Compositions and methods for binding to covalent peptide conjugates

Abstract

Provided herein are compositions and methods that include multivalent polypeptides that demonstrate specific binding to a peptide conjugate / MHC complex comprising a peptide conjugate that is formed by the covalent reaction of a targeted covalent inhibitor with a peptide. The binding partners are provided as antibodies and antibody derivatives that specifically bind to the peptide conjugate / MHC complexes.

Description

COMPOSITIONS AND METHODS FOR BINDING TO COVALENT PEPTIDE CONJUGATESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 637,575, filed on April 23, 2024, the entire content of which is entirely incorporated herein by reference.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under R21 CA267362 and P30 CAO 16087 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0003] There is an ongoing and unmet need for agents that can bind to targets that include drugs that are covalently bound to proteins or peptides. In particular, there is a need to improve the efficacy of targeted therapy and also to increase tumor immunogenicity and the efficacy of immune therapy against cancer driven by intracellular oncogenes and loss of tumor suppressor genes. The disclosure is pertinent to these needs.BRIEF SUMMARY

[0004] Recognized herein are compositions and methods that include binding partners that bind with specificity to target sites on proteins or peptides that comprise a covalently attached molecule. The disclosure illustrates this approach using binding partners in the form of numerous antibodies and antibody derivatives that specifically bind to proteins and peptides that have been covalently modified by attachment of a molecule, wherein the molecules are illustrated by a variety of drugs. Further, the disclosure demonstrates binding partners that bind with specificity to peptides that have been covalently modified by attachment of a small molecule drug are specific for the described covalently modified peptides when presented in the context of a human leukocyte antigen (HLA), wherein HLA is a representative example of a major histocompatibility complex (MHC). Thus, binding partners that are specific for peptide-drug conjugates in an HLA complex are demonstrated. The disclosure includes polynucleotides encoding the described binding partners and cells that are modified to expressthe binding partners. The disclosure includes diagnostic, prophylactic and therapeutic approaches using the binding partners.

[0005] In some aspects, the present disclosure provides a multivalent polypeptide comprising: a first antigen-binding domain that binds to a peptide conjugate / MHC complex, wherein the peptide conjugate / MHC complex comprises a peptide conjugate formed by a covalent reaction of a targeted covalent inhibitor or fragment thereof with a peptide and an MHC; a second antigen-binding domain that binds to a T cell surface protein; and an Fc region comprising a first Fc subunit and a second Fc subunit; wherein the first antigen-binding domain, the second antigen-binding domain, the first Fc subunit, and the second Fc subunit are operably linked to form a single continuous polypeptide chain.

[0006] In some examples, the multivalent polypeptide comprises, from N-terminus to C- terminus, the first antigen-binding domain, the second antigen-binding domain, the first Fc subunit, and the second Fc subunit. In some examples, the multivalent polypeptide comprises, from N-terminus to C-terminus, the first antigen-binding domain, a first linker, the second antigen-binding domain, a second linker, the first Fc subunit, a third linker, and the second Fc subunit. In some examples, the multivalent polypeptide comprises, from N-terminus to C- terminus, the second antigen-binding domain, the first antigen-binding domain, the first Fc subunit, and the second Fc subunit. In some examples, the multivalent polypeptide comprises, from N-terminus to C-terminus, the second antigen-binding domain, a first linker, the first antigen-binding domain, a second linker, the first Fc subunit, a third linker, and the second Fc subunit.

[0007] In some examples, the Fc region comprises an amino acid sequence as set forth in SEQ ID NOs: 64 or 79, or an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 64 or 79.

[0008] In some examples, the first linker, the second linker, and / or the third linker comprises an amino acid sequence as set forth in SEQ ID NOs: 60, 62, 63, 95, or 139. In some examples, the first linker comprises an amino acid sequence as set forth in SEQ ID NO: 62. In some examples, the second linker comprises an amino acid sequence as set forth in SEQ ID NO: 63. In some examples, the third linker comprises an amino acid sequence as set forth in SEQ ID NO: 139 (GGGGSGGGGSGGGGSGGGGSGGGGSGGGGS).

[0009] In some examples, the first linker has a length of from 4-12, 4-10, 4-8, 4-6 or 6 amino acids. In some examples, the first linker comprises an amino acid sequence according to the formula SGxS or GxS, wherein X is 3 or 4. In some examples, the first linker comprises an amino acid sequence according to the formula SGxS, wherein X is 4. In some examples, thefirst linker comprises an amino acid sequence according to the formula SxG, wherein X is 3 or 4.

[0010] In some examples, the second linker has a length of from 3-12, 3-10, 3-8, 3-6 or 4 amino acids. In some examples, the second linker comprises an amino acid sequence according to the formula Gx, wherein X is 3, 4, or 5. In some examples, X is 4. In some examples, the second linker comprises an amino acid sequence according to the formula SGx, wherein X is 3 or 4.

[0011] In some examples, the third linker has a length of from 20-40, 20-35, 25-40, 25-35, 25- 30, 30-35, 28-32 or 30 amino acids. In some examples, the third linker comprises an amino acid sequence according to the formula (GXS)N or GxS, wherein X is 3 or 4 and N is 3, 4, 5, 6, 7, 8, 9 or 10. In some examples, X is 4 and N is 5, 6 or 7. In some examples, X is 4 and N is 6.

[0012] In some examples, the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

[0013] In some examples, the Fc region comprises an Fc-silencing mutation, which Fc- silencing mutation decreases an antibody-directed cytotoxicity effector function.

[0014] In some examples, the Fc-silencing mutation comprises a AAA mutation or a CGC mutation, wherein the AAA mutation comprises L234A, L235A, G237A of a sequence of SEQ ID NO: 140, and wherein the CGC mutation comprises R292C, N297G, V302C of a sequence of SEQ ID NO: 140.

[0015] In some examples, the multivalent polypeptide comprises an amino acid sequence with at least 80% sequence identity to an amino acid sequence as set forth in SEQ ID NOs: 58, 65, 66-78, or 80-92 or at least 90% identical to an amino acid sequence as set forth in SEQ ID NOs: 58, 65, 66-78, or 80-92.

[0016] In some examples, the multivalent polypeptide comprises an amino acid sequence as set forth in SEQ ID NOs: 58, 65, 66-78, or 80-92.

[0017] In some examples, the first antigen-binding domain comprises a first single-chain variable fragment (scFv) comprising a heavy chain variable region (VH) and a light chain variable region (VL). In some examples, the second antigen-binding domain comprises a second single-chain variable fragment (scFv) comprising a heavy chain variable region (VH) and a light chain variable region (VL). In some examples, the multivalent polypeptide comprises, from N-terminus to C-terminus, the VH of the first scFv, the VL of the first scFv, the VH of the second scFv, and the VL of the second scFv. In some examples, the multivalent polypeptide comprises, from N-terminus to C-terminus, the VH of the second scFv, the VL of the second scFv, the VH of the first scFv, and the VL of the first scFv. In some examples, themultivalent polypeptide comprises, from N-terminus to C-terminus, the VL of the first scFv, the VH of the first scFv, the VL of the second scFv, and the VH of the second scFv. In some examples, the multivalent polypeptide comprises, from N-terminus to C-terminus, the VL of the second scFv, the VH of the second scFv, the VL of the first scFv, and the VH of the first scFv. In some examples, the multivalent polypeptide comprises, from N-terminus to C- terminus, the VH of the second scFv, the VL of the second scFv, the VL of the first scFv, and the VH of the first scFv. In some examples, the multivalent polypeptide comprises, from N- terminus to C-terminus, the VH of the first scFv, the VL of the first scFv, the VL of the second scFv, and the VH of the second scFv. In some examples, the multivalent polypeptide comprises, from N-terminus to C-terminus, the VL of the first scFv, the VH of the first scFv, the VH of the second scFv, and the VL of the second scFv. In some examples, the multivalent polypeptide comprises, from N-terminus to C-terminus, the VL of the second scFv, the VH of the second scFv, the VH of the first scFv, and the VL of the first scFv.

[0018] In some aspects, the present disclosure provides a multivalent polypeptide comprising: a first antigen-binding domain that binds to a peptide conjugate / MHC complex, wherein the peptide conjugate / MHC complex comprises a peptide conjugate formed by a covalent reaction of a targeted covalent inhibitor or fragment thereof with a peptide and an MHC; and a second antigen-binding domain that binds to a T cell surface protein; wherein the first antigen-binding domain comprises a first heavy chain variable region (VH) and a first light chain variable region (VL) and the second antigen-binding domain comprises a second VH and a second VL, and wherein the second VL comprises: a CDR-L3 sequence of QQGNTLPWT (SEQ ID NO: 136), a CDR-L2 sequence of YTSRLES (SEQ ID NO: 137), and a CDR-L1 sequence of RASQDIRNYLN (SEQ ID NO: 138).

[0019] In some examples, the multivalent polypeptide comprises an amino acid sequence with at least 80% sequence identity to an amino acid sequence as set forth in SEQ ID NOs: 93 or 98-110.

[0020] In some examples, the multivalent polypeptide comprises an amino acid sequence as set forth in SEQ ID NOs: 93 or 98-110.

[0021] In some examples, the multivalent polypeptide comprises a fusion tag. In some examples, the fusion tag comprises an amino acid sequence as set forth in SEQ ID NO: 96.

[0022] In some examples, the multivalent polypeptide further comprises an Fc region comprising a first Fc subunit and a second Fc subunit. In some examples, the first Fc subunit comprises a protuberance and the second Fc subunit comprises a cavity, wherein the protuberance of the first Fc subunit chain interfaces with the cavity of the second Fc subunit.In some examples, the first Fc subunit comprises an amino acid sequence as set forth in SEQ ID NO: 113. In some examples, the second Fc subunit comprises an amino acid sequence as set forth in SEQ ID NO: 114.

[0023] In some examples, the first Fc subunit and / or the second Fc subunit comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

[0024] In some examples, the first Fc subunit or the second Fc subunit comprises an Fc- silencing mutation. In some examples, the first Fc subunit and the second Fc subunit comprise an Fc-silencing mutation. In some examples, the Fc-silencing mutation of the first Fc subunit comprises L234A, L235A, P329G, or any combination thereof; and / or the Fc-silencing mutation of the second Fc subunit comprises L234A, L235A, P329G, or any combination thereof.

[0025] In some examples, the one or more amino acid substitutions of the first Fc subunit comprise P354C and / or T366W.

[0026] In some examples, the one or more amino acid substitutions of the second Fc subunit comprise Y349C, T366S, M368A, Y407V or any combination thereof.

[0027] In some examples, a polypeptide chain comprising the first Fc subunit comprises an amino acid sequence with at least 80% sequence identity to an amino acid sequence as set forth in SEQ ID NOs: 111 or 115-127. In some examples, a polypeptide chain comprising the first Fc subunit comprises an amino acid sequence as set forth in SEQ ID NOs: 111 or 115-127.

[0028] In some aspects, the present disclosure provides a multivalent polypeptide comprising: a first antigen-binding domain that binds to a peptide conjugate / MHC complex, wherein the peptide conjugate / MHC complex comprises a peptide conjugate formed by a covalent reaction of a targeted covalent inhibitor or fragment thereof with a peptide and an MHC; a second antigen-binding domain that binds to a T cell surface protein; wherein the first antigen-binding domain comprises a first heavy chain variable region (VH) and a first light chain variable region (VL) and the second antigen-binding domain comprises a second VH and a second VL, wherein the first antigen-binding domain and the second antigen-binding domain are linked, and wherein the first VH, the second VH, the first VL, or the second VL is linked to a Fc region having at least a first Fc subunit.

[0029] In some examples, the Fc region comprises the first Fc subunit and a second Fc subunit.

[0030] In some examples, the first Fc subunit and the second Fc subunit is linked by at least one disulfide bond and is not linked to form a continuous polypeptide.

[0031] In some examples, the first Fc subunit comprises a protuberance and the second polypeptide chain comprises a cavity, wherein the protuberance of the first Fc subunit chain interfaces with the cavity of the second Fc subunit. In some examples, the first Fc subunit comprises an amino acid sequence as set forth in SEQ ID NO: 113. In some examples, the second Fc subunit comprises an amino acid sequence as set forth in SEQ ID NO: 114.

[0032] In some examples, the first Fc subunit and / or the second Fc subunit comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

[0033] In some examples, the first Fc subunit or the second Fc subunit comprises an Fc- silencing mutation. In some examples, the first Fc subunit and the second Fc subunit comprise an Fc-silencing mutation. In some examples, the Fc-silencing mutation of the first Fc subunit comprises L234A, L235A, P329G, or any combination thereof; and / or the Fc-silencing mutation of the second Fc subunit comprises L234A, L235A, P329G, or any combination thereof. In some examples, the one or more amino acid substitutions of the first Fc subunit comprise P354C and / or T366W. In some examples, the one or more amino acid substitutions of the second Fc subunit comprise Y349C, T366S, M368A, Y407V or any combination thereof.

[0034] In some examples, a polypeptide chain comprising the first Fc subunit comprises an amino acid sequence with is at least 80% sequence identity to an amino acid sequence as set forth in SEQ ID NOs: 111 or 115-127. In some examples, a polypeptide chain comprising the first Fc subunit comprises an amino acid sequence as set forth in SEQ ID NOs: 111 or 115- 127.

[0035] In some examples, the multivalent polypeptide comprises, from N-terminus to C- terminus, (i) the first VL, the second VH, the second VL, and the first VH; (ii) the second VL, the first VH, the first VL, and the second VH; (iii) the first VL, the second VL, the second VH, and the first VH; (iv) the second VL, the first VL, the first VH, and the second VH; (v) the first VH, the second VL, the second VH, and the first VL; (vi) the first VH, the second VH, the second VL, and the first VL; (vii) the second VH, the first VL, the first VH, the second VL; (viii) the second VH, the first VH, the first VL, and the second VL; (ix) the first VH, the first VL, the second VH, and the second VL; (x) the first VL, the first VH, the second VH, and the second VL; (xi) the first VH, the first VL, the second VL, and the second VH; (xii) the first VL, the first VH, the second VL, and the second VH; (xiii) the second VH, the second VL, the first VH, and the first VL; (xiv) the second VL, the second VH, the first VH, and the first VL;(xv) the second VH, the second VL, the first VL, and the first VH; or (xvi) the second VL, the second VH, the first VL, and the first VH.

[0036] In some examples, the first Fc subunit is linked to the first VH or the second VH.

[0037] In some examples, the multivalent polypeptide comprises at least one linker.

[0038] In some examples, the at least one linker comprises an amino acid sequence as set forth in SEQ ID NOs: 60, 62, 63, 95, or 112.

[0039] In some examples, the multivalent polypeptide comprises, from N-terminus to C- terminus, (i) the first VL, a first linker, the second VH, a second linker, the second VL, a third linker, the first VH, a fourth linker, and the first Fc subunit; (ii) the second VL, a first linker, the first VH, a second linker, the first VL, a third linker, the second VH, a fourth linker, and the first Fc subunit; (iii) the first VL, a first linker, the second VL, a second linker, the second VH, a third linker, the first VH, a fourth linker, and the first Fc subunit; (iv) the second VL, a first linker, the first VL, a second linker, the first VH, a third linker, the second VH, a fourth linker, and the first Fc subunit; (v) the first VH, a first linker, the second VL, a second linker, the second VH, a third linker, the first VL, a fourth linker, and the first Fc subunit; (vi) the first VH, a first linker, the second VH, a second linker, the second VL, a third linker, the first VL, a fourth linker, and the first Fc subunit; (vii) the second VH, a first linker, the first VL, a second linker, the first VH, a third linker, the second VL, a fourth linker, and the first Fc subunit; (viii) the second VH, a first linker, the first VH, a second linker, the first VL, a third linker, the second VL, a fourth linker, and the first Fc subunit; (ix) the first VH, a first linker, the first VL, a second linker, the second VH, a third linker, the second VL, a fourth linker, and the first Fc subunit; (x) the first VL, a first linker, the first VH, a second linker, the second VH, a third linker, the second VL, a fourth linker, and the first Fc subunit; (xi) the first VH, a first linker, the first VL, a second linker, the second VL, a third linker, the second VH, a fourth linker, and the first Fc subunit; (xii) the first VL, a first linker, the first VH, a second linker, the second VL, a third linker, the second VH, a fourth linker, and the first Fc subunit; (xiii) the second VH, a first linker, the second VL, a second linker, the first VH, a third linker, the first VL, a fourth linker, and the first Fc subunit; (xiv) the second VL, a first linker, the second VH, a second linker, the first VH, a third linker, the first VL, a fourth linker, and the first Fc subunit; (xv) the second VH, a first linker, the second VL, a second linker, the first VL, a third linker, the first VH, a fourth linker, and the first Fc subunit; or (xvi) the second VL, a first linker, the second VH, a second linker, the first VL, a third linker, the first VH, a fourth linker, and the first Fc subunit.

[0040] In some examples, the first linker comprises SEQ ID NO: 95, the second linker comprises SEQ ID NO: 60, the third linker comprises SEQ ID NO: 95, and / or the fourth linker comprises SEQ ID NO: 112.

[0041] In some examples, the multivalent polypeptide comprises a polyhistidine-tag and optionally wherein the polyhistidine-tag comprises an amino acid sequence as set forth in SEQ ID NO: 97.

[0042] In some examples, the second antigen-binding domain binds to CD3 epsilon.

[0043] In some examples, the second antigen-binding domain comprises six complementarity determining regions (CDRs) from heavy chain variable region (VH) and light chain variable region (VL) of a UCHT1 antibody, comprising: a CDR-H3 sequence of SGYYGDSDWYFDV (SEQ ID NO: 133), a CDR-H2 sequence of LINPYKGVSTYNQKFKD (SEQ ID NO: 134), a CDR-H1 sequence of GYTMN (SEQ ID NO: 135), a CDR-L3 sequence of QQGNTLPWT (SEQ ID NO: 136), a CDR-L2 sequence of YTSRLES (SEQ ID NO: 137), and a CDR-L1 sequence of RASQDIRNYLN (SEQ ID NO: 138).

[0044] In some examples, the VH comprises a sequence with at least 90% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYK GVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFD VWGQGTLVTVSS (SEQ ID NO: 59). In some examples, the VH comprises a sequence of EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALINPYK GVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYYGDSDWYFD VWGQGTLVTVSS (SEQ ID NO: 59).

[0045] In some examples, the VL comprises a sequence with at least 90% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGV PSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIK (SEQ ID NO: 61). In some examples, the VL comprises a sequence of DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGV PSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIK (SEQ ID NO: 61).

[0046] In some examples, the first antigen-binding domain binds to the peptide conjugate / MHC complex with a greater affinity than to the peptide or a free targeted covalent inhibitor. In some examples, the affinity of the first antigen-binding domain for the peptideconjugate / MHC complex is 100-10,000 times greater than the affinity of the first antigenbinding domain for the peptide or free targeted covalent inhibitor.

[0047] In some examples, the peptide comprises a cysteine residue. In some examples, a peptide conjugate of the peptide conjugate / MHC complex is formed by a covalent reaction between the targeted covalent inhibitor and the cysteine residue in the peptide. In some examples, the peptide comprises a segment of KRASG13C, KRASG12C, KRASG12D, KRASG12R, or KRASG12S. In some examples, the peptide comprises the amino acid sequence of VVVGACGVGK, VVGACGVGK, or KLVVVGACGV. In some examples, the targeted covalent inhibitor is (i) a tri-complex KRASG12Cinhibitor or a KRASG12Cdegrader, (ii) a tricomplex KRASG12Dinhibitor or a KRASG12Ddegrader, (iii) a tri-complex KRASG12Rinhibitor or a KRASG12Rdegrader, (iv) a tri-complex KRASG13Cinhibitor or a KRASG13Cdegrader, or (v) a tri-complex KRASG12Sinhibitor or a KRASG12Sdegrader. In some examples, (i) the peptide comprises a KRASG12Cmutation, and the targeted covalent inhibitor is a KRASG12Cinhibitor, (ii) the peptide comprises a KRASG12Dmutation, and the targeted covalent inhibitor is a KRASG12Dinhibitor, (iii) the peptide comprises a KRASG12Rmutation, and the targeted covalent inhibitor is a KRASG12Rinhibitor, (iv) the peptide comprises a KRASG13Cmutation, and the targeted covalent inhibitor is a KRASG13Cinhibitor, or (v) the peptide comprises a KRASG12Smutation, and the targeted covalent inhibitor is a KRASG12Sinhibitor.

[0048] In some examples, the targeted covalent inhibitor is AMG-510, ARS-1620, ARS-853, ARS-3248, MRTX849, JNJ74699157, LY3499446, LY3537982, MRTX-1257, JDQ443, RMC-6291, RMC-9805, GDC-6036, D-1553, 2E07, 6H05, SML-8-73-1, MK1084, RG6330, BPI-421286, GH35, BEBT-607, JAB-21000, AZD4625, AZD4747, or BI 182391.

[0049] In some examples, the targeted covalent inhibitor is: sotorasib, adagrasib, opnurasib, divarasib, garsorasib, l-[4-[6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4- yl]piperazin- 1 -yl]prop-2-en- 1 -one, 1 -(3 -(4-((4-chl oro-2 -hydroxy-5-( 1 - methylcyclopropyl)phenyl)glycyl)piperazin- 1 -yl)azetidin- 1 -yl)prop-2-en- 1 -one, 1 -(4-(7 -(2-Amino-7-fluoro-l,3-benzothiazol-4-yl)-6-chloro-8-fluoro-quinazolin-4-yl)piperazin-l- yl)prop-2-en-l-one, 2-Amino-4-[(4aS)-8-chloro-10-fluoro-2,3,4,4a,5,6-hexahydro-12-oxo-3- ( 1 -oxo-2-propen- 1 -y 1)- 1 H, 12H-pyrazino[2, 1 -d] [ 1 , 5]benzoxazocin-9-yl]-7- fluorobenzo[b]thiophene-3-carbonitrile, 2-[(2S)-4-[7-(8-methylnaphthalen-l-yl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l -prop-2- enoylpiperazin-2-yl]acetonitrile, 4-(4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-lH-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol, l-[4-(dimethylamino)-4-methylpent-2-ynoyl]-N-[(2S)-l-[[(6S,8S,14S)-22-ethyl-21-[2-[(lS)-l-methoxyethyl]pyridin-3-yl]-18,18-dimethyl-9,15- dioxo-5,16-dioxa-2,10,22,28-tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1 (26), 20, 23 (27),24-tetraen-8-yl]amino]-3 -methyl- 1 -oxobutan-2-yl]-4-fluoro-N- methylpiperidine-4-carboxamide, 1 -((3R, 14aS)- 11 -Chloro-9-fluoro- 10-(2-fluoro-6- hy droxyphenyl)-3 -methyl- 1,3,4,13,14,14a-hexahydro-2H- pyrazino[l',2':5,6][l,5]oxazocino[4,3,2-de]quinazolin-2-yl)prop-2-en-l-one, N-(5-(3,5- dimethoxyphenethyl)-lH-pyrazol-3-yl)-4-((3S,5R)-3,5-dimethylpiperazin-l-yl)benzamide, or [[(2R,3S,4R,5R)-5-(2-amino-6-oxo-lH-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy- hydroxyphosphoryl] 2-[(2-chloroacetyl)amino]ethyl hydrogen phosphate],

[0050] In some examples, the multivalent polypeptide specifically binds to the peptide conjugate / MHC complex comprising a peptide conjugate formed by the covalent reaction of AMG-510 and KRASG12Cpeptide.

[0051] In some examples, the MHC is HLA-A*02:01, HLA-A*03:01, HLA-A* 11:01, HLA- A*68:01, HLA-A*31:01, HLA-A*30:01, HLA-A*33:03, HLA-A*33:01, HLA-A*74:01, HLA-A*34:02, HLA-A*66:01, HLA-A*68:02, HLA-A*02:05, HLA-A*02:02, HLA- A*02:06, or any combination thereof.

[0052] In some examples, the MHC is encoded by an HLA allele of HLA-A3 supertype. In some examples, the HLA allele of the HLA-A3 supertype is selected from the group consisting of HLA-A*03:01, HLA-A* 11 :01, HLA-A*68:01, HLA-A*31 :01, HLA-A*30:01, HLA- A*74:01, HLA-A*34:02, and HLA-A*66:01. In some examples, the MHC is encoded by an HLA allele of HLA-A2 supertype. In some examples, the HLA allele of the HLA-A2 supertype is selected from the group consisting of HLA-A* 02:01, HLA-A*02:02, HLA-A*02:03, HLA- A*02:04, HLA-A*02:05, HLA-A*02:06, HLA-A*02:07, HLA-A*02: 14, HLA-A*02: 17, HLA-A*68:02, and HL A- A* 69:01.

[0053] In some examples, the peptide comprises the amino acid sequence of VVVGACGVGK or VVGACGVGK and the MHC is HLA-A*03:01 or HLA-A* 11 :01. In some examples, the peptide comprises the amino acid sequence of KLWVGACGV and the MHC is HLA- A*02:01.

[0054] In some examples, the first antigen-binding domain is selected from the group consisting of R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, Ri l l, R112, R113, R114, R115, R116, R117, R118, R119, R120, R121, R122, and R123.

[0055] In some examples, the first antigen-binding domain binds to the peptide conjugate / MHC complex with a dissociation constant (KD) of at most 20 nM. In some examples, the first antigen-binding domain binds to the free targeted covalent inhibitor withKD of at least 200 nM. In some examples, the first antigen-binding domain binds to the peptide conjugate / MHC complex with a KD of at most 20 nM, at most 10 nM, at most 5 nM, at most 1 nM, at most 0.1 nM, at most 0.01 nM, at most 0.001 nM, at most 0.1 pM, or at most 0.01 pM. In some examples, the first antigen-binding domain binds to the peptide conjugate / MHC complex with a KD between 0.0001 nM and 10 nM. In some examples, the first antigen-binding domain binds to the free targeted covalent inhibitor with a dissociation constant (KD) of at least about 10, 100, 10,000, or 100,000 times more than the KD of the first antigen-binding domain binding to the peptide conjugate / MHC complex. In some examples, the first antigen-binding domain binds to a free peptide conjugate with a dissociation constant (KD) of more than about 100 nM, more than about 200 nM, more than about 300 nM, more than about 400 nM, more than about 500 nM, more than 1 pM, more than 10 pM, more than 20 pM, more than 30 pM, more than 40 pM, more than 50 pM, or more than 100 pM. In some examples, the first antigenbinding domain binds to a free peptide conjugate with a dissociation constant (KD) that is at least about 10, 100, 10,000, 100,000 times more than the KD of the first antigen-binding domain binding to the peptide conjugate / MHC complex.

[0056] In some examples, the first antigen-binding domain binds to the peptide conjugate / MHC complex with a dissociation rate constant (koff) of at most 20.0 hr’1. In some examples, the first antigen-binding domain binds to the peptide conjugate / MHC complex with a dissociation rate constant (koft) of at most 0.05 hr’1.

[0057] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VL comprises: a light chain complementarity determining region 3 CDR-L3 comprising the amino acid sequence of QQASYVX1X2TIT (SEQ ID NO: 128), wherein Xi is R or W, and X2is H, V, I, or K, and wherein if Xi is R, X2is not K.

[0058] In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of XISX2YSIH (SEQ ID NO: 129), wherein Xi is F or I, and X2is D or S. In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of XiYSIH (SEQ ID NO: 130), wherein Xi is D or S. In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSXIX2X3X4VA (SEQ ID NO: 131), wherein Xi is I, L, Y, or V, X2is S, A, Y, T, H, or L, X3 is H, S, or R, and X4 is T, A, or L. In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of XiASSLYS (SEQ ID NO: 132), wherein Xi is Q, S, or L. In some examples, the VH comprises: a CDR-H1 comprising the amino acid sequence of DYSIH (SEQ ID NO: 3), or a variant thereof comprising 1-3 amino acid changes; a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG(SEQ ID NO: 5), or a variant thereof comprising 1-5 amino acid changes; and / or a CDR-H3 comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6), or a variant thereof comprising 1-3 amino acid changes. In some examples, the VL comprises: a CDR-L1 comprising the amino acid sequence of RASQSVASTVA (SEQ ID NO: 43), or a variant thereof comprising 1-5 amino acid changes; a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8), or a variant thereof comprising 1-5 amino acid changes; and a CDR-L3 comprising the amino acid sequence of QQASYVX1X2TIT (SEQ ID NO: 128), wherein Xi is R or W, and X2 is H, V, I, or K.

[0059] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRHTIT (SEQ ID NO: 9). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSISHTVA. In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRHTIT (SEQ ID NO: 9), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSISHTVA (SEQ ID NO: 7).

[0060] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequenceDIQMTQSPSSLSASVGDRVTITCRASQSISHTVAWYQQKPGKAPKLLIYSASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRHTITFGQGTKVEIKRTV (SEQ ID NO: 2).

[0061] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRVTIT (SEQ ID NO: 13). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLASTVA (SEQ ID NO: 11). In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRVTIT (SEQ ID NO: 13), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLASTVA (SEQ ID NO: 11).

[0062] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequenceDIQMTQSPSSLSASVGDRVTITCRASQSLASTVAWYQQKPGKAPKLLIYQASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRVTITFGQGTKVEIKRTV (SEQ ID NO: 10).

[0063] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRHTIT (SEQ ID NO: 9). In some examples, the VLcomprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSIYSTVA (SEQ ID NO: 15).

[0064] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRHTIT (SEQ ID NO: 9), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSIYSTVA (SEQ ID NO: 15).

[0065] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSIYSTVAWYQQKPGKAPKLLIYSASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRHTITFGQGTKVEIKRTV (SEQ ID NO: 14).

[0066] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRITIT (SEQ ID NO: 17). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLASTVA (SEQ ID NO: 11).

[0067] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRITIT (SEQ ID NO: 17), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLASTVA (SEQ ID NO: 11).

[0068] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLASTVAWYQQKPGKAPKLLIYSASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRITITFGQGTKVEIKRTV (SEQ ID NO: 16).

[0069] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRITIT (SEQ ID NO: 17). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLSSTVA (SEQ ID NO: 19).

[0070] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRITIT (SEQ ID NO: 17), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLSSTVA (SEQ ID NO: 19).

[0071] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLSSTVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRITITFGQGTKVEIKRTV (SEQ ID NO: 18).

[0072] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRVTIT (SEQ ID NO: 13). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLSSTVA (SEQ ID NO: 19).

[0073] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRVTIT (SEQ ID NO: 13), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLSSTVA (SEQ ID NO: 19).

[0074] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLSSTVAWYQQKPGKAPKLLIYSASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRVTITFGQGTKVEIKRTV (SEQ ID NO: 20).

[0075] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the firstantigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRVTIT (SEQ ID NO: 13). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSISSTVA (SEQ ID NO: 22).

[0076] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRVTIT (SEQ ID NO: 13), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSISSTVA (SEQ ID NO: 22).

[0077] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSTVAWYQQKPGKAPKLLIYSASSLYSGVP SRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRVTITFGQGTKVEIKRTV (SEQ ID NO: 21).

[0078] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWHTIT (SEQ ID NO: 26). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of LASSLYS (SEQ ID NO: 25). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSYTSAVA (SEQ ID NO: 24).

[0079] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ IDNO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWHTIT (SEQ ID NO: 26), a CDR-L2 sequence of LASSLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSYTSAVA (SEQ ID NO: 24).

[0080] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSYTSAVAWYQQKPGKAPKLLIYLASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWHTITFGQGTKVEIKRTV (SEQ ID NO: 23).

[0081] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRHTIT (SEQ ID NO: 9). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLAHTVA (SEQ ID NO: 31).

[0082] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQASYVRHTIT (SEQ ID NO: 9), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLAHTVA (SEQ ID NO: 31).

[0083] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 27). In some examples, the VL comprises a sequence with at least 80%sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLAHTVAWYQQKPGKAPKLLIYQASSLYSG VPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRHTITFGQGTKVEIKRTV (SEQ ID NO: 28).

[0084] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSYHHTVA (SEQ ID NO: 33).

[0085] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSYHHTVA (SEQ ID NO: 33).

[0086] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 27). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSYHHTVAWYQQKPGKAPKLLIYQASSLYSG VPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 32).

[0087] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence ofSISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of LASSLYS (SEQ ID NO: 25). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLHRLVA (SEQ ID NO: 37).

[0088] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of LASSLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSLHRLVA (SEQ ID NO: 37).

[0089] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGT MVTVSS (SEQ ID NO: 35). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLHRLVAWYQQKPGKAPKLLIYLASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 36).

[0090] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of LASSLYS (SEQ ID NO: 25). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSYTSTVA (SEQ ID NO: 39).

[0091] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of LASSLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSYTSTVA (SEQ ID NO: 39).

[0092] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 27). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSYTSTVAWYQQKPGKAPKLLIYLASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 38).

[0093] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of LASSLYS (SEQ ID NO: 25). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLLRTVA (SEQ ID NO: 41).

[0094] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of LASSLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSLLRTVA (SEQ ID NO: 41).

[0095] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSSSVGDRVTITCRASQSLLRTVAWYQQKPGKAPKLLIYLASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 40).

[0096] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSVASTVA (SEQ ID NO: 43).

[0097] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSVASTVA (SEQ ID NO: 43).

[0098] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSVASTVAWYQQKPGKAPKLLIYSASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 42).

[0099] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determiningregion 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSVYRTVA (SEQ ID NO: 45).

[0100] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSVYRTVA (SEQ ID NO: 45).

[0101] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSVYRTVAWYQQKPGKAPKLLIYSASSLYSG VPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 44).

[0102] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12). Insome examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLHRTVA (SEQ ID NO: 47).

[0103] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLHRTVA (SEQ ID NO: 47).

[0104] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLHRTVAWYQQKPGKAPKLLIYQASSLYSG VPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 46).

[0105] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLSHTVA (SEQ ID NO: 49).

[0106] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLSHTVA (SEQ ID NO: 49).

[0107] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLSHTVAWYQQKPGKAPKLLIYQASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 48). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLSHTVAWYQQKPGKAPKLLIYQASSLYSGV PSRFSGSRSGTDFTLTISNLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 50).

[0108] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLASTVA (SEQ ID NO: 11).

[0109] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLASTVA (SEQ ID NO: 11).

[0110] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTLVTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLASTVAWYQQKPGKAPKLLIYQASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 51).[OHl] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLAHTVA (SEQ ID NO: 31).

[0112] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLAHTVA (SEQ ID NO: 31).

[0113] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLAHTVAWYQQKPGKAPKLLIYQASSLYSG VPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 52).

[0114] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLHSTVA (SEQ ID NO: 54).

[0115] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLHSTVA (SEQ ID NO: 54).

[0116] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequenceDIQMTQSPSSLSASVGDRVTITCRASQSLHSTVAWYQQKPGKAPKLLIYSASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 53).

[0117] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). Insome examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLHSTVA (SEQ ID NO: 54).

[0118] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLHSTVA (SEQ ID NO: 54).

[0119] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 27). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLHSTVAWYQQKPGKAPKLLIYSASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 55).

[0120] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30). In some examples, the first antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSVYSTVA (SEQ ID NO: 57).

[0121] In some examples, the first antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSVYSTVA (SEQ ID NO: 57).

[0122] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 27). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSVYSTVAWYQQKPGKAPKLLIYSASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 56).

[0123] In some examples, the first antigen-binding domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a CDR-H1 comprising SYSIH (SEQ ID NO: 29); a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5); and a CDR-H3 comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VL comprises: a CDR- L3 sequence of QQAS YVRHTIT (SEQ ID NO: 9), a CDR-L2 sequence of Q AS SLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLAHTVA (SEQ ID NO: 31). In some examples, the VL comprises: a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of Q AS SLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSYHHTVA (SEQ ID NO: 33). In some examples, the VL comprises: a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of LASSLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSYTSTVA (SEQ ID NO: 39). In some examples, the VL comprises: a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLHSTVA (SEQ ID NO: 54). In some examples, the VL comprises: a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSVYSTVA (SEQ ID NO: 57).

[0124] In another aspect, the present disclosure provides a complex comprising the multivalent polypeptide described herein and the peptide conjugate / MHC complex.

[0125] In another aspect, the present disclosure provides a polynucleotide encoding the multivalent polypeptide described herein.

[0126] In another aspect, the present disclosure provides a polynucleotide encoding the heavy chain variable region (VH) and the light chain variable region (VL) of the multivalent polypeptide described herein. In some examples, the polynucleotide is a modified polynucleotide.

[0127] In another aspect, the present disclosure provides a vector comprising the polynucleotide described herein. In some examples, the vector is a viral vector. In some examples, the viral vector is an adenoviral vector, lentiviral vector, retroviral vector, or adeno- associated viral vector.

[0128] In another aspect, the present disclosure provides a cell comprising: the polynucleotide described herein; the vector described herein; a first polynucleotide encoding a VH or heavy chain of the multivalent polypeptide described herein, and a second polynucleotide encoding a VL or light chain of the multivalent polypeptide described herein; or a first vector comprising a first polynucleotide encoding a VH or heavy chain of the multivalent polypeptide described herein, and a second vector comprising a second polynucleotide encoding a VL or light chain of the multivalent polypeptide described herein.

[0129] In another aspect, the present disclosure provides a pharmaceutical composition comprising the multivalent polypeptide described herein, the polynucleotide described herein, the vector described herein, or the host cell described herein, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0130] In another aspect, the present disclosure provides a method of producing a multivalent polypeptide, the method comprising culturing the host cell described herein under suitable conditions to express the polynucleotide or the first polynucleotide and the second polynucleotide and to produce the multivalent polypeptide.

[0131] In another aspect, the present disclosure provides a method of activating an immune cell, the method comprising contacting the immune cell with the multivalent polypeptide described herein.

[0132] In some examples, the immune cell is a T cell. In some examples, subsequent to the contacting, the T cell increases expression of at least one activation marker. In some examples, the at least one activation marker is CD26, CD27, CD28, CD30, CD154, CD40L, CD134. CD25, CD44, CD69, CD137, PD-1, KLRG1, CCR7, CD45RA, HLA-DR, NKG2D, or any combination thereof. In some examples, subsequent to the contacting, the T cell increases expression of PD-1. In some examples, subsequent to the contacting, the T cell increases expression of inducible costimulator (ICOS). In some examples, the contacting increases expression of at least one cytokine or proliferation molecule. In some examples, the at least one cytokine or proliferation molecule is IFNy, TNFa, Granzyme A, Granzyme B, IL-6, perforin, IL-2, granulysin, or any combination thereof.

[0133] In another aspect, the present disclosure provides a method of killing a cancer cell in a subject in need thereof, the method comprising administering to the subject: a targeted covalentinhibitor, and the multivalent polypeptide described herein, the polynucleotide described herein, the vector described herein, the cell described herein, or the pharmaceutical composition described herein.

[0134] In some examples, (a) is administered prior to or concurrently with (b).

[0135] In another aspect, the present disclosure provides a method of targeting a cell that expresses KRASG12Cin a subject in need thereof, the method comprising administering to the subject the multivalent polypeptide described herein, the polynucleotide described herein, the vector described herein, the cell described herein, or the pharmaceutical composition described herein, and wherein the subject has been treated with a KRASG12Ctargeted covalent inhibitor.

[0136] In some examples, the subject has cancer. In some examples, the subject is refractory to a treatment with the KRASG12Ctargeted covalent inhibitor. In some examples, the KRASG12Ctargeted covalent inhibitor is sotorasib.

[0137] In another aspect, the present disclosure provides a composition for use in the manufacture of a medicament for treating a subject in need thereof, comprising the multivalent polypeptide described herein, the polynucleotide described herein, the vector described herein, or the cell described herein.

[0138] In another aspect, the present disclosure provides a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject the multivalent polypeptide described herein or the pharmaceutical composition described herein.

[0139] In some examples, the cancer is renal cell carcinoma, breast cancer, prostate cancer, pancreatic cancer, lung cancer, liver cancer, ovarian cancer, cervical cancer, colon cancer, esophageal cancer, glioma, glioblastoma, brain cancer, stomach cancer, bladder cancer, testicular cancer, thyroid cancer, adrenal cancer, head and neck cancer, melanoma, skin cancer, sarcoma, fibrosarcoma, angiosarcoma, osteosarcoma, rhabdomyosarcoma, leukemia, lymphoma, myeloma, endometrial cancer, or a neuroendocrine tumor.

[0140] In some examples, the method further comprises administering simultaneously a small molecule drug. In some examples, the subject has previously been treated with a KRASG12Ctargeted covalent inhibitor, a KRASG12Cnon-covalent inhibitor, and / or a pan-KRAS inhibitor. In some examples, the subject is refractory to a treatment with the KRASG12Ctargeted covalent inhibitor, a KRASG12Cnon-covalent inhibitor, and / or a pan-KRAS inhibitor. In some examples, the KRASG12Ctargeted covalent inhibitor is sotorasib. In some examples, the pan-KRAS inhibitor is RMC-6236.

[0141] In some examples, the peptide conjugate / MHC complex is a first peptide conjugate / MHC complex and the multivalent polypeptide binds to the first peptideconjugate / MHC complex and a second peptide conjugate / MHC complex different from the first peptide conjugate / MHC complex, wherein each of the first and second peptide conjugate / MHC complexes independently comprises: a different peptide selected from the group consisting of peptides comprising the formula X#X#+lX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9, and X#X#+lX#+2X#+3(X#+4)X#+5X#+6X#+7X#+8X#+9, and X#X#+iX#+2(X#+3)X#+4X#+5X#+6X#+7X#+8X#+9, andX#X#+1 (X#+2)X#+3X#+4X#+5X#+6X#+7X#+8X#+9, and X#+lX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9, and X#-iX#X#+iX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9, wherein the peptide conjugate of the first and second peptide conjugate / MHC complex is formed by the covalent reaction of a targeted covalent inhibitor or fragment thereof with the residue in parenthesis; and (b) the same MHC; wherein the multivalent polypeptide binds to the first peptide conjugate / MHC complex with a KD that is at most 100 nM and binds to the second peptide conjugate / MHC complex with a KD that is at most 100 nM, or wherein when the multivalent polypeptide is contacted to the first peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to a biolayer interferometry analysis and wherein when the multivalent polypeptide is contacted to the second peptide conjugate / MHC complex a maximum wavelength shift of at least 0. 1 nm is observed according to the biolayer interferometry analysis, or wherein when the multivalent polypeptide is contacted to the first peptide conjugate / MHC complex a maximum binding signal of at least 0.1-fold of a reference binding signal is observed according to a biolayer interferometry analysis and wherein when the multivalent polypeptide is contacted to the second peptide conjugate / MHC complex a maximum binding signal of at least 0.1-fold of a reference binding signal is observed according to the biolayer interferometry analysis, and wherein the reference binding signal is the maximum binding signal of the multivalent polypeptide binding to X#X#+iX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9.

[0142] In some examples, the formula X#X#+iX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9 is the formula X7X8X9X10X11X12X13X14X15X16, and wherein X12 is covalently linked to the targeted covalent inhibitor or fragment thereof. In some examples, the peptide conjugate / MHC complex is a first peptide conjugate / MHC complex and the multivalent polypeptide binds to the first peptide conjugate / MHC complex and a second peptide conjugate / MHC complex, wherein each of the first and the second peptide conjugate / MHC complex comprises: a peptide comprising the formula X7X8X9X10X11X12X13X14X15X16; and the same MHC; wherein a first peptide conjugate of the first peptide conjugate / MHC complex is formed by the covalent reaction of a targeted covalent inhibitor or fragment thereof with X12 of the peptide, and wherein a second peptide conjugate of the second peptide conjugate / MHC complex is formed by the covalentreaction of the same targeted covalent inhibitor or fragment thereof with X13 of the peptide; and wherein the multivalent polypeptide binds to the second peptide conjugate / MHC complex with a KD that is at most 100,000-fold higher than the KD of the polypeptide to the first peptide conjugate / MHC complex, or wherein a maximum wavelength shift of the multivalent polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum wavelength shift of the multivalent polypeptide binding to the first peptide conjugate / MHC complex, or wherein a maximum binding signal of the multivalent polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum binding signal of the multivalent polypeptide binding to the first peptide conjugate / MHC complex.

[0143] In some examples, the peptide conjugate / MHC complex is a first peptide conjugate / MHC complex and the multivalent polypeptide binds to the first peptide conjugate / MHC complex and a second peptide conjugate / MHC complex, wherein each of the first and the second peptide conjugate / MHC complex comprises: a peptide comprising the formula X7X8X9X10X11X12X13X14X15X16; and the same MHC; wherein a first peptide conjugate of the first peptide conjugate / MHC complex is formed by the covalent reaction of a targeted covalent inhibitor or fragment thereof with a residue selected from the group consisting of X9, X10, Xu, and X12, and wherein a second peptide conjugate of the second peptide conjugate / MHC complex is formed by the covalent reaction of the same targeted covalent inhibitor or fragment thereof with a residue selected from the group consisting of X13, X14, and X15; wherein the multivalent polypeptide binds to the second peptide conjugate / MHC complex with a KD that is at most 100,000-fold higher that the KD of the polypeptide to the first peptide conjugate / MHC complex, or wherein a maximum wavelength shift of the multivalent polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum wavelength shift of the multivalent polypeptide binding to the first peptide conjugate / MHC complex, or wherein a maximum binding signal of the multivalent polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum binding signal of the multivalent polypeptide binding to the first peptide conjugate / MHC complex.

[0144] In some examples, the peptide conjugate / MHC complex is a first peptide conjugate / MHC complex and the multivalent polypeptide binds to the first peptide conjugate / MHC complex and a second peptide conjugate / MHC complex, wherein each of the first and the second peptide conjugate / MHC complex comprises: a peptide comprising the formula A-B-C, where A comprises no more than three residues having an N-terminal anchorresidue, B comprises at least four but no more than seven residues having a residue covalently linked to a targeted covalent inhibitor or fragment thereof, and C comprises no more than three residues having a C-terminal anchor residue, wherein the N-terminal anchor residues and the C -terminal anchor residue bind to an MHC; and the same MHC; wherein the residue covalently linked to a targeted covalent inhibitor or fragment thereof of the peptide of the first peptide conjugate / MHC complex is different from the residue covalently linked to a targeted covalent inhibitor or fragment thereof of the peptide of the second peptide conjugate / MHC complex; and wherein the multivalent polypeptide binds to the first peptide conjugate / MHC complex with a KD that is at most 100 nM and binds to the second peptide conjugate / MHC complex with a KD that is at most 100 nM, or wherein when the multivalent polypeptide is contacted to the first peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to a biolayer interferometry analysis and wherein when the multivalent polypeptide is contacted to the second peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to the biolayer interferometry analysis, or wherein when the multivalent polypeptide is contacted to the first peptide conjugate / MHC complex a maximum binding signal of at least 0.1-fold of a reference binding signal is observed according to a biolayer interferometry analysis and wherein when the multivalent polypeptide is contacted to the second peptide conjugate / MHC complex a maximum binding signal of at least 0.1 -fold of a reference binding signal is observed according to the biolayer interferometry analysis, and wherein the reference binding signal is the maximum binding signal of the multivalent polypeptide binding to X#X#+1 X#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9.

[0145] In some examples, A comprises two residues X?Xs. In some examples, B comprises seven residues X9X10X11X12X13X14X15. In some examples, C comprises one residue Xi6. In some examples, the formula A-B-C is the formula X7X8X9X10X11X12X13X14X15X16.

[0146] In some examples, a first peptide conjugate of the first peptide conjugate / MHC complex is formed by the covalent reaction of the targeted covalent inhibitor or fragment thereof with X12 of the peptide. In some examples, a second peptide conjugate of the second peptide conjugate / MHC complex is formed by the covalent reaction of the same targeted covalent inhibitor or fragment thereof with X13 of the peptide. In some examples, the multivalent polypeptide binds to the second peptide conjugate / MHC complex with a KD that is at most 100,000-fold higher than the KD of the multivalent polypeptide to the first peptide conjugate / MHC complex.

[0147] In some examples, the polypeptide binds to the second peptide conjugate / MHC complex with an KD that is at most 100,000-fold higher than the KD of the polypeptide to the first peptide conjugate / MHC complex, and wherein the residue covalently linked to a targeted covalent inhibitor or fragment thereof of the peptide of the first peptide conjugate / MHC complex is selected from the group of consisting of X9, X10, Xu, and X12, and the residue covalently linked to a targeted covalent inhibitor or fragment thereof of the peptide of the second peptide conjugate / MHC complex is X13, X14, and X15.

[0148] In some examples, the peptide is a RAS peptide. In some examples, the RAS peptide comprises a mutation. In some examples, the mutation is G12C or G13C. In some examples, the RAS peptide comprises a sequence selected from the group consisting of VVVGACGVGK (SEQ ID NO: 160), VVGACGVGK (SEQ ID NO: 161), and KLVVVGACGV (SEQ ID NO: 159). In some examples, the RAS peptide comprises a sequence selected from the group consisting of VVVGAGCVGK (SEQ ID NO: 180), VVGAGCVGK (SEQ ID NO: 181), or KLWVGAGCV (SEQ ID NO: 182).

[0149] In some examples, the same MHC is selected from the group consisting of HLA- A*03:01, HLA-A*l l:01, HLA-A*02:01, HLA-A*68:01, HLA-A*31:01, HLA-A*30:01, HLA-A*33:03, HLA-A*33:01, HLA-A*74:01, HLA-A*34:02, HLA-A*66:01, HLA- A*68:02, HLA-A*02:05, HLA-A*02:02, HLA-A*02:06.

[0150] In some examples, the MHC is encoded by an HLA allele of HLA-A3 supertype. In some examples, the HLA allele of the HLA-A3 supertype is selected from the group consisting of HLA-A*03:01, HLA-A* 11 :01, HLA-A*68:01, HLA-A*31:01, HLA-A*30:01, HLA- A*74:01, HLA-A*34:02, and HLA-A*66:01. In some examples, the MHC is encoded by an HLA allele of HLA-A2 supertype. In some examples, the HLA allele of the HLA-A2 supertype is selected from the group consisting of HLA-A* 02:01, HLA-A*02:02, HLA-A*02:03, HLA- A*02:04, HLA-A*02:05, HLA-A*02:06, HLA-A*02:07, HLA-A*02: 14, HLA-A*02: 17, HLA-A*68:02, and HL A- A* 69:01.

[0151] In some examples, the targeted covalent inhibitor or fragment thereof comprises sotorasib. In some examples, the peptide is a RAS peptide, and wherein X12 is G12C mutation, and X13 is G13C mutation.

[0152] In some examples, the multivalent polypeptide binds to the first peptide conjugate / MHC complex having a Cys of the G12C mutation covalently linked to the targeted covalent inhibitor or fragment thereof with a KD that is at most 100 nM and binds to the second peptide conjugate / MHC complex having a Cys of the G13C mutation covalently linked to the targeted covalent inhibitor or fragment thereof with a KD that is most 100 nM, or wherein whenthe multivalent polypeptide is contacted to the first peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to a biolayer interferometry analysis and wherein when the multivalent polypeptide is contacted to the second peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to the biolayer interferometry analysis, or wherein when the multivalent polypeptide is contacted to the first peptide conjugate / MHC complex a maximum binding signal of at least 0.1-fold of a reference binding signal is observed according to a biolayer interferometry analysis and wherein when the multivalent polypeptide is contacted to the second peptide conjugate / MHC complex a maximum binding signal of at least 0.1-fold of a reference binding signal is observed according to the biolayer interferometry analysis, and wherein the reference binding signal is the maximum binding signal of the multivalent polypeptide binding to X#X#+1 X#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9.

[0153] In some examples, the polypeptide binds to the second peptide conjugate / MHC complex having a Cys of the G13C mutation covalently linked to the targeted covalent inhibitor or fragment thereof with a KD that is at most 100,000-fold higher that the KD of the polypeptide to the first peptide conjugate / MHC complex having a Cys of the G12C mutation covalently linked to the targeted covalent inhibitor or fragment thereof, or wherein a maximum wavelength shift of the multivalent polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum wavelength shift of the multivalent polypeptide binding to the first peptide conjugate / MHC complex, or wherein a maximum binding signal of the multivalent polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum binding signal of the multivalent polypeptide binding to the first peptide conjugate / MHC complex.

[0154] A polypeptide comprising an antigen-binding domain comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VL comprises: a light chain complementarity determining region 3 CDR-L3 comprising the amino acid sequence of QQASYVX1X2TIT (SEQ ID NO: 128), wherein Xi is R or W, and X2is H, V, I, or K, and wherein if Xi is R, X2 is not K.

[0155] In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of X1SX2YSIH (SEQ ID NO: 129), wherein Xi is F or I, and X2 is D or S. In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of XiYSIH (SEQ ID NO: 130), wherein Xi is D or S. In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSX1X2X3X4VA (SEQ ID NO: 131), wherein Xi is I, L, Y, or V, X2 is S, A, Y, T, H, or L, X3 is H, S, or R, and X4 is T, A, or L. In some examples, the VLcomprises a CDR-L2 comprising the amino acid sequence of XiASSLYS (SEQ ID NO: 132), wherein Xi is Q, S, or L.

[0156] In some examples, the VH comprises: a CDR-H1 comprising the amino acid sequence of DYSIH (SEQ ID NO: 3), or a variant thereof comprising 1-3 amino acid changes; a CDR- H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), or a variant thereof comprising 1-5 amino acid changes; and / or a CDR-H3 comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6), or a variant thereof comprising 1-3 amino acid changes.

[0157] In some examples, the VL comprises: a CDR-L1 comprising the amino acid sequence of RASQSVASTVA (SEQ ID NO: 43), or a variant thereof comprising 1-5 amino acid changes; a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8), or a variant thereof comprising 1-5 amino acid changes; and a CDR-L3 comprising the amino acid sequence of QQ AS YVX1X2TIT (SEQ ID NO: 128), wherein Xi is R or W, and X2is H, V, I, or K.

[0158] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRHTIT (SEQ ID NO: 9). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSISHTVA.

[0159] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRHTIT (SEQ ID NO: 9), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSISHTVA (SEQ ID NO: 7).

[0160] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSISHTVAWYQQKPGKAPKLLIYSASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRHTITFGQGTKVEIKRTV (SEQ ID NO: 2).

[0161] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRVTIT (SEQ ID NO: 13). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLASTVA (SEQ ID NO: 11).

[0162] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRVTIT (SEQ ID NO: 13), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLASTVA (SEQ ID NO: 11).

[0163] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLASTVAWYQQKPGKAPKLLIYQASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRVTITFGQGTKVEIKRTV (SEQ ID NO: 10).

[0164] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3(CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRHTIT (SEQ ID NO: 9). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSIYSTVA (SEQ ID NO: 15).

[0165] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRHTIT (SEQ ID NO: 9), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSIYSTVA (SEQ ID NO: 15).

[0166] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSIYSTVAWYQQKPGKAPKLLIYSASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRHTITFGQGTKVEIKRTV (SEQ ID NO: 14).

[0167] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRITIT (SEQ ID NO: 17). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). Insome examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLASTVA (SEQ ID NO: 11).

[0168] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRITIT (SEQ ID NO: 17), a CDR-L2 sequence of SAS SLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLASTVA (SEQ ID NO: 11).

[0169] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLASTVAWYQQKPGKAPKLLIYSASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRITITFGQGTKVEIKRTV (SEQ ID NO: 16).

[0170] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRITIT (SEQ ID NO: 17). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLSSTVA (SEQ ID NO: 19).

[0171] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRITIT (SEQ ID NO: 17), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLSSTVA (SEQ ID NO: 19).

[0172] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLSSTVAWYQQKPGKAPKLLIYSASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRITITFGQGTKVEIKRTV (SEQ ID NO: 18).

[0173] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRVTIT (SEQ ID NO: 13). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLSSTVA (SEQ ID NO: 19).

[0174] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRVTIT (SEQ ID NO: 13), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLSSTVA (SEQ ID NO: 19).

[0175] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLSSTVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRVTITFGQGTKVEIKRTV (SEQ ID NO: 20).

[0176] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRVTIT (SEQ ID NO: 13). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSISSTVA (SEQ ID NO: 22).

[0177] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRVTIT (SEQ ID NO: 13), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSISSTVA (SEQ ID NO: 22).

[0178] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSTVAWYQQKPGKAPKLLIYSASSLYSGVP SRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRVTITFGQGTKVEIKRTV (SEQ ID NO: 21).

[0179] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, theantigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWHTIT (SEQ ID NO: 26). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of LASSLYS (SEQ ID NO: 25). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSYTSAVA (SEQ ID NO: 24).

[0180] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWHTIT (SEQ ID NO: 26), a CDR-L2 sequence of LASSLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSYTSAVA (SEQ ID NO: 24).

[0181] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSYTSAVAWYQQKPGKAPKLLIYLASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWHTITFGQGTKVEIKRTV (SEQ ID NO: 23).

[0182] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRHTIT (SEQ ID NO: 9). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLAHTVA (SEQ ID NO: 31).

[0183] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ IDNO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQASYVRHTIT (SEQ ID NO: 9), a CDR-L2 sequence of Q AS SLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLAHTVA (SEQ ID NO: 31).

[0184] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 27). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLAHTVAWYQQKPGKAPKLLIYQASSLYSG VPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRHTITFGQGTKVEIKRTV (SEQ ID NO: 28).

[0185] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSYHHTVA (SEQ ID NO: 33).

[0186] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSYHHTVA (SEQ ID NO: 33).

[0187] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 27). In some examples, the VL comprises a sequence with at least 80%sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSYHHTVAWYQQKPGKAPKLLIYQASSLYSG VPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 32).

[0188] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of LASSLYS (SEQ ID NO: 25). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLHRLVA (SEQ ID NO: 37).

[0189] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of LASSLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSLHRLVA (SEQ ID NO: 37).

[0190] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGT MVTVSS (SEQ ID NO: 35). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLHRLVAWYQQKPGKAPKLLIYLASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 36).

[0191] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence ofSISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of LASSLYS (SEQ ID NO: 25). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSYTSTVA (SEQ ID NO: 39).

[0192] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of LASSLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSYTSTVA (SEQ ID NO: 39).

[0193] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 27). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSYTSTVAWYQQKPGKAPKLLIYLASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 38).

[0194] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of LASSLYS (SEQ ID NO: 25). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLLRTVA (SEQ ID NO: 41).

[0195] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of LASSLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSLLRTVA (SEQ ID NO: 41).

[0196] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSSSVGDRVTITCRASQSLLRTVAWYQQKPGKAPKLLIYLASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 40).

[0197] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSVASTVA (SEQ ID NO: 43).

[0198] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSVASTVA (SEQ ID NO: 43).

[0199] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSVASTVAWYQQKPGKAPKLLIYSASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 42).

[0200] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSVYRTVA (SEQ ID NO: 45).

[0201] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSVYRTVA (SEQ ID NO: 45).

[0202] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSVYRTVAWYQQKPGKAPKLLIYSASSLYSG VPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 44).

[0203] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3(CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLHRTVA (SEQ ID NO: 47).

[0204] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLHRTVA (SEQ ID NO: 47).

[0205] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLHRTVAWYQQKPGKAPKLLIYQASSLYSG VPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 46).

[0206] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12). Insome examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLSHTVA (SEQ ID NO: 49).

[0207] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLSHTVA (SEQ ID NO: 49).

[0208] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLSHTVAWYQQKPGKAPKLLIYQASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 48).

[0209] In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLSHTVAWYQQKPGKAPKLLIYQASSLYSGV PSRFSGSRSGTDFTLTISNLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 50).

[0210] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLASTVA (SEQ ID NO: 11).

[0211] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLASTVA (SEQ ID NO: 11).

[0212] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLASTVAWYQQKPGKAPKLLIYQASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 51).

[0213] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLAHTVA (SEQ ID NO: 31).

[0214] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLAHTVA (SEQ ID NO: 31).

[0215] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLAHTVAWYQQKPGKAPKLLIYQASSLYSG VPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 52).

[0216] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLHSTVA (SEQ ID NO: 54).

[0217] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLHSTVA (SEQ ID NO: 54).

[0218] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 1). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLHSTVAWYQQKPGKAPKLLIYSASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 53).

[0219] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3(CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). In some examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLHSTVA (SEQ ID NO: 54).

[0220] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLHSTVA (SEQ ID NO: 54).

[0221] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 27). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLHSTVAWYQQKPGKAPKLLIYSASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 55).

[0222] In some examples, the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5). In some examples, the VH comprises a CDR-H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30). In some examples, the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34). In some examples, the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8). Insome examples, the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSVYSTVA (SEQ ID NO: 57).

[0223] In some examples, the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSVYSTVA (SEQ ID NO: 57).

[0224] In some examples, the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISSSSGST SYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAAMDYWGQGTL VTVSS (SEQ ID NO: 27). In some examples, the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSVYSTVAWYQQKPGKAPKLLIYSASSLYSGV PSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 56).

[0225] In another aspect, the present disclosure provides a polypeptide comprising an antigenbinding domain comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a CDR-H1 comprising SYSIH (SEQ ID NO: 29); a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5); and a CDR-H3 comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6). In some examples, the VL comprises: a CDR-L3 sequence of QQASYVRHTIT (SEQ ID NO: 9), a CDR-L2 sequence of Q AS SLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLAHTVA (SEQ ID NO: 31). In some examples, the antigen-binding domain comprises: a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSYHHTVA (SEQ ID NO:33). In some examples, the antigen-binding domain comprises: a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of LASSLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSYTSTVA (SEQ ID NO: 39). In some examples, the antigen-binding domain comprises: a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO:34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLHSTVA (SEQ ID NO: 54). In some examples, the antigen-binding domain comprises: a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequenceof SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSVYSTVA (SEQ ID NO: 57).

[0226] In another aspect, the present disclosure provides a pharmaceutical composition comprising the multivalent polypeptide described herein, and a pharmaceutically acceptable carrier.

[0227] In another aspect, the present disclosure provides a method of treating a cancer in a subject in need thereof, the method comprising administering the multivalent polypeptide described herein or the pharmaceutical composition described herein.

[0228] In another aspect, the present disclosure provides a polypeptide that binds to a first peptide conjugate / MHC complex and a second peptide conjugate / MHC complex different from the first peptide conjugate / MHC complex, wherein each of the first and second peptide conjugate / MHC complexes independently comprises: a different peptide selected from the group consisting of peptides comprising the formula X#X#+lX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9, and X#X#+lX#+2X#+3(X#+4)X#+5X#+6X#+7X#+8X#+9, and X#X#+iX#+2(X#+3)X#+4X#+5X#+6X#+7X#+8X#+9, andX#X#+i(X#+2)X#+3X#+4X#+5X#+6X#+7X#+8X#+9, and X#. lX#X#+lX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9, and X#+lX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9, wherein the peptide conjugate of the first and second peptide conjugate / MHC complex is formed by the covalent reaction of a targeted covalent inhibitor or fragment thereof with the residue in parenthesis; and (b) the same MHC; wherein the polypeptide binds to the first peptide conjugate / MHC complex with a KD that is at most 100 nM and binds to the second peptide conjugate / MHC complex with a KD that is at most 100 nM, or wherein when the polypeptide is contacted to the first peptide conjugate / MHC complex a maximum wavelength shift of at least 0. 1 nm is observed according to a biolayer interferometry analysis and wherein when the polypeptide is contacted to the second peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to the biolayer interferometry analysis, or wherein when the polypeptide is contacted to the first peptide conjugate / MHC complex a maximum binding signal of at least 0. 1 -fold of a reference binding signal is observed according to a biolayer interferometry analysis and wherein when the polypeptide is contacted to the second peptide conjugate / MHC complex a maximum binding signal of at least 0.1 -fold of a reference binding signal is observed according to the biolayer interferometry analysis, and wherein the reference binding signal is the maximum binding signal of the polypeptide binding tO X#X#+lX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9.

[0229] In some examples, each of the first and second peptide conjugate / MHC complexes independently comprises: a different peptide selected from the group consisting of peptides comprising the formula X#X#+iX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9, and X#X#+lX#+2X#+3(X#+4)X#+5X#+6X#+7X#+8X#+9, and X#X#+lX#+2(X#+3)X#+4X#+5X#+6X#+7X#+8X#+9, and X#X#+ i (X#+2)X#+3X#+4X#+5 X#+6X#+7X#+8X#+9.

[0230] In some examples, each of the first and second peptide conjugate / MHC complexes independently comprises: a different peptide with an amino acid sequence selected from the group consisting of: VVVGACGVGK, VVVGCGGVGK, VVVCAGGVGK, and VVCGAGGVGK.

[0231] In another aspect, the present disclosure provides a polypeptide that binds to a first peptide conjugate / MHC complex and a second peptide conjugate / MHC complex, wherein each of the first and the second peptide conjugate / MHC complex comprises: a peptide comprising the formula X7X8X9X10X11X12X13X14X15X16; and the same MHC; wherein a first peptide conjugate of the first peptide conjugate / MHC complex is formed by the covalent reaction of a targeted covalent inhibitor or fragment thereof with X12 of the peptide, and wherein a second peptide conjugate of the second peptide conjugate / MHC complex is formed by the covalent reaction of the same targeted covalent inhibitor or fragment thereof with X13 of the peptide; wherein the polypeptide binds to the second peptide conjugate / MHC complex with a KD that is at most 100,000-fold higher than the KD of the polypeptide to the first peptide conjugate / MHC complex, or wherein a maximum wavelength shift of the polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum wavelength shift of the polypeptide binding to the first peptide conjugate / MHC complex, or wherein a maximum binding signal of the polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum binding signal of the polypeptide binding to the first peptide conjugate / MHC complex.

[0232] In another aspect, the present disclosure provides a polypeptide that binds to a first peptide conjugate / MHC complex and a second peptide conjugate / MHC complex, wherein each of the first and the second peptide conjugate / MHC complex comprises: a peptide comprising the formula X7X8X9X10X11X12X13X14X15X16; and the same MHC; wherein a first peptide conjugate of the first peptide conjugate / MHC complex is formed by the covalent reaction of a targeted covalent inhibitor or fragment thereof with a residue selected from the group consisting of X9, X10, Xu, and X12, and wherein a second peptide conjugate of the second peptide conjugate / MHC complex is formed by the covalent reaction of the same targeted covalent inhibitor or fragment thereof with a residue selected from the group consisting of X13,Xu, and X15; wherein the polypeptide binds to the second peptide conjugate / MHC complex with a KD that is at most 100,000-fold higher that the KD of the polypeptide to the first peptide conjugate / MHC complex, or wherein a maximum wavelength shift of the polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum wavelength shift of the polypeptide binding to the first peptide conjugate / MHC complex, or wherein a maximum binding signal of the polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum binding signal of the polypeptide binding to the first peptide conjugate / MHC complex.

[0233] In another aspect, the present disclosure provides a polypeptide that binds to a first peptide conjugate / MHC complex and a second peptide conjugate / MHC complex, wherein each of the first and the second peptide conjugate / MHC complex comprises: a peptide comprising the formula A-B-C, where A comprises no more than three residues having an N-terminal anchor residue, B comprises at least four but no more than seven residues having a residue covalently linked to a targeted covalent inhibitor or fragment thereof, and C comprises no more than three residues having a C-terminal anchor residue, wherein the N-terminal anchor residues and the C-terminal anchor residue bind to an MHC; and the same MHC; wherein the residue covalently linked to a targeted covalent inhibitor or fragment thereof of the peptide of the first peptide conjugate / MHC complex is different from the residue covalently linked to a targeted covalent inhibitor or fragment thereof of the peptide of the second peptide conjugate / MHC complex; and wherein the polypeptide binds to the first peptide conjugate / MHC complex with a KD that is at most 100 nM and binds to the second peptide conjugate / MHC complex with a KD that is at most 100 nM, or wherein when the polypeptide is contacted to the first peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to a biolayer interferometry analysis and wherein when the polypeptide is contacted to the second peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to the biolayer interferometry analysis, or wherein when the polypeptide is contacted to the first peptide conjugate / MHC complex a maximum binding signal of at least 0.1-fold of a reference binding signal is observed according to a biolayer interferometry analysis and wherein when the polypeptide is contacted to the second peptide conjugate / MHC complex a maximum binding signal of at least 0.1 -fold of a reference binding signal is observed according to the biolayer interferometry analysis, and wherein the reference binding signal is the maximum binding signal of the polypeptide binding to X#X#+1 X#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9.

[0234] In some examples, A comprises two residues X?Xs. In some examples, B comprises seven residues X9X10X11X12X13X14X15. In some examples, C comprises one residue Xi6. In some examples, the formula A-B-C is the formula X7X8X9X10X11X12X13X14X15X16.

[0235] In some examples, a first peptide conjugate of the first peptide conjugate / MHC complex is formed by the covalent reaction of the targeted covalent inhibitor or fragment thereof with X12 of the peptide. In some examples, a second peptide conjugate of the second peptide conjugate / MHC complex is formed by the covalent reaction of the same targeted covalent inhibitor or fragment thereof with X13 of the peptide.

[0236] In some examples, the polypeptide binds to the second peptide conjugate / MHC complex with a KD that is at most 1000,000-fold higher than the KD of the polypeptide to the first peptide conjugate / MHC complex. In some examples, the polypeptide binds to the second peptide conjugate / MHC complex with an KD that is at most 100,000-fold higher than the KD of the polypeptide to the first peptide conjugate / MHC complex, and wherein the residue covalently linked to the targeted covalent inhibitor or fragment thereof of the peptide of the first peptide conjugate / MHC complex is selected from the group of consisting of X9, X10, Xu, and X12, and the residue covalently linked to the targeted covalent inhibitor or fragment thereof of the peptide of the second peptide conjugate / MHC complex is X13, X14, and X15.

[0237] In some examples, the peptide is a RAS peptide. In some examples, the RAS peptide comprises a mutation. In some examples, the mutation is G12C or G13C. In some examples, the RAS peptide comprises a sequence selected from the group consisting of VVVGACGVGK, VVGACGVGK, and KLVVVGACGV. In some examples, the RAS peptide comprises a sequence selected from the group consisting of VVVGAGCVGK, VVGAGCVGK, or KLWVGAGCV.

[0238] In some examples, the same MHC is selected from the group consisting of HLA- A*03:01, HLA-A*l l:01, HLA-A*02:01, HLA-A*68:01, HLA-A*31:01, HLA-A*30:01, HLA-A*33:03, HLA-A*33:01, HLA-A*74:01, HLA-A*34:02, HLA-A*66:01, HLA- A*68:02, HLA-A*02:05, HLA-A*02:02, and HLA-A*02:06.

[0239] In some examples, the MHC or the same MHC is encoded by an HLA allele of HLA- A3 supertype. In some examples, the HLA allele of the HLA-A3 supertype is selected from the group consisting of HLA-A*03:01, HLA-A*l l:01, HLA-A*68:01, HLA-A*31:01, HLA- A*30:01, HLA-A*74:01, HLA-A*34:02, and HLA-A*66:01. In some examples, the MHC or the same MHC is encoded by an HLA allele of HLA-A2 supertype. In some examples, the HLA allele of the HLA-A2 supertype is selected from the group consisting of HLA- A* 02:01,HLA-A*02:02, HLA-A*02:03, HLA-A*02:04, HLA-A*02:05, HLA-A*02:06, HLA- A*02:07, HLA-A*02: 14, HLA-A*02: 17, HLA-A*68:02, and HLA-A*69:01

[0240] In some examples, the targeted covalent inhibitor or fragment thereof comprises sotorasib. In some examples, the peptide is a RAS peptide, and wherein X12 is G12C mutation, and X13 is G13C mutation.

[0241] In some examples, the polypeptide binds to the first peptide conjugate / MHC complex having a Cys of the G12C mutation covalently linked to the targeted covalent inhibitor or fragment thereof with an KD that is at most 100 nM and binds to the second peptide conjugate / MHC complex having a Cys of the G13C mutation covalently linked to the targeted covalent inhibitor or fragment thereof with an KD that is most 100 nM, or wherein when the polypeptide is contacted to the first peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to a biolayer interferometry analysis and wherein when the polypeptide is contacted to the second peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to the biolayer interferometry analysis, or wherein when the polypeptide is contacted to the first peptide conjugate / MHC complex a maximum binding signal of at least 0.1 -fold of a reference binding signal is observed according to a biolayer interferometry analysis and wherein when the polypeptide is contacted to the second peptide conjugate / MHC complex a maximum binding signal of at least 0.1 -fold of a reference binding signal is observed according to the biolayer interferometry analysis, and wherein the reference binding signal is the maximum binding signal of the polypeptide binding tO X#X#+lX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9.

[0242] In some examples, the polypeptide binds to the second peptide conjugate / MHC complex having a Cys of the G13C mutation covalently linked to the targeted covalent inhibitor or fragment thereof with a KD that is at most 100,000-fold higher that the KD of the polypeptide to the first peptide conjugate / MHC complex having a Cys of the G12C mutation covalently linked to the targeted covalent inhibitor or fragment thereof, or wherein a maximum wavelength shift of the polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum wavelength shift of the polypeptide binding to the first peptide conjugate / MHC complex, or wherein a maximum binding signal of the polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum binding signal of the polypeptide binding to the first peptide conjugate / MHC complex.

[0243] In another aspect, the present disclosure provides a method for increasing a half-life of a peptide conjugate / MHC complex, the method comprising: contacting the peptide conjugate / MHC complex with a multivalent polypeptide, wherein the peptide conjugate / MHCcomplex comprises a peptide conjugate formed by a covalent reaction of a targeted covalent inhibitor or fragment thereof with a peptide and an MHC, and wherein the multivalent polypeptide comprises a first antigen-binding domain, a second antigen-binding domain that binds to a T cell surface protein, and an Fc region comprising a first Fc subunit and a second Fc subunit; and measuring the half-life of the bound peptide conjugate / MHC complex and multivalent polypeptide.

[0244] In some examples, the half-life of the peptide conjugate / MHC complex is between 0.1 and 30 hours. In some examples, the half-life of the peptide conjugate / MHC complex is between 10 and 26 hours. In some examples, the half-life of the peptide conjugate / MHC complex is at least 1 day. In some examples, the contacting occurs at 25 °C or 37 °C.

[0245] In another aspect, the present disclosure provides a method for activating an immune cell, the method comprising: contacting the immune cell with a multivalent polypeptide comprising a first antigen-binding domain, a second antigen-binding domain that binds to a T cell surface protein, and an Fc region comprising a first Fc subunit and a second Fc subunit; and wherein the immune cell expresses a peptide conjugate / MHC complex, wherein the peptide conjugate / MHC complex comprises a peptide conjugate formed by a covalent reaction of a targeted covalent inhibitor or fragment thereof with a peptide and an MHC.

[0246] In some examples, the immune cell is a T cell. In some examples, the contacting increases expression of at least one T cell activation marker. In some examples, the at least one T cell activation marker is CD26, CD27, CD28, CD30, CD154, CD40L, CD134. CD25, CD44, CD69, CD 137, PD-1, KLRG1, CCR7, CD45RA, HLA-DR, NKG2D, or any combination thereof. In some examples, the at least one T cell activation marker is CD25 and / or CD69.

[0247] In some examples, the contacting produces a greater number of CD25+CD69+T cells compared to a number of CD25+CD69+T cells produced from contacting the multivalent polypeptide with an otherwise identical peptide conjugate / MHC complex without the targeted covalent inhibitor. In some examples, the contacting increases expression of IFNy, TNFa, Granzyme A, Granzyme B, IL-6, perforin, IL-2, granulysin, or any combination thereof. In some examples, the contacting increases an expression level of cytokine molecules compared to an expression level of cytokine molecules produced from contacting the multivalent polypeptide with an otherwise identical peptide conjugate / MHC complex without the targeted covalent inhibitor.

[0248] In another aspect, the present disclosure provides a method for treating a cancer in a subject in need thereof, the method comprising administering to the subject a multivalent polypeptide comprising (i) a first antigen-binding domain that binds to a peptideconjugate / MHC complex, wherein the peptide conjugate / MHC complex comprises a peptide conjugate formed by a covalent reaction of a targeted covalent inhibitor or fragment thereof with a peptide and an MHC; (ii) a second antigen-binding domain that binds to a T cell surface protein; and (iii) an Fc region comprising a first Fc subunit and a second Fc subunit; wherein the first antigen-binding domain, the second antigen-binding domain, the first Fc subunit, and the second Fc subunit are operably linked to form a single continuous polypeptide chain.

[0249] In some examples, the cancer is renal cell carcinoma, breast cancer, prostate cancer, pancreatic cancer, lung cancer, liver cancer, ovarian cancer, cervical cancer, colon cancer, esophageal cancer, glioma, glioblastoma, brain cancer, stomach cancer, bladder cancer, testicular cancer, thyroid cancer, adrenal cancer, head and neck cancer, melanoma, skin cancer, sarcoma, fibrosarcoma, angiosarcoma, osteosarcoma, rhabdomyosarcoma, leukemia, lymphoma, myeloma, endometrial cancer, or a neuroendocrine tumor.

[0250] In some examples, the peptide is a RAS peptide. In some examples, the RAS peptide comprises a mutation. In some examples, the mutation is G12C or G13C. In some examples, the RAS peptide comprises a sequence selected from the group consisting of VVVGACGVGK, VVGACGVGK, and KLVVVGACGV. In some examples, the RAS peptide comprises a sequence selected from the group consisting of VVVGAGCVGK, VVGAGCVGK, or KLWVGAGCV.

[0251] In some examples, the same MHC is selected from the group consisting of HLA- A*03:01, HLA-A*l l:01, HLA-A*02:01, HLA-A*68:01, HLA-A*31:01, HLA-A*30:01, HLA-A*33:03, HLA-A*33:01, HLA-A*74:01, HLA-A*34:02, HLA-A*66:01, HLA- A*68:02, HLA-A*02:05, HLA-A*02:02, HLA-A*02:06.

[0252] In some examples, the targeted covalent inhibitor or fragment thereof comprises sotorasib.

[0253] In another aspect, the present disclosure provides a method for stabilizing a peptide conjugate / MHC complex in a subject, the method comprising: administering a multivalent polypeptide to the subject, wherein the multivalent polypeptide comprises a first antigenbinding domain, a second antigen-binding domain that binds to a T cell surface protein, and wherein the peptide conjugate / MHC complex comprises a peptide conjugate formed by a covalent reaction of a targeted covalent inhibitor or fragment thereof with a peptide and an MHC.

[0254] In some examples, the method further comprises, prior to administering the multivalent polypeptide to the subject, administering the targeted covalent inhibitor. In some examples, the subject has a cancer. In some examples, the cancer is refractory or relapsed. In some examples,the subject expresses at least one MHC encoded by an HLA, wherein the HLA is HLA- A*03:01, HLA-A*l l:01, HLA-A*02:01, HLA-A*68:01, HLA-A*31:01, HLA-A*30:01, HLA-A*33:03, HLA-A*33:01, HLA-A*74:01, HLA-A*34:02, HLA-A*66:01, HLA- A*68:02, HLA-A*02:05, HLA-A*02:02, HLA-A*02:06, or any combination thereof.

[0255] In some examples, the method further comprises, prior to administering the multivalent polypeptide to the subject, determining an HLA allele expression of the subject.

[0256] In some examples, the subject expresses an MHC encoded by the HLA wherein the HLA is HLA-A*03:01, HLA-A* 11 :01, HLA-A*02:01, HLA-A*68:01, HLA-A*31:01, HLA- A*30:01, HLA-A*33:03, HLA-A*33:01, HLA-A*74:01, HLA-A*34:02, HLA-A*66:01, HLA-A*68:02, HLA-A*02:05, HLA-A*02:02, HLA-A*02:06, or any combination thereof.

[0257] In some examples, (i) the MHC is encoded by an HLA allele of HLA-A3 supertype, or (ii) the subject expresses an MHC encoded by an HLA allele of HLA- A3 supertype. In some examples, the HLA allele of the HLA-A3 supertype is selected from the group consisting of HLA-A*03:01, HLA-A*l l:01, HLA-A*68:01, HLA-A*31:01, HLA-A*30:01, HLA- A*74:01, HLA-A*34:02, and HLA-A*66:01. In some examples, (i) the MHC is encoded by an HLA allele of HLA-A2 supertype, or (ii) the subject expresses an MHC encoded by an HLA allele of HLA-A2 supertype. In some examples, the HLA allele of the HLA-A2 supertype is selected from the group consisting of HLA-A* 02:01, HLA-A*02:02, HLA-A*02:03, HLA- A*02:04, HLA-A*02:05, HLA-A*02:06, HLA-A*02:07, HLA-A*02: 14, HLA-A*02: 17, HLA-A*68:02, and HL A- A* 69:01

[0258] In some examples, the multivalent polypeptide comprises an Fc region comprising a first Fc subunit and a second Fc subunit. In some examples, the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. In some examples, the Fc region comprises an Fc-silencing mutation, which Fc- silencing mutation decreases an antibody-directed cytotoxicity effector function.

[0259] In some examples, administering the multivalent polypeptide to the subject increases a half-life of the peptide conjugate / MHC complex compared to a half-life of the peptide conjugate / MHC complex following administration of the targeted covalent inhibitor alone. In some examples, administering the multivalent polypeptide to the subject increases an epitope density of the peptide of the peptide conjugate / MHC complex by at least 60%.

[0260] In some examples, the targeted covalent inhibitor is sotorasib. In some examples, the peptide is a RAS peptide. In some examples, the RAS peptide comprises a mutation. In some examples, the mutation is G12C or G13C. In some examples, the RAS peptide comprises asequence selected from the group consisting of VVVGACGVGK, VVGACGVGK, and KLWVGACGV. In some examples, the RAS peptide comprises a sequence selected from the group consisting of VVVGAGC VGK, VVGAGCVGK, or KLVVVGAGC V.

[0261] In some examples, the first antigen-binding domain comprises the scFv described herein, or the first antigen-binding domain is the polypeptide described herein. In some examples, the second antigen-binding domain comprises the scFv described herein, or the second antigen-binding domain is the second antigen-binding domain described herein. In some examples, the multivalent polypeptide is the multivalent polypeptide or the polypeptide described herein.

[0262] In some examples, a density of the peptide conjugate / MHC complex on the surface of cells in the subject in the presence of the multivalent polypeptide is increased by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least at least 90%, or more compared to a density of the peptide conjugate / MHC complex on the surface of cells in the subject in the absence of the multivalent polypeptide.INCORPORATION BY REFERENCE

[0263] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.BRIEF DESCRIPTION OF THE DRAWINGS

[0264] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and the disclosure will be obtained by reference to the following detailed description that sets forth illustrative examples, in which the principles of the invention are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0265] FIGs. 1A-1B show kinetic and thermodynamic parameters for binding of binding partners to captured ligand sotorasib-p7(KRASG12C)-HLA-A*03. FIG. 1A shows parameters for binding at 37 °C and FIG. IB shows parameters for binding at 25 °C.

[0266] FIGs. 2A-2B show kinetic and thermodynamic parameters for binding of binding partners to captured ligand sotorasib-p8(KRASG12C)-HLA-A*03. FIG. 2A shows parameters for binding at 37 °C and FIG. 2B shows parameters for binding at 25 °C.

[0267] FIGs. 3A-3B show kinetic and thermodynamic parameters for binding of binding partners to captured ligand sotorasib-p7(KRASG12C)-HLA-A* 11. FIG. 3A shows parameters for binding at 37 °C and FIG. 3B shows parameters for binding at 25 °C.

[0268] FIGs. 4A-4B show kinetic and thermodynamic parameters for binding of binding partners to captured CD3s / 5. FIG. 4A shows parameters for binding at 37 °C and FIG. 4B shows parameters for binding at 25 °C.

[0269] FIGs. 5A-5D show surface plasmon resonance (SPR) sensorgrams of binding partners R023, R114, R104, and R120 binding to sotorasib-p7(KRASG12C)-HLA-A*03 (FIG. 5A), sotorasib-p8(KRASG12C)-HLA-A*03 (FIG. 5B), sotorasib-p7(KRASG12C)-HLA-A* 11 (FIG. 5C), and CD3s / 5 (FIG. 5D). All assays were performed at 37 °C.

[0270] FIGs. 6A-6D show SPR sensorgrams of binding partners R023, R114, R104, and R120 binding to sotorasib-p7(KRASG12C)-HLA-A*03 (FIG. 6A), sotorasib-p8(KRASG12C)-HLA- A*03 (FIG. 6B), sotorasib-p7(KRASG12C)-HLA-A* 11 (FIG. 6C), and CD3s / 5 (FIG. 6D). All assays were performed at 25 °C.

[0271] FIGs. 7A-7D show pharmacokinetic (PK) data of T cell engager (TCE) AETX-S3-18c- AAA-R114 for plasma and tumor. FIG. 7A shows PK as concentration (pg / mL) over time. FIG. 7B shows PK as concentration (nM) over time. FIG. 7C shows PK as concentration (pg / mL) over time taken from PK Solver software. FIG. 7D shows PK from PK Solver with a half-life of 12.5 days.

[0272] FIG. 7E shows a table with a summary of PK data for TCE AETX-S3-18c-AAA-Rl 14 including a half-life of 302.4 hours. “S3-18c-AAA” is abbreviated as “Fl” for all constructs.

[0273] FIGs. 8A-8D show results from the pharmacodynamic study to characterize TCE AETX-S3-18c-AAA-Rl 14. FIG. 8A shows the study design. FIG. 8B shows a flow cytometry plot depicting activation for intratumoral CD8+and CD4+T cells (CD25+CD69+). FIGs. 8C- 8D show the percentage of CD25+CD69+ cells for intratumoral CD8+ T cells (FIG. 8C) and intratumoral CD4+ T cells (FIG. 8D).

[0274] FIGs. 9A-9C show results from the pharmacodynamic study to characterize T cell activation probed using the PD-1 expression. FIG. 9A shows flow cytometry plot depicting tumor cell activation probed using PD-1 expression. FIGs. 9B-9C show the percentage of PD- 1+ cells for intratumoral CD8+ T cells (FIG. 9B) and intratumoral CD4+ T cells (FIG. 9C).

[0275] FIGs. 10A-10C show results from the pharmacodynamic study to characterize T cell activation probed with inducible costimulator (ICOS). FIG. 10A shows plots for CD8+ and CD4+ T cells with level of ICOS 168 hours after TCE administration, for both AETX-S3-18c- AAA-R114 and control AETX-S3-18c-AAA-RSV. FIGs. 10B-10C show ICOS mean fluorescence intensity (MFI) for intratumoral CD8+ T cells (FIG. 10B) and intratumoral CD4+ T cells (FIG. 10C).

[0276] FIGs. 11A-11E show measures of intratumoral T cell counts. FIG. 11A shows a flow cytometry plot depicting intratumoral T cell counts 48 hours after administration of TCE AETX-S3-18c-AAA-Rl 14 and control AETX-S3-18c-AAA-RSV. Signals for TCRa / p were plotted against forward scatter parameter (FSC-A), a measure for cell size. FIGs. 11B-11C show the number of intratumoral CD8+ T cells (FIG. 11B) and the number of intratumoral CD4+ T cells (FIG. 11C). FIG. 11D shows the T cell proportions across CD8+, CD4+, and CD4-CD8- subpopulations for RSV. FIG. HE shows the T cell proportions across CD8+, CD4+, and CD4-CD8- subpopulations for R114.

[0277] FIGs. 12A-12B show intratumoral Tregcell counts. FIG. 12A shows flow cytometry plots characterizing the positive control ex vivo T cells. CD4 was plotted against CD25, and FOXP3 was plotted against FSC-A. FIG. 12B shows flow cytometry plots for 48 hours after TCE application.

[0278] FIG. 13 shows T cell detection in blood and spleen. The flow cytometry plots depict signals for TCRa / p plotted against forward scatter parameter (FSC-A), a measure for cell size.

[0279] FIGs. 14A-14B show tissue weights. FIG. 14A shows the weights of tumors from mice treated with sotorasib + AETX-S3-18c-AAA-RSV (soto-RSV) and sotorasib + AETX-S3-18c- AAA-R114 (soto-R114), plotted as a function of the time of harvesting, expressed in hours after TCE dosing. FIG. 14B shows tissue weights in spleen for sotorasib-RSV and sotorasib- R114 in hours after TCE dosing.

[0280] FIGs. 15A-15C show ELISA-based analysis of plasma. FIG. 15A shows results of IL- 6 concentration following the dosing of soto-RSV and soto-R114. FIG. 15B shows results of IFNy concentration following the dosing of soto-RSV and soto-Rl 14. FIG. 15C shows results of granulysin concentration following the dosing of soto-RSV and soto-Rl 14.

[0281] FIGs. 16A-16F show results from the IncuCyte®-based T cell-dependent cell killing analysis. TCEs AETX-S3-18c-AAA-R104, R106, R114, R120, R121, R122, and R123 were tested in comparison with AETX-S3-18c-AAA-R023. Engager potency was measured as half maximal effective concentration value with a lower ECso value indicating greater potency. FIGs. 16A-16C show results with NCI-H2122 cells presenting HLA-A*03 (FIG. 16A), NCI-H2030 cells presenting HLA-A* 11 (FIG. 16B), and HOP62 cells presenting both HLA-A*03 and HLA-A*11 (FIG. 16C). FIGs. 16D-16F show EC50 values for the same TCEs across ex vivo expanded T cells from five different donors.

[0282] FIGs. 17A-17R show results from a flow cytometry-based T cell activation analysis. FIGs. 17A-17C show relative T cell activation as fold-change of sotorasib-treated over vehicle (DMSO)-treated target cells across TCEs AETX-S3-18c-AAA-R023, R104, R106, R114, R120, R121, R122, R123, and RSV (control). Percentage of CD25+CD69+ for a sotorasib- treated sample was normalized to that for its corresponding DMSO-treated sample for each PBMC donor. FIGs. 17D-17F show the data of FIGs. 17A-17C normalized to R023 and sotorasib-treated samples, with the average fold-change over tested donors. Results are shown for HL A- A* 03 (FIG. 17D), HLA-A*11 (FIG. 17E), and HL A- A* 03 and HLA-A*11 (FIG. 17F). FIGs. 17G-17I show results of T cell activation as percentage CD25+CD69+ cells for each binder both in presence and absence of sotorasib. Individual data points represent individual donors. For FIGs. 17A-17I, results are for 24 hours post administration. FIGs. 17J- 17L show relative T cell activation as fold-change of sotorasib / DMSO-treated target cells across TCEs AETX-S3-18c-AAA-R023, R104, R106, R114, R120, R121, R122, R123, and RSV (control). Percentage of CD25+CD69+ for a sotorasib-treated sample was normalized to that for its corresponding DMSO-treated sample for each PBMC donor. Data are for donors 8, 9, and 10. FIGs. 17M-17O show the data of FIGs. 17J-17L normalized to R023 and sotorasib- treated samples, with the average fold-change over tested donors. Results are shown for HLA- A*03 (FIG. 17M), HLA-A* 11 (FIG. 17N), and HLA-A*03 and HLA-A*11 (FIG. 170). FIGs. 17P-17R show results of T cell activation as percentage CD25+CD69+ cells for each binder both in presence and absence of sotorasib. Individual data points represent individual donors. For FIGs. 17J-17R, results are for 48 hours post administration. For FIGs. 17G-17I and 17P-17R, the order of each pair of bars, from left-to-right, is: (i) no engager, (ii) R023, (iii) R104, (iv) R106, (v) R114, (vi) R120, (vii) R121, (viii) R122, (ix) R123, and (x) RSV.

[0283] FIGs. 18A-18C show the results of an ELISA-based cytokine analysis for IFNy. TCEs AETX-S3-18c-AAA-R023, R104, R106, R114, R120, R121, R122, R123, and RSV (control) were tested both in the presence and absence of sotorasib. Results are shown for donors 3 and 10 for HLA-A*03 (FIG. 18A), HLA-A* 11 (FIG. 18B), and HLA-A*03 and HLA-A* 11 (FIG. 18C). For FIGs. 18A-18C, the order of each pair of bars, from left-to-right, is: (i) no engager, (ii) R023, (iii) R104, (iv) R106, (v) R114, (vi) R120, (vii) R121, (viii) R122, (ix) R123, and (x) RSV.

[0284] FIGs. 19A-19C show the results of an ELISA-based cytokine analysis for granzyme B. TCEs AETX-S3-18c-AAA-R023, R104, R106, R114, R120, R121, R122, R123, and RSV (control) were tested both in the presence and absence of sotorasib. Results are shown for donors 3 and 10 for HLA-A*03 (FIG. 19A), HLA-A*11 (FIG. 19B), and HLA-A*03 and HLA-A* 11 (FIG. 19C). For FIGs. 19A-19C, the order of each pair of bars, from left-to-right, is: (i) no engager, (ii) R023, (iii) R104, (iv) R106, (v) R114, (vi) R120, (vii) R121, (viii) R122, (ix) R123, and (x) RSV.

[0285] FIGs. 20A-20C show the results of an ELISA-based cytokine analysis for granzyme A. TCEs AETX-S3-18c-AAA-R023, R104, R106, R114, R120, R121, R122, R123, and RSV (control) were tested both in the presence and absence of sotorasib. Results are shown for donors 3 and 10 for HLA-A*03 (FIG. 20A), HLA-A*11 (FIG. 20B), and HLA-A*03 and HLA-A* 11 (FIG. 20C). For FIGs. 20A-20C, the order of each pair of bars, from left-to-right, is: (i) no engager, (ii) R023, (iii) R104, (iv) R106, (v) R114, (vi) R120, (vii) R121, (viii) R122,(ix) R123, and (x) RSV.

[0286] FIGs. 21A-21C show the results of an ELISA-based cytokine analysis for TFNa. TCEs AETX-S3-18c-AAA-R023, R104, R106, R114, R120, R121, R122, R123, and RSV (control) were tested both in the presence and absence of sotorasib. Results are shown for donors 3 and 10 for HLA-A*03 (FIG. 21 A), HLA-A* 11 (FIG. 21B), and HLA-A*03 and HLA-A* 11 (FIG. 21C). For FIGs. 21A-21C, the order of each pair of bars, from left-to-right, is: (i) no engager, (ii) R023, (iii) R104, (iv) R106, (v) R114, (vi) R120, (vii) R121, (viii) R122, (ix) R123, and(x) RSV.

[0287] FIGs. 22A-22C show the results of an ELISA-based cytokine analysis for IL-6. TCEs AETX-S3-18c-AAA-R023, R104, R106, R114, R120, R121, R122, R123, and RSV (control) were tested both in the presence and absence of sotorasib. Results are shown for donors 3 and 10 for HLA-A*03 (FIG. 22A), HLA-A* 11 (FIG. 22B), and HLA-A*03 and HLA-A* 11 (FIG. 22C). For FIGs. 22A-22C, the order of each pair of bars, from left-to-right, is: (i) no engager, (ii) R023, (iii) R104, (iv) R106, (v) R114, (vi) R120, (vii) R121, (viii) R122, (ix) R123, and (x) RSV.

[0288] FIGs. 23A-23C show the results of an ELISA-based cytokine analysis for granulysin. TCEs AETX-S3-18c-AAA-R023, R104, R106, R114, R120, R121, R122, R123, and RSV (control) were tested both in the presence and absence of sotorasib. Results are shown for donors 3 and 10 for HLA-A*03 (FIG. 23 A), HLA-A* 11 (FIG. 23B), and HLA-A*03 and HLA-A* 11 (FIG. 23C). For FIGs. 23A-23C, the order of each pair of bars, from left-to-right,is: (i) no engager, (ii) R023, (iii) R104, (iv) R106, (v) R114, (vi) R120, (vii) R121, (viii) R122, (ix) R123, and (x) RSV.

[0289] FIGs. 24A-24C show the results of an ELISA-based cytokine analysis for perforin. TCEs AETX-S3-18c-AAA-R023, R104, R106, R114, R120, R121, R122, R123, and RSV (control) were tested both in the presence and absence of sotorasib. Results are shown for donors 3 and 10 for HLA-A*03 (FIG. 24A), HLA-A*11 (FIG. 24B), and HLA-A*03 and HLA-A* 11 (FIG. 24C). For FIGs. 24A-24C, the order of each pair of bars, from left-to-right, is: (i) no engager, (ii) R023, (iii) R104, (iv) R106, (v) R114, (vi) R120, (vii) R121, (viii) R122,(ix) R123, and (x) RSV.

[0290] FIGs. 25A-25C show the results of an ELISA-based cytokine analysis for IL-2. TCEs AETX-S3-18c-AAA-R023, R104, R106, R114, R120, R121, R122, R123, and RSV (control) were tested both in the presence and absence of sotorasib. Results are shown for donors 3 and 10 for HLA-A*03 (FIG. 25A), HLA-A* 11 (FIG. 25B), and HLA-A*03 and HLA-A* 11 (FIG. 25C). For FIGs. 25A-25C, the order of each pair of bars, from left-to-right, is: (i) no engager, (ii) R023, (iii) R104, (iv) R106, (v) R114, (vi) R120, (vii) R121, (viii) R122, (ix) R123, and(x) RSV.

[0291] FIGs. 26A-26E show the half-life measures of peptide / MHC class 1 complexes, comparing wild-type peptide in complex with MHC versus soto-peptide conjugate with MHC. FIG. 26A shows wild-type p5 (KLVVVGAGGV) (SED ID NO: 156) vs. soto-p5 (KLVVVGACGV) (SEQ ID NO: 159) in complex with HLA-A*02. FIG. 26B shows wildtype p7 (VVVGAGGVGK) (SEQ ID NO: 157) vs. soto-p7 (VVVGACGVGK) (SEQ ID NO: 160) in complex with HLA-A*03. FIG. 26C shows wild-type p7 (VVVGAGGVGK) (SEQ ID NO: 157) vs. soto-p7 (VVVGACGVGK) (SEQ ID NO: 160) in complex with HLA-A*11. FIG. 26D shows wild-type p8 (VVGAGGVGK) vs. soto-p8 (VVGACGVGK) in complex with HLA-A*03. FIG. 26E shows wild-type p8 (VVGAGGVGK) vs. soto-p8 (VVGACGVGK) in complex with HLA-A* 11.

[0292] FIGs. 27A-27E shows half-life measures of peptide / MHC class 1 complexes with no TCE, a TCE containing binding partner R023, or a TCE containing binding partner R114. FIG. 27A shows wild-type p5 (KLVVVGAGGV) (SED ID NO: 156) in complex with HLA-A*02. FIG. 27B shows wild-type p7 (VVVGAGGVGK) (SEQ ID NO: 157) in complex with HLA- A*03. FIG. 27C shows wild-type p7 (VVVGAGGVGK) (SEQ ID NO: 157) in complex with HLA-A*11. FIG. 27D shows wild-type p8 (VVGAGGVGK) in complex with HLA-A*03. FIG. 27E shows wild-type p8 (VVGAGGVGK) in complex with HLA-A* 11.

[0293] FIGs. 28A-28E show measurements of the half-lives of peptide / MHC class 1 complexes with no TCE, a TCE containing binding partner R023, or a TCE containing binding partner R114. FIG. 28A shows soto-p5 (KLVVVGACGV) (SEQ ID NO: 159) in complex with HLA-A*02. FIG. 28B shows soto-p7 (VVVGACGVGK) (SEQ ID NO: 160) in complex with HLA-A*03. FIG. 28C shows soto-p7 (VVVGACGVGK) (SEQ ID NO: 160) in complex with HLA- A* 11. FIG. 28D shows soto-p8 (VVGACGVGK) in complex with HLA-A*03. FIG. 28E shows soto-p8 (VVGACGVGK) in complex with HLA-A*11.

[0294] FIGs. 29A-29B show measurements of the half-lives of peptide / MHC class 1 complexes with no TCE or a TCE containing an RSV binding partner. FIG. 29A shows soto- p8 (VVGACGVGK) in complex with HLA-A*03. FIG. 29B shows soto-p8 (VVGACGVGK) in complex with HLA-A* 11.

[0295] FIGs. 30A-30C show results of a sotorasib scan. FIG. 30A shows a schematic illustration of the method and the scheme for residues in the panel. The p7WTpeptide has an amino acid sequence as set forth in SEQ ID NO: 157. Anchor residues are underlined in the sequence. FIG. 30B shows BLI sensorgrams of the binder to the tested soto-p7 / MHC complex immobilized on sensor tips. FIG. 30C shows binding signal of the Fab binder to the tested soto-p7 / MHC complexes at 1200 s of the measurement (e.g., Bmax, indicated as the vertical line in FIG. 30B).

[0296] FIGs. 31A-31C depict results of a HLA scan. FIG. 31A shows schematic illustrations of the modified soto-p7 peptides used in the HLA scan. The modified soto-p7 peptides have amino acid sequences as set forth in VVVGACGVK (SEQ ID NO: 183), VVDGACGVY (SEQ ID NO: 184), VLVGACGVV (SEQ ID NO: 185), VYVGACGVL (SEQ ID NO: 186), and VVVGACGVY (SEQ ID NO: 187). Anchor residues are underlined and the sotorasib- conjugated Cys is highlighted. FIG. 31B shows BLI sensorgrams of the binder to the tested soto-p7 / MHC complexes. FIG. 31C shows binding signal of the Fab binder to the tested soto- p7 / MHC complexes at 1200 s of the measurement (e.g., Bmax, indicated as the vertical line in FIG. 4B)

[0297] FIGs. 32A-32C show schematic representations of multivalent polypeptides that serve as TCEs. FIG. 32A shows diabody binders comprising a first VH, a second VH, a first VL, and a second VL. FIG. 32B shows a pair of binders comprising two Fc subunits with a knobin-hole configuration. FIG. 32C shows a pair of binders comprising a single polypeptide chain with two antigen binding domains.

[0298] FIG. 33 shows binding of antibody clones with the indicated binder to the indicated peptide conjugate / MHC complexes. The antibody clones were displayed on the yeast cellsurface, and after initial binding to the indicated biotinylated antigen, the cells were washed and incubated with non-biotinylated competitor (100 nM soto-p8 / A03 complex) for two hours at room temperature. The remaining biotinylated antigen was then detected using a streptavidin-dye conjugate and flow cytometry.

[0299] FIG. 34 shows tumor growth for all tested groups across 20 days post-injection. Treatment with sotorasib + TCE AETX-S3-18c-CGC-R023 (1 mg / kg), sotorasib + TCE AETX-S3-18c-CGC-R023 (3 mg / kg), and sotorasib + TCE HAP-Ab-0018 (1 mg / kg) showed the greatest reduction of tumor volumes at Day 20. “S3-18c-CGC” is abbreviated as “F3” for all constructs.

[0300] FIG. 35 shows tumor growth for all tested groups with individual data points for each animal representing the average over the 20 days of measured tumor volumes. Treatment with sotorasib + TCE AETX-S3-18c-CGC-R023 (1 mg / kg), sotorasib + TCE AETX-S3-18c-CGC- R023 (3 mg / kg), and sotorasib + TCE HAP-Ab-0018 (1 mg / kg) showed the greatest reduction of tumor volumes. “S3-18c-CGC” is abbreviated as “F3” for all constructs.

[0301] FIG. 36 shows selected groups to distinguish the differences in tumor volume between vehicle, sotorasib, sotorasib + AETX-S3-18c-CGC-RSV (control) (at 1 mg / kg and 3 mg / kg), and sotorasib + AETX-S3-18c-CGC-R023 (at 1 mg / kg and 3 mg / kg). The combination of sotorasib + AETX-S3-18c-CGC-R023 at both doses showed the greatest reduction in tumor volumes compared to the other tested conditions. “S3-18c-CGC” is abbreviated as “F3” for all constructs.

[0302] FIGs. 37A-37B show mirror plot visualizations of representative MS2 spectrum of light, endogenous sotorasib-modified KRASG12CMHC-I peptide (soto-p7, top) and an embedded stable isotope labeled (SIL) synthetic peptide standard of the soto-p7 peptide (bottom) in engineered (FIG. 37A) and endogenous (FIG. 37B) cell systems. The left plot in both FIG. 37A and FIG. 37B denotes treatment with DMSO and the right plot denotes treatment with sotorasib.

[0303] FIG. 38 shows a relative abundance of the soto-p7 peptide presented on HLA-A* 11 :01 with sotorasib treatment alone, sotorasib with binder R023 (TCE AETX-S3-18c-AAA-R023), and sotorasib with binder R114 (TCE AETX-S3-18c-AAA-Rl 14). As shown by the increased epitope abundance, TCE AETX-S3-18c-AAA-Rl 14 stabilized presentation of soto-p7. “S3- 18c- AAA” is abbreviated as “Fl” for all constructs.

[0304] FIG. 39 shows a BLI sensorgram of the single chain diabody (scDb) format TCEs containing either the R023 binder or the R011 binder to soto-p7 / MHC complex (HLA-A*03) and measure of dissociation rate.

[0305] FIGs. 40A-40B show drug-peptide EC50 and potency of killing effect on drug-treated cells. FIG. 40A shows the EC50 of scDb format TCEs containing either the R023 binder or the RO 11 binder when using a spiked sotorasib-p7 conjugate. FIG. 40B shows potency against sotorasib-treated cells of a scDb format TCE containing the R023 binder demonstrating a greater effect at 1 pM sotorasib compared to that of a scDb format TCE containing the R011 binder.

[0306] FIG. 41 shows a BLI sensorgram of the binders R120, R114, R104, and R023 (control) with soto-p7 / Al 1 complexes. Binders R120, 104, and 114 showed slower off-rate compared to that of R023.

[0307] FIGs. 42A-42B show drug-peptide EC50 and potency of killing effect on drug-treated cells for scDb format TCEs containing either the R120, R114, R104, or R023 binder with soto- p7 / Al 1 complex. FIG. 42A shows that the scDb format TCEs containing the R120 binder, the R104 binder, and the R114 binder had decreased EC50 compared to that of the scDb format TCE containing the R023 binder, demonstrating better potency. The scDb format TCE containing the R120 binder showed that strongest potency (EC50 = 5 ± 1 nM). FIG. 42B shows that the scDb format TCEs containing the R120 binder, the R104 binder, and the R114 binder demonstrated superior cell-killing effects than the scDb format TCE containing the R023 binder. The scDb format TCEs containing the R120 binder, the R104 binder, and the R114 binder showed greater luminescence (RLI) at lower concentrations compared to the scDb format TCE containing the R023 binder.

[0308] FIG. 43 shows binding data for yeast-displayed (YD) binders R120, R114, R104, and R023 (control). R120, R104, and R114 all showed superior binding with 10 nM soto-p7 / A*l 1 complexes. Binder R114 showed better binding than all other tested binders with 10 nM soto- p7 / A*03 complexes. For FIG. 43, the order of the four bars from left-to-right, for each of R023, R104, R114, and R120, is: (i) No target, (ii) 10 nM soto-p? / A03, 10 nM soto-py / Al l, and bSMPs.

[0309] FIG. 44 shows a BLI sensorgram of the binders R120, R114, R104, and R023 (control) with soto-p7 / A*03 complexes. Binder R114 showed slower off-rate on soto-p7 / A3 compared to R023.

[0310] FIGs. 45A-45B show drug-peptide EC50 and potency of killing effect on drug-treated cells for the scDb format TCEs containing either the R120, R114, R104, or R023 binder with spiked soto-p7 / A03 complex. All scDb format TCEs exhibited similar potency and cell-killing effects compared to that of the scDb format TCE containing the R023 binder.

[0311] FIGs. 46A-46B show the purification of abispecific T cell engager (BiTE)-scFc format TCE containing the R114 binder. FIG. 46A shows a size-exclusion chromatography profile of the BiTE-scFc format TCE containing the R114 binder. FIG. 46B shows results of a SDS- PAGE for the BiTE-scFc format TCE containing the R114 binder.

[0312] FIGs. 47A-47B show comparisons between potency of a scDb format TCE containing the R114 binder and a BiTE-scFc format TCE containing the R114 binder. FIG. 47A shows that the scDb format TCE containing the R114 binder had greater potency (measured as lower ECso) compared to that of the BiTE-scFc format TCE containing the R114 binder against a sotorasib-treated cell line (H2030) expressing HLA-A* 11 :01 and HLA-A*24:02 MHC molecules. FIG. 47B shows that the scDb format TCE containing the R114 binder had greater potency (measured as lower EC50) compared to that of the BiTE-scFc format TCE containing the R114 binder against a sotorasib-treated cell line (H2122) expressing HLA-A*03:01 and HLA-A*01:01 MHC molecules.

[0313] FIGs. 48A-48C show the workflow for the immunopeptidomics analysis. FIG. 48A shows sequences of KRASG12Cepitopes. The p?WTsequence is set forth as VVVGAGGVGK (SEQ ID NO: 157), the p8WTsequence is set forth as VVGAGGVGK (SEQ ID NO: 158), the p? sequence is set forth as VVVGACGVGK (SEQ ID NO: 160), and the p8sequence is set forth as WGACGVGK (SEQ ID NO: 161). The p? and p8epitopes are conjugated to the drug. FIG. 48B shows the targeted MS workflow for identifying and quantifying haptenated MHC- I peptides. FIG. 48C shows a schematic of SureQuant targeted data acquisition and analysis.

[0314] FIGs. 49A-49D show definition of the limit-of-quantification (LOQ). FIG. 49A displays the data for p?, FIG. 49B displays the data for p8, FIG. 49C displays the data for soto- p?, and FIG. 49D displays the data for soto-p8. The data display a linear fit of the normalized intensity ratios (summed hipMHC [single heavy-labeled, 1H] / double heavy-labeled peptide [2H] abundance) of hipMHCs spiked into 5xl07Raji cells (KRASWT) from 0.1-100 fmol (p?, soto-p?) and 1-100 fmol (p8, soto-p8), with 100 fmol of the 2H synthetic standard added prior to analysis for normalization and SureQuant data acquisition triggering. The hipMHC signal of 100 fmol p8 / soto-p8 could not be quantified. Calculated copies-per-cell (CPC) for each hipMHC concentration added are shown to define the limit of quantitation for each peptide. Error bars represent standard deviation from the mean from 3 technical replicates per sample.

[0315] FIGs. 50A-50B show spectral validation for KRASG12Cp*MHC peptides presented on HLA-A* 11 :01. FIG. 50A shows a schematic of cell line engineering for generating HLA / KRASG12Coverexpression A375-derived cell lines. FIG. 50B shows mirror plots depicting the mass spectra for the double heavy-labeled synthetic (bottom) and endogenous(top) peptides. Mass spectra show ps (left) and p? (right) peptides presented on A375-A11KCcells. C: carbamidomethylation.

[0316] FIGs. 51A-51B show spectral validation for KRASG12Cp*MHC peptides presented on HLA-A* 11 :01. FIG. 51A shows mirror plot depicting the mass spectra in each sample for the double heavy-labeled synthetic (bottom, +14 m / z) and endogenous (top) soto-p? peptides in cells treated for 48 hours with DMSO (left) or 3 pM sotorasib (right). Annotated ions labeled depict identified b, y, a, or precursor ion fragments. Underlined amino acids are heavy isotopelabeled (V, K) or sotorasib-modified (C). The soto-p? peptide has an amino acid sequence as set forth in SEQ ID NO: 160, with the sotorasib-conjugated cysteine residue. FIG. 51B shows mass spectra show soto-ps on A375-A11KCcells treated with DMSO (left) or 3 pM sotorasib (right) for 48 h. Annotated ions depict identified b, y, a, or precursor ion fragments. Underlined amino acids are modified as follows: K, V: heavy isotope-labeled, C*: sotorasib-conjugated. The soto-ps peptide has an amino acid sequence as set forth in SEQ ID NO: 161, with the sotorasib-conjugated cysteine residue.

[0317] FIG. 52 shows estimated copies-per-cell of soto-p? presented on A375-A11KCtreated with 3 pM sotorasib between 2 hours and 72 hours. Data points represent n=2 independent biological replicates. Error bars represent std dev.

[0318] FIGs. 53A-53C show spectral validation of additional KRASG12Chapten peptides presented on HLA-A* 11 :01. The figures show mirror plots depicting the mass spectra for the double heavy -labeled synthetic (bottom) and endogenous (top) peptides presented on A375- A11KCcells. FIG. 53A shows cells treated with DMSO (left) or 1 pM divarasib (right) for 48 hours. FIG. 53B shows cells treated with DMSO (left) or 1 pM adagrasib (right) for 48 h. In FIGs. 53A-53B, the p? peptide has an amino acid sequence as set forth in SEQ ID NO: 160, with the drug-conjugated cysteine residue. Annotated ions depict identified b, y, a, or precursor ion fragment. *denotes ions with a loss of 97.09 Da from the drug modification, as depicted in FIG. 53C, for divarasib (left) or adagrasib (right). Underlined amino acids are heavy-isotope labeled (V, K) or drug-modified (C).

[0319] FIGs. 54A-54B show allele screening for HLA-A3 supertype. FIG. 54A shows a table of netMHCpan-4.1 peptide prediction scores (% rank) for p? or OW to model a bulky modified residue (e.g. soto-p?) on selected A3 supertype alleles. % Rank < 0.5 is a predicted strong binder, < 2% a predicted weak binder. FIG. 54B shows sequence logos generated from eluted ligands (mass spectrometry data, netMHCpan-4.1) of A3 supertype alleles with a lysine present in the c-terminal position.

[0320] FIG. 55 shows a table of HLA-A3 supertype alleles summarizing the results of p? / soto- p? targeted MS experiments, with HLA residues at the p*MHC / antibody binding interface identical to those of A*03:01 highlighted. A check mark indicates “detected”, an “X” indicates “undetected”.

[0321] FIGs. 56A-56E show spectral validation of of KRASG12CpMHC presentation and soto-p? presentation on HLA-A3 supertype alleles. FIGs. 56A-56C show mirror plots depicting mass spectra for the double heavy -labeled synthetic (bottom) and endogenous (top) KRASG12Cp? or p8 peptides. Underlined amino acids are heavy-isotope labeled (V, K) or carbamidomethylated (C). FIGs. 56D-56E show mirror plots depicting the mass spectra in each sample for the double heavy-labeled synthetic (bottom) and endogenous (top) soto-p7 peptides in cells treated for 48 h with DMSO or sotorasib in engineered A375 cells. FIG. 56D shows HLA-A*03:01 and FIG. 56E shows HLA-A*68:01. In FIGs. 56A-56E, the soto-p? peptide has an amino acid sequence as set forth in SEQ ID NO: 160, and the ps peptide has an amino acid sequence as set forth in SEQ ID NO: 161.

[0322] FIG. 57 shows estimated copies-per-cell of peptides presented on A375 A11KCcells with no treatment (p? / ps) or with 48 h of 3 pM sotorasib (soto-p? / 8). Data points represent 3 technical replicates.

[0323] FIG. 58 shows mirror plots depicting the mass spectra in each sample for the double heavy-labeled synthetic (bottom) and endogenous (top) soto-p? peptides in cells treated for 48 h with DMSO or sotorasib in NCI-H2122 cells. In FIG. 58, the p? peptide has an amino acid sequence as set forth in SEQ ID NO: 160.

[0324] FIG. 59 shows p / p*MHC complex half-life measured at 37 °C, calculated from 3 technical replicates per peptide. For each HLA condition, from top-to-bottom, the bars represent p?WT, soto-p?, diva-p?, and ada-p?.

[0325] FIG. 60 shows a schematic representation of the structure guided affinity maturation of R023 to R114. In the top panel, the structural representation of the positions of R023 CDRs (shown as tubes) bound to soto-p7 / A* 11. The HLA moiety of the soto-p / MHC is shown in surface representation, while soto-p? is represented as sticks (sotorasib) and tubes (p?). The sidechains of R023 residues located at positions selected for the affinity maturation campaign are represented as spheres. In the bottom panel, CDR sequences of R023 and its descendant R114 clones, and a schematic representation of the affinity maturation process. R023 residues located at positions selected for the affinity maturation campaign are underlined, and mutations introduced in R114 are in bold. “Off-rate sorting” refers to Fluorescence- Activated Cell Sorting (FACS) of yeast libraries, performed upon staining aimed at the identification of binders withlow dissociation from the target. As shown in FIG. 60, the binding partner R023 has a VL with (i) a CDR-L3 having an amino acid sequence of ASYVRKTI (SEQ ID NO: 193), (ii) a CDR- L2 having an amino acid sequence of SAS SLY (SEQ ID NO: 191), and (iii) a CDR-L1 having an amino acid sequence of SVSSAVA (SEQ ID NO: 194). Binding partner R114 has a VL with a (i) CDR-L3 having the amino acid sequence of ASYVWKTI (SEQ ID NO: 190), (ii) a CDR-L2 having the amino acid sequence of SAS SLY (SEQ ID NO: 191), and (iii) a CDR-L1 having the amino acid sequence of SVASTVA (SEQ ID NO: 192).

[0326] FIG. 61 shows binding of yeast-displayed scFv R023 and descendant matured clones to soto-p / MHC antigens, in an “off-rate” setting. Target-bound yeast cells, after removal of unbound soto-p / MHCs, are incubated for two hours with a 10-fold excess of a competitor molecule, to prevent rebinding of dissociated target, and measure signal from remaining bound molecules. The same dot shade indicates the same clone (e.g., R023 is indicated by the dot in the R023 column, and R114 is indicated by arrows).

[0327] FIGs. 62A-62B show binding properties of binder R114. FIG. 62A shows inhibition by free sotorasib of the interaction between scFv R114 displayed on the yeast cell surface and 10 nM soto-p / MHCs (soto-p? / A*03 in light gray, and soto-p? / A*l 1 in dark gray). The binding signal intensity was normalized to the values in the absence of free sotorasib (100%) and in the absence of antigen (0%). IC50 values are reported for each antigen. FIG. 62B shows a schematic representation of the TCE AETX-R114, in the (scFv)2-scFc format.

[0328] FIGs. 63A-63C show sensorgram data for binder R114 and AETX-R114, in the (SCFV)2-SCFC format. FIG. 63A shows SPR sensorgrams of the interaction between AETX- TCEs and the indicated soto-p / MHC antigens. Biotinylated soto-p / MHCs were immobilized, and binding of soluble AETX-TCEs samples was measured using single cycle kinetic experiments. Kinetic values of fitted data are shown in the table. FIG. 63B shows SPR sensorgrams of the interaction between AETX-R114 and the indicated p / p*MHC antigens. Biotinylated antigens were immobilized, and binding of soluble AETX-R114 samples was measured. On the left side of the sensorgrams are reported the sequences of the peptides used in the binding experiment. Explored off-target peptides include KRASWT- and KRASG12W- derived peptides (p?WTand p?W12, respectively). The latter was used to mimic haptenated- peptides with a non-modified peptide, presenting a bulky tryptophan (W12) instead of the hapten of the p*MHC targets. The p?WTsequence is set forth as VVVGAGGVGK (SEQ ID NO: 157), the p? sequence is set forth as VVVGACGVGK (SEQ ID NO: 160) with sotorasib- conjugated cysteine residue, and the p?W12peptide had the amino acid sequence of VVVGAWGVGK (SEQ ID NO: 195). For each sensorgram, next to the sample name isindicated if the antibody is binding to the target (check mark) or not (cross). FIG. 63C shows SPR sensorgram of the interaction between AETX-R114 (analyte) and soto-p? / A*68 (immobilized ligand), using a single cycle kinetic experiment. Kinetic values of fitted data are shown in the table below. AETX-R114 binds with picomolar affinity to sotorasib p*MHCs, including soto-p7 / A*68, and it has no significant binding to closely related pMHCs lacking conjugated-sotorasib.

[0329] FIGs. 64A-64D show half-life data of p*MHCs. FIG. 64A shows proportion of intact p / p*MHC remaining after incubation at 37° C from 0 to 24 h. Complex half-life was determined using a one-phase decay non-linear fit equation. Data points represent 3 technical replicates; error bars are standard deviation. For each plot of FIG. 64A, the top line is soto-p? + AETX-R114, the middle line is p?WT, and the bottom line is soto-p?. FIG. 64B shows calculated p / p*MHC half-lives at 37° C. FIGs. 64C-64D show proportion of intact p / p*MHC remaining after incubation at 37° C from 0 to 24 hours with or without TCE. Complex half-life was determined using a one-phase decay non-linear fit equation. R001 is the predecessor of R023 and has low affinity for soto-p? on A*03 and minimal binding on A*11.

[0330] FIGs. 65A-65B show antibody binding extends half-lives of p*MHCs. FIG. 65A shows proportion of intact p / p*MHC remaining after incubation at 37° C from 0 to 24 h with or without TCE. Complex half-life was determined using a one-phase decay non-linear fit equation. Data points in represent 3 technical replicates and error bars are standard deviation. Haptenated peptide was tested with HLA-A*03 and HLA-A*11. FIG. 65B shows calculated p / p*MHC half-lives measured at 37° C incubated with or without a TCE (3 technical replicates per peptide / antibody pair. For each epitope condition in FIG. 65B, the bars from top-to-bottom represent: “No TCE”, “R001”, “R023”, and “R114”.

[0331] FIG. 66 shows estimated copies-per-cell of A*03 epitopes present onNCI-H2122 cells. Data points represent 3 technical replicates; error bars are standard deviation.

[0332] FIGs. 67A-67B show schematics of p*MHC stabilization. FIG. 67A shows endogenous p*MHC presentation. FIG. 67B shows antibody-stabilized p*MHC presentation.

[0333] FIGs. 68A-68C show viability of KRASG12C-expressing cell lines after 72 h incubation with sotorasib showing three independent trials and 4 technical replicates per datapoint plotted as mean ± standard deviation. Dashed lines indicate growth inhibition in the presence of 300 nM sotorasib, the concentration used in cytotoxicity assays. FIG. 68A shows results for NCI- 142122 cell line, FIG. 68B shows results for NCI-H2030 cell line, and FIG. 68C shows results for HOP-62 cell line.

[0334] FIGs. 69A-69D show results from an Incucyte cytotoxicity analysis. FIGs. 69A-69C show Incucyte analysis of AETX-R114-induced T cell cytotoxicity against cell lines endogenously expressing KRASG12Cin the presence of sotorasib (soto) or vehicle (DMSO). Cell lines were plated in 2D or as 3D spheroids with a 10: 1 E:T ratio of activated human T cells, and cytotoxicity was assessed at 48 hours. Plots show n=3 technical replicates per condition and error bars indicate standard deviation. FIG. 69D shows representative images from Incucyte-based T cell cytotoxicity analysis showing sotorasib-treated eGFP-expressing cell lines in the presence and absence of AETX-R114, in which cell lines were co-cultured with a 10:1 E:T ratio of activated human T cells.

[0335] FIGs. 70A-70C show sotorasib sensitivity of KRASG12Ccell lines and characterization of AETX-R114-induced effector T cell response. FIGs. 70A-70B show flow cytometry analysis of T cell activation in cytotoxicity assays performed as in FIGs. 69A-69C with eGFP- expressing cell lines and a dose response of TCEs at 48 h. Data show mean ± standard deviation of 3 technical replicates per datapoint. FIG. 70C shows ELISA analysis of IFNy in 48 h cytotoxicity assay supernatant. Data show mean ± standard deviation of n=3 technical replicates per datapoint.

[0336] FIGs. 71A-71H show NCI-H2122 HLA isogenic cell line generation and characterization. FIG. 71 A shows a schematic illustrating the CRISPR-Cas9-mediated knockout (KO) of HLA-A*03:01 in NCI-H122 wild-type cells (NCI-H2122A*03-K°). HLA- A*03 supertype alleles were overexpressed in NCI-H2122A*03'K° cells by lentiviral transduction. FIG. 71B shows confirmation of A*03 KO by flow cytometry. FIG. 71C shows western blot confirmation that RAS expression was unchanged by A*03 knockout. FIG. 71D shows sequence logos3 of 9-mer peptides identified by DDA-MS of NCI-H2122A*03-KO HLA isogenic cell lines. Disappearance of the C-terminal lysine and arginine confirms A*03 KO in NCI-H2122A*03'K° cells; re-appearance of lysine and arginine in the engineered KO + HLA cell lines confirms allele expression (compared to that in FIG. 54B). The ”n” describes the number of 9-mer peptides used to generate the sequence logo. FIG. 71E shows percent of peptides predicted to strongly bind (% rank < 0.5%) the endogenously expressed target allele (A*03 for NCI-H2122WT& KO cells) or engineered allele. (-75% of peptides), -20% higher than NCI-H2122WTcells (55% are predicted A*03 binders). FIG. 71F shows total HLA expression (flow cytometry, HLA-ABC clone W6 / 32) of all cell lines. Data points represent 3 technical replicates. Engineered KO + HLA isogenic cell lines exhibited comparable HLA expression, ~2.5x higher than NCI-H2122WTexpression levels. FIGs. 71G-71H show growth curves (FIG. 71G) and doubling times (FIG. 71H) of NCI-H2122-derived cell lines in thepresence or absence of sotorasib. Data points represent the mean of 5 biological replicates. All cell lines show similar doubling times without treatment (left, mean doubling time: 20.5 ± 0.6 h ) or with 300 nM sotorasib treatment (right, mean doubling time: 22.5 h ± 0.8 h).

[0337] FIGs. 72A-72B show results of an Incucyte cytotoxicity assay. Incucyte analysis of AETX-R114-induced T cell cytotoxicity against cell lines endogenously expressing KRASG12Cin the presence of sotorasib (soto) or vehicle (DMSO). Cell lines were plated in 2D or as 3D spheroids with a 10: 1 E:T ratio of activated human T cells, and cytotoxicity was assessed at 48 h. Plots show n=3 technical replicates per condition and error bars indicate standard deviation. In FIG. 72A, 10 nM AETX-RSV or AETX-R114 was used (ns, not significant or p > 0.05 and **** p < o 0001 by two-way ANOVA using Sidak’s multiple comparisons test comparing soto + AETX-RSV and soto + AETX-R114).

[0338] FIGs. 73A-73E show dose-finding and phenotypic analysis of AETX-R114 in an NCI- 142122 CDX model. FIG. 73A shows for a CDX mouse model, NCI-H2122 cells were implanted subcutaneously as a co-mixed xenograft with activated human T cells (n=10 / group; image from BioRender software). Mice were dosed 30 mpk sotorasib daily, IxlO6T cells weekly, and 1 mpk AETX-RSV or 1 mpk AETX-R114 weekly. Tumors were harvested, weighed, and processed for flow cytometry analysis 48 h after the final TCE dose. FIG. 73B shows a schematic showing design of the CDX dose-finding and phenotyping experiment. FIG. 73C shows a time course depicting AETX-R114 plasma and tumor concentrations. Data points show mean ± standard deviation for n=3 biological replicates per condition. FIGs. 73D-73E show kinetics of CD8+ (FIG. 73D) and CD4+ (FIG. 73E) T cell activation after dosing AETX- R114 or AETX-RSV showing representative flow cytometry plots. Data points show mean ± standard deviation with n=3 biological replicates per condition (** p < 0.01, *** p < 0.001 by Student’s t-test comparing AETX-R114 and AETX-RSV at each time point).

[0339] FIG. 74 shows results of a negative control study. IxlO6NCI-H2122 cells were implanted subcutaneously as a co-mixed xenograft with activated human T cells in NOD SCID mice (n=8 / group), which were dosed daily with vehicle or sotorasib, weekly with IxlO6T cells, and weekly with vehicle (PBS) or 1 mpk AETX-RSV. Tumor volumes were assessed through day 20, at which point vehicle group mice reached humane endpoints and all groups were euthanized.

[0340] FIGs. 75A-75E show tumor growth and other phenotypic results following antibody administration. FIG. 75A shows NCI-H2122 tumor growth with AETX-R114 vs AETX-RSV treatment. Data points indicate mean ± SEM (* p < 0.05, ** p < 0.01, *** p < 0.001 by Student’s t-test). FIG. 75B shows Kaplan-Meyer survival curve for AETX-RSV vs AETX-R114 (* p <0.05 by Mantel-Cox test). FIG. 75C shows body weights normalized to starting weight (ns = no significant difference from starting weight for AETX-R114 or AETX-RSV). FIG. 75D shows tumor weights; for two mice in the AETX-R114 group, no tumor was detected (** p < 0.01 by Student’s t-test). FIG. 75E shows spider plots showing tumor growth of individual mice in each group.

[0341] FIGs. 76A-76D show analysis of tumor-infiltrating T cells. FIG. 76A shows numbers of tumor-infiltrating T cells normalized to tumor weight as measured in milligrams (mg) (** p < 0.01 by Student’s t-test). FIG. 76B shows the average proportion of each T cell subset in the tumors. For each bar of the graph, the order of T cell subsets from top-to-bottom is: CD8 CD4' , Treg, CD4+, and CD8+. FIG. 76C shows the gating scheme for flow cytometric analysis of processed NCI-H2122 tumor samples to identify and analyze live T cells. FIG. 76D shows CD8+ and CD4+ T cell numbers per milligram (mg) of tumor in NCI-H2122 tumors with representative flow cytometry plots shown (** p < 0.01 by Student’s t-test).

[0342] FIGs. 77A-77D show analysis of T cell markers. FIGs. 77A-77B show levels of T cell activation markers including CD25 (FIG. 77A) and PD-1 (FIG. 77B) showing quantification for individual mice and representative flow cytometry plots (* p < 0.05, **** p < 0.0001 by Student’s t-test). FIGs. 77C-77D show T cell activation markers including HLA-DR (FIG. 77C) and ICOS (FIG. 77D) showing quantification for individual mice and representative flow cytometry plots (** p < 0.01, *** p < 0.001 by Student’s t-test).DETAILED DESCRIPTION

[0343] While various examples of the invention have been shown and described herein, it will be obvious to those skilled in the art that such examples are provided by way of example only. Numerous variations, changes, and substitutions can occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the examples of the invention described herein can be employed.

[0344] Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed disclosure.

[0345] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0346] Every numerical range given throughout this specification includes its upper and lower values, as well as every narrower numerical range that falls within it, as if such narrower numerical ranges were all expressly written herein.

[0347] As used in the specification and the appended claims, the singular forms “a” “and” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another example includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent “about” it will be understood that the particular value forms another example. The term “about” in relation to a numerical value encompasses variations of + / -10%, + / - 5%, or + / - 1%.

[0348] This disclosure includes every amino acid sequence described herein and all nucleotide sequences encoding the amino acid sequences. Every antibody sequence and antigen-binding fragments of them are included. Polynucleotide and amino acid sequences having from 80- 99% similarity, inclusive, and including all numbers and ranges of numbers there between, with the sequences provided herein, are included in the invention. The polynucleotides provided herein can be modified polynucleotides. All of the amino acid sequences described herein can include amino acid substitutions, such as conservative substitutions, that do not adversely affect the function of the protein that comprises the amino acid sequences. In this regard, the disclosure provides alternative residues for certain positions in described binding partners as described below. In certain examples, the alternative residues were identified by deep mutational scanning, which demonstrates binding functionality for each binding partner that contains the described amino acid change(s). The disclosure includes each binding partner with each alternative residue substituted for the original residue alone and in any combination with the described alternative residues. Thus, any binding partner described herein may have any single described residue change or a combination of described changes. Representative changes for particular antibodies are described in the Tables. The changes may be in CDR1, CDR2, CDR3, and combinations thereof. The changes can also include amino acid insertions. The disclosure includes each amino acid sequence that is encompassed by the description of alternative amino acids by reference to a specific sequence identifier and those described in the aforementioned Tables.

[0349] As described above, the present disclosure provides antibodies and antigen-binding domains or fragments thereof (collectively “binding partners” and each individually a “binding partner”). The term “antibody” includes each binding partner format herein. The antibody cancomprise a polypeptide with an antigen-binding domain or fragment thereof. The binding partners bind with specificity to a protein or fragment thereof, or a peptide provided in peptide form, that comprises a covalently attached molecule. The covalently attached molecule forms a peptide conjugate. A “peptide conjugate” as used herein means any protein or peptide that has been modified so that it is covalently conjugated to another molecule. The peptide conjugate is considered to be a novel antigen, i.e., a neoantigen. The other molecule that is covalently conjugated to the protein or peptide to form the peptide conjugate is not particularly limited, with the proviso that the other molecule is not an additional amino acid that is added to the described peptide conjugates. In some examples, the molecule that is covalently conjugated to the protein or peptide could have or could have had biological activity before conjugation, or it may be biologically inert before conjugation. In some examples, the molecule is a drug, including but not necessarily limited to small molecule drugs. As used herein, the molecule that is covalently attached to a peptide to form peptide conjugate is referred to as a “targeted covalent inhibitor (TCI)” or as a “covalent drug.” Representative and non-limiting examples of drugs that covalently attach to a peptide or protein to form a peptide conjugate are described below. Peptide conjugates include but are not limited to covalently modified full length proteins and fragments thereof. Peptide conjugates include fragments of full length proteins that include a covalent modification and are produced, for example, by intracellular processing. In certain examples, a full length protein may be covalently modified within a cell and subsequently processed such that a peptide conjugate that is a fragment of the full length protein is produced. In an example, the peptide conjugate comprises a fragment of a full-length protein. As described further below, the produced peptide conjugate may be displayed on a cell surface. The cell surface display of the peptide conjugate may be any form of cell surface display, including but not limited to by way of any receptor having an extracellular segment, or it may be displayed by way of any type of major histocompatibility complex (MHC) or human leukocyte antigen (HLA). Non-limiting examples of HLA types that display peptide conjugates, and to which the described binding partners bind with specificity, are described further below.

[0350] As used herein, the term “peptide conjugate / MHC complex” refers to a peptide conjugate comprising: a peptide and a chemical fragment of a targeted covalent inhibitor, presented by a major histocompatibility complex (MHC). For example, the peptide conjugate can be formed by the covalent reaction of a targeted covalent inhibitor with a residue (e.g., a cysteine residue) in a peptide. In some examples, the peptide conjugate is formed by the covalent reaction of AMG-510 with a KRASG12Cpeptide. In some examples, the peptide isexternally introduced as a vaccine. In some examples, the peptide comprises a nucleophilic or an electrophilic residue. In some examples, the residue comprises cysteine, aspartic acid, arginine, serine, or tyrosine. In an example, the MHC is a human leukocyte antigen (HLA). In an example, the HLA is HLA-A*02:01, HLA-A*03:01, or HLA-A*11 :01.

[0351] As used herein, the term “CDR” or “complementarity determining region” means the noncontiguous antigen combining sites found within the variable regions of heavy and light chain polypeptides. These particular regions have been described by, for example, Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest (1991), by Chothia et al., J. Mol. Biol. 196:901-917 (1987), and by MacCallum et al., J. Mol. Biol. 262:732-745 (1996), all of which are herein incorporated by reference in their entireties, where the definitions include overlapping or subsets of amino acid residues when compared against each other. In certain examples, the term “CDR” is a CDR as defined by MacCallum et al., J. Mol. Biol. 262:732-745 (1996) and Martin A. “Protein Sequence and Structure Analysis of Antibody Variable Domains,” in Antibody Engineering, Kontermann and Diibel, eds., Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001). In certain examples, the term “CDR” is a CDR as defined by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest (1991). In certain examples, heavy chain CDRs and light chain CDRs of an antibody are defined using different conventions. In certain examples, heavy chain CDRs and / or light chain CDRs are defined by performing structural analysis of an antibody and identifying residues in the variable region(s) predicted to make contact with an epitope region of a target molecule (e.g., a peptide conjugate). HC CDR1, HC CDR2, and HC CDR3 denote the heavy chain CDRs, and LC CDR1, LC CDR2 and LC CDR3 denote the light chain CDRs. The CDRs for any binders (e.g., binding partners, antigen binding domains, or T cell engagers) described herein can be designated by Kabat numbering scheme. In some cases, the light chain (LC) CDRs can be designated by Kabat numbering scheme. In some cases, the LC CDRs can be designated by Kabat numbering scheme with modifications. In some cases, the heavy chain (HC) CDRs can be designated by Kabat numbering scheme. In some cases, the HC CDRs can be designated by Kabat numbering scheme with modifications.

[0352] The determination of “percent identity” between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be accomplished using a mathematical algorithm. A specific, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin S & Altschul SF (1990) PNAS 87: 2264-2268, modified as in Karlin S & Altschul SF (1993) PNAS 90: 5873-5877, each of which is herein incorporatedby reference in its entirety. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul SF et al., (1990) J Mol Biol 215: 403, which is herein incorporated by reference in its entirety. BLAST nucleotide searches can be performed with the NBLAST nucleotide program parameters set, e.g., for score=100, wordlength=12 to obtain nucleotide sequences homologous to a nucleic acid molecule described herein. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., to score 50, wordlength=3 to obtain amino acid sequences homologous to a protein molecule described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul SF et al., (1997) Nuc Acids Res 25: 3389-3402, which is herein incorporated by reference in its entirety. Alternatively, PSI BLAST can be used to perform an iterated search which detects distant relationships between molecules (Id.). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., of XBLAST and NBLAST) can be used (see, e.g., National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). Another specific, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4: 11-17, which is herein incorporated by reference in its entirety. Such an algorithm is incorporated in the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.

[0353] As used herein, the terms “free targeted covalent inhibitor” or “free drug” refer to a targeted covalent inhibitor that is not covalently linked to a protein or peptide. Once the targeted covalent inhibitor is covalently linked to a protein or peptide, the targeted covalent inhibitor can be referred as a portion or fragment of the free target covalent inhibitor or drug. For example, the protein or fragment thereof can be the chemical fragment that is bonded to the cysteine residue of the peptide upon covalent reaction of the free drug with the cysteine residue of the peptide. As used herein the term “KRASG12C” refers to the KRAS protein (UniProt Accession No. P01116) with a G12C mutation, i.e., a cysteine at amino acid position 12. As used herein the term “KRASG12D” refers to the KRAS protein (UniProt Accession No. P01116) with a G12D mutation, i.e., an aspartic acid at amino acid position 12. As used herein the term “KRASG12R” refers to the KRAS protein (UniProt Accession No. P01116) with a G12R mutation, i.e., an arginine at amino acid position 12. As used herein the term “KRASG12S” refersto the KRAS protein (UniProt Accession No. P01116) with a G12S mutation, i.e., a serine at amino acid position 12.

[0354] In some examples, the binding partners preferentially bind to the protein or peptide or a complex comprising the protein or peptide when covalently bound to the peptide conjugate, relative to the same protein or peptide that is not bound to the drug. Accordingly, binding partners described herein either do not detectably bind, or bind with a lower affinity, to the same protein or fragment thereof in the absence of the covalently attached molecule. In some examples, the binding partners bind to the protein or peptide comprising the covalently attached drug with an affinity that is 10 - 10,000 fold, including all numbers and ranges of numbers from 10-10,000, greater than the affinity for the protein or peptide that does not comprise the covalently bound molecule. In this regard, and without intending to be bound by any particular theory, it is considered that the presence of the covalently bound molecule contributes to the epitope to which the binding partners bind with specificity. Likewise, binding partners of this disclosure preferentially bind to the peptide conjugate relative to binding to the free drug. In some examples, the binding partners bind to the peptide comprising the covalently attached drug (e.g., the peptide-conjugate / MHC complex) with an affinity that is 10-10,000 fold, including all numbers and ranges of numbers from 10-10,000, greater than the affinity for the free drug. In some examples, the interaction between the binding partner and the peptide- conjugate / MHC complex is not inhibited by the free drug. For example, the interaction between the binding partner and the peptide-conjugate / MHC complex is not inhibited by a lOOx, l,000x, 10,000x, 100,000x or more excess of the free drug.

[0355] In some examples, the molecule that is covalently bound to form the peptide conjugate is a drug and may be any targeted covalent inhibitor (TCI), but the covalent drug need not necessarily inhibit the target peptide. In some examples, the molecule reacts with a specific residue within the target protein. In some examples, the molecule reacts at least in part with a segment of the protein or peptide that comprises a nucleophilic, or an electrophilic, residue. In some examples, the segment of the protein or peptide to which the molecule reacts comprises any of Cys, Lys, Tyr, His, Ser, Thr, Tyr, or Arg, the latter being described in Ziyang Zhang, Johannes Morstein, Andrew K. Ecker, Keelan Z. Guiley, and Kevan M. Shokat Journal of the American Chemical Society Article ASAP, DOI: 10.1021 / jacs.2c05377, from which the disclosure is incorporated herein by reference. In some examples, the protein or peptide comprises a selenocysteine. In some examples, the targeted covalent inhibitor reacts with selenocysteine. In some examples, the molecule reacts at least in part with a segment of the protein or peptide that comprises a wild type Cys, or a mutation of a residue to a Cys, and thusmay be covalently attached by a so-called sulfur tether. In some examples, the drug is any drug described in Ghosh AK, Samanta I, Mondal A, Liu WR. Covalent Inhibition in Drug Discovery. ChemMedChem. 2019;14(9):889-906. Doi : 10.1002 / cmdc.201900107, or in De Cesco, et al., European Journal of Medicinal Chemistry 138 (2017) 96el l4, or in Bauer, RA, Drug Discovery Today, Volume 20, Number 9, September 2015, from which the disclosures of compounds that covalently modify protein targets is incorporated herein by reference.

[0356] In non-limiting examples, any of said Asp, Cys, and Arg amino acids are present in the protein or peptide to which the molecule binds because the gene encoding the wild type protein has been mutated to encode a protein that includes one or a combination of the described residues. In non-limiting examples, the molecule binds to a protein or peptide that is correlated with a disease or condition, such as a cancer, an autoimmune disease, or other disease or disorder that is treated with a targeted covalent inhibitor. In some examples, the target (e.g., the protein or peptide to which the molecule covalently binds) is a receptor, including but not necessarily limited to any receptor having a catalytically active segment. In some examples, the drug binds to an enzyme that is not necessarily a receptor, including but not limited to any kinase. In some examples, a protein target comprises a receptor with one or more activating mutations, which promote ligand-independent enzyme activity.

[0357] In some examples, the molecule targets and thus covalently binds to an amino acid sequence present within any of the following proteins and / or variants thereof, which may or may not comprise a mutation, such as a mutation that is related to a particular condition, including but not limited to any type of cancer. In some examples, the protein is any protein described in Visscher M, et al., Covalent targeting of acquired cysteines in cancer. Curr Opin Chem Biol. 2016;30:61-67. Doi: 10.1016 / j.cbpa.2015.11.004, from which the description is incorporated herein by reference. Visscher et al. also teaches methods for identifying disease- associated mutated genes that introduces a Cys residue suitable for covalent modification. In some examples, the protein is KRAS, Bruton's tyrosine kinase (BTK), any member of the epidermal growth factor receptor (EGFR) family, also referred to as the ERBB family, including but not limited to EGFR (ERBB1), HER2 / NEU (ERBB2), HER3 (ERBB3), and HER4 (ERBB4); a fibroblast growth factor receptor (FGFR); the receptor kinase known in the art as MET, BRAF, a cyclin-dependent kinase (CDK); Acetyl Choline Esterase (ACHE); TP53, IDH1, GNAS, FBXW7, CTNNB1, DNMT3A, any cathepsin, including cathepsin B, C, F, H, K, L, O, S, V, W and X; any caspase; any protein involved in obesity, such as Pancreatic lipase and METAP2, or any Cancer Testis Antigen. In some examples, the drug targets and therefore covalently binds to any viral protein, including but not limited to a polymerase, including anyviral DNA polymerase, RNA polymerase, reverse transcriptase, or RNA-dependent RNA polymerase, or a viral protein that is required, for example, viral cell entry, or a protein encoded by any a transposable element. In some examples, the drug targets EGFR and may be selected from PD168393, PF00299804 (dacomitinib), EKB569 (pelitinib), afatinib, WZ4002, osimertinib (formerly known as AZD9291), PF-06459988, nazartinib, naquotinib, olmutinib, avitinib, and rociletinib, neratinib, pyrotinib, poziotinib, and derivatives thereof. In some examples, the drug targets Bruton’s tyrosine kinase (BTK), and may be selected from ibrutinib, acalabrutinib, zanubrutinib, CHMFL-BTK-11, ONO / GS-405, PRN1008, and CC-292. In some examples, the drug targets any p90 ribosomal S6 kinase (RSK), and may be selected from fluoromethylketone (FMK) and dimethyl fumarate. In some examples, the drug targets any FGFR, and may be selected from FIIN-1, FIIN-2, FIIN-3, BGJ398, AZD4547, PRN1371, FGF401. In an example, the targeted covalent inhibitor targets an E3 ligase, such as RNF4, HOIP, RSP5, SMURF1, E6AP, HUWE1, and NEDD4-1. In an example, the targeted covalent inhibitor targets a DDB1- and CUL4- associated factor (DCAF), such as DCAF1 or DCAF15. In an example, the targeted covalent inhibitor targets any cancer testis antigen, any endogenous retroviral protein, a long interspersed element-1 (LINE-1), or a short interspersed element (SINE). In an example, the targeted covalent inhibitor targets a short interspersed element that is optionally Alu. In an example, the targeted covalent inhibitor is iniparib, abiraterone, carfilzomib, afatinib, or neratinib.

[0358] The “antigen-binding site,” or “binding portion” of an antibody molecule refers to the part of an antibody molecule, e.g., an immunoglobulin (Ig) molecule, that participates in antigen binding. In some examples, the antigen binding site is formed by amino acid residues of the variable (V) regions of the heavy (H) and light (L) chains. Three highly divergent stretches within the variable regions of the heavy and light chains, referred to as hypervariable regions, are disposed between more conserved flanking stretches called “framework regions,” (FRs). FRs are amino acid sequences that are naturally found between, and adjacent to, hypervariable regions in immunoglobulins. In some examples, in an antibody molecule, the three hypervariable regions of a light chain and the three hypervariable regions of a heavy chain are disposed relative to each other in three dimensional space to form an antigen-binding surface, which is complementary to the three-dimensional surface of a bound antigen. The three hypervariable regions of each of the heavy and light chains are referred to as “complementaritydetermining regions,” or “CDRs.” The framework region and CDRs have been defined and described, e.g., in Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242,and Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917. Each variable chain (e.g., variable heavy chain and variable light chain) is typically made up of three CDRs and four FRs, arranged from amino-terminus to carboxy -terminus in the amino acid order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0359] As used herein, an “immune cell” refers to any of various cells that function in the immune system, e.g., to protect against agents of infection and foreign matter. In some examples, this term includes leukocytes, e.g., neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Innate leukocytes include phagocytes (e.g., macrophages, neutrophils, and dendritic cells), mast cells, eosinophils, basophils, and natural killer cells. Innate leukocytes identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms, and are mediators in the activation of an adaptive immune response. The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are important types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response. The term “immune cell” includes immune effector cells.

[0360] “Immune effector cell,” as that term is used herein, refers to a cell that is involved in an immune response, e.g., in the promotion of an immune effector response. Examples of immune effector cells include, but are not limited to, T cells, e.g., alpha / beta T cells and gamma / delta T cells, B cells, natural killer (NK) cells, natural killer T (NK T) cells, macrophages, neutrophils, and mast cells.

[0361] The term “effector function” or “effector response” refers to a specialized function of a cell. Effector function of a T cell, for example, may be cytolytic activity or helper activity including the secretion of cytokines.

[0362] The terms “polypeptide”, “peptide” and “protein” (if single chain) are used interchangeably herein to refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by nonamino acids. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. The polypeptide can be isolated from natural sources, can be a produced by recombinant techniques from a eukaryotic or prokaryotic host, or can be a product of synthetic procedures.

[0363] The compositions and methods of the present invention encompass polypeptides and nucleic acids having the sequences specified, or sequences substantially identical or similarthereto, e.g., sequences at least 80%, 85%, 90%, 95% identical or higher to the sequence specified. In the context of an amino acid sequence, the term “substantially identical” is used herein to refer to a first amino acid that contains a sufficient or minimum number of amino acid residues that are i) identical to, or ii) conservative substitutions of aligned amino acid residues in a second amino acid sequence such that the first and second amino acid sequences can have a common structural domain and / or common functional activity. For example, amino acid sequences that contain a common structural domain having at least about 80%, 85%, 90%. 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99%, 99.5%, 99.9%, or 100% sequence identity to a reference sequence, e.g., a sequence provided herein. In the context of nucleotide sequence, the term “substantially identical” is used herein to refer to a first nucleic acid sequence that contains a sufficient or minimum number of nucleotides that are identical to aligned nucleotides in a second nucleic acid sequence such that the first and second nucleotide sequences encode a polypeptide having common functional activity, or encode a common structural polypeptide domain or a common functional polypeptide activity. For example, nucleotide sequences having at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% 99%, 99.5%, 99.9%, or 100% sequence identity to a reference sequence, e.g., a sequence provided herein.

[0364] The term “variant” refers to a polypeptide that has a substantially identical amino acid sequence to a reference amino acid sequence, or is encoded by a substantially identical nucleotide sequence. In some examples, the variant is a functional variant. In some examples, a TCRPV variant can bind to TCRa and form a TCR a:P complex.

[0365] The term “functional variant” refers to a polypeptide that has a substantially identical amino acid sequence to a reference amino acid sequence, or is encoded by a substantially identical nucleotide sequence, and is capable of having one or more activities of the reference amino acid sequence.

[0366] Calculations of homology or sequence identity between sequences (the terms are used interchange-ably herein) are performed as follows. To determine the percent identity of two amino acid sequences, or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In a preferred example, the length of a reference sequence aligned for comparison purposes is at least 30%, preferably at least 40%, more preferably at least 50%, 60%, and even more preferably at least 70%, 80%, 90%, 100% of the length of the reference sequence. The amino acid residues or nucleotides at correspondingamino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein amino acid or nucleic acid “identity” is equivalent to amino acid or nucleic acid “homology”).

[0367] The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. In a preferred example, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch ((1970) J. Mol. Biol. 48:444-453 ) algorithm which has been incorporated into the GAP program in the GCG software package (available at http: / / www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. In yet another preferred example, the percent identity between two nucleotide sequences is determined using the GAP program in the GCG software package (available at http: / / www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. A particularly preferred set of parameters (and the one that should be used unless otherwise specified) are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5.

[0368] The percent identity between two amino acid or nucleotide sequences can be determined using the algorithm of E. Meyers and W. Miller ((1989) CAB IOS, 4: 11-17) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The nucleic acid and protein sequences described herein can be used as a “query sequence” to perform a search against public databases to, for example, identify other family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to a nucleic acid molecule of the invention. BLAST protein searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to protein molecules of the invention. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25:3389- 3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[0369] It is understood that the molecules of the present invention may have additional conservative or non-essential amino acid substitutions, which do not have a substantial effect on their functions.

[0370] The term “amino acid” is intended to embrace all molecules, whether natural or synthetic, which include both an amino functionality and an acid functionality and capable of being included in a polymer of naturally-occurring amino acids. Exemplary amino acids include naturally-occurring amino acids; analogs, derivatives and congeners thereof; amino acid analogs having variant side chains; and all stereoisomers of any of any of the foregoing. As used herein the term “amino acid” includes both the D- or L- optical isomers and peptidomimetics.

[0371] A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyro-sine, phenylalanine, tryptophan, histidine).

[0372] As used herein, the term “molecule” as used in, e.g., antibody molecule, cytokine molecule, receptor molecule, includes full-length, naturally-occurring molecules, as well as variants, e.g., functional variants (e.g., truncations, fragments, mutated (e.g., substantially similar sequences) or derivatized form thereof), so long as at least one function and / or activity of the unmodified (e.g., naturally-occurring) molecule remains.

[0373] As used herein, the term “mutation” refers to an alteration in the nucleotide sequence of the genome of an organism, virus, or extrachromosomal DNA. In some examples, the mutation may be a large-scale mutation, such as amplifications (or gene duplications) or repetitions of a chromosomal segment, deletions of large chromosomal regions, chromosomal rearrangements (e.g., chromosomal translocations, chromosomal inversions, non-homologous chromosomal crossover, and interstitial deletions), and loss of heterozygosity. In some examples, the mutation may be a small-scale mutation, such as insertions, deletions, and substitution mutations. As used herein, the term “substitution mutation” refers to the transition that exchange a single nucleotide for another.Overview

[0374] Covalent inhibitors of the oncoprotein KRAS have significant initial efficacy, but responses lack durability. Covalent inhibitor-modified oncoproteins can be presented as MHC- restricted hapten-peptides (p*MHC) on the cancer cell surface, creating an opportunity to combine targeted therapy with immunotherapy to overcome drug resistance. Tumor antigentargeting immunotherapies in principle can have superior safety and efficacy compared to systemic immunotherapy by immune checkpoint inhibitors, but identifying tumor-specific antigens remains a significant challenge. Unlike patient-specific neoantigens, which may utilize individualized immunotherapeutic development, commonly mutated oncoprotein- derived epitopes presented on major histocompatibility complex (MHC) molecules (e.g., class I MHCs) can provide an opportunity to target cancer-specific antigens shared across patient populations. However, their development has been limited by human leukocyte antigen (HLA) restriction and low pMHC presentation levels, resulting in a limited repertoire of well-validated neoantigen peptide-MHC (pMHC) targets. Additionally, generating high-affinity, highly specific binders to pMHC targets using traditional TCR or TCR-mimicking (TCRm) antibodies can remain challenging due to the subtle differences between many mutant and wild-type antigens.

[0375] Mutated KRASG12Xproteins can be examples of tumor-specific, shared pMHC targets due to their high prevalence and well-characterized epitope landscape across high-frequency HLA alleles. Despite their low surface density (~10 or fewer copies-per-cell), promising immunotherapies, for example on KRASG12Dand KRASG12V, can be pursued. Although KRASG12Cmutations may occur relatively frequently (9% in non-small cell lung cancer, 3% in colorectal cancer, and 1% in pancreatic cancer), the development of KRASG12C-pMHC immunotherapies remains limited. A key challenge can arise from the cysteine residue, which can be prone to heterogeneous post-translational modifications of the thiol group that result in multiple unknown isoforms, effectively diluting an already low-density target. Mass spectrometry techniques to identify KRASG12Cepitopes cleave thiol modifications to enable detection, preventing precise characterization of the cysteine's modification state or states. Thus, innovative strategies are being sought to fully exploit the therapeutic potential of KRASG12Cneoepitopes.

[0376] Synthetic neoantigens formed by proteasome-resistant modification of KRASG12Cpeptides with covalent inhibitors can be loaded onto HLAs as so-called “haptenated peptides” or p* (e.g., peptides still carrying the covalent inhibitor) and presented as p*MHCs on the cancer cell surface as homogeneously modified epitopes. These p*MHCs can be referred to aspeptide conjugate / MHC complexes. The distinct nature of these cancer-specific targets can facilitate their high-specificity targeting by engineered antibodies and enables tumor-specific killing in vitro when antibodies are converted to T cell engagers (TCEs).

[0377] The present disclosure provides compositions and methods that include binding partners that bind with specificity to target sites on proteins or peptides that comprise a covalently attached molecule. The strategies presented in the present disclosure may have the potential to counteract disease progression driven by inherent or acquired resistance to covalent KRASG12Cinhibitors, remaining effective in recurrent settings because the G12C mutation may be retained in resistant cells. Additionally, the strategies provided herein can leverage the immunomodulatory effects of covalent inhibitors such as increased HLA expression and T cell infiltration to enhance therapeutic impact.Multivalent Polypeptides

[0378] In some aspects, provided herein are compositions and methods comprising multivalent polypeptides (e.g., binding partners). The multivalent polypeptide can comprise a first antigenbinding domain. In some examples, the multivalent polypeptide can comprise at least a first antigen-binding domain. The multivalent polypeptide may comprise a second antigen-binding domain. Exemplary multivalent polypeptides can comprise those of FIGs. 32A-32C.

[0379] In some examples, the binding partners preferentially bind to (e.g., specifically bind to) the protein or peptide or a complex comprising the protein or peptide when covalently bound to the peptide conjugate, relative to the same protein or peptide that is not bound to the drug. Accordingly, binding partners described herein either do not detectably bind, or bind with a lower affinity, to the same protein or fragment thereof in the absence of the covalently attached molecule. The term “specifically binds” refers to a molecule (e.g., an antibody or an antigenbinding portion thereof) that binds to an epitope or target or peptide-MHC complex with greater affinity, greater avidity, and / or greater duration to that epitope or target or peptide-MHC complex in a sample than it binds to another epitope or non-target compound or non-target or peptide-MHC complex (e.g., a structurally different antigen, a peptide-MHC complex with a different MHC and different peptide, a peptide-MHC complex with a different MHC and the same peptide or a peptide-MHC complex with the same MHC and different peptide). For example, a molecule (e.g., an antibody or an antigen-binding portion thereof) that specifically binds to an epitope or target or peptide-MHC complex can be an molecule (e.g., an antibody or an antigen-binding portion thereof) that binds this epitope or target or peptide-MHC complex with greater affinity, avidity, more readily, and / or with greater duration than it bindsto other epitopes or targets or peptide-MHC complexes. In some examples, a molecule (e.g., an antibody or an antigen-binding portion thereof) that specifically binds to an epitope or target or peptide-MHC complex is a molecule (e.g., an antibody or an antigen-binding portion thereof) that binds to the epitope or target or peptide-MHC complex with at least 5-fold greater affinity than other epitopes or non-target compounds or non-target peptide-MHC complex, e.g., at least 5-fold, 10-fold, 100-fold, 1,000-fold, 10,000-fold, or greater affinity. A molecule (e.g., an antibody or an antigen-binding portion thereof) that specifically binds to a particular epitope or target or peptide-MHC complex can be exhibited, for example, by a molecule having an equilibrium dissociation constant KD for the epitope or target or peptide-MHC complex to which it binds of, e.g., 104M or smaller, e.g., I O5M, 106M, 107M, 108M, 109M, 1010M, 1011M, or 1012M, such as determined by, e.g., immunoassays, surface plasma resonance (e.g., Biacore™ assay), biolayer interferometry, or other assays known in the art. It will be recognized by one of skill that an antibody that specifically binds to a target from one species may also specifically bind to orthologs of that target. In some examples, the extent of binding of a molecule (e.g., an antibody or an antigen-binding portion thereof) to an unrelated epitope or unrelated target or unrelated peptide-MHC complex is less than about 0.0001%, 0.001%, 0.01%, 0.1%, 1%, 10% or 20% of the binding of the antibody to the epitope or target or peptide- MHC complex as measured, e.g., by an immunoassays, surface plasma resonance (e.g., Biacore™ assay), biolayer interferometry, or other assay known in the art. For example, a multivalent polypeptide may specifically bind to an epitope sequence in complex with an MHC with a binding affinity of at least about 2-fold, 5-fold, 10-fold, 15-fold, 20-fold, 50-fold, 100- fold, 500-fold, 1,000-fold, 5,000-fold, or 10,000-fold greater than a binding affinity of the multivalent polypeptide binding to a different epitope sequence in complex with the same MHC. As another example, a multivalent polypeptide may bind to a peptide-conjugate in complex with an MHC encoded by a specific HLA allele, with a binding affinity of at least about 2-fold, 5-fold, 10-fold, 15-fold, 20-fold, 50-fold, 100-fold, 500-fold, 1,000-fold, 5,000- fold, or 10,000-fold greater than a binding affinity of the multivalent polypeptide binding to the peptide-conjugate in complex with an MHC encoded by a different HLA allele. As another example, a multivalent polypeptide may bind to a peptide-conjugate in complex with an MHC with a binding affinity of at least about 2-fold, 5-fold, 10-fold, 15-fold, 20-fold, 50-fold, 100- fold, 500-fold, 1,000-fold, 5,000-fold, or 10,000-fold greater than a binding affinity of the multivalent polypeptide binding to the peptide-conjugate alone. As another example, a multivalent polypeptide may bind to a peptide-conjugate in complex with an MHC with a binding affinity of at least about 2-fold, 5-fold, 10-fold, 15-fold, 20-fold, 50-fold, 100-fold,500-fold, 1,000-fold, 5,000-fold, or 10,000-fold greater than a binding affinity of the multivalent polypeptide binding to the peptide alone (e.g., without the targeted covalent inhibitor). As another example, a multivalent polypeptide may bind to a peptide-conjugate in complex with an MHC with a binding affinity of at least about 2-fold, 5-fold, 10-fold, 15-fold, 20-fold, 50-fold, 100-fold, 500-fold, 1,000-fold, 5,000-fold, or 10,000-fold greater than a binding affinity of the multivalent polypeptide binding to the free targeted covalent inhibitor (e.g., the targeted covalent inhibitor not covalently linked to a peptide).

[0380] In some examples, the binding partners bind to the protein or peptide comprising the covalently attached drug with an affinity that is 10-10,000 fold, including all numbers and ranges of numbers from 10-10,000, greater than the affinity for the protein or peptide that does not comprise the covalently bound molecule. In this regard, and without intending to be bound by any particular theory, it is considered that the presence of the covalently bound molecule contributes to the epitope to which the binding partners bind with specificity. Likewise, binding partners of this disclosure preferentially bind to the peptide conjugate relative to binding to the free drug. In some examples, the binding partners bind to the peptide comprising the covalently attached drug (e.g., the peptide-conjugate / MHC complex) with an affinity that is 10-10,000 fold, including all numbers and ranges of numbers from 10-10,000, greater than the affinity for the free drug. In some examples, the interaction between the binding partner and the peptide- conjugate / MHC complex is not inhibited by the free drug. For example, the interaction between the binding partner and the peptide-conjugate / MHC complex is not inhibited by a lOOx, l,000x, 10,000x, 100,000x or more excess of the free drug.

[0381] In some examples, the molecule that is covalently bound to form the peptide conjugate is a drug and may be any targeted covalent inhibitor (TCI), but the covalent drug need not necessarily inhibit the target peptide. In some examples, the molecule reacts with a specific residue within the target protein. In some examples, the molecule reacts at least in part with a segment of the protein or peptide that comprises a nucleophilic, or an electrophilic, residue. In some examples, the segment of the protein or peptide to which the molecule reacts comprises any of Cys, Lys, Tyr, His, Ser, Thr, or Arg, the latter being described in Ziyang Zhang, Johannes Morstein, Andrew K. Ecker, Keelan Z. Guiley, and Kevan M. Shokat Journal of the American Chemical Society Article ASAP, DOI: 10.1021 / jacs.2c05377, from which the disclosure is incorporated herein by reference. In some examples, the protein or peptide comprises a selenocysteine. In some examples, the targeted covalent inhibitor reacts with selenocysteine. In some examples, the molecule reacts at least in part with a segment of the protein or peptide that comprises a wild type Cys, or a mutation of a residue to a Cys, and thusmay be covalently attached by a so-called sulfur tether. In some examples, the drug is any drug described in Ghosh AK, Samanta I, Mondal A, Liu WR. Covalent Inhibition in Drug Discovery. ChemMedChem. 2019;14(9):889-906. doi: 10.1002 / cmdc.201900107, or in De Cesco, et al., European Journal of Medicinal Chemistry 138 (2017) 96el l4, or in Bauer, RA, Drug Discovery Today, Volume 20, Number 9, September 2015, from which the disclosures of compounds that covalently modify protein targets is incorporated herein by reference.

[0382] In non-limiting examples, any of said Asp, Cys, and / or Arg amino acids are present in the protein or peptide to which the molecule binds because the gene encoding the wild type protein has been mutated to encode a protein that includes one or a combination of the described residues. In non-limiting examples, the molecule binds to a protein or peptide that is correlated with a disease or condition, such as a cancer, an autoimmune disease, or other disease or disorder that is treated with a targeted covalent inhibitor. In some examples, the target (e.g., the protein or peptide to which the molecule covalently binds) is a receptor, including but not necessarily limited to any receptor having a catalytically active segment. In some examples, the drug binds to an enzyme that is not necessarily a receptor, including but not limited to any kinase. In some examples, a protein target comprises a receptor with one or more activating mutations, which promote ligand-independent enzyme activity.

[0383] In some examples, the molecule that becomes covalently bound to form the peptide conjugate targets any RAS oncogene protein product, including but not necessarily limited to HRAS, NRAS, KRAS4A, and KRAS4B. The amino acid sequences of RAS proteins are known in the art, and residue numbering is identical for the relevant part of all RAS isotypes that are discussed in this disclosure for which the amino acid sequence is available from, for example, UniProt P01116, from which the amino acid sequence is incorporated herein as of the effective filing date of this application or patent. The G12 position is numbered according to the known amino acid sequence, regardless of whether or not the G12 is the twelfth amino acid in an express RAS peptide sequence of this disclosure. The G13 position is numbered according to the known amino acid sequence, regardless of whether or not the G13 is the twelfth amino acid in an express RAS peptide sequence of this disclosure.

[0384] In some examples, the molecule covalently binds to a KRAS protein or peptide that comprises a mutation. In some examples, the mutation is at least one of KRAS residues 12, 13, or 61. Reference to any drug herein includes its name in capitalized and un-capitalized form.

[0385] In some examples, the drug targets a KRAS protein comprising a KRAS G12C mutation. In some examples, the drug targets a KRAS protein comprising a KRAS G12D mutation. In some examples, the drug targets a KRAS protein comprising a KRAS G12Rmutation. In some examples, the drug targets a KRAS protein comprises a KRAS G13C mutation. In some examples, the drug targets a KRAS protein comprising a KRAS G12S mutation. In non-limiting examples, the drug that targets a KRAS protein is selected from 2E07, 6H05, SML-8-73-1, MRTX849, JNJ74699157, LY3499446, ARS-853, ARS-1620, ARS-3284, GDC-6036, D-1553, JDQ443, RMC-6291, RMC-6236, RMC-9805, BI 1823911, MRTX1257, AMG-510, G12Si-l, G12Si-2, G12Si-3, G12Si-4, G12Si-5, or derivatives thereof. Examples of additional compounds that can covalently target a KRAS peptide containing a G12C mutation can be found in Internal Application No. PCT / IB2019 / 050993, Internal Application No. PCT / EP2018 / 083853, and U.S. Application No. US16 / 917,128, each of which is incorporated herein by reference in its entirety. In some examples, the drug comprises a proteolysis targeting chimera (PROTAC) derivative of a covalent drug, In some examples, the PROTAC is LC-1 or LC-2.

[0386] The peptide conjugate described herein can be formed by the covalent reaction of a targeted covalent inhibitor with a KRAS peptide. The peptide conjugate can be formed by the covalent reaction of a targeted covalent inhibitor with a KRASG12Cpeptide, a KRASG12Dpeptide, a KRASG13Cpeptide, a KRASG12Rpeptide, or a KRASG12Speptide. The targeted covalent inhibitor can be any free targeted covalent inhibitor described herein. For example, the targeted covalent inhibitor can be AMG-510 (e.g., sotorasib), MRTX849 (e.g., adagrasib), opnurasib, divarasib, garsorasib, l-[4-[6-chloro-8-fluoro-7-(2-fluoro-6- hydroxyphenyl)quinazolin-4-yl]piperazin-l-yl]prop-2-en-l-one, l-(3-(4-((4-chloro-2- hydroxy-5-(l-methylcyclopropyl)phenyl)glycyl)piperazin-l-yl)azetidin-l-yl)prop-2-en-l- one, l-(4-(7-(2-Amino-7-fluoro-l,3-benzothiazol-4-yl)-6-chloro-8-fluoro-quinazolin-4- yljpiperazin- 1 -yl)prop-2-en- 1 -one, 2-Amino-4-[(4aS)-8-chloro- 10-fluoro-2,3 ,4,4a, 5,6- hexahy dro- 12-oxo-3 -(1 -oxo-2-propen- 1 -y 1 )- 1 H, 12H-pyrazino[2, 1 -d] [ 1 , 5 ]benzoxazocin-9-yl]- 7-fluorobenzo[b]thiophene-3-carbonitrile, 2-[(2S)-4-[7-(8-methylnaphthalen-l-yl)-2-[[(2S)-l- methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l -prop-2- enoylpiperazin-2-yl]acetonitrile, 4-(4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2- (((2R,7aS)-2-fluorohexahydro-lH-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5- ethynyl-6-fluoronaphthalen-2-ol, l-[4-(dimethylamino)-4-methylpent-2-ynoyl]-N-[(2S)-l-[[(6S,8S,14S)-22-ethyl-21-[2-[(lS)-l-methoxyethyl]pyridin-3-yl]-18,18-dimethyl-9,15- dioxo-5,16-dioxa-2,10,22,28-tetrazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1 (26), 20, 23 (27),24-tetraen-8-yl]amino]-3 -methyl- 1 -oxobutan-2-yl]-4-fluoro-N- methylpiperidine-4-carboxamide, or [[(2R,3S,4R,5R)-5-(2-amino-6-oxo-lH-purin-9-yl)-3,4- dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] 2-[(2-chloroacetyl)amino]ethylhydrogen phosphate]. In some examples, the targeted covalent inhibitor can comprise GDC6036, MK-1084, l-((3R,14aS)-l l-Chloro-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-3- methyl-l,3,4,13,14,14a-hexahydro-2H-pyrazino[l',2':5,6][l,5]oxazocino[4,3,2-de]quinazolin- 2-yl)prop-2-en-l-one (e.g., AZD4625), or N-(5-(3,5-dimethoxyphenethyl)-lH-pyrazol-3-yl)- 4-((3S,5R)-3,5-dimethylpiperazin-l-yl)benzamide (e.g., AZD4747). In some examples, the targeted covalent inhibitor can be a beta-lactone (e.g., G12Si-l, G12Si-2, G12Si-3, G12Si-4, or G12Si-5).

[0387] In some examples, the targeted covalent inhibitor is (i) a tri-complex KRASG12Cinhibitor or a KRASG12Cdegrader, (ii) a tri-complex KRASG12Dinhibitor or a KRASG12Ddegrader, (iii) a tri-complex KRASG12Rinhibitor or a KRASG12Rdegrader, (iv) a tri-complex KRASG13Cinhibitor or a KRASG13Cdegrader, (v) a tri-complex KRASG12Sinhibitor or a KRASG12Sdegrader, or any combination thereof.

[0388] In some cases, the peptide conjugate can be formed by the covalent reaction of AMG- 510 with a KRASG12Cpeptide. The peptide can comprise or consist of the amino acid sequence of VVVGACGVGK, VVGACGVGK, or KLVVVGACGV. In some examples, the peptide can comprise a KRASG12Cmutation, and the targeted covalent inhibitor is a KRASG12Cinhibitor, (ii) the peptide can comprise a KRASG12Dmutation, and the targeted covalent inhibitor is a KRASG12Dinhibitor, (iii) the peptide can comprise a KRASG12Rmutation, and the targeted covalent inhibitor is a KRASG12Rinhibitor, (iv) the peptide can comprise a KRASG12Cmutation, and the targeted covalent inhibitor is a KRASG12Cinhibitor, or (v) the peptide can comprise a KRASG12Smutation, and the targeted covalent inhibitor is a KRASG12Sinhibitor.

[0389] In some examples, the peptide comprises the amino acid sequence of VVVGACGVGK and the MHC is HLA-A*02:01, HLA-A* 11 :01, HLA-A*03:01, or any combination thereof. In some examples, the peptide comprises the amino acid sequence of VVGACGVGK and the MHC is HLA-A*02:01, HLA-A* 11 :01, HLA-A*03:01, or any combination thereof. In some examples, the peptide comprises the amino acid sequence of KLVVVGACGV and the MHC is HLA-A*02:01, HLA-A* 11 :01, HLA-A*03:01, or any combination thereof.

[0390] The antigen-binding domain of the polypeptide described herein or the binding partner described herein can bind to a peptide conjugate complexed with different HLAs. In some examples, the peptide conjugate / MHC complex comprises an HLA molecule is selected from the group consisting of HLA- A* 03:01, HLA-A*l l :01, HLA-A*02:01, HLA-A*68:01, HLA- A*31 :01, HLA-A*30:01, HLA-A*33:03, HLA-A*33:01, HLA-A*74:01, HLA-A*34:02, HLA-A*66:01, HLA-A*68:02, HLA-A*02:05, HLA-A*02:02, and HLA-A*02:06. For example, in certain some examples, the antigen-binding domain can have specificity to: (i) apeptide conjugate / MHC complex comprising VVGACGVGK conjugated to a targeted covalent inhibitor or fragment thereof presented by HLA-A*03:01, (ii) a peptide conjugate / MHC complex comprising VVVGACGVGK conjugated to a targeted covalent inhibitor or fragment thereof presented by HLA-A*03:01, or (iii) both. In certain other examples, the antigen-binding domain can have specificity to: (i) a peptide conjugate / MHC complex comprising VVVGACGVGK conjugated to a targeted covalent inhibitor or fragment thereof presented by HLA-A*03:01, (ii) a peptide conjugate / MHC complex comprising VVVGACGVGK conjugated to a targeted covalent inhibitor or fragment thereof presented by HLA-A* 11:01, or (iii) both. In other examples, the antigen-binding domain can have specificity to: (i) a peptide conjugate / MHC complex comprising VVGACGVGK conjugated to a targeted covalent inhibitor or fragment thereof presented by HLA-A*03:01, (ii) a peptide conjugate / MHC complex comprising VVVGACGVGK conjugated to a targeted covalent inhibitor or fragment thereof presented by HLA-A*03:01, (iii) a peptide conjugate / MHC complex comprising VVVGACGVGK conjugated to a targeted covalent inhibitor or fragment thereof presented by HLA-A* 11 :01, (iv) a peptide conjugate / MHC complex comprising KLWVGACGV conjugated to a targeted covalent inhibitor or fragment thereof presented by HLA-A*02:01, or (v) any combination of (i) - (iv) (e.g., (i) and (ii); or (i), (ii), and (iv)), or (vi) all of (i)-(iv). In certain specific examples, the polypeptide binds to: (i) a peptide conjugate / HLA-A*03:01 MHC complex containing a peptide consisting of the amino acid sequence VVGACGVGK, (ii) a peptide conjugate / HLA-A*03:01 MHC complex containing a peptide consisting of the amino acid sequence VVVGACGVGK, (iii) a peptide conjugate / HLA- A* 11 :01 MHC complex containing a peptide consisting of the amino acid sequence VVVGACGVGK, and / or (iv) a peptide conjugate / HLA-A*02:01 MHC complex containing a peptide consisting of the amino acid sequence KLWVGACGV. In still other examples, the polypeptide binds to: (i) a peptide conjugate / HLA-A*03:01 MHC complex containing a peptide consisting of the amino acid sequence VVGACGVGK and a peptide conjugate / HLA- A*03:01 MHC complex containing a peptide consisting of the amino acid sequence VVVGACGVGK; (ii) a peptide conjugate / HLA-A*03 :01 MHC complex containing a peptide consisting of the amino acid sequence VVVGACGVGK and a peptide conjugate / HLA- A* 11 :01 MHC complex containing a peptide consisting of the amino acid sequence VVVGACGVGK; (iii) a peptide conjugate / HLA-A*02:01 MHC complex containing a peptide consisting of the amino acid sequence KLWVGACGV; or any combination of (i)-(iii) (e.g., (i) and (ii); or (i) and (iii)); or all of (i) - (iii).

[0391] In some examples, the peptide conjugate / MHC complex comprises an HLA molecule encoded by an HLA allele belonging to the HLA-A3 supertype. In some examples, the HLA allele of the HLA-A3 supertype can be HLA-A*03:01, HLA-A*ll:01, HLA-A*68:01, HLA- A*31:01, HLA-A*30:01, HLA-A*74:01, HLA-A*34:02, HLA-A*66:01, HLA-A*03:02, HLA-A*03:04, HLA-A*03:05, HLA-A*03:06, HLA-A*03:07, HLA-A*03:08, HLA- A*03:10, HLA-A*03:12, HLA-A*03:13, HLA-A*03:14, HLA-A*03:16, HLA-A*03:17, HLA-A* 11:02, HLA-A* 11:03, HLA-A* 11:04, HLA-A* 11:05, HLA-A* 11:07, HLA- A*ll:08, HLA-A*ll:09, HLA-A*ll:10, HLA-A*11:12, HLA-A*11:13, HLA-A*11:14, HLA-A*11:15, HLA-A*11:16, HLA-A*ll:20, HLA-A*11:21, HLA-A*11:23, HLA- A*31:03, HLA-A*31:04, HLA-A*31:05, HLA-A*31:06, HLA-A*31:09, HLA-A*31:11, HLA-A*33:04, HLA-A*33:05, HLA-A*33:06, HLA-A*33:07, HLA-A*34:02, HLA- A*34:03, HLA-A*34:04, HLA-A*34:06, HLA-A*66:02, HLA-A*66:03, HLA-A*66:04, HLA-A*68:03, HLA-A*68:04, HLA-A*68:08, HLA-A*68:09, HLA-A*68:10, HLA- A*68:12, HLA-A*68:13, HLA-A*68:14, HLA-A*68:16, HLA-A*68:19, HLA-A*68:21, HLA-A*68:22, HLA-A*68:24, HLA-A*68:25, HLA-A*68:26, HLA-A*74:02, HLA- A*74:03, HLA-A*74:04, HLA-A*74:05, HLA-A*74:07, HLA-A*74:08, HLA-A*74:09, HLA-A*74: 11, or any combination thereof. In some examples, the HLA allele of the HLA-A3 supertype can be HLA-A*03:01, HLA-A*ll:01, HLA-A*68:01, HLA-A*31:01, HLA- A*30:01, HLA-A*74:01, HLA-A*34:02, HLA-A*66:01, or any combination thereof.

[0392] In some examples, the peptide conjugate / MHC complex comprises an HLA molecule encoded by an HLA allele belonging to the HLA-A2 supertype. In some examples, the HLA allele of the HLA-A2 supertype can be HLA-A*02:01, HLA-A*02:02, HLA-A*02:03, HLA- A*02:04, HLA-A*02:05, HLA-A*02:06, HLA-A*02:07, HLA-A*02:14, HLA-A*02:17, HLA-A*68:02, HLA-A*69:01, HLA-A*02:09, HLA-A*02:ll, HLA-A*02:12, HLA- A*02:13, HLA-A*02:15, HLA-A*02:16, HLA-A*02:18, HLA-A*02:19, HLA-A*02:20, HLA-A*02:21, HLA-A*02:22, HLA-A*02:24, HLA-A*02:25, HLA-A*02:26, HLA- A*02:27, HLA-A*02:28, HLA-A*02:30, HLA-A*02:31, HLA-A*02:36, HLA-A*02:37, HLA-A*02:38, HLA-A*02:39, HLA-A*02:40, HLA-A*02:43, HLA-A*02:44, HLA- A*02:45, HLA-A*02:46, HLA-A*02:47, HLA-A*02:48, HLA-A*02:49, HLA-A*02:51, HLA-A*02:54, HLA-A*02:56, HLA-A*02:57, HLA-A*02:58, HLA-A*02:59, HLA- A*02:61, HLA-A*02:62, HLA-A*02:63, HLA-A*02:66, HLA-A*02:67, HLA-A*02:68, HLA-A*02:69, HLA-A*02:70, HLA-A*02:71, HLA-A*02:72, HLA-A*02:74, HLA- A*02:75, HLA-A*02:77, HLA-A*02:78, HLA-A*02:79, HLA-A*02:82, HLA-A*02:83, HLA-A*02:85, HLA-A*02:86, HLA-A*68:27, HLA-A*68:28, or any combination thereof. Insome examples, the HLA allele of the HLA-A2 supertype can be HLA-A*02:01, HLA- A*02:02, HLA-A*02:03, HLA-A*02:04, HLA-A*02:05, HLA-A*02:06, HLA-A*02:07, HLA-A*02: 14, HLA-A*02: 17, HLA-A*68:02, HLA-A*69:01, or any combination thereof.

[0393] The targeted covalent inhibitor that targets the peptide conjugate / MHC complex can have a chemical structure comprising C-Rl, where C is a chemical fragment linked to R1 of any Compound 1 illustrated below:

[0394] R1 group of the C-Rl chemical structure of the covalent inhibitor can be any of the structures illustrated below.

[0395] The targeted covalent inhibitor with the structure comprising C-Rl can form a covalent bond to several different amino acid residues on the peptide. For example, the targeted covalent inhibitor can form a covalent bond to the cysteine residue in a peptide comprising the amino acid sequence of VVVGACGVGK, VVGACGVGK, or KLVVVGACGV. In other examples, the targeted covalent inhibitor can form a covalent bond to the aspartic acid residue, the serine residue, or the arginine residue in a peptide comprising the amino acid sequence of VVVGADGVGK, VVGADGVGK, or KLVVVGADGV. In some examples, the antigenbinding domain of the polypeptide recognizes the C portion of the targeted covalent inhibitor with the structure comprising C-Rl of the peptide conjugate / MHC complex. In certain other examples, the antigen-binding domain of the polypeptide recognizes C portion but not R1 portion of the targeted covalent inhibitor of the peptide conjugate / MHC complex.

[0396] Small molecules (e.g., targeted covalent inhibitors) having an electrophilic warhead group can undergo covalent reaction with a cysteine residue of a peptide to form a peptide- small molecule conjugate. This type of reaction is illustrated in the following scheme for AMG- 510 (sotorasib).

[0397] In some examples, the multivalent polypeptide (e.g., binding partner) described herein binds with specificity to a site comprising a neoantigen that includes a covalently linked small molecule drug or other covalently linked molecule as a component of an antigen in a specific MHC context.

[0398] In some examples, the peptide comprises an amino acid sequence as set forth in Table1Table 1. Exemplary peptide sequences.

[0399] In an aspect, provided herein is a multivalent polypeptide (e.g., binding partner) comprising a first-antigen binding domain and a second antigen-binding domain. The first antigen-binding domain can bind to a peptide conjugate / MHC complex, wherein the peptide conjugate is formed by the covalent reaction of a targeted covalent inhibitor with a peptide. In some examples, the binding partner binds to the peptide conjugate / MHC complex with a greater affinity than to the peptide or free targeted covalent inhibitor. In some examples, thesecond antigen-binding domain can bind to a T cell surface protein. In some examples, the multivalent polypeptide comprises an Fc region, wherein the Fc region comprises a first Fc subunit and a second Fc subunit. In some examples, the multivalent polypeptide comprises a single continuous polypeptide chain. The single polypeptide chain can be formed by operably linking a first-antigen binding domain, a second antigen-binding domain, a first Fc subunit, and a second Fc subunit of a multivalent polypeptide described herein.

[0400] In some examples, the binding partner is an intact antibody, a bispecific antibody, a multispecific antibody, an antigen-binding (Fab) fragment, an Fab’ fragment, an (Fab’)2 fragment, an Fd, an Fv, a dAb, a single domain fragment or single monomeric variable antibody domain, a single-chain Diabody (scDb), a diabody (Db), a dual-affinity retargeting (DART) molecule, a single-chain variable fragment (scFv), a camelid antibody, a bi-specific T cell engager (BiTE), bispecific killer cell engager (BiKE), CrossMab, a tri-specific binding partner, a chimeric antigen receptor (CAR), a monobody (aka Adnectin), a DARPin, an anticalin, an affibody, or an affimer. In some examples, the binding partner is bispecific. The binding partners of this disclosure can be a Bi-specific T-cell engager (BiTE). BiTE therapies can be used to connect a subject’s endogenous T cells to cancerous cells. A BiTE molecule can comprise two Fv fragments from monoclonal antibodies, joined by a peptide linker. A BiTE molecule can comprise a first antigen-binding domain and a second antigen-binding domain. The first antigen-binding domain can be specific for and bind to a T cell antigen. The second antigen-binding domain can bind to a tumor antigen (e.g., a tumor-associated antigen) expressed on the surface of cancerous cells. In some examples, the BiTE molecule can specifically bind to a peptide conjugate / MHC complex and a T cell surface antigen. In some examples, the T cell surface antigen is CD3 (e.g., CD3 epsilon, CD3 delta, or CD3 gamma), a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, ICOS, CD28, CD27, HVEM, LIGHT, CD40, 4-1BB (CD137), 0X40, DR3, GITR, CD30, TIM1, SLAM (e.g., a SLAM family member), CD2, CD4, CD8, or CD226. In some examples, the binding partner specifically binds to the peptide conjugate / MHC complex and a T cell antigen. In some examples, the binding partner specifically binds to the peptide conjugate / MHC complex and human CD3. In some examples, the polypeptide may be a BiKE or a C AR-NK. The polypeptide may be a BiKE or a CAR-NK comprising a blockade of a killer cell immunoglobulin-like receptor (KIR), NKG2A, immunoglobulin-like transcript (ILT), or any combination thereof. The polypeptide may be a tri-specific antibody.

[0401] In some examples, the binding partner can comprise a cytokine or fragment thereof. In some examples, the binding partner can comprise IL-2, IL-7, IL-15, IL-12, IL-18, or IL-21, oran interferon (IFN). In some examples, the cytokine can be selected from the group consisting of IFNy, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, IL-18, IL-23, IL-24, IL-27, IL-28a, IL-28b, IL-29, KGF, IFN a (e.g., INF a 2b), IFN 0, IFN , and GM-CSF. The cytokine may be a modified cytokine. In some examples, the cytokine may be a modified (or mutated) cytokine (e.g., IL-2, IL-7, IL-8, IL-15, IL-17, IL-18, IL-21, or any combination thereof). In some examples, the polypeptide can comprise an agonist (e.g., an agonist to CD28 or 4- IBB).

[0402] In some examples, the binding partners described herein can be used to carry drugs or toxins. The binding partner may be provided as an immunotoxin or in the form of antibodydrug conjugates (ADCs). In some examples, the binding partner described herein may be linked to an enzyme. In some examples, the binding partner described herein may be linked to sialidase. Conjugation of sialidase to the binding partner may inactivate one or more inhibitory receptors (e.g., 1, 2, 3, 4, 5, or more inhibitory receptors) at once.

[0403] In some examples, the multivalent polypeptide may be specific for a peptide- conjugate / MHC complex comprising a specific MHC. In some cases, the MHC can be HLA- A*02:01. In some cases, the MHC can be HLA-A*03:01. In some cases, the MHC can be HLA-A*03:01. In some cases, the MHC can be HLA-A* 11 :01. In some cases, the MHC can be HLA-A*68:01. In some cases, the MHC can be HLA-A*31:01. In some cases, the MHC can be HLA-A*30:01. In some cases, the MHC can be HLA-A*33:03. In some cases, the MHC can be HLA-A*33:01. In some cases, the MHC can be HLA-A*74:01. In some cases, the MHC can be HLA-A*34:02. In some cases, the MHC can be HLA-A*66:01. In some cases, the MHC can be HLA-A*68:02. In some cases, the MHC can be HLA-A*02:05. In some cases, the MHC can be HLA-A*02:02. In some cases, the MHC can be HLA-A*02:06.

[0404] In some examples, the multivalent polypeptide comprises a configuration from N- terminus to C-terminus. In some examples, the multivalent polypeptide comprises, from N- terminus to C-terminus, the first antigen-binding domain, the second antigen-binding domain, the first Fc subunit, and the second Fc subunit. In some examples, the multivalent polypeptide comprises, from N-terminus to C-terminus, the first antigen-binding domain, a first linker, the second antigen-binding domain, a second linker, the first Fc subunit, a third linker, and the second Fc subunit. The multivalent polypeptide may comprise a linker. The multivalent polypeptide may not comprise a linker.

[0405] In some examples, the multivalent polypeptide comprises from N-terminus to C- terminus, the second antigen-binding domain, the first antigen-binding domain, the first Fc subunit, and the second Fc subunit. In some examples, the multivalent polypeptide comprises from N-terminus to C-terminus, the second antigen-binding domain, a first linker, the firstantigen-binding domain, a second linker, the first Fc subunit, a third linker, and the second Fc subunit. In some examples, the Fc region may comprise an amino acid sequence as set forth in any one of SEQ ID NOs: 64 or 79. In some examples, the Fc region may comprise an amino acid sequence comprising at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.5%, at least about 99.9%, or greater than about 99.9% sequence identity to an amino acid sequence as set forth in SEQ ID NO: 64 or 79.

[0406] In some examples, a linker (e.g., a first linker, a second linker, a third linker, a fourth linker, a fifth linker, or a sixth linker) of a multivalent polypeptide may comprise an amino acid sequence as set forth in any one of SEQ ID NOs: 60, 62, 63, 95, or 139. The multivalent polypeptide may comprise at least one linker (e.g., two linkers, three linkers, four linkers, five linkers, or more). In some examples, a first linker can comprise an amino acid sequence as set forth in SEQ ID NO: 62. In some examples, a second linker can comprise an amino acid sequence as set forth in SEQ ID NO: 63. In some examples, a third linker can comprise an amino acid sequence as set forth in SEQ ID NO: 139. In some examples, SEQ ID NO: 139 can comprise GGGGSGGGGSGGGGSGGGGSGGGGSGGGGS.

[0407] A linker can be any length. In some examples, a linker (e.g., a first linker, a second linker, a third linker, a fourth linker, a fifth linker, or a sixth linker) can be at least about 2 amino acid residues, at least about 3 amino acid residues, at least about 4 amino acid residues, at least about 5 amino acid residues, at least about 6 amino acid residues, at least about 7 amino acid residues, at least about 8 amino acid residues, at least about 9 amino acid residues, at least about 10 amino acid residues, at least about 11 amino acid residues, at least about 12 amino acid residues, at least about 13 amino acid residues, at least about 14 amino acid residues, at least about 15 amino acid residues, at least about 20 amino acid residues, at least about 25 amino acid residues, at least about 30 amino acid residues, or greater than 30 amino acid residues. In some examples, a linker (e.g., a first linker, a second linker, a third linker, a fourth linker, a fifth linker, or a sixth linker) can be at most about 30 amino acid residues, at most about 25 amino acid residues, at most about 20 amino acid residues, at most about 15 amino acid residues, at most about 14 amino acid residues, at most about 13 amino acid residues, at most about 12 amino acid residues, at most about 11 amino acid residues, at most about 10 amino acid residues, at most about 10 amino acid residues, at most about 9 amino acid residues, at most about 8 amino acid residues, at most about 7 amino acid residues, at most about 6 amino acid residues, at most about 5 amino acid residues, at most about 4 amino acid residues, at mostabout 3 amino acid residues, at most about 2 amino acid residues, or less than about 2 amino acid residues.

[0408] In some examples, a linker (e.g., a first linker, a second linker, a third linker, a fourth linker, a fifth linker, or a sixth linker) can be from about 3 amino acid residues to about 40 amino acid residues. In some examples, a linker (e.g., a first linker, a second linker, a third linker, a fourth linker, a fifth linker, or a sixth linker) can be from about 3 amino acid residues to about 4 amino acid residues, about 3 amino acid residues to about 5 amino acid residues, about 3 amino acid residues to about 6 amino acid residues, about 3 amino acid residues to about 7 amino acid residues, about 3 amino acid residues to about 8 amino acid residues, about 3 amino acid residues to about 9 amino acid residues, about 3 amino acid residues to about 10 amino acid residues, about 3 amino acid residues to about 15 amino acid residues, about 3 amino acid residues to about 20 amino acid residues, about 3 amino acid residues to about 30 amino acid residues, about 3 amino acid residues to about 40 amino acid residues, about 4 amino acid residues to about 5 amino acid residues, about 4 amino acid residues to about 6 amino acid residues, about 4 amino acid residues to about 7 amino acid residues, about 4 amino acid residues to about 8 amino acid residues, about 4 amino acid residues to about 9 amino acid residues, about 4 amino acid residues to about 10 amino acid residues, about 4 amino acid residues to about 15 amino acid residues, about 4 amino acid residues to about 20 amino acid residues, about 4 amino acid residues to about 30 amino acid residues, about 4 amino acid residues to about 40 amino acid residues, about 5 amino acid residues to about 6 amino acid residues, about 5 amino acid residues to about 7 amino acid residues, about 5 amino acid residues to about 8 amino acid residues, about 5 amino acid residues to about 9 amino acid residues, about 5 amino acid residues to about 10 amino acid residues, about 5 amino acid residues to about 15 amino acid residues, about 5 amino acid residues to about 20 amino acid residues, about 5 amino acid residues to about 30 amino acid residues, about 5 amino acid residues to about 40 amino acid residues, about 6 amino acid residues to about 7 amino acid residues, about 6 amino acid residues to about 8 amino acid residues, about 6 amino acid residues to about 9 amino acid residues, about 6 amino acid residues to about 10 amino acid residues, about 6 amino acid residues to about 15 amino acid residues, about 6 amino acid residues to about 20 amino acid residues, about 6 amino acid residues to about 30 amino acid residues, about 6 amino acid residues to about 40 amino acid residues, about 7 amino acid residues to about 8 amino acid residues, about 7 amino acid residues to about 9 amino acid residues, about 7 amino acid residues to about 10 amino acid residues, about 7 amino acid residues to about 15 amino acid residues, about 7 amino acid residues to about 20 amino acidresidues, about 7 amino acid residues to about 30 amino acid residues, about 7 amino acid residues to about 40 amino acid residues, about 8 amino acid residues to about 9 amino acid residues, about 8 amino acid residues to about 10 amino acid residues, about 8 amino acid residues to about 15 amino acid residues, about 8 amino acid residues to about 20 amino acid residues, about 8 amino acid residues to about 30 amino acid residues, about 8 amino acid residues to about 40 amino acid residues, about 9 amino acid residues to about 10 amino acid residues, about 9 amino acid residues to about 15 amino acid residues, about 9 amino acid residues to about 20 amino acid residues, about 9 amino acid residues to about 30 amino acid residues, about 9 amino acid residues to about 40 amino acid residues, about 10 amino acid residues to about 15 amino acid residues, about 10 amino acid residues to about 20 amino acid residues, about 10 amino acid residues to about 30 amino acid residues, about 10 amino acid residues to about 40 amino acid residues, about 15 amino acid residues to about 20 amino acid residues, about 15 amino acid residues to about 30 amino acid residues, about 15 amino acid residues to about 40 amino acid residues, about 20 amino acid residues to about 30 amino acid residues, about 20 amino acid residues to about 40 amino acid residues, or about 30 amino acid residues to about 40 amino acid residues.

[0409] In some examples, the linker may be an amino acid sequence according to the formula SGxS or GxS, and X can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some examples, X can be 3 or 4. In some examples, the linker may be an amino acid sequence according to the formula Gx, and X can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some examples, X can be 3 or 4. In some examples, the linker may be an amino acid sequence according to the formula (GXS)N or GxS, and X can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 and N can be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some examples, X can be 4 and N can be 4, 5, or 6. In some examples, the linker can be an amino acid sequence according to the formula SxG, and X can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some examples, X may be 3 or 4. In some examples, the linker can be an amino acid sequence according to the formula SGx, and X can be 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some examples, X may be 3 or 4.

[0410] In some examples, an Fc region of a multivalent polypeptide described herein may comprise one or more amino acid substitutions relative to a wild-type Fc region. The wild-type Fc region can comprise an Fc region of a heavy chain constant region. In some examples, the heavy chain constant region can be a wild-type IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, or IgA2. In some examples, the Fc region comprises at least one amino acid substitution relative to a wild-type heavy chain constant region as set forth in any one of SEQ ID NOs: 140-147. In some examples, the Fc region comprises a Fc region with at least about 90%, at least about91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.5%, at least about 99.9%, or greater than about 99.9% sequence identity to an amino acid sequence as set forth in any one of SEQ ID NOs: 140-147. In some examples, the Fc region comprises an amino acid sequence as set forth in any one of SEQ ID NOs: 140-147.In some examples, the Fc region comprises a Fc region with at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.5%, at least about 99.9%, or greater than about 99.9% sequence identity to an amino acid sequence as set forth in Table 2. In some examples, the Fc region comprises an amino acid sequence as set forth in Table 2.Table 2. Immunoglobulin Fc Region Sequences.

[0411] In some examples, the Fc region (e.g., a subunit of the Fc region) can comprise a mutation. The mutation may be an Fc-silencing mutation. In some examples, the Fc mutation decreases an effector function. The Fc-silencing mutation may decrease an antibody dependent cell mediated cytotoxicity (ADCC) effector function, an antibody dependent cell mediated phagocytosis (ADCP), a complement-dependent cytotoxicity (CDC), or any combination thereof. The Fc mutation (e.g., Fc-silencing mutation) can comprise a AAA mutation, a CGC mutation, or any combination thereof. An AAA mutation may comprise a mutation at any amino acid residue position of an amino acid sequence of SEQ ID NO: 140. A CGC mutation may comprise a mutation at any amino acid residue position of an amino acid sequence of SEQ ID NO: 140. Amino acid positions can be referenced according to the positions of wild-type heavy chain using EU indexing. In some examples, the Fc mutation (e.g., Fc-silencing mutation) can comprise a mutation at a leucine of position 234 (e.g., L234), a leucine of position 235 (e.g., L235), a glycine of position 237 (e.g., G237), or any combination thereof, at residue position(s) of an amino acid sequence set forth in SEQ ID NO: 140. In some examples, the Fc mutation (e.g., Fc-silencing mutation) comprises at least one AAA mutationcomprising L234A, L235A, G237A, or any combination thereof, of a sequence as set forth in SEQ ID NO: 140. In some examples, the Fc mutation (e.g., Fc-silencing mutation) can comprise a mutation at an arginine of position 292 (e.g., R292), an asparagine of position 297 (e.g., N297), a valine of position 302 (e.g., V302), or any combination thereof, at residue position(s) of an amino acid sequence set forth in SEQ ID NO: 140. In some examples, the Fc mutation (e.g., Fc-silencing mutation) comprises at least one CGC mutation comprising R292C, N297G, V302C, or any combination thereof, of a sequence as set forth in SEQ ID NO: 140.

[0412] The multivalent polypeptide (e.g., binding partner) described herein may comprise an amino acid sequence as set forth in any one of SEQ ID NOs: 58, 65, 66-78, or 80-92. In some examples, the multivalent polypeptide (e.g., binding partner) described herein may comprise a sequence comprising at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.5%, at least about 99.9%, or greater than about 99.9% sequence identity to an amino acid sequence as set forth in any one of SEQ ID NOs: 58, 65, 66-78, or 80-92. In some examples, the multivalent polypeptide (e.g., binding partner) described herein may comprise a sequence comprising at most about 100%, at most about 99.9%, at most about 99.5%, at most about 99%, at most about 98.5%, at most about 98%, at most about 97%, at most about 96%, at most about 95%, at most about 94%, at most about 93%, at most about 92%, at most about 91%, at most about 90%, at most about 85%, at most about 80%, at most about 75%, or less than about 75% sequence identity to an amino acid sequence as set forth in any one of SEQ ID NOs: 58, 65, 66-78, or 80-92.

[0413] In some examples, a first antigen-binding domain and a second antigen-binding domain of the multivalent polypeptide are the same binder. In some examples, a first antigen-binding domain and a second antigen-binding domain of the multivalent polypeptide are different binders. In some examples, at least one antigen-binding domain of the multivalent polypeptide comprises a single-chain variable fragment (scFv). In some examples, the first antigen-binding domain of the multivalent polypeptide comprises a first scFv. In some examples, the second antigen-binding domain of the multivalent polypeptide comprises a second scFv.

[0414] In some examples, the configuration of the antigen-binding domains of the multivalent polypeptide may provide an advantage in binding the target peptide-conjugate / MHC complex. In some examples, a multivalent polypeptide can comprise, from N-terminus to C-terminus, a configuration comprising: the VH of the first scFv (VH1), the VL of the first scFv (VL1), theVH of the second scFv (VH2), and the VL of the second scFv (VL2). In some examples, a multivalent polypeptide can comprise, from N-terminus to C-terminus, a configuration comprising: VH2-VL2-VH1-VL1, VL1-VH1-VL2-VH2, VL2-VH2-VL1-VH1, VH2-VL2- VL1-VH1, VH1-VL1-VL2-VH2, VL1-VH1-VH2-VL2, or VL2-VH2-VH I -VL I . In some examples, a linker may be inserted between the VH of the first scFv (VH1) and the VL of the first scFv (VL1), the VH of the first scFv (VH1) and the VL of the second scFv (VL2), the VH of the first scFv (VH1) and the VH of the second scFv (VH2), the VL of the first scFv (VL1) and the VL of the second scFv (VL2), the VL of the first scFv (VL1) and the VH of the second scFv (VH2), the VL of the second scFv (VL2) and the VH of the second scFv (VH2), or any combination thereof.

[0415] The multivalent polypeptides (e.g., T cell engagers) described herein may be designated “S3 -18c- AAA”, “S3 -18a- AAA”, “S3-18c-CGC”, or “ SC- 18a-CGC” followed by a binder from Table 7 (e.g., S3-18C-AAA-R114). The T cell engager can comprise an antibody (e.g., R114) linked to an antibody that binds to CD3s (e.g., UCHT1 antibody) and linked to Fc subunits in a continuous polypeptide chain (see FIG. 32C). In some cases, a “Fl” notation can be used interchangeably with “S3 -18c- AAA” for a T cell engager described herein. In some cases, a “F2” notation can be used interchangeably with “S3-18a-AAA” for a T cell engager described herein. In some cases, a “F3” notation can be used interchangeably with “S3-18c-CGC” for a T cell engager described herein. In some cases, a “F4” notation can be used interchangeably with “S3-18a-CGC” for a T cell engager described herein.

[0416] In some examples, the multivalent polypeptide (e.g., T cell engager) described herein may comprise one or more amino acid sequences as set forth in Table 3. In some cases, the multivalent polypeptide described herein can comprise a VL chain of any one of the binding partners (see e.g., Table 7) described herein with or without the “RTV” residues at the C- terminus.Table 3. Exemplary construct sequences (scFv)i-scFc format.

[0417] In an aspect, the present disclosure provides a multivalent polypeptide (e.g., binding partner) that specifically binds to a peptide conjugate / MHC complex, wherein the peptide conjugate / MHC complex comprises: (a) a peptide conjugate formed by the covalent reaction of a targeted covalent inhibitor or fragment thereof with a peptide; and (b) an MHC.

[0418] In some examples, the multivalent polypeptide (e.g., binding partner or T cell engager) described herein comprises a first antigen-binding domain comprising a heavy chain variable region (VH) comprising a sequence that may be at least about 80%, least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.5%, at least about 99.9%, or greater than about 99.9%, or 100% sequence identity to any one amino acid sequence as set forth in SEQ ID NOs: 1 or 27. In some examples, the multivalent polypeptide (e.g., binding partner or T cell engager) described herein comprises a first antigen-binding domain comprising a heavy chain variable region (VH) comprising a sequence that may be at most about 99.9%, at most about 99.5%, at most about 99%, at most about 98.5%, at most about 98%, at most about 97%, at most about 96%, at most about 95%, at most about 94%, at most about 93%, at most about 92%, at most about 91%, at most about 90%, at most about 85%, at most about 80%, or less than about 80% sequence identity to any one amino acid sequence as set forth in SEQ ID NOs: 1 or 27. In some cases, the first antigen-binding domain of the multivalent polypeptide described herein comprises a VH comprising a sequence as set forth in any one of SEQ ID NOs: 1 or 27.

[0419] In some examples, the multivalent polypeptide (e.g., binding partner or T cell engager) described herein comprises a first antigen-binding domain comprising a light chain variable region (VL) comprising a sequence that may be at least about 80%, least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about98.5%, at least about 99%, at least about 99.5%, at least about 99.9%, or greater than about 99.9% sequence identity to any one amino acid sequence as set forth in SEQ ID NOs: 16, 20, 42, 52, 53, 55, 56, or 162-167. In some examples, the multivalent polypeptide (e.g., binding partner or T cell engager) described herein comprises a first antigen-binding domain comprising a light chain variable region (VL) comprising a sequence that may be at most about 99.9%, at most about 99.5%, at most about 99%, at most about 98.5%, at most about 98%, at most about 97%, at most about 96%, at most about 95%, at most about 94%, at most about 93%, at most about 92%, at most about 91%, at most about 90%, at most about 85%, at most about 80%, or less than about 80% sequence identity to any one amino acid sequence as set forth in SEQ ID NOs: 16, 20, 42, 52, 53, 55, 56, or 162-167. In some cases, the first antigenbinding domain of the multivalent polypeptide described herein comprises VL comprising a sequence as set forth in any one of SEQ ID NOs: 16, 20, 42, 52, 53, 55, 56, or 162-167.

[0420] In another aspect, the present disclosure provides a multivalent polypeptide (e.g., binding partner) that binds to a peptide conjugate / MHC complex and may not comprise a single continuous polypeptide chain. In some examples, the multivalent polypeptide can comprise a first antigen-binding domain and a second antigen-binding domain. In some examples, the first antigen-binding domain comprises a first heavy chain variable region (VH) and a first light chain variable region (VL) and the second antigen-binding domain comprises a second VH and a second VL. In some examples, the first antigen binding domain can bind to the peptide conjugate / MHC complex and the second antigen-binding domain can bind to a T cell surface protein. The T cell surface protein can be a TCR alpha chain, a TCR beta chain, a TCR gamma chain, a TCR delta chain, CD3s, CD35, CD3y, ICOS, CD28, CD27, HVEM, LIGHT, CD40, 4-1BB (CD137), 0X40, DR3, GITR, CD30, TIM1, SLAM (e.g, a SLAM family member), CD2, CD4, CD8, or CD226. In some examples, the T cell surface protein comprises CD3s, CD35, CD3y, TCRa, TCRP, TCR5, TCRy, or CD3(^. In some examples, the T cell surface protein is CD3 (e.g., CD3s).

[0421] In some examples, the second antigen-binding domain comprises complementarity determining regions (CDRs) from a heavy chain variable region (VH) and a light chain variable region (VL) of a UCHT1 antibody. In some examples, an amino acid sequence of a CDR of the second antigen-binding domain may comprise a sequence as set forth in Table 4. In some examples, an amino acid sequence of a HC CDR3, HC CDR2, and HC CDR1 may comprise an amino acid sequence as set forth in SEQ ID NOs: 133, 134, and 135, respectively. In some examples, an amino acid sequence of a HC CDR3, HC CDR2, and HC CDR1 may comprise at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.5%, at least about 99.9%, or greater than about 99.9% sequence identity to an amino acid sequence as set forth in SEQ ID NOs: 133, 134, and 135, respectively. In some examples, an amino acid sequence of a HC CDR3, HC CDR2, and HC CDR1 may comprise at most about 99.9%, at most about 99.5%, at most about 99%, at most about 98.5%, at most about 98%, at most about 97%, at most about 96%, at most about 95%, at most about 94%, at most about 93%, at most about 92%, at most about 91%, at most about 90%, or less than about 90% sequence identity to an amino acid sequence as set forth in SEQ ID NOs: 133, 134, and 135, respectively. In some examples, an amino acid sequence of a LC CDR3, LC CDR2, and LC CDR1 may comprise an amino acid sequence as set forth in SEQ ID NOs: 136, 137, and 138, respectively. In some examples, an amino acid sequence of a LC CDR3, LC CDR2, and LC CDR1 may comprise at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.5%, at least about 99.9%, or greater than about 99.9% sequence identity to an amino acid sequence as set forth in SEQ ID NOs: 136, 137, and 138, respectively. In some examples, an amino acid sequence of a LC CDR3, LC CDR2, and LC CDR1 may comprise at most about 99.9%, at most about 99.5%, at most about 99%, at most about 98.5%, at most about 98%, at most about 97%, at most about 96%, at most about 95%, at most about 94%, at most about 93%, at most about 92%, at most about 91%, at most about 90%, or less than about 90% sequence identity to an amino acid sequence as set forth in SEQ ID NOs: 136, 137, and 138, respectively.

[0422] In some examples, the second antigen-binding domain of a multivalent polypeptide as described herein can comprise a VL comprising a sequence that may be at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.5%, at least about 99.9%, or greater than about 99.9% sequence identity to an amino acid sequence as set forth in SEQ ID NO: 61. In some examples, the second antigen-binding domain of a multivalent polypeptide as described herein can comprise a VL comprising a sequence that may be at most about 99.9%, at most about 99.5%, at most about 99%, at most about 98.5%, at most about 98%, at most about 97%, at most about 96%, at most about 95%, at most about 94%, at most about 93%, at most about 92%, at most about 91%, at most about 90%, at most about 85%, or less than about 85% sequence identity to an amino acid sequence as set forth in SEQ ID NO: 61. In some examples,the second antigen-binding domain of a multivalent polypeptide as described herein can comprise a VL comprising a sequence as set forth in SEQ ID NO: 61.

[0423] In some examples, the second antigen-binding domain of a multivalent polypeptide as described herein can comprise a VH comprising a sequence that may be at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.5%, at least about 99.9%, or greater than about 99.9% sequence identity to an amino acid sequence as set forth in SEQ ID NO: 59. In some examples, the second antigen-binding domain of a multivalent polypeptide as described herein can comprise a VH comprising a sequence that may be at most about 99.9%, at most about 99.5%, at most about 99%, at most about 98.5%, at most about 98%, at most about 97%, at most about 96%, at most about 95%, at most about 94%, at most about 93%, at most about 92%, at most about 91%, at most about 90%, at most about 85%, or less than about 85% sequence identity to an amino acid sequence as set forth in SEQ ID NO: 59. In some examples, the second antigen-binding domain of a multivalent polypeptide as described herein can comprise a VH comprising a sequence as set forth in SEQ ID NO: 59.

[0424] The UCHT1 antibody or fragment thereof described herein (e.g., second antigenbinding domain) can comprise a VH having at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.5%, at least about 99.9%, or greater than about 99.9% sequence identity to an amino acid sequence as set forth in SEQ ID NO: 141. The UCHT1 antibody or fragment thereof described herein (e.g., second antigen-binding domain) can comprise a VH having at most about 99.9%, at most about 99.5%, at most about 99%, at most about 98.5%, at most about 98%, at most about 97%, at most about 96%, at most about 95%, at most about 94%, at most about 93%, at most about 92%, at most about 91%, at most about 90%, at most about 85%, or less than about 85% sequence identity to an amino acid sequence as set forth in SEQ ID NO: 59. In some examples, the second antigen-binding domain of a multivalent polypeptide as described herein can comprise a VH comprising a sequence as set forth in SEQ ID NO: 141.

[0425] The UCHT1 antibody or fragment thereof described herein (e.g., second antigenbinding domain) can comprise a VL having at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.5%, at least about 99.9%, or greater than about 99.9% sequence identityto an amino acid sequence as set forth in SEQ ID NO: 142. The UCHT1 antibody or fragment thereof described herein (e.g., second antigen-binding domain) can comprise a VL having at most about 99.9%, at most about 99.5%, at most about 99%, at most about 98.5%, at most about 98%, at most about 97%, at most about 96%, at most about 95%, at most about 94%, at most about 93%, at most about 92%, at most about 91%, at most about 90%, at most about 85%, or less than about 85% sequence identity to an amino acid sequence as set forth in SEQ ID NO: 59. In some examples, the second antigen-binding domain of a multivalent polypeptide as described herein can comprise a VH comprising a sequence as set forth in SEQ ID NO: 142.

[0426] Any UCHT1 in a T cell engager (TCE) construct described herein may comprise the UCHT1 antibody or fragment thereof comprising a VH having at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.5%, at least about 99.9%, or greater than about 99.9% sequence identity to an amino acid sequence as set forth in SEQ ID NO: 141, and / or a VL having at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.5%, at least about 99.9%, or greater than about 99.9% sequence identity to an amino acid sequence as set forth in SEQ ID NO: 142.

[0427] In some examples, the second antigen-binding domain of a multivalent polypeptide as described herein can comprise a VH and / or VL as set forth in Table 4. In some examples, the second antigen-binding domain of a multivalent polypeptide as described herein can comprise a HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, LC CDR3, or any combination thereof, as set forth in Table 4.Table 4. UCHT1 Sequences

[0428] In some examples, the first antigen-binding domain and the second antigen-binding domain comprise a diabody. In some examples, the multivalent polypeptide comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 98.5%, at least about 99%, at least about 99.5%, at least about 99.9%, or greater than 99.9% sequence identity to any one of the amino acid sequences as set forth in SEQ ID NOs: 93 or 98-110. In some examples, the multivalent polypeptide comprises an amino acid sequence as set forth in SEQ ID NOs: 93 or 98-110.

[0429] The multivalent polypeptide may comprise a fusion tag. The fusion tag can comprise a protein or peptide fused to the multivalent polypeptide. The fusion tag may assist in detection of the polypeptide or an area of the polypeptide. The fusion tag may be an epitope tag, an affinity tag, a fluorescent tag, or any combination thereof. In some examples, the fusion tag may be an AviTag™. In some examples, the fusion tag may be a histidine tag (His-tag). The fusion tag may comprise a tag selected from the group consisting of CBP, GST, strep-tag, c- myc, hemagglutinin (HA), DDDK tag, T7 tag, V5 tag, GFP, ALFA tag, and mCherry. In some examples, the fusion tag comprises an amino acid sequence as set forth in SEQ ID NO:...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A multivalent polypeptide comprising: a first antigen-binding domain that binds to a peptide conjugate / MHC complex, wherein the peptide conjugate / MHC complex comprises a peptide conjugate formed by a covalent reaction of a targeted covalent inhibitor or fragment thereof with a peptide and an MHC; a second antigen-binding domain that binds to a T cell surface protein; and an Fc region comprising a first Fc subunit and a second Fc subunit; wherein the first antigen-binding domain, the second antigen-binding domain, the first Fc subunit, and the second Fc subunit are operably linked to form a single continuous polypeptide chain.

2. The multivalent polypeptide of claim 1, wherein the multivalent polypeptide comprises, from N-terminus to C-terminus, the first antigen-binding domain, the second antigen-binding domain, the first Fc subunit, and the second Fc subunit.

3. The multivalent polypeptide of claim 1, wherein the multivalent polypeptide comprises, from N-terminus to C-terminus, the first antigen-binding domain, a first linker, the second antigen-binding domain, a second linker, the first Fc subunit, a third linker, and the second Fc subunit.

4. The multivalent polypeptide of claim 1, wherein the multivalent polypeptide comprises, from N-terminus to C-terminus, the second antigen-binding domain, the first antigen-binding domain, the first Fc subunit, and the second Fc subunit.

5. The multivalent polypeptide of claim 1, wherein the multivalent polypeptide comprises, from N-terminus to C-terminus, the second antigen-binding domain, a first linker, the first antigen-binding domain, a second linker, the first Fc subunit, a third linker, and the second Fc subunit.

6. The multivalent polypeptide of any one of claims 1-5, wherein the Fc region comprises an amino acid sequence as set forth in SEQ ID NOs: 64 or 79, or an amino acid sequence with at least 90% sequence identity to SEQ ID NO: 64 or 79.

7. The multivalent polypeptide of claim 3 or 5, wherein the first linker, the second linker, and / or the third linker comprises an amino acid sequence as set forth in SEQ ID NOs: 60, 62, 63, 95, 139, or 174.

8. The multivalent polypeptide of claim 7, wherein the first linker comprises an amino acid sequence as set forth in SEQ ID NO: 62.

9. The multivalent polypeptide of claim 7, wherein the second linker comprises an amino acid sequence as set forth in SEQ ID NO: 63.

10. The multivalent polypeptide of claim 7, wherein the third linker comprises an amino acid sequence as set forth in SEQ ID NO: 139 (GGGGSGGGGSGGGGSGGGGSGGGGSGGGGS).

11. The multivalent polypeptide of any one of claims 3, 5, and 7-10, wherein the first linker has a length of from 4-12, 4-10, 4-8, 4-6 or 6 amino acids.

12. The multivalent polypeptide of claim 11, wherein the first linker comprises an amino acid sequence according to the formula SGxS or GxS, wherein X is 3 or 4.

13. The multivalent polypeptide of claim 11 or 12, wherein the first linker comprises an amino acid sequence according to the formula SGxS, wherein X is 4.

14. The multivalent polypeptide of claim 11, wherein the first linker comprises an amino acid sequence according to the formula SxG, wherein X is 3 or 4.

15. The multivalent polypeptide of any one of claims 3, 5, and 7-13, wherein the second linker has a length of from 3-12, 3-10, 3-8, 3-6 or 4 amino acids.

16. The multivalent polypeptide of claim 15, wherein the second linker comprises an amino acid sequence according to the formula Gx, wherein X is 3, 4, or 5.

17. The multivalent polypeptide of claim 16, wherein X is 4.

18. The multivalent polypeptide of claim 15, wherein the second linker comprises an amino acid sequence according to the formula SGx, wherein X is 3 or 4.

19. The multivalent polypeptide of any one of claims 3, 5, and 7-18, wherein the third linker has a length of from 20-40, 20-35, 25-40, 25-35, 25-30, 30-35, 28-32 or 30 amino acids.

20. The multivalent polypeptide of claim 19, wherein the third linker comprises an amino acid sequence according to the formula (GXS)N or GxS, wherein X is 3 or 4 and N is 3, 4, 5, 6, 7, 8, 9 or 10.

21. The multivalent polypeptide of claim 20, wherein X is 4 and N is 5, 6 or 7.

22. The multivalent polypeptide of claim 20, wherein X is 4 and N is 6.

23. The multivalent polypeptide of any one of claims 1-22, wherein the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

24. The multivalent polypeptide of any one of claims 1-23, wherein the Fc region comprises an Fc-silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function.

25. The multivalent polypeptide of claim 24, wherein the Fc-silencing mutation comprises a AAA mutation or a CGC mutation, wherein the AAA mutation comprises L234A, L235A, G237A of a sequence of SEQ ID NO: 140, and wherein the CGC mutation comprises R292C, N297G, V302C of a sequence of SEQ ID NO: 140.

26. The multivalent polypeptide of any one of claims 1-25, wherein the multivalent polypeptide comprises an amino acid sequence with at least 80% sequence identity to an amino acid sequence as set forth in SEQ ID NOs: 58, 65, 66-78, or 80-92 or at least 90% identical to an amino acid sequence as set forth in SEQ ID NOs: 58, 65, 66- 78, or 80-92.

27. The multivalent polypeptide of any one of claims 1-26, wherein the multivalent polypeptide comprises an amino acid sequence as set forth in SEQ ID NOs: 58, 65, 66-78, or 80-92.

28. The multivalent polypeptide of any one of claims 1-27, wherein the first antigenbinding domain comprises a first single-chain variable fragment (scFv) comprising a heavy chain variable region (VH) and a light chain variable region (VL).

29. The multivalent polypeptide of claim 28, wherein the second antigen-binding domain comprises a second single-chain variable fragment (scFv) comprising a heavy chain variable region (VH) and a light chain variable region (VL).

30. The multivalent polypeptide of claim 29, wherein the multivalent polypeptide comprises, from N-terminus to C-terminus, the VH of the first scFv, the VL of the first scFv, the VH of the second scFv, and the VL of the second scFv.

31. The multivalent polypeptide of claim 29, wherein the multivalent polypeptide comprises, from N-terminus to C-terminus, the VH of the second scFv, the VL of the second scFv, the VH of the first scFv, and the VL of the first scFv.

32. The multivalent polypeptide of claim 29, wherein the multivalent polypeptide comprises, from N-terminus to C-terminus, the VL of the first scFv, the VH of the first scFv, the VL of the second scFv, and the VH of the second scFv.

33. The multivalent polypeptide of claim 29, wherein the multivalent polypeptide comprises, from N-terminus to C-terminus, the VL of the second scFv, the VH of the second scFv, the VL of the first scFv, and the VH of the first scFv.

34. The multivalent polypeptide of claim 29, wherein the multivalent polypeptide comprises, from N-terminus to C-terminus, the VH of the second scFv, the VL of the second scFv, the VL of the first scFv, and the VH of the first scFv.

35. The multivalent polypeptide of claim 29, wherein the multivalent polypeptide comprises, from N-terminus to C-terminus, the VH of the first scFv, the VL of the first scFv, the VL of the second scFv, and the VH of the second scFv.

36. The multivalent polypeptide of claim 29, wherein the multivalent polypeptide comprises, from N-terminus to C-terminus, the VL of the first scFv, the VH of the first scFv, the VH of the second scFv, and the VL of the second scFv.

37. The multivalent polypeptide of claim 29, wherein the multivalent polypeptide comprises, from N-terminus to C-terminus, the VL of the second scFv, the VH of the second scFv, the VH of the first scFv, and the VL of the first scFv.

38. A multivalent polypeptide comprising: a first antigen-binding domain that binds to a peptide conjugate / MHC complex, wherein the peptide conjugate / MHC complex comprises a peptide conjugate formed by a covalent reaction of a targeted covalent inhibitor or fragment thereof with a peptide and an MHC; and a second antigen-binding domain that binds to a T cell surface protein; wherein the first antigen-binding domain comprises a first heavy chain variable region (VH) and a first light chain variable region (VL) and the second antigen-binding domain comprises a second VH and a second VL, and wherein the second VL comprises: a CDR-L3 sequence of QQGNTLPWT (SEQ ID NO: 136), a CDR-L2 sequence of YTSRLES (SEQ ID NO: 137), and a CDR-L1 sequence of RASQDIRNYLN (SEQ ID NO: 138).

39. The multivalent polypeptide of claim 38, wherein the multivalent polypeptide comprises an amino acid sequence with at least 80% sequence identity to an amino acid sequence as set forth in SEQ ID NOs: 93 or 98-110.

40. The multivalent polypeptide of claim 38 or 39, wherein the multivalent polypeptide comprises an amino acid sequence as set forth in SEQ ID NOs: 93 or 98-110.

41. The multivalent polypeptide of any one of claims 38-40, wherein the multivalent polypeptide comprises a fusion tag.

42. The multivalent polypeptide of claim 41, wherein the fusion tag comprises an amino acid sequence as set forth in SEQ ID NO: 96.

43. The multivalent polypeptide of any one of claims 38-42, wherein the multivalent polypeptide further comprises an Fc region comprising a first Fc subunit and a second Fc subunit.

44. The multivalent polypeptide of claim 43, wherein the first Fc subunit comprises a protuberance and the second Fc subunit comprises a cavity, wherein the protuberance of the first Fc subunit chain interfaces with the cavity of the second Fc subunit.

45. The multivalent polypeptide of claim 43 or 44, wherein the first Fc subunit comprises an amino acid sequence as set forth in SEQ ID NO: 113.

46. The multivalent polypeptide of any one of claims 43-45, wherein the second Fc subunit comprises an amino acid sequence as set forth in SEQ ID NO: 114.

47. The multivalent polypeptide of any one of claims 43-46, wherein the first Fc subunit and / or the second Fc subunit comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

48. The multivalent polypeptide of any one of claims 43-47, wherein the first Fc subunit or the second Fc subunit comprises an Fc-silencing mutation.

49. The multivalent polypeptide of any one of claims 43-47, wherein the first Fc subunit and the second Fc subunit comprise an Fc-silencing mutation.

50. The multivalent polypeptide of claim 48 or 49, wherein:(a) the Fc-silencing mutation of the first Fc subunit comprises L234A, L235A, P329G, or any combination thereof; and / or(b) the Fc-silencing mutation of the second Fc subunit comprises L234A, L235A, P329G, or any combination thereof.

51. The multivalent polypeptide of any one of claims 47-50, wherein the one or more amino acid substitutions of the first Fc subunit comprise P354C and / or T366W.

52. The multivalent polypeptide of any one of claims 47-51, wherein the one or more amino acid substitutions of the second Fc subunit comprise Y349C, T366S, M368A, Y407V or any combination thereof.

53. The multivalent polypeptide of any one of claims 43-52, wherein a polypeptide chain comprising the first Fc subunit comprises an amino acid sequence with at least 80% sequence identity to an amino acid sequence as set forth in SEQ ID NOs: 111 or 115- 127.

54. The multivalent polypeptide of any one of claims 43-52, wherein a polypeptide chain comprising the first Fc subunit comprises an amino acid sequence as set forth in SEQ ID NOs: 111 or 115-127.

55. A multivalent polypeptide comprising: a first antigen-binding domain that binds to a peptide conjugate / MHC complex, wherein the peptide conjugate / MHC complex comprises a peptide conjugate formed by a covalent reaction of a targeted covalent inhibitor or fragment thereof with a peptide and an MHC; a second antigen-binding domain that binds to a T cell surface protein; wherein the first antigen-binding domain comprises a first heavy chain variable region (VH) and a first light chain variable region (VL) and the second antigen-binding domain comprises a second VH and a second VL, wherein the first antigen-binding domain and the second antigen-binding domain are linked, and wherein the first VH, the second VH, the first VL, or the second VL is linked to a Fc region having at least a first Fc subunit.

56. The multivalent polypeptide of claim 55, wherein the Fc region comprises the first Fc subunit and a second Fc subunit.

57. The multivalent polypeptide of claim 55 or 56, wherein the first Fc subunit and the second Fc subunit is linked by at least one disulfide bond and is not linked to form a continuous polypeptide.

58. The multivalent polypeptide of any one of claims 55-57, wherein the first Fc subunit comprises a protuberance and the second polypeptide chain comprises a cavity, wherein the protuberance of the first Fc subunit chain interfaces with the cavity of the second Fc subunit.

59. The multivalent polypeptide of any one of claims 55-58, wherein the first Fc subunit comprises an amino acid sequence as set forth in SEQ ID NO: 113.

60. The multivalent polypeptide of claim 55 or 56, wherein the second Fc subunit comprises an amino acid sequence as set forth in SEQ ID NO: 114.

61. The multivalent polypeptide of any one of claims 55-60, wherein the first Fc subunit and / or the second Fc subunit comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

62. The multivalent polypeptide of any one of claims 55-61, wherein the first Fc subunit or the second Fc subunit comprises an Fc-silencing mutation.

63. The multivalent polypeptide of any one of claims 55-61, wherein the first Fc subunit and the second Fc subunit comprise an Fc-silencing mutation.

64. The multivalent polypeptide of claim 62 or 63, wherein:(a) the Fc-silencing mutation of the first Fc subunit comprises L234A, L235A, P329G, or any combination thereof; and / or(b) the Fc-silencing mutation of the second Fc subunit comprises L234A, L235A, P329G, or any combination thereof.

65. The multivalent polypeptide of any one of claims 61-64, wherein the one or more amino acid substitutions of the first Fc subunit comprise P354C and / or T366W.

66. The multivalent polypeptide of any one of claims 61-65, wherein the one or more amino acid substitutions of the second Fc subunit comprise Y349C, T366S, M368A, Y407V or any combination thereof.

67. The multivalent polypeptide of any one of claims 55-66, wherein a polypeptide chain comprising the first Fc subunit comprises an amino acid sequence with is at least 80% sequence identity to an amino acid sequence as set forth in SEQ ID NOs: 111 or 115- 127.

68. The multivalent polypeptide of any one of claims 55-66, wherein a polypeptide chain comprising the first Fc subunit comprises an amino acid sequence as set forth in SEQ ID NOs: 111 or 115-127.

69. The multivalent polypeptide of any one of claims 38-68, wherein the multivalent polypeptide comprises, from N-terminus to C-terminus, (i) the first VL, the second VH, the second VL, and the first VH; (ii) the second VL, the first VH, the first VL, and the second VH; (iii) the first VL, the second VL, the second VH, and the first VH; (iv) the second VL, the first VL, the first VH, and the second VH; (v) the first VH, the second VL, the second VH, and the first VL; (vi) the first VH, the second VH, the second VL, and the first VL; (vii) the second VH, the first VL, the first VH, the second VL; (viii) the second VH, the first VH, the first VL, and the second VL; (ix) the first VH, the first VL, the second VH, and the second VL; (x) the first VL, the first VH, the second VH, and the second VL; (xi) the first VH, the first VL, the second VL, and the second VH; (xii) the first VL, the first VH, the second VL, and the second VH; (xiii) the second VH, the second VL, the first VH, and the first VL; (xiv) the second VL, the second VH, the first VH, and the first VL; (xv) the second VH, the second VL, the first VL, and the first VH; or (xvi) the second VL, the second VH, the first VL, and the first VH.

70. The multivalent polypeptide of claim 69, wherein the first Fc subunit is linked to the first VH or the second VH.

71. The multivalent polypeptide of any one of claims 38-69, wherein the multivalent polypeptide comprises at least one linker.

72. The multivalent polypeptide of claim 71, wherein the at least one linker comprises an amino acid sequence as set forth in SEQ ID NOs: 60, 62, 63, 95, or 112.

73. The multivalent polypeptide of any one of claims 55-68, wherein the multivalent polypeptide comprises, from N-terminus to C-terminus, (i) the first VL, a first linker, the second VH, a second linker, the second VL, a third linker, the first VH, a fourth linker, and the first Fc subunit; (ii) the second VL, a first linker, the first VH, a second linker, the first VL, a third linker, the second VH, a fourth linker, and the first Fc subunit; (iii) the first VL, a first linker, the second VL, a second linker, the second VH, a third linker, the first VH, a fourth linker, and the first Fc subunit; (iv) the second VL, a first linker, the first VL, a second linker, the first VH, a third linker, the second VH, a fourth linker, and the first Fc subunit; (v) the first VH, a first linker, the second VL, a second linker, the second VH, a third linker, the first VL, a fourth linker, and the first Fc subunit; (vi) the first VH, a first linker, the second VH, a second linker, the second VL, a third linker, the first VL, a fourth linker, and the first Fc subunit; (vii) the second VH, a first linker, the first VL, a second linker, the first VH, a third linker, the second VL, a fourth linker, and the first Fc subunit; (viii) the second VH, a first linker, the first VH, a second linker, the first VL, a third linker, the second VL, a fourth linker, and the first Fc subunit; (ix) the first VH, a first linker, the first VL, a second linker, the second VH, a third linker, the second VL, a fourth linker, and the first Fc subunit; (x) the first VL, a first linker, the first VH, a second linker, the second VH, a third linker, the second VL, a fourth linker, and the first Fc subunit; (xi) the first VH, a first linker, the first VL, a second linker, the second VL, a third linker, the second VH, a fourth linker, and the first Fc subunit; (xii) the first VL, a first linker, the first VH, a second linker, the second VL, a third linker, the second VH, a fourth linker, and the first Fc subunit; (xiii) the second VH, a first linker, the second VL, a second linker, the first VH, a third linker, the first VL, a fourth linker, and the first Fc subunit; (xiv) the second VL, a first linker, the second VH, a second linker, the first VH, a third linker, the first VL, a fourth linker, and the first Fc subunit; (xv) the second VH, a first linker, the second VL, a second linker, the first VL, a third linker, the first VH, a fourth linker, and the first Fc subunit; or (xvi) thesecond VL, a first linker, the second VH, a second linker, the first VL, a third linker, the first VH, a fourth linker, and the first Fc subunit.

74. The multivalent polypeptide of claim 73, wherein the first linker comprises SEQ ID NO: 95, the second linker comprises SEQ ID NO: 60, the third linker comprises SEQ ID NO: 95, and / or the fourth linker comprises SEQ ID NO: 112.

75. The multivalent polypeptide of any one of claims 38-72, wherein the multivalent polypeptide comprises a polyhistidine-tag and optionally wherein the polyhistidine- tag comprises an amino acid sequence as set forth in SEQ ID NO: 97.

76. The multivalent polypeptide of any one of claims 1-75, wherein the second antigenbinding domain binds to CD3 epsilon.

77. The multivalent polypeptide of any one of claims 1-76, wherein the second antigenbinding domain comprises six complementarity determining regions (CDRs) from heavy chain variable region (VH) and light chain variable region (VL) of a UCHT1 antibody, comprising: a CDR-H3 sequence of SGYYGDSDWYFDV (SEQ ID NO: 133), a CDR-H2 sequence of LINPYKGVSTYNQKFKD (SEQ ID NO: 134), a CDR-H1 sequence of GYTMN (SEQ ID NO: 135), a CDR-L3 sequence of QQGNTLPWT (SEQ ID NO: 136), a CDR-L2 sequence of YTSRLES (SEQ ID NO: 137), and a CDR-L1 sequence of RASQDIRNYLN (SEQ ID NO: 138).

78. The multivalent polypeptide of claim 77, wherein the VH comprises a sequence with at least 90% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALI NPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYY GDSDWYFDVWGQGTLVTVSS (SEQ ID NO: 59).

79. The multivalent polypeptide of claim 77 or 78, wherein the VH comprises a sequence of EVQLVESGGGLVQPGGSLRLSCAASGYSFTGYTMNWVRQAPGKGLEWVALI NPYKGVSTYNQKFKDRFTISVDKSKNTAYLQMNSLRAEDTAVYYCARSGYY GDSDWYFDVWGQGTLVTVSS (SEQ ID NO: 59).

80. The multivalent polypeptide of any one of claims 77-79, wherein the VL comprises a sequence with at least 90% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIK (SEQ ID NO: 61).

81. The multivalent polypeptide of any one of claims 77-80, wherein the VL comprises a sequence of DIQMTQSPSSLSASVGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSR LESGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGNTLPWTFGQGTKVEIK (SEQ ID NO: 61).

82. The multivalent polypeptide of any one of claims 1-81, wherein the first antigenbinding domain binds to the peptide conjugate / MHC complex with a greater affinity than to the peptide or a free targeted covalent inhibitor.

83. The multivalent polypeptide of claim 82, wherein the affinity of the first antigenbinding domain for the peptide conjugate / MHC complex is 100-10,000 times greater than the affinity of the first antigen-binding domain for the peptide or free targeted covalent inhibitor.

84. The multivalent polypeptide of any one of claims 1-83, wherein the peptide comprises a cysteine residue.

85. The multivalent polypeptide of claim 84, wherein a peptide conjugate of the peptide conjugate / MHC complex is formed by a covalent reaction between the targeted covalent inhibitor and the cysteine residue in the peptide.

86. The multivalent polypeptide of any one of claims 1-85, wherein the peptide comprises a segment of KRASG13C, KRASG12C, KRASG12D, KRASG12R, or KRASG12S.

87. The multivalent polypeptide of any one of claims 1-86, wherein the peptide comprises the amino acid sequence of VVVGACGVGK, VVGACGVGK, or KLWVGACGV.

88. The multivalent polypeptide of any one of claims 1-87, wherein the targeted covalent inhibitor is (i) a tri-complex KRASG12Cinhibitor or a KRASG12Cdegrader, (ii) a tricomplex KRASG12Dinhibitor or a KRASG12Ddegrader, (iii) a tri-complex KRASG12Rinhibitor or a KRASG12Rdegrader, (iv) a tri-complex KRASG13Cinhibitor or a KRASG13Cdegrader, or (v) a tri-complex KRASG12Sinhibitor or a KRASG12Sdegrader.

89. The multivalent polypeptide of claim 88, wherein (i) the peptide comprises a KRASG12Cmutation, and the targeted covalent inhibitor is a KRASG12Cinhibitor, (ii) the peptide comprises a KRASG12Dmutation, and the targeted covalent inhibitor is a KRASG12Dinhibitor, (iii) the peptide comprises a KRASG12Rmutation, and the targeted covalent inhibitor is a KRASG12Rinhibitor, (iv) the peptide comprises aKRASG13Cmutation, and the targeted covalent inhibitor is a KRASG13Cinhibitor, or (v) the peptide comprises a KRASG12Smutation, and the targeted covalent inhibitor is a KRASG12Sinhibitor.

90. The multivalent polypeptide of any one of claims 1-89, wherein the targeted covalent inhibitor is AMG-510, ARS-1620, ARS-853, ARS-3248, MRTX849, JNJ74699157, LY3499446, LY3537982, MRTX-1257, JDQ443, RMC-6291, RMC-9805, GDC- 6036, D-1553, 2E07, 6H05, SML-8-73-1, MK1084, RG6330, BPI-421286, GH35, BEBT-607, JAB-21000, AZD4625, AZD4747, or BI 182391.

91. The multivalent polypeptide of any one of claims 1-89, wherein the targeted covalent inhibitor is: sotorasib, adagrasib, opnurasib, divarasib, garsorasib, l-[4-[6-chloro-8- fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl]piperazin-l-yl]prop-2-en-l-one,1-(3-(4-((4-chloro-2-hydroxy-5-(l-methylcyclopropyl)phenyl)glycyl)piperazin-l- yl)azetidin- 1 -yl)prop-2-en- 1 -one, 1 -(4-(7-(2- Amino-7-fluoro- 1 ,3 -benzothiazol-4-yl)- 6-chloro-8-fluoro-quinazolin-4-yl)piperazin- 1 -yl)prop-2-en- 1 -one, 2-Amino-4-[(4aS)- 8-chloro-10-fluoro-2,3,4,4a,5,6-hexahydro-12-oxo-3-(l-oxo-2-propen-l-yl)-lH,12H- pyrazino[2,l-d][l,5]benzoxazocin-9-yl]-7-fluorobenzo[b]thiophene-3-carbonitrile, 2- [(2S)-4-[7-(8-methylnaphthalen-l-yl)-2-[[(2S)-l-methylpyrrolidin-2-yl]methoxy]-6,8- dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-l-prop-2-enoylpiperazin-2-yl]acetonitrile, 4-(4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro- lH-pyrrolizin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6- fhioronaphthalen-2-ol, l-[4-(dimethylamino)-4-methylpent-2-ynoyl]-N-[(2S)-l- [[(6S,8S,14S)-22-ethyl-21-[2-[(lS)-l-methoxyethyl]pyridin-3-yl]-18,18-dimethyl-9, 15-di oxo-5, 16-dioxa-2, 10,22,28- tetrazapentacyclo[18.5.2.12,6.110, 14.023, 27]nonacosa-l(26), 20, 23(27), 24-tetraen-8- yl]amino]-3-methyl-l-oxobutan-2-yl]-4-fluoro-N-methylpiperidine-4-carboxamide, 1- ((3 R, 14aS)- 11 -Chi oro-9-fluoro-10-(2-fluoro-6-hydroxyphenyl)-3 -methyl- l,3,4,13,14,14a-hexahydro-2H-pyrazino[l',2':5,6][l,5]oxazocino[4,3,2-de]quinazolin-2-yl)prop-2-en-l-one, N-(5-(3,5-dimethoxyphenethyl)-lH-pyrazol-3-yl)-4-((3S,5R)- 3,5-dimethylpiperazin-l-yl)benzamide, or [[(2R,3S,4R,5R)-5-(2-amino-6-oxo-lH- purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] 2-[(2- chloroacetyl)amino]ethyl hydrogen phosphate],92. The multivalent polypeptide of claim 90, wherein the multivalent polypeptide specifically binds to the peptide conjugate / MHC complex comprising a peptide conjugate formed by the covalent reaction of AMG-510 and KRASG12Cpeptide.

93. The multivalent polypeptide of any one of claims 1-92, wherein the MHC is HLA-A*02:01, HLA-A*03:01, HLA-A*l l:01, HLA-A*68:01, HLA-A*31:01, HLA- A*30:01, HLA-A*33:03, HLA-A*33:01, HLA-A*74:01, HLA-A*34:02, HLA- A*66:01, HLA-A*68:02, HLA-A*02:05, HLA-A*02:02, HLA-A*02:06, or any combination thereof.

94. The multivalent polypeptide of any one of claims 1-92, wherein the MHC is encoded by an HLA allele of HL A- A3 supertype.

95. The multivalent polypeptide of claim 94, wherein the HLA allele of the HL A- A3 supertype is selected from the group consisting of HLA- A* 03:01, HLA-A* 11 :01, HLA-A*68:01, HLA-A*31:01, HLA-A*30:01, HLA-A*74:01, HLA-A*34:02, and HLA-A*66:01.

96. The multivalent polypeptide of any one of claims 1-92, wherein the MHC is encoded by an HLA allele of HLA-A2 supertype.

97. The multivalent polypeptide of claim 96, wherein the HLA allele of the HLA-A2 supertype is selected from the group consisting of HLA- A* 02:01, HLA-A*02:02, HLA-A*02:03, HLA-A*02:04, HLA-A*02:05, HLA-A*02:06, HLA-A*02:07, HLA- A*02: 14, HLA-A*02: 17, HLA-A*68:02, and HLA-A*69:01.

98. The multivalent polypeptide of any one of claims 93-95, wherein the peptide comprises the amino acid sequence of VVVGACGVGK or VVGACGVGK and the MHC is HL A- A* 03:01 or HLA-A* 11 :01.

99. The multivalent polypeptide of any one of claims 93, 96, and 97, wherein the peptide comprises the amino acid sequence of KLVVVGACGV and the MHC is HLA- A*02:01.

100. The multivalent polypeptide of any one of claims 1-99, wherein the first antigenbinding domain is selected from the group consisting of R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, Ri l l, R112, R113, R114, R115, R116, R117, R118, R119, R120, R121, R122, and R123.

101. The multivalent polypeptide of any one of claims 1-100, wherein the first antigenbinding domain binds to the peptide conjugate / MHC complex with a dissociation constant (KD) of at most 20 nM.

102. The multivalent polypeptide of any one of claims 82-101, wherein the first antigenbinding domain binds to the free targeted covalent inhibitor with KD of at least 200 nM.

103. The multivalent polypeptide of any one of claims 1-102, wherein the first antigenbinding domain binds to the peptide conjugate / MHC complex with a KD of at most 20 nM, at most 10 nM, at most 5 nM, at most 1 nM, at most 0.1 nM, at most 0.01 nM, at most 0.001 nM, at most 0.1 pM, or at most 0.01 pM.

104. The multivalent polypeptide of claim 103, wherein the first antigen-binding domain binds to the peptide conjugate / MHC complex with a KD between 0.0001 nM and 10 nM.

105. The multivalent polypeptide of any one of claims 82-104, wherein the first antigenbinding domain binds to the free targeted covalent inhibitor with a dissociation constant (KD) of at least about 10, 100, 10,000, or 100,000 times more than a KD of the first antigen-binding domain binding to the peptide conjugate / MHC complex.

106. The multivalent polypeptide of any one of claims 1-105, wherein the first antigenbinding domain binds to a free peptide conjugate with a dissociation constant (KD) of more than about 100 nM, more than about 200 nM, more than about 300 nM, more than about 400 nM, more than about 500 nM, more than 1 pM, more than 10 pM, more than 20 pM, more than 30 pM, more than 40 pM, more than 50 pM, or more than 100 pM.

107. The multivalent polypeptide of any one of claims 1-105, wherein the first antigenbinding domain binds to a free peptide conjugate with a dissociation constant (KD) that is at least about 10, 100, 10,000, 100,000 times more than a KD of the first antigen-binding domain binding to the peptide conjugate / MHC complex.

108. The multivalent polypeptide of any one of claims 1-107, wherein the first antigenbinding domain binds to the peptide conjugate / MHC complex with a dissociation rate constant (koff) of at most 20.0 hr1.

109. The multivalent polypeptide of any one of claims 1-108, wherein the first antigenbinding domain binds to the peptide conjugate / MHC complex with a dissociation rate constant (koff) of at most 0.05 hr’1.

110. The multivalent polypeptide of any one of claims 1-109, wherein the first antigenbinding domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VL comprises: a light chain complementarity determining region 3 CDR-L3 comprising the amino acid sequence of QQASYVX1X2TIT (SEQ ID NO: 128), wherein Xi is R or W, and X2is H, V, I, or K, and wherein if Xi is R, X2is not K.

111. The multivalent polypeptide of claim 110, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of X1SX2YSIH (SEQ ID NO: 129), wherein Xi is F or I, and X2 is D or S.

112. The multivalent polypeptide of claim 110, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of XiYSIH (SEQ ID NO: 130), wherein Xi is D or S.

113. The multivalent polypeptide of any one of claims 110-112, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSX1X2X3X4VA (SEQ ID NO: 131), wherein Xi is I, L, Y, or V, X2is S, A, Y, T, H, or L, X3is H, S, or R, and X4 is T, A, or L.

114. The multivalent polypeptide of any one of claims 110-113, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of XiASSLYS (SEQ ID NO: 132), wherein Xi is Q, S, or L.

115. The multivalent polypeptide of any one of claims 112-114, wherein the VH comprises:(a) a CDR-H1 comprising the amino acid sequence of DYSIH (SEQ ID NO: 3), or a variant thereof comprising 1-3 amino acid changes;(b) a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), or a variant thereof comprising 1-5 amino acid changes; and / or(c) a CDR-H3 comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6), or a variant thereof comprising 1-3 amino acid changes.

116. The multivalent polypeptide of any one of claims 110-115, wherein the VL comprises:(a) a CDR-L1 comprising the amino acid sequence of RASQSVASTVA (SEQ ID NO: 43), or a variant thereof comprising 1-5 amino acid changes;(b) a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8), or a variant thereof comprising 1-5 amino acid changes; and(c) a CDR-L3 comprising the amino acid sequence of QQASYVX1X2TIT (SEQ ID NO: 128), wherein Xi is R or W, and X2is H, V, I, or K.

117. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

118. The multivalent polypeptide of claim 117, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

119. The multivalent polypeptide of claim 117 or 118, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

120. The multivalent polypeptide of any one of claims 117-119, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRHTIT (SEQ ID NO: 9).

121. The multivalent polypeptide of claim 120, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

122. The multivalent polypeptide of claim 120 or 121, wherein the VL comprises a CDR- L1 comprising the amino acid sequence of RASQSISHTVA.

123. The multivalent polypeptide of any one of claims 117-122, wherein the first antigenbinding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRHTIT (SEQ ID NO: 9), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSISHTVA (SEQ ID NO: 7).

124. The multivalent polypeptide of any one of claims 117-123, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

125. The multivalent polypeptide of any one of claims 120-124, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSISHTVAWYQQKPGKAPKLLIYSASSL YSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRHTITFGQGTKVEI KRTV (SEQ ID NO: 2).

126. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

127. The multivalent polypeptide of claim 126, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

128. The multivalent polypeptide of claim 126 or 127, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

129. The multivalent polypeptide of any one of claims 126-128, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRVTIT (SEQ ID NO: 13).

130. The multivalent polypeptide of claim 129, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12).

131. The multivalent polypeptide of claim 129 or 130, wherein the VL comprises a CDR- L1 comprising the amino acid sequence of RASQSLASTVA (SEQ ID NO: 11).

132. The multivalent polypeptide of any one of claims 126-131, wherein the first antigenbinding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRVTIT (SEQ ID NO: 13), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLASTVA (SEQ ID NO: 11).

133. The multivalent polypeptide of any one of claims 126-132, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

134. The multivalent polypeptide of any one of claims 129-133, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLASTVAWYQQKPGKAPKLLIYQASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRVTITFGQGTKVE IKRTV (SEQ ID NO: 10).

135. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

136. The multivalent polypeptide of claim 135, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

137. The multivalent polypeptide of claim 135 or 136, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

138. The multivalent polypeptide of any one of claims 135-137, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein theVL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRHTIT (SEQ ID NO: 9).

139. The multivalent polypeptide of claim 138, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

140. The multivalent polypeptide of claim 138 or 139, wherein the VL comprises a CDR-LI comprising the amino acid sequence of RASQSIYSTVA (SEQ ID NO: 15).

141. The multivalent polypeptide of any one of claims 135-140, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRHTIT (SEQ ID NO: 9), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSIYSTVA (SEQ ID NO: 15).

142. The multivalent polypeptide of any one of claims 135-141, wherein the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

143. The multivalent polypeptide of any one of claims 138-142, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSIYSTVAWYQQKPGKAPKLLIYSASSL YSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRHTITFGQGTKVEI KRTV (SEQ ID NO: 14).

144. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

145. The multivalent polypeptide of claim 144, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

146. The multivalent polypeptide of claim 144 or 145, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

147. The multivalent polypeptide of any one of claims 144-146, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein theVL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRITIT (SEQ ID NO: 17).

148. The multivalent polypeptide of claim 147, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

149. The multivalent polypeptide of claim 147 or 148, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLASTVA (SEQ ID NO: 11).

150. The multivalent polypeptide of any one of claims 144-149, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVRITIT (SEQ ID NO: 17), a CDR-L2 sequence of SAS SLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLASTVA (SEQ ID NO: 11).

151. The multivalent polypeptide of any one of claims 144-150, wherein the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

152. The multivalent polypeptide of any one of claims 147-151, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLASTVAWYQQKPGKAPKLLIYSASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRITITFGQGTKVEI KRTV (SEQ ID NO: 16).

153. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

154. The multivalent polypeptide of claim 153, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

155. The multivalent polypeptide of claim 153 or 154, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

156. The multivalent polypeptide of any one of claims 153-155, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRITIT (SEQ ID NO: 17).

157. The multivalent polypeptide of claim 156, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

158. The multivalent polypeptide of claim 156 or 157, wherein the VL comprises a CDR- L1 comprising the amino acid sequence of RASQSLSSTVA (SEQ ID NO: 19).

159. The multivalent polypeptide of any one of claims 153-158, wherein the first antigenbinding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRITIT (SEQ ID NO: 17), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLSSTVA (SEQ ID NO: 19).

160. The multivalent polypeptide of any one of claims 153-159, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

161. The multivalent polypeptide of any one of claims 156-160, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLSSTVAWYQQKPGKAPKLLIYSASSL YSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRITITFGQGTKVEIK RTV (SEQ ID NO: 18).

162. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

163. The multivalent polypeptide of claim 163, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

164. The multivalent polypeptide of claim 163 or 164, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

165. The multivalent polypeptide of any one of claims 163-165, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein theVL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRVTIT (SEQ ID NO: 13).

166. The multivalent polypeptide of claim 165, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

167. The multivalent polypeptide of claim 165 or 166, wherein the VL comprises a CDR-LI comprising the amino acid sequence of RASQSLSSTVA (SEQ ID NO: 19).

168. The multivalent polypeptide of any one of claims 163-167, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRVTIT (SEQ ID NO: 13), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLSSTVA (SEQ ID NO: 19).

169. The multivalent polypeptide of any one of claims 163-168, wherein the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

170. The multivalent polypeptide of any one of claims 165-169, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLSSTVAWYQQKPGKAPKLLIYSASSL YSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRVTITFGQGTKVEI KRTV (SEQ ID NO: 20).

171. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

172. The multivalent polypeptide of claim 171, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

173. The multivalent polypeptide of claim 171 or 172, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

174. The multivalent polypeptide of any one of claims 171-173, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRVTIT (SEQ ID NO: 13).

175. The multivalent polypeptide of claim 174, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

176. The multivalent polypeptide of claim 174 or 175, wherein the VL comprises a CDR- L1 comprising the amino acid sequence of RASQSISSTVA (SEQ ID NO: 22).

177. The multivalent polypeptide of any one of claims 171-176, wherein the first antigenbinding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVRVTIT (SEQ ID NO: 13), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSISSTVA (SEQ ID NO: 22).

178. The multivalent polypeptide of any one of claims 171-177, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

179. The multivalent polypeptide of any one of claims 174-178, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSTVAWYQQKPGKAPKLLIYSASSL YSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRVTITFGQGTKVEI KRTV (SEQ ID NO: 21).

180. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

181. The multivalent polypeptide of claim 180, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

182. The multivalent polypeptide of claim 180 or 181, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

183. The multivalent polypeptide of any one of claims 180-182, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein theVL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWHTIT (SEQ ID NO: 26).

184. The multivalent polypeptide of claim 183, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of LASSLYS (SEQ ID NO: 25).

185. The multivalent polypeptide of claim 183 or 184, wherein the VL comprises a CDR-LI comprising the amino acid sequence of RASQSYTSAVA (SEQ ID NO: 24).

186. The multivalent polypeptide of any one of claims 180-185, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWHTIT (SEQ ID NO: 26), a CDR-L2 sequence of LASSLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSYTSAVA (SEQ ID NO: 24).

187. The multivalent polypeptide of any one of claims 180-186, wherein the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

188. The multivalent polypeptide of any one of claims 183-187, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSYTSAVAWYQQKPGKAPKLLIYLASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWHTITFGQGTKVE IKRTV (SEQ ID NO: 23).

189. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

190. The multivalent polypeptide of claim 189, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

191. The multivalent polypeptide of claim 189 or 190, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30).

192. The multivalent polypeptide of any one of claims 189-191, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein theVL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVRHTIT (SEQ ID NO: 9).

193. The multivalent polypeptide of claim 192, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12).

194. The multivalent polypeptide of claim 192 or 193, wherein the VL comprises a CDR-LI comprising the amino acid sequence of RASQSLAHTVA (SEQ ID NO: 31).

195. The multivalent polypeptide of any one of claims 189-194, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQASYVRHTIT (SEQ ID NO: 9), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLAHTVA (SEQ ID NO: 31).

196. The multivalent polypeptide of any one of claims 189-195, wherein the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 27).

197. The multivalent polypeptide of any one of claims 192-196, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLAHTVAWYQQKPGKAPKLLIYQASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRHTITFGQGTKVE IKRTV (SEQ ID NO: 28).

198. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

199. The multivalent polypeptide of claim 198, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

200. The multivalent polypeptide of claim 198 or 199, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30).

201. The multivalent polypeptide of any one of claims 198-200, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein theVL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34).

202. The multivalent polypeptide of claim 201, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12).

203. The multivalent polypeptide of claim 201 or 202, wherein the VL comprises a CDR-LI comprising the amino acid sequence of RASQSYHHTVA (SEQ ID NO: 33).

204. The multivalent polypeptide of any one of claims 198-203, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSYHHTVA (SEQ ID NO: 33).

205. The multivalent polypeptide of any one of claims 198-204, wherein the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 27).

206. The multivalent polypeptide of any one of claims 201-205, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSYHHTVAWYQQKPGKAPKLLIYQASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 32).

207. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

208. The multivalent polypeptide of claim 207, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

209. The multivalent polypeptide of claim 207 or 208, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

210. The multivalent polypeptide of any one of claims 207-209, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein theVL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34).

211. The multivalent polypeptide of claim 210, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of LASSLYS (SEQ ID NO: 25).

212. The multivalent polypeptide of claim 210 or 211, wherein the VL comprises a CDR-LI comprising the amino acid sequence of RASQSLHRLVA (SEQ ID NO: 37).

213. The multivalent polypeptide of any one of claims 207-212, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of LAS SLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSLHRLVA (SEQ ID NO: 37).

214. The multivalent polypeptide of any one of claims 207-213, wherein the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTMVTVSS (SEQ ID NO: 35).

215. The multivalent polypeptide of any one of claims 210-214, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLHRLVAWYQQKPGKAPKLLIYLASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 36).

216. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

217. The multivalent polypeptide of claim 216, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

218. The multivalent polypeptide of claim 216 or 217, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30).

219. The multivalent polypeptide of any one of claims 216-218, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein theVL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34).

220. The multivalent polypeptide of claim 219, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of LASSLYS (SEQ ID NO: 25).

221. The multivalent polypeptide of claim 219 or 220, wherein the VL comprises a CDR-LI comprising the amino acid sequence of RASQSYTSTVA (SEQ ID NO: 39).

222. The multivalent polypeptide of any one of claims 216-221, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of LAS SLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSYTSTVA (SEQ ID NO: 39).

223. The multivalent polypeptide of any one of claims 216-222, wherein the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 27).

224. The multivalent polypeptide of any one of claims 219-223, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSYTSTVAWYQQKPGKAPKLLIYLASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 38).

225. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

226. The multivalent polypeptide of claim 225, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

227. The multivalent polypeptide of claim 225 or 226, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

228. The multivalent polypeptide of any one of claims 225-227, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein theVL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34).

229. The multivalent polypeptide of claim 228, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of LASSLYS (SEQ ID NO: 25).

230. The multivalent polypeptide of claim 228 or 229, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLLRTVA (SEQ ID NO: 41).

231. The multivalent polypeptide of any one of claims 225-230, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of LAS SLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSLLRTVA (SEQ ID NO: 41).

232. The multivalent polypeptide of any one of claims 225-231, wherein the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

233. The multivalent polypeptide of any one of claims 228-232, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSSSVGDRVTITCRASQSLLRTVAWYQQKPGKAPKLLIYLASSL YSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEI KRTV (SEQ ID NO: 40).

234. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

235. The multivalent polypeptide of claim 234, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

236. The multivalent polypeptide of claim 234 or 235, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

237. The multivalent polypeptide of any one of claims 234-236, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein theVL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34).

238. The multivalent polypeptide of claim 237, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

239. The multivalent polypeptide of claim 237 or 238, wherein the VL comprises a CDR-LI comprising the amino acid sequence of RASQSVASTVA (SEQ ID NO: 43).

240. The multivalent polypeptide of any one of claims 234-239, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SAS SLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSVASTVA (SEQ ID NO: 43).

241. The multivalent polypeptide of any one of claims 234-240, wherein the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

242. The multivalent polypeptide of any one of claims 237-241, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSVASTVAWYQQKPGKAPKLLIYSASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 42).

243. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

244. The multivalent polypeptide of claim 243, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

245. The multivalent polypeptide of claim 243 or 244, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

246. The multivalent polypeptide of any one of claims 243-245, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein theVL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34).

247. The multivalent polypeptide of claim 246, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

248. The multivalent polypeptide of claim 246 or 247, wherein the VL comprises a CDR-LI comprising the amino acid sequence of RASQSVYRTVA (SEQ ID NO: 45).

249. The multivalent polypeptide of any one of claims 243-248, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SAS SLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSVYRTVA (SEQ ID NO: 45).

250. The multivalent polypeptide of any one of claims 243-249, wherein the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

251. The multivalent polypeptide of any one of claims 246-250, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSVYRTVAWYQQKPGKAPKLLIYSASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 44).

252. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

253. The multivalent polypeptide of claim 252, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

254. The multivalent polypeptide of claim 252 or 253, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

255. The multivalent polypeptide of any one of claims 252-254, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein theVL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34).

256. The multivalent polypeptide of claim 255, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12).

257. The multivalent polypeptide of claim 255 or 256, wherein the VL comprises a CDR-LI comprising the amino acid sequence of RASQSLHRTVA (SEQ ID NO: 47).

258. The multivalent polypeptide of any one of claims 252-257, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of Q AS SLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLHRTVA (SEQ ID NO: 47).

259. The multivalent polypeptide of any one of claims 252-258, wherein the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

260. The multivalent polypeptide of any one of claims 255-259, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLHRTVAWYQQKPGKAPKLLIYQASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 46).

261. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

262. The multivalent polypeptide of claim 261, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

263. The multivalent polypeptide of claim 261 or 262, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

264. The multivalent polypeptide of any one of claims 261-263, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein theVL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34).

265. The multivalent polypeptide of claim 264, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12).

266. The multivalent polypeptide of claim 264 or 265, wherein the VL comprises a CDR-LI comprising the amino acid sequence of RASQSLSHTVA (SEQ ID NO: 49).

267. The multivalent polypeptide of any one of claims 261-266, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of Q AS SLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLSHTVA (SEQ ID NO: 49).

268. The multivalent polypeptide of any one of claims 261-267, wherein the VH comprises a sequence with at least 80% sequence identity to the sequenceEVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

269. The multivalent polypeptide of any one of claims 264-268, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLSHTVAWYQQKPGKAPKLLIYQASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 48).

270. The multivalent polypeptide of any one of claims 264-269, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLSHTVAWYQQKPGKAPKLLIYQASSLYSGVPSRFSGSRSGTDFTLTISNLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 50).

271. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

272. The multivalent polypeptide of claim 271, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

273. The multivalent polypeptide of claim 271 or 272, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

274. The multivalent polypeptide of any one of claims 271-273, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34).

275. The multivalent polypeptide of claim 274, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12).

276. The multivalent polypeptide of claim 274 or 275, wherein the VL comprises a CDR- L1 comprising the amino acid sequence of RASQSLASTVA (SEQ ID NO: 11).

277. The multivalent polypeptide of any one of claims 271-276, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of Q AS SLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLASTVA (SEQ ID NO: 11).

278. The multivalent polypeptide of any one of claims 271-277, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

279. The multivalent polypeptide of any one of claims 274-278, wherein the VL comprises a sequence with at least 80% sequence identity to the sequenceDIQMTQSPSSLSASVGDRVTITCRASQSLASTVAWYQQKPGKAPKLLIYQASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 51).

280. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

281. The multivalent polypeptide of claim 280, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

282. The multivalent polypeptide of claim 280 or 281, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

283. The multivalent polypeptide of any one of claims 280-282, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34).

284. The multivalent polypeptide of claim 283, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12).

285. The multivalent polypeptide of claim 283 or 284, wherein the VL comprises a CDR- L1 comprising the amino acid sequence of RASQSLAHTVA (SEQ ID NO: 31).

286. The multivalent polypeptide of any one of claims 280-285, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of Q AS SLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLAHTVA (SEQ ID NO: 31).

287. The multivalent polypeptide of any one of claims 280-286, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

288. The multivalent polypeptide of any one of claims 283-287, wherein the VL comprises a sequence with at least 80% sequence identity to the sequenceDIQMTQSPSSLSASVGDRVTITCRASQSLAHTVAWYQQKPGKAPKLLIYQASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 52).

289. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

290. The multivalent polypeptide of claim 289, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

291. The multivalent polypeptide of claim 289 or 290, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

292. The multivalent polypeptide of any one of claims 289-291, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34).

293. The multivalent polypeptide of claim 292, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

294. The multivalent polypeptide of claim 292 or 293, wherein the VL comprises a CDR- L1 comprising the amino acid sequence of RASQSLHSTVA (SEQ ID NO: 54).

295. The multivalent polypeptide of any one of claims 289-294, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SAS SLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLHSTVA (SEQ ID NO: 54).

296. The multivalent polypeptide of any one of claims 289-295, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

297. The multivalent polypeptide of any one of claims 292-296, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLHSTVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 53).

298. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

299. The multivalent polypeptide of claim 298, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

300. The multivalent polypeptide of claim 298 or 299, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30).

301. The multivalent polypeptide of any one of claims 298-300, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34).

302. The multivalent polypeptide of claim 301, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

303. The multivalent polypeptide of claim 301 or 302, wherein the VL comprises a CDR- L1 comprising the amino acid sequence of RASQSLHSTVA (SEQ ID NO: 54).

304. The multivalent polypeptide of any one of claims 298-303, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SAS SLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLHSTVA (SEQ ID NO: 54).

305. The multivalent polypeptide of any one of claims 298-304, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 27).

306. The multivalent polypeptide of any one of claims 301-305, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLHSTVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEIKRTV (SEQ ID NO: 55).

307. The multivalent polypeptide of any one of claims 110-116, wherein the first antigenbinding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

308. The multivalent polypeptide of claim 307, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

309. The multivalent polypeptide of claim 307 or 308, wherein the VH comprises a CDR- H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30).

310. The multivalent polypeptide of any one of claims 307-309, wherein the first antigenbinding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQASYVWKTIT (SEQ ID NO: 34).

311. The multivalent polypeptide of claim 310, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

312. The multivalent polypeptide of claim 310 or 311, wherein the VL comprises a CDR- L1 comprising the amino acid sequence of RASQSVYSTVA (SEQ ID NO: 57).

313. The multivalent polypeptide of any one of claims 307-312, wherein the first antigen- binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQASYVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SAS SLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSVYSTVA (SEQ ID NO: 57).

314. The multivalent polypeptide of any one of claims 307-313, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISSSSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 27).

315. The multivalent polypeptide of any one of claims 310-314, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSVYSTVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 56).

316. The multivalent polypeptide of any one of claims 1-109, wherein the first antigenbinding domain comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a CDR-H1 comprising SYSIH (SEQ ID NO: 29); a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5); and a CDR-H3 comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

317. The multivalent polypeptide of claim 316, wherein the VL comprises: a CDR-L3 sequence of QQAS YVRHTIT (SEQ ID NO: 9), a CDR-L2 sequence of Q AS SLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLAHTVA (SEQ ID NO: 31).

318. The multivalent polypeptide of claim 316, wherein the VL comprises: a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of Q AS SLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSYHHTVA (SEQ ID NO: 33).

319. The multivalent polypeptide of claim 316, wherein the VL comprises: a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of LAS SLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSYTSTVA (SEQ ID NO: 39).

320. The multivalent polypeptide of claim 316, wherein the VL comprises: a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SAS SLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLHSTVA (SEQ ID NO: 54).

321. The multivalent polypeptide of claim 316, wherein the VL comprises: a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SAS SLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSVYSTVA (SEQ ID NO: 57).

322. A complex comprising the multivalent polypeptide of any one of claims 1-321 and the peptide conjugate / MHC complex.

323. A polynucleotide encoding the multivalent polypeptide of any one of claims 1-321.

324. A polynucleotide encoding the heavy chain variable region (VH) and the light chain variable region (VL) of the multivalent polypeptide of any one of claims 1-321.

325. A vector comprising the polynucleotide of claim 323 or 324.

326. The vector of claim 325, wherein the vector is a viral vector.

327. The vector of claim 326, wherein the viral vector is an adenoviral vector, lentiviral vector, retroviral vector, or adeno-associated viral vector.

328. A cell comprising:(a) the polynucleotide of claim 323 or 324;(b) the vector of any one of claims 325-327;(c) a first polynucleotide encoding a VH or heavy chain of the multivalent polypeptide of any one of claims 1-321, and a second polynucleotide encoding a VL or light chain of the multivalent polypeptide of any one of claims 1-321; or(d) a first vector comprising a first polynucleotide encoding a VH or heavy chain of the multivalent polypeptide of any one of claims 1-321, and a second vector comprising a second polynucleotide encoding a VL or light chain of the multivalent polypeptide of any one of claims 1-321.

329. A pharmaceutical composition comprising the multivalent polypeptide of any one of claims 1-321, the polynucleotide of claim 323 or 324, the vector of any one of claims 325-327, or the host cell of claim 328, and a pharmaceutically acceptable carrier, diluent, or excipient.

330. A method of producing a multivalent polypeptide, the method comprising culturing the host cell of claim 328 under suitable conditions to express the polynucleotide or the first polynucleotide and the second polynucleotide and to produce the multivalent polypeptide.

331. A method of activating an immune cell, the method comprising contacting the immune cell with the multivalent polypeptide of any one of claims 1-321.

332. The method of claim 331, wherein the immune cell is a T cell.

333. The method of claim 332, wherein subsequent to the contacting, the T cell increases expression of at least one activation marker.

334. The method of claim 333, wherein the at least one activation marker is CD26, CD27, CD28, CD30, CD154, CD40L, CD134. CD25, CD44, CD69, CD137, PD-1, KLRG1, CCR7, CD45RA, HLA-DR, NKG2D, or any combination thereof.

335. The method of any one of claims 331-334, wherein subsequent to the contacting, the T cell increases expression of PD-1.

336. The method of any one of claims 331-335, wherein subsequent to the contacting, the T cell increases expression of inducible costimulator (ICOS).

337. The method of any one of claims 331-336, wherein the contacting increases expression of at least one cytokine or proliferation molecule.

338. The method of claim 337, wherein the at least one cytokine or proliferation molecule is IFNy, TNFa, Granzyme A, Granzyme B, IL-6, perforin, IL-2, granulysin, or any combination thereof.

339. A method of killing a cancer cell in a subject in need thereof, the method comprising administering to the subject:(a) a targeted covalent inhibitor, and(b) the multivalent polypeptide of any one of claims 1-321, the polynucleotide of claim 323 or 324, the vector of any one of claims 325-327, the cell of claim 328, or the pharmaceutical composition of claim 329.

340. The method of claim 339, wherein (a) is administered prior to or concurrently with (b).

341. A method of targeting a cell that expresses KRASG12Cin a subject in need thereof, the method comprising administering to the subject the multivalent polypeptide of any one of claims 1-321, the polynucleotide of claim 323 or 324, the vector of any one of claims 325-327, the cell of claim 328, or the pharmaceutical composition of claim 329, and wherein the subject has been treated with a KRASG12Ctargeted covalent inhibitor.

342. The method of claim 340, wherein the subject has cancer.

343. The method of claim 340 or 342, wherein the subject is refractory to a treatment with the KRASG12Ctargeted covalent inhibitor.

344. The method of any one of claims 340-343, wherein the KRASG12Ctargeted covalent inhibitor is sotorasib.

345. A composition for use in the manufacture of a medicament for treating a subject in need thereof, comprising the multivalent polypeptide of any one of claims 1-321, the polynucleotide of claim 323 or 324, the vector of any one of claims 325-327, or the cell of claim 328.

346. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject the multivalent polypeptide of any one of claims 1-321 or the pharmaceutical composition of claim 329.

347. The method of claim 346, wherein the cancer is renal cell carcinoma, breast cancer, prostate cancer, pancreatic cancer, lung cancer, liver cancer, ovarian cancer, cervical cancer, colon cancer, esophageal cancer, glioma, glioblastoma, brain cancer, stomachcancer, bladder cancer, testicular cancer, thyroid cancer, adrenal cancer, head and neck cancer, melanoma, skin cancer, sarcoma, fibrosarcoma, angiosarcoma, osteosarcoma, rhabdomyosarcoma, leukemia, lymphoma, myeloma, endometrial cancer, or a neuroendocrine tumor.

348. The method of claim 346 or 347, wherein the method further comprises administering simultaneously a small molecule drug.

349. The method of any one of claims 346-348, wherein the subject has previously been treated with a KRASG12Ctargeted covalent inhibitor, a KRASG12Cnon-covalent inhibitor, and / or a pan-KRAS inhibitor.

350. The method of claim 349, wherein the subject is refractory to a treatment with the KRASG12Ctargeted covalent inhibitor, a KRASG12Cnon-covalent inhibitor, and / or a pan-KRAS inhibitor.

351. The method of claim 349 or 350, wherein the KRASG12Ctargeted covalent inhibitor is sotorasib.

352. The method of claim 349 or 350, wherein the pan-KRAS inhibitor is RMC-6236.

353. The multivalent polypeptide of any one of claims 1-321 or the polypeptide of any one of claims 371-582, wherein the peptide conjugate / MHC complex is a first peptide conjugate / MHC complex and the multivalent polypeptide binds to the first peptide conjugate / MHC complex and a second peptide conjugate / MHC complex different from the first peptide conjugate / MHC complex, wherein each of the first and second peptide conjugate / MHC complexes independently comprises:(a) a different peptide selected from the group consisting of peptides comprising the formulaX#X#+i X#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9, and X#X#+iX#+2X#+3(X#+4)X#+5X#+6X#+7X#+8X#+9, and X#X#+iX#+2(X#+3)X#+4X#+5X#+6X#+7X#+8X#+9, and X#X#+i (X#+2)X#+3X#+4X#+5X#+6X#+7X#+8X#+9, and X#+i X#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9, and X#.1 X#X#+ 1 X#+2X#+3X#+4(X#+5 )X#+6X#+7X#+8X#+9 , wherein the peptide conjugate of the first and second peptide conjugate / MHC complex is formed by the covalent reaction of a targeted covalent inhibitor or fragment thereof with the residue in parenthesis; and(b) the same MHC;wherein the multivalent polypeptide binds to the first peptide conjugate / MHC complex with a KD that is at most 100 nM and binds to the second peptide conjugate / MHC complex with a KD that is at most 100 nM, or wherein when the multivalent polypeptide is contacted to the first peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to a biolayer interferometry analysis and wherein when the multivalent polypeptide is contacted to the second peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to the biolayer interferometry analysis, or wherein when the multivalent polypeptide is contacted to the first peptide conjugate / MHC complex a maximum binding signal of at least 0.1 -fold of a reference binding signal is observed according to a biolayer interferometry analysis and wherein when the multivalent polypeptide is contacted to the second peptide conjugate / MHC complex a maximum binding signal of at least 0.1 -fold of a reference binding signal is observed according to the biolayer interferometry analysis, and wherein the reference binding signal is the maximum binding signal of the multivalent polypeptide binding to X#X#+iX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9.

354. The multivalent polypeptide or polypeptide of claim 353, wherein the formula X#X#+iX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9 is the formula X7X8X9X10X11X12X13X14X15X16, and wherein X12 is covalently linked to the targeted covalent inhibitor or fragment thereof.

355. The multivalent polypeptide of any one of claims 1-321 or the polypeptide of any one of claims 380-622, wherein the peptide conjugate / MHC complex is a first peptide conjugate / MHC complex and the multivalent polypeptide binds to the first peptide conjugate / MHC complex and a second peptide conjugate / MHC complex, wherein each of the first and the second peptide conjugate / MHC complex comprises:(a) a peptide comprising the formula X7X8X9X10X11X12X13X14X15X16; and(b) the same MHC; wherein a first peptide conjugate of the first peptide conjugate / MHC complex is formed by the covalent reaction of a targeted covalent inhibitor or fragment thereof with X12 of the peptide, and wherein a second peptide conjugate of the second peptide conjugate / MHC complex is formed by the covalent reaction of the same targeted covalent inhibitor or fragment thereof with X13 of the peptide; andwherein the multivalent polypeptide binds to the second peptide conjugate / MHC complex with a KD that is at most 100,000-fold higher than the KD of the polypeptide to the first peptide conjugate / MHC complex, or wherein a maximum wavelength shift of the multivalent polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum wavelength shift of the multivalent polypeptide binding to the first peptide conjugate / MHC complex, or wherein a maximum binding signal of the multivalent polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum binding signal of the multivalent polypeptide binding to the first peptide conjugate / MHC complex.

356. The multivalent polypeptide of any one of claims 1-321 or the polypeptide of any one of claims 380-622, wherein the peptide conjugate / MHC complex is a first peptide conjugate / MHC complex and the multivalent polypeptide binds to the first peptide conjugate / MHC complex and a second peptide conjugate / MHC complex, wherein each of the first and the second peptide conjugate / MHC complex comprises:(a) a peptide comprising the formula X7X8X9X10X11X12X13X14X15X16; and(b) the same MHC; wherein a first peptide conjugate of the first peptide conjugate / MHC complex is formed by the covalent reaction of a targeted covalent inhibitor or fragment thereof with a residue selected from the group consisting of X9, X10, Xu, and X12, and wherein a second peptide conjugate of the second peptide conjugate / MHC complex is formed by the covalent reaction of the same targeted covalent inhibitor or fragment thereof with a residue selected from the group consisting of X13, X14, and X15; wherein the multivalent polypeptide binds to the second peptide conjugate / MHC complex with a KD that is at most 100,000-fold higher that the KD of the polypeptide to the first peptide conjugate / MHC complex, or wherein a maximum wavelength shift of the multivalent polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum wavelength shift of the multivalent polypeptide binding to the first peptide conjugate / MHC complex, or wherein a maximum binding signal of the multivalent polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximumbinding signal of the multivalent polypeptide binding to the first peptide conjugate / MHC complex.

357. The multivalent polypeptide of any one of claims 1-321 or the polypeptide of any one of claims 380-622, wherein the peptide conjugate / MHC complex is a first peptide conjugate / MHC complex and the multivalent polypeptide binds to the first peptide conjugate / MHC complex and a second peptide conjugate / MHC complex, wherein each of the first and the second peptide conjugate / MHC complex comprises: a peptide comprising the formula A-B-C, where A comprises no more than three residues having an N-terminal anchor residue, B comprises at least four but no more than seven residues having a residue covalently linked to a targeted covalent inhibitor or fragment thereof, and C comprises no more than three residues having a C-terminal anchor residue, wherein the N-terminal anchor residues and the C-terminal anchor residue bind to an MHC; and the same MHC; wherein the residue covalently linked to a targeted covalent inhibitor or fragment thereof of the peptide of the first peptide conjugate / MHC complex is different from the residue covalently linked to a targeted covalent inhibitor or fragment thereof of the peptide of the second peptide conjugate / MHC complex; and wherein the multivalent polypeptide binds to the first peptide conjugate / MHC complex with a KD that is at most 100 nM and binds to the second peptide conjugate / MHC complex with a KD that is at most 100 nM, or wherein when the multivalent polypeptide is contacted to the first peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to a biolayer interferometry analysis and wherein when the multivalent polypeptide is contacted to the second peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to the biolayer interferometry analysis, or wherein when the multivalent polypeptide is contacted to the first peptide conjugate / MHC complex a maximum binding signal of at least 0.1 -fold of a reference binding signal is observed according to a biolayer interferometry analysis and wherein when the multivalent polypeptide is contacted to the second peptide conjugate / MHC complex a maximum binding signal of at least 0.1-fold of a reference binding signal is observed according to the biolayer interferometry analysis, and wherein the referencebinding signal is the maximum binding signal of the multivalent polypeptide binding tO X#X#+lX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9.

358. The multivalent polypeptide or polypeptide of claim 357, wherein A comprises two residues X?Xs.

359. The multivalent polypeptide or polypeptide of claim 357 or 358, wherein B comprises seven residues X9X10X11X12X13X14X15.

360. The multivalent polypeptide or polypeptide of any one of claims 357-359, wherein C comprises one residue Xi6.

361. The multivalent polypeptide or polypeptide of any one of claims 357-360, wherein the formula A-B-C is the formula X7X8X9X10X11X12X13X14X15X16.

362. The multivalent polypeptide or polypeptide of claim 361, wherein a first peptide conjugate of the first peptide conjugate / MHC complex is formed by the covalent reaction of the targeted covalent inhibitor or fragment thereof with X12 of the peptide.

363. The multivalent polypeptide or polypeptide of claim 361 or 362, wherein a second peptide conjugate of the second peptide conjugate / MHC complex is formed by the covalent reaction of the same targeted covalent inhibitor or fragment thereof with X13 of the peptide.

364. The multivalent polypeptide or polypeptide of claim 363, wherein the multivalent polypeptide binds to the second peptide conjugate / MHC complex with a KD that is at most 100,000-fold higher than the KD of the multivalent polypeptide to the first peptide conjugate / MHC complex.

365. The multivalent polypeptide or polypeptide of any one of claims 359-364, wherein the polypeptide binds to the second peptide conjugate / MHC complex with an KD that is at most 100,000-fold higher than the KD of the polypeptide to the first peptide conjugate / MHC complex, and wherein the residue covalently linked to a targeted covalent inhibitor or fragment thereof of the peptide of the first peptide conjugate / MHC complex is selected from the group of consisting of X9, X10, Xu, and X12, and the residue covalently linked to a targeted covalent inhibitor or fragment thereof of the peptide of the second peptide conjugate / MHC complex is X13, X14, and X15.

366. The multivalent polypeptide or polypeptide of any one of claims 353-365, wherein the peptide is a RAS peptide.

367. The multivalent polypeptide or polypeptide of claim 366, wherein the RAS peptide comprises a mutation.

368. The multivalent polypeptide or polypeptide of claim 367, wherein the mutation is G12C or G13C.

369. The multivalent polypeptide or polypeptide of any one of claims 366-368, wherein the RAS peptide comprises a sequence selected from the group consisting of VVVGACGVGK, VVGACGVGK, and KLVVVGACGV.

370. The multivalent polypeptide or polypeptide of any one of claims 366-368, wherein the RAS peptide comprises a sequence selected from the group consisting of VVVGAGCVGK, VVGAGCVGK, or KLVVVGAGCV371. The multivalent polypeptide or polypeptide of any one of claims 353-370, wherein the same MHC is selected from the group consisting of HLA- A* 03:01, HLA-A*11 :01, HLA-A*02:01, HLA-A*68:01, HLA-A*31:01, HLA-A*30:01, HLA-A*33:03, HLA- A*33:01, HLA-A*74:01, HLA-A*34:02, HLA-A*66:01, HLA-A*68:02, HLA- A*02:05, HLA-A*02:02, HLA-A*02:06.

372. The multivalent polypeptide or polypeptide of any one of claims 353-370, wherein the MHC is encoded by an HLA allele of HLA-A3 supertype.

373. The multivalent polypeptide or polypeptide of claim 372, wherein the HLA allele of the HLA-A3 supertype is selected from the group consisting of HLA- A* 03 :01, HLA- A*l l:01, HLA-A*68:01, HLA-A*31:01, HLA-A*30:01, HLA-A*74:01, HLA- A*34:02, and HLA-A*66:01.

374. The multivalent polypeptide or polypeptide of any one of claims 353-370, wherein the MHC is encoded by an HLA allele of HLA-A2 supertype.

375. The multivalent polypeptide or polypeptide of claim 374, wherein the HLA allele of the HLA-A2 supertype is selected from the group consisting of HLA- A* 02:01, HLA- A*02:02, HLA-A*02:03, HLA-A*02:04, HLA-A*02:05, HLA-A*02:06, HLA- A*02:07, HLA-A*02: 14, HLA-A*02: 17, HLA-A*68:02, and HLA-A*69:01.

376. The multivalent polypeptide or polypeptide of any one of claims 353-375, wherein the targeted covalent inhibitor or fragment thereof comprises sotorasib.

377. The multivalent polypeptide or polypeptide of any one of claims 354-356 and 361- 376, wherein the peptide is a RAS peptide, and wherein X12 is G12C mutation, and X13 is G13C mutation.

378. The multivalent polypeptide or polypeptide of claim 377, wherein the multivalent polypeptide binds to the first peptide conjugate / MHC complex having a Cys of the G12C mutation covalently linked to the targeted covalent inhibitor or fragment thereof with a KD that is at most 100 nM and binds to the second peptideconjugate / MHC complex having a Cys of the G13C mutation covalently linked to the targeted covalent inhibitor or fragment thereof with a KD that is most 100 nM, or wherein when the multivalent polypeptide is contacted to the first peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to a biolayer interferometry analysis and wherein when the multivalent polypeptide is contacted to the second peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to the biolayer interferometry analysis, or wherein when the multivalent polypeptide is contacted to the first peptide conjugate / MHC complex a maximum binding signal of at least 0.1 -fold of a reference binding signal is observed according to a biolayer interferometry analysis and wherein when the multivalent polypeptide is contacted to the second peptide conjugate / MHC complex a maximum binding signal of at least 0.1-fold of a reference binding signal is observed according to the biolayer interferometry analysis, and wherein the reference binding signal is the maximum binding signal of the multivalent polypeptide binding tO X#X#+lX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9.

379. The multivalent polypeptide or polypeptide of claim 377, wherein the polypeptide binds to the second peptide conjugate / MHC complex having a Cys of the G13C mutation covalently linked to the targeted covalent inhibitor or fragment thereof with a KD that is at most 100,000-fold higher that the KD of the polypeptide to the first peptide conjugate / MHC complex having a Cys of the G12C mutation covalently linked to the targeted covalent inhibitor or fragment thereof, or wherein a maximum wavelength shift of the multivalent polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum wavelength shift of the multivalent polypeptide binding to the first peptide conjugate / MHC complex, or wherein a maximum binding signal of the multivalent polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum binding signal of the multivalent polypeptide binding to the first peptide conjugate / MHC complex.

380. A polypeptide comprising an antigen-binding domain comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VL comprises: a light chain complementarity determining region 3 CDR-L3 comprisingthe amino acid sequence of QQASYVX1X2TIT (SEQ ID NO: 128), wherein Xi is R or W, and X2 is H, V, I, or K, and wherein if Xi is R, X2 is not K.

381. The polypeptide of claim 380, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of X1SX2YSIH (SEQ ID NO: 129), wherein Xi is F or I, and X2 is D or S.

382. The polypeptide of claim 380, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of XiYSIH (SEQ ID NO: 130), wherein Xi is D or S.

383. The polypeptide of any one of claims 380-382, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSX1X2X3X4VA (SEQ ID NO: 131), wherein Xi is I, L, Y, or V, X2 is S, A, Y, T, H, or L, X3 is H, S, or R, and X4 is T, A, or L.

384. The polypeptide of any one of claims 380-383, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of XiASSLYS (SEQ ID NO: 132), wherein Xi is Q, S, or L.

385. The polypeptide of any one of claims 382-384, wherein the VH comprises:(a) a CDR-H1 comprising the amino acid sequence of DYSIH (SEQ ID NO: 3), or a variant thereof comprising 1-3 amino acid changes;(b) a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), or a variant thereof comprising 1-5 amino acid changes; and / or(c) a CDR-H3 comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6), or a variant thereof comprising 1-3 amino acid changes.

386. The polypeptide of any one of claims 380-385, wherein the VL comprises:(a) a CDR-L1 comprising the amino acid sequence of RASQSVASTVA (SEQ ID NO: 43), or a variant thereof comprising 1-5 amino acid changes;(b) a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8), or a variant thereof comprising 1-5 amino acid changes; and(c) a CDR-L3 comprising the amino acid sequence of QQASYVX1X2TIT (SEQ ID NO: 128), wherein Xi is R or W, and X2 is H, V, I, or K.

387. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

388. The polypeptide of claim 387, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

389. The polypeptide of claim 387 or 388, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

390. The polypeptide of any one of claims 387-389, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVRHTIT (SEQ ID NO: 9).

391. The polypeptide of claim 390, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

392. The polypeptide of claim 390 or 391, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSISHTVA.

393. The polypeptide of any one of claims 387-392, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVRHTIT (SEQ ID NO: 9), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSISHTVA (SEQ ID NO: 7).

394. The polypeptide of any one of claims 387-393, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

395. The polypeptide of any one of claims 390-394, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSISHTVAWYQQKPGKAPKLLIYSASSL YSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRHTITFGQGTKVEI KRTV (SEQ ID NO: 2).

396. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

397. The polypeptide of claim 396, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

398. The polypeptide of claim 396 or 397, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

399. The polypeptide of any one of claims 396-398, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVRVTIT (SEQ ID NO: 13).

400. The polypeptide of claim 399, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12).

401. The polypeptide of claim 399 or 400, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLASTVA (SEQ ID NO: 11).

402. The polypeptide of any one of claims 396-401, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVRVTIT (SEQ ID NO: 13), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLASTVA (SEQ ID NO: 11).

403. The polypeptide of any one of claims 396-402, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

404. The polypeptide of any one of claims 399-403, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLASTVAWYQQKPGKAPKLLIYQASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRVTITFGQGTKVE IKRTV (SEQ ID NO: 10).

405. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

406. The polypeptide of claim 405, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

407. The polypeptide of claim 405 or 406, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

408. The polypeptide of any one of claims 405-407, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVRHTIT (SEQ ID NO: 9).

409. The polypeptide of claim 408, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

410. The polypeptide of claim 408 or 409, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSIYSTVA (SEQ ID NO: 15).

411. The polypeptide of any one of claims 405-410, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVRHTIT (SEQ ID NO: 9), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSIYSTVA (SEQ ID NO: 15).

412. The polypeptide of any one of claims 405-411, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

413. The polypeptide of any one of claims 408-412, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSIYSTVAWYQQKPGKAPKLLIYSASSL YSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRHTITFGQGTKVEI KRTV (SEQ ID NO: 14).

414. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

415. The polypeptide of claim 414, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

416. The polypeptide of claim 414 or 415, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

417. The polypeptide of any one of claims 414-416, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVRITIT (SEQ ID NO: 17).

418. The polypeptide of claim 417, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

419. The polypeptide of claim 417 or 418, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLASTVA (SEQ ID NO: 11).

420. The polypeptide of any one of claims 414-419, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVRITIT (SEQ ID NO: 17), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLASTVA (SEQ ID NO: 11).

421. The polypeptide of any one of claims 414-420, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

422. The polypeptide of any one of claims 417-421, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLASTVAWYQQKPGKAPKLLIYSASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRITITFGQGTKVEI KRTV (SEQ ID NO: 16).

423. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

424. The polypeptide of claim 423, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

425. The polypeptide of claim 423 or 424, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

426. The polypeptide of any one of claims 423-425, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVRITIT (SEQ ID NO: 17).

427. The polypeptide of claim 426, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

428. The polypeptide of claim 426 or 427, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLSSTVA (SEQ ID NO: 19).

429. The polypeptide of any one of claims 423-428, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVRITIT (SEQ ID NO: 17), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLSSTVA (SEQ ID NO: 19).

430. The polypeptide of any one of claims 423-429, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

431. The polypeptide of any one of claims 426-430, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLSSTVAWYQQKPGKAPKLLIYSASSL YSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRITITFGQGTKVEIK RTV (SEQ ID NO: 18).

432. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

433. The polypeptide of claim 432, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

434. The polypeptide of claim 432 or 433, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

435. The polypeptide of any one of claims 432-434, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVRVTIT (SEQ ID NO: 13).

436. The polypeptide of claim 435, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

437. The polypeptide of claim 435 or 436, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLSSTVA (SEQ ID NO: 19).

438. The polypeptide of any one of claims 432-437, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVRVTIT (SEQ ID NO: 13), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLSSTVA (SEQ ID NO: 19).

439. The polypeptide of any one of claims 432-438, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

440. The polypeptide of any one of claims 435-439, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLSSTVAWYQQKPGKAPKLLIYSASSL YSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRVTITFGQGTKVEI KRTV (SEQ ID NO: 20).

441. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

442. The polypeptide of claim 441, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

443. The polypeptide of claim 441 or 442, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

444. The polypeptide of any one of claims 441-443, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVRVTIT (SEQ ID NO: 13).

445. The polypeptide of claim 444, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

446. The polypeptide of claim 444 or 445, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSISSTVA (SEQ ID NO: 22).

447. The polypeptide of any one of claims 441-446, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVRVTIT (SEQ ID NO: 13), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSISSTVA (SEQ ID NO: 22).

448. The polypeptide of any one of claims 441-447, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

449. The polypeptide of any one of claims 444-448, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSISSTVAWYQQKPGKAPKLLIYSASSL YSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRVTITFGQGTKVEI KRTV (SEQ ID NO: 21).

450. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

451. The polypeptide of claim 450, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

452. The polypeptide of claim 450 or 451, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

453. The polypeptide of any one of claims 450-452, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVWHTIT (SEQ ID NO: 26).

454. The polypeptide of claim 453, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of LASSLYS (SEQ ID NO: 25).

455. The polypeptide of claim 453 or 454, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSYTSAVA (SEQ ID NO: 24).

456. The polypeptide of any one of claims 450-455, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVWHTIT (SEQ ID NO: 26), a CDR-L2 sequence of LASSLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSYTSAVA (SEQ ID NO: 24).

457. The polypeptide of any one of claims 450-456, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

458. The polypeptide of any one of claims 453-457, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSYTSAVAWYQQKPGKAPKLLIYLASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWHTITFGQGTKVE IKRTV (SEQ ID NO: 23).

459. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

460. The polypeptide of claim 459, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

461. The polypeptide of claim 459 or 460, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30).

462. The polypeptide of any one of claims 459-461, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVRHTIT (SEQ ID NO: 9).

463. The polypeptide of claim 462, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12).

464. The polypeptide of claim 462 or 463, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLAHTVA (SEQ ID NO: 31).

465. The polypeptide of any one of claims 459-464, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQAS YVRHTIT (SEQ ID NO: 9), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLAHTVA (SEQ ID NO: 31).

466. The polypeptide of any one of claims 459-465, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 27).

467. The polypeptide of any one of claims 462-466, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLAHTVAWYQQKPGKAPKLLIYQASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVRHTITFGQGTKVE IKRTV (SEQ ID NO: 28).

468. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

469. The polypeptide of claim 468, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

470. The polypeptide of claim 468 or 469, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30).

471. The polypeptide of any one of claims 468-470, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVWKTIT (SEQ ID NO: 34).

472. The polypeptide of claim 471, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12).

473. The polypeptide of claim 471 or 472, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSYHHTVA (SEQ ID NO: 33).

474. The polypeptide of any one of claims 468-473, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSYHHTVA (SEQ ID NO: 33).

475. The polypeptide of any one of claims 468-474, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 27).

476. The polypeptide of any one of claims 471-475, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSYHHTVAWYQQKPGKAPKLLIYQASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 32).

477. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

478. The polypeptide of claim 477, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

479. The polypeptide of claim 477 or 478, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

480. The polypeptide of any one of claims 477-479, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVWKTIT (SEQ ID NO: 34).

481. The polypeptide of claim 480, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of LASSLYS (SEQ ID NO: 25).

482. The polypeptide of claim 480 or 481, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLHRLVA (SEQ ID NO: 37).

483. The polypeptide of any one of claims 477-482, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of LASSLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSLHRLVA (SEQ ID NO: 37).

484. The polypeptide of any one of claims 477-483, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTMVTVSS (SEQ ID NO: 35).

485. The polypeptide of any one of claims 480-484, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLHRLVAWYQQKPGKAPKLLIYLASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 36).

486. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

487. The polypeptide of claim 486, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

488. The polypeptide of claim 486 or 487, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30).

489. The polypeptide of any one of claims 486-488, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVWKTIT (SEQ ID NO: 34).

490. The polypeptide of claim 489, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of LASSLYS (SEQ ID NO: 25).

491. The polypeptide of claim 489 or 490, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSYTSTVA (SEQ ID NO: 39).

492. The polypeptide of any one of claims 486-491, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of LASSLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSYTSTVA (SEQ ID NO: 39).

493. The polypeptide of any one of claims 486-492, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 27).

494. The polypeptide of any one of claims 489-493, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSYTSTVAWYQQKPGKAPKLLIYLASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 38).

495. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

496. The polypeptide of claim 495, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

497. The polypeptide of claim 495 or 496, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

498. The polypeptide of any one of claims 495-497, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVWKTIT (SEQ ID NO: 34).

499. The polypeptide of claim 498, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of LASSLYS (SEQ ID NO: 25).

500. The polypeptide of claim 498 or 499, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLLRTVA (SEQ ID NO: 41).

501. The polypeptide of any one of claims 495-500, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of LASSLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSLLRTVA (SEQ ID NO: 41).

502. The polypeptide of any one of claims 495-501, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

503. The polypeptide of any one of claims 498-502, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSSSVGDRVTITCRASQSLLRTVAWYQQKPGKAPKLLIYLASSL YSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVEI KRTV (SEQ ID NO: 40).

504. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

505. The polypeptide of claim 504, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

506. The polypeptide of claim 504 or 505, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

507. The polypeptide of any one of claims 504-506, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVWKTIT (SEQ ID NO: 34).

508. The polypeptide of claim 507, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

509. The polypeptide of claim 507 or 508, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSVASTVA (SEQ ID NO: 43).

510. The polypeptide of any one of claims 504-509, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSVASTVA (SEQ ID NO: 43).

511. The polypeptide of any one of claims 504-510, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

512. The polypeptide of any one of claims 507-511, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSVASTVAWYQQKPGKAPKLLIYSASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 42).

513. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

514. The polypeptide of claim 513, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

515. The polypeptide of claim 513 or 514, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

516. The polypeptide of any one of claims 513-515, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVWKTIT (SEQ ID NO: 34).

517. The polypeptide of claim 516, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

518. The polypeptide of claim 516 or 517, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSVYRTVA (SEQ ID NO: 45).

519. The polypeptide of any one of claims 513-518, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSVYRTVA (SEQ ID NO: 45).

520. The polypeptide of any one of claims 513-519, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

521. The polypeptide of any one of claims 516-520, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSVYRTVAWYQQKPGKAPKLLIYSASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 44).

522. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

523. The polypeptide of claim 522, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

524. The polypeptide of claim 522 or 523, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

525. The polypeptide of any one of claims 522-524, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVWKTIT (SEQ ID NO: 34).

526. The polypeptide of claim 525, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12).

527. The polypeptide of claim 525 or 526, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLHRTVA (SEQ ID NO: 47).

528. The polypeptide of any one of claims 522-527, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLHRTVA (SEQ ID NO: 47).

529. The polypeptide of any one of claims 522-528, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

530. The polypeptide of any one of claims 525-529, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLHRTVAWYQQKPGKAPKLLIYQASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 46).

531. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

532. The polypeptide of claim 531, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

533. The polypeptide of claim 531 or 532, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

534. The polypeptide of any one of claims 531-533, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVWKTIT (SEQ ID NO: 34).

535. The polypeptide of claim 534, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12).

536. The polypeptide of claim 534 or 535, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLSHTVA (SEQ ID NO: 49).

537. The polypeptide of any one of claims 531-536, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLSHTVA (SEQ ID NO: 49).

538. The polypeptide of any one of claims 531-537, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

539. The polypeptide of any one of claims 534-538, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLSHTVAWYQQKPGKAPKLLIYQASS LYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 48).

540. The polypeptide of any one of claims 534-538, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLSHTVAWYQQKPGKAPKLLIYQASSLYSGVPSRFSGSRSGTDFTLTISNLQPEDFATYYCQQASYVWKTITFGQGTKV EIKRTV (SEQ ID NO: 50).

541. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

542. The polypeptide of claim 541, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

543. The polypeptide of claim 541 or 542, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

544. The polypeptide of any one of claims 541-543, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVWKTIT (SEQ ID NO: 34).

545. The polypeptide of claim 544, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12).

546. The polypeptide of claim 544 or 545, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLASTVA (SEQ ID NO: 11).

547. The polypeptide of any one of claims 541-546, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLASTVA (SEQ ID NO: 11).

548. The polypeptide of any one of claims 541-547, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

549. The polypeptide of any one of claims 544-548, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLASTVAWYQQKPGKAPKLLIYQASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 51).

550. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

551. The polypeptide of claim 550, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

552. The polypeptide of claim 550 or 551, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

553. The polypeptide of any one of claims 550-552, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVWKTIT (SEQ ID NO: 34).

554. The polypeptide of claim 553, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of QASSLYS (SEQ ID NO: 12).

555. The polypeptide of claim 553 or 554, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLAHTVA (SEQ ID NO: 31).

556. The polypeptide of any one of claims 550-555, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of QASSLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLAHTVA (SEQ ID NO: 31).

557. The polypeptide of any one of claims 550-556, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

558. The polypeptide of any one of claims 553-557, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLAHTVAWYQQKPGKAPKLLIYQASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 52).

559. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

560. The polypeptide of claim 559, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

561. The polypeptide of claim 559 or 560, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of FSDYSIH (SEQ ID NO: 4).

562. The polypeptide of any one of claims 559-561, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVWKTIT (SEQ ID NO: 34).

563. The polypeptide of claim 562, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

564. The polypeptide of claim 562 or 563, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLHSTVA (SEQ ID NO: 54).

565. The polypeptide of any one of claims 559-564, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of FSDYSIH (SEQ ID NO: 4), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLHSTVA (SEQ ID NO: 54).

566. The polypeptide of any one of claims 559-565, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 1).

567. The polypeptide of any one of claims 562-566, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLHSTVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 53).

568. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

569. The polypeptide of claim 568, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

570. The polypeptide of claim 568 or 569, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30).

571. The polypeptide of any one of claims 568-570, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVWKTIT (SEQ ID NO: 34).

572. The polypeptide of claim 571, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

573. The polypeptide of claim 571 or 572, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSLHSTVA (SEQ ID NO: 54).

574. The polypeptide of any one of claims 568-573, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLHSTVA (SEQ ID NO: 54).

575. The polypeptide of any one of claims 568-574, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 27).

576. The polypeptide of any one of claims 571-575, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSLHSTVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 55).

577. The polypeptide of any one of claims 380-386, wherein the antigen-binding domain comprises a heavy chain variable region (VH), and wherein the VH comprises a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

578. The polypeptide of claim 577, wherein the VH comprises a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5).

579. The polypeptide of claim 577 or 578, wherein the VH comprises a CDR-H1 comprising the amino acid sequence of ISSYSIH (SEQ ID NO: 30).

580. The polypeptide of any one of claims 577-579, wherein the antigen-binding domain further comprises a light chain variable region (VL), and wherein the VL comprises a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence of QQAS YVWKTIT (SEQ ID NO: 34).

581. The polypeptide of claim 580, wherein the VL comprises a CDR-L2 comprising the amino acid sequence of SASSLYS (SEQ ID NO: 8).

582. The polypeptide of claim 580 or 581, wherein the VL comprises a CDR-L1 comprising the amino acid sequence of RASQSVYSTVA (SEQ ID NO: 57).

583. The polypeptide of any one of claims 577-582, wherein the antigen-binding domain comprises: a CDR-H3 sequence of GGWIAAMDY (SEQ ID NO: 6), a CDR-H2 sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5), a CDR-H1 sequence of ISSYSIH (SEQ ID NO: 30), a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SASSLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSVYSTVA (SEQ ID NO: 57).

584. The polypeptide of any one of claims 577-583, wherein the VH comprises a sequence with at least 80% sequence identity to the sequence EVQLVESGGGLVQPGGSLRLSCAASGFTISSYSIHWVRQAPGKGLEWVASISS SSGSTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGGWIAA MDYWGQGTLVTVSS (SEQ ID NO: 27).

585. The polypeptide of any one of claims 580-584, wherein the VL comprises a sequence with at least 80% sequence identity to the sequence DIQMTQSPSSLSASVGDRVTITCRASQSVYSTVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASYVWKTITFGQGTKVE IKRTV (SEQ ID NO: 56).

586. A polypeptide comprising an antigen-binding domain comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises: a CDR-H1 comprising SYSIH (SEQ ID NO: 29); a CDR-H2 comprising the amino acid sequence of SISSSSGSTSYADSVKG (SEQ ID NO: 5); and a CDR-H3 comprising the amino acid sequence of GGWIAAMDY (SEQ ID NO: 6).

587. The polypeptide of claim 586, wherein the VL comprises: a CDR-L3 sequence of QQAS YVRHTIT (SEQ ID NO: 9), a CDR-L2 sequence of Q AS SLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSLAHTVA (SEQ ID NO: 31).

588. The polypeptide of claim 586, wherein the antigen-binding domain comprises: a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of Q AS SLYS (SEQ ID NO: 12), and a CDR-L1 sequence of RASQSYHHTVA (SEQ ID NO: 33).

589. The polypeptide of claim 586, wherein the antigen-binding domain comprises: a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of LAS SLYS (SEQ ID NO: 25), and a CDR-L1 sequence of RASQSYTSTVA (SEQ ID NO: 39).

590. The polypeptide of claim 586, wherein the antigen-binding domain comprises: a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SAS SLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSLHSTVA (SEQ ID NO: 54).

591. The polypeptide of claim 586, wherein the antigen-binding domain comprises: a CDR-L3 sequence of QQAS YVWKTIT (SEQ ID NO: 34), a CDR-L2 sequence of SAS SLYS (SEQ ID NO: 8), and a CDR-L1 sequence of RASQSVYSTVA (SEQ ID NO: 57).

592. The polypeptide of any one of claims 380-591, wherein the polypeptide binds to a peptide conjugate / MHC complex comprising a peptide conjugate formed by a covalent reaction of a targeted covalent inhibitor or fragment thereof with a peptide and an MHC.

593. A pharmaceutical composition comprising the multivalent polypeptide of any one of claims 380-591, and a pharmaceutically acceptable carrier.

594. A method of treating a cancer in a subject in need thereof, the method comprising administering the multivalent polypeptide of any one of claims 380-591 or the pharmaceutical composition of claim 593.

595. A polypeptide that binds to a first peptide conjugate / MHC complex and a second peptide conjugate / MHC complex different from the first peptide conjugate / MHC complex, wherein each of the first and second peptide conjugate / MHC complexes independently comprises:(a) a different peptide selected from the group consisting of peptides comprising the formulaX#X#+iX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9, and X#X#+i X#+2X#+3 (X#+4)X#+5 X#+6X#+7X#+8X#+9 , and X#X#+i X#+2(X#+3 )X#+4X#+5 X#+6X#+7X#+8X#+9 , and X#X#+i (X#+2)X#+3X#+4X#+5X#+6X#+7X#+8X#+9, and X#. i X#X#+ 1 X#+2X#+3 X#+4(X#+5 )X#+6X#+7X#+8X#+9 , and X#+lX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9, wherein the peptide conjugate of the first and second peptide conjugate / MHC complex is formed by the covalent reaction of a targeted covalent inhibitor or fragment thereof with the residue in parenthesis; and(b) the same MHC; wherein the polypeptide binds to the first peptide conjugate / MHC complex with a KD that is at most 100 nM and binds to the second peptide conjugate / MHC complex with a KD that is at most 100 nM, or wherein when the polypeptide is contacted to the first peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to a biolayer interferometry analysis and wherein when the polypeptide is contacted to the second peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to the biolayer interferometry analysis, or wherein when the polypeptide is contacted to the first peptide conjugate / MHC complex a maximum binding signal of at least 0.1-fold of a reference binding signal is observed according to a biolayer interferometry analysis and wherein when the polypeptide is contacted to the second peptide conjugate / MHC complex a maximum binding signal of at least 0.1-fold of a reference binding signal is observed accordingto the biolayer interferometry analysis, and wherein the reference binding signal is the maximum binding signal of the polypeptide binding toX#X#+1 X#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9.

596. The polypeptide of claim 595, wherein each of the first and second peptide conjugate / MHC complexes independently comprises: a different peptide selected from the group consisting of peptides comprising the formula X#X#+iX#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9, andX#X#+i X#+2X#+3 (X#+4)X#+5 X#+6X#+7X#+8X#+9 , and X#X#+i X#+2(X#+3 )X#+4X#+5 X#+6X#+7X#+8X#+9 , and X#X#+1 (X#+2)X#+3X#+4X#+5X#+6X#+7X#+8X#+9.

597. The polypeptide of claim 595, wherein each of the first and second peptide conjugate / MHC complexes independently comprises: a different peptide with an amino acid sequence selected from the group consisting of: VVVGACGVGK, VVVGCGGVGK, VVVCAGGVGK, and VVCGAGGVGK.

598. A polypeptide that binds to a first peptide conjugate / MHC complex and a second peptide conjugate / MHC complex, wherein each of the first and the second peptide conjugate / MHC complex comprises:(a) a peptide comprising the formula X7X8X9X10X11X12X13X14X15X16; and(b) the same MHC; wherein a first peptide conjugate of the first peptide conjugate / MHC complex is formed by the covalent reaction of a targeted covalent inhibitor or fragment thereof with X12 of the peptide, and wherein a second peptide conjugate of the second peptide conjugate / MHC complex is formed by the covalent reaction of the same targeted covalent inhibitor or fragment thereof with X13 of the peptide; wherein the polypeptide binds to the second peptide conjugate / MHC complex with a KD that is at most 100,000-fold higher than the KD of the polypeptide to the first peptide conjugate / MHC complex, or wherein a maximum wavelength shift of the polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum wavelength shift of the polypeptide binding to the first peptide conjugate / MHC complex, or wherein a maximum binding signal of the polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum binding signal of the polypeptide binding to the first peptide conjugate / MHC complex.

599. A polypeptide that binds to a first peptide conjugate / MHC complex and a second peptide conjugate / MHC complex, wherein each of the first and the second peptide conjugate / MHC complex comprises:(a) a peptide comprising the formula X7X8X9X10X11X12X13X14X15X16; and(b) the same MHC; wherein a first peptide conjugate of the first peptide conjugate / MHC complex is formed by the covalent reaction of a targeted covalent inhibitor or fragment thereof with a residue selected from the group consisting of X9, X10, Xu, and X12, and wherein a second peptide conjugate of the second peptide conjugate / MHC complex is formed by the covalent reaction of the same targeted covalent inhibitor or fragment thereof with a residue selected from the group consisting of X13, X14, and X15; wherein the polypeptide binds to the second peptide conjugate / MHC complex with a KD that is at most 100,000-fold higher that the KD of the polypeptide to the first peptide conjugate / MHC complex, or wherein a maximum wavelength shift of the polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum wavelength shift of the polypeptide binding to the first peptide conjugate / MHC complex, or wherein a maximum binding signal of the polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum binding signal of the polypeptide binding to the first peptide conjugate / MHC complex.

600. A polypeptide that binds to a first peptide conjugate / MHC complex and a second peptide conjugate / MHC complex, wherein each of the first and the second peptide conjugate / MHC complex comprises: a peptide comprising the formula A-B-C, where A comprises no more than three residues having an N-terminal anchor residue, B comprises at least four but no more than seven residues having a residue covalently linked to a targeted covalent inhibitor or fragment thereof, and C comprises no more than three residues having a C-terminal anchor residue, wherein the N-terminal anchor residues and the C-terminal anchor residue bind to an MHC; and the same MHC; wherein the residue covalently linked to a targeted covalent inhibitor or fragment thereof of the peptide of the first peptide conjugate / MHC complex is different from the residue covalently linked to a targeted covalent inhibitor or fragment thereof of the peptide of the second peptide conjugate / MHC complex; andwherein the polypeptide binds to the first peptide conjugate / MHC complex with a KD that is at most 100 nM and binds to the second peptide conjugate / MHC complex with a KD that is at most 100 nM, or wherein when the polypeptide is contacted to the first peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to a biolayer interferometry analysis and wherein when the polypeptide is contacted to the second peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to the biolayer interferometry analysis, or wherein when the polypeptide is contacted to the first peptide conjugate / MHC complex a maximum binding signal of at least 0.1-fold of a reference binding signal is observed according to a biolayer interferometry analysis and wherein when the polypeptide is contacted to the second peptide conjugate / MHC complex a maximum binding signal of at least 0.1-fold of a reference binding signal is observed according to the biolayer interferometry analysis, and wherein the reference binding signal is the maximum binding signal of the polypeptide binding toX#X#+1 X#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9.

601. The polypeptide of claim 600, wherein A comprises two residues X?Xs.

602. The polypeptide of claim 600 or 601, wherein B comprises seven residues X9XioXiiXi2Xi3Xi4Xi5.

603. The polypeptide of any one of claims 600-602, wherein C comprises one residue Xi6.

604. The polypeptide of any one of claims 600-603, wherein the formula A-B-C is the formula X7X8X9X10X11X12X13X14X15X16.

605. The polypeptide of claim 604, wherein a first peptide conjugate of the first peptide conjugate / MHC complex is formed by the covalent reaction of the targeted covalent inhibitor or fragment thereof with X12 of the peptide.

606. The polypeptide of claim 604 or 605, wherein a second peptide conjugate of the second peptide conjugate / MHC complex is formed by the covalent reaction of the same targeted covalent inhibitor or fragment thereof with X13 of the peptide.

607. The polypeptide of claim 606, wherein the polypeptide binds to the second peptide conjugate / MHC complex with a KD that is at most 1000,000-fold higher than the KD of the polypeptide to the first peptide conjugate / MHC complex.

608. The polypeptide of any one of claims 602-607, wherein the polypeptide binds to the second peptide conjugate / MHC complex with an KD that is at most 100,000-fold higher than the KD of the polypeptide to the first peptide conjugate / MHC complex,and wherein the residue covalently linked to the targeted covalent inhibitor or fragment thereof of the peptide of the first peptide conjugate / MHC complex is selected from the group of consisting of X9, X10, Xu, and X12, and the residue covalently linked to the targeted covalent inhibitor or fragment thereof of the peptide of the second peptide conjugate / MHC complex is X13, X14, and X15.

609. The polypeptide of any one of claims 595-608, wherein the peptide is a RAS peptide.

610. The polypeptide of claim 609, wherein the RAS peptide comprises a mutation.

611. The polypeptide of claim 610, wherein the mutation is G12C or G13C.

612. The polypeptide of any one of claims 609-611, wherein the RAS peptide comprises a sequence selected from the group consisting of VVVGACGVGK, VVGACGVGK, and KLVVVGACGV.

613. The polypeptide of any one of claims 609-611, wherein the RAS peptide comprises a sequence selected from the group consisting of VVVGAGCVGK, VVGAGCVGK, or KLWVGAGCV.

614. The polypeptide of any one of claims 592 and 595-613, wherein the MHC or the same MHC is selected from the group consisting of HLA- A* 03:01, HLA-A* 11 :01, HLA- A*02:01, HLA-A*68:01, HLA-A*31:01, HLA-A*30:01, HLA-A*33:03, HLA- A*33:01, HLA-A*74:01, HLA-A*34:02, HLA-A*66:01, HLA-A*68:02, HLA- A*02:05, HLA-A*02:02, and HLA-A*02:06.

615. The polypeptide of any one of claims 592 and 595-613, wherein the MHC or the same MHC is encoded by an HLA allele of HLA-A3 supertype.

616. The polypeptide of claim 615, wherein the HLA allele of the HLA- A3 supertype is selected from the group consisting of HL A- A* 03:01, HLA-A* 11 :01, HLA-A*68:01, HLA-A*31 :01, HLA-A*30:01, HLA-A*74:01, HLA-A*34:02, and HLA-A*66:01.

617. The polypeptide of any one of claims 592 and 595-613, wherein the MHC or the same MHC is encoded by an HLA allele of HLA-A2 supertype.

618. The polypeptide of claim 617, wherein the HLA allele of the HLA-A2 supertype is selected from the group consisting of HL A- A* 02:01, HLA-A*02:02, HLA-A*02:03, HLA-A*02:04, HLA-A*02:05, HLA-A*02:06, HLA-A*02:07, HLA-A*02: 14, HLA- A*02: 17, HLA-A*68:02, and HLA-A*69:01.

619. The polypeptide of any one of claims 595-618, wherein the targeted covalent inhibitor or fragment thereof comprises sotorasib.

620. The polypeptide of any one of claims 597-600 and 604-619, wherein the peptide is a RAS peptide, and wherein X12 is G12C mutation, and X13 is G13C mutation.

621. The polypeptide of claim 620, wherein the polypeptide binds to the first peptide conjugate / MHC complex having a Cys of the G12C mutation covalently linked to the targeted covalent inhibitor or fragment thereof with an KD that is at most 100 nM and binds to the second peptide conjugate / MHC complex having a Cys of the G13C mutation covalently linked to the targeted covalent inhibitor or fragment thereof with an KD that is most 100 nM, or wherein when the polypeptide is contacted to the first peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to a biolayer interferometry analysis and wherein when the polypeptide is contacted to the second peptide conjugate / MHC complex a maximum wavelength shift of at least 0.1 nm is observed according to the biolayer interferometry analysis, or wherein when the polypeptide is contacted to the first peptide conjugate / MHC complex a maximum binding signal of at least 0.1-fold of a reference binding signal is observed according to a biolayer interferometry analysis and wherein when the polypeptide is contacted to the second peptide conjugate / MHC complex a maximum binding signal of at least 0.1-fold of a reference binding signal is observed according to the biolayer interferometry analysis, and wherein the reference binding signal is the maximum binding signal of the polypeptide binding to X#X#+1 X#+2X#+3X#+4(X#+5)X#+6X#+7X#+8X#+9.

622. The polypeptide of claim 620, wherein the polypeptide binds to the second peptide conjugate / MHC complex having a Cys of the G13C mutation covalently linked to the targeted covalent inhibitor or fragment thereof with a KD that is at most 100,000-fold higher that the KD of the polypeptide to the first peptide conjugate / MHC complex having a Cys of the G12C mutation covalently linked to the targeted covalent inhibitor or fragment thereof, or wherein a maximum wavelength shift of the polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum wavelength shift of the polypeptide binding to the first peptide conjugate / MHC complex, or wherein a maximum binding signal of the polypeptide binding to the second peptide conjugate / MHC complex is at least 10-fold less than a maximum binding signal of the polypeptide binding to the first peptide conjugate / MHC complex.

623. A method for stabilizing a peptide conjugate / MHC complex, the method comprising: (a) contacting the peptide conjugate / MHC complex with a multivalent polypeptide, wherein the peptide conjugate / MHC complex comprises a peptideconjugate formed by a covalent reaction of a targeted covalent inhibitor or fragment thereof with a peptide and an MHC, and wherein the multivalent polypeptide comprises a first antigen-binding domain, a second antigen-binding domain that binds to a T cell surface protein, and an Fc region comprising a first Fc subunit and a second Fc subunit; and(b) measuring the half-life of the bound peptide conjugate / MHC complex and multivalent polypeptide.

624. The method of claim 623, wherein the half-life of the peptide conjugate / MHC complex is between 0.1 and 30 hours.

625. The method of claim 624, wherein the half-life of the peptide conjugate / MHC complex is between 10 and 26 hours.

626. The method of claim 623, wherein the half-life of the peptide conjugate / MHC complex is at least 1 day.

627. The method of any one of claims 623-626, wherein the contacting occurs at 25 °C or 37 °C.

628. A method for activating an immune cell, the method comprising: contacting the immune cell with a multivalent polypeptide comprising a first antigen-binding domain, a second antigen-binding domain that binds to a T cell surface protein, and an Fc region comprising a first Fc subunit and a second Fc subunit; and wherein the immune cell expresses a peptide conjugate / MHC complex, wherein the peptide conjugate / MHC complex comprises a peptide conjugate formed by a covalent reaction of a targeted covalent inhibitor or fragment thereof with a peptide and an MHC.

629. The method of claim 628, wherein the immune cell is a T cell.

630. The method of claim 628 or 629, wherein the contacting increases expression of at least one T cell activation marker.

631. The method of claim 630, wherein the at least one T cell activation marker is CD26, CD27, CD28, CD30, CD154, CD40L, CD134. CD25, CD44, CD69, CD137, PD-1, KLRG1, CCR7, CD45RA, HLA-DR, NKG2D, or any combination thereof.

632. The method of claim 630 or 631, wherein the at least one T cell activation marker is CD25 and / or CD69.

633. The method of any one of claims 628-632, wherein the contacting produces a greater number of CD25+CD69+T cells compared to a number of CD25+CD69+T cellsproduced from contacting the multivalent polypeptide with an otherwise identical peptide conjugate / MHC complex without the targeted covalent inhibitor.

634. The method of any one of claims 628-633, wherein the contacting increases expression of IFNy, TNFa, Granzyme A, Granzyme B, IL-6, perforin, IL-2, granulysin, or any combination thereof.

635. The method of any one of claims 628-634, wherein the contacting increases an expression level of cytokine molecules compared to an expression level of cytokine molecules produced from contacting the multivalent polypeptide with an otherwise identical peptide conjugate / MHC complex without the targeted covalent inhibitor.

636. A method for treating a cancer in a subject in need thereof, the method comprising administering to the subject a multivalent polypeptide comprising (i) a first antigenbinding domain that binds to a peptide conjugate / MHC complex, wherein the peptide conjugate / MHC complex comprises a peptide conjugate formed by a covalent reaction of a targeted covalent inhibitor or fragment thereof with a peptide and an MHC; (ii) a second antigen-binding domain that binds to a T cell surface protein; and (iii) an Fc region comprising a first Fc subunit and a second Fc subunit; wherein the first antigen-binding domain, the second antigen-binding domain, the first Fc subunit, and the second Fc subunit are operably linked to form a single continuous polypeptide chain.

637. The method of claim 636, wherein the cancer is renal cell carcinoma, breast cancer, prostate cancer, pancreatic cancer, lung cancer, liver cancer, ovarian cancer, cervical cancer, colon cancer, esophageal cancer, glioma, glioblastoma, brain cancer, stomach cancer, bladder cancer, testicular cancer, thyroid cancer, adrenal cancer, head and neck cancer, melanoma, skin cancer, sarcoma, fibrosarcoma, angiosarcoma, osteosarcoma, rhabdomyosarcoma, leukemia, lymphoma, myeloma, endometrial cancer, or a neuroendocrine tumor.

638. The method of any one of claims 623-637, wherein the peptide is a RAS peptide.

639. The method of claim 638, wherein the RAS peptide comprises a mutation.

640. The method of claim 639, wherein the mutation is G12C or G13C.

641. The method of any one of claims 638-640, wherein the RAS peptide comprises a sequence selected from the group consisting of VVVGACGVGK, VVGACGVGK, and KLVVVGACGV.

642. The method of any one of claims 638-640, wherein the RAS peptide comprises a sequence selected from the group consisting of VVVGAGCVGK, VVGAGCVGK, or KLWVGAGCV.

643. The method of any one of claims 623-642, wherein the MHC is selected from the group consisting of HL A-A* 03:01, HLA-A*l l:01, HLA-A*02:01, HLA-A*68:01, HLA-A*31:01, HLA-A*30:01, HLA-A*33:03, HLA-A*33:01, HLA-A*74:01, HLA- A*34:02, HLA-A*66:01, HLA-A*68:02, HLA-A*02:05, HLA-A*02:02, HLA- A*02:06.

644. The method of any one of claims 623-643, wherein the targeted covalent inhibitor or fragment thereof comprises sotorasib.

645. A method for stabilizing a peptide conjugate / MHC complex in a subject, the method comprising: administering a multivalent polypeptide to the subject, wherein the multivalent polypeptide comprises a first antigen-binding domain, a second antigenbinding domain that binds to a T cell surface protein, and wherein the peptide conjugate / MHC complex comprises a peptide conjugate formed by a covalent reaction of a targeted covalent inhibitor or fragment thereof with a peptide and an MHC.

646. The method of claim 645, further comprising, prior to administering the multivalent polypeptide to the subject, administering the targeted covalent inhibitor.

647. The method of claim 645 or 646, wherein the subject has a cancer.

648. The method of any one of claims 645-647, wherein the cancer is refractory or relapsed.

649. The method of any one of claims 645-648, wherein the subject expresses at least one MHC encoded by an HL A, wherein the HL A is HLA-A*03:01, HLA-A* 11:01, HLA- A*02:01, HLA-A*68:01, HLA-A*31:01, HLA-A*30:01, HLA-A*33:03, HLA- A*33:01, HLA-A*74:01, HLA-A*34:02, HLA-A*66:01, HLA-A*68:02, HLA- A*02:05, HLA-A*02:02, HLA-A*02:06, or any combination thereof.

650. The method of any one of claims 645-648, further comprising, prior to administering the multivalent polypeptide to the subject, determining an HLA allele expression of the subject.

651. The method of claim 650, wherein the subject expresses an MHC encoded by the HLA wherein the HLA is HLA-A*03:01, HLA-A* 11 :01, HLA-A*02:01, HLA- A*68:01, HLA-A*31 :01, HLA-A*30:01, HLA-A*33:03, HLA-A*33:01, HLA-A*74:01, HLA-A*34:02, HLA-A*66:01, HLA-A*68:02, HLA-A*02:05, HLA- A*02:02, HLA-A*02:06, or any combination thereof.

652. The method of any one of claims 623-650, wherein (i) the MHC is encoded by an HL A allele of HLA-A3 supertype, or (ii) the subject expresses an MHC encoded by an HL A allele of HLA-A3 supertype.

653. The method of claim 652, wherein the HLA allele of the HLA-A3 supertype is selected from the group consisting of HL A- A* 03:01, HLA-A* 11 :01, HLA-A*68:01, HLA-A*31:01, HLA-A*30:01, HLA-A*74:01, HLA-A*34:02, and HLA-A*66:01.

654. The method of any one of claims 623-650, wherein (i) the MHC is encoded by an HLA allele of HLA-A2 supertype, or (ii) the subject expresses an MHC encoded by an HLA allele of HLA-A2 supertype.

655. The method of claim 654, wherein the HLA allele of the HLA-A2 supertype is selected from the group consisting of HL A- A* 02:01, HLA-A*02:02, HLA-A*02:03, HLA-A*02:04, HLA-A*02:05, HLA-A*02:06, HLA-A*02:07, HLA-A*02: 14, HLA- A*02: 17, HLA-A*68:02, and HLA-A*69:01.

656. The method of any one of claims 645-655, wherein the multivalent polypeptide comprises an Fc region comprising a first Fc subunit and a second Fc subunit.

657. The method of claim 656, wherein the Fc region comprises one or more amino acid substitutions relative to a wild-type Fc region selected from the group consisting of heavy chain constant regions of human IgE, IgM, IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

658. The method of claim 656 or 657, wherein the Fc region comprises an Fc-silencing mutation, which Fc-silencing mutation decreases an antibody-directed cytotoxicity effector function.

659. The method of any one of claims 645-658, wherein administering the multivalent polypeptide to the subject increases a half-life of the peptide conjugate / MHC complex compared to a half-life of the peptide conjugate / MHC complex following administration of the targeted covalent inhibitor alone.

660. The method of any one of claims 645-659, wherein administering the multivalent polypeptide to the subject increases an epitope density of the peptide of the peptide conjugate / MHC complex by at least 60%.

661. The method of any one of claims 645-660, wherein the targeted covalent inhibitor is sotorasib.

662. The method of any one of claims 645-661, wherein the peptide is a RAS peptide.

663. The method of claim 662, wherein the RAS peptide comprises a mutation.

664. The method of claim 663, wherein the mutation is G12C or G13C.

665. The method of any one of claims 662-664, wherein the RAS peptide comprises a sequence selected from the group consisting of VVVGACGVGK, VVGACGVGK, and KLVVVGACGV.

666. The method of any one of claims 662-664, wherein the RAS peptide comprises a sequence selected from the group consisting of VVVGAGCVGK, VVGAGCVGK, or KLWVGAGCV.

667. The method of any one of claims 645-666, wherein the first antigen-binding domain comprises the scFv of any one of claims 28-37, or the first antigen-binding domain is the polypeptide of any one of claims 380-591.

668. The method of any one of claims 645-667, wherein the second antigen-binding domain comprises the scFv of any one of claims 29-37, or the second antigen-binding domain is the second antigen-binding domain of any one of claims 1-321.

669. The method of any one of claims 645-668, wherein the multivalent polypeptide is the multivalent polypeptide of any one of claims 1-321 and 353-379, or the polypeptide of any one of claims 595-622.

670. The method of any one of claims 645-669, wherein a density of the peptide conjugate / MHC complex on the surface of cells in the subject in the presence of the multivalent polypeptide is increased by at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least at least 90%, or more compared to a density of the peptide conjugate / MHC complex on the surface of cells in the subject in the absence of the multivalent polypeptide.

671. The polynucleotide of claim 323 or 324, wherein the polynucleotide is a modified polynucleotide.