MICA antigen (see, e.g., Fig. 2; SEQ ID NOs: 12-13 and 15-17). In certain embodiments, the (variant) MICA / B ABD of the subject antibody is capable of binding to MICB, as measured by at least one of: (i) a Biacore assay, (ii) a SPR assay, (iii) a BLI assay (e.g., an Octet assay), (iv) flow cytometry, or any combination thereof. In particular embodiments, the (variant) MICA / B ABD is capable of binding a human MICB antigen (see, e.g., Fig.3; SEQ ID NOs: 18-19 and 21). In particular embodiments, the (variant) MICA / B ABD is capable of binding the ECD of a human MICB antigen (see, e.g., Fig.3; SEQ ID NOs: 18-19 and 21).

[0217] In one embodiment, the variant VH and / or VL domain is at least about 90%, about 95%,about 96%, about 97%, about 98%, or about 99% identical to the VHand / or VLof a MICA / B ABD as described herein, including the figures and sequence listing. In exemplary embodiments, the variant VH and / or VL domain is at least about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to the VH and / or VL of one of the following MICA / B binding domain VH / VLpairs: (i) SEQ ID Nos: 244 and 248 for D94837_1E11_1 [MICA / B]_H0_D94837_1E11_1 [MICA / B]_L0, respectively, (ii) SEQ ID Nos: 252 and 256 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L1, respectively, (iii) SEQ ID Nos: 260 and 264 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L2, respectively, (iv) SEQ ID Nos: 268 and 272 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L1, respectively, (v) SEQ ID Nos: 276 and 280 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L2, respectively, (vi) SEQ ID Nos: 284 and 288 for 2E5 [MICA / B]_H0_2E5 [MICA / B]_L0, respectively, (vii) SEQ ID Nos:Attorney Docket: 51096.4019 / WO 292 and 296 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L1, respectively, (viii) SEQ ID Nos: 300 and 304 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L2, respectively, (ix) SEQ ID Nos: 308 and 312 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L1, respectively, (x) SEQ ID Nos: 316 and 320 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L2, respectively, (xi) SEQ ID Nos: 324 and 328 for D94852_2E12 [MICA / B]_H0_D94852_2E12 [MICA / B]_L0, respectively, (xii) SEQ ID Nos: 332 and 336 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L1, respectively, (xiii) SEQ ID Nos: 340 and 344 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L2, respectively, (xiv) SEQ ID Nos: 348 and 352 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L1, respectively, (xv) SEQ ID Nos: 356 and 360 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L2, respectively, (xvi) SEQ ID Nos: 364 and 368 for D99136_2F7 [MICA / B]_H0_D99136_2F7 [MICA / B]_L0, respectively, (xvii) SEQ ID Nos: 372 and 376 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L1, respectively, (xviii) SEQ ID Nos: 380 and 384 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L2, respectively, (xix) SEQ ID Nos: 388 and 392 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L1, respectively, (xx) SEQ ID Nos: 396 and 400 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L2, respectively, (xxi) SEQ ID Nos: 404 and 408 for D103388_1C7 [MICA / B]_H0_D103388_1C7 [MICA / B]_L0, respectively, (xxii) SEQ ID Nos: 412 and 416 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L1, respectively, (xxiii) SEQ ID Nos: 420 and 424 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L2, respectively, (xxiv) SEQ ID Nos: 428 and 432 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L1, respectively, (xxv) SEQ ID Nos: 436 and 440 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L2, respectively, (xxvi) SEQ ID Nos: 444 and 448 for D103388_1D7 [MICA / B]_H0_D103388_1D7 [MICA / B]_L0, respectively, (xxvii) SEQ ID Nos: 452 and 456 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L1, respectively, (xxviii) SEQ ID Nos: 460 and 464 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L2, respectively, (xxix) SEQ ID Nos: 468 and 472 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L1, respectively, (xxx) SEQ ID Nos: 476 and 480 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L2, respectively, (xxxi) SEQ ID Nos: 484 and 488 for D105317_1A2 [MICA / B]_H0_D105317_1A2 [MICA / B]_L0, respectively, (xxxii) SEQ ID Nos: 492 and 496 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L1, respectively, (xxxiii) SEQ ID Nos: 500 and 504 for D105317_1A2Attorney Docket: 51096.4019 / WO [MICA / B]_H1_D105317_1A2 [MICA / B]_L2, respectively, (xxxiv) SEQ ID Nos: 508 and 512 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L1, respectively, (xxxv) SEQ ID Nos: 516 and 520 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L2, respectively, (xxxvi) SEQ ID Nos: 524 and 528 for D99136_2C11 [MICA / B]_H0_D99136_2C11 [MICA / B]_L0, respectively, (xxxvii) SEQ ID Nos: 532 and 536 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L1, respectively, (xxxviii) SEQ ID Nos: 540 and 544 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L2, respectively, (xxxix) SEQ ID Nos: 548 and 552 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L1, respectively, (xl) SEQ ID Nos: 556 and 560 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L2, respectively, (xli) SEQ ID Nos: 564 and 568 for D103388_1B11-2 [MICA / B]_H0_D103388_1B11-2 [MICA / B]_L0, respectively, (xlii) SEQ ID Nos: 572 and 576 for D105317_1B6 [MICA / B]_H0_D105317_1B6 [MICA / B]_L0, respectively, (xliii) SEQ ID Nos: 580 and 584 for D105317_1C8 [MICA / B]_H0_D105317_1C8 [MICA / B]_L0, respectively, (xliv) SEQ ID Nos: 588 and 592 for D105317_1F6 [MICA / B]_H0_D105317_1F6 [MICA / B]_L0, respectively, (xlv) SEQ ID Nos: 596 and 600 for D105317_1F7 [MICA / B]_H0_D105317_1F7 [MICA / B]_L0, respectively, (xlvi) SEQ ID Nos: 604 and 608 for D94837_1D3 [MICA / B]_H0_D94837_1D3 [MICA / B]_L0, respectively, (xlvii) SEQ ID Nos: 612 and 616 for D94837_1D8 [MICA / B]_H0_D94837_1D8 [MICA / B]_L0, respectively, (xlviii) SEQ ID Nos: 620 and 624 for D94837_1D9 [MICA / B]_H0_D94837_1D9 [MICA / B]_L0, respectively, (xlix) SEQ ID Nos: 628 and 632 for D94837_1E1 [MICA / B]_H0_D94837_1E1 [MICA / B]_L0, respectively, (l) SEQ ID Nos: 636 and 640 for D94852_2D4 [MICA / B]_H0_D94852_2D4 [MICA / B]_L0, respectively, (li) SEQ ID Nos: 644 and 648 for D94852_2G8 [MICA / B]_H0_D94852_2G8 [MICA / B]_L0, respectively, (lii) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, respectively, (liii) SEQ ID Nos: 660 and 664 for D94837_3B12 [MICA / B]_H0_D94837_3B12 [MICA / B]_L0, respectively, (liv) SEQ ID Nos: 668 and 672 for D99122_1H7 [MICA / B]_H0_D99122_1H7 [MICA / B]_L0, respectively, (lv) SEQ ID Nos: 676 and 680 for D99136_2E8 [MICA / B]_H0_D99136_2E8 [MICA / B]_L0, respectively, (lvi) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, respectively, (lvii) SEQ ID Nos: 684 and 688 for 3F9[MICA / B]_H0_3F9[MICA / B]_L0, respectively, (lviii) SEQ ID Nos: 692 and 696 for 6E1[MICA / B]_H0_6E1[MICA / B]_L0, respectively, (lix) SEQ ID Nos: 700 and 704 forAttorney Docket: 51096.4019 / WO 7C6[MICA / B]_H0_7C6[MICA / B]_L0, respectively, (lx) SEQ ID Nos: 708 and 712 for 13A9 [MICA / B]_H0_13A9 [MICA / B]_L0, respectively, or (lxi) SEQ ID Nos: 716 and 720 for 1D5 [MICA / B]_H0_1D5 [MICA / B]_L0, respectively. In some embodiments, the (variant) MICA / B ABD includes a VHthat is at least about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to a VH domain depicted in Figs.16 and 17 (see, e.g., SEQ ID NOs: 244, 252, 260, 268, 276, 284, 292, 300, 308, 316, 324, 332, 340, 348, 356, 364, 372, 380, 388, 396, 404, 412, 420, 428, 436, 444, 452, 460, 468, 476, 484, 492, 500, 508, 516, 524, 532, 540, 548, 556, 564, 572, 580, 588, 596, 604, 612, 620, 628, 636, 644, 652, 660, 668, 676, 652, 684, 692, 700, 708, and 716). In some embodiments, the (variant) MICA / B ABD includes a VL that is at least about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to a VLdomain depicted in Figs.16 and 17 (see, e.g., SEQ ID NOs: 248, 256, 264, 272, 280, 288, 296, 304, 312, 320, 328, 336, 344, 352, 360, 368, 376, 384, 392, 400, 408, 416, 424, 432, 440, 448, 456, 464, 472, 480, 488, 496, 504, 512, 520, 528, 536, 544, 552, 560, 568, 576, 584, 592, 600, 608, 616, 624, 632, 640, 648, 656, 664, 672, 680, 656, 688, 696, 704, 712, and 720). In some embodiments, the (variant) MICA / B ABD include a VH and / or a VL that is at least about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% identical to a VH domain and / or a VLdomain depicted in Figs.16 and 17 (see, e.g., SEQ ID NOs: 244, 252, 260, 268, 276, 284, 292, 300, 308, 316, 324, 332, 340, 348, 356, 364, 372, 380, 388, 396, 404, 412, 420, 428, 436, 444, 452, 460, 468, 476, 484, 492, 500, 508, 516, 524, 532, 540, 548, 556, 564, 572, 580, 588, 596, 604, 612, 620, 628, 636, 644, 652, 660, 668, 676, 652, 684, 692, 700, 708, and 716-248, 256, 264, 272, 280, 288, 296, 304, 312, 320, 328, 336, 344, 352, 360, 368, 376, 384, 392, 400, 408, 416, 424, 432, 440, 448, 456, 464, 472, 480, 488, 496, 504, 512, 520, 528, 536, 544, 552, 560, 568, 576, 584, 592, 600, 608, 616, 624, 632, 640, 648, 656, 664, 672, 680, 656, 688, 696, 704, 712, and 720). In certain embodiments, the (variant) MICA / B ABD of the subject antibody is capable of binding to MICA as measured by at least one of: (i) a Biacore assay, (ii) a SPR assay, (iii) a BLI assay (e.g., an Octet assay), (iv) flow cytometry, or any combination thereof. In particular embodiments, the (variant) MICA / B ABD is capable of binding a human MICA antigen (see, e.g., Fig.2; SEQ ID NOs: 12-13 and 15-17). In particular embodiments, the (variant) MICA / B ABD is capable of binding the ECD of a human MICA antigen (see, e.g., Fig. 2; SEQ ID NOs: 12-13 and 15-17). In certain embodiments, the (variant) MICA / B ABD of the subject antibody is capable of binding to MICB as measured by at least one of: (i) a BiacoreAttorney Docket: 51096.4019 / WO assay, (ii) a SPR assay, (iii) a BLI assay (e.g., an Octet assay), (iv) flow cytometry, or any combination thereof. In particular embodiments, the (variant) MICA / B ABD is capable of binding a human MICB antigen (see, e.g., Fig.3; SEQ ID NOs: 18-19 and 21). In particular embodiments, the (variant) MICA / B ABD is capable of binding the ECD of a human MICB antigen (see, e.g., Fig.3; SEQ ID NOs: 18-19 and 21). B. CD3 Antigen Binding Domains

[0218] The heterodimeric bispecific antibodies of the present disclosure (e.g., anti-MICA / B ×anti-CD3 antibodies) also include an ABD that binds to human epsilon CD3 (CD3ε).

[0219] Suitable sets of 6 CDRs and / or VH and VL domains, as well as scFv sequences, aredepicted in Fig.15. CD3 binding domain sequences that are of particular use include, but are not limited to, anti-CD3 H1.30_L1.47, anti-CD3 H1.32_L1.47, anti-CD3 H1.89_L1.47, anti-CD3 H1.90_L1.47, anti-CD3 H1.33_L1.47, anti-CD3 H1.31_L1.47, anti- CD3 L1.47_H1.30, anti- CD3 L1.47_H1.32, anti-CD3 L1.47_H1.89, anti-CD3 L1.47_H1.90, anti-CD3 L1.47_H1.33, and anti-CD3 L1.47_H1.31 as depicted in Fig.15. In some embodiments, the anti-CD3 ABD is a scFv domain, the VH and VL domains can be in either orientation.

[0220] As will be appreciated by those in the art, suitable CD3 binding domains can comprise aset of 6 CDRs as depicted in Fig.15, either as they are underlined or, in the case where a different numbering scheme is used as described herein and as shown in Table 2, as the CDRs that are identified using other alignments within the VH and VL sequences of those depicted in Figs.15A-15F. Suitable ABDs can also include the entire VH and VL sequences as depicted in these sequences and Figures, used as scFvs or as Fabs. In many of the embodiments herein that contain an Fv to CD3, it is the scFv monomer that binds CD3.

[0221] In addition to the parental CDR sets disclosed in the figures and sequence listing thatform an ABD to CD3, provided herein are variant CD3 ABDS having CDRs that include at least one modification of the CD3 ABD CDRs disclosed herein (e.g., Figs.15A-15F and the sequence listing). In one embodiment, the CD3 ABD of the subject heterodimeric antibody (e.g., anti- MICA / B × anti-CD3 antibody) includes a set of 6 CDRs with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid modifications as compared to the 6 CDRs of a CD3 ABD as described herein, including the figures and sequence listing. In exemplary embodiments, the CD3 ABD of the subjectAttorney Docket: 51096.4019 / WO heterodimeric antibody includes a set of 6 CDRs with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid modifications as compared to the 6 CDRs of one of the following CD3 binding domains: anti- CD3 H1.30_L1.47, anti-CD3 H1.32_L1.47, anti-CD3 H1.89_L1.47, anti-CD3 H1.90_L1.47, anti-CD3 H1.33_L1.47, anti-CD3 H1.31_L1.47, anti-CD3 L1.47_H1.30, anti-CD3 L1.47_H1.32, anti-CD3 L1.47_H1.89, anti-CD3 L1.47_H1.90, anti-CD3 L1.47_H1.33, and anti-CD3 L1.47_H1.31 (Figs.15A-15F). In certain embodiments, the CD3 ABD of the subject antibody is capable of binding CD3 antigen, as measured by at least one of a Biacore, surface plasmon resonance (SPR), flow cytometry, and / or BLI (biolayer interferometry, e.g., Octet assay) assay, with the latter finding particular use in many embodiments. In particular embodiments, the CD3ABD is capable of binding human CD3.

[0222] In some embodiments, the CD3 ABD of the subject antibody includes 6 CDRs that are atleast 90, 95, 97, 98 or 99% identical to the 6 CDRs of a CD3 ABD as described herein, including the figures and sequence listing. In exemplary embodiments, the CD3 ABD of the subject antibody includes 6 CDRs that are at least 90, 95, 97, 98 or 99% identical to the 6 CDRs of one of the following CD3 binding domains: anti-CD3 H1.30_L1.47, anti-CD3 H1.32_L1.47, anti- CD3 H1.89_L1.47, anti-CD3 H1.90_L1.47, anti-CD3 H1.33_L1.47, anti- CD3 H1.31_L1.47, anti-CD3 L1.47_H1.30, anti-CD3 L1.47_H1.30, anti-CD3 L1.47_H1.32, anti-CD3 L1.47_H1.89, anti-CD3 L1.47_H1.90, anti-CD3 L1.47_H1.33, and anti-CD3 L1.47_H1.31 (Figs.15A-15F). In certain embodiments, the CD3 ABD is capable of binding to the CD3, as measured by at least one of a Biacore, surface plasmon resonance (SPR), flow cytometry, and / or BLI (biolayer interferometry, e.g., Octet assay) assay, with the latter finding particular use in many embodiments. In particular embodiments, the CD3 ABD is capable of binding human CD3 antigen.

[0223] In another exemplary embodiment, the CD3 ABD of the subject antibody includes thevariable heavy (VH) domain and variable light (VL) domain of any one of the CD3 binding domains described herein, including the figures and sequence listing. In an exemplary embodiment, the CD3 ABD of the subject antibody includes a first-binding subunit comprising the variable heavy (VH) domain and a second-binding subunit comprising variable light (VL) domain. In some instances, the variable heavy (VH) domain of the first-binding subunit comprises a VH complementarity determining region (HCDR)1, HCDR2, and HCDR3, and the variable light (VL) domain of the second-binding subunit comprises the VL complementarityAttorney Docket: 51096.4019 / WO determining region (LCDR)1, LCDR2, and LCDR3.

[0224] In some embodiments, the subject antibody includes a CD3 ABD that includes a variableheavy domain and / or a variable light domain that are variants of a CD3 ABD VH and VL domain disclosed herein. In one embodiment, the variant VH domain and / or VL domain has from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid changes from a VH and / or VL domain of a CD3 ABD described herein, including the figures and sequence listing. In exemplary embodiments, the variant VH domain and / or VL domain has from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid changes from a VH and / or VL domain of one of the following CD3 binding domains: anti-CD3 H1.30_L1.47, anti-CD3 H1.32_L1.47, anti-CD3 H1.89_L1.47, anti-CD3 H1.90_L1.47, anti-CD3 H1.33_L1.47, anti-CD3 H1.31_L1.47, anti-CD3 L1.47_H1.30, anti-CD3 L1.47_H1.30, anti-CD3 L1.47_H1.32, anti-CD3 L1.47_H1.89, anti- CD3 L1.47_H1.90, anti-CD3 L1.47_H1.33, and anti-CD3 L1.47_H1.31 (Figs.15A-15F). In some embodiments, the changes are in a VH domain depicted in Figs.15A-15F. In some embodiments, the changes are in a VL domain are depicted in Figs.15A-15F. In some embodiments, the changes are in a VH and VL domain are depicted in Figs.15A-15F. In some embodiments, one or more amino acid changes are in the VH and / or VL framework regions (FR1, FR2, FR3, and / or FR4). In some embodiments, one or more amino acid changes are in one or more CDRs. In certain embodiments, the CD3 ABD of the subject antibody is capable of binding to CD3, as measured at least one of a Biacore, surface plasmon resonance (SPR), flow cytometry, and / or BLI (biolayer interferometry, e.g., Octet assay) assay, with the latter finding particular use in many embodiments. In particular embodiments, the CD3 ABD is capable of binding human CD3 antigen.

[0225] In one embodiment, the variant VH and / or VL domain is at least 90, 91, 92, 93, 94, 95,96, 97, 98 or 99% identical to the VH and / or VL of a CD3 ABD as described herein, including the figures and sequence listing. In exemplary embodiments, the variant VH and / or VL domain is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to the VH and / or VL of one of the following CD3 binding domains: anti-CD3 H1.30_L1.47, anti-CD3 H1.32_L1.47, anti-CD3 H1.89_L1.47, anti-CD3 H1.90_L1.47, anti-CD3 H1.33_L1.47, anti-CD3 H1.31_L1.47, anti-CD3 L1.47_H1.30, anti -CD 3 L1.47_H1.30, anti-CD3 L1.47_H1.32, anti-CD3 L1.47_H1.89, anti- CD3 L1.47_H1.90, anti-CD3 L1.47_H1.33, and anti-CD3 L1.47_H1.31 (Figs.15A-15F). In some embodiments, the CD3 ABD includes a VH that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to VH domain depicted in Figs.15A-15F. In some embodiments, the CD3 ABDAttorney Docket: 51096.4019 / WO includes a VL that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to VL domain depicted in Figs.15A-15F. In some embodiments, the CD3 ABD includes a VH and a VL that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% identical to a VH domain and a VL domain depicted in Figs.15A-15F. In certain embodiments, the CD3 ABD is capable of binding to CD3 (see, e.g., Fig.1), as measured by at least one of a Biacore, surface plasmon resonance (SPR), flow cytometry, and / or BLI (biolayer interferometry, e.g., Octet assay) assay, with the latter finding particular use in many embodiments. In particular embodiments, the CD3 ABD is capable of binding human CD3 antigen (see, e.g., Fig.1). In particular embodiments, the CD3 ABD is capable of binding human CD3 antigen with improved characteristics compared to another means of binding CD3, such as human CD3. In some instances, the improved characteristics are relevant or essential for any one or more of the following: inhibiting or reducing CD3-mediated activity, treating a CD3-associated disease and / or a MICA / B-associated disease, and manufacturing a medicament for the treatment of a CD3-associated disease and / or a MICA / B-associated disease.

[0226] In addition to the CD3 ABDs (also referred to as anti-CD3 and αCD3 ABDs) of Figs.15A-15F, additional ABDs of use in the invention include those depicted in Figures 14 and 15 of WO2014 / 145806, hereby expressly incorporated herein in their entirety including the Figures and Legends therein.

[0227] The disclosed herein anti-CD3 antigen binding molecules can comprise a single-chainvariable fragment (scFv) comprising at least 95% sequence identity to the amino acid sequence of Figure 15A-Figure 15F. In some variation, the scFv comprises at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 124, 134, 144, 154, 164, 174, 184, 194, 204, 214, 224, or 234 as shown in Figure 15A-Figure 15F. At least 95% sequence identity includes, for example, 96%, 97%, 98%, and 99% sequence identity. In some variation, the scFv comprises the amino acid sequence of SEQ ID NO: 124, 134, 144, 154, 164, 174, 184, 194, 204, 214, 224, or 234 as shown in Figure 15A-Figure 15F. C. Linkers

[0228] As shown herein, there are a number of suitable linkers (for use as either domain linkersor scFv linkers) that can be used to covalently attach the recited domains (e.g., scFvs, Fabs, FcAttorney Docket: 51096.4019 / WO domains, etc.), including traditional peptide bonds, generated by recombinant techniques. Exemplary linkers to attach domains of the subject antibody to each other are depicted in Fig.8. In some embodiments, the linker peptide may predominantly include the following amino acid residues: Gly, Ser, Ala, or Thr. The linker peptide should have a length that is adequate to link two molecules in such a way that they assume the correct conformation relative to one another so that they retain the desired activity. In one embodiment, the linker is from about 1 to 50 amino acids in length, preferably about 1 to 30 amino acids in length. In one embodiment, linkers of 1 to 20 amino acids in length may be used, with from about 5 to about 10 amino acids finding use in some embodiments. Useful linkers include glycine-serine polymers, including for example (GS)n, (GSGGS)n (SEQ ID NO: 3), (GGGGS)n (SEQ ID NO: 2), and (GGGS)n (SEQ ID NO: 4), where n is an integer of at least one (and generally from 3 to 4), glycine-alanine polymers, alanine-serine polymers, and other flexible linkers, some of which are shown in Fig.8. Alternatively, a variety of nonproteinaceous polymers, including but not limited to polyethylene glycol (PEG), polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol, may find use as linkers.

[0229] Other linker sequences may include any sequence of any length of CL / CH1 domain butnot all residues of CL / CH1 domain; for example, the first 5-12 amino acid residues of the CL / CH1 domains. Linkers can be derived from immunoglobulin light chain, for example Cκ or Cλ. Linkers can be derived from immunoglobulin heavy chains of any isotype, including for example Cγ1, Cγ2, Cγ3, Cγ4, Cα1, Cα2, Cδ, Cε, and Cμ. Linker sequences may also be derived from other proteins such as Ig-like proteins (e.g., TCR, FcR, KIR), hinge region-derived sequences, and other natural sequences from other proteins.

[0230] ] In some embodiments, the linker is a “domain linker,” used to link any two domains asoutlined herein together. For example, in Fig.8 there may be a domain linker that attaches the C- terminus of a CH1 domain of a Fab to the N-terminus of a scFv, with another optional domain linker attaching the C-terminus of the scFv to a CH2 domain (although in many embodiments the hinge is used as this domain linker). While any suitable linker can be used, many embodiments utilize a glycine-serine polymer as the domain linker, including for example (GS)n, (GSGGS)n (SEQ ID NO: 3), (GGGGS)n (SEQ ID NO: 2), and (GGGS)n (SEQ ID NO: 4), where n is an integer of at least one (and generally from 3 to 4 to 5) as well as any peptide sequence that allows for recombinant attachment of the two domains with sufficient length and flexibility to allowAttorney Docket: 51096.4019 / WO each domain to retain its biological function. In some cases, and with attention being paid to “strandedness,” as outlined below, charged domain linkers, as used in some embodiments of scFv linkers can be used. Exemplary useful domain linkers are depicted in Fig.8.

[0231] With particular reference to the domain linker used to attach the scFv domain to the Fcdomain in the “2 + 1” format, there are several domain linkers that find particular use, including “full hinge C220S variant,” “flex half hinge,” “charged half hinge 1,” and “charged half hinge 2” as shown in Fig.8.

[0232] In some embodiments, the linker is a “scFv linker,” used to covalently attach the VH andVL domains as discussed herein. In many cases, the scFv linker is a charged scFv linker, a number of which are shown in Fig.7. Accordingly, in some embodiments, the antibodies described herein further provide charged scFv linkers, to facilitate the separation in pI between a first and a second monomer. That is, by incorporating a charged scFv linker, either positive or negative (or both, in the case of scaffolds that use scFvs on different monomers), this allows the monomer comprising the charged linker to alter the pI without making further changes in the Fc domains. These charged linkers can be substituted into any scFv containing standard linkers. Again, as will be appreciated by those in the art, charged scFv linkers are used on the correct “strand” or monomer, according to the desired changes in pI. For example, as discussed herein, to make 1 + 1 Fab-scFv-Fc format heterodimeric antibody, the original pI of the Fv region for each of the desired antigen binding domains are calculated, and one is chosen to make an scFv, and depending on the pI, either positive or negative linkers are chosen.

[0233] Charged domain linkers can also be used to increase the pI separation of the monomers ofthe antibodies described herein as well, and thus those included in Fig.8 can be used in any embodiment herein where a linker is utilized. V. Antibodies

[0234] The antibodies provided herein include different antibody domains as is more fullydescribed above. As described herein and known in the art, the antibodies include different domains within the heavy and light chains, which can be overlapping as well. These domains include, but are not limited to, the Fc domain, the CH1 domain, the CH2 domain, the CH3 domain, the hinge domain, the heavy constant domain (CH1-hinge-Fc domain or CH1-hinge-Attorney Docket: 51096.4019 / WO CH2-CH3), the variable heavy domain, the variable light domain, the light constant domain, Fab domains and scFv domains. It should be noted that the term “Fc domain” includes both the CH2- CH3 (and optionally the hinge, hinge-CH2-CH3) of a single monomer, as well as the dimer of two Fc domains that self-assemble. That is, the heavy chain of an antibody has an Fc domain that is a single polypeptide, while the assembled bispecific antibody has an Fc domain that contains two polypeptides. Various antibody domains included in the bispecific, heterodimeric antibodies are more fully described below.

[0235] In particular, the formats depicted in Figs. 18A-18N are usually referred to as“heterodimeric antibodies,” meaning that the protein has at least two associated Fc sequences self-assembled into a heterodimeric Fc domain and at least two Fv regions, whether as Fabs or as scFvs.

[0236] Described below are useful variant Fc domains that include amino acid modifications(i.e., substitutions, insertions, or deletions) to enhance FcγR-mediated cytotoxicity, increase serum half-life, and facilitate the self-assembly and / or purification of the heterodimeric antibodies provided. Also, exemplary anti-CD3 × anti-MICA / B bispecific antibodies that include such variant Fc domains are described below and set forth in the Figures and the corresponding sequences. A. Chimeric and Humanized Antibodies

[0237] In certain embodiments, the antibodies described herein comprise a heavy chain variableregion from a particular germline heavy chain immunoglobulin gene and / or a light chain variable region from a particular germline light chain immunoglobulin gene. For example, such antibodies may comprise or consist of a human antibody comprising heavy or light chain variable regions that are “the product of” or “derived from” a particular germline sequence. A human antibody that is “the product of” or “derived from” a human germline immunoglobulin sequence can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequences of human germline immunoglobulins and selecting the human germline immunoglobulin sequence that is closest in sequence (i.e., greatest % identity) to the sequence of the human antibody (using the methods outlined herein). A human antibody that is “the product of” or “derived from” a particular human germline immunoglobulin sequence mayAttorney Docket: 51096.4019 / WO contain amino acid differences as compared to the germline sequence, due to, for example, naturally-occurring somatic mutations or intentional introduction of site-directed mutation. However, a humanized antibody typically is at least 90% identical in amino acids sequence to an amino acid sequence encoded by a human germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from human sequences when compared to the germline immunoglobulin amino acid sequences of other species (e.g., murine germline sequences). In certain cases, a humanized antibody may be at least 95, 96, 97, 98 or 99%, or even at least 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by the germline immunoglobulin gene. Typically, a humanized antibody derived from a particular human germline sequence will display no more than 10-20 amino acid differences from the amino acid sequence encoded by the human germline immunoglobulin gene (prior to the introduction of any skew, pI and ablation variants herein; that is, the number of variants is generally low, prior to the introduction of the variants described herein). In certain cases, the humanized antibody may display no more than 5, or even no more than 4, 3, 2, or 1 amino acid difference from the amino acid sequence encoded by the germline immunoglobulin gene (again, prior to the introduction of any skew, pI and ablation variants herein; that is, the number of variants is generally low, prior to the introduction of the variants described herein). In some embodiments, the amino acid differences are in one or more of the 6 CDRs. In some embodiments, the amino acid differences are in a VH and / or VL framework region.

[0238] In one embodiment, the parent antibody has been affinity matured, as is known in the art.Structure-based methods may be employed for humanization and affinity maturation, for example as described in U.S. Ser. No.11 / 004,590. Selection based methods may be employed to humanize and / or affinity mature antibody variable regions, including but not limited to methods described in Wu et al., 1999, J. Mol. Biol.294:151-162; Baca et al., 1997, J. Biol. Chem. 272(16):10678-10684; Rosok et al., 1996, J. Biol. Chem.271(37): 22611-22618; Rader et al., 1998, Proc. Natl. Acad. Sci. USA 95: 8910-8915; Krauss et al., 2003, Protein Engineering 16(10):753-759, all entirely incorporated by reference. Other humanization methods may involve the grafting of only parts of the CDRs, including but not limited to methods described in U.S. Ser. No.09 / 810,510; Tan et al., 2002, J. Immunol.169:1119-1125; De Pascalis et al., 2002, J. Immunol.169:3076-3084, all entirely incorporated by reference.Attorney Docket: 51096.4019 / WO B. Fc Variants for Increasing Antibody-Dependent Cellular Cytotoxicity (ADCC)

[0239] There are a number of useful Fc substitutions that can be made to alter binding to one ormore of the FcγR receptors. Substitutions that result in increased binding (or in some cases, decreased binding) can be useful. For example, it is known that increased binding to FcγRIIIa can result in increased ADCC (antibody dependent cell-mediated cytotoxicity). In some instances, decreased binding to FcγRIIb (an inhibitory receptor) can be beneficial as well. Amino acid substitutions that find use in the present invention include those listed in U.S. Ser. No. 11 / 124,620 (particularly Figure 41), U.S. Ser. Nos.11 / 174,287, 11 / 396,495, 11 / 538,406, all of which are expressly incorporated herein by reference in their entirety and specifically for the variants disclosed therein.

[0240] In some embodiments, provided herein are bispecific antibodies containing Fc variantsthat increase antibody-dependent cellular cytotoxicity (ADCC; the cell-mediated reaction wherein nonspecific cytotoxic cells that express FcγRs recognize bound antibody on a target cell and subsequently cause lysis of the target cell) activity of the antibodies. In other words, the heterodimeric antibodies encompassed by the disclosure herein include amino acid substitutions in each or both of the Fc monomeric domains of a parental sequence, usually IgG1, that can enhance ADCC.

[0241] In some embodiments, the Fc ADCC variants (e.g., ADCC-enhanced Fc variants)comprise amino acid substitution(s) selected from the group including: E333A, K334A, S239D, S239E, I332D, I332E, S239D / I332E, S239E / I332E, S239D / I332D, S239E / I332D, S239D / A330L / I332E, S239D / A330L, A330L / I332E, F243L, F243L / R292P / Y300L / V305I / P396L, I332E / P247I / A339Q, S298A / E333A, S298A / E333A / K334A, V264I / I332E, S298A, S298A / I332E, S239Q / I332E, D265G, Y296Q, S298T, L328I / I332E, V264T, V266I, S239D / I332N, S239E / I332N, S239E / I332Q, S239N / I332E, S239Q / I332D, K326E, A330Y / I332E, V264I / A330Y / I332E, A330L / I332E, V264I / A330L / I332E, L234D, L234E, L234I, L235D, L235T, A330F, L328V / I332E, S239Q / V264I / I332E, S239E / V264I / A330Y / I332E, K274R, N276Y, S324T, K334I, K334F, L234I / L235D, L235D / S239D / A330Y / I332E, S239D / V240I / A330Y / I332E, S239D / V264T / A330Y / I332E, S239D / K326E / A330Y / I332E, S239D / K326T / A330Y / I332E, E298R, S324G, E272R, P227G, G236S, D221K, H224E, K246H, D249Y, R255Y, E258H,Attorney Docket: 51096.4019 / WO T260H, G281D, E283H, E283L, V284E, S239D / 3272I / I332E, S239D / E272Y / A330L / I332E, S239D / E272I / A330L / I332E, S239D / K274E / I332E, S239D / K326T / I332E, S239D / K326E / I332E and S239D / K274E / A330L / I332E, according to EU numbering. In some embodiments, the amino acid substitution(s) present in an Fc ADCC variants are selected from the group including: E333A, K334A, S239D, S239E, I332D, I332E, S239D / I332E, S239E / I332E, S239D / I332D, S239E / I332D, S239D / A330L / I332E, S239D / A330L, A330L / I332E, S239D / I332N, S239N / I332D, A330Y / I332E, A330L / I332E, L328V / I332E, L328T / I332E, S239Q / V264I / I332E, S239E / V264I / A330Y / I332E, L235D / S239D / A330Y / I332E, S239D / V240I / A330Y / I332E, S239D / V264T / A330Y / I332E, S239D / K326E / A330Y / I32E, S234D / K326T / A330Y / I332E, E274R, P227G, G236S, D221K, H224E, K246H, D249Y, R255Y, E258H, E258Y, T260H, E283H, E283L, V284E, S239D / 3272I / I332E, S239D / E272Y / A330L / I332E, S239D / E272I / A330L / I332E, S239D / K274E / I332E, S239D / K326T / I332E, S239D / K326E / I332E and S239D / K274E / A330L / I332E, according to EU numbering.

[0242] In some embodiments, a first Fc domain and / or a second Fc domain of the bispecificantibody provided comprise an Fc ADCC variant selected from the group including: E333A, K334A, S298A / E333A, S298A / E333A / K334A, S239D, S239E, I332D, I332E, S239D / I332E, S239E / I332E, S239D / I332D, S239E / I332D, S239D / A330L / I332E, S239D / A330L, A330L / I332E, S239D / I332N, S239N / I332D, A330Y / I332E, A330L / I332E, L328V / I332E, L328T / I332E, S239Q / V264I / I332E, S239E / V264I / A330Y / I332E, L235D / S239D / A330Y / I332E, S239D / V240I / A330Y / I332E, S239D / V264T / A330Y / I332E, S239D / K326E / A330Y / I32E, S234D / K326T / A330Y / I332E, E274R, P227G, G236S, D221K, H224E, K246H, D249Y, R255Y, E258H, E258Y, T260H, E283H, E283L, V284E, S239D / 3272I / I332E, S239D / E272Y / A330L / I332E, S239D / E272I / A330L / I332E, S239D / K274E / I332E, S239D / K326T / I332E, S239D / K326E / I332E and S239D / K274E / A330L / I332E, according to EU numbering.

[0243] In some embodiments, one or more of these variants can be included either in both of theFc monomeric domains or in only one of the Fc monomeric domains of a heterodimeric antibody. In some embodiments, an anti-CD3 × anti-MICA / B bispecific antibody described includes ADCC-enhanced variants which includes one or more amino acid modifications in a first Fc domain and / or a second Fc domain, in other words, in the Fc domain of a first monomer, in the Fc domain of a second monomer, or in the Fc domains of both monomers. In someAttorney Docket: 51096.4019 / WO instances, a first Fc domain includes an Fc ADCC variant, and a second Fc domain does not include an Fc ADCC variant, resulting in an asymmetrical distribution of Fc ADCC variants. In other instances, a first Fc domain includes an Fc ADCC variant, and a second Fc domain includes an Fc ADCC variant. In one embodiment, the Fc ADCC variant of the first and second Fc domains can be the same amino acid substitution. Also, in one embodiment, the Fc ADCC variant of the first and second Fc domains can be different amino acid substitution.

[0244] In some embodiments, the Fc ADCC variants described bind with greater affinity to theFcγRIIIa (CD16A) human receptor. In some embodiments, the Fc variants have affinity for FcγRIIIa (CD16A) that is at least 1-fold, 5-fold, 10-fold, 100-fold, 200-fold, or 300-fold greater than that of the parental Fc domain.

[0245] In some embodiments, the Fc ADCC variants described can mediate effector functionmore effectively in the presence of effector cells. In some embodiments, the Fc variants mediate ADCC that is greater than that mediated by the parental Fc domain. In certain embodiments, the Fc variants mediate ADCC that is at least 5-fold, 10-fold, 20-fold, 30-fold, 40-fold, or 50-fold greater than that mediated by the parental Fc domain.

[0246] Additional detailed descriptions of Fc variants that may enhance ADCC are provided inWO2004 / 029207, which is expressly incorporated herein by reference in its entirety and specifically for the variants disclosed therein. 1. Fc v90 Variants

[0247] In some embodiments, an Fc domain with enhanced binding to human FcγRIIIa (CD16A)and thus increased ADCC activity (“an Fc ADCC variant”) utilizes the amino acid substitutions S239D / I332E (sometimes referred to as the “v90 variants”) in the CH2 domain of one or both of the monomeric Fc domains, according to EU numbering. In some embodiments, a bispecific antibody described herein comprises the Fc v90 variants (e.g., amino acid substitutions S239D / I332E) in both Fc domains. In some embodiments, a bispecific antibody described herein comprises the Fc v90 variants in only one of the monomeric Fc domains. In some embodiments, the antibody comprises the Fc v90 variants in one of the monomeric Fc domains and lacks the Fc v90 variants in another Fc domain. In some embodiments, the antibody comprises the Fc v90 variants in an Fc domain and an amino acid substitution S239D in the CH2 domain of another Fc domain, according to EU numbering. In certain embodiments, the antibody comprises the Fc v90Attorney Docket: 51096.4019 / WO variants in an Fc domain and an amino acid substitution I332E in the CH2 domain of another Fc domain, according to EU numbering. In some embodiments, the antibody comprises the Fc v90 variants in an Fc domain and lacks an amino acid substitution selected from S239D, I332E and S239D / I332E in the CH2 domain of another Fc domain, according to EU numbering. In some embodiments, one monomeric Fc domain comprises the S239D variant and the other comprises the I332E variant. In some embodiments, one monomeric Fc domain comprises the S239D variant and the other comprises no Fc ADCC variant. In some embodiments, one monomeric Fc domain comprises the I332E variant and the other comprises no Fc ADCC variant.

[0248] As will be appreciated by those in the art, in the case of these asymmetrical Fc ADCCvariants, which monomer receives which variant(s) can be based on the “strandedness” outlined herein; that is, it may be useful to calculate the pI of different combinations and utilize the Fc ADCC variants such that the pIs of the two monomers are different to facilitate purification.

[0249] In some embodiments, monomer 1 comprises a first Fc v90 variants, and monomer 2comprises the amino acid substitution S239D or I332E. In some embodiments, monomer 1 comprises the Fc V90 variants, and monomer 2 does not comprise the amino acid substitution(s) S239D, I332E or S239D / I332E. In some embodiments, at least one of the Fc domains of the bispecific antibody comprises the Fc v90 variants. A first Fc domain may comprise the Fc v90 variants, or it may comprise a parental sequence relative to the Fc v90 variants (e.g., a wild-type Fc domain, a Fc domain with one or more amino acid modifications that improves ADCC but does not include S239D, I332E or S239D / I332E substitutions, and the like). In such instances where at least one of the Fc domains comprises a parental sequence, relative to the Fc v90 variants, for the purposes of this section, this Fc domain may be referred to as a “WT Fc domain” with respect to the S239 and I332 positions of the Fc domain. In some embodiments, the antibody described herein comprises an Fc domain having an amino acid substitution of either S239D, I332E, or S239D / I332E, and another Fc domain having an amino acid substitution of either S239D, I332E, or S239D / I332E. In some embodiments, the antibody described herein comprises an Fc domain having an amino acid substitution of either S239D, I332E, or S239D / I332E, and another Fc domain without an amino acid substitution of either S239D, I332E, or S239D / I332E.

[0250] In some embodiments, the first Fc domain and the second Fc domain contain a set ofADCC-enhanced variant substitutions (first Fc domain variant : second Fc domain variant)Attorney Docket: 51096.4019 / WO selected from the group including: S239 : I332E; S239D : S239D; S239D : WT; S239D : S239D / I332E; S239D / I332E : WT; S239D / I332E : S239D; S239D / I332E : I332E; S239D / I332E : S239D / I332E; I332E : WT; I332E : I332E; I332E : S239D; I332E : S239D / I332E; WT : S239D; WT : I332E; WT : S239D / I332E, according to EU numbering. In some embodiments, monomer 1 and monomer 2 contain a set of ADCC-enhanced variant substitutions (monomer 1 : monomer 2) selected from the group including: S239 : I332E; S239D : S239D; S239D : WT; S239D : S239D / I332E; S239D / I332E : WT; S239D / I332E : S239D; S239D / I332E : I332E; S239D / I332E : S239D / I332E; I332E : WT; I332E : I332E; I332E : S239D; I332E : S239D / I332E; WT : S239D; WT : I332E; WT : S239D / I332E, according to EU numbering.

[0251] In some embodiments, Fc domains with enhanced ADCC can further comprise one ormore additional modifications at one or more of the following positions, including, but not limited to, 236, 243, 298, 299, or 330 in the CH2 domain, according to EU numbering. In some embodiments, the Fc variant domains comprise an amino acid substitution including, but not limited to: 236A, 243L, 298A, 299T, or 330L in the CH2 domain, according to EU numbering.

[0252] In some embodiments, an ADCC-enhanced Fc variant further includes, but is not limited,an amino acid substitution at one or more positions of the CH2 domain, according to EU numbering selected from the group including: position 236, 243, 298, 299, and 330. In some embodiments, an ADCC-enhanced Fc variant includes an amino acid substitution selected from the group including: 236A, 243L, 298A, 299T, 330L, 239D / 332E, 236A / 332E, 239D / 332E / 330L, 332E / 330L, and any combination thereof in the CH2 domain, according to EU numbering. In some embodiments, the first Fc domain and / or the second Fc domain comprises an ADCC-enhanced Fc variant including, but not limited to, an amino acid substitution selected from the group including: 236A, 243L, 298A, 299T, 330L, 239D / 332E, 236A / 332E, 239D / 332E / 330L, 332E / 330L, and any combination thereof in the CH2 domain, according to EU numbering, such that the Fc ADCC variant is the same in both Fc domain. Alternatively, the Fc ADCC variant is a different variant in each of the Fc domains.

[0253] Engineered antibodies comprising such ADCC-enhanced Fc variants can also havehigher-affinity FcγRIIIa binding, thus resulting in stronger ADCC activity with NK cells. Bispecific antibodies having a variant Fc domain described herein can be useful and effective for NK cell-mediated killing of tumor cells.Attorney Docket: 51096.4019 / WO 2. Fc Variants to Increase Binding to FcγRIIIa / CD16A

[0254] There are additional Fc substitutions that find use in enhancing FcγRIIIa binding. In someembodiments, the Fc domains of the bispecific antibodies provided include one or more Fc domains having increased binding to FcγRIIIa as compared to human IgG1 produced in standard research and production cell lines. In some embodiments, the Fc variants with improved binding affinity to at least FcγRIIIa have amino acid substitution(s) selected from the group including: V264I / I332E, S298A, S298A / I332E, S298A / E333A / K334A, S239Q / I332E, D265G, Y296Q, S298T, L328I / I332E, V264T, V266I, S239D / I332N, S239E / I332N, S239E / I332Q, S239N / I332E, S239Q / I332D, K326E, A330Y / I332E, V264I / A330Y / I332E, A330L / I332E, V264I / A330L / I332E, L234D, L234E, L234I, L235D, L235T, A330F, L328V / I332E, S239Q / V264I / I332E, S239E / V264I / A330Y / I332E, K274R, N276Y, S324T, K334I, K334F, L234I / L235D, L235D / S239D / A330Y / I332E, S239D / V240I / A330Y / I332E, S239D / V264T / A330Y / I332E, S239D / K326E / A330Y / I332E, S239D / K326T / A330Y / I332E, E298R, S324G, E272R, P227G, G236S, D221K, H224E, K246H, D249Y, R255Y, E258H, T260H, G281D, E283H, E283L, V284E, S239D / 3272I / I332E, S239D / E272Y / A330L / I332E, S239D / E272I / A330L / I332E, S239D / K274E / I332E, S239D / K326T / I332E, S239D / K326E / I332E and S239D / K274E / A330L / I332E, according to EU numbering of the Fc domain. Additional Fc variants with enhanced binding affinity, specificity, and / or avidity to FcγRIIIa are disclosed the specification and Figure 41 of U.S. Pat. No.8,188,231.

[0255] The described bispecific antibodies contain such Fc variants that provide enhancedeffector function and substantial increases in affinity for FcγRIIIa. In some embodiments, the Fc variants improve binding to FcγRIIIa allotypes such as, for example, both V158 and F158 polymorphic forms of FcγRIIIa. The FcγR binding affinities of these Fc variants can be evaluated using assay recognized by those skilled in the art including, but not limited to, a Surface Plasmon Resonance (SPR) and / or a BLI binding assay (such as Biacore, Octet, or Carterra LSA). C. Fc Variants for Increasing Binding to FcRn

[0256] Provided herein are additional Fc substitutions that find use in increased binding to theFcRn receptor and increased serum half-life, as specifically disclosed in U.S. Ser. No. 12 / 341,769, hereby incorporated by reference in its entirety, including, but not limited to,Attorney Docket: 51096.4019 / WO N434S, N434A, M428L, V308F, V259I, M428L / N434S, M428L / N434A, V259I / V308F, Y436I / M428L, Y436I / N434S, Y436V / N434S, Y436V / M428L, M252Y / S254T / T256E, and V259I / V308F / M428L. Such modification may be included in one or both Fc domains of the subject antibody.

[0257] In some embodiments, additional Fc variants can increase serum half-life of a bispecificantibody compared to a parental Fc domain. In some embodiments, the Fc variants have one or more amino acid modifications (i.e., substitutions, insertions or deletions) at one or more of the following amino acid residues or positions selected from the group including: 234, 235, 238, 250, 252, 254, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 322, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424, 428, and 434, according to EU numbering of the Fc region.

[0258] In some embodiments, the Fc variants have one or more amino acid substitutions selectedfrom the group including: 234F, 235Q, 250E, 250Q, 252T, 252Y, 254T, 256E, 428L, 428F, 434S, 434A, 428L / 434S, 428L / 434A, 252Y / 254T / 256E, 234F / 235Q / 252T / 254T / 256E / 322Q, 250E / 428F, 250E / 428L, 250Q / 428F, and 250Q / 428L, according to EU numbering.

[0259] In some embodiments, antibodies described can include M428L / N434S orM428L / N434A substitutions in one or both Fc domains, which can result in longer half-life in serum. In more embodiments, a first Fc domain or a second Fc domain include M428L / N434S substitutions. In more embodiments, a first Fc domain and a second Fc domain include M428L / N434S substitutions. In certain embodiments, a first Fc domain or a second Fc domain include M428L / N434A substitutions. In certain embodiments, a first Fc domain and a second Fc domain include M428L / N434Asubstitutions. Such substitutions can result in longer half-life in serum of molecules comprising such. D. Fc Variants for Heterodimeric Antibodies

[0260] In some embodiments, the bispecific antibodies provided herein are heterodimericbispecific antibodies that include two variant Fc domain sequences. Such variant Fc domains include amino acid modifications to facilitate the self-assembly and / or purification of the heterodimeric antibodies.

[0261] An ongoing problem in antibody technologies is the desire for “bispecific” antibodies thatbind to two different antigens simultaneously, in general thus allowing the different antigens toAttorney Docket: 51096.4019 / WO be brought into proximity and resulting in new functionalities and new therapies. In general, these antibodies are made by including genes for each heavy and light chain into the host cells. This generally results in the formation of the desired heterodimer (A-B), as well as the two homodimers (A-A and B-B (not including the light chain heterodimeric issues)). However, a major obstacle in the formation of bispecific antibodies is the difficulty in biasing the formation of the desired heterodimeric antibody over the formation of the homodimers and / or purifying the heterodimeric antibody away from the homodimers.

[0262] There are a number of mechanisms that can be used to generate the subject heterodimericantibodies. In addition, as will be appreciated by those in the art, these different mechanisms can be combined to ensure high heterodimerization. Amino acid modifications that facilitate the production and purification of heterodimers are collectively referred to generally as “heterodimerization variants.” As discussed below, heterodimerization variants include “skew” variants (e.g., the “knobs and holes” and the “charge pairs” variants described below) as well as “pI variants,” which allow purification of heterodimers from homodimers. As is generally described in U.S. Pat. No.9,605,084, hereby incorporated by reference in its entirety and specifically as below for the discussion of heterodimerization variants, useful mechanisms for heterodimerization include “knobs and holes” (“KIH”) as described in U.S. Pat. No.9,605,084, “electrostatic steering” or “charge pairs” as described in U.S. Pat. No.9,605,084, pI variants as described in U.S. Pat. No.9,605,084, and general additional Fc variants as outlined in U.S. Pat. No.9,605,084 and below.

[0263] Heterodimerization variants that are useful for the formation and purification of thesubject heterodimeric antibodies away from homodimers are further discussed in detailed below.

[0264] There are a number of suitable pairs of sets of heterodimerization skew variants. Thesevariants come in “pairs” of “sets.” That is, one set of the pair is incorporated into the first monomer and the other set of the pair is incorporated into the second monomer. It should be noted that these sets do not necessarily behave as “knobs in holes” variants, with a one-to-one correspondence between a residue on one monomer and a residue on the other; that is, these pairs of sets form an interface between the two monomers that encourages heterodimer formation and discourages homodimer formation, allowing the percentage of heterodimers that spontaneously form under biological conditions to be over 90%, rather than the expected 50% (25 homodimerAttorney Docket: 51096.4019 / WO A / A:50% heterodimer A / B:25% homodimer B / B). 1. Skew Variants

[0265] In some embodiments, the heterodimeric antibody includes skew (e.g., steric) variantswhich are one or more amino acid modifications in a first Fc domain (A) and / or a second Fc domain (B) that favor the formation of Fc heterodimers (Fc dimers that include the first and the second Fc domain; (A-B) over Fc homodimers (Fc dimers that include two of the first Fc domain or two of the second Fc domain; A-A or B-B). Suitable skew variants are included in the Fig.29 of U.S. Publ. App. No.2016 / 0355608, hereby incorporated by reference in its entirety and specifically for its disclosure of skew variants, as well as in Figs.4, 9, and 10 described herein.

[0266] Thus, suitable Fc heterodimerization variant pairs that will permit the formation ofheterodimeric Fc regions are shown in the figures including Figs.4, 9, and 10. Thus, a first Fc domain has first Fc heterodimerization variants and the second Fc domain has second Fc heterodimerization variants selected from the pairs in Figs.4, 9, and 10.

[0267] One mechanism is generally referred to in the art as “knobs and holes,” referring toamino acid engineering that creates steric influences to favor heterodimeric formation and disfavor homodimeric formation can also optionally be used; this is sometimes referred to as “knobs and holes,” as described in U.S. Ser. No.61 / 596,846, Ridgway et al., Protein Engineering 9(7):617 (1996); Atwell et al., J. Mol. Biol., 270:26 (1997); U.S. Pat. No.8,216,805, all of which are hereby incorporated by reference in their entirety. The Figures identify a number of “monomer A-monomer B” pairs that rely on “knobs and holes”. In addition, as described in Merchant et al., Nature Biotech., 16:677 (1998), these “knobs and hole” mutations can be combined with disulfide bonds to skew formation to heterodimerization.

[0268] An additional mechanism that finds use in the generation of heterodimers is sometimesreferred to as “electrostatic steering” as described in Gunasekaran et al., J. Biol. Chem., 285(25):19637 (2010), hereby incorporated by reference in its entirety. This is sometimes referred to herein as “charge pairs”. In this embodiment, electrostatics are used to skew the formation towards heterodimerization. As those in the art will appreciate, these variants may also have an effect on pI, and thus on purification, and thus could in some cases also be considered pI variants. However, as these were generated to force heterodimerization and were not used as purification tools, they are classified as “steric variants”. These include, but are not limited to,Attorney Docket: 51096.4019 / WO D221E / P228E / L368E paired with D221R / P228R / K409R (e.g., these are “monomer corresponding sets”) and C220E / P228E / 368E paired with C220R / E224R / P228R / K409R.

[0269] In some embodiments, the skew variants advantageously and simultaneously favorheterodimerization based on both the “knobs and holes” mechanism as well as the “electrostatic steering” mechanism. In some embodiments, the heterodimeric antibody includes one or more sets of such heterodimerization skew variants. These variants come in “pairs” of “sets.” That is, one set of the pair is incorporated into the first monomer and the other set of the pair is incorporated into the second monomer. It should be noted that these sets do not necessarily behave as “knobs in holes” variants, with a one-to-one correspondence between a residue on one monomer and a residue on the other. That is, these pairs of sets may instead form an interface between the two monomers that encourages heterodimer formation and discourages homodimer formation, allowing the percentage of heterodimers that spontaneously form under biological conditions to be over 90%, rather than the expected 50% (25% homodimer A / A:50% heterodimer A / B:25% homodimer B / B). Exemplary heterodimerization skew variants are depicted in Fig.11. Such skew variants include, but are not limited to: S364K / E357Q:L368D / K370S; L368D / K370S:S364K; L368E / K370S:S364K; T411E / K360E / Q362E:D401K; L368D / K370S:S364K / E357L; K370S:S364K / E357Q (EU numbering). In terms of nomenclature, the pair “S364K / E357Q:L368D / K370S” means that one of the monomers has the double variant set S364K / E357Q and the other has the double variant set L368D / K370S.

[0270] In exemplary embodiments, the heterodimeric antibody includes Fc heterodimerizationvariants as sets: S364K / E357Q:L368D / K370S; L368D / K370S:S364K; L368E / K370S:S364K; T411E / K360E / Q362E:D401K; L368D / K370S:S364K / E357L; K370S:S364K / E357Q; or a T366S / L368A / Y407V:T366W (optionally including a bridging disulfide, T366S / L368A / Y407V / Y349C:T366W / S354C or T366S / L368A / Y407V / S354C:T366W / Y349C) are all skew variant amino acid substitution sets of Fc heterodimerization variants. In an exemplary embodiment, the heterodimeric antibody includes a “S364K / E357Q:L368D / K370S” amino acid substitution set. In terms of nomenclature, the pair “S364K / E357Q:L368D / K370S” means that one of the monomers includes an Fc domain that includes the amino acid substitutions S364K and E357Q and the other monomer includes an Fc domain that includes the amino acid substitutions L368D and K370S; as above, the “strandedness” of these pairs dependsAttorney Docket: 51096.4019 / WO on the starting pI.

[0271] In some embodiments, the skew variants provided herein can be optionally andindependently incorporated with any other modifications, including, but not limited to, other skew variants (see, e.g., in Fig.37 of US Publ. App. No.2012 / 0149876, herein incorporated by reference, particularly for its disclosure of skew variants), pI variants, isotypic variants, FcRn variants, ablation variants, etc. into one or both of the first and second Fc domains of the heterodimeric antibody. Further, individual modifications can also independently and optionally be included or excluded from the subject the heterodimeric antibody.

[0272] Additional monomer A and monomer B variants that can be combined with othervariants, optionally and independently in any amount, such as pI variants outlined herein or other steric variants that are shown in Fig.37 of US 2012 / 0149876, the figure and legend and SEQ ID NOS: of which are incorporated expressly by reference herein.

[0273] In some embodiments, the steric variants outlined herein can be optionally andindependently incorporated with any pI variant (or other variants such as, for example, Fc ADCC variants, FcRn variants, etc.) into one or both monomers, and can be independently and optionally included or excluded from the proteins of the antibodies described herein.

[0274] A subset of skew variants is “knobs in holes” (KIH) variants. Exemplary “knob-in-hole”variants are depicted in Fig.7 of U.S. Pat. No.8,216,805, which is incorporated herein by reference. Such “knob-in-hole” variants include, but are not limited to: an amino acid substitution at position 347, 349, 350, 351, 357, 366, 368, 370, 392, 394, 395, 397, 398, 399, 405, 407 and / or 409 of the CH3 constant domain of an IgG such as an IgG1, IgG2a, IgG2b, or IgG4 (Kabat numbering). In some embodiments, the “knob-in-hole “ variants include, but are not limited to: an amino acid substitution at Y349, L351, E357, T366, L368, K370, N390, K392, T394, D399, S400, F405, Y407, K409, R409, T411, or any combination thereof of the CH3 domain of an IgG such as an IgG1, IgG2a, IgG2b, IgG4 (EU numbering). In some embodiments, the “knob-in-hole” variants include, but are not limited to: one or more amino acid substitutions including Y349D / E, L351D / K / Y, E357K, T366A / K / Y, L368E, K370E, N390D / K / R, K392E / F / L / M / R, T394W, D399K / R / W / Y, S400D / E / K / R, F405A / I / M / S / T / V / W, Y407A / Y, K409E / D / F, R409E / D / F, and T411D / E / K / N / Q / R / W.

[0275] In some embodiments, such variants include one or more amino acid substitutionsAttorney Docket: 51096.4019 / WO including, but not limited to: Y349C, E357K, S354C, T366S, T366W, T366Y, L368A, K370E, T394S T394W, D399K, F405A, F405W, Y407A, Y407T, Y407V, R409D, T366Y / F405A, T394W / Y407T, T366W / F405W, T394S / Y407A, F405W / Y407A, and T366W / T394S (EU numbering). In some embodiments, these variants include knob:hole paired substitutions including, but not limited to: T366W:Y407V; S354C / T366W:Y349C / T366S / Y407V; Y349C / T366W:S354C / T366S / L368A / Y407V; Y349C / T366W / R409D / K370E:S354C / T366S / L368A / Y407V / D399K / E357K; R409D / K370E:D399K / E357K; T366W:T366S / L368A / Y407V; T366W / R409D / K370E:T366S / L368A / Y407V / D399K / E357K; T366W:T366S / L368A / Y407V; T366W / Y366Y:T366S / L368A / T394W / F405A / Y407V; Y349C / T366W:S354C / T366S / L368A / Y407V; Y349C / T366W / R409D / K370E:S354C / T366S / L368A / Y407V / D399K / E357K paired substitutions, according to EU numbering.

[0276] Additional exemplary “knob-in-hole” variants as described by the amino acidsubstitutions of the CH3 domains can be found in, for example, Carter et al., J. Immunol. Methods, 248(1-2):7-15 (2001), Merchant et al. Nat. Biotechnol.16(7):677-81 (1998), Ridgway et al. Protein Eng.9(7):617-2 (1996), and U.S. Patent Nos.8,216,805 and 10,287,352, the disclosures of which are herein incorporated by reference in their entireties. 2. pI (Isoelectric Point) Variants for Heterodimers

[0277] In some embodiments, the heterodimeric antibody includes purification variants thatadvantageously allow for the separation of heterodimeric antibody (e.g., anti-CD3 × anti- MICA / B bispecific antibody) from homodimeric proteins.

[0278] There are several basic mechanisms that can lead to ease of purifying heterodimericantibodies. For example, modifications to one or both of the antibody heavy chain monomers A and B such that each monomer has a different pI allows for the isoelectric purification of heterodimeric A-B antibody from monomeric A-A and B-B proteins. Alternatively, some scaffold formats, such as the “1 + 1 Fab-scFv-Fc” format and the “2 + 1 Fab2-scFv-Fc” format, also allows separation on the basis of size. As described above, it is also possible to “skew” the formation of heterodimers over homodimers using skew variants. Thus, a combination of heterodimerization skew variants and pI variants find particular use in the heterodimericAttorney Docket: 51096.4019 / WO antibodies provided herein.

[0279] Additionally, as more fully outlined below, depending on the format of the heterodimericantibody, pI variants either contained within the constant region and / or Fc domains of a monomer, and / or domain linkers can be used. In some embodiments, the heterodimeric antibody includes additional modifications for alternative functionalities that can also create pI changes, such as Fc, FcRn and KO variants.

[0280] In some embodiments, the subject heterodimeric antibodies provided herein include atleast one monomer with one or more modifications that alter the pI of the monomer (i.e., a “pI variant”). In general, as will be appreciated by those in the art, there are two general categories of pI variants: those that increase the pI of the protein (basic changes) and those that decrease the pI of the protein (acidic changes). As described herein, all combinations of these variants can be done: one monomer may be wild type, or a variant that does not display a significantly different pI from wild-type, and the other can be either more basic or more acidic. Alternatively, each monomer is changed, one to more basic and one to more acidic.

[0281] Depending on the format of the heterodimer antibody, pI variants can be either containedwithin the constant and / or Fc domains of a monomer, or charged linkers, either domain linkers or scFv linkers, can be used. That is, antibody formats that utilize scFv(s) such as “1 + 1 Fab-scFv- Fc,” format can include charged scFv linkers (either positive or negative), that give a further pI boost for purification purposes. As will be appreciated by those in the art, some 1 + 1 Fab-scFv- Fc formats are useful with just charged scFv linkers and no additional pI adjustments, although the antibodies described herein do provide pI variants that are on one or both of the monomers, and / or charged domain linkers as well. In addition, additional amino acid engineering for alternative functionalities may also confer pI changes, such as Fc, FcRn and KO variants.

[0282] In subject heterodimeric antibodies for which pI is used as a separation mechanism toallow the purification of heterodimeric proteins, amino acid variants are introduced into one or both of the monomer polypeptides. That is, the pI of one of the monomers (referred to herein for simplicity as “monomer A”) can be engineered away from monomer B, or both monomer A and B can be changed, with the pI of monomer A increasing and the pI of monomer B decreasing. As is outlined more fully below, the pI changes of either or both monomers can be done by removing or adding a charged residue (e.g., a neutral amino acid is replaced by a positively orAttorney Docket: 51096.4019 / WO negatively charged amino acid residue, e.g., glycine to glutamic acid), changing a charged residue from positive or negative to the opposite charge (e.g., aspartic acid to lysine) or changing a charged residue to a neutral residue (e.g., loss of a charge; lysine to serine). A number of these variants are shown in the Figs.4, 5, and 10.

[0283] Thus, in some embodiments, the subject heterodimeric antibody includes amino acidmodifications in the constant regions that alter the isoelectric point (pI) of at least one, if not both, of the monomers of a dimeric protein to form “pI antibodies”) by incorporating amino acid substitutions (“pI variants” or “pI substitutions”) into one or both of the monomers. As shown herein, the separation of the heterodimers from the two homodimers can be accomplished if the pIs of the two monomers differ by as little as 0.1 pH unit, with 0.2, 0.3, 0.4 and 0.5 or greater all finding use in the antibodies described herein.

[0284] As will be appreciated by those in the art, the number of pI variants to be included oneach or both monomer(s) to achieve good separation will depend in part on the starting pI of the components, for example in the 1 + 1 Fab-scFv-Fc and 2 + 1 Fab2-scFv-Fc formats, the starting pI of the scFv and Fab(s) of interest. That is, to determine which monomer to engineer or in which “direction” (e.g., more positive, or more negative), the Fv sequences of the two target antigens are calculated and a decision is made from there. As is known in the art, different Fvs will have different starting pIs which are exploited in the antibodies described herein. In general, as outlined herein, the pIs are engineered to result in a total pI difference of each monomer of at least about 0.1 logs, with 0.2 to 0.5 being preferred as outlined herein.

[0285] In the case where pI variants are used to achieve heterodimerization, by using theconstant region(s) of the heavy chain(s), a more modular approach to designing and purifying bispecific proteins, including antibodies, is provided. Thus, in some embodiments, heterodimerization variants (including skew and pI heterodimerization variants) are not included in the variable regions, such that each individual antibody must be engineered. In addition, in some embodiments, the possibility of immunogenicity resulting from the pI variants is significantly reduced by importing pI variants from different IgG isotypes such that pI is changed without introducing significant immunogenicity. Thus, an additional problem to be solved is the elucidation of low pI constant domains with high human sequence content, e.g., the minimization or avoidance of non-human residues at any particular position. Alternatively, or in addition toAttorney Docket: 51096.4019 / WO isotypic substitutions, the possibility of immunogenicity resulting from the pI variants is significantly reduced by utilizing isosteric substitutions (e.g., Asn to Asp; and Gln to Glu).

[0286] As discussed below, a side benefit that can occur with this pI engineering is also theextension of serum half-life and increased FcRn binding. That is, as described in US Publ. App. No. US 2012 / 0028304 (incorporated by reference in its entirety), lowering the pI of antibody constant domains (including those found in antibodies and Fc fusions) can lead to longer serum retention in vivo. These pI variants for increased serum half-life also facilitate pI changes for purification.

[0287] In addition, it should be noted that the pI variants give an additional benefit for theanalytics and quality control process of bispecific antibodies, as the ability to either eliminate, minimize, and distinguish when homodimers are present is significant. Similarly, the ability to reliably test the reproducibility of the heterodimeric antibody production is important.

[0288] In general, embodiments of particular use rely on sets of variants that include skewvariants, which encourage heterodimerization formation over homodimerization formation, coupled with pI variants, which increase the pI difference between the two monomers to facilitate purification of heterodimers away from homodimers.

[0289] Exemplary combinations of pI variants are shown in Figs. 4 and 5, and Fig. 30 of U.S.Publ. App. No.2016 / 0355608, all of which are herein incorporated by reference in its entirety and specifically for the disclosure of pI variants. Preferred combinations of pI variants are shown in Figs.4, 5, and 10. As outlined herein and shown in the figures, these changes are shown relative to IgG1, but all isotypes can be altered this way, as well as isotype hybrids. In the case where the heavy chain constant domain is from IgG2-4, R133E and R133Q can also be used.

[0290] In one embodiment, a preferred combination of pI variants has one monomer (thenegative Fab side) comprising 208D / 295E / 384D / 418E / 421D variants (N208D / Q295E / N384D / Q418E / N421D when relative to human IgG1) and a second monomer (the positive scFv side) comprising a positively charged scFv linker, including (GKPGS)4 (SEQ ID NO: 1). However, as will be appreciated by those in the art, the first monomer includes a CH1 domain, including position 208. Accordingly, in constructs that do not include a CH1 domain (for example for fusion proteins that do not utilize a CH1 domain on one of the domains), a preferred negative pI variant Fc set includes 295E / 384D / 418E / 421D variantsAttorney Docket: 51096.4019 / WO (Q295E / N384D / Q418E / N421D when relative to human IgG1).

[0291] Accordingly, in some embodiments, one monomer has a set of substitutions from Fig. 4and the other monomer has a charged linker (either in the form of a charged scFv linker because that monomer comprises an scFv or a charged domain linker, as the format dictates, which can be selected from those depicted in Figs.8 and 9.

[0292] In some embodiments, modifications are made in the hinge of the Fc domain, includingpositions 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, and 230 based on EU numbering. Thus, pI mutations and particularly substitutions can be made in one or more of positions 216-230, with 1, 2, 3, 4 or 5 mutations finding use. Again, all possible combinations are contemplated, alone or with other pI variants in other domains.

[0293] Specific substitutions that find use in lowering the pI of hinge domains include, but arenot limited to, a deletion at position 221, a non-native valine or threonine at position 222, a deletion at position 223, a non-native glutamic acid at position 224, a deletion at position 225, a deletion at position 235 and a deletion or a non-native alanine at position 236. In some cases, only pI substitutions are done in the hinge domain, and in others, these substitution(s) are added to other pI variants in other domains in any combination.

[0294] In some embodiments, mutations can be made in the CH2 region, including positions233, 234, 235, 236, 274, 296, 300, 309, 320, 322, 326, 327, 334 and 339, based on EU numbering. It should be noted that changes in 233-236 can be made to increase effector function (along with 327A) in the IgG2 backbone. Again, all possible combinations of these 14 positions can be made; e.g., may include a variant Fc domain with 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 CH2 pI substitutions.

[0295] Specific substitutions that find use in lowering the pI of CH2 domains include, but are notlimited to, a non-native glutamine or glutamic acid at position 274, a non-native phenylalanine at position 296, a non-native phenylalanine at position 300, a non-native valine at position 309, a non-native glutamic acid at position 320, a non-native glutamic acid at position 322, a non-native glutamic acid at position 326, a non-native glycine at position 327, a non-native glutamic acid at position 334, a non-native threonine at position 339, and all possible combinations within CH2 and with other domains.Attorney Docket: 51096.4019 / WO

[0296] In this embodiment, the modifications can be independently and optionally selected fromposition 355, 359, 362, 384, 389, 392, 397, 418, 419, 444 and 447 (EU numbering) of the CH3 region. Specific substitutions that find use in lowering the pI of CH3 domains include, but are not limited to, a non-native glutamine or glutamic acid at position 355, a non-native serine at position 384, a non-native asparagine or glutamic acid at position 392, a non-native methionine at position 397, a non-native glutamic acid at position 419, a non-native glutamic acid at position 359, a non-native glutamic acid at position 362, a non-native glutamic acid at position 389, a non-native glutamic acid at position 418, a non-native glutamic acid at position 444, and a deletion or non-native aspartic acid at position 447.

[0297] In general, as will be appreciated by those in the art, there are two general categories ofpI variants: those that increase the pI of the protein (basic changes) and those that decrease the pI of the protein (acidic changes). As described herein, all combinations of these variants can be done: one monomer may be wild type, or a variant that does not display a significantly different pI from wild-type, and the other can be either more basic or more acidic. Alternatively, each monomer is changed, one to more basic and one to more acidic.

[0298] Preferred combinations of pI variants are shown in Fig. 5. As outlined herein and shownin the figures, these changes are shown relative to IgG1, but all isotypes can be altered this way, as well as isotype hybrids. In the case where the heavy chain constant domain is from IgG2 or IgG4, R133E and R133Q can also be used.

[0299] In one embodiment of the formats, a preferred combination of pI variants has onemonomer (the negative Fab side) comprising 208D / 295E / 384D / 418E / 421D variants (N208D / Q295E / N384D / Q418E / N421D when relative to human IgG1) and a second monomer (the positive scFv side) comprising a positively charged scFv linker, including (GKPGS)4 (SEQ ID NO: 1). However, as will be appreciated by those in the art, the first monomer includes a CH1 domain, including position 208. Accordingly, in constructs that do not include a CH1 domain (for example for antibodies that do not utilize a CH1 domain on one of the domains, for example in a dual scFv format or a “one-armed” format), a preferred negative pI variant Fc set includes 295E / 384D / 418E / 421D variants (Q295E / N384D / Q418E / N421D when relative to human IgG1).

[0300] Accordingly, in some embodiments, one monomer has a set of substitutions from thefigures and the other monomer has a charged linker (either in the form of a charged scFv linkerAttorney Docket: 51096.4019 / WO because that monomer comprises an scFv or a charged domain linker, as the format dictates, which can be selected from those depicted in Figs.7 and 8. 3. Isotypic Variants:

[0301] In addition, many embodiments of the antibodies described herein rely on the“importation” of pI amino acids at particular positions from one IgG isotype into another, thus reducing or eliminating the possibility of unwanted immunogenicity being introduced into the variants. A number of these are shown in Fig.21 of U.S. Publ. App. No.2014 / 0370013, hereby incorporated by reference. That is, IgG1 is a common isotype for therapeutic antibodies for a variety of reasons, including high effector function. However, the heavy constant region of IgG1 has a higher pI than that of IgG2 (8.10 versus 7.31). By introducing IgG2 residues at particular positions into the IgG1 backbone, the pI of the resulting monomer is lowered (or increased) and additionally exhibits longer serum half-life. For example, IgG1 has a glycine (pI 5.97) at position 137, and IgG2 has a glutamic acid (pI 3.22); importing the glutamic acid will affect the pI of the resulting protein. As is described below, a number of amino acid substitutions are generally required to significant affect the pI of the variant antibody. However, it should be noted as discussed below that even changes in IgG2 molecules allow for increased serum half-life.

[0302] In other embodiments, non-isotypic amino acid changes are made, either to reduce theoverall charge state of the resulting protein (e.g., by changing a higher pI amino acid to a lower pI amino acid), or to allow accommodations in structure for stability, etc. as is further described below.

[0303] In addition, by pI engineering both the heavy and light constant domains, significantchanges in each monomer of the heterodimer can be seen. As discussed herein, having the pIs of the two monomers differ by at least 0.5 can allow separation by ion exchange chromatography or isoelectric focusing, or other methods sensitive to isoelectric point. 4. Calculating pI:

[0304] The pI of each monomer can depend on the pI of the variant heavy chain constant domainand the pI of the total monomer, including the variant heavy chain constant domain and the fusion partner. Thus, in some embodiments, the change in pI is calculated on the basis of the variant heavy chain constant domain, using the chart in the Fig.19 of U.S. Publ. App. No.Attorney Docket: 51096.4019 / WO 2014 / 0370013. As discussed herein, which monomer to engineer is generally decided by the inherent pI of the Fv and scaffold regions. Alternatively, the pI of each monomer can be compared. 5. pI Variants that also Confer Better FcRn In Vivo Binding

[0305] In the case where the pI variant decreases the pI of the monomer, they can have the addedbenefit of improving serum retention in vivo.

[0306] Although still under examination, Fc regions are believed to have longer half-lives invivo, because binding to FcRn at pH 6 in an endosome sequesters the Fc (Ghetie and Ward, 1997, Immunol Today, 18(12): 592-598, entirely incorporated by reference). The endosomal compartment then recycles the Fc to the cell surface. Once the compartment opens to the extracellular space, the higher pH 7.4, induces the release of Fc back into the blood. In mice, Dall'Acqua et al. showed that Fc mutants with increased FcRn binding at pH 6 and pH 7.4 actually had reduced serum concentrations and the same half-life as wild-type Fc (Dall'Acqua et al., 2002, J. Immunol.169:5171-5180, entirely incorporated by reference). The increased affinity of Fc for FcRn at pH 7.4 is thought to forbid the release of the Fc back into the blood. Therefore, the Fc mutations that will increase Fc's half-life in vivo will ideally increase FcRn binding at the lower pH while still allowing release of Fc at higher pH. The amino acid histidine changes its charge state in the pH range of 6.0 to 7.4. Therefore, it is not surprising to find His residues at important positions in the Fc / FcRn complex.

[0307] Recently it has been suggested that antibodies with variable regions that have lowerisoelectric points may also have longer serum half-lives (Igawa et al., 2010, PEDS, 23(5): 385- 392, entirely incorporated by reference). However, the mechanism of this is still poorly understood. Moreover, variable regions differ from antibody to antibody. Constant region variants with reduced pI and extended half-life would provide a more modular approach to improving the pharmacokinetic properties of antibodies, as described herein. 6. Additional Fc Variants for Additional Functionality

[0308] In addition to the heterodimerization variants discussed above, there are a number ofuseful Fc amino acid modification that can be made for a variety of reasons, including, but not limited to, altering binding to one or more FcγR receptors, altered binding to FcRn receptors,Attorney Docket: 51096.4019 / WO etc., as discussed herein.

[0309] Accordingly, the antibodies provided herein (heterodimeric, as well as homodimeric) caninclude such amino acid modifications with or without the heterodimerization variants outlined herein (e.g., the pI variants and steric variants). Each set of variants can be independently and optionally included or excluded from any particular heterodimeric protein. 7. Additional Heterodimerization Variants

[0310] In some embodiments, the first Fc domain comprises one or more amino acidsubstitutions selected from the group including: L351Y, D399R, D399K, S400D, S400E, S400R, S400K, F405A, F405I, F405M, F405T, F405S, F405V, F405W, Y407A, Y407I, Y407L, Y407V, and any combination thereof, and the second Fc domain comprises one or more amino acid substitutions selected from the group including: T350V, T366A, T366I, T366L, T366M, T366Y, T366S, T366C, T366V, T366W, N390D, N390E, N390R, K392L, K392M, K392I, K392D, K392E, T394W, K409F, K409W, T411N, T411R, T411Q, T411K, T411D, T411E, T411W, and any combination thereof.

[0311] In some embodiments, other heterodimerization pair variants include, but are not limitedto, amino acid substitutions of L234A / L235A: wildtype; L234A / L235A : L234K / L235K; L234D / L235E : L234K / L235K; E233A / L234D / L235E : E233A / L234R / L235R; L234D / L235E : E233K / L234R / L235R; E233A / L234K / L235A : E233K / L234A / L235K; E269Q / D270N: E269K / D270R; and WT : L235K / A327K of the CH2 domain, according to the EU numbering.

[0312] In some embodiments, the first and / or second Fc domains comprise one or more aminoacid substitutions selected from the group including: S239D, D265S, S267D, E269K, S298A, K326E, A330L and I332E. In certain instances, the Fc paired variants include, but are not limited to, S239D / D265S / I332E / E269K : S239D / D265S / S298A; S239D / K326E / A330L / I332E : S298A or S239D / K326E / A330L / I332E / E269K : S298A of the CH2 domain, according to EU numbering.

[0313] Additional descriptions of useful heterodimeric variants are disclosed in U.S. Patent Nos.9,732,155; 10,457,742 and 10,875,931 and U.S. Publ. App. Nos.2021 / 0277150 and 2020 / 0087414, the disclosures of which, including the description of Fc domain variants are herein incorporated by reference in their entireties.Attorney Docket: 51096.4019 / WO E. Ablation Variants

[0314] While in general NK engager multispecific antibodies retain at binding to CD16A(including “wild type” binding or increased binding to CD16A as outlined above), in some cases, surprisingly, NK engager activity can be seen even when binding to CD16A has been reduced or ablated. Accordingly, provided is another category of functional Fc variants to include are “FcγR ablation variants” or “Fc knock out (FcKO or KO)” variants. In these embodiments, it is desirable to reduce or remove the normal binding of the Fc domain to one or more or all of the Fcγ receptors (e.g., FcγR1, FcγRIIa, FcγRIIb, FcγRIIIa, etc.) to avoid additional mechanisms of action. That is, for example, in many embodiments, particularly in the use of bispecific antibodies that bind a target antigen monovalently it is generally desirable to ablate FcγRIIIa binding to eliminate or significantly reduce ADCC activity. Wherein one of the Fc domains comprises one or more Fcγ receptor ablation variants. These ablation variants are depicted in Fig. 6, and each can be independently and optionally included or excluded, with preferred aspects utilizing ablation variants selected from the group including G236R / L328R, E233P / L234V / L235A / G236del / S239K, E233P / L234V / L235A / G236del / S267K, E233P / L234V / L235A / G236del / S239K / A327G, E233P / L234V / L235A / G236del / S267K / A327G and E233P / L234V / L235A / G236del. It should be noted that the ablation variants referenced herein ablate FcγR binding but generally not FcRn binding.

[0315] As is known in the art, the Fc domain of human IgG1 has the highest binding to the Fcγreceptors, and thus ablation variants can be used when the constant domain (or Fc domain) in the backbone of the heterodimeric antibody is IgG1. Alternatively, or in addition to ablation variants in an IgG1 background, mutations at the glycosylation position 297 (generally to A or S) can significantly ablate binding to FcγRIIIa, for example. Human IgG2 and IgG4 have naturally reduced binding to the Fcγ receptors, and thus those backbones can be used with or without the ablation variants. F. Combination of Heterodimeric and Fc Variants

[0316] As will be appreciated by those in the art, all of the recited heterodimerization variants(including skew and / or pI variants) can be optionally and independently combined in any way, as long as they retain their “strandedness” or “monomer partition.” In addition, all of these variantsAttorney Docket: 51096.4019 / WO can be combined into any of the heterodimerization formats.

[0317] In the case of pI variants, while embodiments finding particular use are shown in theFigures, other combinations can be generated, following the basic rule of altering the pI difference between two monomers to facilitate purification.

[0318] In addition, any of the heterodimerization variants, skew, and pI, are also independentlyand optionally combined with Fc ADCC variants, Fc variants, FcRn variants, or Fc ablation variants, as generally outlined herein.

[0319] Exemplary combination of variants that are included in some embodiments of theheterodimeric 1 + 1 Fab × scFv, 1 + 1 empty × Fab-scFv, 2 + 1 Fab × Fab-scFv, 2 + 1 Fab2 × scFv, and 2 + 1 mAb-scFv format antibodies are included in Fig.18. In certain embodiments, the antibody is a heterodimeric 1 + 1 Fab × scFv, 1 + 1 empty × Fab-scFv, 2 + 1 Fab × Fab-scFv, 2 + 1 Fab2 × scFv, and 2 + 1 mAb-scFv formats format antibody as shown in Fig.18.

[0320] Accordingly, the antibodies provided herein (heterodimeric, as well as homodimeric) caninclude such amino acid modifications with or without the heterodimerization variants outlined herein (e.g., the pI variants and steric variants). Each set of variants can be independently and optionally included or excluded from any particular heterodimeric protein. G. Afucosylated Fc Domains

[0321] In some embodiments, the increased binding of a Fc domain to CD16A is the result ofproducing the NKE in a cell line that reduces or eliminates the incorporation of fucose into the glycosylation of the NKE. See, for example, Pereira et al., MAbs (2018) 10(5):693-711.

[0322] In some embodiments, antibodies comprising Fc domains described are produced in ahost cell such that the Fc domains have reduced fucosylation or no fucosylation compared to a parental Fc domain. In some instances, antibodies described are produced in a genetically modified host cell, wherein the genetic modification to the host cell results in the overexpression of β(1,4)-N-acetylglucosaminyltransferase III (GnTIII), a glycosyltransferase catalyzing the formation of bisected oligosaccharides, which are generally also non-fucosylated. N- glycosylation of the Fc domain can play a role in binding to FcγR; and afucosylation of the N- glycan can increase the binding capacity of the Fc domain to FcγRIIIa. As discussed in further detail above, an increase in FcγRIIIa binding can enhance ADCC, which can be advantageous inAttorney Docket: 51096.4019 / WO certain antibody therapeutic applications in which cytotoxicity is desirable.

[0323] In some embodiments, an Fc domain is engineered such that it has reduced fucosylationor no fucosylation, compared to a parental Fc domain. In the context of an Fc domain, the terms “afucosylation,” “afucosylated,” “defucosylation,” and “defucosylated” are used interchangeably, and generally refer to the absence or removal of core-fucose from the N-glycan attached to the CH2 domain of an Fc domain. For instance, an afucosylated antibody lacks core fucosylation in the Fc domain. As used herein, the phrase “a low level of fucosylation” or “reduced fucosylation” generally refers to an overall fucosylation level in a specific Fc domain that is no more than about 10.0%, no more than 5.0%, no more than 2.5%, no more than 1.0%, no more than about 0.5%, no more than 0.25%, no more than about 0.1%, or no more than 0.01%, compared to the fucosylation level of parental Fc domain. The term “% fucosylation” generally refers to the level of fucosylation in a specific Fc domain compared to that of a parental Fc domain. The % fucosylation can be measured according to any suitable method known in the relevant art, such as, for example, by mass spectrometry (MS), HPLC-Chip Cube MS (Agilent), and reverse phase-HPLC.

[0324] In some embodiments, a particular level of fucosylation is desired. In some embodiments,a Fc variant is provided, wherein the Fc variant comprises a particular level of afucosylation. In some further embodiments, the fucosylation level of the Fc variant is no more than about 10.0%, no more than about 9.0%, no more than about 8.0%, no more than about 7.0%, no more than about 6.0%, no more than about 5.0%, no more than about 4.0%, no more than about 3.0%, no more than about 2.0%, no more than about 1.5%, no more than about 1.0%, no more than about 0.5%, no more than 0.25%, no more than about 0.1%, or no more than 0.01%, compared to that of a parental Fc domain.

[0325] In some embodiments, antibodies comprising afucosylated Fc domains can be enriched(to obtain a particular level of afucosylation) by affinity chromatography using resins conjugated with a fucose binding moiety, such as, for example, an antibody or lectin specific for fucose, with some embodiments finding particular utility when fucose is present in a 1-6 linkage (see, e.g., Kobayashi et al., 2012, J. Biol. Chem.287:33973-82).

[0326] In some embodiments, the fucosylated species of the Fc domain can be separated fromthe afucosylated species of the Fc domain (to obtain a particular level of afucosylation) using anAttorney Docket: 51096.4019 / WO anti-fucose specific antibody in an affinity column. Alternatively, or in addition to, afucosylated species can be separated from fucosylated species based on the differential binding affinity to FcγRIIIa using affinity chromatography (again, to obtain a particular level of afucosylation). H. Useful Formats of the Invention

[0327] As will be appreciated by those in the art, and discussed more fully below, theheterodimeric bispecific antibodies provided herein can take on a wide variety of configurations, as are generally depicted in Figs.18A-18N. Some figures depict “single ended” configurations, where there is one type of specificity on one “arm” of the molecule and a different specificity on the other “arm.” Other figures depict “dual ended” configurations, where there is at least one type of specificity at the “top” of the molecule and one or more different specificities at the “bottom” of the molecule. Thus, in some embodiments, the antibodies described herein are directed to novel immunoglobulin compositions that co-engage a first antigen and a second antigen that are different.

[0328] As will be appreciated by those in the art, the heterodimeric formats of the antibodiesdescribed herein can have different valences (e.g., bivalent, trivalent, etc.), as well as specificity (e.g., bispecific). That is, in some embodiments, heterodimeric antibodies of the antibodies described herein can be bivalent and bispecific, wherein one target antigen (for instance and merely as an example, CD3) is bound by a first binding domain and the other target antigen (for instance and merely as an example, MICA / B) is bound by a second binding domain. In other embodiments, the heterodimeric antibodies can be trivalent and bispecific, wherein the first target antigen is bound by two binding domains (i.e., a first binding domain and a second binding domain) and the second target antigen is bound by another and different binding domain.

[0329] The antibodies described herein utilize anti-MICA / B ABDs in combination with anti-CD3 ABDs. As will be appreciated by those in the art, any collection of anti-MICA / B CDRs, anti-MICA / B variable light and variable heavy domains, Fabs, and scFvs as described herein, and depicted in any of the figures can be used. Similarly, any of the anti-CD3 ABDs can be used, whether CDRs, variable light and variable heavy domains, Fabs, and scFvs as described herein, and depicted in any of the Figures can be used, optionally and independently combined in any combination.Attorney Docket: 51096.4019 / WO 1.1 + 1 Fab × scFv Format

[0330] One heterodimeric scaffold that finds particular use in the antibodies described herein isthe “1 + 1 Fab × scFv” format (also referred to herein as the “1 + 1 Fab-scFv-Fc” or “bottle- opener” format), as is shown in Fig.18A. In this embodiment, one heavy chain monomer of the antibody contains a single chain Fv (“scFv,” as described below) and an Fc domain. The scFv includes a variable heavy domain (VH1) and a variable light domain (VL1), wherein the VH1 is attached to the VL1 using an scFv linker that can be charged (see, e.g., Fig.7; SEQ ID NOs: 22- 49). The scFv is attached to the heavy chain using a domain linker (see, e.g., Fig.8; SEQ ID NOs: 50-78). The other heavy chain monomer is a “regular” heavy chain (VH-CH1-hinge-CH2- CH3). The 1 + 1 Fab × scFv format also includes a light chain that interacts with the VH-CH1 to form a Fab. This structure is sometimes referred to herein as the “bottle-opener” format due to a rough visual similarity to a bottle-opener. The two heavy chain monomers are brought together by the use of amino acid variants (e.g., heterodimerization variants, discussed above) in the constant regions (e.g., the Fc domain, the CH1 domain, and / or the hinge region) that promote the formation of heterodimeric antibodies, as is described more fully below.

[0331] There are several distinct advantages to the present “1 + 1 Fab × scFv” format. As isknown in the art, antibody analogs relying on two scFv constructs often have stability and aggregation problems, which can be alleviated in the antibodies described herein by the addition of a “regular” heavy and light chain pairing. In addition, as opposed to formats that rely on two heavy chains and two light chains, there is no issue with the incorrect pairing of heavy and light chains (e.g., heavy 1 pairing with light 2, etc.).

[0332] Many of the embodiments outlined herein rely in general on the 1 + 1 Fab × scFv or“bottle opener” format antibody that comprises a first monomer comprising an scFv, comprising a variable heavy and a variable light domain, covalently attached using an scFv linker (charged, in many but not all instances), where the scFv is covalently attached to the N-terminus of a first Fc domain, usually through a domain linker. The domain linker can be either charged or uncharged, and exogenous or endogenous (e.g., all or part of the native hinge domain). Any suitable linker can be used to attach the scFv to the N-terminus of the first Fc domain. In some embodiments, the domain linker is chosen from the domain linkers in Fig.8. The second monomer of the 1 + 1 Fab × scFv format or “bottle opener” format is a heavy chain, and theAttorney Docket: 51096.4019 / WO composition further comprises a light chain.

[0333] In general, in many preferred embodiments, the scFv is the domain that binds to CD3,and the Fab forms a MICA / B binding domain. However, in several preferred embodiments, the scFv is the domain that binds to MICA / B, and the Fab forms a CD3 binding domain.

[0334] In addition, the Fc domains of the antibodies described herein generally include FcADCC variants, skew variants (e.g., a set of amino acid substitutions as shown in the figures, with particularly useful skew variants being selected from the group including: (i) S364K / E357Q:L368D / K370S, (ii) L368D / K370S:S364K, (iii) L368E / K370S:S364K, (iv) T411T / E360E / Q362E:D401K, (v) L368D / K370S:S364K / E357L, (vi) K370S:S364K / E357Q, (vii) T366S / L368A / Y407V:T366W, and (viii) T366S / L368A / Y407V / Y349C:T366W / S354C), optionally ablation variants (including those shown in Fig.6), optionally charged scFv linkers (including those shown in Fig.7), and the heavy chain comprises pI variants (including those shown in Figs.5 and 9).

[0335] In certain embodiments the 1 + 1 Fab × scFv scaffold format includes a first monomerthat includes a scFv-domain linker-CH2-CH3 monomer, a second monomer that includes a first variable heavy domain-CH1-hinge-cH2-CH3 monomer, and a third monomer that includes a first variable light domain. In some embodiments, the CH2-CH3 of the first monomer is a first variant Fc domain and the CH2-CH3 of the second monomer is a second variant Fc domain. In some embodiments, the scFv includes a scFv variable heavy domain and a scFv variable light domain that form a CD3 binding moiety. In other embodiments, the scFv includes a scFv variable heavy domain and a scFv variable light domain that form a MICA / B binding moiety. In certain embodiments, the scFv variable heavy domain and scFv variable light domain are covalently attached using an scFv linker (charged, in many but not all instances; see, e.g., Fig.7 and SEQ ID NOs: 22-49)). In some embodiments, the first variable heavy domain and first variable light domain form a MICA / B binding domain. In other embodiments, the first variable heavy domain and first variable light domain form a CD3 binding domain.

[0336] Any suitable CD3 ABD and / or MICA / B ABD can be included in the 1 + 1 Fab × scFvformat antibody, including those provided herein. CD3 binding domain sequences finding particular use in these embodiments include, but are not limited to VH and VL domains selected from VH / VLpairs selected from the group including: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47,Attorney Docket: 51096.4019 / WO H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.31, or variants thereof (see, e.g., Figs.15A-15F). MICA / B ABDs that are of particular use in these embodiments include, but are not limited to, VHand VLdomains selected from VH / VLpairs selected from the group including: (i) SEQ ID Nos: 244 and 248 for D94837_1E11_1 [MICA / B]_H0_D94837_1E11_1 [MICA / B]_L0, (ii) SEQ ID Nos: 252 and 256 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L1, (iii) SEQ ID Nos: 260 and 264 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L2, (iv) SEQ ID Nos: 268 and 272 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L1, (v) SEQ ID Nos: 276 and 280 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L2, (vi) SEQ ID Nos: 284 and 288 for 2E5 [MICA / B]_H0_2E5 [MICA / B]_L0, (vii) SEQ ID Nos: 292 and 296 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L1, (viii) SEQ ID Nos: 300 and 304 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L2, (ix) SEQ ID Nos: 308 and 312 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L1, (x) SEQ ID Nos: 316 and 320 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L2, (xi) SEQ ID Nos: 324 and 328 for D94852_2E12 [MICA / B]_H0_D94852_2E12 [MICA / B]_L0, (xii) SEQ ID Nos: 332 and 336 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L1, (xiii) SEQ ID Nos: 340 and 344 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L2, (xiv) SEQ ID Nos: 348 and 352 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L1, (xv) SEQ ID Nos: 356 and 360 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L2, (xvi) SEQ ID Nos: 364 and 368 for D99136_2F7 [MICA / B]_H0_D99136_2F7 [MICA / B]_L0, (xvii) SEQ ID Nos: 372 and 376 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L1, (xviii) SEQ ID Nos: 380 and 384 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L2, (xix) SEQ ID Nos: 388 and 392 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L1, (xx) SEQ ID Nos: 396 and 400 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L2, (xxi) SEQ ID Nos: 404 and 408 for D103388_1C7 [MICA / B]_H0_D103388_1C7 [MICA / B]_L0, (xxii) SEQ ID Nos: 412 and 416 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L1, (xxiii) SEQ ID Nos: 420 and 424 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L2, (xxiv) SEQ ID Nos: 428 and 432 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L1, (xxv) SEQ ID Nos: 436 and 440 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L2, (xxvi) SEQ ID Nos: 444 and 448 for D103388_1D7 [MICA / B]_H0_D103388_1D7 [MICA / B]_L0, (xxvii) SEQ ID Nos: 452 and 456Attorney Docket: 51096.4019 / WO for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L1, (xxviii) SEQ ID Nos: 460 and 464 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L2, (xxix) SEQ ID Nos: 468 and 472 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L1, (xxx) SEQ ID Nos: 476 and 480 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L2, (xxxi) SEQ ID Nos: 484 and 488 for D105317_1A2 [MICA / B]_H0_D105317_1A2 [MICA / B]_L0, (xxxii) SEQ ID Nos: 492 and 496 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L1, (xxxiii) SEQ ID Nos: 500 and 504 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L2, (xxxiv) SEQ ID Nos: 508 and 512 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L1, (xxxv) SEQ ID Nos: 516 and 520 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L2, (xxxvi) SEQ ID Nos: 524 and 528 for D99136_2C11 [MICA / B]_H0_D99136_2C11 [MICA / B]_L0, (xxxvii) SEQ ID Nos: 532 and 536 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L1, (xxxviii) SEQ ID Nos: 540 and 544 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L2, (xxxix) SEQ ID Nos: 548 and 552 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L1, (xl) SEQ ID Nos: 556 and 560 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L2, (xli) SEQ ID Nos: 564 and 568 for D103388_1B11-2 [MICA / B]_H0_D103388_1B11-2 [MICA / B]_L0, (xlii) SEQ ID Nos: 572 and 576 for D105317_1B6 [MICA / B]_H0_D105317_1B6 [MICA / B]_L0, (xliii) SEQ ID Nos: 580 and 584 for D105317_1C8 [MICA / B]_H0_D105317_1C8 [MICA / B]_L0, (xliv) SEQ ID Nos: 588 and 592 for D105317_1F6 [MICA / B]_H0_D105317_1F6 [MICA / B]_L0, (xlv) SEQ ID Nos: 596 and 600 for D105317_1F7 [MICA / B]_H0_D105317_1F7 [MICA / B]_L0, (xlvi) SEQ ID Nos: 604 and 608 for D94837_1D3 [MICA / B]_H0_D94837_1D3 [MICA / B]_L0, (xlvii) SEQ ID Nos: 612 and 616 for D94837_1D8 [MICA / B]_H0_D94837_1D8 [MICA / B]_L0, (xlviii) SEQ ID Nos: 620 and 624 for D94837_1D9 [MICA / B]_H0_D94837_1D9 [MICA / B]_L0, (xlix) SEQ ID Nos: 628 and 632 for D94837_1E1 [MICA / B]_H0_D94837_1E1 [MICA / B]_L0, (l) SEQ ID Nos: 636 and 640 for D94852_2D4 [MICA / B]_H0_D94852_2D4 [MICA / B]_L0, (li) SEQ ID Nos: 644 and 648 for D94852_2G8 [MICA / B]_H0_D94852_2G8 [MICA / B]_L0, (lii) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, (liii) SEQ ID Nos: 660 and 664 for D94837_3B12 [MICA / B]_H0_D94837_3B12 [MICA / B]_L0, (liv) SEQ ID Nos: 668 and 672 for D99122_1H7 [MICA / B]_H0_D99122_1H7 [MICA / B]_L0, (lv) SEQ ID Nos: 676 and 680 for D99136_2E8 [MICA / B]_H0_D99136_2E8 [MICA / B]_L0, (lvi) SEQ ID Nos: 652 and 656 forAttorney Docket: 51096.4019 / WO D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, (lvii) SEQ ID Nos: 684 and 688 for 3F9[MICA / B]_H0_3F9[MICA / B]_L0, (lviii) SEQ ID Nos: 692 and 696 for 6E1[MICA / B]_H0_6E1[MICA / B]_L0, (lix) SEQ ID Nos: 700 and 704 for 7C6[MICA / B]_H0_7C6[MICA / B]_L0, (lx) SEQ ID Nos: 708 and 712 for 13A9 [MICA / B]_H0_13A9 [MICA / B]_L0, and (lxi) SEQ ID Nos: 716 and 720 for 1D5 [MICA / B]_H0_1D5 [MICA / B]_L0, or variants thereof (see, e.g., Figs.16 and 17).

[0337] Similarly, any suitable MICA / B ABD and / or CD3 ABD can be included in the 1 + 1 Fab× scFv format antibody, including those provided herein. MICA / B binding domain sequences finding particular use in these embodiments include, but are not limited to: (i) SEQ ID Nos: 244 and 248 for D94837_1E11_1 [MICA / B]_H0_D94837_1E11_1 [MICA / B]_L0, (ii) SEQ ID Nos: 252 and 256 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L1, (iii) SEQ ID Nos: 260 and 264 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L2, (iv) SEQ ID Nos: 268 and 272 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L1, (v) SEQ ID Nos: 276 and 280 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L2, (vi) SEQ ID Nos: 284 and 288 for 2E5 [MICA / B]_H0_2E5 [MICA / B]_L0, (vii) SEQ ID Nos: 292 and 296 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L1, (viii) SEQ ID Nos: 300 and 304 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L2, (ix) SEQ ID Nos: 308 and 312 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L1, (x) SEQ ID Nos: 316 and 320 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L2, (xi) SEQ ID Nos: 324 and 328 for D94852_2E12 [MICA / B]_H0_D94852_2E12 [MICA / B]_L0, (xii) SEQ ID Nos: 332 and 336 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L1, (xiii) SEQ ID Nos: 340 and 344 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L2, (xiv) SEQ ID Nos: 348 and 352 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L1, (xv) SEQ ID Nos: 356 and 360 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L2, (xvi) SEQ ID Nos: 364 and 368 for D99136_2F7 [MICA / B]_H0_D99136_2F7 [MICA / B]_L0, (xvii) SEQ ID Nos: 372 and 376 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L1, (xviii) SEQ ID Nos: 380 and 384 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L2, (xix) SEQ ID Nos: 388 and 392 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L1, (xx) SEQ ID Nos: 396 and 400 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L2, (xxi) SEQ ID Nos: 404 and 408 for D103388_1C7 [MICA / B]_H0_D103388_1C7 [MICA / B]_L0, (xxii) SEQ ID Nos: 412 and 416 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L1, (xxiii) SEQ ID Nos: 420Attorney Docket: 51096.4019 / WO and 424 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L2, (xxiv) SEQ ID Nos: 428 and 432 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L1, (xxv) SEQ ID Nos: 436 and 440 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L2, (xxvi) SEQ ID Nos: 444 and 448 for D103388_1D7 [MICA / B]_H0_D103388_1D7 [MICA / B]_L0, (xxvii) SEQ ID Nos: 452 and 456 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L1, (xxviii) SEQ ID Nos: 460 and 464 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L2, (xxix) SEQ ID Nos: 468 and 472 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L1, (xxx) SEQ ID Nos: 476 and 480 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L2, (xxxi) SEQ ID Nos: 484 and 488 for D105317_1A2 [MICA / B]_H0_D105317_1A2 [MICA / B]_L0, (xxxii) SEQ ID Nos: 492 and 496 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L1, (xxxiii) SEQ ID Nos: 500 and 504 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L2, (xxxiv) SEQ ID Nos: 508 and 512 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L1, (xxxv) SEQ ID Nos: 516 and 520 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L2, (xxxvi) SEQ ID Nos: 524 and 528 for D99136_2C11 [MICA / B]_H0_D99136_2C11 [MICA / B]_L0, (xxxvii) SEQ ID Nos: 532 and 536 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L1, (xxxviii) SEQ ID Nos: 540 and 544 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L2, (xxxix) SEQ ID Nos: 548 and 552 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L1, (xl) SEQ ID Nos: 556 and 560 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L2, (xli) SEQ ID Nos: 564 and 568 for D103388_1B11-2 [MICA / B]_H0_D103388_1B11-2 [MICA / B]_L0, (xlii) SEQ ID Nos: 572 and 576 for D105317_1B6 [MICA / B]_H0_D105317_1B6 [MICA / B]_L0, (xliii) SEQ ID Nos: 580 and 584 for D105317_1C8 [MICA / B]_H0_D105317_1C8 [MICA / B]_L0, (xliv) SEQ ID Nos: 588 and 592 for D105317_1F6 [MICA / B]_H0_D105317_1F6 [MICA / B]_L0, (xlv) SEQ ID Nos: 596 and 600 for D105317_1F7 [MICA / B]_H0_D105317_1F7 [MICA / B]_L0, (xlvi) SEQ ID Nos: 604 and 608 for D94837_1D3 [MICA / B]_H0_D94837_1D3 [MICA / B]_L0, (xlvii) SEQ ID Nos: 612 and 616 for D94837_1D8 [MICA / B]_H0_D94837_1D8 [MICA / B]_L0, (xlviii) SEQ ID Nos: 620 and 624 for D94837_1D9 [MICA / B]_H0_D94837_1D9 [MICA / B]_L0, (xlix) SEQ ID Nos: 628 and 632 for D94837_1E1 [MICA / B]_H0_D94837_1E1 [MICA / B]_L0, (l) SEQ ID Nos: 636 and 640 for D94852_2D4 [MICA / B]_H0_D94852_2D4 [MICA / B]_L0, (li) SEQ ID Nos: 644 and 648 for D94852_2G8 [MICA / B]_H0_D94852_2G8 [MICA / B]_L0, (lii) SEQ IDAttorney Docket: 51096.4019 / WO Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, (liii) SEQ ID Nos: 660 and 664 for D94837_3B12 [MICA / B]_H0_D94837_3B12 [MICA / B]_L0, (liv) SEQ ID Nos: 668 and 672 for D99122_1H7 [MICA / B]_H0_D99122_1H7 [MICA / B]_L0, (lv) SEQ ID Nos: 676 and 680 for D99136_2E8 [MICA / B]_H0_D99136_2E8 [MICA / B]_L0, (lvi) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, (lvii) SEQ ID Nos: 684 and 688 for 3F9[MICA / B]_H0_3F9[MICA / B]_L0, (lviii) SEQ ID Nos: 692 and 696 for 6E1[MICA / B]_H0_6E1[MICA / B]_L0, (lix) SEQ ID Nos: 700 and 704 for 7C6[MICA / B]_H0_7C6[MICA / B]_L0, (lx) SEQ ID Nos: 708 and 712 for 13A9 [MICA / B]_H0_13A9 [MICA / B]_L0, and (lxi) SEQ ID Nos: 716 and 720 for 1D5 [MICA / B]_H0_1D5 [MICA / B]_L0, or variants thereof (see, e.g., Figs.16 and 17). CD3 ABDs that are of particular use in these embodiments include, but are not limited to, VHand VLdomains selected from VH / VL pairs selected from the group including: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.31, or variants thereof (see, e.g., Figs.15A-15F). In particular embodiments, the αCD3 VH / VL pairs are selected from the group including: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.31, or a variant thereof (see, e.g., Figs.15A-15F).

[0338] In particular embodiments, the αMICA / B VH / VL pairs are selected from the groupincluding: (i) SEQ ID Nos: 244 and 248 for D94837_1E11_1 [MICA / B]_H0_D94837_1E11_1 [MICA / B]_L0, (ii) SEQ ID Nos: 252 and 256 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L1, (iii) SEQ ID Nos: 260 and 264 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L2, (iv) SEQ ID Nos: 268 and 272 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L1, (v) SEQ ID Nos: 276 and 280 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L2, (vi) SEQ ID Nos: 284 and 288 for 2E5 [MICA / B]_H0_2E5 [MICA / B]_L0, (vii) SEQ ID Nos: 292 and 296 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L1, (viii) SEQ ID Nos: 300 and 304 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L2, (ix) SEQ ID Nos: 308 and 312 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L1, (x) SEQ ID Nos: 316 and 320 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L2, (xi) SEQ ID Nos: 324 and 328 for D94852_2E12 [MICA / B]_H0_D94852_2E12 [MICA / B]_L0, (xii) SEQ ID Nos: 332 and 336 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L1, (xiii) SEQ ID Nos:Attorney Docket: 51096.4019 / WO 340 and 344 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L2, (xiv) SEQ ID Nos: 348 and 352 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L1, (xv) SEQ ID Nos: 356 and 360 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L2, (xvi) SEQ ID Nos: 364 and 368 for D99136_2F7 [MICA / B]_H0_D99136_2F7 [MICA / B]_L0, (xvii) SEQ ID Nos: 372 and 376 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L1, (xviii) SEQ ID Nos: 380 and 384 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L2, (xix) SEQ ID Nos: 388 and 392 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L1, (xx) SEQ ID Nos: 396 and 400 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L2, (xxi) SEQ ID Nos: 404 and 408 for D103388_1C7 [MICA / B]_H0_D103388_1C7 [MICA / B]_L0, (xxii) SEQ ID Nos: 412 and 416 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L1, (xxiii) SEQ ID Nos: 420 and 424 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L2, (xxiv) SEQ ID Nos: 428 and 432 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L1, (xxv) SEQ ID Nos: 436 and 440 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L2, (xxvi) SEQ ID Nos: 444 and 448 for D103388_1D7 [MICA / B]_H0_D103388_1D7 [MICA / B]_L0, (xxvii) SEQ ID Nos: 452 and 456 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L1, (xxviii) SEQ ID Nos: 460 and 464 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L2, (xxix) SEQ ID Nos: 468 and 472 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L1, (xxx) SEQ ID Nos: 476 and 480 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L2, (xxxi) SEQ ID Nos: 484 and 488 for D105317_1A2 [MICA / B]_H0_D105317_1A2 [MICA / B]_L0, (xxxii) SEQ ID Nos: 492 and 496 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L1, (xxxiii) SEQ ID Nos: 500 and 504 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L2, (xxxiv) SEQ ID Nos: 508 and 512 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L1, (xxxv) SEQ ID Nos: 516 and 520 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L2, (xxxvi) SEQ ID Nos: 524 and 528 for D99136_2C11 [MICA / B]_H0_D99136_2C11 [MICA / B]_L0, (xxxvii) SEQ ID Nos: 532 and 536 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L1, (xxxviii) SEQ ID Nos: 540 and 544 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L2, (xxxix) SEQ ID Nos: 548 and 552 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L1, (xl) SEQ ID Nos: 556 and 560 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L2, (xli) SEQ ID Nos: 564 and 568 for D103388_1B11-2 [MICA / B]_H0_D103388_1B11-2 [MICA / B]_L0, (xlii)Attorney Docket: 51096.4019 / WO SEQ ID Nos: 572 and 576 for D105317_1B6 [MICA / B]_H0_D105317_1B6 [MICA / B]_L0, (xliii) SEQ ID Nos: 580 and 584 for D105317_1C8 [MICA / B]_H0_D105317_1C8 [MICA / B]_L0, (xliv) SEQ ID Nos: 588 and 592 for D105317_1F6 [MICA / B]_H0_D105317_1F6 [MICA / B]_L0, (xlv) SEQ ID Nos: 596 and 600 for D105317_1F7 [MICA / B]_H0_D105317_1F7 [MICA / B]_L0, (xlvi) SEQ ID Nos: 604 and 608 for D94837_1D3 [MICA / B]_H0_D94837_1D3 [MICA / B]_L0, (xlvii) SEQ ID Nos: 612 and 616 for D94837_1D8 [MICA / B]_H0_D94837_1D8 [MICA / B]_L0, (xlviii) SEQ ID Nos: 620 and 624 for D94837_1D9 [MICA / B]_H0_D94837_1D9 [MICA / B]_L0, (xlix) SEQ ID Nos: 628 and 632 for D94837_1E1 [MICA / B]_H0_D94837_1E1 [MICA / B]_L0, (l) SEQ ID Nos: 636 and 640 for D94852_2D4 [MICA / B]_H0_D94852_2D4 [MICA / B]_L0, (li) SEQ ID Nos: 644 and 648 for D94852_2G8 [MICA / B]_H0_D94852_2G8 [MICA / B]_L0, (lii) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, (liii) SEQ ID Nos: 660 and 664 for D94837_3B12 [MICA / B]_H0_D94837_3B12 [MICA / B]_L0, (liv) SEQ ID Nos: 668 and 672 for D99122_1H7 [MICA / B]_H0_D99122_1H7 [MICA / B]_L0, (lv) SEQ ID Nos: 676 and 680 for D99136_2E8 [MICA / B]_H0_D99136_2E8 [MICA / B]_L0, (lvi) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, (lvii) SEQ ID Nos: 684 and 688 for 3F9[MICA / B]_H0_3F9[MICA / B]_L0, (lviii) SEQ ID Nos: 692 and 696 for 6E1[MICA / B]_H0_6E1[MICA / B]_L0, (lix) SEQ ID Nos: 700 and 704 for 7C6[MICA / B]_H0_7C6[MICA / B]_L0, (lx) SEQ ID Nos: 708 and 712 for 13A9 [MICA / B]_H0_13A9 [MICA / B]_L0, and (lxi) SEQ ID Nos: 716 and 720 for 1D5 [MICA / B]_H0_1D5 [MICA / B]_L0, or a variant thereof (see, e.g., Figs.16 and 17).

[0339] In some embodiments, the 1 + 1 Fab × scFv format includes Fc ADCC variants, skewvariants, pI variants, and / or ablation variants. Accordingly, some embodiments include 1 + 1 Fab × scFv formats that comprise: (i) a first monomer (the “scFv monomer”) that comprises a charged scFv linker (with the “+H” sequence of Fig.7 (i.e., SEQ ID NO: 31) being preferred in some embodiments), the skew variants S364K / E357Q, the ablation variants E233P / L234V / L235A / G236del / S267K, and an scFv that binds to a first target antigen as outlined herein, (ii) a second monomer (the “Fab monomer”) that comprises the skew variants L368D / K370S, the pI variants N208D / Q295E / N384D / Q418E / N421D, the ablation variants E233P / L234V / L235A / G236del / S267K, and a variable heavy domain (VH), and (iii) a light chain that includes a variable light domain (VL) and a constant light domain (CL), wherein numberingAttorney Docket: 51096.4019 / WO is according to EU numbering. In some embodiments, the first target antigen is CD3, and the first variable heavy domain and the first variable light domain make up a MICA / B binding moiety. In other embodiments, the first target antigen is MICA / B, and the first variable heavy domain and the first variable light domain make up a CD3 binding moiety. CD3 binding domain sequences finding particular use in these embodiments include, but are not limited to: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.31, or variants thereof (see, e.g., Figs.15A-15F). MICA / B binding domain sequences finding particular use in these embodiments include, but are not limited to: (i) SEQ ID Nos: 244 and 248 for D94837_1E11_1 [MICA / B]_H0_D94837_1E11_1 [MICA / B]_L0, (ii) SEQ ID Nos: 252 and 256 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L1, (iii) SEQ ID Nos: 260 and 264 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L2, (iv) SEQ ID Nos: 268 and 272 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L1, (v) SEQ ID Nos: 276 and 280 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L2, (vi) SEQ ID Nos: 284 and 288 for 2E5 [MICA / B]_H0_2E5 [MICA / B]_L0, (vii) SEQ ID Nos: 292 and 296 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L1, (viii) SEQ ID Nos: 300 and 304 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L2, (ix) SEQ ID Nos: 308 and 312 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L1, (x) SEQ ID Nos: 316 and 320 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L2, (xi) SEQ ID Nos: 324 and 328 for D94852_2E12 [MICA / B]_H0_D94852_2E12 [MICA / B]_L0, (xii) SEQ ID Nos: 332 and 336 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L1, (xiii) SEQ ID Nos: 340 and 344 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L2, (xiv) SEQ ID Nos: 348 and 352 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L1, (xv) SEQ ID Nos: 356 and 360 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L2, (xvi) SEQ ID Nos: 364 and 368 for D99136_2F7 [MICA / B]_H0_D99136_2F7 [MICA / B]_L0, (xvii) SEQ ID Nos: 372 and 376 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L1, (xviii) SEQ ID Nos: 380 and 384 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L2, (xix) SEQ ID Nos: 388 and 392 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L1, (xx) SEQ ID Nos: 396 and 400 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L2, (xxi) SEQ ID Nos: 404 and 408 for D103388_1C7 [MICA / B]_H0_D103388_1C7 [MICA / B]_L0, (xxii) SEQ ID Nos: 412 and 416 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L1, (xxiii) SEQ ID Nos: 420 and 424Attorney Docket: 51096.4019 / WO for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L2, (xxiv) SEQ ID Nos: 428 and 432 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L1, (xxv) SEQ ID Nos: 436 and 440 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L2, (xxvi) SEQ ID Nos: 444 and 448 for D103388_1D7 [MICA / B]_H0_D103388_1D7 [MICA / B]_L0, (xxvii) SEQ ID Nos: 452 and 456 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L1, (xxviii) SEQ ID Nos: 460 and 464 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L2, (xxix) SEQ ID Nos: 468 and 472 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L1, (xxx) SEQ ID Nos: 476 and 480 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L2, (xxxi) SEQ ID Nos: 484 and 488 for D105317_1A2 [MICA / B]_H0_D105317_1A2 [MICA / B]_L0, (xxxii) SEQ ID Nos: 492 and 496 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L1, (xxxiii) SEQ ID Nos: 500 and 504 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L2, (xxxiv) SEQ ID Nos: 508 and 512 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L1, (xxxv) SEQ ID Nos: 516 and 520 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L2, (xxxvi) SEQ ID Nos: 524 and 528 for D99136_2C11 [MICA / B]_H0_D99136_2C11 [MICA / B]_L0, (xxxvii) SEQ ID Nos: 532 and 536 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L1, (xxxviii) SEQ ID Nos: 540 and 544 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L2, (xxxix) SEQ ID Nos: 548 and 552 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L1, (xl) SEQ ID Nos: 556 and 560 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L2, (xli) SEQ ID Nos: 564 and 568 for D103388_1B11-2 [MICA / B]_H0_D103388_1B11-2 [MICA / B]_L0, (xlii) SEQ ID Nos: 572 and 576 for D105317_1B6 [MICA / B]_H0_D105317_1B6 [MICA / B]_L0, (xliii) SEQ ID Nos: 580 and 584 for D105317_1C8 [MICA / B]_H0_D105317_1C8 [MICA / B]_L0, (xliv) SEQ ID Nos: 588 and 592 for D105317_1F6 [MICA / B]_H0_D105317_1F6 [MICA / B]_L0, (xlv) SEQ ID Nos: 596 and 600 for D105317_1F7 [MICA / B]_H0_D105317_1F7 [MICA / B]_L0, (xlvi) SEQ ID Nos: 604 and 608 for D94837_1D3 [MICA / B]_H0_D94837_1D3 [MICA / B]_L0, (xlvii) SEQ ID Nos: 612 and 616 for D94837_1D8 [MICA / B]_H0_D94837_1D8 [MICA / B]_L0, (xlviii) SEQ ID Nos: 620 and 624 for D94837_1D9 [MICA / B]_H0_D94837_1D9 [MICA / B]_L0, (xlix) SEQ ID Nos: 628 and 632 for D94837_1E1 [MICA / B]_H0_D94837_1E1 [MICA / B]_L0, (l) SEQ ID Nos: 636 and 640 for D94852_2D4 [MICA / B]_H0_D94852_2D4 [MICA / B]_L0, (li) SEQ ID Nos: 644 and 648 for D94852_2G8 [MICA / B]_H0_D94852_2G8 [MICA / B]_L0, (lii) SEQ IDAttorney Docket: 51096.4019 / WO Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, (liii) SEQ ID Nos: 660 and 664 for D94837_3B12 [MICA / B]_H0_D94837_3B12 [MICA / B]_L0, (liv) SEQ ID Nos: 668 and 672 for D99122_1H7 [MICA / B]_H0_D99122_1H7 [MICA / B]_L0, (lv) SEQ ID Nos: 676 and 680 for D99136_2E8 [MICA / B]_H0_D99136_2E8 [MICA / B]_L0, (lvi) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, (lvii) SEQ ID Nos: 684 and 688 for 3F9[MICA / B]_H0_3F9[MICA / B]_L0, (lviii) SEQ ID Nos: 692 and 696 for 6E1[MICA / B]_H0_6E1[MICA / B]_L0, (lix) SEQ ID Nos: 700 and 704 for 7C6[MICA / B]_H0_7C6[MICA / B]_L0, (lx) SEQ ID Nos: 708 and 712 for 13A9 [MICA / B]_H0_13A9 [MICA / B]_L0, and (lxi) SEQ ID Nos: 716 and 720 for 1D5 [MICA / B]_H0_1D5 [MICA / B]_L0, or variants thereof (see, e.g., Figs.16 and 17).

[0340] In some embodiments, the 1 + 1 Fab × scFv format includes skew variants (see, e.g., thefigures), pI variants (see, e.g., the figures), ablation variants (see, e.g., the figures, and / or FcRn variants. Accordingly, some embodiments include 1 + 1 Fab × scFv formats that comprise: (i) a first monomer (the “scFv monomer”) that comprises a charged scFv linker (see, Fig.7), the skew variants S364K / E357Q, the ablation variants E233P / L234V / L235A / G236del / S267K, the FcRn variants M428L / N434S and an scFv that binds to a first target antigen as outlined herein, (ii) a second monomer (the “Fab monomer”) that comprises the skew variants L368D / K370S, the pI variants N208D / Q295E / N384D / Q418E / N421D, the ablation variants E233P / L234V / L235A / G236del / S267K, the FcRn variants M428L / N434S, and a variable heavy domain, and (iii) a light chain that includes a variable light domain (VL) and a constant light domain (CL), wherein numbering is according to EU numbering. In some embodiments, the first target antigen is CD3, and the first variable heavy domain and the first variable light domain make up a MICA / B binding moiety. In other embodiments, the first target antigen is MICA / B, and the first variable heavy domain and the first variable light domain make up a CD3 binding moiety. CD3 binding domain sequences finding particular use in these embodiments include, but are not limited to: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.31, or variants thereof (see, e.g., Figs.15A-15F). MICA / B binding domain sequences finding particular use in these embodiments include, but are not limited to: (i) SEQ ID Nos: 244 and 248 for D94837_1E11_1 [MICA / B]_H0_D94837_1E11_1 [MICA / B]_L0, (ii) SEQ ID Nos: 252 and 256 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L1, (iii) SEQ IDAttorney Docket: 51096.4019 / WO Nos: 260 and 264 for D94837_1E11_1 [MICA / B]_H1_D94837_1E11_1 [MICA / B]_L2, (iv) SEQ ID Nos: 268 and 272 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L1, (v) SEQ ID Nos: 276 and 280 for D94837_1E11_1 [MICA / B]_H2_D94837_1E11_1 [MICA / B]_L2, (vi) SEQ ID Nos: 284 and 288 for 2E5 [MICA / B]_H0_2E5 [MICA / B]_L0, (vii) SEQ ID Nos: 292 and 296 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L1, (viii) SEQ ID Nos: 300 and 304 for 2E5 [MICA / B]_H1_2E5 [MICA / B]_L2, (ix) SEQ ID Nos: 308 and 312 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L1, (x) SEQ ID Nos: 316 and 320 for 2E5 [MICA / B]_H2_2E5 [MICA / B]_L2, (xi) SEQ ID Nos: 324 and 328 for D94852_2E12 [MICA / B]_H0_D94852_2E12 [MICA / B]_L0, (xii) SEQ ID Nos: 332 and 336 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L1, (xiii) SEQ ID Nos: 340 and 344 for D94852_2E12 [MICA / B]_H1_D94852_2E12 [MICA / B]_L2, (xiv) SEQ ID Nos: 348 and 352 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L1, (xv) SEQ ID Nos: 356 and 360 for D94852_2E12 [MICA / B]_H2_D94852_2E12 [MICA / B]_L2, (xvi) SEQ ID Nos: 364 and 368 for D99136_2F7 [MICA / B]_H0_D99136_2F7 [MICA / B]_L0, (xvii) SEQ ID Nos: 372 and 376 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L1, (xviii) SEQ ID Nos: 380 and 384 for D99136_2F7 [MICA / B]_H1_D99136_2F7 [MICA / B]_L2, (xix) SEQ ID Nos: 388 and 392 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L1, (xx) SEQ ID Nos: 396 and 400 for D99136_2F7 [MICA / B]_H2_D99136_2F7 [MICA / B]_L2, (xxi) SEQ ID Nos: 404 and 408 for D103388_1C7 [MICA / B]_H0_D103388_1C7 [MICA / B]_L0, (xxii) SEQ ID Nos: 412 and 416 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L1, (xxiii) SEQ ID Nos: 420 and 424 for D103388_1C7 [MICA / B]_H1_D103388_1C7 [MICA / B]_L2, (xxiv) SEQ ID Nos: 428 and 432 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L1, (xxv) SEQ ID Nos: 436 and 440 for D103388_1C7 [MICA / B]_H2_D103388_1C7 [MICA / B]_L2, (xxvi) SEQ ID Nos: 444 and 448 for D103388_1D7 [MICA / B]_H0_D103388_1D7 [MICA / B]_L0, (xxvii) SEQ ID Nos: 452 and 456 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L1, (xxviii) SEQ ID Nos: 460 and 464 for D103388_1D7 [MICA / B]_H1_D103388_1D7 [MICA / B]_L2, (xxix) SEQ ID Nos: 468 and 472 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L1, (xxx) SEQ ID Nos: 476 and 480 for D103388_1D7 [MICA / B]_H2_D103388_1D7 [MICA / B]_L2, (xxxi) SEQ ID Nos: 484 and 488 for D105317_1A2 [MICA / B]_H0_D105317_1A2 [MICA / B]_L0, (xxxii) SEQ ID Nos: 492 and 496 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L1, (xxxiii) SEQ ID Nos: 500Attorney Docket: 51096.4019 / WO and 504 for D105317_1A2 [MICA / B]_H1_D105317_1A2 [MICA / B]_L2, (xxxiv) SEQ ID Nos: 508 and 512 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L1, (xxxv) SEQ ID Nos: 516 and 520 for D105317_1A2 [MICA / B]_H2_D105317_1A2 [MICA / B]_L2, (xxxvi) SEQ ID Nos: 524 and 528 for D99136_2C11 [MICA / B]_H0_D99136_2C11 [MICA / B]_L0, (xxxvii) SEQ ID Nos: 532 and 536 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L1, (xxxviii) SEQ ID Nos: 540 and 544 for D99136_2C11 [MICA / B]_H1_D99136_2C11 [MICA / B]_L2, (xxxix) SEQ ID Nos: 548 and 552 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L1, (xl) SEQ ID Nos: 556 and 560 for D99136_2C11 [MICA / B]_H2_D99136_2C11 [MICA / B]_L2, (xli) SEQ ID Nos: 564 and 568 for D103388_1B11-2 [MICA / B]_H0_D103388_1B11-2 [MICA / B]_L0, (xlii) SEQ ID Nos: 572 and 576 for D105317_1B6 [MICA / B]_H0_D105317_1B6 [MICA / B]_L0, (xliii) SEQ ID Nos: 580 and 584 for D105317_1C8 [MICA / B]_H0_D105317_1C8 [MICA / B]_L0, (xliv) SEQ ID Nos: 588 and 592 for D105317_1F6 [MICA / B]_H0_D105317_1F6 [MICA / B]_L0, (xlv) SEQ ID Nos: 596 and 600 for D105317_1F7 [MICA / B]_H0_D105317_1F7 [MICA / B]_L0, (xlvi) SEQ ID Nos: 604 and 608 for D94837_1D3 [MICA / B]_H0_D94837_1D3 [MICA / B]_L0, (xlvii) SEQ ID Nos: 612 and 616 for D94837_1D8 [MICA / B]_H0_D94837_1D8 [MICA / B]_L0, (xlviii) SEQ ID Nos: 620 and 624 for D94837_1D9 [MICA / B]_H0_D94837_1D9 [MICA / B]_L0, (xlix) SEQ ID Nos: 628 and 632 for D94837_1E1 [MICA / B]_H0_D94837_1E1 [MICA / B]_L0, (l) SEQ ID Nos: 636 and 640 for D94852_2D4 [MICA / B]_H0_D94852_2D4 [MICA / B]_L0, (li) SEQ ID Nos: 644 and 648 for D94852_2G8 [MICA / B]_H0_D94852_2G8 [MICA / B]_L0, (lii) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, (liii) SEQ ID Nos: 660 and 664 for D94837_3B12 [MICA / B]_H0_D94837_3B12 [MICA / B]_L0, (liv) SEQ ID Nos: 668 and 672 for D99122_1H7 [MICA / B]_H0_D99122_1H7 [MICA / B]_L0, (lv) SEQ ID Nos: 676 and 680 for D99136_2E8 [MICA / B]_H0_D99136_2E8 [MICA / B]_L0, (lvi) SEQ ID Nos: 652 and 656 for D88487_2A8 [MICA / B]_H0_D88487_2A8 [MICA / B]_L0, (lvii) SEQ ID Nos: 684 and 688 for 3F9[MICA / B]_H0_3F9[MICA / B]_L0, (lviii) SEQ ID Nos: 692 and 6...

Claims

Attorney Docket: 51096.4019 / WO CLAIMS WHAT IS CLAIMED IS:

1. A bispecific antibody that binds MICA / B and CD3, comprising: (a) a first monomer, comprising: (i) an anti-CD3 scFv comprising, from N-terminus to C-terminus: (1) a first variable heavy (VH1) domain, an scFv linker, and a first variable light (VL1) domain, or (2) a first variable light (VL1) domain, an scFv linker, and a first variable heavy (VH1) domain; and (ii) a first Fc domain comprising, from N-terminus to C-terminus: a constant domain 2 of a heavy chain (CH2) and a constant domain 3 of a heavy chain (CH3), wherein the C-terminus of the anti-CD3 scFv is covalently attached to the N-terminus of the first Fc domain using a domain linker; (b) a second monomer comprising, from N-terminus to C-terminus: a second variable heavy (VH2) domain, a constant domain 1 of a heavy chain (CH1), a constant domain 2 of a heavy chain (CH2), a constant domain 3 of a heavy chain (CH3), wherein VH2 is a second variable heavy domain and CH2-CH3 is a second Fc domain; and (c) a common light chain comprising, from N-terminus to C-terminus: a second variable light (VL2) domain and a constant domain light chain (CL), wherein the second variable heavy (VH2) domain and the second variable light (VL2) domain form a MICA / B antigen binding domain.

2. The bispecific antibody according to claim 1, wherein the MICA / B antigen binding domain comprises a set of vhCDR1-3 and vlCDR1-3 from a variable heavy domain and variable light domain pair, wherein the set of vhCDR1-3 and vlCDR1-3 is selected from the group consisting of: D99136_2C11 [MICA / B]_H0, D99136_2C11 [MICA / B]_H1, D99136_2C11 [MICA / B]_H2, D94837_1E11_1 [MICA / B]_H0, D94837_1E11_1 [MICA / B]_H1, D94837_1E11_1 [MICA / B]_H2 for the set of vhCDR1-3, and D99136_2C11 [MICA / B]_L0, D99136_2C11 [MICA / B]_L1, D99136_2C11 [MICA / B]_L2, D94837_1E11_1 [MICA / B]_L0,Attorney Docket: 51096.4019 / WO D94837_1E11_1 [MICA / B]_L1, D94837_1E11_1 [MICA / B]_L2 for the set of vlCDR1-3.

3. The bispecific antibody according to claim 1 or 2, wherein the MICA / B antigen binding domain comprises a variable heavy domain and variable light domain pair selected from the group consisting of: D99136_2C11 [MICA / B]_H0L0, D99136_2C11 [MICA / B]_H1L1, D99136_2C11 [MICA / B]_H1L2, D99136_2C11 [MICA / B]_H2L1, D99136_2C11 [MICA / B]_H2L2, D94837_1E11_1 [MICA / B]_H0L0, D94837_1E11_1 [MICA / B]_H1L1, D94837_1E11_1 [MICA / B]_H1L2. D94837_1E11_1 [MICA / B]_H2L1, and D94837_1E11_1 [MICA / B]_H2L2.

4. The bispecific antibody according to any one of claims 1-3, wherein the anti-CD3 scFv comprises a first variable heavy VH1 domain and first variable light VL1 domain pair selected from the group consisting of: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.

31.

5. The bispecific antibody according to any one of claims 1-4, wherein the first variable light (VL1) domain of the anti-CD3 scFv is covalently attached to the N-terminus of the first Fc domain using the domain linker.

6. The bispecific antibody according to any one of claims 1-4, wherein the first variable heavy (VH1) domain of the anti-CD3 scFv is covalently attached to the N-terminus of the first Fc domain using the domain linker.

7. A bispecific antibody that binds MICA / B and CD3, comprising: (a) a first monomer, comprising: (i) an anti-MICA / B scFv comprising, from N-terminus to C-terminus: (1) a first variable heavy (VH1) domain, an scFv linker, and a first variable light (VL1) domain, or (2) a first variable light (VL1) domain, an scFv linker, and a first variable heavy (VH1) domain; and (ii) a first Fc domain comprising, from N-terminus to C-terminus: a constant domain 2 of a heavy chain (CH2) and a constant domain 3 of a heavy chainAttorney Docket: 51096.4019 / WO (CH3), wherein the C-terminus of the anti-MICA / B scFv is covalently attached to the N-terminus of the first Fc domain using a domain linker; (b) a second monomer comprising, from N-terminus to C-terminus: a second variable (VH2) domain, a constant domain 1 of a heavy chain (CH1), a constant domain 2 of a heavy chain (CH2), a constant domain 3 of a heavy chain (CH3), wherein CH2-CH3 is a second Fc domain; and (c) a common light chain comprising, from N-terminus to C-terminus: a second variable light (VL2) domain and a constant domain light chain (CL), wherein the second variable heavy (VH2) domain and the second variable light (VL2) domain form a CD3 antigen binding domain.

8. The bispecific antibody according to claim 7, wherein the CD3 antigen binding domain comprises a set of vhCDR1-3 and vlCDR1-3 from a variable heavy domain and variable light domain pair selected from the group consisting of: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.

31.

9. The bispecific antibody according to claim 7 or 8, wherein the CD3 antigen binding domain comprises a variable heavy domain and variable light domain pair selected from the group consisting of: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.

31.

10. The bispecific antibody according to any one of claims 7-9, wherein the anti-MICA / B scFv comprises a set of vhCDR1-3 and vlCDR1-3 from a first variable heavy VH1 domain and first variable light VL1 domain pair, wherein the set of vhCDR1-3 and vlCDR1-3 is selected from the group consisting of: D99136_2C11 [MICA / B]_H0, D99136_2C11 [MICA / B]_H1, D99136_2C11 [MICA / B]_H2, D94837_1E11_1 [MICA / B]_H0, D94837_1E11_1 [MICA / B]_H1, D94837_1E11_1 [MICA / B]_H2 for the set of vhCDR1-3, and D99136_2C11 [MICA / B]_L0, D99136_2C11 [MICA / B]_L1, D99136_2C11 [MICA / B]_L2, D94837_1E11_1 [MICA / B]_L0, D94837_1E11_1 [MICA / B]_L1, D94837_1E11_1 [MICA / B]_L2 for the set of vlCDR1-3.Attorney Docket: 51096.4019 / WO 11. The bispecific antibody according to any one of claims 7-10, wherein the anti-MICA / B scFv comprises a first variable heavy domain and first variable light domain pair selected from the group consisting of: D99136_2C11 [MICA / B]_H0L0, D99136_2C11 [MICA / B]_H1L1, D99136_2C11 [MICA / B]_H1L2, D99136_2C11 [MICA / B]_H2L1, D99136_2C11 [MICA / B]_H2L2, D94837_1E11_1 [MICA / B]_H0L0, D94837_1E11_1 [MICA / B]_H1L1, D94837_1E11_1 [MICA / B]_H1L2. D94837_1E11_1 [MICA / B]_H2L1, and D94837_1E11_1 [MICA / B]_H2L2.

12. The bispecific antibody according to any one of claims 7-11, wherein the first variable light (VL1) domain of the anti-MICA / B scFv is covalently attached to the N-terminus of the first Fc domain using the domain linker.

13. The bispecific antibody according to any one of claims 7-11, wherein the first variable heavy (VH1) domain of the anti-MICA / B scFv is covalently attached to the N-terminus of the first Fc domain using the domain linker.

14. The bispecific antibody according to any one of claims 1-13, wherein the scFv linker is a charged scFv linker.

15. The bispecific antibody according to claim 14, wherein the scFv linker is a charged scFv linker having the amino acid sequence (GKPGS)4(SEQ ID NO: 1).

16. The bispecific antibody according to any one of claims 1-15, wherein the first and second Fc domains are each variant Fc domains.

17. The bispecific antibody according to claim 16, wherein the first and / or second variant Fc domains comprise one or more FcγRIIIA (CD16a) binding variant substitutions.

18. The bispecific antibody according to claim 17, wherein the one or more FcγRIIIA (CD16a) binding variant substitutions are selected from the group consisting of: (i) 236A, (ii) 239D, (iii) 239E, (iv) 243L, (v) 298A, (vi) 299T, (vii) 332E, (viii) 332D, (ix) 239D / 332E, (x) 236A / 332E, (xi) 239D / 332E / 330L, and (xii) 332E / 330L, wherein numbering is according to EU numbering.

19. The bispecific antibody according to claim 18, wherein the first and second variant Fc domains comprise a set of FcγRIIIA (CD16a) binding variant substitutions selected from theAttorney Docket: 51096.4019 / WO group consisting of: (i) S239D / I332E : S239D / I332E, (ii) S239D : S239D, (iii) I332E : I332E, (iv) WT : S239D / I332E, (v) WT : S239D, (vi) WT : I332E, (vii) S239D / I332E : WT, (viii) S239D : WT, (ix) I332E : WT, (x) S239D / I332E : S239D, (xi) S239D / I332E : I332E, (xii) S239D : S239D / I332E, (xiii) I332E : S239D / I332E, (xiv) S239D : I332E, and (xv) I332E : S239D, wherein numbering is according to EU numbering.

20. The bispecific antibody according to any one of claims 17-19, wherein the first and / or second variant Fc domains comprise the FcγRIIIA (CD16a) binding variant substitutions of S239D / I332E, wherein numbering is according to EU numbering.

21. The bispecific antibody according to claim 20, wherein the first and second variant Fc domains comprise a set of heterodimerization variants selected from the group consisting of: (i) S364K / E357Q : L368D / K370S, (ii) S364K : L368D / K370S, (iii) S364K : L368E / K370S, (iv) D401K : T411E / K360E / Q362E, and (v) T366W : T366S / L368A / Y407V, wherein numbering is according to EU numbering.

22. The bispecific antibody according to any one of claims 17-21, wherein the first and second variant Fc domains further comprise one or more ablation variants.

23. The bispecific antibody according to claim 22, wherein the one or more ablation variants are E233P / L234V / L235A / G236del / S267K, wherein numbering is according to EU numbering.

24. The bispecific antibody according to any one of claims 1-23, wherein the first and / or second variant Fc domains comprises one or more pI variants.

25. The bispecific antibody according to claim 24, wherein the one or more pI variants are N208D / Q295E / N384D / Q418E / N421D, wherein numbering is according to EU numbering.

26. The bispecific antibody according to any one of claims 1-25, wherein the first monomer comprises amino acid variants S364K / E357Q / E233P / L234V / L235A / G236del / S267K, wherein the second monomer comprises amino acid variants L368D / K370S / N208D / Q295E / N384D / Q418E / N421D / E233P / L234V / L235A / G236del / S267K, and wherein numbering is according to EU numbering.

27. The bispecific antibody according to any one of claims 1-26, wherein the first and secondAttorney Docket: 51096.4019 / WO monomers each further comprise amino acid variants M428L / N434S, M428L / N434A or M252Y / S254T / T256E, wherein numbering is according to EU numbering.

28. The bispecific antibody according to any one of claims 1-27 selected from the group consisting of: XENP50442, XENP50444, and XENP50445.

29. A nucleic acid composition comprising nucleic acids encoding the first and second monomers and the light chain of the antibody according to any one of claims 1-28.

30. An expression vector comprising the nucleic acids according to claim 29.

31. A host cell transformed with an expression vector according to claim 30.

32. A method of making a bispecific antibody comprising: (a) culturing the host cell according to claim 31 under conditions wherein the bispecific antibody is expressed; and (b) recovering the bispecific antibody.

33. A bispecific antibody, comprising: (a) a first monomer comprising, from N-terminus to C-terminus: a first variable heavy (VH1) domain, a first constant domain 1 of a heavy chain (CH1), a(n) (optional) hinge domain, the first VH1 domain, the first CH1 domain, a constant domain 2 of a heavy chain (CH2), a constant domain 3 of a heavy chain (CH3), wherein CH2-CH3 is a first Fc domain; (b) a light chain comprising, from N-terminus to C-terminus: a first variable light (VL1) domain and a constant domain light chain (CL), wherein the VH1 and VL1 form MICA / B antigen binding domains; and (c) a second monomer comprising, from N-terminus to C-terminus: an anti-CD3 scFv and a second Fc domain, wherein the scFv is covalently attached to the N-terminus of the second Fc domain using a second linker.

34. The bispecific antibody according to claim 33, wherein the anti-CD3 scFv comprises, from N-terminus to C-terminus: (1) a second variable heavy (VH2) domain, an scFv linker, and aAttorney Docket: 51096.4019 / WO second variable light (VL2) domain, or (2) a second variable light (VL2) domain, an scFv linker, and a second variable heavy (VH2) domain.

35. The bispecific antibody according to claim 33 or 34, wherein the anti-CD3 scFv comprises a set of vhCDR1-3 and vlCDR1-3 from a variable heavy domain and variable light domain pair selected from the group consisting of: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.31, as depicted in Figure 15.

36. The bispecific antibody according to any one of claims 33-35, wherein the anti-CD3 scFv comprises a variable heavy domain and variable light domain pair selected from the group consisting of: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.31, as depicted in Figure 15.

37. The bispecific antibody according to any one of claims 33-36, wherein each of the MICA / B antigen binding domains comprise a set of vhCDR1-3 and vlCDR1-3 from a variable heavy domain and variable light domain pair, wherein the set of vhCDR1-3 and vlCDR1-3 is selected from the group consisting of: D99136_2C11 [MICA / B]_H0, D99136_2C11 [MICA / B]_H1, D99136_2C11 [MICA / B]_H2, D94837_1E11_1 [MICA / B]_H0, D94837_1E11_1 [MICA / B]_H1, and D94837_1E11_1 [MICA / B]_H2 for the set of vhCDR1-3, and D99136_2C11 [MICA / B]_L0, D99136_2C11 [MICA / B]_L1, D99136_2C11 [MICA / B]_L2, D94837_1E11_1 [MICA / B]_L0, D94837_1E11_1 [MICA / B]_L1, and D94837_1E11_1 [MICA / B]_L2 for the set of vlCDR1-3, as depicted in Figure 16.

38. The bispecific antibody according to any one of claims 33-37, wherein each of the MICA / B antigen binding domains comprise a variable heavy domain and variable light domain pair selected from the group consisting of: D99136_2C11 [MICA / B]_H0L0, D99136_2C11 [MICA / B]_H1L1, D99136_2C11 [MICA / B]_H1L2, D99136_2C11 [MICA / B]_H2L1, D99136_2C11 [MICA / B]_H2L2, D94837_1E11_1 [MICA / B]_H0L0, D94837_1E11_1 [MICA / B]_H1L1, D94837_1E11_1 [MICA / B]_H1L2. D94837_1E11_1 [MICA / B]_H2L1, and D94837_1E11_1 [MICA / B]_H2L2, as depicted in Figure 16.Attorney Docket: 51096.4019 / WO 39. A bispecific antibody, comprising: (a) a first monomer comprising, from N-terminus to C-terminus: a first variable heavy (VH1) domain, a first constant domain 1 of a heavy chain (CH1), a(n) (optional) hinge domain, the first VH1 domain, the first CH1 domain, a constant domain 2 of a heavy chain (CH2), a constant domain 3 of a heavy chain (CH3), wherein CH2-CH3 is a first Fc domain; (b) a light chain comprising, from N-terminus to C-terminus: a first variable light (VL1) domain and a constant domain light chain (CL), wherein the VH1 and VL1 form CD3 antigen binding domains; and (c) a second monomer comprising, from N-terminus to C-terminus: an anti-MICA / B scFv and a second Fc domain, wherein the scFv is covalently attached to the N-terminus of the second Fc domain using a second linker.

40. The bispecific antibody according to claim 39, wherein the anti-MICA / B scFv comprises, from N-terminus to C-terminus: (1) a second variable heavy (VH2) domain, an scFv linker, and a second variable light (VL2) domain, or (2) a second variable light (VL2) domain, an scFv linker, and a second variable heavy (VH2) domain.

41. The bispecific antibody according to claim 39 or 40, wherein the anti-MICA / B scFv comprises a set of vhCDR1-3 and vlCDR1-3 from a variable heavy domain and variable light domain pair, wherein the set of vhCDR1-3 and vlCDR1-3 is selected from the group consisting of: D99136_2C11 [MICA / B]_H0, D99136_2C11 [MICA / B]_H1, D99136_2C11 [MICA / B]_H2, D94837_1E11_1 [MICA / B]_H0, D94837_1E11_1 [MICA / B]_H1, and D94837_1E11_1 [MICA / B]_H2 for the set of vhCDR1-3, and D99136_2C11 [MICA / B]_L0, D99136_2C11 [MICA / B]_L1, D99136_2C11 [MICA / B]_L2, D94837_1E11_1 [MICA / B]_L0, D94837_1E11_1 [MICA / B]_L1, and D94837_1E11_1 [MICA / B]_L2 for the set of vlCDR1-3, as depicted in Figure 16.

42. The bispecific antibody according to any one of claims 39-41, wherein the anti-MICA / B scFv comprises a variable heavy domain and variable light domain pair selected from the group consisting of: D99136_2C11 [MICA / B]_H0L0, D99136_2C11 [MICA / B]_H1L1, D99136_2C11 [MICA / B]_H1L2, D99136_2C11 [MICA / B]_H2L1, D99136_2C11 [MICA / B]_H2L2,Attorney Docket: 51096.4019 / WO D94837_1E11_1 [MICA / B]_H0L0, D94837_1E11_1 [MICA / B]_H1L1, D94837_1E11_1 [MICA / B]_H1L2. D94837_1E11_1 [MICA / B]_H2L1, and D94837_1E11_1 [MICA / B]_H2L2, as depicted in Figure 16.

43. The bispecific antibody according to any one of claims 39-42, wherein each of the CD3 antigen binding domains comprise a set of vhCDR1-3 and vlCDR1-3 from a variable heavy domain and variable light domain pair, wherein the set of vhCDR1-3 and vlCDR1-3 is selected from the group consisting of: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.31, as depicted in Figure 15.

44. The bispecific antibody according to any one of claims 39-43, wherein each of the CD3 antigen binding domains comprise a variable heavy domain and variable light domain pair selected from the group consisting of: H1.30_L1.47, H1.32_L1.47, H1.89_L1.47, H1.90_L1.47, H1.33_L1.47, H1.31_L1.47, L1.47_H1.30, L1.47_H1.32, L1.47_H1.89, L1.47_H1.90, L1.47_H1.33, and L1.47_H1.31, as depicted in Figure 15.

45. The bispecific antibody according to any one of claims 33-44, wherein the scFv linker is a charged scFv linker.

46. The bispecific antibody according to claim 45, wherein the scFv linker is a charged scFv linker having the amino acid sequence (GKPGS)4 (SEQ ID NO: 1).

47. The bispecific antibody according to any one of claims 33-46, wherein the first and second linkers are each domain linkers.

48. The bispecific antibody according to any one of claims 33-47, wherein the first and second Fc domains are each variant Fc domains.

49. The bispecific antibody according to claim 48, wherein the first and / or second variant Fc domains comprise one or more FcγRIIIA (CD16a) binding variant substitutions.

50. The bispecific antibody according to claim 49, wherein the one or more FcγRIIIA (CD16a) binding variant substitutions are selected from the group consisting of: (i) 236A, (ii) 239D, (iii) 239E, (iv) 243L, (v) 298A, (vi) 299T, (vii) 332E, (viii) 332D, (ix) 239D / 332E, (x) 236A / 332E,Attorney Docket: 51096.4019 / WO (xi) 239D / 332E / 330L, and (xii) 332E / 330L, wherein numbering is according to EU numbering.

51. The bispecific antibody according to any one of claims 48-50, wherein the first and second variant Fc domains comprise a set of FcγRIIIA (CD16a) binding variant substitutions selected from the group consisting of: (i) S239D / I332E : S239D / I332E, (ii) S239D : S239D, (iii) I332E : I332E, (iv) WT : S239D / I332E, (v) WT : S239D, (vi) WT : I332E, (vii) S239D / I332E : WT, (viii) S239D : WT, (ix) I332E : WT, (x) S239D / I332E : S239D, (xi) S239D / I332E : I332E, (xii) S239D : S239D / I332E, (xiii) I332E : S239D / I332E, (xiv) S239D : I332E, and (xv) I332E : S239D, wherein numbering is according to EU numbering.

52. The bispecific antibody according to any one of claims 48-51, wherein the first and / or second variant Fc domains comprise the FcγRIIIA (CD16a) binding variant substitutions of S239D / I332E, wherein numbering is according to EU numbering.

53. The bispecific antibody according to claim 52, wherein the first and second variant Fc domains comprise a set of heterodimerization variants selected from the group consisting of: (i) S364K / E357Q : L368D / K370S, (ii) S364K : L368D / K370S, (iii) S364K : L368E / K370S, (iv) D401K : T411E / K360E / Q362E, and (v) T366W : T366S / L368A / Y407V, wherein numbering is according to EU numbering.

54. The bispecific antibody according to any one of claims 48-53, wherein the first and second Fc variant domains further comprise one or more ablation variants.

55. The bispecific antibody according to claim 54, wherein the one or more ablation variants are E233P / L234V / L235A / G236del / S267K, wherein numbering is according to EU numbering.

56. The bispecific antibody according to any one of claims 33-55, wherein the first and / or second variant Fc domain further comprises one or more pI variants.

57. The bispecific antibody according to claim 56, wherein the one or more pI variants are N208D / Q295E / N384D / Q418E / N421D, wherein numbering is according to EU numbering.

58. The bispecific antibody according to any one of claims 33-57, wherein the first monomer comprises amino acid variants S364K / E357Q / E233P / L234V / L235A / G236del / S267K, wherein the second monomer comprises amino acid variantsAttorney Docket: 51096.4019 / WO L368D / K370S / N208D / Q295E / N384D / Q418E / N421D / E233P / L234V / L235A / G236del / S267K, and wherein numbering is according to EU numbering.

59. The bispecific antibody according to any one of claims 33-58, wherein the first and second monomers each further comprise amino acid variants M428L / N434S, M428L / N434A or M252Y / S254T / T256E, wherein numbering is according to EU numbering.

60. The bispecific antibody according to any one of claims 33-59 is selected from the group consisting of: XENP50514, XENP50515, XENP50516, XENP50517, XENP50518, and XENP50519.

61. A nucleic acid composition comprising nucleic acids encoding the first and second monomers and the light chain of the antibody according to any one of claims 33-60.

62. An expression vector comprising the nucleic acids according to claim 61.

63. A host cell transformed with an expression vector according to claim 62.

64. A method of making a bispecific antibody comprising: (a) culturing the host cell according to claim 63 under conditions wherein the bispecific antibody is expressed; and (b) recovering the bispecific antibody.

65. A bispecific antibody comprising: (a) a means for binding MICA / B; and (b) a means for binding CD3.

66. A pharmaceutical composition comprising: the bispecific antibody according to any one of claims 1-28, 33-60, and 65; and a pharmaceutically acceptable carrier.

67. A pharmaceutical composition comprising: (a) a first composition comprising a means for binding MICA / B; and (b) a second composition comprising a means for binding CD3.

68. A pharmaceutical composition comprising: (a) a means for binding MICA / B; (b) a means for binding CD3; and (c) a pharmaceutically acceptable carrier.Attorney Docket: 51096.4019 / WO 69. The bispecific antibody according to any one of claims 1-28, 33-60, and 65 or the pharmaceutical composition according to any one of claims 66-68 for use in the treatment of a MICA / B-associated disease and / or CD3-associated disease in a subject in need thereof.

70. The bispecific antibody according to any one of claims 1-28, 33-60, and 65 or the pharmaceutical composition according to any one of claims 66-68 for inhibiting or reducing MICA / B-mediated activity and / or CD3-mediated activity in a subject in need thereof.

71. The bispecific antibody according to any one of claims 1-28, 33-60, and 65 or the pharmaceutical composition according to any one of claims 66-68 for use in the manufacture of a medicament for the treatment of a MICA / B-associated disease and / or CD3-associated disease in a subject in need thereof.

72. The bispecific antibody according to any one of claims 1-28, 33-60, and 65 or the pharmaceutical composition according to any one of claims 66-68 for use in the manufacture of a medicament for inhibiting or reducing MICA / B-mediated activity and / or CD3-mediated activity in a subject in need thereof.

73. The bispecific antibody according to any one of claims 1-28, 33-60, and 65 or the pharmaceutical composition according to any one of claims 66-68, wherein the subject is a human subject.

74. A kit comprising the bispecific antibody according to any one of claims 1-28, 33-60, and 65 or the pharmaceutical composition of any one of claims 66-68.

75. A vessel or delivery device comprising the bispecific antibody according to any one of claims 1-28, 33-60, and 65 or the pharmaceutical composition according to any one of claims 66- 68.

76. A method of treating cancer in a subject in need thereof, the method comprising administering the bispecific antibody of any one of claims 1-28, 33-60, and 65 or the pharmaceutical composition of any one of claims 66-68 to the subject.

77. A method of reducing tumor growth or inhibiting cancer cell proliferation in a subject in need thereof, the method comprising: administering the bispecific antibody of any one of claimsAttorney Docket: 51096.4019 / WO 1-28, 33-60, and 65 or the pharmaceutical composition of any one of claims 66-68 to the subject.

78. A method of treating a MICA / B-associated disease and / or CD3-associated disease in a subject in need thereof, comprising administering to the subject the bispecific antibody of any one of claims 1-28, 33-60, and 65 or the pharmaceutical composition of any one of claims 66-68.

79. A method for inhibiting or reducing MICA / B-mediated activity and / or CD3-mediated activity in a subject in need thereof, comprising administering to the subject the bispecific antibody of any one of claims 1-28, 33-60, and 65 or the pharmaceutical composition of any one of claims 66-68.

80. The method according to any one of claims 76-79, wherein the subject is a human subject.

81. The method according to claim 80, wherein the human subject has cancer, was diagnosed with cancer, or has at least one symptom associated with cancer.

82. Use of the bispecific antibody according to any one of claims 1-28, 33-60, and 65 or the pharmaceutical composition according to any one of claims 66-68 for treating a MICA / B- associated disease and / or CD3-associated disease in a subject in need thereof.

83. Use of the bispecific antibody according to any one of claims 1-28, 33-60, and 65 or the pharmaceutical composition according to any one of claims 66-68 in the manufacture of a medicament for the treatment of a MICA / B-associated disease and / or CD3-associated disease in a subject in need thereof.

84. Use of the bispecific antibody according to any one of claims 1-28, 33-60, and 65 or the pharmaceutical composition according to any one of claims 66-68 in the manufacture of a medicament for inhibiting or reducing MICA / B-mediated activity and / or CD3-mediated activity in a subject in need thereof.

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