Anti-STEAP1 antigen binding molecules and uses thereof

Abstract

The present invention provides monospecific and multispecific antigen binding molecules and compositions thereof. The invention also features methods of treating a disease or condition, such as cancer, methods of inhibiting tumor growth, kits for use with one or more methods.

Description

[0001] Sequence Listing

[0002] This application contains a sequence listing, which has been submitted electronically in XML format and is incorporated herein by reference in its entirety. The XML copy was created on July 18, 2023, is named "50474-301WO2_Sequence_Listing", and is 170,087 bytes in size. Technical Field

[0003] The present invention relates to antigen-binding molecules that bind to STEAP1, including monospecific and multispecific antibodies, compositions thereof, and methods of treating diseases such as cancer. Background Art

[0004] Cancer is a heterogeneous disease that evolves at the genetic, phenotypic and pathological levels. Current therapies include chemotherapy, radiotherapy, surgery, hormone therapy, targeted therapy, immunotherapy and stem cell transplantation. Targeted therapy and immunotherapy have shown promise in mediating effective tumor cell killing. However, the presence of intratumoral heterogeneity, cancer subtypes and mutations that cause acquired drug resistance brings challenges to target selection. There is still a need to develop therapeutic agents that identify one or more targets shared in different cancer subtypes and those cancer subtypes that acquire drug resistance through mutation. Summary of the Invention

[0005] At least one aspect of the invention described herein relates to a multispecific antigen-binding molecule comprising: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3 of a VH sequence selected from the group consisting of SEQ ID NOs: 7, 17 to 25, 30 to 34, 38, and 68; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3 of a VL sequence selected from the group consisting of SEQ ID NOs: 8, 26 to 29, 39, and 69; and (B) a second antigen-binding domain that binds to a T cell receptor.

[0006] At least another aspect of the invention described herein relates to a multispecific antigen-binding molecule comprising: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3; and (B) a second antigen-binding domain that binds to a T cell receptor; wherein:

[0007] CDR-H1 contains Xaa 1 Xaa 2 YMA (SEQ ID NO: 35); wherein Xaa 1 is Asp(D) or Asn(N); and Xaa 2 is His (H), Tyr (Y) or Phe (F);

[0008] CDR-H2 contains YIXaa 3 YGX 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36); wherein Xaa 3 Asp(D) or Ser(S); Xaa 4 is Gly(G), Asp(D) or Leu(L); Xaa 5 is Ser(S), Asp(D) or Asn(N); and Xaa 6 is Ser (S) or Tyr (Y);

[0009] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO: 37); wherein Xaa 7 is Phe(F) or Tyr(Y); Xaa 8 is Asn(N) or Asp(D); and Xaa 9 is Ala (A) or Gly (G);

[0010] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.

[0011] In some embodiments, CDR-H1 comprises the amino acid sequence of SEQ ID NO: 10, 1, or 9.

[0012] In some embodiments, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, 11, 12, or 13.

[0013] In some embodiments, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15.

[0014] In some embodiments, the first antigen binding domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 10; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 16; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0015] In some embodiments, the first antigen binding domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0016] In some embodiments, the first antigen binding domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 9; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 11; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0017] In some embodiments, the first antigen binding domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 9; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0018] In some embodiments, the first antigen binding domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 9; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 14; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0019] In some embodiments, the first antigen binding domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 10; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 13; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 15; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0020] In some embodiments, the multispecific antigen-binding molecule is a humanized antibody.

[0021] In some embodiments, the first antigen binding domain and the second antigen binding domain each independently comprise an IgG framework region, optionally an IgG1 or IgG4 framework region.

[0022] In some embodiments, the first antigen binding domain comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence comprising at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO: 7, 17-25, 30-34, 38 or 68.

[0023] In some embodiments, the first antigen binding domain comprises an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO: 8, 26-29, 39 or 69.

[0024] In some embodiments, the first antigen-binding domain comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 68; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 69.

[0025] In some embodiments, the first antigen-binding domain comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 34; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 27.

[0026] In some embodiments, the first antigen-binding domain comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:30; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:27.

[0027] In some embodiments, the first antigen-binding domain comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:31; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:27.

[0028] In some embodiments, the first antigen-binding domain comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:32; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:27.

[0029] In some embodiments, the first antigen-binding domain comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 33; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 27.

[0030] In some embodiments, the T cell receptor is cluster of differentiation 3 (CD3).

[0031] In some embodiments, the second antigen binding domain that binds to CD3 comprises an anti-CD3 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-CD3 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the sequence of SEQ ID NOs: 48 to 53, respectively.

[0032] In some embodiments, the second antigen binding domain that binds to CD3 comprises an anti-CD3 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:54, and a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:55.

[0033] In some embodiments, the second antigen binding domain that binds to CD3 comprises an anti-CD3 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-CD3 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the sequence of SEQ ID NOs: 40 to 45, respectively.

[0034] In some embodiments, the second antigen binding domain that binds to CD3 comprises an anti-CD3 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:46, and an anti-CD3 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:47.

[0035] In some embodiments, the multispecific antigen-binding molecule comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH11) domain, a first CH2 (CH21) domain, a first CH3 (CH31) domain, a second CH1 (CH12) domain, a second CH2 (CH22) domain, and a second CH3 (CH32) domain.

[0036] In some embodiments, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

[0037] In some embodiments, the CH31 and CH32 domains each comprise a protrusion or a cavity, and wherein the protrusion or the cavity in the CH31 domain can be positioned in the cavity or the protrusion, respectively, of the CH32 domain.

[0038] In some embodiments, the CH31 and CH32 domains meet at the interface between the protrusion and the cavity.

[0039] In some embodiments, the CH21 and CH22 domains each comprise a protrusion or a cavity, and wherein the protrusion or the cavity in the CH21 domain can be positioned within the cavity or the protrusion, respectively, of the CH22 domain.

[0040] In some embodiments, the CH21 and CH22 domains meet at the interface between the protrusion and the cavity.

[0041] In some embodiments, the first antigen binding domain comprises an anti-STEAP1 heavy chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO: 83 and an anti-STEAP1 light chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO: 82; and the second antigen binding domain comprises an anti-CD 65 heavy chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO: 85 and an anti-CD 65 light chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO: 84.

[0042] In some embodiments, the antigen binding molecule comprises an anti-STEAP1 heavy chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO: 85 and an anti-STEAP1 light chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO: 84; and the second antigen binding domain comprises an anti-CD3 heavy chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO: 83 and an anti-CD3 light chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO: 82.

[0043] In some embodiments, the multispecific antigen-binding molecule comprises an anti-STEAP1 heavy chain comprising SEQ ID NO:73, an anti-STEAP1 light chain comprising SEQ ID NO:72, an anti-CD3 heavy chain comprising SEQ ID NO:79, and an anti-CD3 light chain comprising SEQ ID NO:78.

[0044] In some embodiments, the multispecific antigen-binding molecule comprises an anti-STEAP1 heavy chain comprising SEQ ID NO:73, an anti-STEAP1 light chain comprising SEQ ID NO:72, an anti-CD3 heavy chain comprising SEQ ID NO:81, and an anti-CD3 light chain comprising SEQ ID NO:80.

[0045] In some embodiments, the multispecific antigen-binding molecule comprises an anti-STEAP1 heavy chain comprising SEQ ID NO:71, an anti-STEAP1 light chain comprising SEQ ID NO:70, an anti-CD3 heavy chain comprising SEQ ID NO:79, and an anti-CD3 light chain comprising SEQ ID NO:78.

[0046] In some embodiments, the multispecific antigen-binding molecule comprises an anti-STEAP1 heavy chain comprising SEQ ID NO:71, an anti-STEAP1 light chain comprising SEQ ID NO:70, an anti-CD3 heavy chain comprising SEQ ID NO:81, and an anti-CD3 light chain comprising SEQ ID NO:80.

[0047] In some embodiments, the antigen binding molecule is a single-chain Fv (scFv), a trispecific (Fab3), a bispecific (Fab2), a diabody ((VL-VH)2 or (VH-VL)2), a triabody (trivalent), a tetrabody (tetravalent), a minibody ((scFV-CH)2), a bispecific single-chain Fv (bis-scFv), IgGδCH2, scFv-Fc or (scFv)2-Fc.

[0048] In some embodiments, the multispecific antigen-binding molecule is a multispecific antibody, preferably a bispecific or trispecific antibody.

[0049] In some embodiments, the multispecific antigen-binding molecule further comprises a third antigen-binding domain that binds to a tumor-associated antigen. In some embodiments, the tumor-associated antigen is a receptor expressed on prostate cancer cells or Ewing's sarcoma. In some embodiments, the tumor-associated antigen is prostate-specific membrane antigen (PSMA), STEAP2, prostate stem cell antigen (PSCA), epithelial cell adhesion molecule (EpCAM), prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), or HBA-71.

[0050] In some embodiments, the multispecific antigen-binding molecule binds to human STEAP1, cynomolgus monkey STEAP1, or a combination thereof, preferably wherein the multispecific antigen-binding molecule binds to human STEAP1 of SEQ ID NO:65.

[0051] In some embodiments, the first antigen binding domain binds to at least one, at least two, at least three, at least four, or at least five residues selected from Ser101, His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of STEAP1, wherein residue positions 101, 102, 103, 195, 198, 202, and 281 correspond to positions 101, 102, 103, 195, 198, 202, and 281 as shown in SEQ ID NO: 65. In some embodiments, the first antigen binding domain binds to Ser101, His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of STEAP1. In some embodiments, the heavy chain variable region of the first antigen binding domain forms hydrogen bonds with at least one, at least two, at least three, at least four, or at least five residues selected from Ser101, His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of STEAP1. In some embodiments, at least one, at least two, at least three, at least four, or at least five residues selected from Leu56, Ser73, Asn74, Gly101, Tyr103, and Tyr107 of the heavy chain variable region of the first antigen binding domain form hydrogen bonds with at least one, at least two, at least three, at least four, or at least five residues selected from Ser101, His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of STEAP1, wherein the residue positions of the heavy chain variable region of the first antigen binding domain correspond to positions 56, 73, 74, 101, 103, and 107 shown in SEQ ID NO: 18.

[0052] In some embodiments, the first antigen binding domain binds to at least one, at least two, or at least three residues selected from Gln201, Gln202, Asn203, and Lys204 of STEAP1, wherein residue positions 201, 202, 203, and 204 correspond to positions 201, 202, 203, and 204 as shown in SEQ ID NO: 65. In some embodiments, the first antigen binding domain binds to Gln201, Gln202, Asn203, and Lys204 of STEAP1. In some embodiments, the light chain variable region of the first antigen binding domain forms a hydrogen bond with at least one residue selected from Gln201 and Gln202 of STEAP1. In some embodiments, at least one residue selected from Tyr53 and Tyr54 of the light chain variable region of the first antigen binding domain forms a hydrogen bond with at least one residue selected from Gln201 and Gln202, wherein the residue positions of the light chain variable region of the first antigen binding domain correspond to positions 53 and 54 as shown in SEQ ID NO: 18. In some embodiments, the residues of the light chain variable region of the first antigen binding domain form a van der Waals interaction with at least one residue selected from Asn203 and Lys204 of STEAP1.

[0053] In some embodiments, the multispecific antigen-binding molecule has a C of about 11, 11.5, 12, 12.6, 13, 13.5, 15, 18, 20, 23.4, 25, 27.9, 29.1, or 30 μg / mL. max .

[0054] In some embodiments, the multispecific antigen-binding molecule has a C of about 11 μg / mL to about 30 μg / mL. max .

[0055] In some embodiments, the multispecific antigen-binding molecule has a C of about 20 μg / mL to about 28 μg / mL. max .

[0056] In some embodiments, the multispecific antigen-binding molecule has a C of about 24 μg / mL. max .

[0057] In some embodiments, the multispecific antigen-binding molecule has an EC of about 0.6, 0.56, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.05 or less. 50 .

[0058] In some embodiments, the multispecific antigen-binding molecule has an EC of about 0.05 to about 0.8. 50 .

[0059] In some embodiments, EC 50 The EC was determined in a 72-hour cell killing assay using human CD8+ T cells and LNCaP-X1.2 cells expressing STEAP1. 50 is from about 0.05 to about 0.4.

[0060] In some embodiments, EC 50 is about 0.08 or about 0.3.

[0061] In some embodiments, EC 50 The EC was determined in a 72-hour cell killing assay using human CD8+ T cells and LNCaPX1.2KO3-13 cells expressing STEAP1. 50 is from about 0.1 to about 0.8.

[0062] In some embodiments, EC 50 is about 0.1 or about 0.7.

[0063] In some embodiments, the multispecific antigen-binding molecule monovalently binds to STEAP1.

[0064] At least another aspect of the invention described herein relates to an antigen-binding molecule that binds to STEAP1, the antigen-binding molecule comprising: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3 of a VH sequence selected from the group consisting of SEQ ID NOs: 7, 17 to 25, 30 to 34, 38, and 68; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3 of a VL sequence selected from the group consisting of SEQ ID NOs: 8, 26 to 29, 39, and 69.

[0065] At least another aspect of the invention described herein relates to an antigen-binding molecule that binds to STEAP1, the antigen-binding molecule comprising: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3; wherein

[0066] CDR-H1 contains Xaa 1 Xaa 2 YMA (SEQ ID NO: 35); wherein Xaa 1 is Asp(D) or Asn(N); and Xaa 2 is His (H), Tyr (Y) or Phe (F);

[0067] CDR-H2 contains YIXaa3 YGX 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36); wherein Xaa 3 Asp(D) or Ser(S); Xaa 4 is Gly(G), Asp(D) or Leu(L); Xaa 5 is Ser(S), Asp(D) or Asn(N); and Xaa 6 is Ser (S) or Tyr (Y);

[0068] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO: 37); wherein Xaa 7 is Phe(F) or Tyr(Y); Xaa 8 is Asn(N) or Asp(D); and Xaa 9 is Ala (A) or Gly (G);

[0069] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.

[0070] In some embodiments, CDR-H1 comprises the amino acid sequence of SEQ ID NO: 10, 1, or 9. In some embodiments, CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, 11, 12, or 13. In some embodiments, CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15.

[0071] In some embodiments, the antigen binding molecule comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 10; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 16; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0072] In some embodiments, the antigen binding molecule comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0073] In some embodiments, the antigen binding molecule comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 9; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 11; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0074] In some embodiments, the antigen binding molecule comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 9; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0075] In some embodiments, the antigen binding molecule comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 9; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 14; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0076] In some embodiments, the antigen binding molecule comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 10; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 13; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 15; CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0077] In some embodiments, the antigen binding molecule is a humanized antibody.

[0078] In some embodiments, the antigen binding molecule comprises an IgG framework region, optionally an IgG1 framework region.

[0079] In some embodiments, the antigen binding molecule comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO: 7, 17-25, 30-34, 38 or 68.

[0080] In some embodiments, the antigen binding domain comprises an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO: 8, 26-29, 39 or 69.

[0081] In some embodiments, the antigen binding molecule comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 68; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 69.

[0082] In some embodiments, the antigen binding molecule comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 34; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 27.

[0083] In some embodiments, the antigen binding molecule comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 30; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 27.

[0084] In some embodiments, the antigen binding molecule comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 31; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 27.

[0085] In some embodiments, the antigen binding molecule comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 32; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 27.

[0086] In some embodiments, the antigen binding molecule comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 33; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 27.

[0087] In some embodiments, the antigen binding molecule comprises an anti-STEAP1 heavy chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:83 and an anti-CD3 light chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:82.

[0088] In some embodiments, the antigen binding molecule comprises an anti-STEAP1 heavy chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:85 and an anti-CD3 light chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:84.

[0089] In some embodiments, the antigen binding molecule comprises an anti-STEAP1 heavy chain comprising SEQ ID NO: 73 and an anti-CD3 light chain comprising SEQ ID NO: 72. In some embodiments, the antigen binding molecule comprises an anti-STEAP1 heavy chain comprising SEQ ID NO: 71 and an anti-STEAP1 light chain comprising SEQ ID NO: 70.

[0090] In some embodiments, the antigen binding molecule is a full-length antibody or a fragment thereof.

[0091] In some embodiments, the antigen binding molecule is Fab, Fab', F(ab')2, Fv, Fd, single-chain Fv (scFv), trispecific (Fab3), bispecific (Fab2), diabody ((VL-VH)2 or (VH-VL)2), triabody (trivalent), tetrabody (tetravalent), minibody ((scFV-CH)2), bispecific single-chain Fv (bis-scFv), IgGδCH2, scFv-Fc or (scFv)2-Fc.

[0092] In some embodiments, the antigen binding molecule is a multispecific antibody, preferably wherein the antigen binding molecule is a bispecific antibody or a trispecific antibody.

[0093] In some embodiments, the antigen binding molecule further comprises an antigen binding domain that binds to a T cell receptor. In some embodiments, the T cell receptor is cluster of differentiation 3 (CD3).

[0094] In some embodiments, the antigen binding domain that binds to CD3 comprises an anti-CD3 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3, and an anti-CD3 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequence of SEQ ID NOs: 48 to 53, respectively.

[0095] In some embodiments, the antigen binding domain that binds to CD3 comprises: an anti-CD3 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:54; and an anti-CD3 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:55.

[0096] In some embodiments, the antigen binding domain that binds to CD3 comprises an anti-CD3 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3, and an anti-CD3 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 respectively comprise the amino acid sequence of SEQ ID NOs: 40 to 45.

[0097] In some embodiments, the antigen binding domain that binds to CD3 comprises an anti-CD3 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:46, and an anti-CD3 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:47.

[0098] In some embodiments, the antigen binding molecule further comprises an additional antigen binding domain that binds to a tumor-associated antigen. In some embodiments, the tumor-associated antigen is a receptor expressed on prostate cancer cells or Ewing's sarcoma. In some embodiments, the tumor-associated antigen is prostate-specific membrane antigen (PSMA), STEAP2, prostate stem cell antigen (PSCA), epithelial cell adhesion molecule (EpCAM), prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), or HBA-71.

[0099] In some embodiments, the antigen binding molecule binds to human STEAP1, cynomolgus monkey STEAP1, or a combination thereof, preferably wherein the antigen binding molecule binds to human STEAP1 of SEQ ID NO:65.

[0100] In some embodiments, the antigen binding molecule binds to at least one, at least two, at least three, at least four, or at least five residues selected from Ser101, His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of STEAP1, wherein residue positions 101, 102, 103, 195, 198, 202, and 281 correspond to positions 101, 102, 103, 195, 198, 202, and 281 as shown in SEQ ID NO: 65. In some embodiments, the antigen binding molecule binds to Ser101, His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of STEAP1. In some embodiments, the heavy chain variable region of the antigen binding molecule forms hydrogen bonds with at least one, at least two, at least three, at least four, or at least five residues selected from Ser101, His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of STEAP1. In some embodiments, at least one, at least two, at least three, at least four, or at least five residues selected from Leu56, Ser73, Asn74, Gly101, Tyr103, and Tyr107 of the heavy chain variable region of the antigen binding molecule form hydrogen bonds with at least one, at least two, at least three, at least four, or at least five residues selected from Ser101, His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of STEAP1, wherein the residue positions of the heavy chain variable region of the antigen binding molecule correspond to positions 56, 73, 74, 101, 103, and 107 shown in SEQ ID NO: 18.

[0101] In some embodiments, the antigen-binding molecule binds to at least one, at least two, or at least three residues selected from Gln201, Gln202, Asn203, and Lys204 of STEAP1, wherein residue positions 201, 202, 203, and 204 correspond to positions 201, 202, 203, and 204 as shown in SEQ ID NO: 65. In some embodiments, the antigen-binding molecule binds to Gln201, Gln202, Asn203, and Lys204 of STEAP1. In some embodiments, the light chain variable region of the antigen-binding molecule forms a hydrogen bond with at least one residue selected from Gln201 and Gln202 of STEAP1. In some embodiments, at least one residue selected from Tyr53 and Tyr54 of the light chain variable region of the antigen-binding molecule forms a hydrogen bond with at least one residue selected from Gln201 and Gln202, wherein the residue positions of the light chain variable region of the antigen-binding molecule correspond to positions 53 and 54 as shown in SEQ ID NO: 18. In some embodiments, the residues of the light chain variable region of the antigen binding molecule form van der Waals interactions with at least one residue selected from Asn203 and Lys204 of STEAP1.

[0102] In some embodiments, the antigen binding molecule binds monovalently to STEAP1.

[0103] At least another aspect of the invention described herein relates to an antibody comprising a first antigen binding domain that binds to human STEAP1 at one or more residues selected from Ser101, His102, Gln103, Trp195, Gln198, Gln202, and Lys281, wherein residue positions 101, 102, 103, 195, 198, 202, and 281 correspond to positions 101, 102, 103, 195, 198, 202, and 281 as set forth in SEQ ID NO:65.

[0104] In some embodiments, the first antigen-binding domain binds to at least one, at least two, at least three, at least four, or at least five residues selected from Ser101, His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of SEQ ID NO: 65. In some embodiments, the first antigen-binding domain binds to Ser101, His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of SEQ ID NO: 65. In some embodiments, the heavy chain variable region of the first antigen-binding domain forms hydrogen bonds with at least one, at least two, at least three, at least four, or at least five residues selected from Ser101, His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of STEAP1. In some embodiments, at least one, at least two, at least three, at least four, or at least five residues selected from Leu56, Ser73, Asn74, Gly101, Tyr103, and Tyr107 of the heavy chain variable region of the first antigen binding domain form hydrogen bonds with at least one, at least two, at least three, at least four, or at least five residues selected from Ser101, His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of STEAP1, wherein the residue positions of the heavy chain variable region of the first antigen binding domain correspond to positions 56, 73, 74, 101, 103, and 107 shown in SEQ ID NO: 18.

[0105] In some embodiments, the first antigen-binding domain comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3 of a VH sequence selected from the group consisting of SEQ ID NOs: 7, 17 to 25, 30 to 34, 38, and 68; and three CDRs of an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3 of a VL sequence selected from the group consisting of SEQ ID NOs: 8, 26 to 29, 39, and 69.

[0106] In some embodiments, the first antigen binding domain comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence comprising at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO: 7, 17-25, 30-34, 38 or 68.

[0107] In some embodiments, the first antigen binding domain comprises: an anti-STEAP1 light chain variable region comprising a VL sequence that is at least 80%, 85%, 90%, 95% or 100% identical to SEQ ID NO: 8, 26-29, 39 or 69.

[0108] In some embodiments, the antibody further comprises a second antigen binding domain that binds to a T cell receptor. In some embodiments, the T cell receptor is cluster of differentiation 3 (CD3).

[0109] In some embodiments, the second antigen binding domain that binds to CD3 comprises an anti-CD3 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3, and an anti-CD3 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequence of SEQ ID NOs: 48 to 53, respectively.

[0110] In some embodiments, the second antigen binding domain that binds to CD3 comprises: an anti-CD3 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:54; and an anti-CD3 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:55.

[0111] In some embodiments, the second antigen binding domain that binds to CD3 comprises an anti-CD3 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3, and an anti-CD3 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3, wherein CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 respectively comprise the amino acid sequence of SEQ ID NOs: 40 to 45.

[0112] In some embodiments, the second antigen binding domain that binds to CD3 comprises: an anti-CD3 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:46; and an anti-CD3 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO:47.

[0113] In some embodiments, the multispecific antigen-binding molecule further comprises a third antigen-binding domain that binds to a tumor-associated antigen. In some embodiments, the tumor-associated antigen is a receptor expressed on prostate cancer cells. In some embodiments, the tumor-associated antigen is prostate-specific membrane antigen (PSMA), STEAP2, prostate stem cell antigen (PSCA), epithelial cell adhesion molecule (EpCAM), prostate-specific antigen (PSA), or prostatic acid phosphatase (PAP).

[0114] At least another aspect of the invention described herein relates to one or more isolated nucleic acids that, alone or together, encode a multispecific antigen-binding molecule described herein, an antigen-binding molecule described herein, or an antibody described herein.

[0115] At least another aspect of the invention described herein relates to one or more vectors, which alone or together comprise an isolated nucleic acid described herein.

[0116] At least another aspect of the present invention as described herein relates to one or more host cells, which individually or together comprise the isolated nucleic acid as described herein or the vector as described herein. In some embodiments, the host cell is a mammalian cell. In some embodiments, the mammalian cell is a Chinese hamster ovary (CHO) cell. In some embodiments, the host cell is an insect cell. In some embodiments, the host cell is a prokaryotic cell.

[0117] At least another aspect of the invention described herein relates to a method of producing a multispecific antigen-binding molecule, an antigen-binding molecule, or an antibody described herein, comprising culturing a host cell described herein in a culture medium. In some embodiments, the method further comprises harvesting the multispecific antigen-binding molecule, an antigen-binding molecule, or an antibody described herein from the host cell or culture medium.

[0118] At least another aspect of the invention described herein relates to a pharmaceutical composition comprising a multispecific antigen-binding molecule, an antigen-binding molecule, or an antibody as described herein. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, or diluent.

[0119] In some embodiments, the pharmaceutical composition is used as a medicament. In some embodiments, the pharmaceutical composition is used to treat or delay the progression of a cancer expressing STEAP1. In some embodiments, the pharmaceutical composition is used to treat or delay the progression of prostate cancer or Ewing's sarcoma.

[0120] At least another aspect of the invention described herein relates to the use of a multispecific antigen-binding molecule described herein, an antigen-binding molecule described herein, or an antibody described herein for treating or delaying progression of a STEAP1-expressing cancer in a subject in need thereof.

[0121] At least another aspect of the invention described herein relates to the use of a multispecific antigen-binding molecule described herein, an antigen-binding molecule described herein, or an antibody described herein for inhibiting or reducing the proliferation of cancer cells expressing STEAP1.

[0122] In some embodiments, the cancer expressing STEAP1 is a solid tumor.

[0123] In some embodiments, the cancer expressing STEAP1 is prostate cancer or Ewing's sarcoma.

[0124] In some embodiments, the multispecific antigen-binding molecules described herein, the antigen-binding molecules described herein, or the antibodies described herein are to be used in combination with additional therapeutic agents or additional treatment regimens.

[0125] In some embodiments, the additional therapeutic agent comprises a chemotherapeutic agent, an immunotherapeutic agent, a targeted therapy, a radiation therapy, or a combination thereof.

[0126] In some embodiments, the additional therapeutic agent comprises a first-line, second-line, or third-line therapy.

[0127] In some embodiments, the additional treatment option comprises surgery.

[0128] In some embodiments, a multispecific antigen-binding molecule described herein, an antigen-binding molecule described herein, or an antibody described herein and an additional therapeutic agent are administered simultaneously.

[0129] In some embodiments, a multispecific antigen-binding molecule described herein, an antigen-binding molecule described herein, or an antibody described herein and the additional therapeutic agent are administered sequentially.

[0130] In some embodiments, a multispecific antigen-binding molecule described herein, an antigen-binding molecule described herein, or an antibody described herein is administered prior to administration of an additional therapeutic agent.

[0131] In some embodiments, a multispecific antigen-binding molecule described herein, an antigen-binding molecule described herein, or an antibody described herein is administered after administration of an additional therapeutic agent.

[0132] In some embodiments, a multispecific antigen-binding molecule described herein, an antigen-binding molecule described herein, or an antibody described herein is to be administered systemically.

[0133] In some embodiments, a multispecific antigen-binding molecule described herein, an antigen-binding molecule described herein, or an antibody described herein is to be administered topically.

[0134] In some embodiments, the multispecific antigen-binding molecules described herein, the antigen-binding molecules described herein, or the antibodies described herein are to be administered by parenteral administration.

[0135] In some embodiments, a multispecific antigen-binding molecule described herein, an antigen-binding molecule described herein, or an antibody described herein is to be administered intravenously or subcutaneously.

[0136] In some embodiments, the subject is a human.

[0137] At least another aspect of the invention described herein relates to the use of a multispecific antigen-binding molecule described herein, an antigen-binding molecule described herein, or an antibody described herein in the manufacture of a medicament for treating or delaying progression of a cancer expressing STEAP1, optionally for treating or delaying progression of prostate cancer or Ewing's sarcoma.

[0138] At least another aspect of the invention described herein relates to use of a multispecific antigen-binding molecule described herein, an antigen-binding molecule described herein, or an antibody described herein in the manufacture of a medicament for inhibiting or reducing the proliferation of cancer cells (optionally prostate cancer cells or Ewing's sarcoma cells) expressing STEAP1.

[0139] At least another aspect of the invention described herein relates to a method for treating or delaying progression of a STEAP1-expressing cancer in a subject in need thereof, comprising administering to the subject an effective amount of a multispecific antigen-binding molecule, an antigen-binding molecule, or an antibody described herein.

[0140] In some embodiments, the cancer expressing STEAP1 is a solid tumor. In some embodiments, the cancer expressing STEAP1 is prostate cancer or Ewing's sarcoma.

[0141] In some embodiments, the method further comprises administering to the subject an additional therapeutic agent or additional treatment regimen. In some embodiments, the additional therapeutic agent comprises a chemotherapeutic agent, an immunotherapeutic agent, a targeted therapy, a radiation therapy, or a combination thereof. In some embodiments, the additional therapeutic agent comprises a first-line, second-line, or third-line therapy. In some embodiments, the additional treatment regimen comprises surgery.

[0142] In some embodiments, the additional therapeutic agent is administered concurrently with a multispecific antigen-binding molecule described herein, an antigen-binding molecule described herein, or an antibody described herein.

[0143] In some embodiments, the additional therapeutic agent is administered sequentially with the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein.

[0144] In some embodiments, a multispecific antigen-binding molecule described herein, an antigen-binding molecule described herein, or an antibody described herein is administered prior to administration of an additional therapeutic agent.

[0145] In some embodiments, a multispecific antigen-binding molecule described herein, an antigen-binding molecule described herein, or an antibody described herein is administered after administration of an additional therapeutic agent.

[0146] In some embodiments, the multispecific antigen-binding molecules described herein, the antigen-binding molecules described herein, or the antibodies described herein are administered systemically. In some embodiments, the multispecific antigen-binding molecules described herein, the antigen-binding molecules described herein, or the antibodies described herein are administered topically. In some embodiments, the multispecific antigen-binding molecules described herein, the antigen-binding molecules described herein, or the antibodies described herein are administered parenterally. In some embodiments, the multispecific antigen-binding molecules described herein, the antigen-binding molecules described herein, or the antibodies described herein are administered intravenously or subcutaneously.

[0147] In some embodiments, the subject is a human.

[0148] At least another aspect of the invention described herein relates to a method of inhibiting or reducing proliferation of a cell expressing STEAP1, comprising contacting the cell with a multispecific antigen-binding molecule described herein, an antigen-binding molecule described herein, or an antibody described herein for a period of time sufficient to inhibit proliferation of the cell.

[0149] In some embodiments, the cell is a prostate cancer cell or an Ewing's sarcoma cell. In some embodiments, the method is an in vivo method. In some embodiments, the method is an in vitro or ex vivo method.

[0150] At least another aspect of the invention described herein relates to a kit comprising a multispecific antigen-binding molecule described herein, an antigen-binding molecule described herein, an antibody described herein, an isolated nucleic acid described herein, a vector described herein, a host cell described herein, or a pharmaceutical composition described herein, optionally comprising a set of instructions. BRIEF DESCRIPTION OF THE DRAWINGS

[0151] Figure 1AScreening for selected rat monoclonal antibodies that specifically bind to cells expressing STEAP 1 is shown. The rat monoclonal antibodies are STEAP 1-44, STEAP 1-45, STEAP 1-81, STEAP 1-75, STEAP 1-103, STEAP 1-10, STEAP 1-23, STEAP 1-67, STEAP 1-34, STEAP 1-19, and STEAP 1-92.

[0152] Figure 1B Screening of selected rat monoclonal antibodies that specifically bind to cells expressing STEAP1 is shown. The rat monoclonal antibodies are STEAP1-48, STEAP1-15, STEAP1-28, STEAP1-95, STEAP1-54, STEAP1-69, STEAP1-2, STEAP1-59, STEAP1-49, and STEAP1-62. Ab120 is a control antibody.

[0153] Figure 1C Binding of antibody STEAP1-44 in a titration assay is shown. Arrows indicate the minimum concentrations of STEAP1-44 observed to bind to 293-hSTEAP1, PC3-hSTEAP1, LNCaP X1.2, and 22Rv1 cells, which are 0.39 nM, 6.25 nM, 3.125 nM, and 12.5 nM, respectively.

[0154] Figure 2 Variable region sequences of the antibody STEAP1-44 and STEAP1-44 clonal variants obtained by deep sequencing are shown, aligned with the closest rat germline segment sequence (top sequence). For the clonal variants obtained by deep sequencing ("NGS"), only the heavy chain is provided. They were combined with the STEAP1-44 light chain to generate the full-length antibody, thereby sharing the light chain. Assumed somatic mutations are shown with a black background. CDR boundaries according to the Kabat and Chothia systems are shown above the alignment, with Kabat CDR boundaries underlined. Residue numbering is according to the Kabat system. Dots represent sequence differences introduced by the alignment software. Germline segment names are shown in the alignment. The SEQ ID NOs for the Kabat CDRs and VH and VL sequences are shown in Table 1. The SEQ ID NOs for the Chothia CDRs are shown in Table 2.

[0155] Figure 3 Scores for somatic mutations in the STEAP1-44 clonotype panel from a deep sequencing dataset are shown. Sequence read counts for each amino acid mutation at each position are shown. Black boxes indicate germline wild-type residues. Residues highlighted in gray indicate the most common somatic mutations in the CDR regions.

[0156] Figure 4A Shown are tests of STEAP1-44 clonal variants binding to STEAP1 on the cell surface.

[0157] Figure 4B Shown are tests of STEAP1-44 clone variants binding to soluble recombinant STEAP1.

[0158] Figure 5A The light chain variable region sequences of the humanized variants of STEAP1-44 are shown aligned with the humanized framework. Differences between the variants and the humanized variants are shown with a black background. CDR boundaries according to the Kabat and Chothia systems are shown above the alignment, with Kabat CDR boundaries underlined. Residue numbering is according to the Kabat system. Dots represent sequence differences introduced by the alignment software. The SEQ ID NOs for the Kabat CDR and VL sequences are shown in Table 1. The SEQ ID NOs for the Chothia CDRs are shown in Table 2.

[0159] Figure 5B The heavy chain variable region sequences of the humanized STEAP1-44 variants are shown aligned with the humanized framework. Differences between the variants and the humanized framework are shown with a black background. CDR boundaries according to the Kabat and Chothia systems are shown above the alignment, with Kabat CDR boundaries underlined. Residue numbering is according to the Kabat system. Dots represent sequence differences introduced by the alignment software. The SEQ ID NOs for the Kabat CDR and VH sequences are shown in Table 1. The SEQ ID NOs for the Chothia CDRs are shown in Table 2.

[0160] Figure 6A Shown are the median fluorescence units (MFI) of the humanized variants of the antibody tested at two different concentrations. The variants are ranked from left to right from strongest to weakest binding, in the same order at both concentrations tested.

[0161] Figure 6B Shown is a humanized variant huAb44.v6 with somatic mutations testing of five NGS-based variants for binding to LNCaP-X1.2 cells expressing STEAP 1. huAb44.v6 is the parental humanized clone, chAb44 is a human IgG1 with the rat variable domains of Ab44, and huAb44.v6.01 to 05 are sequence variants of huAb44.v6 with somatic mutations identified by library NGS.

[0162] Figure 6CThe sequence of the humanized antibody variant huAb44.v6.05 is shown aligned with the humanized antibody huAb44.v6. The differences in huAb44.v6.05 relative to huAb44.v6 are shown with a black background. The CDR boundaries according to the Kabat and Chothia systems are shown above the alignment, with the Kabat CDR boundaries underlined. Residue numbering is according to the Kabat system. The SEQ ID NOs for the Kabat CDRs and VH and VL region sequences are shown in Table 1. The SEQ ID NOs for the Chothia CDRs are shown in Table 2.

[0163] Figure 7A Shown is a bispecific anti-STEAP1 / anti-CD3 antibody tested in a cell killing assay using human CD8+ T cells and LNCaP-X1.2 cells expressing STEAP1. The anti-CD3 arm of the TDB molecule is designated MD1.

[0164] Figure 7B Shown are bispecific anti-STEAP1 / anti-CD3 antibodies tested in a cell killing assay using human CD8+ T cells and LNCaP-X1.2 cells expressing STEAP1. The anti-CD3 arm of the TDB molecule is denoted as MD1 or 40G5c.

[0165] picture Figure 8A Shown are the levels of STEAP1 in gene-edited LNCaPX1.2 sublines (LNCaP-X1.2-KO-3-13, LNCaP-X1.KO-2-11) measured by fluorescence-activated cell sorting (FACS) analysis or Western blot. LNCaP-X1.2-KO-2-8 lacks STEAP1 expression.

[0166] Figure 8B Shown are huAb44v6.05 TDB tested in cell killing assays with human CD8+ T cells and the indicated cell lines.

[0167] Figure 8C Target-dependent T cell activation (24 hours) of huAb44.v6.05 / 40G5c is shown.

[0168] Figure 8D Target-dependent cytokine secretion of huAb44.v6.05 / 40G5c is shown (24 hours).

[0169] Figure 9STEAP1-TDB is shown to inhibit the growth of established LNCaP-X1.2, LNCaP-X1.2-KO-3-13, and LNCaP-X1.KO-2-11 tumors in NSG mice supplemented with human PBMCs. Animals received a single IV dose of STEAP1-TDB on day 0, as designated. Doses ranged from 0.1 mg / kg to 0.5 mg / kg. Individual tumor volumes are plotted for each treatment group. The dashed line indicates the fitted tumor volume for the control group (vehicle), and the solid line indicates the individual tumors.

[0170] Figure 10A Shown are concentration-time curves of anti-STEAP1 antibodies following a single intravenous dose of 1 mg / kg in female SCID mice.

[0171] Figure 10B Shown are concentration-time curves of anti-STEAP1 / CD3 TDB and anti-gD following a single intravenous dose of 1 mg / kg in female SCID mice.

[0172] Figure 10C Shown are the concentration-time curves of huAb44.v6.05 / 40G5c and huAb44.v6.05 / MD1 TDB following intravenous administration in cynomolgus monkeys.

[0173] Figure 11A Cryo-EM reconstruction of STEAP1 in complex with Ab44 is shown with a resolution of approximately An isosurface rendering of the complex of a STEAP1 homotrimer (arrows 1, 2, and 3 represent protomers) with three Ab44 fabs (arrow 4 represents the heavy chain, arrow 5 represents the light chain, and arrow 6 represents the constant region) is shown. The extracellular loops ECL1, ECL2, and ECL3 of STEAP1 are indicated by arrows 7, 8, and 9, respectively.

[0174] Figure 11B A strip rendering of the structure is shown. A side view (along the plane of the membrane, equivalent to Figure A) and a top view are shown. For clarity, only the heme from one subunit is shown (indicated by arrow 10). The remaining arrows are numbered the same as Figure 11A The same as in .

[0175] Figure 12A The interaction between Ab44 Fab and STEAP1 subunit A is shown (two orthogonal side views rotated 90 degrees are shown). STEAP1 residues within are shown as spheres. The arrows are numbered with Figure 11B For clarity, STEAP1 subunits B and C have been omitted.

[0176] Figure 12BShown is the interaction between Ab44 Fab and the adjacent subunit B of STEAP1. The view is the same as in panel A. For clarity, STEAP1 subunits A and C have been omitted. The arrows are numbered as in panel A. Figure 11B The same as in .

[0177] Figure 13A Surface images of the STEAP1:Fab44 complex are shown. Surfaces hidden by complex formation are indicated by arrows 1 (Fab A to STEAP1 subunit A) and 2 (Fab A to STEAP1 subunit B); hidden surfaces representing homologous interactions are indicated by arrows 3 (Fab A to Fab B) or 4 (Fab A to Fab C). STEAP1 monomers are represented by the letters A, B, and C. Arrow 5 represents the light chain, and arrows 6, 7, and 8 represent the heavy chain.

[0178] Figure 13B A detailed illustration of the same surface is shown, showing the surface area measurements of each hidden surface.

[0179] Figure 14 Figure 2 shows the organization of Ab44 and Vandortuzumab upon binding to STEAP1. Multiple polar homologous Fab interactions (shown as spheres) were observed along the three-fold axis of the STEAP1:Ab44 structure, primarily driven by LC-LC contacts (left panel, viewed from the extracellular side). In contrast, limited interactions were observed between the Vandortuzumab Fabs (right panel). Arrow 1 indicates the light chain, and arrows 2, 3, and 4 indicate the heavy chain. For clarity, the STEAP1 homotrimer (located in the center of Fab A) is not shown. , except for residues within , which are shown as spheres).

[0180] Figure 15 Sequence alignments for humans, cynomolgus monkeys, and orangutans are shown. The expected transmembrane helix is ​​highlighted in yellow, and extracellular loops 1, 2, and 3 are highlighted in green, red, and orange boxes, respectively.

[0181] Figure 16 A sequence alignment of the variable regions of humanized antibody variants huAb44.v6, huAb44.v6.01, huAb44.v6.02, huAb44.v6.03, huAb44.v6.04, and huAb44.v6.05 is shown. The CDR sequences according to the Kabat definition are underlined. The SEQ ID NOs for the Kabat CDRs and VH and VL sequences are shown in Table 1. The SEQ ID NOs for the Chothia CDRs are shown in Table 2.

[0182] Figure 17The sequence alignment of the STEAP1-specific variable regions of the bispecific antibodies is shown. The CDR sequences according to the Kabat definition are underlined. The SEQ ID NOs of the Kabat CDRs and VH and VL sequences are shown in Table 1. The SEQ ID NOs of the Chothia CDRs are shown in Table 2.

[0183] Figure 18 The sequence alignment of the CD3-specific variable regions of the bispecific antibodies is shown. The CDR sequences according to the Kabat definition are underlined. The SEQ ID NOs of the Kabat CDRs and VH and VL sequences are shown in Table 1. The SEQ ID NOs of the Chothia CDRs are shown in Table 2.

[0184] Figure 19 Shown is the sequence alignment of the STEAP1 specific chain constant region.

[0185] Figure 20 Sequence alignment of the CD3-specific chain constant regions is shown.

[0186] Figure 21 A sequence alignment of the variable regions of rabbit anti-human STEAP1 antibodies is shown. CDR boundaries according to the Kabat and Chothia systems are shown above the alignment, with Kabat CDR boundaries underlined. Residue numbering is according to the Kabat system. Dots represent sequence differences introduced by the alignment software. The SEQ ID NOs for the Kabat CDRs and VH and VL sequences are shown in Table 1. The SEQ ID NOs for the Chothia CDRs are shown in Table 2.

[0187] Figure 22 Comparison of binding of huAb44v6.05 and vendotuzumab to LNCaP-X1.2 cells expressing STEAP1 as assessed by FACS is shown. The MFI of the antibody variants was tested at the indicated concentrations. The EC50 for vendotuzumab was 3.5 nM, and the EC50 for huAb44.v6.05 was 1.9 nM.

[0188] Figure 23A Figure 2 shows bispecific anti-STEAP1 / anti-CD3 antibodies tested in a cell killing assay using human CD8+ T cells and STEAP1-expressing LNCaP-X1.2 cells. TDBs containing vendotumab and huAb44v6.05 were compared. The anti-CD3 arm of the TDB molecule was either MD1 or 40G5c, as indicated.

[0189] Figure 23BFigure 2 shows bispecific anti-STEAP1 / anti-CD3 antibodies tested in a cell killing assay using human CD8+ T cells and LNCaPX1.2KO3-13 cells expressing STEAP1. TDBs containing vendotumab and huAb44v6.05 were compared. The anti-CD3 arm of the TDB molecule was either MD1 or 40G5c, as indicated.

[0190] 24A to 24D is a series of graphs showing a comparison of huAb44.v6.05 / 40G5c and vendotuzumab / 40G5c TDB in a T cell activation assay. Figure 24A Shown are the results of CD4 T cell activation using LNCaP-X12 cells. Figure 24B Shown are the results of CD8 T cell activation using LNCaP-X12 cells. Figure 24C Shown are the results of CD4 T cell activation using LNCaP-X1.2-KO-3-13 cells. Figure 24D Shown are the results of CD8 T cell activation using LNCaP-X1.2-KO-3-13 cells. For each of these experiments, the PBMC to target ratio was 10:1 and the incubation time was 24 hours.

[0191] Figures 25A to 25J is a series of graphs showing a comparison of huAb44.v6.05 / 40G5c and vendotumab / 40G5c in a cytokine secretion assay at 24 hours. Figures 25A to 25E Results for LNCaP-X1.2 cells are shown, and Figures 25F to 25J Results for LNCaP-X1.2-KO-3-13 cells are shown. Figure 25A and Figure 25F Interferon (IFN) gamma secretion is shown. Figure 25B and Figure 25G Tumor necrosis factor (TNF) alpha secretion is shown. Figure 25C and Figure 25H IL-2 secretion is shown. Figure 25D and Figure 25I IL-6 secretion is shown. Figure 25E and Figure 25J Granzyme B secretion is shown. DETAILED DESCRIPTION

[0192] I. Definition

[0193] As used herein, the term "about" refers to the common error range of the corresponding value that is readily known to those skilled in the art. References to "about" values ​​or parameters herein include (and describe) embodiments involving the value or parameter itself.

[0194] "Affinity" refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, as used herein, "binding affinity" refers to intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y can generally be measured by the equilibrium dissociation constant (K D ). Affinity can be measured by conventional methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

[0195] As used herein, the term "binds to" refers to a measurable and reproducible interaction, such as the binding between a target and an antigen binding molecule (e.g., an antibody), which can determine the presence of a target in the presence of a population of heterologous molecules (including biomolecules). For example, an antigen binding molecule that specifically binds to a target (which may be an epitope) is an antigen binding molecule that binds to the target with an affinity, associativity, or ease and / or duration that is superior to the affinity, associativity, or ease and / or duration that it binds to other targets. In one embodiment, the extent to which an antigen binding molecule binds to an unrelated target is less than about 10% of the extent to which the antigen binding molecule binds to the target, as determined by surface plasmon resonance (SPR), radioimmunoassay (RIA), or kinetic exclusion assay. In certain embodiments, an antigen binding molecule that specifically binds to a target has an equilibrium dissociation constant (K) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, or ≤0.1 nM. D In certain embodiments, the antigen binding molecules specifically bind to an epitope on a protein that is conserved among proteins of different species. In another embodiment, specific binding may include but does not require exclusive binding.

[0196] As used herein, the term "antigen binding molecule" refers to a molecule that specifically binds to a target epitope, antigen, ligand or receptor. Binding domain includes, but is not limited to, antibodies (e.g., monoclonal antibodies, polyclonal antibodies, recombinant antibodies, humanized antibodies and chimeric antibodies), antibody fragments or portions thereof (e.g., Fab fragments, Fab'2, scFv antibodies, SMIPs, domain antibodies, double antibodies, microantibodies, scFv-Fc, affibodies, nanoantibodies and the VH and / or VL domains of antibodies), receptors, ligands, aptamers and other molecules with determined binding partners. "Affinity maturation" antibodies refer to antibodies with one or more changes in one or more complementary determining regions (CDRs) or highly variable regions (HVRs), which, compared to parent antibodies without such changes, result in improvements in the affinity of antibodies to antigens.

[0197] The term "antigen binding domain" refers to a portion of a compound or molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Molecules with an antigen binding portion include, but are not limited to, antibodies (e.g., monoclonal antibodies, polyclonal antibodies, recombinant antibodies, humanized antibodies, and chimeric antibodies), antibody fragments or portions thereof (e.g., Fab fragments, Fab'2, scFv antibodies, SMIPs, domain antibodies, diabodies, miniantibodies, scFv-Fc, affibodies, nanobodies, and VH and / or VL domains of antibodies), receptors, ligands, aptamers, and other molecules with defined binding partners.

[0198] The term "antibody" herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific or trispecific antibodies), and antibody fragments, so long as they exhibit the intended antigen-binding activity.

[0199] "Antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody and binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv and scFab); single-domain antibodies (dAbs); and multispecific antibodies formed from antibody fragments. For a review of certain antibody fragments, see Holliger and Hudson, Nat. Biotech. 23:1126-1136 (2005).

[0200] A "single-chain variable fragment" or "scFv" is a fusion protein of the heavy chain variable domain (VH) and light chain variable domain (VL) of an antibody, connected by a linker. In particular, the linker is a short polypeptide of 10 to about 25 amino acids and is generally rich in glycine for flexibility and rich in serine or threonine for solubility, and can connect the N-terminus of the VH to the C-terminus of the VL, or vice versa. Despite the removal of the constant region and the introduction of a linker, the protein retains the specificity of the original antibody. For a review of scFv fragments, see, for example, Pluckthün in The harmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315 (1994); see also WO 93 / 16185; and U.S. Pat. Nos. 5,571,894 and 5,587,458.

[0201] "Single-chain Fab fragments" or "scFab" are polypeptides consisting of an antibody heavy chain variable domain (VH), an antibody heavy chain constant domain 1 (CH1), an antibody light chain variable domain (VL), an antibody light chain constant domain (CL), and a linker, wherein the antibody domains and the linker have one of the following orders in the N-terminal to C-terminal direction: a) VH-CH1-linker-VL-CL, b) VL-CL-linker-VH-CH1, c) VH-CL-linker-VL-CH1, or d) VL-CH1-linker-VH-CL. In particular, the linker is a polypeptide of at least 30 amino acids, preferably between 32 and 50 amino acids. The single-chain Fab fragments are stabilized via the natural disulfide bonds between the CL domain and the CH1 domain. In addition, these single-chain Fab fragments can be further stabilized by generating interchain disulfide bonds by inserting cysteine ​​residues (e.g., position 44 in the variable heavy chain and position 100 in the variable light chain according to Kabat numbering).

[0202] The term "cross-Fab fragment" or "xFab fragment" or "cross Fab fragment" refers to a Fab fragment in which the variable regions or constant regions of the heavy and light chains are exchanged. The cross Fab fragment contains a polypeptide chain consisting of the light chain variable region (VL) and the heavy chain constant region 1 (CH1), and a polypeptide chain consisting of the heavy chain variable region (VH) and the light chain constant region (CL). Asymmetric Fab arms can also be engineered by introducing charged or uncharged amino acid mutations into the domain interface to guide correct Fab pairing. See, for example, WO 2016 / 172485.

[0203] The term "antigen" refers to a protein or non-protein molecule to which an antigen binding molecule (eg, an antibody) binds. Antigens may include proteins, protein fragments, or haptens.

[0204] The term "epitope" refers to a site on an antigen, whether proteinaceous or non-proteinaceous, to which an anti-STEAP1 antigen-binding molecule (e.g., an anti-STEAP1 antibody) binds. An epitope can be formed by a continuous stretch of amino acids (linear epitope) or by the inclusion of non-contiguous amino acids (conformational epitope), for example, due to antigen folding, i.e., due to the tertiary folding of the protein antigen. Linear epitopes typically remain bound to the anti-STEAP1 antigen-binding molecule after exposure of the protein antigen to a denaturant, while conformational epitopes are typically destroyed after denaturant treatment. An epitope comprises at least 3, at least 4, at least 5, at least 6, at least 7, or 8 to 10 amino acids in a unique three-dimensional conformation.

[0205] Screening for antigen-binding molecules (e.g., antibodies) that bind to a specific epitope (i.e., those that bind to the same epitope) can be performed using routine methods in this field, such as, but not limited to, alanine scanning, peptide blotting (see Meth. Mol. Biol. 248 (2004) 443-463), peptide cleavage analysis, epitope excision, epitope extraction, chemical modification of antigens (see Prot. Sci. 9 (2000) 487-496), and cross-blocking (see "Antibodies", Harlow and Lane (Cold Spring Harbor Press, Cold Spring Harb., NY).

[0206] Antigen structure-based antibody profiling (ASAP), also known as modification-assisted profiling (MAP), allows for the binning of a large number of monoclonal antibodies that specifically bind to STEAP1 based on the binding profile of each antibody to a chemically or enzymatically modified antigen surface (see, e.g., US 2004 / 0101920). The antibodies in each group bind to the same epitope, which can be a unique epitope that is significantly different from or partially overlaps with the epitope represented by another group.

[0207] Additionally, competitive binding can be used to readily determine whether an antigen-binding molecule (e.g., an antibody) binds to the same epitope of STEAP1 or competes for binding with a reference anti-STEAP1 antibody. For example, an "antigen-binding molecule that binds to the same epitope as a reference anti-STEAP1 antibody" refers to an antigen-binding molecule that blocks binding of the reference anti-STEAP1 antibody to its antigen by 50% or more in a competition assay, whereas the reference antibody blocks binding of the antigen-binding molecule to its antigen by 50% or more in a competition assay. For another example, to determine whether an antigen-binding molecule binds to the same epitope as a reference anti-STEAP1 antibody, the reference antibody is allowed to bind to STEAP1 under saturating conditions. After removing excess reference anti-STEAP1 antibody, the ability of the anti-STEAP1 antigen-binding molecule to bind to STEAP1 is assessed. If the anti-STEAP1 antibody is able to bind to STEAP1 after saturating binding of the reference anti-STEAP1 antigen-binding molecule, it can be concluded that the anti-STEAP1 antigen-binding molecule binds to a different epitope than the reference anti-STEAP1 antibody. However, if the anti-STEAP1 antigen-binding molecule fails to bind to STEAP1 after saturation binding by the reference anti-STEAP1 antibody, the anti-STEAP1 antigen-binding molecule likely binds to the same epitope as the reference anti-STEAP1 antibody. To confirm whether the antigen-binding molecule binds to the same epitope or whether binding is simply hindered due to steric factors, conventional assays can be used (e.g., peptide mutagenesis and binding analysis using ELISA, RIA, surface plasmon resonance, flow cytometry, or any other quantitative or qualitative antibody binding assay available in the art). This assay can be performed in two setups, using two molecules as saturating antibodies. If only the first (saturating) antibody is able to bind to STEAP1 in both setups, it can be concluded that the anti-STEAP1 antigen-binding molecule and the reference anti-STEAP1 antibody compete for binding to STEAP1.

[0208] The term "STEAP1" refers to any STEAP1 from any vertebrate source, including mammals, such as primates (e.g., humans or non-human primates) and rodents (e.g., mice and rats). The term encompasses "full-length" STEAP1 and naturally occurring STEAP1 variants, such as splice variants or allelic variants. STEAP1 is a member of the six-segment transmembrane epithelial antigen of the prostate (STEAP) family of proteins. The STEAP protein family includes five members: STEAP1, STEAP2, STEAP3, STEAP4, and STEAP5. STEAP1, STEAP2, and STEAP4 have been observed to be overexpressed in various cancer cells, while being minimally expressed in normal tissues. STEAP1 include, for example, human STEAP1 (UniProtKB Reference No.: Q9UHE8-1; SEQ ID NO: 65), cynomolgus monkey STEAP1 (UniProtKB Reference No.: A0A2K5X1J3; SEQ ID NO: 66), and orangutan STEAP1 (UniProtKB Reference No.: H2PMZ0; SEQ ID NO: 67).

[0209] The following is an exemplary amino acid sequence of human STEAP1:

[0210] MESRKDITNQEELWKMKPRRNLEEDDYLHKDTGETSMLKRPVLLHLHQTAHADEFDCPSELQHTQELFPQWHLPIKIAAIIASLTFLYTLLREVIHPLATSHQQYFYKIPILVINKVLPMVSITLLALVYLPGVIAAIVQLHNGTKYKKFPHWLDKWMLTRKQFGLLSFFF AVLHAIYSLSYPMRRSYRYKLLNWAYQQVQQNKEDAWIEHDVWRMEIYVSLGIVGLAILALLAVTSIPSVSDSLTWREFHYIQSKLGIVSLLLGTIHALIFAWNKWIDIKQFVWYTPPTFMIAVFLPIVVLIFKSILFLPCLRKKILKIRHGWEDVTKINKTEICSQL(SEQ ID NO:65).

[0211] The following is an exemplary amino acid sequence of cynomolgus monkey (long-tailed macaque) STEAP1:

[0212] MESRKDITNEEELWKMKPRRNLEEDDYLHKDTGETSMLKRPVLLHLHQTAHADEFDCPSELQHTQELFPQWHLPIKIAAIIASLTFLYTLLREVIHPLATSHQQYFYKIPILVINKVLPMVSITLLALVYLPGVIAAIVQLHNGTKYKKFPHWLDKWMLTRKQFGLLSFFFAVLHAIYSLSYPMRRSYRYKLLNWAYQQVQQNKEDAWIEHDVWRMEIYVSLGIVGLAILALLAVTSIPSVSDSLTWREFHYIQSKLGIVSLLLATIHALIFAWNKWIDIKQFVWYTPPTFMIAVFLPVVVLIFKSILFLPCLRKKILKIRHGWEDVTKINKMEISSQL(SEQ ID NO:66).

[0213] The following is an exemplary amino acid sequence of STEAP1 from Pongo abelii:

[0214] MESRKDITNQEELWKMKPRRNLEEDDYLHKDTGETSMLKRPVLLHLHQTAHADEFDCPSELQQTRELFPQWHLPIKIAAIIASLTFLYTLLREVIHPLATSHQQYFYKIPILVINKVLPMVSITLLALVYLPGVIAAIVQLHNGTKYKKFPHWLDKWMLTRKQFGLLSFFFAVLHAIYSLSYPMRRSYRYKLLNWAYQQVQQNKEDAWIEHDVWRMEIYVSLGIVGLAILALLAVTSIPSVSDSLTWREFHYIQSKLGIVSLLLGTIHALIFAWNKWIDIKQFVWYTPPTFMIAVILPIVVLIFKSILFLPCLRKKILKIRHGWEDVTKINKTEISSQL(SEQ ID NO:67).

[0215] The term "anti-STEAP1 antigen-binding molecule" or "antigen-binding molecule that binds to STEAP1" refers to any molecule that can bind to STEAP1 with sufficient affinity such that the molecule can be used as a diagnostic and / or therapeutic agent targeting STEAP1. In one embodiment, the extent of binding of the anti-STEAP1 antigen-binding molecule to an unrelated non-STEAP1 protein is less than about 10% of the extent of binding of the antigen-binding molecule to STEAP1, for example, as determined by surface plasmon resonance (SPR), radioimmunoassay (RIA), or kinetic exclusion assay. In certain aspects, the anti-STEAP1 antigen binding molecule has a ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 -8 M or lower, such as 10 - 8 M to 10 -13 M, for example 10 -9 M to 10 -13 The dissociation constant (K D ). When the antigen-binding molecule has a K of 1 μM or less D When an antigen-binding molecule specifically binds to STEAP1, the antigen-binding molecule is said to "specifically bind" to STEAP1. In certain aspects, the anti-STEAP1 antigen-binding molecule binds to an epitope of STEAP1 that is conserved among STEAPs of different species.

[0216] The term "anti-STEAP1 antibody" or "antibody that binds to STEAP1" refers to an antibody that binds to STEAP1 with sufficient affinity to allow the molecule to be used as a diagnostic and / or therapeutic agent targeting STEAP1. In one embodiment, the extent of binding of the anti-STEAP1 antibody to an unrelated, non-STEAP1 protein is less than about 10% of the extent of binding of the antibody to STEAP1, for example, as determined by surface plasmon resonance (SPR), radioimmunoassay (RIA), or kinetic exclusion assay. In certain aspects, the anti-STEAP1 antibody has a ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 -8 M or lower, such as 10 -8 M to 10 -13 M, for example 10 -9 M to 10 -13 The dissociation constant (K D ). When the antibody has a K of 1 μM or less DWhen an antibody specifically binds to STEAP1, the antibody is said to "specifically bind" to STEAP1. In certain aspects, an anti-STEAP1 antibody binds to an epitope of STEAP1 that is conserved among STEAPs from different species.

[0217] Unless otherwise indicated, the term "cluster of differentiation 3" or "CD3" as used herein refers to any native CD3 from any vertebrate source, including, for example, primates (e.g., humans) and rodents (e.g., mice and rats), including, for example, CD3ε, CD3γ, CD3α, and CD3β chains. The term encompasses "full-length" unprocessed CD3 (e.g., unprocessed or unmodified CD3ε or CD3γ), as well as any form of CD3 produced by processing in cells. The term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, a human CD3ε protein (NCBI RefSeq No. NP_000724) having a length of 207 amino acids and a human CD3γ protein (NCBI RefSeq No. NP_000064) having a length of 182 amino acids.

[0218] The terms "anti-CD3 antibody" and "antibody that binds to CD3" refer to an antibody that binds to CD3 with sufficient affinity to allow the antibody to be used as a diagnostic and / or therapeutic agent targeting CD3. In one embodiment, the extent of binding of the anti-CD3 antibody to unrelated, non-CD3 proteins is less than about 10% of the extent of binding of the antibody to CD3, as determined, for example, by surface plasmon resonance (SPR), radioimmunoassay (RIA), or kinetic exclusion assay. In certain embodiments, the antibody that binds to CD3 has a specific activity of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g., 10 -8 M or smaller, for example, 10 -8 M to 10 -13 M, for example, 10 -9 M to 10 -13 The dissociation constant (K D). In certain embodiments, the anti-CD3 antibodies bind to an epitope of CD3 that is conserved in CD3 from different species. In some embodiments, the anti-CD3 antibodies are described in International Patent Application Publication No. WO 2015 / 095392, which is incorporated herein by reference in its entirety. In some embodiments, the anti-CD3 antibodies are described in U.S. Patent No. 10,174,124, which is incorporated herein by reference in its entirety. In other embodiments, the anti-CD3 antibodies are described in International Patent Application No. PCT / US2020 / 064635, which is incorporated herein by reference in its entirety.

[0219] In some embodiments, the anti-CD3 antibody is 40G5c. In some embodiments, the anti-CD3 antibody is 38E4V1.MD1. The CDRs and VH and VL sequences of 40G5c and 38E4V1.MD1 are listed in Tables 1 and 2.

[0220] In some aspects, two antibodies are considered to bind to the same or overlapping epitope if a 1-fold, 5-fold, 10-fold, 20-fold, or 100-fold excess of one antibody inhibits the binding of the other antibody by at least 50%, at least 75%, at least 90%, or even 99% or more (as measured by a competitive binding assay) (see, e.g., Junghans et al., Cancer Res. 50 (1990) 1495-1502).

[0221] In some aspects, two antibodies are considered to bind to the same epitope if substantially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody also reduce or eliminate binding of the other antibody. Two antibodies are considered to have "overlapping epitopes" if only a subset of amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other antibody.

[0222] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0223] The "class" of an antibody refers to the type of constant domain or constant region possessed by the heavy chain of the antibody. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these antibodies can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. In some aspects, the antibody is an IgG1 isotype. In some aspects, the antibody is an IgG1 isotype with P329G, L234A, and L235A mutations to reduce the effector function of the Fc region. In other aspects, the antibody is an IgG2 isotype. In some aspects, the antibody is an IgG4 isotype with an S228P mutation in the hinge region to improve the stability of the IgG4 antibody. The heavy chain constant domains corresponding to different classes of immunoglobulins are referred to as α, δ, ε, γ, and μ, respectively. The light chain of an antibody can be classified into one of two types based on the amino acid sequence of its constant domain, which are called kappa (κ) and lambda (λ).

[0224] As used herein, the term "hypervariable region" or "HVR" refers to each of the regions of an antibody variable domain that are hypervariable in sequence and determine antigen binding specificity, such as the "complementarity determining regions" ("CDRs").

[0225] Typically, antibodies contain six CDRs; three in VH (CDR-H1, CDR-H2, CDR-H3) and three in VL (CDR-L1, CDR-L2, CDR-L3). Exemplary CDRs herein include:

[0226] (a) Hypervariable loops occurring at the following amino acid residues: 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987));

[0227] (b) CDRs occurring at amino acid residues 24 to 34 (L1), 50 to 56 (L2), 89 to 97 (L3), 31 to 35b (H1), 50 to 65 (H2), and 95 to 102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991)); and

[0228] (c) Antigenic contact points occur at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)).

[0229] Unless otherwise indicated, CDRs are determined according to the method described in Kabat et al., supra. One skilled in the art will appreciate that CDR names may also be determined according to the method described in Chothia, supra, the method described in McCallum, supra, or any other scientifically accepted nomenclature system.

[0230] The term "variable region" or "variable domain" refers to the domain of an antibody heavy chain or light chain that participates in binding of the antibody to the antigen. The variable domains of the heavy and light chains (VH and VL, respectively) of natural antibodies generally have similar structures, and each domain comprises four conserved framework regions (FRs) and three complementarity determining regions (CDRs) or hypervariable regions (HVRs). (See, e.g., Kindt et al., Kuby Immunology, 6th ed., WH Freeman and Co., p. 91 (2007)). A single VH or VL domain may be sufficient to confer antigen binding specificity. In addition, antibodies that bind to a specific antigen can be isolated using the VH or VL domains from antibodies that bind to the antigen, respectively, to screen for libraries of complementary VL or VH domains. See, e.g., Portolano et al., J. Immunol. 150: 880-887 (1993); Clarkson et al., Nature 352: 624-628 (1991).

[0231] "Constant region derived from human origin" or "human constant region" refers to the constant heavy chain region and / or constant light chain region kappa or lambda region of a human antibody of subclass IgG1, IgG2, IgG3 or IgG4. Such constant regions are well known in the art and are described, for example, in Kabat, EA et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991) (see also, for example, Johnson and Wu, Nucleic Acids Res. 28 (2000) 214-218; Kabat et al., Proc. Natl. Acad. Sci. USA 72 (1975) 2785-2788). Unless otherwise indicated herein, the numbering of amino acid residues in the constant region is according to the EU numbering system (also known as Kabat's EU index) as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991), NIH Publication 91-3242.

[0232] The terms "Fc region" or "Fc domain" are used interchangeably herein and refer to the C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, the human IgG heavy chain Fc region extends from Cys226 or from Pro230 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. The term encompasses truncated Fc regions, such as those with a C-terminal truncation (e.g., a ΔGK truncation, e.g., as described in Hu et al., Biotechnol. Prog. 2017, 33:786–794 and Jiang et al., J. Pharm. Sci. 2016, 105:2066–2072. Unless otherwise indicated herein, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD, 1991. As used herein, a "subunit" of an Fc domain refers to one of the two polypeptides that form a dimeric Fc domain, i.e., a polypeptide comprising the C-terminal constant region of an immunoglobulin heavy chain, which polypeptide is capable of stable self-association. In one embodiment, a subunit of an IgG Fc domain comprises an IgG CH2 and IgG CH3 constant domains.

[0233] "Framework" or "FR" refers to the variable domain residues other than the complementarity determining region (CDR) or hypervariable region (HVR) residues. The FR of a variable domain is typically composed of the following four FR domains: FR1, FR2, FR3, and FR4. Thus, the CDR and FR sequences typically appear in the following sequence in VH (or VL): FR1-CDR-H1 (CDR-L1)-FR2-CDR-H2 (CDR-L2)-FR3-CDR-H3 (CDR-L3)-FR4.

[0234] The terms "full length antibody," "intact antibody," and "whole antibody" are used interchangeably herein to refer to an antibody that has a structure substantially similar to a native antibody structure, or has heavy chains that contain an Fc region as defined herein.

[0235] A "human antibody" is an antibody having an amino acid sequence corresponding to the amino acid sequence of an antibody produced by a human or human cell, or derived from a non-human antibody using a full repertoire of human antibodies or other human antibody coding sequences. This definition of a human antibody specifically excludes humanized antibodies comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227: 381 (1991); Marks et al., J. Mol. Biol., 222: 581 (1991). Methods for preparing human monoclonal antibodies are also described in: Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147 (1): 86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5:368-74 (2001). Human antibodies are prepared by administering an antigen to a transgenic animal that has been engineered to produce such antibodies in response to antigenic challenge but whose endogenous loci have been disabled, e.g., a xenogeneic mouse (see, e.g., regarding XENOMOUSE). TM Nos. 6,075,181 and 6,150,584 for human antibodies generated via human B-cell hybridoma technology. See also, e.g., Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006) for human antibodies generated via human B-cell hybridoma technology.

[0236] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. In general, the selection of human immunoglobulin VL or VH sequences is from a subset of variable domain sequences. Typically, the subset of sequences is a subset as described in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), Volumes 1-3. In one embodiment, for VL, the subgroup is subgroup κI as described in Kabat et al. in the aforementioned literature. In one embodiment, for VH, the subgroup is subgroup III as described in Kabat et al. in the aforementioned literature.

[0237] "Humanization" refers to a chimeric antibody comprising amino acid residues from non-human CDRs or HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody will comprise substantially all of at least one (and typically two) variable domains, wherein all or substantially all of the CDRs or HVRs correspond to those of non-human antibodies, and all or substantially all of the FRs correspond to those of human antibodies. A humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, such as a non-human antibody, refers to an antibody that has undergone humanization.

[0238] As used herein, term " monoclonal antibody " refers to the antibody obtained from a substantially homogeneous antibody population, that is, except possible variant antibodies (for example, containing naturally occurring mutations or producing in the production process of monoclonal antibody preparations, such variants are usually present in small amounts), the individual antibodies comprising the population have identity and / or combine identical epitopes. Contrary to the polyclonal antibody preparations generally comprising different antibodies for different determinants (epitopes), each monoclonal antibody in the monoclonal antibody preparation is directed to a single determinant on the antigen. Therefore, the modifier " monoclonal " represents that the feature of antibody is obtained from a substantially homogeneous antibody population, and should not be construed as needing to produce antibody by any ad hoc method. For example, the monoclonal antibody to be used according to the present invention can be prepared by various techniques, including but not limited to hybridoma method, recombinant DNA method, phage display method and the method utilizing the transgenic animal containing all or part of human immunoglobulin locus, such methods and other exemplary methods for the preparation of monoclonal antibodies are described herein.

[0239] As used herein, the term "monospecific" refers to an antigen-binding molecule that binds to a single antigen (e.g., STEAP1). As used herein, the term "multispecific" refers to an antigen-binding molecule that binds to multiple different antigens (e.g., STEAP1 and CD3). For example, a "multispecific antibody" is a monoclonal antibody that has binding specificity for at least two different sites (i.e., different epitopes on different antigens or different epitopes on the same antigen).

[0240] "Natural antibodies" refer to naturally occurring immunoglobulin molecules with different structures. For example, natural IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons, consisting of two identical light chains and two identical heavy chains bonded by disulfide bonds. From the N-terminus to the C-terminus, each heavy chain has a variable region (Vh), also referred to as a variable heavy chain domain or a heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also referred to as a variable light chain domain or a light chain variable domain, followed by a constant light chain (CL) domain. The light chain of an antibody can be classified into one of two types based on the amino acid sequence of its constant domain, which are called kappa (κ) and lambda (λ).

[0241] " amino acid sequence identity percentage (%) " relative to reference polypeptide sequence is defined as after comparing candidate sequence with reference polypeptide sequence and introducing room (if necessary) to realize maximum sequence identity percentage, and for the purpose of comparison, without considering any conservative substitution as a component of sequence identity, the percentage that the amino acid residue in the candidate sequence is identical with the amino acid residue in the reference polypeptide sequence. Comparison for determining amino acid sequence identity percentage can be achieved in a variety of ways within the scope of the art, for example, using publicly available computer software, such as BLAST, BLAST-2, Clustal W, Megalign (DNASTAR) software or FASTA program package. Those skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithm required for maximum alignment over the full length of the compared sequence. Alternatively, sequence comparison computer program ALIGN-2 can be used to generate identity percentage values. The ALIGN-2 sequence comparison computer program was written by Genentech, Inc. and the source code has been filed with user documentation in the US Copyright Office, Washington DC, 20559, where it is registered under US Copyright Registration No. TXU510087 and is described in WO 2001 / 007611.

[0242] Unless otherwise indicated, for the purposes of this article, amino acid sequence identity percentage values ​​are generated using the BLOSUM50 comparison matrix using the ggsearch program of the FASTA package, version 36.3.8c or higher. The FASTA package was developed by Pearson and Lipman, Proc. Natl. Acad. Sci. USA 85:2444-2448 (1988); Pearson Meth. Enzymol. 266:227-258 (1996); and Pearson et al., Genomics 46:24-36 (1997), and is publicly accessible at www.fasta.bioch.virginia.edu / fasta_www2 / fasta_down.shtml or www.ebi.ac.uk / Tools / sss / fasta. Alternatively, sequences can be compared using a public server accessible at fasta.bioch.virginia.edu / fasta_www2 / index.cgi using the ggsearch (global protein:protein) program and default options (BLOSUM50; open: -10; ext: -2; Ktup = 2) to ensure a global rather than a local alignment. The percent amino acid identity is given in the output alignment header.

[0243] An "isolated" antibody is one that has been separated from components of its natural environment. In some aspects, the antibody is purified to a purity greater than 95% or 99% as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reversed-phase HPLC). For a review of methods for assessing antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0244] The term "nucleic acid molecule" or "polynucleotide" includes any compound and / or substance comprising a nucleotide polymer. Each nucleotide is composed of a base, particularly a purine or pyrimidine base (i.e., cytosine (C), guanine (G), adenine (A), thymine (T) or uracil (U)), a sugar (i.e., deoxyribose or ribose) and a phosphate group. Typically, nucleic acid molecules are described by a base sequence, wherein the base represents the primary structure (linear structure) of the nucleic acid molecule. The base sequence is typically expressed as from 5' to 3'. In this article, the term nucleic acid molecule encompasses deoxyribonucleic acid (DNA) (including, for example, complementary DNA (cDNA) and genomic DNA), ribonucleic acid (RNA) (particularly messenger RNA (mRNA)), synthetic forms of DNA or RNA, and mixed polymers comprising two or more of these molecules. Nucleic acid molecules can be linear or cyclic. In addition, the term nucleic acid molecule includes sense and antisense strands, as well as single-stranded and double-stranded forms. In addition, the nucleic acid molecules described herein can contain naturally occurring or non-naturally occurring nucleotides. Examples of non-naturally occurring nucleotides include modified nucleotide bases with derivatized sugar or phosphate backbone bonds or chemically modified residues. Nucleic acid molecules also include DNA and RNA molecules suitable for directly expressing vectors of antibodies of the present invention in vitro and / or in vivo, for example, in a host or patient. Such DNA (e.g., cDNA) or RNA (e.g., mRNA) vectors can be unmodified or modified. For example, mRNA can be chemically modified to enhance the stability of the RNA vector and / or the expression of the encoding molecule, thereby injecting the mRNA into the subject to produce antibodies (see, e.g., Stadler et al., Nat. Med. 23 (7): 815-817, 2017 or EP 2 101 823 B1).

[0245] An "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. Isolated nucleic acids include nucleic acid molecules contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location.

[0246] "Isolated nucleic acid encoding an anti-STEAP1 antibody" refers to one or more nucleic acid molecules encoding the heavy and light chains of an anti-STEAP1 antibody (or fragments thereof), including such nucleic acid molecules in a single vector or separate vectors, and such nucleic acid molecules present in one or more locations in a host cell.

[0247] "Isolated nucleic acid encoding an anti-CD3 antibody" refers to one or more nucleic acid molecules encoding the heavy and light chains of an anti-CD3 antibody (or fragments thereof), including such nucleic acid molecules in a single vector or separate vectors, and such nucleic acid molecules present in one or more locations in a host cell.

[0248] As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it is linked. The term includes vectors that are self-replicating nucleic acid structures, as well as vectors that are incorporated into the genome of a host cell into which they have been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors."

[0249] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and progeny derived from the primary transformed cell, regardless of the number of passages. Progeny may not be identical to the nucleic acid content of the parent cell but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected in the original transformed cell are included herein.

[0250] The term "pharmaceutical formulation" refers to a preparation that is in a form that permits the biological activity of the active ingredient contained therein to be effective, and that contains no additional components that are unacceptably toxic to a subject to which the formulation would be administered.

[0251] "Pharmaceutically acceptable carrier" refers to a component of a pharmaceutical preparation other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0252] As used herein, "administering" means a method of administering a dose of a compound (e.g., an antigen binding molecule of the invention or a nucleic acid encoding an antigen binding molecule of the invention) or composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition comprising an antigen binding molecule of the invention) to a subject. The compositions used in the methods described herein can be administered, for example, intramuscularly, intravenously, intradermally, transcutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctivally, intracapsularly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, topically, by inhalation, by injection, by infusion, by continuous infusion, by local perfusion directly into target cells, by catheter, by lavage, in the form of an emulsion or in the form of a lipid composition. The method of administration can vary depending on a variety of factors (e.g., the compound or composition to be administered and the severity of the condition, disease or disorder to be treated).

[0253] As used herein, "treatment" (and grammatical variations thereof, such as "treat" or "treating") refers to clinical intervention that attempts to alter the natural course of the individual being treated, and can be performed for prevention or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing the occurrence or recurrence of disease, alleviating symptoms, diminishing any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, ameliorating or alleviating the disease state, and alleviating or improving prognosis. In some embodiments, the antibodies of the invention are used to delay the development of disease or slow the progression of disease.

[0254] As used herein, "delaying progression" of a condition or disease means slowing, hindering, slowing, postponing, stabilizing, and / or postponing the development of a disease or condition (e.g., a cell proliferative disorder, e.g., cancer). Such a delay can be of varying lengths of time, depending on the medical history and / or the individual being treated. It will be apparent to one skilled in the art that a substantial or significant delay can actually encompass prevention, as the individual will not develop the disease. For example, the development of advanced cancers, such as metastases, can be delayed.

[0255] "Reduce" or "inhibit" means the ability to cause an overall decrease, for example, an overall decrease of 20% or more, 50% or more, or 75%, 85%, 90%, 95% or more. In certain embodiments, reduction or inhibition may refer to the effector function of the antigen-binding molecule mediated by the Fc region of the antibody, such effector functions specifically including complement dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP).

[0256] The terms "cancer" and "cancerous" refer to or describe a physiological condition in mammals that is typically characterized by uncontrolled cell growth. This definition includes both benign and malignant cancers. "Early stage cancer" or "early stage tumor" means a cancer that is non-invasive or metastatic or classified as stage 0, 1, or 2 cancer. Examples of cancer include, but are not limited to, solid tumors such as brain cancer, breast cancer, colorectal cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, gastric cancer, or thyroid cancer; hematologic malignancies such as Burkitt's lymphoma (BL), multiple myeloma, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), or Waldenstrom's macroglobulinemia (WM).

[0257] As used herein, the term "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, as well as all precancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" are not mutually exclusive herein.

[0258] The term "STEAP1-expressing cancer" refers to a cancer characterized by overexpression of STEAP1 in cancer cells compared to the expression level of STEAP1 in equivalent non-cancerous cells. Examples of STEAP1-expressing cancers include, but are not limited to, breast cancer, bladder cancer, cervical cancer, colorectal cancer, Ewing's sarcoma, lung cancer, ovarian cancer, and prostate cancer.

[0259] Prostate cancer is one of the most common cancers in men. Prostate cancer types may include prostate adenocarcinoma, prostate sarcoma, prostate transitional cell carcinoma, prostate small cell carcinoma, prostate neuroendocrine tumors, and castration-resistant prostate cancer (CRPC). Prostate cancer can also be classified based on molecular markers. For example, prostate cancer can be divided into cancers with rearrangements of ETS family transcription factors (e.g., ERG, ETV1, ETV4, and FLI1) and cancers with negative ETS factors. ETS-positive prostate cancer may also include changes in PI3K and p53 signaling. ETS-negative prostate cancer may show recurrent mutations in SPOP, FOXA1, and IDH1; loss of CHD1; and overexpression of SPINK1. In some cases, prostate cancer is metastatic prostate cancer (e.g., metastatic castration-resistant prostate cancer). In other cases, prostate cancer is recurrent or refractory prostate cancer.

[0260] Ewing sarcoma (also known as Ewing's sarcoma or Ewing's tumor) is a cancer of the bones and soft tissues (e.g., cartilage or nerves). There are several types of Ewing sarcoma, such as skeletal Ewing sarcoma, extraskeletal Ewing sarcoma, peripheral primitive neuroectodermal tumor (pPNET), and Askin tumor. The cause of Ewing sarcoma is unknown. Symptoms include pain and swelling at the tumor site.

[0261] As used herein, the term "tumor antigen" is understood to mean those antigens that are presented on tumor cells. These antigens can be presented on the cell surface using an extracellular portion, which is typically combined with the transmembrane and cytoplasmic portions of the molecule. These antigens can sometimes only be presented by tumor cells and not by normal cells. Tumor antigens may be expressed only on tumor cells or may express tumor-specific mutations compared to normal cells. In this case, they are referred to as tumor-specific antigens. More commonly, tumor antigens are presented by both tumor cells and normal cells, and are referred to as tumor-associated antigens. These tumor-associated antigens may be overexpressed compared to normal cells or, because the structure of tumor tissue is less compact than that of normal tissue, can be used for antibody binding in tumor cells. Exemplary tumor antigens include, but are not limited to, prostate-specific membrane antigen (PSMA), prostate stem cell antigen (PSCA), epithelial cell adhesion molecule (EpCAM), prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), STEAP2, and HBA-71. In some instances, TAAs for prostate cancer include prostate-specific membrane antigen (PSMA), prostate stem cell antigen (PSCA), epithelial cell adhesion molecule (EpCAM), prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP). In some instances, TAAs for Ewing sarcoma include HBA-71, a carbohydrate-coated antigen located on the cell surface of tumor cells.

[0262] The term "T cell receptor" or TCR refers to a receptor expressed on T cells. Exemplary T cell receptors include, but are not limited to, CD3.

[0263] An "effective amount" of a bispecific antigen binding molecule of the invention, or a composition thereof (e.g., a pharmaceutical composition) is at least the minimum amount required to achieve a desired therapeutic or preventive outcome, such as a measurable improvement or prevention of a particular disorder (e.g., a cell proliferative disorder, such as cancer). The effective amount herein can vary depending on factors such as the patient's disease state, age, sex, and weight, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also an amount in which the beneficial effects of the treatment outweigh any toxic or deleterious effects of the treatment. For preventive uses, beneficial or expected results include, for example, eliminating or reducing risk, reducing severity, or delaying the onset of disease, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that arise during the course of disease progression. For therapeutic uses, beneficial or expected results include clinical outcomes, such as reducing one or more symptoms caused by the disease, improving the quality of life of the patient, reducing the dose of other drugs required to treat the disease, enhancing the effects of other drugs (such as by targeting, delaying disease progression, and / or prolonging survival). In the case of cancer or tumors, an effective amount of a drug may reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down or expect to stop to some extent) cancer cell infiltration into surrounding organs; inhibit (i.e., slow down and expect to stop to some extent) tumor metastasis; inhibit the growth of the tumor to some extent; and / or alleviate one or more symptoms associated with the condition to some extent. An effective amount can be administered one or more times. For the purposes of the present invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly prevent or treat. As understood in a clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" may be considered in the context of administering one or more therapeutic agents, and an effective amount of a single agent may be considered if the desired result can be obtained or achieved in combination with one or more other agents.

[0264] As used herein, "first-line therapy" includes the primary treatment for a subject with cancer. In some cases, the cancer is a primary cancer. In other cases, the cancer is a metastatic or recurrent cancer. In some cases, the first-line treatment includes chemotherapy. In other cases, the first-line treatment includes radiation therapy. A skilled artisan will readily appreciate that different first-line treatments may be appropriate for different types of cancer.

[0265] In some cases, the additional therapeutic agent comprises a second-line therapy, a third-line therapy, a fourth-line therapy, or a fifth-line therapy. As used herein, second-line therapy encompasses treatment used after the primary or first-line therapy has stopped. Third-line therapy, fourth-line therapy, or fifth-line therapy encompasses subsequent treatment. As indicated by the naming convention, third-line therapy encompasses a course of treatment after the primary and second-line therapies have stopped.

[0266] As used herein, the terms "subject," "patient," or "subject" are used interchangeably and each refers to a mammal. Mammals include, but are not limited to, domesticated animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain aspects, the subject, patient, or experimenter is a human.

[0267] II. Composition

[0268] In one aspect, the present invention is based, in part, on antigen-binding molecules (e.g., monospecific and / or multispecific antigen-binding molecules). In some embodiments, the antigen-binding molecules bind to STEAP1. In some embodiments, the antigen-binding molecules are multispecific antigen-binding molecules that bind to STEAP1 and one or more additional antigens of interest. In certain embodiments, the multispecific antigen-binding molecules bind monovalently to STEAP1. The antigen-binding molecules of the present invention can be used, for example, to treat cancer (e.g., a cancer that expresses STEAP1) or delay its progression.

[0269] Exemplary Antigen Binding Molecules Binding to STEAP1

[0270] Antigen-binding molecules that bind to STEAP1

[0271] In some embodiments, the present invention provides isolated antigen-binding molecules that bind to STEAP1. In some embodiments, the antigen-binding molecules of the present invention comprise at least one, at least two, at least three, at least four, at least five, or all six CDRs as shown in Table 1 (Kabat) or Table 2 (Chothia). In some cases, the antigen-binding molecules comprise VH and / or VL as shown in Table 1.

[0272] Table 1

[0273]

[0274]

[0275] Table 2

[0276]

[0277]

[0278] In some embodiments, the antigen binding molecule that binds to STEAP1 comprises: an anti-STEAP1 heavy chain variable region (VH) comprising, consisting essentially of, or consisting of CDR-H1, CDR-H2, and / or CDR-H3 of a VH sequence selected from the group consisting of SEQ ID NOs: 7, 17 to 25, 30 to 34, and 38; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3 of a VL sequence selected from the group consisting of SEQ ID NOs: 8, 26 to 29, 39, and 69. In some cases, at least one, at least two, at least three, at least four, at least five, or all six CDRs are selected from a CDR comprising a VH sequence of SEQ ID NOs: 7, 17 to 25, 30 to 34, 38, and 68 and a VL sequence selected from the group consisting of SEQ ID NOs: 8, 26 to 29, 39, and 69. In some cases, the six CDRs are defined according to Kabat numbering (see Table 1). In other cases, the six CDRs are defined according to Chothia numbering (see Table 2). In additional cases, the six CDRs are defined according to EU numbering.

[0279] In some embodiments, the antigen-binding molecule that binds to STEAP1 comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3; wherein:

[0280] CDR-H1 contains Xaa 1 Xaa 2 YMA (SEQ ID NO: 35);

[0281] in

[0282] Xaa 1 is Asp(D) or Asn(N); and

[0283] Xaa 2 is His (H), Tyr (Y) or Phe (F);

[0284] CDR-H2 contains YIXaa 3 YGX 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36);

[0285] in

[0286] Xaa 3 is Asp(D) or Ser(S);

[0287] Xaa 4 is Gly (G), Asp (D) or Leu (L);

[0288] Xaa 5 is Ser(S), Asp(D) or Asn(N); and

[0289] Xaa 6 is Ser (S) or Tyr (Y);

[0290] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0291] in

[0292] Xaa 7 is Phe(F) or Tyr(Y);

[0293] Xaa 8 is Asn(N) or Asp(D); and

[0294] Xaa 9 is Ala (A) or Gly (G);

[0295] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0296] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0297] CDR-L3 comprises the amino acid sequence of SEQ ID NO:6.

[0298] In some cases, the anti-STEAP1 antigen binding molecule comprises at least two, at least three, at least four, at least five, or all six of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

[0299] In some embodiments, the antigen-binding molecule that binds to STEAP1 comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3; wherein:

[0300] CDR-H1 comprises the amino acid sequence of SEQ ID NO: 10, 1 or 9;

[0301] CDR-H2 contains YIXaa3 YGX 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36);

[0302] in

[0303] Xaa 3 is Asp(D) or Ser(S);

[0304] Xaa 4 is Gly (G), Asp (D) or Leu (L);

[0305] Xaa 5 is Ser(S), Asp(D) or Asn(N); and

[0306] Xaa 6 is Ser (S) or Tyr (Y);

[0307] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0308] in

[0309] Xaa 7 is Phe(F) or Tyr(Y);

[0310] Xaa 8 is Asn(N) or Asp(D); and

[0311] Xaa 9 is Ala (A) or Gly (G);

[0312] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0313] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0314] CDR-L3 comprises the amino acid sequence of SEQ ID NO:6.

[0315] In some cases, the anti-STEAP1 antigen binding molecule comprises at least two, at least three, at least four, at least five, or all six of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

[0316] In some embodiments, the antigen binding molecule that binds to STEAP1 comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3;

[0317] in

[0318] CDR-H1 comprises the amino acid sequence of SEQ ID NO: 10, 1 or 9;

[0319] CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, 11, 12 or 13;

[0320] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0321] in

[0322] Xaa 7 is Phe(F) or Tyr(Y);

[0323] Xaa 8 is Asn(N) or Asp(D); and

[0324] Xaa 9 is Ala (A) or Gly (G);

[0325] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0326] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0327] CDR-L3 comprises the amino acid sequence of SEQ ID NO:6.

[0328] In some cases, the anti-STEAP1 antigen binding molecule comprises at least two, at least three, at least four, at least five, or all six of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

[0329] In some embodiments, the antigen binding molecule that binds to STEAP1 comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3;

[0330] in

[0331] CDR-H1 contains Xaa 1 Xaa 2 YMA (SEQ ID NO: 35);

[0332] in

[0333] Xaa 1 is Asp(D) or Asn(N); and

[0334] Xaa 2 is His (H), Tyr (Y) or Phe (F);

[0335] CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, 11, 12 or 13;

[0336] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0337] in

[0338] Xaa 7 is Phe(F) or Tyr(Y);

[0339] Xaa 8 is Asn(N) or Asp(D); and

[0340] Xaa 9 is Ala (A) or Gly (G);

[0341] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0342] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0343] CDR-L3 comprises the amino acid sequence of SEQ ID NO:6.

[0344] In some cases, the anti-STEAP1 antigen binding molecule comprises at least two, at least three, at least four, at least five, or all six of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

[0345] In some embodiments, the antigen binding molecule that binds to STEAP1 comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3;

[0346] in

[0347] CDR-H1 contains Xaa 1 Xaa 2 YMA (SEQ ID NO: 35);

[0348] in

[0349] Xaa 1 is Asp(D) or Asn(N); and

[0350] Xaa 2 is His (H), Tyr (Y) or Phe (F);

[0351] CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, 11, 12 or 13;

[0352] CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14 or 15;

[0353] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0354] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0355] CDR-L3 comprises the amino acid sequence of SEQ ID NO:6.

[0356] In some cases, the anti-STEAP1 antigen binding molecule comprises at least two, at least three, at least four, at least five, or all six of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

[0357] In some embodiments, the antigen binding molecule that binds to STEAP1 comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3;

[0358] in

[0359] CDR-H1 contains Xaa 1 Xaa2 YMA (SEQ ID NO: 35);

[0360] in

[0361] Xaa 1 is Asp(D) or Asn(N); and

[0362] Xaa 2 is His (H), Tyr (Y) or Phe (F);

[0363] CDR-H2 contains YIXaa 3 YGX 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36);

[0364] in

[0365] Xaa 3 is Asp(D) or Ser(S);

[0366] Xaa 4 is Gly (G), Asp (D) or Leu (L);

[0367] Xaa 5 is Ser(S), Asp(D) or Asn(N); and

[0368] Xaa 6 is Ser (S) or Tyr (Y);

[0369] CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14 or 15;

[0370] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0371] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0372] CDR-L3 comprises the amino acid sequence of SEQ ID NO:6.

[0373] In some cases, the anti-STEAP1 antigen binding molecule comprises at least two, at least three, at least four, at least five, or all six of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

[0374] In some embodiments, the antigen binding molecule that binds to STEAP1 comprises an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3;

[0375] in

[0376] CDR-H1 comprises the amino acid sequence of SEQ ID NO: 10, 1 or 9;

[0377] CDR-H2 contains YIXaa 3 YGX 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36);

[0378] in

[0379] Xaa 3 is Asp(D) or Ser(S);

[0380] Xaa 4 is Gly (G), Asp (D) or Leu (L);

[0381] Xaa 5 is Ser(S), Asp(D) or Asn(N); and

[0382] Xaa 6 is Ser (S) or Tyr (Y);

[0383] CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14 or 15;

[0384] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0385] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0386] CDR-L3 comprises the amino acid sequence of SEQ ID NO:6.

[0387] In some cases, the anti-STEAP1 antigen binding molecule comprises at least two, at least three, at least four, at least five, or all six of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

[0388] In some embodiments, an antigen-binding molecule that binds to STEAP1 comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3; wherein CDR-H1 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 10, 1, or 9; CDR-H2 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 2, 11, 12, or 13; CDR-H3 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15; CDR-L1 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprises In some cases, the anti-STEAP1 antigen-binding molecule comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 5; and / or CDR-L3 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 6. In some cases, the anti-STEAP1 antigen-binding molecule comprises at least two, at least three, at least four, at least five, or all six CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

[0389] In some cases, the antigen binding molecule comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 1; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 2; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.

[0390] In some cases, the antigen binding molecule comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:9; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:11; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:3; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:6.

[0391] In some cases, the antigen binding molecule comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:9; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:12; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:3; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:6.

[0392] In some cases, the antigen binding molecule comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:9; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:12; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:14; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:6.

[0393] In some cases, the antigen binding molecule comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 10; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 13; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 15; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.

[0394] In some cases, the antigen binding molecule comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 10; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 2; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 16; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.

[0395] In some embodiments, the antigen binding molecule that binds to STEAP1 comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3; wherein

[0396] CDR-H1 contains GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63);

[0397] in

[0398] Xaa 10 is Asn(N) or Asp(D); and

[0399] Xaa 11 is Tyr (Y), Phe (F) or His (H);

[0400] CDR-H2 contains Xaa 12YGX 13 Xaa 14 (SEQ ID NO: 64);

[0401] in

[0402] Xaa 12 is Asp(D) or Ser(S);

[0403] Xaa 13 is Gly(G), Asp(D) or Leu(L); and

[0404] Xaa 14 is Ser(S), Asp(D) or Asn(N);

[0405] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0406] in

[0407] Xaa 7 is Phe(F) or Tyr(Y);

[0408] Xaa 8 is Asn(N) or Asp(D); and

[0409] Xaa 9 is Ala (A) or Gly (G);

[0410] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0411] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0412] CDR-L3 comprises the amino acid sequence of SEQ ID NO:6.

[0413] In some cases, the anti-STEAP1 antigen binding molecule comprises at least two, at least three, at least four, at least five, or all six of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

[0414] In some embodiments, the antigen binding molecule that binds to STEAP1 comprises an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3; wherein

[0415] CDR-H1 comprises the amino acid sequence of SEQ ID NO: 56, 58 or 59;

[0416] CDR-H2 contains Xaa 12 YGX 13 Xaa 14 (SEQ ID NO: 64);

[0417] in

[0418] Xaa 12 is Asp(D) or Ser(S);

[0419] Xaa 13 is Gly(G), Asp(D) or Leu(L); and

[0420] Xaa 14 is Ser(S), Asp(D) or Asn(N);

[0421] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0422] in

[0423] Xaa 7 is Phe(F) or Tyr(Y);

[0424] Xaa 8 is Asn(N) or Asp(D); and

[0425] Xaa 9 is Ala (A) or Gly (G);

[0426] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0427] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0428] CDR-L3 comprises the amino acid sequence of SEQ ID NO:6.

[0429] In some cases, the anti-STEAP1 antigen binding molecule comprises at least two, at least three, at least four, at least five, or all six of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

[0430] In some embodiments, the antigen binding molecule that binds to STEAP1 comprises an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3; wherein

[0431] CDR-H1 comprises the amino acid sequence of SEQ ID NO: 56, 58 or 59;

[0432] CDR-H2 comprises the amino acid sequence of SEQ ID NO: 57, 60, 61 or 62;

[0433] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0434] in

[0435] Xaa 7 is Phe(F) or Tyr(Y);

[0436] Xaa 8 is Asn(N) or Asp(D); and

[0437] Xaa 9 is Ala (A) or Gly (G);

[0438] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0439] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0440] CDR-L3 comprises the amino acid sequence of SEQ ID NO:6.

[0441] In some cases, the anti-STEAP1 antigen binding molecule comprises at least two, at least three, at least four, at least five, or all six of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

[0442] In some embodiments, the antigen binding molecule that binds to STEAP1 comprises an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3; wherein

[0443] CDR-H1 contains GFTFSXaa 10 Xaa 11 (SEQ ID NO:63);

[0444] in

[0445] Xaa 10 is Asn(N) or Asp(D); and

[0446] Xaa 11 is Tyr (Y), Phe (F) or His (H);

[0447] CDR-H2 comprises the amino acid sequence of SEQ ID NO: 57, 60, 61 or 62;

[0448] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0449] in

[0450] Xaa 7 is Phe(F) or Tyr(Y);

[0451] Xaa 8 is Asn(N) or Asp(D); and

[0452] Xaa 9 is Ala (A) or Gly (G);

[0453] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0454] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0455] CDR-L3 comprises the amino acid sequence of SEQ ID NO:6.

[0456] In some cases, the anti-STEAP1 antigen binding molecule comprises at least two, at least three, at least four, at least five, or all six of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

[0457] In some embodiments, the antigen binding molecule that binds to STEAP1 comprises an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3; wherein

[0458] CDR-H1 contains GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63);

[0459] in

[0460] Xaa 10 is Asn(N) or Asp(D); and

[0461] Xaa 11 is Tyr (Y), Phe (F) or His (H);

[0462] CDR-H2 comprises the amino acid sequence of SEQ ID NO: 57, 60, 61 or 62;

[0463] CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14 or 15;

[0464] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0465] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0466] CDR-L3 comprises the amino acid sequence of SEQ ID NO:6.

[0467] In some cases, the anti-STEAP1 antigen binding molecule comprises at least two, at least three, at least four, at least five, or all six of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

[0468] In some embodiments, the antigen binding molecule that binds to STEAP1 comprises an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3; wherein

[0469] CDR-H1 contains GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63);

[0470] in

[0471] Xaa 10 is Asn(N) or Asp(D); and

[0472] Xaa 11is Tyr (Y), Phe (F) or His (H);

[0473] CDR-H2 contains Xaa 12 YGX 13 Xaa 14 (SEQ ID NO: 64);

[0474] in

[0475] Xaa 12 is Asp(D) or Ser(S);

[0476] Xaa 13 is Gly(G), Asp(D) or Leu(L); and

[0477] Xaa 14 is Ser(S), Asp(D) or Asn(N);

[0478] CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14 or 15;

[0479] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0480] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0481] CDR-L3 comprises the amino acid sequence of SEQ ID NO:6.

[0482] In some cases, the anti-STEAP1 antigen binding molecule comprises at least two, at least three, at least four, at least five, or all six of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

[0483] In some embodiments, the antigen binding molecule that binds to STEAP1 comprises an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3; wherein

[0484] CDR-H1 comprises the amino acid sequence of SEQ ID NO: 56, 58 or 59;

[0485] CDR-H2 contains Xaa 12 YGX 13 Xaa 14 (SEQ ID NO: 64);

[0486] in

[0487] Xaa 12 is Asp(D) or Ser(S);

[0488] Xaa 13 is Gly(G), Asp(D) or Leu(L); and

[0489] Xaa 14 is Ser(S), Asp(D) or Asn(N);

[0490] CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14 or 15;

[0491] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0492] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0493] CDR-L3 comprises the amino acid sequence of SEQ ID NO:6.

[0494] In some cases, the anti-STEAP1 antigen binding molecule comprises at least two, at least three, at least four, at least five, or all six of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

[0495] In some embodiments, the antigen binding molecule that binds to STEAP1 comprises a heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3; wherein CDR-H1 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 56, 58, or 59; CDR-H2 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 57, 60, 61, or 62; CDR-H3 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15; CDR-L1 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 5; and / or CDR-L3 comprises NO: 6. In some cases, the anti-STEAP1 antigen-binding molecule comprises at least two, at least three, at least four, at least five, or all six CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3.

[0496] In some cases, the antigen binding molecule comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:56; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:57; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:3; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:6.

[0497] In some cases, the antigen binding molecule comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:58; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:60; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:3; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:6.

[0498] In some cases, the antigen binding molecule comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:58; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:61; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:3; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:6.

[0499] In some cases, the antigen binding molecule comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:58; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:61; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:14; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:6.

[0500] In some cases, the antigen binding molecule comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:59; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:62; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:15; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:6.

[0501] In some cases, the antigen binding molecule comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:59; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:57; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:16; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:6.

[0502] The antigen binding molecules of the present invention can be humanized antibodies. In some cases, the antigen binding molecules of the present invention comprise constant regions derived from IgG framework regions. In some cases, the IgG framework regions are IgG1, IgG2, or IgG4 framework regions. In some cases, the IgG framework regions are IgG1 framework regions.

[0503] In some embodiments, the antigen binding molecule comprises a heavy chain variable region comprising one or more (e.g., 1, 2, 3, or all 4) of the following: a framework region (FR)-H1 sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 110; a FR-H2 sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 118; a FR-H3 sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 119; NO: 112 has a FR-H3 that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 113; and / or a FR-H4 that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 113. In some embodiments, the antigen binding molecule comprises a heavy chain variable region comprising a FR-H2 that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 118. In some embodiments, the antigen binding molecule comprises a heavy chain variable region comprising a FR-H2 having the amino acid sequence of SEQ ID NO: 118. In other embodiments, the antigen binding molecule comprises a heavy chain variable region comprising a FR-H2 having the amino acid sequence of SEQ ID NO: 120.

[0504] In some embodiments, the antigen binding molecule comprises a heavy chain variable region comprising one or more (e.g., 1, 2, 3, or all 4) of the following: a FR-H1 sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 110; a FR-H2 sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 111; a FR-H3 sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 112; a FR-H4 sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: NO: 112 has an FR-H3 that has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity; and / or an FR-H4 that has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 113.

[0505] In some embodiments, the antigen binding molecule comprises a light chain variable region comprising one or more (e.g., 1, 2, 3, or all 4) of the following: an FR-L1 having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 114; an FR-L2 having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 119; an FR-L3 having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 119; NO: 116 has an FR-L3 that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 116; and / or an FR-L4 that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 117. In some embodiments, the antigen binding molecule comprises a heavy chain variable region comprising an FR-L2 that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 119. In some embodiments, the antigen binding molecule comprises a heavy chain variable region comprising FR-L2 having the amino acid sequence of SEQ ID NO: 119. In other embodiments, the antigen binding molecule comprises a heavy chain variable region comprising FR-H2 having the amino acid sequence of SEQ ID NO: 121.

[0506] In some embodiments, the antigen binding molecule comprises a light chain variable region comprising one or more (e.g., 1, 2, 3, or all 4) of the following: an FR-L1 having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 114; an FR-L2 having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 115; an FR-L3 having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 116; NO: 116 having an FR-L3 that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 116; and / or an FR-L4 that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 117.

[0507] For example, in some cases, the antigen-binding molecule comprises: FR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 110; FR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 111; FR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 112; FR-H4 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 113; FR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 114; FR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 115; FR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 116; and FR-L4 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 117.

[0508] In some embodiments, the antigen binding molecule comprises a heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 7, 17-25, 30-34, 38, or 68. In some cases, the heavy chain variable region comprises a VH sequence having at least 90% sequence identity to SEQ ID NO: 7, 17-25, 30-34, 38, or 68. In some cases, the heavy chain variable region comprises a VH sequence having at least 95% sequence identity to SEQ ID NO: 7, 17-25, 30-34, 38, or 68. In some cases, the heavy chain variable region comprises a VH sequence having at least 98% sequence identity to SEQ ID NO: 7, 17-25, 30-34, 38, or 68. In some cases, the heavy chain variable region comprises a VH sequence that has at least 99% sequence identity to SEQ ID NO: 7, 17-25, 30-34, 38, or 68. In some cases, the heavy chain variable region comprises a VH sequence that has 100% sequence identity to SEQ ID NO: 7, 17-25, 30-34, 38, or 68. In certain aspects, the VH sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains a substitution (e.g., a retention substitution), insertion, or deletion relative to SEQ ID NO: 7, 17-25, 30-34, 38, or 68, but an anti-STEAP1 antibody comprising the sequence retains the ability to bind to STEAP1. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in SEQ ID NO: 7, 17-25, 30-34, 38, or 68. In certain aspects, substitutions, insertions, or deletions occur in regions outside of the CDRs (ie, in the FRs).

[0509] In some embodiments, the antigen binding molecule comprises a light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 8, 26-29, 39, or 69. In some cases, the light chain variable region comprises a VL sequence having at least 90% sequence identity to SEQ ID NO: 8, 26-29, 39, or 69. In some cases, the light chain variable region comprises a VL sequence having at least 95% sequence identity to SEQ ID NO: 8, 26-29, 39, or 69. In some cases, the light chain variable region comprises a VL sequence having at least 98% sequence identity to SEQ ID NO: 8, 26-29, 39, or 69. In some cases, the light chain variable region comprises a VL sequence that has at least 99% sequence identity to SEQ ID NO: 8, 26-29, 39, or 69. In some cases, the light chain variable region comprises a VL sequence that has 100% sequence identity to SEQ ID NO: 8, 26-29, 39, or 69. In certain aspects, the VL sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains a substitution (e.g., a retention substitution), insertion, or deletion relative to SEQ ID NO: 8, 26-25, 29-34, 39, or 69, but an anti-STEAP1 antibody comprising the sequence retains the ability to bind to STEAP1. In certain aspects, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in SEQ ID NO: 8, 26-29, 39, or 69. In certain aspects, substitutions, insertions, or deletions occur in regions outside of the CDRs (ie, in the FRs).

[0510] In some embodiments, the antigen binding molecule of any of the preceding embodiments is characterized in that the VH and VL regions comprise one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 9; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 11; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3. In some cases, the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 58; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 60; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3. In some embodiments, the VH region comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 30 (e.g., at least 95% sequence identity to SEQ ID NO: 30, at least 96% sequence identity to SEQ ID NO: 30, at least 97% sequence identity to SEQ ID NO: 30, at least 98% sequence identity to SEQ ID NO: 30, at least 99% sequence identity to SEQ ID NO: 30, or 100% sequence identity to SEQ ID NO: 30). In some embodiments, the VL region comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6. In some embodiments, the VL region comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 27 (e.g., at least 95% sequence identity to SEQ ID NO: 27, at least 96% sequence identity to SEQ ID NO: 27, at least 97% sequence identity to SEQ ID NO: 27, at least 98% sequence identity to SEQ ID NO: 27, at least 99% sequence identity to SEQ ID NO: 27, or 100% sequence identity to SEQ ID NO: 27).

[0511] In some embodiments, the antigen binding molecule of any of the preceding embodiments is characterized in that the VH and VL regions comprise one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 9; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 12; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3. In some cases, the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 58; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 61; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3. In some embodiments, the VH region comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 31 (e.g., at least 95% sequence identity to SEQ ID NO: 31, at least 96% sequence identity to SEQ ID NO: 31, at least 97% sequence identity to SEQ ID NO: 31, at least 98% sequence identity to SEQ ID NO: 31, at least 99% sequence identity to SEQ ID NO: 31, or 100% sequence identity to SEQ ID NO: 31). In some embodiments, the VL region comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6. In some embodiments, the VL region comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 27 (e.g., at least 95% sequence identity to SEQ ID NO: 27, at least 96% sequence identity to SEQ ID NO: 27, at least 97% sequence identity to SEQ ID NO: 27, at least 98% sequence identity to SEQ ID NO: 27, at least 99% sequence identity to SEQ ID NO: 27, or 100% sequence identity to SEQ ID NO: 27).

[0512] In some embodiments, the antigen binding molecule of any of the preceding embodiments is characterized in that the VH and VL regions comprise one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 9; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 12; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 14. In some cases, the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 58; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 61; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 14. In some embodiments, the VH region comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 95% sequence identity to SEQ ID NO: 32, at least 96% sequence identity to SEQ ID NO: 32, at least 97% sequence identity to SEQ ID NO: 32, at least 98% sequence identity to SEQ ID NO: 32, at least 99% sequence identity to SEQ ID NO: 32, or 100% sequence identity to SEQ ID NO: 32). In some embodiments, the VL region comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6. In some embodiments, the VL region comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 27 (e.g., at least 95% sequence identity to SEQ ID NO: 27, at least 96% sequence identity to SEQ ID NO: 27, at least 97% sequence identity to SEQ ID NO: 27, at least 98% sequence identity to SEQ ID NO: 27, at least 99% sequence identity to SEQ ID NO: 27, or 100% sequence identity to SEQ ID NO: 27).

[0513] In some embodiments, the antigen binding molecule of any of the preceding embodiments is characterized in that the VH and VL regions comprise one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 10; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 13; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 15. In some cases, the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 59; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 62; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 15. In some embodiments, the VH region comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 33 (e.g., at least 95% sequence identity to SEQ ID NO: 33, at least 96% sequence identity to SEQ ID NO: 33, at least 97% sequence identity to SEQ ID NO: 33, at least 98% sequence identity to SEQ ID NO: 33, at least 99% sequence identity to SEQ ID NO: 33, or 100% sequence identity to SEQ ID NO: 33). In some embodiments, the VL region comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6. In some embodiments, the VL region comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 27 (e.g., at least 95% sequence identity to SEQ ID NO: 27, at least 96% sequence identity to SEQ ID NO: 27, at least 97% sequence identity to SEQ ID NO: 27, at least 98% sequence identity to SEQ ID NO: 27, at least 99% sequence identity to SEQ ID NO: 27, or 100% sequence identity to SEQ ID NO: 27).

[0514] In some embodiments, the antigen binding molecule of any of the preceding embodiments is characterized in that the VH and VL regions comprise one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 10; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 2; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 16. In some cases, the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 59; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 57; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 16. In some embodiments, the VH region comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 95% sequence identity to SEQ ID NO: 34, at least 96% sequence identity to SEQ ID NO: 34, at least 97% sequence identity to SEQ ID NO: 34, at least 98% sequence identity to SEQ ID NO: 34, at least 99% sequence identity to SEQ ID NO: 34, or 100% sequence identity to SEQ ID NO: 34) to SEQ ID NO: 34. In some embodiments, the VL region comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6. In some embodiments, the VL region comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 27 (e.g., at least 95% sequence identity to SEQ ID NO: 27, at least 96% sequence identity to SEQ ID NO: 27, at least 97% sequence identity to SEQ ID NO: 27, at least 98% sequence identity to SEQ ID NO: 27, at least 99% sequence identity to SEQ ID NO: 27, or 100% sequence identity to SEQ ID NO: 27).

[0515] In some embodiments, the VH region comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 95% sequence identity to SEQ ID NO: 68, at least 96% sequence identity to SEQ ID NO: 68, at least 97% sequence identity to SEQ ID NO: 68, at least 98% sequence identity to SEQ ID NO: 68, at least 99% sequence identity to SEQ ID NO: 68, or 100% sequence identity to SEQ ID NO: 68). In some embodiments, the VL region comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6. In some embodiments, the VL region comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 69 (e.g., at least 95% sequence identity to SEQ ID NO: 69, at least 96% sequence identity to SEQ ID NO: 69, at least 97% sequence identity to SEQ ID NO: 69, at least 98% sequence identity to SEQ ID NO: 69, at least 99% sequence identity to SEQ ID NO: 69, or 100% sequence identity to SEQ ID NO: 69).

[0516] In some embodiments, the antigen binding molecule of any of the preceding embodiments is characterized in that the VH and VL regions comprise one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 35; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 36; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 37. In some cases, the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 63; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 64; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 37. In some embodiments, the VH region comprises an amino acid sequence having at least 90% sequence identity (e.g., at least 95% sequence identity to SEQ ID NO: 38, at least 96% sequence identity to SEQ ID NO: 38, at least 97% sequence identity to SEQ ID NO: 38, at least 98% sequence identity to SEQ ID NO: 38, at least 99% sequence identity to SEQ ID NO: 38, or 100% sequence identity to SEQ ID NO: 38). In some embodiments, the VL region comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6. In some embodiments, the VL region comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 39 (e.g., at least 95% sequence identity to SEQ ID NO: 39, at least 96% sequence identity to SEQ ID NO: 39, at least 97% sequence identity to SEQ ID NO: 39, at least 98% sequence identity to SEQ ID NO: 39, at least 99% sequence identity to SEQ ID NO: 39, or 100% sequence identity to SEQ ID NO: 39).

[0517] In some embodiments, the antigen binding molecule binds to an epitope on STEAP1 that comprises one or more amino acid residues selected from Ser101, His102, Gln103, and Lys281 of STEAP1. In some embodiments, the epitope comprises amino acid residue Ser101 of ECL1 of STEAP1. In some embodiments, the epitope comprises amino acid residue His102 of ECL1 of STEAP1. In some embodiments, the epitope comprises amino acid residue Gln103 of ECL1 of STEAP1. In some embodiments, the epitope comprises amino acid residue Lys281 of ECL3 of STEAP1. In some embodiments, the epitope comprises Ser101, His102, Gln103 of ECL1 of STEAP1, and Lys281 of ECL3 of STEAP1. In some embodiments, the epitope further comprises one or more additional amino acid residues selected from Trp195, Gln198, Gln201, Gln202, Asn203, and Lys204 of ECL2 of STEAP1. In some embodiments, the epitope does not comprise amino acid residue Gln104 of STEAP1. In some embodiments, the epitope does not comprise amino acid residue Tyr107 of STEAP1. In some embodiments, the epitope does not comprise amino acid residue Asn194 of STEAP1. In some embodiments, the epitope does not comprise amino acid residue Glu205 of STEAP1. In some embodiments, the epitope does not comprise amino acid residue Ala207 of STEAP1.

[0518] In some embodiments, the antigen binding molecules have a K of about 100 nM or less. D Binding to human STEAP1, as determined by kinetic exclusion In some embodiments, the antigen binding molecules are expressed with a K between about 10 pM and about 100 nM. D In some embodiments, the antigen binding molecule binds to human STEAP1 with a K between about 100 pM and about 50 nM. D In some embodiments, the antigen binding molecule binds to human STEAP1 with a K of between about 1 nM and about 30 nM. D Binds to human STEAP1. In some embodiments, the antigen binding molecule has a K of about 100 nM or less D Binding to cynomolgus monkey STEAP1, as determined by kinetic exclusion In some embodiments, the antigen binding molecules are expressed with a K between about 10 pM and about 100 nM. D In some embodiments, the antigen binding molecules bind to cynomolgus monkey STEAP1 with a K between about 100 pM and about 50 nM. DIn some embodiments, the antigen binding molecules bind to cynomolgus monkey STEAP1 with a K of between about 1 nM and about 30 nM. D Binds to cynomolgus monkey STEAP1.

[0519] Multispecific antigen-binding molecules

[0520] In some embodiments, the present invention provides isolated multispecific antigen-binding molecules comprising a first antigen-binding domain that binds to STEAP1 as described above. In some cases, the multispecific antigen-binding molecule monovalently binds to STEAP1. In some cases, the multispecific antigen-binding molecule further comprises a second binding domain that binds to a T cell receptor. In additional cases, the multispecific antigen-binding molecule comprises a third binding domain that binds to an additional antigen (e.g., a tumor-associated antigen).

[0521] In some embodiments, the multispecific antigen-binding molecules of the present invention are bispecific antigen-binding molecules (e.g., bispecific antibodies) comprising a first antigen-binding domain that binds to STEAP1 and a second antigen-binding domain that binds to a T cell receptor. Exemplary T cell receptors include cluster of differentiation 3 (CD3). In some cases, the second antigen-binding domain comprises an antibody or fragment thereof that binds to CD3. Exemplary antigen-binding domains that bind to CD3 include, but are not limited to, 40G5c and 38E4v1.MD1. Additional antigen-binding domains that bind to CD3 (e.g., UCHT1.v9, 38E4v11, 30E4c, SP34v52, etc.) are described in U.S. Patent No. 10,174,124, WO2015 / 095392, WO2016 / 205520, and International Patent Application No. PCT / US2020 / 064635, each of which is incorporated herein by reference in its entirety.

[0522] In some embodiments, the second antigen-binding domain binds to an epitope on CD3 that comprises amino acid residue Glu6 of CD3. In some embodiments, the epitope further comprises one or more additional amino acid residues selected from Gln1, Asp2, and Met7 of CD3. In some embodiments, the epitope comprises amino acid residues Gln1, Asp2, Glu6, and Met7 of CD3. In some embodiments, the epitope does not comprise amino acid residue Glu5 of CD3. In some embodiments, the epitope does not comprise amino acid residues Gly3 and Glu5 of CD3. In some embodiments, the epitope consists of amino acid residues Gln1, Asp2, Glu6, and Met7 of CD3. In some embodiments, the second antigen-binding domain is capable of binding to a human CD3 polypeptide or a cynomolgus monkey CD3 polypeptide. In some embodiments, the human CD3 polypeptide or the cynomolgus monkey CD3 polypeptide is a human CD3 epsilon polypeptide or a cynomolgus monkey CD3 epsilon polypeptide, respectively. In some embodiments, the human CD3 polypeptide or the cynomolgus monkey CD3 polypeptide is a human CD3 gamma polypeptide or a cynomolgus monkey CD3 gamma polypeptide, respectively. In some embodiments, the second antigen binding domain has a K of about 100 nM or less. D In some embodiments, the second antigen binding domain binds to human CD3 epsilon polypeptide with a K of between about 10 pM and about 100 nM. D In some embodiments, the second antigen binding domain binds to human CD3 epsilon. D In some embodiments, the second antigen binding domain binds to human CD3 epsilon. D Binds to human CD3e.

[0523] In some embodiments, the second antigen binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 38E4v1.MD1. In some cases, the second antigen binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs, wherein CDR-H1 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:40, CDR-H2 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:41, CDR-H3 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:42, CDR-L1 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:43, CDR-L2 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:44; or CDR-L3 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:45. In some cases, the second antigen binding domain comprises a VH sequence that has at least 80% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 46. In some cases, the second antigen binding domain comprises a VL sequence that has at least 80% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 47. In certain aspects, the VH or VL sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains a substitution (e.g., a retention substitution), insertion, or deletion relative to SEQ ID NO: 46 or 47, but the multispecific antibody comprising that sequence retains the ability to bind to CD3. In some aspects, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in SEQ ID NO: 46 or 47. In some aspects, the substitutions, insertions, or deletions occur in regions outside of the CDRs (i.e., in the FRs).

[0524] In some embodiments, the second antigen binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of 40G5c. In some cases, the second antigen binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs, wherein CDR-H1 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:48, CDR-H2 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:49, CDR-H3 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:50, CDR-L1 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:51, CDR-L2 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:52; or CDR-L3 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:53. In some cases, the second antigen-binding domain comprises a VH sequence that has at least 80% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 54. In some cases, the second antigen-binding domain comprises a VL sequence that has at least 80% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 55. In certain aspects, the VH or VL sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains a substitution (e.g., a retention substitution), insertion, or deletion relative to SEQ ID NO: 54 or 55, but the multispecific antibody comprising that sequence retains the ability to bind to CD3. In some aspects, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in SEQ ID NO: 54 or 55. In some aspects, the substitutions, insertions, or deletions occur in regions outside of the CDRs (i.e., in the FRs).

[0525] In some embodiments, the multispecific antigen-binding molecule comprises: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3 of a VH sequence selected from the group consisting of SEQ ID NOs: 7, 17 to 25, 30 to 34, 38, and 68; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3 of a VL sequence selected from the group consisting of SEQ ID NOs: 8, 26 to 29, 39, and 69; and (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, at least one, at least two, at least three, at least four, at least five, or all six CDRs are selected from the CDRs of the VH sequences of SEQ ID NOs: 7, 17 to 25, 30 to 34, 38, and 68 and the CDRs of the VL sequences of SEQ ID NOs: 8, 26 to 29, 39, and 69. In some cases, at least one, at least two, at least three, at least four, at least five, or all six CDRs are selected from the CDRs of 40G5c or 38E4v1.MD1. In some cases, the six CDRs are defined according to Kabat numbering. In other cases, the six CDRs are defined according to Chothia numbering. In additional cases, the six CDRs are defined according to EU numbering.

[0526] In some embodiments, the multispecific antigen-binding molecule comprises: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3;

[0527] in

[0528] CDR-H1 contains Xaa 1 Xaa 2 YMA (SEQ ID NO: 35);

[0529] in

[0530] Xaa 1 is Asp(D) or Asn(N); and

[0531] Xaa 2 is His (H), Tyr (Y) or Phe (F);

[0532] CDR-H2 contains YIXaa 3 YGX 4 Xaa5 TXaa 6 YGDSVKG (SEQ ID NO: 36);

[0533] in

[0534] Xaa 3 is Asp(D) or Ser(S);

[0535] Xaa 4 is Gly (G), Asp (D) or Leu (L);

[0536] Xaa 5 is Ser(S), Asp(D) or Asn(N); and

[0537] Xaa 6 is Ser(S) or Tyr(Y); and

[0538] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0539] in

[0540] Xaa 7 is Phe(F) or Tyr(Y);

[0541] Xaa 8 is Asn(N) or Asp(D); and

[0542] Xaa 9 is Ala (A) or Gly (G);

[0543] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0544] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0545] CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and

[0546] (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the first antigen-binding domain comprises at least two, at least three, at least four, at least five, or all six CDRs of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3. In some cases, the second antigen-binding domain binds to CD3. In some cases, the second antigen-binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs of 40G5c or 38E4v1.MD1.

[0547] In some embodiments, the multispecific antigen-binding molecule comprises: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3;

[0548] in

[0549] CDR-H1 comprises the amino acid sequence of SEQ ID NO: 10, 1 or 9;

[0550] CDR-H2 contains YIXaa 3 YGX 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36);

[0551] in

[0552] Xaa 3 is Asp(D) or Ser(S);

[0553] Xaa 4 is Gly (G), Asp (D) or Leu (L);

[0554] Xaa 5 is Ser(S), Asp(D) or Asn(N); and

[0555] Xaa 6 is Ser (S) or Tyr (Y);

[0556] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0557] in

[0558] Xaa 7 is Phe(F) or Tyr(Y);

[0559] Xaa 8 is Asn(N) or Asp(D); and

[0560] Xaa 9 is Ala (A) or Gly (G);

[0561] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0562] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0563] CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and

[0564] (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the first antigen-binding domain comprises at least two, at least three, at least four, at least five, or all six CDRs of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3. In some cases, the second antigen-binding domain binds to CD3. In some cases, the second antigen-binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs of 40G5c or 38E4v1.MD1.

[0565] In some embodiments, the multispecific antigen-binding molecule comprises: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3;

[0566] in

[0567] CDR-H1 comprises the amino acid sequence of SEQ ID NO: 10, 1 or 9;

[0568] CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, 11, 12 or 13;

[0569] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0570] in

[0571] Xaa 7 is Phe(F) or Tyr(Y);

[0572] Xaa 8 is Asn(N) or Asp(D); and

[0573] Xaa 9 is Ala (A) or Gly (G);

[0574] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0575] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0576] CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and

[0577] (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the first antigen-binding domain comprises at least two, at least three, at least four, at least five, or all six CDRs of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3. In some cases, the second antigen-binding domain binds to CD3. In some cases, the second antigen-binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs of 40G5c or 38E4v1.MD1.

[0578] In some embodiments, the multispecific antigen-binding molecule comprises: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3;

[0579] in

[0580] CDR-H1 contains Xaa 1 Xaa 2 YMA (SEQ ID NO: 35);

[0581] in

[0582] Xaa 1 is Asp(D) or Asn(N); and

[0583] Xaa 2 is His (H), Tyr (Y) or Phe (F);

[0584] CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, 11, 12 or 13;

[0585] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0586] in

[0587] Xaa 7 is Phe(F) or Tyr(Y);

[0588] Xaa 8 is Asn(N) or Asp(D); and

[0589] Xaa 9 is Ala (A) or Gly (G);

[0590] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0591] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0592] CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and

[0593] (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the first antigen-binding domain comprises at least two, at least three, at least four, at least five, or all six CDRs of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3. In some cases, the second antigen-binding domain binds to CD3. In some cases, the second antigen-binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs of 40G5c or 38E4V1.MD1.

[0594] In some embodiments, the multispecific antigen-binding molecule comprises: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3;

[0595] in

[0596] CDR-H1 contains Xaa 1 Xaa 2YMA (SEQ ID NO: 35);

[0597] in

[0598] Xaa 1 is Asp(D) or Asn(N); and

[0599] Xaa 2 is His (H), Tyr (Y) or Phe (F);

[0600] CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, 11, 12 or 13;

[0601] CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14 or 15;

[0602] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0603] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0604] CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and

[0605] (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the first antigen-binding domain comprises at least two, at least three, at least four, at least five, or all six CDRs of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3. In some cases, the second antigen-binding domain binds to CD3. In some cases, the second antigen-binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs of 40G5c or 38E4V1.MD1.

[0606] In some embodiments, the multispecific antigen-binding molecule comprises: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3;

[0607] in

[0608] CDR-H1 contains Xaa 1 Xaa 2 YMA (SEQ ID NO: 35);

[0609] in

[0610] Xaa 1 is Asp(D) or Asn(N); and

[0611] Xaa 2 is His (H), Tyr (Y) or Phe (F);

[0612] CDR-H2 contains YIXaa 3 YGX 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36);

[0613] in

[0614] Xaa 3 is Asp(D) or Ser(S);

[0615] Xaa 4 is Gly (G), Asp (D) or Leu (L);

[0616] Xaa 5 is Ser(S), Asp(D) or Asn(N); and

[0617] Xaa 6 is Ser (S) or Tyr (Y);

[0618] CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14 or 15;

[0619] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0620] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0621] CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and

[0622] (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the first antigen-binding domain comprises at least two, at least three, at least four, at least five, or all six CDRs of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3. In some cases, the second antigen-binding domain binds to CD3. In some cases, the second antigen-binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs of 40G5c or 38E4V1.MD1.

[0623] In some embodiments, the multispecific antigen-binding molecule comprises: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3;

[0624] in

[0625] CDR-H1 comprises the amino acid sequence of SEQ ID NO: 10, 1 or 9;

[0626] CDR-H2 contains YIXaa 3 YGX 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36);

[0627] in

[0628] Xaa 3 is Asp(D) or Ser(S);

[0629] Xaa 4 is Gly (G), Asp (D) or Leu (L);

[0630] Xaa 5 is Ser(S), Asp(D) or Asn(N); and

[0631] Xaa 6 is Ser (S) or Tyr (Y);

[0632] CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14 or 15;

[0633] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0634] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0635] CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and

[0636] (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the first antigen-binding domain comprises at least two, at least three, at least four, at least five, or all six CDRs of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3. In some cases, the second antigen-binding domain binds to CD3. In some cases, the second antigen-binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs of 40G5c or 38E4V1.MD1.

[0637] In some embodiments, the multispecific antigen-binding molecule comprises (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3; wherein CDR-H1 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 10, 1, or 9; CDR-H2 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 2, 11, 12, or 13; CDR-H3 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15; CDR-L1 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprises In some cases, the first antigen-binding domain comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:5; and / or CDR-L3 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:6; and (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the first antigen-binding domain comprises at least two, at least three, at least four, at least five, or all six CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3. In some cases, the second antigen-binding domain binds to CD3. In some cases, the second antigen-binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs of 40G5c or 38E4V1.MD1.

[0638] In some cases, the first antigen binding domain comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 1; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 2; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.

[0639] In some cases, the first antigen binding domain comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:9; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:11; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:3; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:6.

[0640] In some cases, the first antigen binding domain comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:9; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:12; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:3; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:6.

[0641] In some cases, the first antigen binding domain comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:9; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:12; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:14; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:6.

[0642] In some cases, the first antigen binding domain comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 10; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 13; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 15; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.

[0643] In some cases, the first antigen binding domain comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 10; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 2; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 16; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.

[0644] In some embodiments, the multispecific antigen-binding molecule comprises: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3;

[0645] in

[0646] CDR-H1 contains GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63);

[0647] in

[0648] Xaa 10 is Asn(N) or Asp(D); and

[0649] Xaa 11 is Tyr (Y), Phe (F) or His (H);

[0650] CDR-H2 contains Xaa 12 YGX 13 Xaa 14 (SEQ ID NO: 64);

[0651] in

[0652] Xaa 12 is Asp(D) or Ser(S);

[0653] Xaa 13 is Gly(G), Asp(D) or Leu(L); and

[0654] Xaa 14 is Ser(S), Asp(D) or Asn(N);

[0655] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0656] in

[0657] Xaa 7 is Phe(F) or Tyr(Y);

[0658] Xaa 8 is Asn(N) or Asp(D); and

[0659] Xaa9 is Ala (A) or Gly (G);

[0660] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0661] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0662] CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and

[0663] (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the first antigen-binding domain comprises at least two, at least three, at least four, at least five, or all six CDRs of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3. In some cases, the second antigen-binding domain binds to CD3. In some cases, the second antigen-binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs of 40G5c or 38E4V1.MD1.

[0664] In some embodiments, the multispecific antigen-binding molecule comprises: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3;

[0665] in

[0666] CDR-H1 comprises the amino acid sequence of SEQ ID NO: 56, 58 or 59;

[0667] CDR-H2 contains Xaa 12 YGX 13 Xaa 14 (SEQ ID NO: 64);

[0668] in

[0669] Xaa 12 is Asp(D) or Ser(S);

[0670] Xaa 13 is Gly(G), Asp(D) or Leu(L); and

[0671] Xaa 14 is Ser(S), Asp(D) or Asn(N);

[0672] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0673] in

[0674] Xaa 7 is Phe(F) or Tyr(Y);

[0675] Xaa 8 is Asn(N) or Asp(D); and

[0676] Xaa 9 is Ala (A) or Gly (G);

[0677] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0678] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0679] CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and

[0680] (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the first antigen-binding domain comprises at least two, at least three, at least four, at least five, or all six CDRs of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3. In some cases, the second antigen-binding domain binds to CD3. In some cases, the second antigen-binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs of 40G5c or 38E4V1.MD1.

[0681] In some embodiments, the multispecific antigen-binding molecule comprises: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3;

[0682] in

[0683] CDR-H1 comprises the amino acid sequence of SEQ ID NO: 56, 58 or 59;

[0684] CDR-H2 comprises the amino acid sequence of SEQ ID NO: 57, 60, 61 or 62;

[0685] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0686] in

[0687] Xaa 7 is Phe(F) or Tyr(Y);

[0688] Xaa 8 is Asn(N) or Asp(D); and

[0689] Xaa 9 is Ala (A) or Gly (G);

[0690] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0691] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0692] CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and

[0693] (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the first antigen-binding domain comprises at least two, at least three, at least four, at least five, or all six CDRs of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3. In some cases, the second antigen-binding domain binds to CD3. In some cases, the second antigen-binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs of 40G5c or 38E4V1.MD1.

[0694] In some embodiments, the multispecific antigen-binding molecule comprises: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3;

[0695] in

[0696] CDR-H1 contains GFTFSXaa 10 Xaa 11 (SEQ ID NO:63);

[0697] in

[0698] Xaa 10 is Asn(N) or Asp(D); and

[0699] Xaa 11 is Tyr (Y), Phe (F) or His (H);

[0700] CDR-H2 comprises the amino acid sequence of SEQ ID NO: 57, 60, 61 or 62;

[0701] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0702] in

[0703] Xaa 7 is Phe(F) or Tyr(Y);

[0704] Xaa 8 is Asn(N) or Asp(D); and

[0705] Xaa 9 is Ala (A) or Gly (G);

[0706] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0707] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0708] CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and

[0709] (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the first antigen-binding domain comprises at least two, at least three, at least four, at least five, or all six CDRs of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3. In some cases, the second antigen-binding domain binds to CD3. In some cases, the second antigen-binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs of 40G5c or 38E4V1.MD1.

[0710] In some embodiments, the multispecific antigen-binding molecule comprises: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3;

[0711] in

[0712] CDR-H1 contains GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63);

[0713] in

[0714] Xaa 10 is Asn(N) or Asp(D); and

[0715] Xaa 11 is Tyr (Y), Phe (F) or His (H);

[0716] CDR-H2 comprises the amino acid sequence of SEQ ID NO: 57, 60, 61 or 62;

[0717] CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14 or 15;

[0718] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0719] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0720] CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and

[0721] (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the first antigen-binding domain comprises at least two, at least three, at least four, at least five, or all six CDRs of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3. In some cases, the second antigen-binding domain binds to CD3. In some cases, the second antigen-binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs of 40G5c or 38E4V1.MD1.

[0722] In some embodiments, the multispecific antigen-binding molecule comprises: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3;

[0723] in

[0724] CDR-H1 contains GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63);

[0725] in

[0726] Xaa 10 is Asn(N) or Asp(D); and

[0727] Xaa 11 is Tyr (Y), Phe (F) or His (H);

[0728] CDR-H2 contains Xaa 12 YGX 13 Xaa 14 (SEQ ID NO: 64);

[0729] in

[0730] Xaa 12 is Asp(D) or Ser(S);

[0731] Xaa 13 is Gly(G), Asp(D) or Leu(L); and

[0732] Xaa 14 is Ser(S), Asp(D) or Asn(N);

[0733] CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14 or 15;

[0734] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0735] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0736] CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and

[0737] (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the first antigen-binding domain comprises at least two, at least three, at least four, at least five, or all six CDRs of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3. In some cases, the second antigen-binding domain binds to CD3. In some cases, the second antigen-binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs of 40G5c or 38E4V1.MD1.

[0738] In some embodiments, the multispecific antigen-binding molecule comprises: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3;

[0739] in

[0740] CDR-H1 comprises the amino acid sequence of SEQ ID NO: 56, 58 or 59;

[0741] CDR-H2 contains Xaa 12 YGX 13 Xaa 14 (SEQ ID NO: 64);

[0742] in

[0743] Xaa 12 is Asp(D) or Ser(S);

[0744] Xaa 13 is Gly(G), Asp(D) or Leu(L); and

[0745] Xaa 14 is Ser(S), Asp(D) or Asn(N);

[0746] CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14 or 15;

[0747] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0748] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0749] CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and

[0750] (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the first antigen-binding domain comprises at least two, at least three, at least four, at least five, or all six CDRs of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3. In some cases, the second antigen-binding domain binds to CD3. In some cases, the second antigen-binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs of 40G5c or 38E4V1.MD1.

[0751] In some embodiments, the multispecific antigen-binding molecule comprises (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3; wherein CDR-H1 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 56, 58, or 59; CDR-H2 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 57, 60, 61, or 62; CDR-H3 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15; CDR-L1 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprises In some cases, the first antigen-binding domain comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:5; and / or CDR-L3 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:6; and (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the first antigen-binding domain comprises at least two, at least three, at least four, at least five, or all six CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3. In some cases, the second antigen-binding domain binds to CD3. In some cases, the second antigen-binding domain comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs of 40G5c or 38E4V1.MD1.

[0752] In some cases, the first antigen binding domain comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:56; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:57; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:3; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:6.

[0753] In some cases, the first antigen binding domain comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:58; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:60; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:3; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:6.

[0754] In some cases, the first antigen binding domain comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:58; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:61; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:3; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:6.

[0755] In some cases, the first antigen binding domain comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:58; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:61; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:14; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:6.

[0756] In some cases, the first antigen binding domain comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:59; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:62; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:15; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:6.

[0757] In some cases, the first antigen binding domain comprises: a CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:59; a CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:57; a CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:16; a CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:4; a CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:5; and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:6.

[0758] The multispecific antigen-binding molecules of the present invention can be humanized antibodies. In some cases, the first antigen-binding domain and / or the second antigen-binding domain each independently comprise a constant region derived from an IgG framework region. In some cases, the IgG framework region is an IgG1, IgG2, or IgG4 framework region. In some cases, the IgG framework region is an IgG1 framework region.

[0759] In some embodiments, the multispecific antigen-binding molecule comprises (A) a first antigen-binding domain comprising a heavy chain variable region comprising one or more (e.g., 1, 2, 3, or all 4) of the following: a framework region FR-H1 sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 110; a framework region FR-H2 sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 111; a framework region FR-H3 sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 112; a framework region FR-H4 sequence having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 113; a framework region FR-H5 sequence having at least 80%, 85%, 90%, NO: 112 has an FR-H3 that has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity; and / or an FR-H4 that has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence of SEQ ID NO: 113.

[0760] In some embodiments, the multispecific antigen-binding molecule comprises (A) a first antigen-binding domain comprising a light chain variable region comprising one or more (e.g., 1, 2, 3, or all 4) of the following: an FR-L1 having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 114; an FR-L2 having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 115; an FR-L3 having at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 116; NO: 116 having an FR-L3 that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 116; and / or an FR-L4 that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence of SEQ ID NO: 117.

[0761] For example, in some embodiments, a multispecific antigen-binding molecule comprises (A) a first antigen-binding domain comprising: FR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 110; FR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 111; FR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 112; FR-H4 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 113; FR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 114; FR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 115; FR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 116; and FR-L4 comprising The amino acid sequence of NO:117, consists essentially of it, or consists of it.

[0762] In some embodiments, the multispecific antigen-binding molecule comprises: (A) a first antigen-binding domain comprising a VH sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 7, 17-25, 30-34, 38, or 68; and (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the VH sequence of the first antigen-binding domain comprises at least 90% sequence identity to SEQ ID NO: 7, 17-25, 30-34, 38, or 68. In some cases, the VH sequence of the first antigen-binding domain comprises at least 95% sequence identity to SEQ ID NO: 7, 17-25, 30-34, 38, or 68. In some cases, the VH sequence of the first antigen binding domain comprises at least 98% sequence identity to SEQ ID NO: 7, 17-25, 30-34, 38, or 68. In some cases, the VH sequence of the first antigen binding domain comprises at least 99% sequence identity to SEQ ID NO: 7, 17-25, 30-34, 38, or 68. In some cases, the VH sequence of the first antigen binding domain comprises 100% sequence identity to SEQ ID NO: 7, 17-25, 30-34, 38, or 68. In some cases, the second antigen binding domain binds to CD3. In some cases, the second antigen binding domain comprises a VH sequence that has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 46 or 54. In some cases, the VH sequence of the second antigen binding domain comprises at least 95% sequence identity to SEQ ID NO: 46 or 54. In some cases, the VH sequence of the second antigen binding domain comprises at least 99% sequence identity to SEQ ID NO: 46 or 54. In some cases, the VH sequence of the second antigen binding domain comprises 100% sequence identity to SEQ ID NO: 46 or 54.

[0763] In some embodiments, the multispecific antigen-binding molecule comprises: (A) a first antigen-binding domain comprising a VL sequence that is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 8, 26-29, 39, or 69; and (B) a second antigen-binding domain that binds to a T cell receptor. In some cases, the VL sequence comprises a VL sequence that is at least 90% identical to SEQ ID NO: 8, 26-29, 39, or 69. In some cases, the VL sequence comprises at least 95% identical to SEQ ID NO: 8, 26-29, 39, or 69. In some cases, the VL sequence comprises at least 98% identical to SEQ ID NO: 8, 26-29, 39, or 69. In some cases, the VL sequence comprises at least 99% sequence identity to SEQ ID NO: 8, 26 to 29, 39 or 69. In some cases, the VL sequence comprises 100% sequence identity to SEQ ID NO: 8, 26 to 29, 39 or 69. In some cases, the second antigen binding domain binds to CD3. In some cases, the second antigen binding domain comprises a VH sequence that has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 47 or 55. In some cases, the VL sequence of the second antigen binding domain comprises at least 95% sequence identity to SEQ ID NO: 47 or 55. In some cases, the VL sequence of the second antigen binding domain comprises at least 99% sequence identity to SEQ ID NO: 47 or 55. In some cases, the VL sequence of the second antigen binding domain comprises 100% sequence identity to SEQ ID NO:47 or 55.

[0764] In some embodiments, the multispecific antigen-binding molecules of the present invention comprise a first antigen-binding domain that binds to STEAP1 and comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs as shown in Tables 1 or 2. In some cases, the first antigen-binding domain comprises a VH and / or VL as shown in Table 1. In some cases, the multispecific antigen-binding molecule comprises a second antigen-binding domain that binds to a T cell receptor (e.g., CD3). In some cases, the second antigen-binding domain that binds to CD3 comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs as shown in Tables 1 or 2. In some cases, the second antigen-binding domain that binds to CD3 comprises a VH and / or VL as shown in Table 1.

[0765] In some embodiments, the multispecific antigen-binding molecule of any of the preceding embodiments comprises a first antigen-binding domain that binds to STEAP1 and a second antigen-binding domain that binds to a T cell receptor (e.g., CD3). In some embodiments, the first antigen-binding domain is characterized by VH and VL regions, wherein the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 9; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 11; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3. In some cases, the VH region of the first antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:58; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:60; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:3. In some embodiments, the VH region of the first antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 30 (e.g., at least 95% sequence identity to SEQ ID NO: 30, at least 96% sequence identity to SEQ ID NO: 30, at least 97% sequence identity to SEQ ID NO: 30, at least 98% sequence identity to SEQ ID NO: 30, at least 99% sequence identity to SEQ ID NO: 30, or 100% sequence identity to SEQ ID NO: 30). In some embodiments, the VL region of the first antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.In some embodiments, the VL region of the first antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 27 (e.g., at least 95% sequence identity to SEQ ID NO: 27, at least 96% sequence identity to SEQ ID NO: 27, at least 97% sequence identity to SEQ ID NO: 27, at least 98% sequence identity to SEQ ID NO: 27, at least 99% sequence identity to SEQ ID NO: 27, or 100% sequence identity to SEQ ID NO: 27). In some cases, the second antigen binding domain is characterized by VH and VL regions, wherein the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:40 or 48; (b) CDR-H2 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:41 or 49; or (c) CDR-H3 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:42 or 50. In some embodiments, the VH region of the second antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 46 or 54 (e.g., at least 95% sequence identity to SEQ ID NO: 46 or 54, at least 96% sequence identity to SEQ ID NO: 46 or 54, at least 97% sequence identity to SEQ ID NO: 46 or 54, at least 98% sequence identity to SEQ ID NO: 46 or 54, at least 99% sequence identity to SEQ ID NO: 46 or 54, or 100% sequence identity to SEQ ID NO: 46 or 54). In some embodiments, the VL region of the second antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 43 or 51; (b) CDR-L2 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 44 or 52; or (c) CDR-L3 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 45 or 53.In some embodiments, the VL region of the second antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 47 or 55 (e.g., at least 95% sequence identity to SEQ ID NO: 47 or 55, at least 96% sequence identity to SEQ ID NO: 47 or 55, at least 97% sequence identity to SEQ ID NO: 47 or 55, at least 98% sequence identity to SEQ ID NO: 47 or 55, at least 99% sequence identity to SEQ ID NO: 47 or 55, or 100% sequence identity to SEQ ID NO: 47 or 55).

[0766] In some embodiments, the multispecific antigen-binding molecule of any of the preceding embodiments comprises a first antigen-binding domain that binds to STEAP1 and a second antigen-binding domain that binds to a T cell receptor (e.g., CD3). In some embodiments, the first antigen-binding domain is characterized by VH and VL regions, wherein the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 9; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 12; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3. In some cases, the VH region of the first antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:58; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:61; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:3. In some embodiments, the VH region of the first antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 31 (e.g., at least 95% sequence identity to SEQ ID NO: 31, at least 96% sequence identity to SEQ ID NO: 31, at least 97% sequence identity to SEQ ID NO: 31, at least 98% sequence identity to SEQ ID NO: 31, at least 99% sequence identity to SEQ ID NO: 31, or 100% sequence identity to SEQ ID NO: 31). In some embodiments, the VL region of the first antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.In some embodiments, the VL region of the first antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 27 (e.g., at least 95% sequence identity to SEQ ID NO: 27, at least 96% sequence identity to SEQ ID NO: 27, at least 97% sequence identity to SEQ ID NO: 27, at least 98% sequence identity to SEQ ID NO: 27, at least 99% sequence identity to SEQ ID NO: 27, or 100% sequence identity to SEQ ID NO: 27). In some cases, the second antigen binding domain is characterized by VH and VL regions, wherein the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:40 or 48; (b) CDR-L2 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:41 or 49; or (c) CDR-L3 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:42 or 50. In some embodiments, the VH region of the second antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 46 or 54 (e.g., at least 95% sequence identity to SEQ ID NO: 46 or 54, at least 96% sequence identity to SEQ ID NO: 46 or 54, at least 97% sequence identity to SEQ ID NO: 46 or 54, at least 98% sequence identity to SEQ ID NO: 46 or 54, at least 99% sequence identity to SEQ ID NO: 46 or 54, or 100% sequence identity to SEQ ID NO: 46 or 54). In some embodiments, the VL region of the second antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 43 or 51; (b) CDR-L2 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 44 or 52; or (c) CDR-L3 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 45 or 53.In some embodiments, the VL region of the second antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 47 or 55 (e.g., at least 95% sequence identity to SEQ ID NO: 47 or 55, at least 96% sequence identity to SEQ ID NO: 47 or 55, at least 97% sequence identity to SEQ ID NO: 47 or 55, at least 98% sequence identity to SEQ ID NO: 47 or 55, at least 99% sequence identity to SEQ ID NO: 47 or 55, or 100% sequence identity to SEQ ID NO: 47 or 55).

[0767] In some embodiments, the multispecific antigen-binding molecule of any of the preceding embodiments comprises a first antigen-binding domain that binds to STEAP1 and a second antigen-binding domain that binds to a T cell receptor (e.g., CD3). In some embodiments, the first antigen-binding domain is characterized by VH and VL regions, wherein the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 9; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 12; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 14. In some cases, the VH region of the first antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:58; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:61; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:14. In some embodiments, the VH region of the first antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 32 (e.g., at least 95% sequence identity to SEQ ID NO: 32, at least 96% sequence identity to SEQ ID NO: 32, at least 97% sequence identity to SEQ ID NO: 32, at least 98% sequence identity to SEQ ID NO: 32, at least 99% sequence identity to SEQ ID NO: 32, or 100% sequence identity to SEQ ID NO: 32). In some embodiments, the VL region of the first antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.In some embodiments, the VL region of the first antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 27 (e.g., at least 95% sequence identity to SEQ ID NO: 27, at least 96% sequence identity to SEQ ID NO: 27, at least 97% sequence identity to SEQ ID NO: 27, at least 98% sequence identity to SEQ ID NO: 27, at least 99% sequence identity to SEQ ID NO: 27, or 100% sequence identity to SEQ ID NO: 27). In some cases, the second antigen binding domain is characterized by VH and VL regions, wherein the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:40 or 48; (b) CDR-L2 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:41 or 49; or (c) CDR-L3 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:42 or 50. In some embodiments, the VH region of the second antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 46 or 54 (e.g., at least 95% sequence identity to SEQ ID NO: 46 or 54, at least 96% sequence identity to SEQ ID NO: 46 or 54, at least 97% sequence identity to SEQ ID NO: 46 or 54, at least 98% sequence identity to SEQ ID NO: 46 or 54, at least 99% sequence identity to SEQ ID NO: 46 or 54, or 100% sequence identity to SEQ ID NO: 46 or 54). In some embodiments, the VL region of the second antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 43 or 51; (b) CDR-L2 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 44 or 52; or (c) CDR-L3 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 45 or 53.In some embodiments, the VL region of the second antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 47 or 55 (e.g., at least 95% sequence identity to SEQ ID NO: 47 or 55, at least 96% sequence identity to SEQ ID NO: 47 or 55, at least 97% sequence identity to SEQ ID NO: 47 or 55, at least 98% sequence identity to SEQ ID NO: 47 or 55, at least 99% sequence identity to SEQ ID NO: 47 or 55, or 100% sequence identity to SEQ ID NO: 47 or 55).

[0768] In some embodiments, the multispecific antigen-binding molecule of any of the preceding embodiments comprises a first antigen-binding domain that binds to STEAP1 and a second antigen-binding domain that binds to a T cell receptor (e.g., CD3). In some embodiments, the first antigen-binding domain is characterized by VH and VL regions, wherein the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 10; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 13; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 15. In some cases, the VH region of the first antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:59; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:62; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:15. In some embodiments, the VH region of the first antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 33 (e.g., at least 95% sequence identity to SEQ ID NO: 33, at least 96% sequence identity to SEQ ID NO: 33, at least 97% sequence identity to SEQ ID NO: 33, at least 98% sequence identity to SEQ ID NO: 33, at least 99% sequence identity to SEQ ID NO: 33, or 100% sequence identity to SEQ ID NO: 33). In some embodiments, the VL region of the first antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.In some embodiments, the VL region of the first antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 27 (e.g., at least 95% sequence identity to SEQ ID NO: 27, at least 96% sequence identity to SEQ ID NO: 27, at least 97% sequence identity to SEQ ID NO: 27, at least 98% sequence identity to SEQ ID NO: 27, at least 99% sequence identity to SEQ ID NO: 27, or 100% sequence identity to SEQ ID NO: 27). In some cases, the second antigen binding domain is characterized by VH and VL regions, wherein the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:40 or 48; (b) CDR-L2 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:41 or 49; or (c) CDR-L3 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:42 or 50. In some embodiments, the VH region of the second antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 46 or 54 (e.g., at least 95% sequence identity to SEQ ID NO: 46 or 54, at least 96% sequence identity to SEQ ID NO: 46 or 54, at least 97% sequence identity to SEQ ID NO: 46 or 54, at least 98% sequence identity to SEQ ID NO: 46 or 54, at least 99% sequence identity to SEQ ID NO: 46 or 54, or 100% sequence identity to SEQ ID NO: 46 or 54). In some embodiments, the VL region of the second antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 43 or 51; (b) CDR-L2 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 44 or 52; or (c) CDR-L3 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 45 or 53.In some embodiments, the VL region of the second antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 47 or 55 (e.g., at least 95% sequence identity to SEQ ID NO: 47 or 55, at least 96% sequence identity to SEQ ID NO: 47 or 55, at least 97% sequence identity to SEQ ID NO: 47 or 55, at least 98% sequence identity to SEQ ID NO: 47 or 55, at least 99% sequence identity to SEQ ID NO: 47 or 55, or 100% sequence identity to SEQ ID NO: 47 or 55).

[0769] In some embodiments, the multispecific antigen-binding molecule of any of the preceding embodiments comprises a first antigen-binding domain that binds to STEAP1 and a second antigen-binding domain that binds to a T cell receptor (e.g., CD3). In some embodiments, the first antigen-binding domain is characterized by VH and VL regions, wherein the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 10; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 2; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 16. In some cases, the VH region of the first antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:59; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:57; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:16. In some embodiments, the VH region of the first antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 34 (e.g., at least 95% sequence identity to SEQ ID NO: 34, at least 96% sequence identity to SEQ ID NO: 34, at least 97% sequence identity to SEQ ID NO: 34, at least 98% sequence identity to SEQ ID NO: 34, at least 99% sequence identity to SEQ ID NO: 34, or 100% sequence identity to SEQ ID NO: 34). In some embodiments, the VL region of the first antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.In some embodiments, the VL region of the first antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 27 (e.g., at least 95% sequence identity to SEQ ID NO: 27, at least 96% sequence identity to SEQ ID NO: 27, at least 97% sequence identity to SEQ ID NO: 27, at least 98% sequence identity to SEQ ID NO: 27, at least 99% sequence identity to SEQ ID NO: 27, or 100% sequence identity to SEQ ID NO: 27). In some cases, the second antigen binding domain is characterized by VH and VL regions, wherein the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:40 or 48; (b) CDR-L2 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:41 or 49; or (c) CDR-L3 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:42 or 50. In some embodiments, the VH region of the second antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 46 or 54 (e.g., at least 95% sequence identity to SEQ ID NO: 46 or 54, at least 96% sequence identity to SEQ ID NO: 46 or 54, at least 97% sequence identity to SEQ ID NO: 46 or 54, at least 98% sequence identity to SEQ ID NO: 46 or 54, at least 99% sequence identity to SEQ ID NO: 46 or 54, or 100% sequence identity to SEQ ID NO: 46 or 54). In some embodiments, the VL region of the second antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 43 or 51; (b) CDR-L2 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 44 or 52; or (c) CDR-L3 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 45 or 53.In some embodiments, the VL region of the second antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 47 or 55 (e.g., at least 95% sequence identity to SEQ ID NO: 47 or 55, at least 96% sequence identity to SEQ ID NO: 47 or 55, at least 97% sequence identity to SEQ ID NO: 47 or 55, at least 98% sequence identity to SEQ ID NO: 47 or 55, at least 99% sequence identity to SEQ ID NO: 47 or 55, or 100% sequence identity to SEQ ID NO: 47 or 55).

[0770] In some embodiments, the multispecific antigen-binding molecule of any of the preceding embodiments comprises a first antigen-binding domain that binds to STEAP1 and a second antigen-binding domain that binds to a T cell receptor (e.g., CD3). In some embodiments, the first antigen-binding domain is characterized by VH and VL regions, wherein the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 35; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 36; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 37. In some cases, the VH region of the first antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:63; (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:64; or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:37. In some embodiments, the VH region of the first antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 38 (e.g., at least 95% sequence identity to SEQ ID NO: 38, at least 96% sequence identity to SEQ ID NO: 38, at least 97% sequence identity to SEQ ID NO: 38, at least 98% sequence identity to SEQ ID NO: 38, at least 99% sequence identity to SEQ ID NO: 38, or 100% sequence identity to SEQ ID NO: 38). In some embodiments, the VL region of the first antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.In some embodiments, the VL region of the first antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 39 (e.g., at least 95% sequence identity to SEQ ID NO: 39, at least 96% sequence identity to SEQ ID NO: 39, at least 97% sequence identity to SEQ ID NO: 39, at least 98% sequence identity to SEQ ID NO: 39, at least 99% sequence identity to SEQ ID NO: 39, or 100% sequence identity to SEQ ID NO: 39). In some cases, the second antigen binding domain is characterized by VH and VL regions, wherein the VH region comprises one, two, or all three of the following CDRs: (a) CDR-H1 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:40 or 48; (b) CDR-L2 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:41 or 49; or (c) CDR-L3 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO:42 or 50. In some embodiments, the VH region of the second antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 46 or 54 (e.g., at least 95% sequence identity to SEQ ID NO: 46 or 54, at least 96% sequence identity to SEQ ID NO: 46 or 54, at least 97% sequence identity to SEQ ID NO: 46 or 54, at least 98% sequence identity to SEQ ID NO: 46 or 54, at least 99% sequence identity to SEQ ID NO: 46 or 54, or 100% sequence identity to SEQ ID NO: 46 or 54). In some embodiments, the VL region of the second antigen binding domain comprises one, two, or all three of the following CDRs: (a) CDR-L1 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 43 or 51; (b) CDR-L2 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 44 or 52; or (c) CDR-L3 comprising, consisting essentially of, or consisting of an amino acid sequence of SEQ ID NO: 45 or 53.In some embodiments, the VL region of the second antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 47 or 55 (e.g., at least 95% sequence identity to SEQ ID NO: 47 or 55, at least 96% sequence identity to SEQ ID NO: 47 or 55, at least 97% sequence identity to SEQ ID NO: 47 or 55, at least 98% sequence identity to SEQ ID NO: 47 or 55, at least 99% sequence identity to SEQ ID NO: 47 or 55, or 100% sequence identity to SEQ ID NO: 47 or 55).

[0771] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises a first antigen-binding domain that binds to STEAP1 and a second antigen-binding domain that binds to a T cell receptor (e.g., CD3). In some embodiments, the VH region of the first antigen-binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 68 (e.g., at least 95% sequence identity to SEQ ID NO: 68, at least 96% sequence identity to SEQ ID NO: 68, at least 97% sequence identity to SEQ ID NO: 68, at least 98% sequence identity to SEQ ID NO: 68, at least 99% sequence identity to SEQ ID NO: 68, or 100% sequence identity to SEQ ID NO: 68). In some embodiments, the VL region of the first antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 69 (e.g., at least 95% sequence identity to SEQ ID NO: 69, at least 96% sequence identity to SEQ ID NO: 69, at least 97% sequence identity to SEQ ID NO: 69, at least 98% sequence identity to SEQ ID NO: 69, at least 99% sequence identity to SEQ ID NO: 69, or 100% sequence identity to SEQ ID NO: 69). In some embodiments, the VH region of the second antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 46 or 54 (e.g., at least 95% sequence identity to SEQ ID NO: 46 or 54, at least 96% sequence identity to SEQ ID NO: 46 or 54, at least 97% sequence identity to SEQ ID NO: 46 or 54, at least 98% sequence identity to SEQ ID NO: 46 or 54, at least 99% sequence identity to SEQ ID NO: 46 or 54, or 100% sequence identity to SEQ ID NO: 46 or 54). In some embodiments, the VL region of the second antigen binding domain comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 47 or 55 (e.g., at least 95% sequence identity to SEQ ID NO: 47 or 55, at least 96% sequence identity to SEQ ID NO: 47 or 55, at least 97% sequence identity to SEQ ID NO: 47 or 55, at least 98% sequence identity to SEQ ID NO: 47 or 55, at least 99% sequence identity to SEQ ID NO: 47 or 55, or 100% sequence identity to SEQ ID NO: 47 or 55).

[0772] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises: an anti-STEAP1 heavy chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:83; and an anti-STEAP1 light chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:82.

[0773] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises: an anti-STEAP1 heavy chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:85; and an anti-STEAP1 light chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:84.

[0774] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises: an anti-CD3 heavy chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:83; and an anti-CD3 light chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:82.

[0775] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises: an anti-CD3 heavy chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:85; and an anti-CD3 light chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:84.

[0776] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises: an anti-STEAP1 heavy chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:71; and an anti-STEAP1 light chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:70.

[0777] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises: an anti-STEAP1 heavy chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:73; and an anti-STEAP1 light chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:72.

[0778] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises: an anti-STEAP1 heavy chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:75; and an anti-STEAP1 light chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:74.

[0779] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises: an anti-STEAP1 heavy chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:77; and an anti-STEAP1 light chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:76.

[0780] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises: an anti-STEAP1 heavy chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 122; and an anti-STEAP1 light chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 123.

[0781] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises: an anti-STEAP1 heavy chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 126; and an anti-STEAP1 light chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 127.

[0782] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises: an anti-STEAP1 heavy chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 130; and an anti-STEAP1 light chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 131.

[0783] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises: an anti-STEAP1 heavy chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 134; and an anti-STEAP1 light chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 135.

[0784] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises: an anti-STEAP1 heavy chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 138; and an anti-STEAP1 light chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 139.

[0785] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises: an anti-STEAP1 heavy chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 142; and an anti-STEAP1 light chain constant region that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 143.

[0786] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises an anti-CD3 heavy chain that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:79; and an anti-CD3 light chain that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:78.

[0787] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises an anti-CD3 heavy chain that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:81; and an anti-CD3 light chain that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO:80.

[0788] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises an anti-CD3 heavy chain that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 124; and an anti-CD3 light chain that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 125.

[0789] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises an anti-CD3 heavy chain that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 128; and an anti-CD3 light chain that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 129.

[0790] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises an anti-CD3 heavy chain that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 132; and an anti-CD3 light chain that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 133.

[0791] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises: an anti-CD3 heavy chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 136; and an anti-CD3 light chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 137.

[0792] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises an anti-CD3 heavy chain that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 140; and an anti-CD3 light chain that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 141.

[0793] In some embodiments, the multispecific antigen-binding molecule of any preceding embodiment comprises an anti-CD3 heavy chain that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 144; and an anti-CD3 light chain that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NO: 145.

[0794] In some embodiments, the multispecific antigen-binding molecule comprises an anti-STEAP1 heavy chain comprising SEQ ID NO:122, an anti-STEAP1 light chain comprising SEQ ID NO:123, an anti-CD3 heavy chain comprising SEQ ID NO:124, and an anti-CD3 light chain comprising SEQ ID NO:125.

[0795] In some embodiments, the multispecific antigen-binding molecule comprises an anti-STEAP1 heavy chain comprising SEQ ID NO:126, an anti-STEAP1 light chain comprising SEQ ID NO:127, an anti-CD3 heavy chain comprising SEQ ID NO:128, and an anti-CD3 light chain comprising SEQ ID NO:129.

[0796] In some embodiments, the multispecific antigen-binding molecule comprises an anti-STEAP1 heavy chain comprising SEQ ID NO:130, an anti-STEAP1 light chain comprising SEQ ID NO:131, an anti-CD3 heavy chain comprising SEQ ID NO:132, and an anti-CD3 light chain comprising SEQ ID NO:133.

[0797] In some embodiments, the multispecific antigen-binding molecule comprises an anti-STEAP1 heavy chain comprising SEQ ID NO: 134, an anti-STEAP1 light chain comprising SEQ ID NO: 135, an anti-CD3 heavy chain comprising SEQ ID NO: 136, and an anti-CD3 light chain comprising SEQ ID NO: 137.

[0798] In some embodiments, the multispecific antigen-binding molecule comprises an anti-STEAP1 heavy chain comprising SEQ ID NO:138, an anti-STEAP1 light chain comprising SEQ ID NO:139, an anti-CD3 heavy chain comprising SEQ ID NO:140, and an anti-CD3 light chain comprising SEQ ID NO:141.

[0799] In some embodiments, the multispecific antigen-binding molecule comprises an anti-STEAP1 heavy chain comprising SEQ ID NO: 142, an anti-STEAP1 light chain comprising SEQ ID NO: 143, an anti-CD3 heavy chain comprising SEQ ID NO: 144, and an anti-CD3 light chain comprising SEQ ID NO: 145.

[0800] In some embodiments, the multispecific antigen-binding molecule further comprises a third antigen-binding domain. The third antigen-binding domain can be an antigen expressed on the surface of a cell. The antigen can be expressed on the surface of cells obtained from a solid tumor. The antigen can be expressed on the surface of prostate cancer, Ewing's sarcoma, lung cancer, colorectal cancer, breast cancer, bladder cancer, ovarian cancer, or cervical cancer cells.

[0801] In some embodiments, the antigen is a tumor-associated antigen (TAA). A TAA can be a receptor expressed on the surface of cells of prostate cancer, Ewing's sarcoma, lung cancer, colorectal cancer, breast cancer, bladder cancer, ovarian cancer, or cervical cancer. In some cases, a TAA is a receptor expressed on the surface of prostate cancer cells. In some cases, a TAA is a receptor expressed on Ewing's sarcoma cells. Exemplary tumor-associated antigens include, but are not limited to, prostate-specific membrane antigen (PSMA), prostate stem cell antigen (PSCA), epithelial cell adhesion molecule (EpCAM), prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), STEAP2, and HBA-71.

[0802] In some cases, the multispecific antigen-binding molecule further comprises a third antigen-binding domain that binds to a tumor-associated antigen. In some cases, the third antigen-binding domain binds to a TAA of prostate cancer, Ewing's sarcoma, lung cancer, colorectal cancer, breast cancer, bladder cancer, ovarian cancer, or cervical cancer. In some cases, the third antigen-binding domain binds to prostate-specific membrane antigen (PSMA), prostate stem cell antigen (PSCA), epithelial cell adhesion molecule (EpCAM), prostate-specific antigen (PSA), or prostatic acid phosphatase (PAP), STEAP2, or HBA-71. In some cases, the third antigen-binding domain binds to PSMA. In some cases, the third antigen-binding domain binds to PSCA. In some cases, the third antigen-binding domain binds to EpCAM. In some cases, the third antigen-binding domain binds to PSA. In some cases, the third antigen-binding domain binds to PAP. In some cases, the third antigen-binding domain binds to STEAP2. In some cases, the third antigen-binding domain binds to HBA-71.

[0803] In some embodiments, the multispecific antigen-binding molecule has a K of less than 100 nM, less than 75 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 1 nM, or less. D Binds to human STEAP1.

[0804] In some embodiments, the multispecific antigen-binding molecules are present at a concentration of about 1 nM to about 100 nM, about 1 nM to about 75 nM, about 1 nM to about 50 nM, about 1 nM to about 40 nM, about 1 nM to about 30 nM, about 1 nM to about 20 nM, about 1 nM to about 10 nM, about 1 nM to about 5 nM, about 5 nM to about 100 nM, about 5 nM to about 75 nM, about 5 nM to about 50 nM, about 5 nM to about 40 nM, about 5 nM to about 30 nM. , about 5nM to about 20nM, about 5nM to about 10nM, about 10nM to about 100nM, about 10nM to about 75nM, about 10nM to about 50nM, about 10nM to about 40nM, about 10nM to about 30nM, about 10nM to about 20nM, about 15nM to about 100nM, about 15nM to about 75nM, about 15nM to about 50nM, about 15nM to about 40nM, about 15nM to about 30nM, about 15nM to about about 20 nM, about 20 nM to about 100 nM, about 20 nM to about 75 nM, about 20 nM to about 50 nM, about 20 nM to about 40 nM, about 20 nM to about 30 nM, about 25 nM to about 100 nM, about 25 nM to about 75 nM, about 25 nM to about 50 nM, about 25 nM to about 40 nM, about 25 nM to about 30 nM, about 30 nM to about 100 nM, about 30 nM to about 75 nM, about 30 nM to about 50 nM nM, about 30 nM to about 40 nM, about 35 nM to about 100 nM, about 35 nM to about 75 nM, about 35 nM to about 50 nM, about 35 nM to about 40 nM, about 40 nM to about 100 nM, about 40 nM to about 75 nM, about 40 nM to about 50 nM, about 45 nM to about 100 nM, about 45 nM to about 75 nM, about 45 nM to about 50 nM, about 50 nM to about 100 nM, about 50 nM to about 75 nM,

[0805] A K of about 70 nM to about 100 nM, about 70 nM to about 75 nM, about 80 nM to about 100 nM, or about 90 nM to about 100 nM DIn some embodiments, the multispecific antigen-binding molecule binds to human STEAP1 at about 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 11 nM, about 12 nM, about 13 nM, about 14 nM, about 15 nM, about 16 nM, about 17 nM, about 18 nM, about 19 nM, about 20 nM, about 21 nM, about 22 nM, about 23 nM, about 24 nM, about 25 nM, about 26 nM, about 27 nM, about 28 nM, about 29 nM, about 30 nM, about 31 nM, about 32 nM, about 33 nM, about 34 nM, about 35 nM, about 36 nM, about 37 nM, about 38 nM, about 39 nM, about 40 nM, about 41 nM, about 42 nM, about 43 nM, about 44 nM, about 45 nM, about 46 nM, about 47 nM, about 48 nM, about 49 nM, about 50 nM, about 51 nM, about 52 nM, about 53 nM, about 54 nM, about 55 nM, about 56 nM, about 57 nM, about 58 nM, about 59 nM, about 60 nM, about 5 nM, about 26 nM, about 27 nM, about 28 nM, about 29 nM, about 30 nM, about 31 nM, about 32 nM, about 33 nM, about 34 nM, about 35 nM, about 36 nM, about 37 nM, about 38 nM, about 39 nM, about 40 nM, about 41 nM, about 42 nM, about 43 nM, about 44 nM, about 45 nM, about 46 nM, about 47 nM, about 48 nM, about 49 nM, or about 50 nM. D Binds to human STEAP1. In some embodiments, the multispecific antigen-binding molecule binds to human STEAP1 with a K of about 29 nM. D Binds to human STEAP1. In some embodiments, K D Using kinetic exclusion assay Determine as described in Example 8.

[0806] In some embodiments, the multispecific antigen-binding molecule has a K of less than 100 nM, less than 75 nM, less than 50 nM, less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 1 nM, or less. D Binds to cynomolgus monkey STEAP1.

[0807] In some embodiments, the multispecific antigen-binding molecules are present at a concentration of about 1 nM to about 100 nM, about 1 nM to about 75 nM, about 1 nM to about 50 nM, about 1 nM to about 40 nM, about 1 nM to about 30 nM, about 1 nM to about 20 nM, about 1 nM to about 10 nM, about 1 nM to about 5 nM, about 5 nM to about 100 nM, about 5 nM to about 75 nM, about 5 nM to about 50 nM, about 5 nM to about 40 nM, about 5 nM to about 30 nM. , about 5nM to about 20nM, about 5nM to about 10nM, about 10nM to about 100nM, about 10nM to about 75nM, about 10nM to about 50nM, about 10nM to about 40nM, about 10nM to about 30nM, about 10nM to about 20nM, about 15nM to about 100nM, about 15nM to about 75nM, about 15nM to about 50nM, about 15nM to about 40nM, about 15nM to about 30nM, about 15nM to about about 20 nM, about 20 nM to about 100 nM, about 20 nM to about 75 nM, about 20 nM to about 50 nM, about 20 nM to about 40 nM, about 20 nM to about 30 nM, about 25 nM to about 100 nM, about 25 nM to about 75 nM, about 25 nM to about 50 nM, about 25 nM to about 40 nM, about 25 nM to about 30 nM, about 30 nM to about 100 nM, about 30 nM to about 75 nM, about 30 nM to about 50 nM nM, about 30 nM to about 40 nM, about 35 nM to about 100 nM, about 35 nM to about 75 nM, about 35 nM to about 50 nM, about 35 nM to about 40 nM, about 40 nM to about 100 nM, about 40 nM to about 75 nM, about 40 nM to about 50 nM, about 45 nM to about 100 nM, about 45 nM to about 75 nM, about 45 nM to about 50 nM, about 50 nM to about 100 nM, about 50 nM to about 75 nM,

[0808] A K of about 70 nM to about 100 nM, about 70 nM to about 75 nM, about 80 nM to about 100 nM, or about 90 nM to about 100 nM D In some embodiments, the multispecific antigen-binding molecule binds to cynomolgus monkey STEAP1 with a K of 1 nM, about 2 nM, about 3 nM, about 4 nM, about 5 nM, about 6 nM, about 7 nM, about 8 nM, about 9 nM, about 10 nM, about 11 nM, about 12 nM, about 13 nM, about 14 nM, about 15 nM, about 16 nM, about 17 nM, about 18 nM, about 19 nM, about 20 nM, about 21 nM, about 22 nM, about 23 nM, about 24 nM, or about 25 nM. D Binds to cynomolgus monkey STEAP1. In some embodiments, the multispecific antigen-binding molecule binds to cynomolgus monkey STEAP1 with a K of about 14 nM. DBinds to cynomolgus monkey STEAP1. In some embodiments, K D Using kinetic exclusion assay Determine as described in Example 8.

[0809] In some embodiments, the multispecific antigen-binding molecule has a C of up to or about 15, 20, 25, or 30 μg / mL. max In some cases, the multispecific antigen-binding molecule has a C of about 11, 11.5, 12, 12.1, 12.6, 13, 13.2, 13.5, 15, 15.3, 18, 20, 23.4, 25, 27.9, 29.1, or 30 μg / mL. max .

[0810] In some embodiments, the multispecific antigen-binding molecule has an antigen-binding activity of about 10 μg / mL to about 30 μg / mL (e.g., about 10 μg / mL to about 30 μg / mL, about 10 μg / mL to about 28 μg / mL, about 10 μg / mL to about 26 μg / mL, about 10 μg / mL to about 24 μg / mL, about 10 μg / mL to about 22 μg / mL, about 10 μg / mL to about 20 μg / mL, about 10 μg / mL to about 18 μg / mL, about 10 μg / mL to about 16 μg / mL, about 10 μg / mL to about 14 μg / mL, about 10 μg / mL to about 12 μg / mL, about 12 μg / mL to about 30 μg / mL, about 12 μg / mL to about about 28 μg / mL, about 12 μg / mL to about 26 μg / mL, about 12 μg / mL to about 24 μg / mL, about 12 μg / mL to about 22 μg / mL, about 12 μg / mL to about 20 μg / mL, about 12 μg / mL to about 18 μg / mL, about 12 μg / mL to about 16 μg / mL, about 12 μg / mL to about 14 μg / mL, about 14 μg / mL to about 30 μg / mL, about 14 μg / mL to about 28 μg / mL, about 14 μg / mL to about 26 μg / mL, about 14 μg / mL to about 24 μg / mL, about 14 μg / mL to about 22 μg / mL, about 14 μg / mL to about 20 μg / mL, about 14 μg / mL mL to about 18 μg / mL, about 14 μg / mL to about 16 μg / mL, about 16 μg / mL to about 30 μg / mL, about 16 μg / mL to about 28 μg / mL, about 16 μg / mL to about 26 μg / mL, about 16 μg / mL to about 24 μg / mL, about 16 μg / mL to about 22 μg / mL, about 16 μg / mL to about 20 μg / mL, about 16 μg / mL to about 18 μg / mL, about 18 μg / mL to about 30 μg / mL, about 18 μg / mL to about 28 μg / mL, about 18 μg / mL to about 26 μg / mL, about 18 μg / mL to about 24 μg / mL, about 18 μg / mL to about 22 μg / mL, about 18 μg / mL to about 20 μg / mL, about 20 μg / mL to about 30 μg / mL, about 20 μg / mL to about 28 μg / mL, about 20 μg / mL to about 26 μg / mL, about 20 μg / mL to about 24 μg / mL, about 20 μg / mL to about 22 μg / mL, about 22 μg / mL to about 30 μg / mL, about 22 μg / mL to about 28 μg / mL, about 22 μg / mL to about 26 μg / mL, about 22 μg / mL to about 24 μg / mL, about 24 μg / mL to about 30 μg / mL, about 24 μg / mL to about 28 μg / mL, about 22 μg / mL to about 26 μg / mL, about 22 μg / mL to about 24 μg / mL,about 26 μg / mL to about 30 μg / mL, about 26 μg / mL to about 28 μg / mL, or about 28 μg / mL to about 30 μg / mL) of C, max In some embodiments, the multispecific antigen-binding molecule has a C of about 20 μg / mL to about 28 μg / mL (e.g., about 20 μg / mL, about 21 μg / mL, about 22 μg / mL, about 23 μg / mL, about 24 μg / mL, about 25 μg / mL, about 26 μg / mL, about 27 μg / mL, or about 28 μg / mL). max In some embodiments, the multispecific antigen-binding molecule has a C of about 24 μg / mL. max In some embodiments, C max Can be determined as described in Example 9 (in female SCID mice). In some embodiments, C max It can be determined as described in Example 10 (in cynomolgus monkeys).

[0811] In some embodiments, the multispecific antigen-binding molecule has an EC of about 0.6, 0.56, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.05 or less. 50 In some cases, the multispecific antigen-binding molecule has an EC of about 0.5 or less. 50 In some cases, the multispecific antigen-binding molecule has an EC of about 0.4 or less. 50 In some cases, the multispecific antigen-binding molecule has an EC of about 0.3 or less. 50 In some cases, the multispecific antigen-binding molecule has an EC of about 0.2 or less. 50 In some cases, the multispecific antigen-binding molecule has an EC of about 0.1 or less. 50 .

[0812] In some embodiments, the multispecific antigen-binding molecule has a molecular weight of about 0.05 to about 0.8 (e.g., about 0.05 to about 0.8, about 0.05 to about 0.75, about 0.05 to about 0.70, about 0.05 to about 0.65, about 0.05 to about 0.6, about 0.05 to about 0.55, about 0.05 to about 0.5, about 0.05 to about 0.45, about 0.05 to about 0.4, about 0.05 to about 0.35, about 0.05 to about 0.3, about 0.05 to about 0.25, about 0.05 to about 0.2, about 0.05 to about 0.15, about 0.05 to about 0.1, about 0.05 to about 0.09, about 0.05 to about 0.08, about 0.05 to about 0.07, about 0.05 to about about 0.06, about 0.06 to about 0.8, about 0.06 to about 0.75, about 0.06 to about 0.70, about 0.06 to about 0.65, about 0.06 to about 0.6, about 0.06 to about 0.55, about 0.06 to about 0.5, about 0.06 to about 0.45, about 0.06 to about 0.4, about 0.06 to about 0.35, about 0.06 to about 0.3, about 0.06 to about 0.25, about 0.06 to about 0.2, about 0.06 to about 0.15, about 0.06 to about 0.1, about 0.06 to about 0.09, about 0.06 to about 0.08, about 0.06 to about 0.07, about 0.07 to about 0.8, about 0.07 to about 0.75, about 0.07 to about 0.70, about 0.07 to about 0.65, about 0.07 to about 0.6, about 0.07 to about 0.55, about 0.07 to about 0.5, about 0.07 to about 0.45, about 0.07 to about 0.4, about 0.07 to about 0.35, about 0.07 to about 0.3, about 0.07 to about 0.25, about 0.07 to about 0.2, about 0.07 to about 0.15, about 0.07 to about 0.1, about 0.07 to about 0.09, about 0.07 to about 0.08, about 0.08 to about 0.8, about 0.08 to about 0.75, about 0.08 to about 0.70, about 0.08 to about 0.65, about 0.08 to about 0.6, about 0.08 to about 0.55, about 0.08 to about 0.5, about 0.08 to about 0.45, about 0.08 to about 0.4, about 0.08 to about 0.35, about 0.08 to about 0.3, about 0.08 to about 0.25, about 0.08 to about 0.2, about 0.08 to about 0.15, about 0.08 to about 0.1, about 0.08 to about 0.09, about 0.09 to about 0.8, about 0.09 to about 0.75, about 0.09 to about 0.70, about 0.09 to about 0.65, about 0.09 to about 0.6, about 0.09 to about 0.55, about 0.09 to about 0.5, about 0.09 to about 0.45, about 0.09 to about 0.4, about 0.09 to about 0.35, about 0.09 to about 0.3, about 0.09 to about 0.25, about 0.09 to about 0.2, about 0.0.9 to about 0.15, about 0.09 to about 0.1, about 0.1 to about 0.8, about 0.1 to about 0.75, about 0.1 to about 0.70, about 0.1 to about 0.65, about 0.1 to about 0.6, about 0.1 to about 0.55, about 0.1 to about 0.5, about 0.1 to about 0.45, about 0.1 to about 0.4, about 0.1 to about 0.35, about 0.1 to about 0.3, about 0.1 to about 0.25, about 0.1 to about 0.2, about 0.1 to about 0.15, about 0.15 to about 0.8, about 0.15 to about 0.75, about 0.15 to about 0.70, about 0.15 to about 0.65, about 0.15 to about 0.6, about 0.15 to about 0.55, about 0.15 to about 0.5, about 0.15 to about 0.45, about 0.15 to about 0.4, about 0.15 to about 0.35, about 0.15 to about 0.3, about 0.15 to about 0.25, about 0.15 to about 0.2, about 0.2 to about 0.8, about 0.2 to about 0.75, about 0.2 to about 0.70, about 0.2 to about 0.65, about 0.2 to about 0.6, about 0.2 to about 0.55, about 0.2 to about 0.5, about 0.2 to about 0.45, about 0.2 to about 0.4, about 0.2 to about 0.35, about 0.2 to about 0.3, about 0.2 to about 0.25, about 0.25 to about 0.8, about 0.25 to about 0.75, about 0.25 to about 0.70, about 0.25 to about 0.65, about 0.25 to about 0.6, about 0.25 to about 0.55, about 0.25 to about 0.5, about 0.25 to about 0.45, about 0.25 to about 0.4, about 0.25 to about 0.35, about 0.25 to about 0.3, about 0.3 to about 0.8, about 0.3 to about 0.75, about 0.3 to about 0.70, about 0.3 to about 0.65, about 0.3 to about 0.6, about 0.3 to about 0.55, about 0.3 to about 0.5, about 0.3 to about 0.45, about 0.3 to about 0.4, about 0.3 to about 0.35, about 0.35 to about 0.8, about 0.35 to about 0.75, about 0.35 to about 0.70, about 0.35 to about 0.65, about 0.35 to about 0.6, about 0.35 to about 0.55, about 0.35 to about 0.5, about 0.35 to about 0.45, about 0.35 to about 0.4, about 0.4 to about 0.8, about 0.4 to about 0.75, about 0.4 to about 0.70, about 0.4 to about 0.65, about 0.4 to about 0.6, about 0.4 to about 0.55, about 0.4 to about 0.5, about 0.4 to about 0.45, about 0.45 to about 0.8, about 0.45 to about 0.75, about 0.45 to about 0.70, about 0.45 to about 0.65, about 0.45 to about 0.55, about 0.45 to about 0.56, an EC of about 0.5 to about 0.55, about 0.55 to about 0.8, about 0.55 to about 0.75, about 0.55 to about 0.70, about 0.55 to about 0.65, about 0.55 to about 0.6, about 0.6 to about 0.8, about 0.6 to about 0.75, about 0.6 to about 0.70, about 0.6 to about 0.65, about 0.65 to about 0.8, about 0.65 to about 0.75, about 0.65 to about 0.70, about 0.7 to about 0.8, about 0.7 to about 0.75, or about 0.75 to about 0.8). 50 .

[0813] In some embodiments, EC 50 The results were determined in a 72-hour cell killing assay using human CD8+ T cells and LNCaP-X1.2 cells expressing STEAP1. 50 is about 0.05 to about 0.4 (e.g., about 0.05, about 0.06, about 0.07, about 0.08, about 0.09, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, or about 0.4). In some embodiments, EC 50 is about 0.08 or about 0.3. In some embodiments, EC 50 In some embodiments, EC 50 It is about 0.3.

[0814] In some embodiments, EC 50 The results were determined in a 72-hour cell killing assay using human CD8+ T cells and LNCaPX1.2KO3-13 cells expressing STEAP1. 50 is from about 0.1 to about 0.8 (e.g., about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0.55, about 0.6, about 0.65, about 0.7, about 0.75, or about 0.8). In some embodiments, EC 50 is about 0.1 or about 0.7. In some embodiments, EC 50 In some embodiments, EC 50 It is about 0.7.

[0815] In some embodiments, the multispecific antigen-binding molecule binds monovalently to STEAP1. In other embodiments, the multispecific antigen-binding molecule binds multivalently (eg, bivalently) to STEAP1.

[0816] Antibodies that bind to specific STEAP1 epitopes

[0817] In certain embodiments, the antibodies of the present invention comprise a first antigen-binding domain that binds to a STEAP1 protein. In some cases, the first antigen-binding domain binds to a human STEAP1 protein. In other cases, the first antigen-binding domain binds to a primate STEAP1 protein (e.g., a STEAP1 protein from a cynomolgus monkey or an orangutan).

[0818] In some embodiments, the antibody comprises a first antigen-binding domain that binds to human STEAP1 at one or more residues selected from Ser101, His102, Gln103, Trp195, Gln198, Gln202, and Lys281, wherein residue positions 101, 102, 103, 195, 198, 202, and 281 correspond to positions 101, 102, 103, 195, 198, 202, and 281 as shown in SEQ ID NO: 65. In some cases, the first antigen-binding domain binds to at least one residue selected from Ser101, His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of SEQ ID NO: 65.

[0819] In some cases, a residue from the first antigen binding domain forms a hydrogen bond with at least one residue selected from Ser101, His102, Gln103, Trp195, Gln198, Gln202, and Lys281. In some cases, at least one residue selected from Leu56, Ser73, Asn74, Gly101, Tyr103, and Tyr107 of the VH of the first antigen binding domain forms a hydrogen bond with at least one residue selected from Ser101, His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of STEAP1, wherein residue positions 56, 73, 74, 101, 103, and 107 correspond to positions 56, 73, 74, 101, 103, and 107 set forth in SEQ ID NO: 18. In some cases, at least one residue selected from Tyr35 or Tyr54 of the VL of the first antigen binding domain forms a hydrogen bond with at least one residue selected from Gln202 or Gln201, wherein residue positions 35 and 54 correspond to positions 35 and 54 as shown in SEQ ID NO: 8. In some cases, residues Asn203 and / or Lys204 of human STEAP1 form van der Waals interactions with one or more VL CDR residues. In some cases, the residues forming hydrogen bonds are as shown in Table 3.

[0820] Table 3

[0821]

[0822] In some embodiments, the antibodies of the present invention are monospecific antibodies as described above in Section A, "Antigen Binding Molecules that Bind to STEAP1." In some cases, the antibodies comprise: a VH region comprising CDR-H1, CDR-H2, and CDR-H3 of a VH sequence selected from SEQ ID NOs: 7, 17 to 25, 30 to 34, 38, and 68; and a VL region comprising CDR-L1, CDR-L2, and CDR-L3 of a VL sequence selected from SEQ ID NOs: 8, 26 to 29, 39, and 69. In some cases, the antibodies comprise six CDRs, wherein:

[0823] CDR-H1 contains Xaa 1 Xaa 2 YMA (SEQ ID NO: 35);

[0824] in

[0825] Xaa 1 is Asp(D) or Asn(N); and

[0826] Xaa 2 is His (H), Tyr (Y) or Phe (F);

[0827] CDR-H2 contains YIXaa 3 YGX 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36);

[0828] in

[0829] Xaa 3 is Asp(D) or Ser(S);

[0830] Xaa 4 is Gly (G), Asp (D) or Leu (L);

[0831] Xaa 5 is Ser(S), Asp(D) or Asn(N); and

[0832] Xaa 6 is Ser (S) or Tyr (Y);

[0833] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0834] in

[0835] Xaa 7 is Phe(F) or Tyr(Y);

[0836] Xaa 8 is Asn(N) or Asp(D); and

[0837] Xaa 9 is Ala (A) or Gly (G);

[0838] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0839] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and

[0840] CDR-L3 comprises the amino acid sequence of SEQ ID NO:6.

[0841] In some cases, the antibody comprises six CDRs, wherein:

[0842] CDR-H1 contains GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63);

[0843] in

[0844] Xaa 10 is Asn(N) or Asp(D); and

[0845] Xaa 11 is Tyr (Y), Phe (F) or His (H);

[0846] CDR-H2 contains Xaa 12 YGX 13 Xaa 14 (SEQ ID NO: 64);

[0847] in

[0848] Xaa 12 is Asp(D) or Ser(S);

[0849] Xaa 13 is Gly(G), Asp(D) or Leu(L); and

[0850] Xaa 14 is Ser(S), Asp(D) or Asn(N);

[0851] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8Xaa 9 (SEQ ID NO:37);

[0852] in

[0853] Xaa 7 is Phe(F) or Tyr(Y);

[0854] Xaa 8 is Asn(N) or Asp(D); and

[0855] Xaa 9 is Ala (A) or Gly (G);

[0856] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0857] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and

[0858] CDR-L3 comprises the amino acid sequence of SEQ ID NO:6.

[0859] In some embodiments, the antibodies of the present invention are multispecific antibodies as described above in Section B, "Multispecific Antigen-Binding Molecules." In some cases, the antibodies comprise: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and / or CDR-H3 of a VH sequence selected from SEQ ID NOs: 7, 17 to 25, 30 to 34, 38, and 68; and / or an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and / or CDR-L3 of a VL sequence selected from SEQ ID NOs: 8, 26 to 29, 39, and 69; and (B) a second antigen-binding domain that binds to a T cell receptor (e.g., CD3).

[0860] In some cases, the antibody comprises: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3;

[0861] in

[0862] CDR-H1 contains Xaa 1 Xaa 2 YMA (SEQ ID NO: 35);

[0863] in

[0864] Xaa 1 is Asp(D) or Asn(N); and

[0865] Xaa 2 is His (H), Tyr (Y) or Phe (F);

[0866] CDR-H2 contains YIXaa 3 YGX 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36);

[0867] in

[0868] Xaa 3 is Asp(D) or Ser(S);

[0869] Xaa 4 is Gly (G), Asp (D) or Leu (L);

[0870] Xaa 5 is Ser(S), Asp(D) or Asn(N); and

[0871] Xaa 6 is Ser(S) or Tyr(Y); and

[0872] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0873] in

[0874] Xaa 7 is Phe(F) or Tyr(Y);

[0875] Xaa 8 is Asn(N) or Asp(D); and

[0876] Xaa 9 is Ala (A) or Gly (G);

[0877] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0878] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0879] CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and

[0880] (B) a second antigen-binding domain that binds to a T cell receptor (eg, CD3).

[0881] In some embodiments, the antibody comprises: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3;

[0882] in

[0883] CDR-H1 contains GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63);

[0884] in

[0885] Xaa 10 is Asn(N) or Asp(D); and

[0886] Xaa 11 is Tyr (Y), Phe (F) or His (H);

[0887] CDR-H2 contains Xaa 12 YGX 13 Xaa 14 (SEQ ID NO: 64);

[0888] in

[0889] Xaa 12 is Asp(D) or Ser(S);

[0890] Xaa 13 is Gly(G), Asp(D) or Leu(L); and

[0891] Xaa 14 is Ser(S), Asp(D) or Asn(N);

[0892] CDR-H3 contains RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO:37);

[0893] in

[0894] Xaa 7 is Phe(F) or Tyr(Y);

[0895] Xaa 8 is Asn(N) or Asp(D); and

[0896] Xaa 9 is Ala (A) or Gly (G);

[0897] CDR-L1 comprises the amino acid sequence of SEQ ID NO: 4;

[0898] CDR-L2 comprises the amino acid sequence of SEQ ID NO: 5; and / or

[0899] CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and

[0900] (B) a second antigen-binding domain that binds to a T cell receptor (eg, CD3).

[0901] Peptide linker fusing the first antigen-binding domain and the second antigen-binding domain

[0902] In some embodiments, the multispecific antigen-binding molecules of the present invention (e.g., bispecific or trispecific antigen-binding molecules) are characterized in that the C-terminus of the first antigen-binding domain is fused to the N-terminus of the second antigen-binding domain via a peptide connector. The length of the peptide connector may be 5 to 20 amino acids (e.g., 5 to 10, 10 to 15, or 15 to 20, such as 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids in length). In some embodiments, the peptide connector comprises the native amino acid sequence of the variable heavy chain hinge region (e.g., DKTHT). In some embodiments, the peptide connector comprises (Gly4Ser) n Connector (or (G4S) n Connector), wherein n is 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 2 to 6, 2 to 6, 3 to 6, or 4 to 6. In some cases, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, the peptide connector comprises a G4SG2 connector. In some embodiments, the peptide connector comprises a G4SG2 connector and a hinge region (e.g., DKTHT). In some embodiments, the peptide connector comprises a plurality of glycine, alanine, or a combination thereof.

[0903] Fc domain

[0904] The antigen binding molecules of the present invention (e.g., monospecific and / or multispecific antigen binding molecules such as bispecific or trispecific antigen binding molecules) can be characterized by an Fc domain. The Fc domain can be an IgG Fc domain (e.g., IgG1, IgG2 or IgG4 Fc domain). For example, the Fc domain can be a human Fc domain. In certain embodiments, the Fc domain comprises one or more amino acid substitutions that reduce the binding and / or effector functions of Fc receptors. For example, in certain embodiments, one or more amino acid substitutions that reduce the binding and / or effector functions of Fc receptors are located at one or more positions of the group selected from L234, L235 and P329 (e.g., wherein the first Fc subunit and the second Fc subunit each include an amino acid substitution of L234A, L235A and P329G). Fc receptors can be, for example, Fc γ receptors. Therefore, the antigen binding molecules of the present invention (e.g., monospecific and / or multispecific antigen binding molecules such as bispecific or trispecific antigen binding molecules) can be configured to reduce antibody-dependent cell-mediated cytotoxicity (ADCC).

[0905] In some cases, the Fc domain comprises a modification configured to promote association of the first Fc subunit with the second Fc subunit. "Knob-in-hole" engineering of bispecific antibodies can be utilized to generate a first arm comprising a knob and a second arm comprising a hole, wherein the knob of the first arm can bind to the hole. In one embodiment, the knob of a multispecific antigen-binding molecule of the present invention can be an anti-STEAP1 arm. Alternatively, the knob of a multispecific antigen-binding molecule of the present invention can be an anti-CD3 arm. In one embodiment, the hole of a multispecific antigen-binding molecule of the present invention can be an anti-STEAP1 arm. Alternatively, the hole of a multispecific antigen-binding molecule of the present invention can be an anti-CD3 arm. Multispecific antigen-binding molecules such as bispecific antibodies can also be engineered using immunoglobulin crossover (also known as Fab domain exchange or CrossMab format) technology (see, for example, WO 2009 / 080253; Schaefer et al., Proc. Natl. Acad. Sci. USA, 108: 11187-11192 (2011). Multispecific antibodies can also be prepared by the following methods: Engineered electrostatic steering effects for preparing antibody Fc-heterodimer molecules (WO 2009 / 089004A1); cross-linking two or more antibodies or fragments (see, e.g., U.S. Patent No. 4,676,980; and Brennan et al., Science, 229:81 (1985)); or by using leucine zippers to create bispecific antibodies (see, e.g., Kostelny et al., J. Immunol., 148(5):1547-1553 (1992)).

[0906] Amino acid residues in the CH3 domain of the second Fc subunit can be replaced with amino acid residues having a larger side chain volume, thereby generating a protrusion (e.g., a knob) within the CH3 domain of the second Fc subunit, which can be positioned within a cavity (e.g., a hole) within the CH3 domain of the first Fc subunit, and amino acid residues in the CH3 domain of the first Fc subunit can be replaced with amino acid residues having a smaller side chain volume, thereby generating a cavity (e.g., a hole) within the CH3 domain of the first Fc subunit, which can be positioned within the protrusion (e.g., knob) within the CH3 domain of the second Fc subunit. In some embodiments, the CH3 domain of the second Fc subunit comprises an amino acid substitution of T366, and the CH3 domain of the first Fc subunit comprises an amino acid substitution of one, two, or all three of T366, L368, and / or Y407 (all EU numbering). In some embodiments, the CH3 domain of the second Fc subunit comprises an amino acid substitution of T366W, and the CH3 domain of the first Fc subunit comprises an amino acid substitution at one, two, or all three of T366S, L368A, and / or Y407V (all EU numbering).

[0907] In some embodiments, the multispecific antigen-binding molecules described herein comprise: an anti-STEAP1 arm comprising N297G (EU numbering) and T366W (EU numbering) substitutions in the heavy chain, and an anti-CD3 arm comprising N297G (EU numbering), T366S (EU numbering), L368A (EU numbering), and Y407V (EU numbering) substitutions in the heavy chain. In some embodiments, the multispecific antigen-binding molecules described herein comprise: an anti-STEAP1 arm comprising N297G (EU numbering) and T366W (EU numbering) substitutions in the heavy chain, and an anti-CD3 arm comprising N297G (EU numbering), T366S (EU numbering), L368A (EU numbering), and Y407V (EU numbering) substitutions in the heavy chain.

[0908] In some embodiments, the multispecific antigen-binding molecules described herein comprise: a) a first heavy chain / light chain pair that binds to a first antigen, the first heavy chain / light chain pair comprising a first heavy chain polypeptide (H1) and a first light chain polypeptide (L1), and b) a second heavy chain / light chain pair that binds to a second antigen, the second heavy chain / light chain pair comprising a second heavy chain polypeptide (H2) and a second light chain polypeptide (L2), wherein each H1 and H2 comprises a heavy chain variable domain (VH) and a heavy chain constant domain (CH1), and and each of L1 and L2 comprises a light chain variable domain (VL) and a light chain constant domain (VL), wherein: (i) the amino acid at S183 (EU numbering) in the CH1 domain of H1 is replaced with a positively charged residue, the amino acid at Q39 (Kabat numbering) in the VH domain of H1 is replaced with a negatively charged residue, the amino acid at V133 (EU numbering) in the CL domain of L1 is replaced with a negatively charged residue, and the amino acid at Q38 (Kabat numbering) in the VL domain of L1 is replaced with a negatively charged residue. the amino acid at Q39 (Kabat numbering) in the VH domain of H2 is replaced with a positively charged residue, and the amino acid at Q38 (Kabat numbering) in the VL domain of L2 is replaced with a negatively charged residue; or (ii) the amino acid at S183 (EU numbering) in the CH1 domain of H1 is replaced with a negatively charged residue, the amino acid at Q39 (Kabat numbering) in the VH domain of H1 is replaced with a positively charged residue, the amino acid at V133 (EU numbering) in the CL domain of L1 is replaced with a positively charged residue, and the amino acid at Q38 (Kabat numbering) in the VL domain of L1 is replaced with a negatively charged residue; and the amino acid at Q39 (Kabat numbering) in the VH domain of H2 is replaced with a negatively charged residue, and the amino acid at Q38 (Kabat numbering) in the VL domain of L2 is replaced with a positively charged residue. In some embodiments, the positively charged residue is selected from R and K, and the negatively charged residue is selected from D and E. In some embodiments, the positively charged residue is R. In other embodiments, the positively charged residue is K. In some embodiments, the negatively charged residue is D. In other embodiments, the negatively charged residue is E. In some embodiments, the first antigen is STEAP1 and the second antigen is CD3. In other embodiments, the first antigen is CD3 and the second antigen is STEAP1.

[0909] For example, in some embodiments, the multispecific antigen-binding molecules described herein comprise: an anti-STEAP1 arm comprising a first heavy chain polypeptide (H1) and a first light chain polypeptide (L1), and an anti-CD3 arm comprising a second heavy chain polypeptide (H2) and a second light chain polypeptide (L2), wherein each of H1 and H2 comprises a heavy chain variable domain (VH) and a heavy chain constant domain (CH1), and each of L1 and L2 comprises a light chain variable domain (VL) and a light chain constant domain (VL), wherein: (i) the amino acid at S183 (EU numbering) in the CH1 domain of H1 is replaced with an R or K residue, the amino acid at Q39 (Kabat numbering) in the VH domain of H1 is replaced with a D or E residue, the amino acid at V133 (EU numbering) in the CL domain of L1 is replaced with a D or E residue, and the amino acid at Q38 (Kabat numbering) in the VL domain of L1 is replaced with a R or K residue; and the amino acid at Q39 (Kabat numbering) in the VH domain of H2 is replaced with an R or K residue, and the amino acid at Q38 (Kabat numbering) in the VL domain of L2 is replaced with a D or E residue; or (ii) the amino acid at S183 (EU numbering) in the CH1 domain of H1 is replaced with a D or E residue, the amino acid at Q39 (Kabat numbering) in the VH domain of H1 is replaced with an R or K residue, the amino acid at V133 (EU numbering) in the CL domain of L1 is replaced with an R or K residue, and the amino acid at Q38 (Kabat numbering) in the VL domain of L1 is replaced with a D or E residue; and the amino acid at Q39 (Kabat numbering) in the VH domain of H2 is replaced with a D or E residue, and the amino acid at Q38 (Kabat numbering) in the VL domain of L2 is replaced with an R or K residue.

[0910] In some embodiments, the multispecific antigen-binding molecules described herein comprise: an anti-STEAP1 arm comprising a first heavy chain polypeptide (H1) and a first light chain polypeptide (L1), and an anti-CD3 arm comprising a second heavy chain polypeptide (H2) and a second light chain polypeptide (L2), wherein each of H1 and H2 comprises a heavy chain variable domain (VH) and a heavy chain constant domain (CH1), and each of L1 and L2 comprises a light chain variable domain (VL) and a light chain constant domain (VL), wherein: (i) the amino acid at S183 (EU numbering) in the CH1 domain of H1 is replaced with a K residue, the amino acid at Q39 (Kabat numbering) in the VH domain of H1 is replaced with an E residue, the amino acid at V133 (EU numbering) in the CL domain of L1 is replaced with an E residue, and the amino acid at Q38 (Kabat numbering) in the VL domain of L1 is replaced with a and the amino acid at Q39 (Kabat numbering) in the VH domain of H2 is replaced with a K residue, and the amino acid at Q38 (Kabat numbering) in the VL domain of L2 is replaced with an E residue; or (ii) the amino acid at S183 (EU numbering) in the CH1 domain of H1 is replaced with an E residue, the amino acid at Q39 (Kabat numbering) in the VH domain of H1 is replaced with a K residue, the amino acid at V133 (EU numbering) in the CL domain of L1 is replaced with a K residue, and the amino acid at Q38 (Kabat numbering) in the VL domain of L1 is replaced with an E residue; and the amino acid at Q39 (Kabat numbering) in the VH domain of H2 is replaced with an E residue, and the amino acid at Q38 (K...

Claims

1. A multispecific antigen-binding molecule comprising: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2 and CDR-H3 of a VH sequence selected from SEQ ID NOs: 7, 17 to 25, 30 to 34, 38 and 68; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2 and CDR-L3 of a VL sequence selected from SEQ ID NOs: 8, 26 to 29, 39 and 69; and (B) a second antigen-binding domain that binds to a T cell receptor.

2. A multispecific antigen-binding molecule comprising: (A) a first antigen-binding domain that binds to STEAP1 and comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2 and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2 and CDR-L3; in CDR-H1 containing Xaa 1 Xaa 2 YMA (SEQ ID NO:35); in XA 1 is Asp(D) or Asn(N); and XA 2 is His (H), Tyr (Y) or Phe (F); CDR-H2 contains YIXaa 3 YDGXaa 4 Xaa 5 TXaa 6 YGDSVKG(SEQ ID NO:36); in XA 3 Asp(D) or Ser(S); XA 4 is Gly (G), Asp (D) or Leu (L); XA 5 is Ser(S), Asp(D) or Asn(N); and XA 6 is Ser(S) or Tyr(Y); and CDR-H3 contains RSGXaa 7 YHVGYAMXa 8 XA 9 (SEQ ID NO:37); wherein XA 7 is Phe(F) or Tyr(Y); XA 8 is Asn(N) or Asp(D); and XA 9 is Ala (A) or Gly (G); CDR-L1 comprises the amino acid sequence of SEQ ID NO:4; CDR-L2 comprises the amino acid sequence of SEQ ID NO:5; and CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and (B) The second antigen binding domain, which binds to the T cell receptor.

3. The multispecific antigen-binding molecule of claim 1 or 2, wherein CDR-H1 comprises the amino acid sequence of SEQ ID NO:10, 1 or 9. 4 . The multispecific antigen-binding molecule of claim 1 , wherein the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, 11, 12 or 13. 5 . The multispecific antigen-binding molecule of any one of claims 1 to 4 , wherein the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14 or 15.

6. The multispecific antigen-binding molecule of any one of claims 1 to 5, wherein the first antigen-binding domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 10; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 16; CDR-L1 comprising the amino acid sequence of SEQ ID NO:4; CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; and CDR-L3 comprises the amino acid sequence of SEQ ID NO:

6.

7. The multispecific antigen-binding molecule of any one of claims 1 to 5, wherein the first antigen-binding domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising the amino acid sequence of SEQ ID NO:4; CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; and CDR-L3 comprises the amino acid sequence of SEQ ID NO:

6.

8. The multispecific antigen-binding molecule of any one of claims 1 to 5, wherein the first antigen-binding domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO:9; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 11; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising the amino acid sequence of SEQ ID NO:4; CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; and CDR-L3 comprises the amino acid sequence of SEQ ID NO:

6.

9. The multispecific antigen-binding molecule of any one of claims 1 to 5, wherein the first antigen-binding domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO:9; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising the amino acid sequence of SEQ ID NO:4; CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; and CDR-L3 comprises the amino acid sequence of SEQ ID NO:

6.

10. The multispecific antigen-binding molecule of any one of claims 1 to 5, wherein the first antigen-binding domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO:9; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 14; CDR-L1 comprising the amino acid sequence of SEQ ID NO:4; CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; and CDR-L3 comprises the amino acid sequence of SEQ ID NO:

6.

11. The multispecific antigen-binding molecule of any one of claims 1 to 5, wherein the first antigen-binding domain comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 10; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 13; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 15; CDR-L1 comprising the amino acid sequence of SEQ ID NO:4; CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; and CDR-L3 comprises the amino acid sequence of SEQ ID NO:

6. 12 . The multispecific antigen-binding molecule of claim 1 , wherein the multispecific antigen-binding molecule is a humanized antibody.

13. The multispecific antigen-binding molecule of any one of claims 1 to 12, wherein the first antigen-binding domain and the second antigen-binding domain each independently comprise an IgG framework region, optionally an IgG1 or IgG4 framework region.

14. The multispecific antigen-binding molecule of any one of claims 1 to 13, wherein the first antigen-binding domain comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:7, 17 to 25, 30 to 34, 38 or 68.

15. The multispecific antigen-binding molecule of any one of claims 1 to 14, wherein the first antigen-binding domain comprises: an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO: 8, 26 to 29, 39 or 69.

16. The multispecific antigen-binding molecule of any one of claims 1 to 15, wherein the first antigen-binding domain comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:68; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

69.

17. The multispecific antigen-binding molecule of any one of claims 1 to 15, wherein the first antigen-binding domain comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:34; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

27.

18. The multispecific antigen-binding molecule of any one of claims 1 to 15, wherein the first antigen-binding domain comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO: 30; and an anti-STEAP1 light chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

30. NO:27 has a VL sequence with at least 80%, 85%, 90%, 95% or 100% sequence identity.

19. The multispecific antigen-binding molecule of any one of claims 1 to 15, wherein the first antigen-binding domain comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:31; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

27.

20. The multispecific antigen-binding molecule of any one of claims 1 to 15, wherein the first antigen-binding domain comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:32; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

27.

21. The multispecific antigen-binding molecule of any one of claims 1 to 15, wherein the first antigen-binding domain comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:33; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

27.

22. The multispecific antigen-binding molecule of any one of claims 1 to 21, wherein the T cell receptor is cluster of differentiation 3 (CD3).

23. The multispecific antigen-binding molecule of claim 22, wherein the second antigen-binding domain that binds to CD3 comprises: an anti-CD3 heavy chain variable region (VH) comprising CDR-H1, CDR-H2 and CDR-H3; and an anti-CD3 light chain variable region (VL) comprising CDR-L1, CDR-L2 and CDR-L3, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 comprise the sequences of SEQ ID NOs: 48 to 53, respectively.

24. The multispecific antigen-binding molecule of claim 23, wherein the second antigen-binding domain that binds to CD3 comprises: an anti-CD3 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:54; and a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

55.

25. The multispecific antigen-binding molecule of claim 22, wherein the second antigen-binding domain that binds to CD3 comprises: an anti-CD3 heavy chain variable region (VH) comprising CDR-H1, CDR-H2 and CDR-H3; and an anti-CD3 light chain variable region (VL) comprising CDR-L1, CDR-L2 and CDR-L3, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 comprise the sequences of SEQ ID NOs: 40 to 45, respectively.

26. The multispecific antigen-binding molecule of claim 25, wherein the second antigen-binding domain that binds to CD3 comprises: an anti-CD3 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:46; and an anti-CD3 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

47.

27. A multispecific antigen-binding molecule according to any one of claims 1 to 26, wherein the multispecific antigen-binding molecule comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH11) domain, a first CH2 (CH21) domain, a first CH3 (CH31) domain, a second CH1 (CH12) domain, a second CH2 (CH22) domain and a second CH3 (CH32) domain.

28. The multispecific antigen-binding molecule of claim 27, wherein at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.

29. The multispecific antigen-binding molecule of claim 28, wherein the CH31 domain and the CH32 domain each comprise a protrusion or a cavity, and wherein the protrusion or the cavity in the CH31 domain is positionable in the cavity or the protrusion in the CH32 domain, respectively.

30. The multispecific antigen-binding molecule of claim 29, wherein the CH31 domain and the CH32 domain meet at the interface between the protrusion and the cavity.

31. A multispecific antigen-binding molecule according to any one of claims 27 to 30, wherein the CH21 domain and the CH22 domain each comprise a protrusion or a cavity, and wherein the protrusion or the cavity in the CH21 domain is positionable in the cavity or the protrusion in the CH22 domain, respectively.

32. The multispecific antigen-binding molecule of claim 31, wherein the CH21 domain and the CH22 domain meet at the interface between the protrusion and the cavity.

33. The multispecific antigen-binding molecule of any one of claims 22 and 27 to 32, wherein the first antigen-binding domain comprises: an anti-STEAP1 heavy chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:83; and an anti-STEAP1 light chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:82; and wherein the second antigen-binding domain comprises: an anti-CD3 heavy chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:85; and an anti-CD3 light chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

84.

34. The multispecific antigen-binding molecule of any one of claims 22 and 27 to 32, wherein the first antigen-binding domain comprises: an anti-STEAP1 heavy chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:85; and an anti-STEAP1 light chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:84; and wherein the second antigen-binding domain comprises: an anti-CD3 heavy chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:83; and an anti-CD3 light chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

82.

35. The multispecific antigen-binding molecule of any one of claims 22 and 27 to 32, wherein the multispecific antigen-binding molecule comprises an anti-STEAP1 heavy chain comprising SEQ ID NO: 73, an anti-STEAP1 light chain comprising SEQ ID NO: 72, an anti-CD3 heavy chain comprising SEQ ID NO: 81, and an anti-CD3 light chain comprising SEQ ID NO:

80.

36. The multispecific antigen-binding molecule of any one of claims 22 and 27 to 32, wherein the multispecific antigen-binding molecule comprises an anti-STEAP1 heavy chain comprising SEQ ID NO: 73, an anti-STEAP1 light chain comprising SEQ ID NO: 72, an anti-CD3 heavy chain comprising SEQ ID NO: 79, and an anti-CD3 light chain comprising SEQ ID NO:

78.

37. The multispecific antigen-binding molecule of any one of claims 1 to 36, wherein the antigen-binding molecule is a single-chain Fv (scFv), a trispecific (Fab3), a bispecific (Fab2), a diabody ((V L -V H )2 or (V H -V L )2), trivalent antibody (trivalent), tetravalent antibody (quadrivalent), mini antibody (scF V -C H )2), bispecific single-chain Fv (bi-scFv), IgGδCH2, scFv-Fc or (scFv)2-Fc.

38. The multispecific antigen-binding molecule of any one of claims 1 to 37, wherein the multispecific antigen-binding molecule is a multispecific antibody, preferably a bispecific or trispecific antibody.

39. The multispecific antigen-binding molecule of any one of claims 1 to 38, wherein the multispecific antigen-binding molecule further comprises a third antigen-binding domain that binds to a tumor-associated antigen.

40. The multispecific antigen-binding molecule of claim 39, wherein the tumor-associated antigen is a receptor expressed on prostate cancer cells or Ewing's sarcoma.

41. The multispecific antigen-binding molecule of claim 39 or 40, wherein the tumor-associated antigen is prostate-specific membrane antigen (PSMA), STEAP2, prostate stem cell antigen (PSCA), epithelial cell adhesion molecule (EpCAM), prostate-specific antigen (PSA), prostatic acid phosphatase (PAP) or HBA-71.

42. The multispecific antigen-binding molecule of any one of claims 1 to 41, wherein the multispecific antigen-binding molecule binds to human STEAP1, cynomolgus monkey STEAP1, or a combination thereof, preferably wherein the multispecific antigen-binding molecule binds to human STEAP1 of SEQ ID NO:

65.

43. The multispecific antigen-binding molecule of any one of claims 1 to 42, wherein the first antigen-binding domain binds to at least one residue selected from Ser101, His102, Gln103 and Lys281 of STEAP1, wherein residue positions 101, 102, 103 and 281 correspond to positions 101, 102, 103 and 281 shown in SEQ ID NO:

65.

44. The multispecific antigen-binding molecule of any one of claims 1 to 43, wherein the first antigen-binding domain binds to Ser101, His102, Gln103, and Lys281 of STEAP1.

45. The multispecific antigen-binding molecule of any one of claims 1 to 44, wherein the multispecific antigen-binding molecule has a C of about 11, 11.5, 12, 12.6, 13, 13.5, 15, 18, 20, 23.4, 25, 27.9, 29.1, or 30 μg / mL. max .

46. ​​The multispecific antigen-binding molecule of any one of claims 1 to 44, wherein the multispecific antigen-binding molecule has a C of about 11 μg / mL to about 30 μg / mL. max .

47. The multispecific antigen-binding molecule of claim 46, wherein the multispecific antigen-binding molecule has a C of about 20 μg / mL to about 28 μg / mL. max .

48. The multispecific antigen-binding molecule of claim 47, wherein the multispecific antigen-binding molecule has a C of about 24 μg / mL. max .

49. The multispecific antigen-binding molecule of any one of claims 1 to 48, wherein the multispecific antigen-binding molecule has an EC of about 0.6, 0.56, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2, 0.15, 0.1, 0.09, 0.05 or less. 50 .

50. The multispecific antigen-binding molecule of any one of claims 1 to 48, wherein the multispecific antigen-binding molecule has an EC of about 0.05 to about 0.

8. 50 .

51. The multispecific antigen-binding molecule of claim 50, wherein the EC 50 was determined in a 72-hour cell killing assay using human CD8+ T cells and LNCaP-X1.2 cells expressing STEAP1, and the EC 50 From about 0.05 to about 0.

4.

52. The multispecific antigen-binding molecule of claim 51, wherein the EC 50 It is about 0.08 or about 0.

3.

53. The multispecific antigen-binding molecule of claim 50, wherein the EC 50 was determined in a 72-hour cell killing assay using human CD8+ T cells and LNCaPX1.2KO3-13 cells expressing STEAP1, and the EC 50 From about 0.1 to about 0.

8.

54. The multispecific antigen-binding molecule of claim 53, wherein the EC 50 It is about 0.1 or about 0.

7.

55. An antigen binding molecule that binds to STEAP1, the antigen binding molecule comprising: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2 and CDR-H3 of a VH sequence selected from SEQ ID NOs: 7, 17 to 25, 30 to 34, 38 and 68; and An anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2 and CDR-L3 of a VL sequence selected from the group consisting of SEQ ID NOs: 8, 26 to 29, 39 and 69.

56. An antigen binding molecule that binds to STEAP1, the antigen binding molecule comprising: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2 and CDR-H3; and an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2 and CDR-L3; in CDR-H1 containing Xaa 1 Xaa 2 YMA (SEQ ID NO:35); in XA 1 is Asp(D) or Asn(N); and XA 2 is His (H), Tyr (Y) or Phe (F); CDR-H2 contains YIXaa 3 YDGXaa 4 Xaa 5 TXaa 6 YGDSVKG(SEQ ID NO:36); in XA 3 Asp(D) or Ser(S); XA 4 is Gly (G), Asp (D) or Leu (L); XA 5 is Ser(S), Asp(D) or Asn(N); and XA 6 is Ser(S) or Tyr(Y); CDR-H3 contains RSGXaa 7 YHVGYAMXa 8 XA 9 (SEQ ID NO:37); wherein XA 7 is Phe(F) or Tyr(Y); XA 8 is Asn(N) or Asp(D); and XA 9 is Ala (A) or Gly (G); CDR-L1 comprises the amino acid sequence of SEQ ID NO:4; CDR-L2 comprises the amino acid sequence of SEQ ID NO:5; and CDR-L3 comprises the amino acid sequence of SEQ ID NO:

6.

57. The antigen binding molecule of claim 55 or 56, wherein the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 10, 1 or 9.

58. according to any one of claims 55 to 57 antigen binding molecules, wherein said CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, 11, 12 or 13.

59. according to any one of claims 55 to 58 antigen binding molecules, wherein said CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14 or 15.

60. The antigen binding molecule according to any one of claims 55 to 59, wherein the antigen binding molecule comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 10; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 16; CDR-L1 comprising the amino acid sequence of SEQ ID NO:4; CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; and CDR-L3 comprises the amino acid sequence of SEQ ID NO:

6.

61. The antigen binding molecule according to any one of claims 55 to 59, wherein the antigen binding molecule comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising the amino acid sequence of SEQ ID NO:4; CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; and CDR-L3 comprises the amino acid sequence of SEQ ID NO:

6.

62. The antigen binding molecule according to any one of claims 55 to 59, wherein the antigen binding molecule comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO:9; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 11; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising the amino acid sequence of SEQ ID NO:4; CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; and CDR-L3 comprises the amino acid sequence of SEQ ID NO:

6.

63. The antigen binding molecule according to any one of claims 55 to 59, wherein the antigen binding molecule comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO:9; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising the amino acid sequence of SEQ ID NO:4; CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; and CDR-L3 comprises the amino acid sequence of SEQ ID NO:

6.

64. The antigen binding molecule according to any one of claims 55 to 59, wherein the antigen binding molecule comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO:9; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 14; CDR-L1 comprising the amino acid sequence of SEQ ID NO:4; CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; and CDR-L3 comprises the amino acid sequence of SEQ ID NO:

6.

65. The antigen binding molecule according to any one of claims 55 to 59, wherein the antigen binding molecule comprises: CDR-H1 comprising the amino acid sequence of SEQ ID NO: 10; CDR-H2 comprising the amino acid sequence of SEQ ID NO: 13; CDR-H3 comprising the amino acid sequence of SEQ ID NO: 15; CDR-L1 comprising the amino acid sequence of SEQ ID NO:4; CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; and CDR-L3 comprises the amino acid sequence of SEQ ID NO:

6.

66. The antigen binding molecule according to any one of claims 55 to 65, wherein the antigen binding molecule is a humanized antibody.

67. The antigen binding molecule according to any one of claims 55 to 66, wherein the antigen binding molecule comprises an IgG framework region, optionally an IgG1 framework region.

68. The antigen binding molecule according to any one of claims 55 to 67, comprising: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:7, 17 to 25, 30 to 34, 38 or 68.

69. The antigen binding molecule of any one of claims 55 to 68, comprising: an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO: 8, 26 to 29, 39 or 69.

70. The antigen binding molecule according to any one of claims 55 to 69, comprising: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO: 68; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

69.

71. The antigen binding molecule according to any one of claims 55 to 69, comprising: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:34; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

27.

72. The antigen binding molecule according to any one of claims 55 to 69, comprising: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:30; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

27.

73. The antigen binding molecule according to any one of claims 55 to 69, comprising: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:31; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

27.

74. The antigen binding molecule according to any one of claims 55 to 69, comprising: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:32; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

27.

75. The antigen binding molecule according to any one of claims 55 to 69, comprising: an anti-STEAP1 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:33; and an anti-STEAP1 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

27.

76. An antigen binding molecule according to any one of claims 55 to 75, wherein the antigen binding molecule comprises: an anti-STEAP1 heavy chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:83; and an anti-STEAP1 light chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:82; or wherein the antigen binding molecule comprises: an anti-STEAP1 heavy chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:85; and an anti-STEAP1 light chain constant region sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

84.

77. The antigen binding molecule of claim 76, wherein the antigen binding molecule comprises an anti-STEAP1 heavy chain comprising SEQ ID NO: 73 and an anti-STEAP1 light chain comprising SEQ ID NO:

72.

78. The antigen binding molecule according to any one of claims 55 to 77, wherein the antigen binding molecule is a full-length antibody or a fragment thereof.

79. according to any one of claims 55 to 78 antigen binding molecules, wherein the antigen binding molecule is Fab, Fab ', F (ab ') 2, Fv, Fd, single chain Fv (scFv), tri-specific (Fab3), bi-specific (Fab2), diabody ((V L -V H )2 or (V H -V L )2), trivalent antibody (trivalent), tetravalent antibody (quadrivalent), mini antibody (scF V -C H )2), bispecific single-chain Fv (bi-scFv), IgGδCH2, scFv-Fc or (scFv)2-Fc.

80. An antigen binding molecule according to any one of claims 55 to 79, wherein the antigen binding molecule further comprises an antigen binding domain that binds to a T cell receptor.

81. The antigen binding molecule according to any one of claims 55 to 80, wherein the antigen binding molecule is a multispecific antibody, preferably wherein the antigen binding molecule is a bispecific antibody or a trispecific antibody.

82. The antigen binding molecule of claim 80 or 81, wherein the T cell receptor is cluster of differentiation 3 (CD3).

83. An antigen binding molecule according to claim 82, wherein the antigen binding domain that binds to CD3 comprises: an anti-CD3 heavy chain variable region (VH) comprising CDR-H1, CDR-H2 and CDR-H3; and an anti-CD3 light chain variable region (VL) comprising CDR-L1, CDR-L2 and CDR-L3, wherein CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 respectively comprise the amino acid sequences of SEQ ID NOs: 48 to 53.

84. An antigen binding molecule according to claim 83, wherein the antigen binding domain that binds to CD3 comprises: an anti-CD3 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity with SEQ ID NO:54; and an anti-CD3 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity with SEQ ID NO:

55.

85. An antigen binding molecule according to claim 82, wherein the antigen binding domain that binds to CD3 comprises: an anti-CD3 heavy chain variable region (VH) comprising CDR-H1, CDR-H2 and CDR-H3; and an anti-CD3 light chain variable region (VL) comprising CDR-L1, CDR-L2 and CDR-L3, wherein CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 respectively comprise the amino acid sequences of SEQ ID NOs: 40 to 45.

86. An antigen binding molecule according to claim 83, wherein the antigen binding domain that binds to CD3 comprises: an anti-CD3 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity with SEQ ID NO:46; and an anti-CD3 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity with SEQ ID NO:

47.

87. The antigen binding molecule of claim 82, wherein the antigen binding molecule comprises an anti-CD3 heavy chain comprising SEQ ID NO: 79 and an anti-CD3 light chain comprising SEQ ID NO:

78.

88. The antigen binding molecule of claim 82, wherein the antigen binding molecule comprises an anti-CD3 heavy chain comprising SEQ ID NO:81 and an anti-CD3 light chain comprising SEQ ID NO:

80.

89. An antigen binding molecule according to any one of claims 55 to 88, wherein the antigen binding molecule further comprises an additional antigen binding domain that binds to a tumor associated antigen.

90. The antigen binding molecule according to claim 89, wherein the tumor-associated antigen is a receptor expressed on prostate cancer cells or Ewing's sarcoma.

91. An antigen binding molecule according to claim 89 or 90, wherein the tumor-associated antigen is prostate-specific membrane antigen (PSMA), STEAP2, prostate stem cell antigen (PSCA), epithelial cell adhesion molecule (EpCAM), prostate-specific antigen (PSA), prostatic acid phosphatase (PAP) or HBA-71.

92. The antigen binding molecule according to any one of claims 55 to 91, wherein the antigen binding molecule binds to human STEAP1, cynomolgus monkey STEAP1 or a combination thereof, preferably wherein the antigen binding molecule binds to human STEAP1 of SEQ ID NO:

65.

93. The antigen binding molecule according to any one of claims 55 to 92, wherein the antigen binding molecule binds to at least one residue selected from Ser101, His102, Gln103 and Lys281 of STEAP1, wherein residue positions 101, 102, 103 and 281 correspond to positions 101, 102, 103 and 281 shown in SEQ ID NO:

65.

94. An antigen binding molecule according to any one of claims 55 to 93, wherein the antigen binding molecule binds to Ser101, His102, Gln103 and Lys281 of SEQ ID NO:

65.

95. An antibody comprising a first antigen binding domain that binds to human STEAP1 at one or more residues selected from Ser101, His102, Gln103 and Lys281, wherein residue positions 101, 102, 103 and 281 correspond to positions 101, 102, 103 and 281 as shown in SEQ ID NO:

65.

96. The antibody of claim 95, wherein the first antigen binding domain binds to Ser101, His102, Gln103, and Lys281 of SEQ ID NO:

65.

97. The antibody of claim 95 or 96, wherein the heavy chain variable region of the first antigen binding domain forms a hydrogen bond with at least one residue selected from Ser101, His102, Gln103 and Lys281.

98. The antibody of any one of claims 95 to 97, wherein Leu56, Ser73 and Asn74 of the heavy chain variable region of the first antigen binding domain form hydrogen bonds with Ser101, His102, Gln103 and Lys281 of STEAP1, wherein the residue positions of the heavy chain variable region correspond to positions 56, 73 and 74 shown in SEQ ID NO:

18.

99. The antibody according to any one of claims 95 to 98, wherein the first antigen binding domain comprises: an anti-STEAP1 heavy chain variable region (VH) comprising CDR-H1, CDR-H2 and CDR-H3 of a VH sequence selected from SEQ ID NOs: 7, 17 to 25, 30 to 34, 38 and 68; and three CDRs of an anti-STEAP1 light chain variable region (VL) comprising CDR-L1, CDR-L2 and CDR-L3 of a VL sequence selected from SEQ ID NOs: 8, 26 to 29, 39 and 69.

100. The antibody of any one of claims 95 to 99, wherein the first antigen binding domain comprises: an anti-STEAP1 heavy chain variable region comprising a VH sequence comprising at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:7, 17 to 25, 30 to 34, 38 or 68.

101. The antibody of any one of claims 95 to 100, wherein the first antigen binding domain comprises: an anti-STEAP1 light chain variable region comprising a VL sequence comprising at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:8, 26 to 29, 39 or 69.

102. The antibody of any one of claims 95 to 101, wherein the antibody further comprises a second antigen binding domain that binds to a T cell receptor.

103. The antibody of claim 102, wherein the T cell receptor is cluster of differentiation 3 (CD3).

104. The antibody of claim 103, wherein the second antigen-binding domain that binds to CD3 comprises an anti-CD3 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3, and an anti-CD3 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs: 48 to 53, respectively.

105. The antibody of claim 104, wherein the second antigen binding domain that binds to CD3 comprises: an anti-CD3 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:54; and an anti-CD3 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

55.

106. The antibody of claim 103, wherein the second antigen-binding domain that binds to CD3 comprises an anti-CD3 heavy chain variable region (VH) comprising CDR-H1, CDR-H2, and CDR-H3, and an anti-CD3 light chain variable region (VL) comprising CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise the amino acid sequences of SEQ ID NOs: 40 to 45, respectively.

107. The antibody of claim 106, wherein the second antigen binding domain that binds to CD3 comprises: an anti-CD3 heavy chain variable region comprising a VH sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:46; and an anti-CD3 light chain variable region comprising a VL sequence having at least 80%, 85%, 90%, 95% or 100% sequence identity to SEQ ID NO:

47.

108. The antibody of any one of claims 95 to 107, wherein the multispecific antigen-binding molecule further comprises a third antigen-binding domain that binds to a tumor-associated antigen.

109. The antibody of claim 108, wherein the tumor-associated antigen is a receptor expressed on prostate cancer cells.

110. The antibody of claim 108 or 109, wherein the tumor-associated antigen is prostate-specific membrane antigen (PSMA), STEAP2, prostate stem cell antigen (PSCA), epithelial cell adhesion molecule (EpCAM), prostate-specific antigen (PSA) or prostatic acid phosphatase (PAP).

111. One or more isolated nucleic acids, which, alone or together, encode a multispecific antigen-binding molecule according to any one of claims 1 to 54, an antigen-binding molecule according to any one of claims 55 to 94, or an antibody according to any one of claims 95 to 110.

112. One or more vectors, which alone or together comprise the isolated nucleic acid according to claim 111.

113. One or more host cells, which contain, alone or together, the isolated nucleic acid according to claim 111 or the vector according to claim 112.

114. The host cell of claim 113, wherein the host cell is a mammalian cell.

115. The host cell of claim 114, wherein the mammalian cell is a Chinese Hamster Ovary (CHO) cell.

116. The host cell of claim 113, wherein the host cell is an insect cell.

117. The host cell of claim 113, wherein the host cell is a prokaryotic cell.

118. A method for producing a multispecific antigen-binding molecule according to any one of claims 1 to 54, an antigen-binding molecule according to any one of claims 55 to 94, or an antibody according to any one of claims 95 to 110, the method comprising culturing a host cell according to any one of claims 113 to 117 in a culture medium.

119. The method of claim 118, further comprising harvesting the multispecific antigen-binding molecule of any one of claims 1 to 54, the antigen-binding molecule of any one of claims 55 to 94, or the antibody of any one of claims 95 to 110 from the host cell or the culture medium.

120. A pharmaceutical composition comprising the multispecific antigen-binding molecule of any one of claims 1 to 54, the antigen-binding molecule of any one of claims 55 to 94, or the antibody of any one of claims 95 to 110.

121. The pharmaceutical composition of claim 120, further comprising a pharmaceutically acceptable carrier, excipient or diluent.

122. A pharmaceutical composition according to claim 120 or 121 for use as a medicament.

123. The pharmaceutical composition according to claim 120 or 121, for use in treating cancer expressing STEAP1 or delaying its progression.

124. The pharmaceutical composition of claim 120 or 121, for use in treating or delaying progression of prostate cancer or Ewing's sarcoma.

125. The multispecific antigen-binding molecule of any one of claims 1 to 54, the antigen-binding molecule of any one of claims 55 to 94, or the antibody of any one of claims 95 to 110 for use in treating or delaying progression of a cancer expressing STEAP1 in a subject in need thereof.

126. The multispecific antigen-binding molecule of any one of claims 1 to 54, the antigen-binding molecule of any one of claims 55 to 94, or the antibody of any one of claims 95 to 110, for use in inhibiting or reducing the proliferation of cancer cells expressing STEAP1.

127. The multispecific antigen-binding molecule for use, the antigen-binding molecule for use or the antibody for use according to claim 125 or 126, wherein the cancer expressing STEAP1 is a solid tumor.

128. The multispecific antigen-binding molecule for use, the antigen-binding molecule for use, or the antibody for use according to any one of claims 125 to 127, wherein the cancer expressing STEAP1 is prostate cancer or Ewing's sarcoma.

129. The multispecific antigen-binding molecule for use, the antigen-binding molecule for use or the antibody for use according to any one of claims 125 to 128, to be used in combination with an additional therapeutic agent or an additional therapeutic regimen.

130. The multispecific antigen-binding molecule for use, the antigen-binding molecule for use, or the antibody for use according to claim 129, wherein the additional therapeutic agent comprises a chemotherapeutic agent, an immunotherapeutic agent, a targeted therapy, a radiation therapy, or a combination thereof.

131. The multispecific antigen binding molecule for use, the antigen binding molecule for use, or the antibody for use according to claim 129 or 130, wherein the additional therapeutic agent comprises a first-line, second-line or third-line therapy.

132. The multispecific antigen-binding molecule for use, the antigen-binding molecule for use, or the antibody for use according to claim 129, wherein the additional treatment regimen comprises surgery.

133. The multispecific antigen-binding molecule for use, the antigen-binding molecule for use or the antibody for use according to any one of claims 129 to 131, wherein the multispecific antigen-binding molecule, the antigen-binding molecule or the antibody and the additional therapeutic agent are to be administered simultaneously.

134. The multispecific antigen-binding molecule for use, the antigen-binding molecule for use or the antibody for use according to any one of claims 129 to 131, wherein the multispecific antigen-binding molecule, the antigen-binding molecule or the antibody and the additional therapeutic agent are to be administered sequentially.

135. The multispecific antigen-binding molecule for use, the antigen-binding molecule for use or the antibody for use according to any one of claims 129 to 131, wherein the multispecific antigen-binding molecule, the antigen-binding molecule or the antibody is to be administered first before administering the additional therapeutic agent.

136. The multispecific antigen-binding molecule for use, the antigen-binding molecule for use, or the antibody for use according to any one of claims 129 to 131, wherein the multispecific antigen-binding molecule, the antigen-binding molecule or the antibody is to be administered after administration of the additional therapeutic agent.

137. The multispecific antigen-binding molecule for use, the antigen-binding molecule for use, or the antibody for use according to any one of claims 125 to 136, wherein the multispecific antigen-binding molecule, the antigen-binding molecule or the antibody is to be administered systemically.

138. The multispecific antigen-binding molecule for use, the antigen-binding molecule for use, or the antibody for use according to any one of claims 125 to 136, wherein the multispecific antigen-binding molecule, the antigen-binding molecule or the antibody is to be administered topically.

139. The multispecific antigen-binding molecule for use, the antigen-binding molecule for use, or the antibody for use according to any one of claims 125 to 136, wherein the multispecific antigen-binding molecule, the antigen-binding molecule or the antibody is to be administered by parenteral administration.

140. The multispecific antigen-binding molecule for use, the antigen-binding molecule for use, or the antibody for use according to any one of claims 125 to 136, wherein the multispecific antigen-binding molecule, the antigen-binding molecule or the antibody is to be administered intravenously or subcutaneously.

141. The multispecific antigen-binding molecule for use, the antigen-binding molecule for use, or the antibody for use according to any one of claims 125 to 136, wherein the subject is a human.

142. Use of the multispecific antigen-binding molecule of any one of claims 1 to 54, the antigen-binding molecule of any one of claims 55 to 94, or the antibody of any one of claims 95 to 110 in the manufacture of a medicament for treating or delaying progression of a cancer expressing STEAP1 in a subject in need thereof, optionally for treating or delaying progression of prostate cancer or Ewing's sarcoma.

143. Use of the multispecific antigen-binding molecule of any one of claims 1 to 54, the antigen-binding molecule of any one of claims 55 to 94, or the antibody of any one of claims 95 to 110 in the manufacture of a medicament, optionally for treating prostate cancer cells or Ewing's sarcoma cells.

144. A method for treating or delaying progression of a cancer expressing STEAP1 in a subject in need thereof, the method comprising administering to the subject an effective amount of the multispecific antigen-binding molecule of any one of claims 1 to 54, the antigen-binding molecule of any one of claims 55 to 94, or the antibody of any one of claims 95 to 110.

145. The method of claim 144, wherein the cancer expressing STEAP1 is a solid tumor.

146. The method of claim 144 or 145, wherein the cancer expressing STEAP1 is prostate cancer or Ewing's sarcoma.

147. The method of any one of claims 144 to 146, further comprising administering to the subject an additional therapeutic agent or an additional treatment regimen.

148. The method of claim 147, wherein the additional therapeutic agent comprises a chemotherapeutic agent, an immunotherapeutic agent, a targeted therapy, a radiation therapy, or a combination thereof.

149. The method of claim 148, wherein the additional therapeutic agent comprises a first-line, second-line, or third-line therapy.

150. The method of claim 148, wherein the additional treatment option comprises surgery.

151. The method of any one of claims 144 to 150, wherein the multispecific antigen-binding molecule, the antigen-binding molecule or the antibody and the additional therapeutic agent are administered simultaneously.

152. The method of any one of claims 144 to 150, wherein the multispecific antigen-binding molecule, the antigen-binding molecule or the antibody and the additional therapeutic agent are administered sequentially.

153. The method of claim 152, wherein the multispecific antigen-binding molecule, the antigen-binding molecule, or the antibody is administered first prior to administration of the additional therapeutic agent.

154. The method of claim 152, wherein the multispecific antigen-binding molecule, the antigen-binding molecule, or the antibody is administered after administration of the additional therapeutic agent.

155. The method of any one of claims 144 to 154, wherein the multispecific antigen-binding molecule, the antigen-binding molecule, or the antibody is administered systemically.

156. The method of any one of claims 144 to 154, wherein the multispecific antigen-binding molecule, the antigen-binding molecule, or the antibody is administered topically.

157. The method of any one of claims 144 to 156, wherein the multispecific antigen-binding molecule, the antigen-binding molecule, or the antibody is administered by parenteral administration.

158. The method of any one of claims 144 to 157, wherein the multispecific antigen-binding molecule, the antigen-binding molecule, or the antibody is administered intravenously or subcutaneously.

159. The method of any one of claims 144 to 158, wherein the subject is a human.

160. A method of inhibiting or reducing proliferation of a cell expressing STEAP1, the method comprising contacting the cell with a multispecific antigen-binding molecule according to any one of claims 1 to 54, an antigen-binding molecule according to any one of claims 55 to 94, or an antibody according to any one of claims 95 to 110 for a time sufficient to inhibit proliferation of the cell.

161. The method of claim 160, wherein the cell is a prostate cancer cell or an Ewing's sarcoma cell.

162. The method of claim 160 or 161, wherein the method is an in vivo method.

163. The method of claim 160 or 161, wherein the method is an in vitro or ex vivo method.

164. A kit comprising a multispecific antigen-binding molecule according to any one of claims 1 to 54, an antigen-binding molecule according to any one of claims 55 to 94, or an antibody according to any one of claims 95 to 110, an isolated nucleic acid according to claim 111, a vector according to claim 112, a host cell according to any one of claims 113 to 117, or a pharmaceutical composition according to any one of claims 120 to 124, optionally comprising a set of instructions.

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