WO2024020564A1 - Molécules de liaison à l'antigène anti-steap1 et leurs utilisations - Google Patents

Molécules de liaison à l'antigène anti-steap1 et leurs utilisations Download PDF

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WO2024020564A1
WO2024020564A1 PCT/US2023/070740 US2023070740W WO2024020564A1 WO 2024020564 A1 WO2024020564 A1 WO 2024020564A1 US 2023070740 W US2023070740 W US 2023070740W WO 2024020564 A1 WO2024020564 A1 WO 2024020564A1
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cdr
seq
antigen
binding molecule
amino acid
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PCT/US2023/070740
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WO2024020564A8 (fr
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Meredith Carroll HAZEN
Isidro Hotzel
Julien LAFRANCE-VANASSE
Gabriele Maria SCHAEFER
Dhaya Seshasayee
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Genentech, Inc.
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Publication of WO2024020564A1 publication Critical patent/WO2024020564A1/fr
Publication of WO2024020564A8 publication Critical patent/WO2024020564A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3069—Reproductive system, e.g. ovaria, uterus, testes, prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • the present invention relates to antigen-binding molecules that bind to STEAP1 , including monospecific and multispecific antibodies, compositions thereof, and methods for treating diseases such as cancer.
  • Cancer is a heterogeneous disease which evolves at the genetic, phenotypic, and pathological levels.
  • Current therapies include chemotherapy, radiation therapy, surgery, hormone therapy, targeted therapy, immunotherapy, and stem cell transplant.
  • Targeted therapy and immunotherapy have shown promise in mediating potent killing of tumor cells.
  • intratumoral heterogeneity, cancer subtypes, and mutations leading to acquired resistance present challenges in target selection.
  • therapeutic agents that recognize one or more targets shared among the different cancer subtypes and those that acquired resistance driving by mutations.
  • 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 SEQ ID NOs: 7, 17-25, 30-34, 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, 26-29, 39 and 69; and (B) a second antigen-binding domain that binds to a T cell receptor.
  • VH anti- STEAP1 heavy chain variable region
  • VL anti-STEAP1 light chain variable region
  • 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:
  • CDR-H1 comprises 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);
  • CDR-H2 comprises YIXaa 3 YDGXaa 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36); wherein Xaa 3 is 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); CDR-H3 comprises 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);
  • the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 10,
  • the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2,
  • the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15.
  • 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.
  • 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.
  • 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: 1 1 ; 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.
  • 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.
  • 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.
  • 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.
  • the multispecific antigen-binding molecule is a humanized antibody.
  • the first antigen-binding domain and the second antigen-binding domain each independently comprises an IgG framework region, optionally an IgG 1 or lgG4 framework region.
  • 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, 17-25, 30-34, 38, or 68.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the T cell receptor is cluster of differentiation 3 (CD3).
  • 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: 48-53, respectively.
  • VH anti-CD3 heavy chain variable region
  • VL anti- CD3 light chain variable region
  • 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.
  • 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 NO: 40-45, respectively.
  • VH anti-CD3 heavy chain variable region
  • VL anti- CD3 light chain variable region
  • 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.
  • 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 (CH1 1 ) domain, a first CH2 (CH2 1 ) domain, a first CH3 (CH3 1 ) domain, a second CH1 (CH1 2 ) domain, a second CH2 (CH2 2 ) domain, and a second CH3 (CH3 2 ) domain.
  • At least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain.
  • the CH3 1 and CH3 2 domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH3 1 domain is positionable in the cavity or protuberance, respectively, in the CH3 2 domain.
  • the CH3 1 and CH3 2 domains meet at an interface between said protuberance and cavity.
  • the CH2 1 and CH2 2 domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2 1 domain is positionable in the cavity or protuberance, respectively, in the CH2 2 domain.
  • the CH2 1 and CH2 2 domains meet at an interface between said protuberance and cavity.
  • 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 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 light chain constant region sequence having at least 80%, 85%, 90%, 95%, or 100% sequence identity to SEQ ID NO: 84.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the antigen-binding molecule is a 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), lgGdeltaCH2, scFv-Fc, or (scFv)2-Fc.
  • the multispecific antigen-binding molecule is a multispecific antibody, preferably a bispecific or trispecific antibody.
  • the multispecific antigen-binding molecule further comprises a third antigen-binding domain that binds to a tumor-associated antigen.
  • the tumor- associated antigen is a receptor expressed on a prostate cancer cell or Ewing sarcoma.
  • 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 .
  • 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 the human STEAP1 of SEQ ID NO: 65.
  • the first antigen-binding domain binds to at least one, at least two, at least three, at least four, or at least five residue selected from Seri 01 , His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of STEAP1 , wherein the residue positions 101 , 102, 103, 195, 198, 202, and 281 correspond to positions 101 , 102, 103, 195, 198, 202, and 281 set forth in SEQ ID NO: 65.
  • the first antigen-binding domain binds to Ser101 , His102, Gln103, Trp195, G In 198, Gln202, and Lys281 of STEAP1 .
  • the heavy chain variable region of the first antigen-binding domain forms a hydrogen bond with at least one, at least two, at least three, at least four, or at least five residue selected from Ser101 , His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of STEAP1 .
  • At least one, at least two, at least three, at least four, or at least five residue selected from Leu56, Ser73, Asn74, G ly 101 , Tyr103, and Tyr107 of the heavy chain variable region of the first antigen-binding domain forms a hydrogen bond with at least one, at least two, at least three, at least four, or at least five residue selected from Seri 01 , His102, Gin 103, 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 set forth in SEQ ID NO: 18.
  • the first antigen-binding domain binds to at least one, at least two, or at least three residue selected from Gln201 , Gln202, Asn203 and Lys204 of STEAP1 , wherein the residue positions 201 , 202, 203 and 204 correspond to positions 201 , 202, 203 and 204 set forth in SEQ ID NO: 65.
  • the first antigen-binding domain binds to Gln201 , Gln202, Asn203 and Lys204 of STEAP1 .
  • 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 .
  • 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 set forth in SEQ ID NO: 18.
  • a residue of the light chain variable region of the first antigen-binding domain forms Van der Waals interactions with at least one residue selected from Asn203 and Lys204 of STEAP1 .
  • the multispecific antigen-binding molecule has a Cmax of about 11 , 11.5, 12, 12.6, 13, 13.5, 15, 18, 20, 23.4, 25, 27.9, 29.1 , or 30 ⁇ g/mL.
  • the multispecific antigen-binding molecule has a Cmax of about 11 ⁇ g/mL to about 30 ⁇ g/mL.
  • the multispecific antigen-binding molecule has a Cmax of about 20 ⁇ g/mL to about 28 ⁇ g/mL.
  • the multispecific antigen-binding molecule has a Cmax of about 24 ⁇ g/mL.
  • the multispecific antigen-binding molecule has an EC 50 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 lower. In some embodiments, the multispecific antigen-binding molecule has an EC 50 of about 0.05 to about 0.8.
  • the EC 50 is determined in a cell killing assay at 72 hours with human CD8+ T cells and STEAP1 -expressing LNCaP-X1 .2 cells, and the EC 50 is about 0.05 to about 0.4.
  • the EC 50 is about 0.08 or about 0.3.
  • the EC 50 is determined in a cell killing assay at 72 hours with human CD8+ T cells and STEAP1 -expressing LNCaPXI .2KO3-13 cells, and the EC 50 is about 0.1 to about 0.8.
  • the EC 50 is about 0.1 or about 0.7.
  • the multispecific antigen-binding molecule binds to STEAP1 monovalently.
  • At least another aspect of the invention described herein relates to an antigen-binding molecule that binds to STEAP1 , 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, 17-25, 30-34, 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, 26-29, 39, and 69.
  • VH anti-STEAP1 heavy chain variable region
  • VL anti-STEAP1 light chain variable region
  • At least another aspect of the invention described herein relates to an antigen-binding molecule that binds to STEAP1 , 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
  • VH anti-STEAP1 heavy chain variable region
  • VL anti-STEAP1 light chain variable region
  • CDR-H1 comprises 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);
  • CDR-H2 comprises YIXaa 3 YDGXaa 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36); wherein Xaa 3 is 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);
  • CDR-H3 comprises 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);
  • the CDR-H1 comprises the amino acid sequence of SEQ ID NO: 10,
  • the CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2,
  • the CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the antigen-binding molecule is a humanized antibody.
  • the antigen-binding molecule comprises an IgG framework region, optionally an IgG 1 framework region.
  • 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.
  • the antigen-binding molecule 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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. 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.
  • the antigen-binding molecule is a full-length antibody or a fragment thereof.
  • the antigen-binding molecule is a 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), lgGdeltaCH2, scFv-Fc, or (scFv)2-Fc.
  • the antigen-binding molecule is a multispecific antibody, preferably wherein the antigen-binding molecule is a bispecific antibody or a trispecific antibody.
  • the antigen-binding molecule further comprises an antigen-binding domain that binds to a T cell receptor.
  • the T cell receptor is cluster of differentiation 3 (CD3).
  • 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 sequences of SEQ ID NOs: 48-53, respectively.
  • VH anti-CD3 heavy chain variable region
  • VL anti-CD3 light chain variable region
  • 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.
  • 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 sequences of SEQ ID NO: 40-45, respectively.
  • VH anti-CD3 heavy chain variable region
  • VL anti-CD3 light chain variable region
  • 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.
  • the antigen-binding molecule further comprises an additional antigen- binding domain that binds to a tumor-associated antigen.
  • the tumor- associated antigen is a receptor expressed on a prostate cancer cell or Ewing sarcoma.
  • 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 .
  • the antigen-binding molecule binds to human STEAP1 , cynomolgus monkey STEAP1 , or a combination thereof, preferably wherein the antigen-binding molecule binds to the human STEAP1 of SEQ ID NO: 65.
  • the antigen-binding molecule binds to at least one, at least two, at least three, at least four, or at least five residue selected from Seri 01 , His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of STEAP1 , wherein the residue positions 101 , 102, 103, 195, 198, 202, and 281 correspond to positions 101 , 102, 103, 195, 198, 202, and 281 set forth in SEQ ID NO: 65.
  • the antigen-binding molecule binds to Seri 01 , His102, Gln103, Trp195, G In 198, Gln202, and Lys281 of STEAP1 .
  • the heavy chain variable region of the antigen-binding molecule forms a hydrogen bond 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 .
  • At least one, at least two, at least three, at least four, or at least five residues selected from Leu56, Ser73, Asn74, Gly 101 , Tyr103, and Tyr107 of the heavy chain variable region of the antigen-binding molecule forms a hydrogen bond with at least one, at least two, at least three, at least four, or at least five residues selected from Seri 01 , His102, Gin 103, 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 set forth in SEQ ID NO: 18.
  • the antigen-binding molecule binds to at least one, at least two, at or at least three residue selected from Gln201 , Gln202, Asn203 and Lys204 of STEAP1 , wherein the residue positions 201 , 202, 203 and 204 correspond to positions 201 , 202, 203 and 204 set forth in SEQ ID NO: 65.
  • the antigen-binding molecule binds to Gln201 , Gln202, Asn203 and Lys204 of STEAP1 .
  • 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 .
  • 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 set forth in SEQ ID NO: 18.
  • a residue of the light chain variable region of the antigen-binding molecule forms Van der Waals interactions with at least one residue selected from Asn203 and Lys204 of STEAP1 .
  • the antigen-binding molecule binds to STEAP1 monovalently.
  • 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 the residue positions 101 , 102, 103, 195, 198, 202, and 281 correspond to positions 101 , 102, 103, 195, 198, 202, and 281 set forth in SEQ ID NO: 65.
  • the first antigen-binding domain binds to at least one, at least two, at least three, at least four, or at least five residue selected from Seri 01 , 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, Gin 198, Gln202, and Lys281 of SEQ ID NO: 65.
  • the heavy chain variable region of the first antigen-binding domain forms a hydrogen bond with at least one, at least two, at least three, at least four, or at least five residues selected from Seri 01 , His102, G In 103, Trp195, G In 198, Gln202, and Lys281 of STEAP1 .
  • At least one, at least two, at least three, at least four, or at least five residues selected from Leu56, Ser73, Asn74, G ly 101 , Tyr103, and Tyr107 of the heavy chain variable region of the first antigen-binding domain forms a hydrogen bond with at least one, at least two, at least three, at least four, or at least five residues selected from Seri 01 , His102, G In 103, Trp195, G In 198, 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 set forth in SEQ ID NO: 18.
  • 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 NO: 7, 17-25, 30-34, 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 NO: 8, 26-29, 39, and 69.
  • VH anti-STEAP1 heavy chain variable region
  • CDR-H2 CDR-H2
  • CDR-H3 of a VH sequence selected from SEQ ID NO: 7, 17-25, 30-34, 38, and 68
  • VL anti-STEAP1 light chain variable region
  • 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.
  • 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, 26-29, 39, or 69.
  • the antibody further comprises a second antigen-binding domain that binds to a T cell receptor.
  • the T cell receptor is cluster of differentiation 3 (CD3).
  • 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 NO: 48-53, respectively.
  • VH anti-CD3 heavy chain variable region
  • VL anti- CD3 light chain variable region
  • 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.
  • 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 NO: 40-45, respectively.
  • VH anti-CD3 heavy chain variable region
  • VL anti- CD3 light chain variable region
  • 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.
  • the multispecific antigen-binding molecule further comprises a third antigen-binding domain that binds to a tumor-associated antigen.
  • the tumor- associated antigen is a receptor expressed on a prostate cancer cell.
  • 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).
  • PSMA prostate-specific membrane antigen
  • PSCA prostate stem cell antigen
  • EpCAM epithelial cell adhesion molecule
  • PSA prostate-specific antigen
  • PAP prostatic acid phosphatase
  • At least another aspect of the invention described herein relates to one or more isolated nucleic acids individually or together encoding the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein.
  • At least another aspect of the invention described herein relates to one or more vectors individually or together comprising the isolated nucleic acid(s) described herein.
  • At least another aspect of the invention described herein relates to one or more host cells individually or together comprising the isolated nucleic acid(s) described herein or the vector(s) described herein.
  • the host cell is a mammalian cell.
  • the mammalian cell is a Chinese hamster ovary (CHO) cell.
  • the host cell is an insect cell.
  • the host cell is a prokaryotic cell.
  • At least another aspect of the invention described herein relates to a method of producing the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein, comprising culturing the host cell(s) described herein in a culture medium.
  • the method further comprises harvesting the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein from the host cell(s) or the culture medium.
  • At least another aspect of the invention described herein relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the multispecific antigen-binding molecule described herein, the antigen- binding molecule described herein, or the antibody described herein.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, or diluent.
  • the pharmaceutical composition is for use as a medicament. In some embodiments, the pharmaceutical composition is for use in treating or delaying progression of a STEAP1 expressing cancer. In some embodiments, the pharmaceutical composition is for use in treating or delaying progression of prostate cancer or Ewing sarcoma.
  • At least another aspect of the invention described herein relates to use of the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein for use in treating or delaying progression of a STEAP1 -expressing cancer in a subject in need thereof.
  • At least another aspect of the invention described herein relates to use of the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein for use in inhibiting or reducing the proliferation of a STEAP1 expressing cancer cell.
  • the STEAP1 -expressing cancer is a solid tumor.
  • the STEAP1 -expressing cancer is prostate cancer or Ewing sarcoma.
  • the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein is to be used in combination with an additional therapeutic agent or an additional therapeutic regimen.
  • the additional therapeutic agent comprises a chemotherapeutic agent, an immunotherapeutic agent, a targeted therapy, radiation therapy, or a combination thereof.
  • the additional therapeutic agent comprises a first-line, second-line, or third-line therapy.
  • the additional therapeutic regimen comprises surgery.
  • the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein and the additional therapeutic agent are to be administered simultaneously.
  • the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein and the additional therapeutic agent are to be administered sequentially.
  • the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein is to be administered first prior to administering the additional therapeutic agent.
  • the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein is to be administered after administering the additional therapeutic agent.
  • the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein is to be administered systemically.
  • the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein is to be administered locally.
  • the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein is to be administered by parenteral administration.
  • the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein is to be administered intravenously or subcutaneously.
  • the subject is a human.
  • At least another aspect of the invention described herein relates to use of the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein in the manufacture of a medicament for treating or delaying progression of a STEAP1 expressing cancer, optionally for treating or delaying progression of prostate cancer or Ewing sarcoma.
  • At least another aspect of the invention described herein relates to use of the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein in the manufacture of a medicament for inhibiting or reducing the proliferation of a STEAP1 expressing cancer cell, optionally a prostate cancer cell or Ewing sarcoma cell.
  • 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 the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein.
  • the STEAP1 expressing cancer is a solid tumor. In some embodiments, the STEAP1 expressing cancer is prostate cancer or Ewing sarcoma.
  • the method further comprises administering to the subject an additional therapeutic agent or an additional therapeutic regimen.
  • the additional therapeutic agent comprises a chemotherapeutic agent, an immunotherapeutic agent, a targeted therapy, radiation therapy, or a combination thereof.
  • the additional therapeutic agent comprises a first-line, second-line, or third-line therapy.
  • the additional therapeutic regimen comprises surgery.
  • the additional therapeutic agent are administered simultaneously with the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein.
  • the additional therapeutic agent are administered sequentially with the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein.
  • the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein is administered first prior to administering the additional therapeutic agent.
  • the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein is administered after administering the additional therapeutic agent.
  • the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein is administered systemically. In some embodiments, the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein is administered locally. In some embodiments, the multispecific antigen-binding molecule described herein, the antigen- binding molecule described herein, or the antibody described herein is administered by parenteral administration. In some embodiments, the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein is administered intravenously or subcutaneously.
  • the subject is a human.
  • At least another aspect of the invention described herein relates to a method of inhibiting or reducing the proliferation of a STEAP1 expressing cell, comprising contacting the cell with , the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, or the antibody described herein for a time sufficient to inhibit proliferation of the cell.
  • the cell is a prostate cancer cell or Ewing sarcoma cell.
  • the method is an in vivo method. In some embodiments the method is an in vitro or an ex vivo method.
  • At least another aspect of the invention described herein relates to a kit comprising the multispecific antigen-binding molecule described herein, the antigen-binding molecule described herein, the antibody described herein, the isolated nucleic acid(s) described herein, the vector(s) described herein, the host cell(s) described herein, or the pharmaceutical composition described herein, optionally comprising a set of instructions.
  • FIG. 1 A illustrates screening of select rat monoclonal antibodies for specific binding to STEAP1 -expressing cells.
  • the rat monoclonal antibodies are STEAP1 -44, STEAP1 -45, STEAP1 -81 , STEAP1 -75, STEAP1 -103, STEAP1 -10, STEAP1 -23, STEAP1 -67, STEAP1 -34, STEAP1 -19, and STEAP1 -92.
  • FIG. 1 B illustrates screening of select rat monoclonal antibodies for specific binding to STEAP1 -expressing cells.
  • 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 the control antibody.
  • FIG. 1 C shows binding of antibody STEAP1 -44 in a titration assay.
  • Arrows indicate the minimal concentration in which binding of STEAP1 -44 to 293-hSTEAP1 , PC3-hSTEAP1 , LNCaP X1 .2, and 22Rv1 cells was observed, which was 0.39 nM, 6.25 nM, 3.125 nM, and 12.5 nM, respectively.
  • FIG. 2 illustrates variable region sequences of antibody STEAP1 -44 and STEAP1 -44 clonal variants obtained by deep sequencing aligned to closest rat germline segment sequences (top sequences).
  • NGS deep sequencing
  • CDR boundaries according to the Kabat and Chothia systems shown above the alignments, with Kabat CDRs boundaries underlined. Residue numbering is according to the Kabat system. Dots represent sequence gaps introduced by aligning software. Germline segment names are shown in the alignments.
  • the SEQ ID NOs for the Kabat CDRs and the VH and VL sequences are shown in Table 1 .
  • the SEQ ID NOs for the Chothia CDRs are shown in Table 2.
  • FIG. 3 illustrates scoring of somatic mutations in the STEAP1 -44 clonotype group in the deep sequencing dataset. Sequence read counts with each of the amino acid mutations are shown for each position. Black boxes indicate germline segment wild-type residue. Residues highlighted in grey show the most prevalent somatic mutations in CDR regions.
  • FIG. 4A shows testing of STEAP1 -44 clonal variants binding to STEAP1 on surface of cells.
  • FIG. 4B shows testing of STEAP1 -44 clonal variants binding to soluble recombinant STEAP1 .
  • FIG. 5A shows light chain variable region sequences of STEAP1 -44 humanization variants aligned to humanization frameworks. Differences in variants with humanization variants are shown in black background. CDR boundaries according to the Kabat and Chothia systems shown above the alignments, with Kabat CDRs boundaries underlined. Residue numbering is according to the Kabat system. Dots represent sequence gaps introduced by aligning software.
  • the SEQ ID NOs for the Kabat CDRs and the VL sequences are illustrated in Table 1 .
  • the SEQ ID NOs for the Chothia CDRs are illustrated in Table 2.
  • FIG. 5B shows heavy chain variable region sequences of STEAP1 -44 humanization variants aligned to humanization frameworks. Differences in variants with humanization frameworks are shown in black background. CDR boundaries according to the Kabat and Chothia systems shown above the alignments, with Kabat CDRs boundaries underlined. Residue numbering is according to the Kabat system. Dots represent sequence gaps introduced by aligning software.
  • the SEQ ID NOs for the Kabat CDRs and the VH sequences are illustrated in Table 1 .
  • the SEQ ID NOs for the Chothia CDRs are illustrated in Table 2.
  • FIG. 6A shows median fluorescence units (MFI) for antibody humanization variants tested at two different concentrations. Variants are ranked from strongest to weakest binding from left to right, in the same order in both concentrations tested.
  • MFI median fluorescence units
  • FIG. 6B shows humanized variant huAb44.v6 with the somatic mutations of 5 NGS-based variants were tested for binding to LNCaP-X1 .2 cells expressing STEAP1 .
  • huAb44.v6 is the parental humanized clone
  • chAb44 is a human lgG1 with the rat variable domains of Ab44
  • huAb44.v6.01 to 05 are the sequence variants of huAb44.v6 with somatic mutations identified by repertoire NGS.
  • FIG. 6C shows sequence of humanized antibody variant huAb44.v6.05 aligned to humanized antibody huAb44.v6. Differences in huAb44.v6.05 relative huAb44.v6 are shown in black background.
  • the SEQ ID NOs for the Kabat CDRs and VH and VL region sequences are illustrated in Table 1 .
  • the SEQ ID NOs for the Chothia CDRs are illustrated in Table 2.
  • FIG. 7A shows bispecific anti-STEAP1/anti-CD3 antibodies tested in cell killing assays with human CD8+ T cells and STEAP1 -expressing LNCaP-X1 .2 cells.
  • the anti-CD3 arm of the TDB molecules is indicated as MD1 .
  • FIG. 7B shows bispecific anti-STEAP1/anti-CD3 antibodies tested in cell killing assays with human CD8+ T cells and STEAP1 -expressing LNCaP-X1 .2 cells.
  • the anti-CD3 arm of the TDB molecules is indicated as either MD1 or 40G5c.
  • FIG. 8A shows STEAP1 levels in gene editing-modified LNCaPXI .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.
  • FIG. 8B shows huAb44v6.05 TDBs were tested in cell killing assays with human CD8+ T cells and indicated cell lines.
  • FIG. 8C shows target-dependent T cell activation (24 h) for huAb44.v6.05/40G5c.
  • FIG. 8D shows target-dependent cytokine secretion (24 h) for huAb44.v6.05/40G5c.
  • FIG. 9 illustrates STEAP1 -TDBs suppressing growth of established LNCaP-X1 .2, LNCaP- XI .2-KO-3-13, and LNCaP-X1 .KO-2-11 tumors in NSG mice supplemented with human PBMCs.
  • Animals received a single IV dose at day 0 of indicated STEAP1 -TDB.
  • Doses varied from 0.1 mg/kg to 0.5 mg/kg. Individual tumor volumes were plotted for every treatment group. Dotted lines indicate the fitted tumor volume for the control group (vehicle), solid lines indicate individual tumors.
  • FIG. 10A illustrates concentration-time profiles of anti-STEAP1 antibodies following a single intravenous dose of 1 mg/kg in female SCID mouse.
  • FIG. 10B shows concentration-time profiles of anti-STEAP1/CD3 TDBs and anti-gD following a single intravenous dose of 1 mg/kg in female SCID mouse.
  • FIG. 10C shows concentration-time profiles of huAb44.v6.05/40G5c and huAb44.v6.05/MD1 TDBs following intravenous administration in cynomolgus monkeys.
  • FIG. 11 A shows cryo-EM reconstruction of STEAP1 in complex with Ab44 at a resolution of ⁇ 3 A.
  • An isosurface rendering of the STEAP1 homotrimer (arrows 1 , 2, and 3 indicate protomers) in complex with three Ab44 Fabs (arrow 4 indicates heavy chains, arrow 5 indicates light chains, arrow 6 indicates constant regions) is shown.
  • STEAP1 extracellular loops ECL1 , ECL2 and ECL3 are indicated by arrows 7, 8 and 9, respectively.
  • FIG. 11 B shows ribbon rendering of the structure.
  • a side view (along the plane of the membrane, equivalent to panel A) and a top view are shown.
  • heme from only one subunit is shown (indicated by arrow 10). Numbering of the remaining arrows is the same as in FIG. 11 A.
  • FIG. 12A shows interactions between Ab44 Fab and STEAP1 subunit A (two orthogonal side views rotated by 90 degrees are shown). STEAP1 residues located within 4 A of Ab44 Fab are shown in spheres. Numbering of the arrows is the same as in FIG. 11 B. STEAP1 subunits B and C have been omitted for clarity.
  • FIG. 12B shows interactions between Ab44 Fab and STEAP1 neighboring subunit B. Views are identical to panel A. STEAP1 subunits A and C have been omitted for clarity. Numbering of the arrows is the same as in FIG. 11 B.
  • FIG. 13A shows surface representation of the STEAP1 :Fab44 complex.
  • the surfaces buried by complex formation are indicated by arrow 1 (Fab A to STEAP1 subunit A) and arrow 2 (Fab A to STEAP1 subunit B); surfaces buried representing homotypic interactions are indicated by arrow 3 (Fab A to Fab B) or arrow 4 (Fab A to Fab C).
  • STEAP1 monomers are indicated by letters A, B, and C.
  • Light chains are indicated by arrow 5 and heavy chains are indicated by arrows 6, 7, and 8.
  • FIG. 13B shows open-book representation of the same surfaces with surface area measurements for each buried surface indicated.
  • FIG. 14 shows organization of Ab44 and Vandortuzumab upon binding to STEAP1 .
  • Multiple polar homotypic Fab interactions (shown in spheres) are observed along the three-fold axis of the STEAP1 :Ab44 structure and are mostly driven by LC-LC contacts (left panel, viewed from the extracellular side). In contrast, limited interactions are observed between Vandortuzumab Fabs (right panel).
  • Light chains are indicated by arrow 1 and heavy chains are indicated by arrows 2, 3, and 4.
  • STEAP1 homotrimer is not shown (except for the residues located within 4 A of Fab A, represented in spheres).
  • FIG. 15 shows sequence alignment of human, Macaca fascicularis and Pongo abelii. Expected transmembrane helices are highlighted in yellow and extracellular loops 1 , 2 and 3 are highlighted in green, red and orange boxes, respectively.
  • FIG. 16 shows sequence alignment of variable regions of humanized antibody variant huAb44.v6, huAb44.v6.01 , huAb44.v6.02, huAb44.v6.03, huAb44.v6.04, and huAb44.v6.05.
  • CDR sequences according to Kabat definition are underlined.
  • the SEQ ID NOs for the Kabat CDRs and the VH and VL sequences are illustrated in Table 1 .
  • the SEQ ID NOs for the Chothia CDRs are illustrated in Table 2.
  • FIG. 17 shows sequence alignment of STEAP1 -specific variable regions of bispecific antibodies.
  • CDR sequences according to Kabat definition are underlined.
  • the SEQ ID NOs for the Kabat CDRs and the VH and VL sequences are illustrated in Table 1 .
  • the SEQ ID NOs for the Chothia CDRs are illustrated in Table 2.
  • FIG. 18 shows sequence alignment of CD3-specific variable regions of bispecific antibodies.
  • CDR sequences according to Kabat definition are underlined.
  • the SEQ ID NOs for the Kabat CDRs and the VH and VL sequences are illustrated in Table 1 .
  • the SEQ ID NOs for the Chothia CDRs are illustrated in Table 2.
  • FIG. 19 shows sequence alignment of constant regions of STEAP1 -specific chains.
  • FIG. 20 shows sequence alignment of constant regions of CD3-specific chains.
  • FIG. 21 shows sequence alignment of variable regions of rabbit anti-human STEAP1 antibodies.
  • the SEQ ID NOs for the Kabat CDRs and the VH and VL sequences are shown in Table 1 .
  • the SEQ ID NOs for the Chothia CDRs are shown in Table 2.
  • FIG. 22 shows a comparison of binding of huAb44v6.05 and vandortuzumab to LNCaP-X1 .2 cells expressing STEAP1 as assessed by FACS. MFI for antibody variants was tested at the indicated concentrations. The EC50 for vandortuzumab was 3.5 nM, and the EC50 for huAb44.v6.05 was 1 .9 nM.
  • FIG. 23A shows bispecific anti-STEAP1/anti-CD3 antibodies tested in cell killing assays with human CD8+ T cells and STEAP1 -expressing LNCaP-X1.2 cells. Vandortuzumab- and huAb44v6.05- containing TDBs were compared. The anti-CD3 arm of the TDB molecules was either MD1 or 40G5c, as indicated.
  • FIG. 23B shows bispecific anti-STEAP1/anti-CD3 antibodies tested in cell killing assays with human CD8+ T cells and STEAP1 -expressing LNCaPXI .2KO3-13 cells. Vandortuzumab- and huAb44v6.05-containing TDBs were compared. The anti-CD3 arm of the TDB molecules was either MD1 or 40G5c, as indicated.
  • FIGS. 24A-24D are a series of graphs showing a comparison of huAb44.v6.05/40G5c and vandortuzumab/40G5c TDBs in a T-cell activation assay.
  • Fig. 24A shows results of CD4 T cell activation using LNCaP-X12 cells.
  • Fig. 24B shows results of CD8 T cell activation using LNCaP-X12 cells.
  • Fig. 24C shows results of CD4 T cell activation using LNCaP-X1 .2-KO-3-13 cells.
  • Fig. 24D shows results of CD8 T cell activation using LNCaP-X1 .2-KO-3-13 cells.
  • the ratio of PBMCs to target was 10:1 , and the incubation time was 24 h.
  • FIGS. 25A-25J are a series of graphs showing a comparison of huAb44.v6.05/40G5c and vandortuzumab/40G5c in a cytokine secretion assay at 24 h.
  • Figs. 25A-25E show results with LNCaP-X1 .2 cells
  • Figs. 25F-25J show results with LNCaP-X1 .2-KO-3-13 cells.
  • Figs. 25A and 25F show interferon (IFN) gamma secretion.
  • Figs. 25B and 25G show tumor necrosis factor (TNF) alpha secretion.
  • FIGS. 25C and 25H show IL-2 secretion.
  • Figs. 25D and 25I show IL-6 secretion.
  • Figs. 25E and 25J show granzyme B secretion.
  • Binding affinity refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen).
  • binding affinity refers to intrinsic binding affinity which reflects a 1 :1 interaction between members of a binding pair (e.g., antibody and antigen).
  • the affinity of a molecule X for its partner Y can generally be represented by the equilibrium dissociation constant (K D ). Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described in the following.
  • the term “binds to” refers to measurable and reproducible interactions such as binding between a target and an antigen-binding molecule (e.g., an antibody), which is determinative of the presence of the target in the presence of a heterogeneous population of molecules including biological molecules.
  • an antigen-binding molecule that specifically binds to a target is an antigen-binding molecule that binds this target with greater affinity, avidity, more readily, and/or with greater duration than it binds to other targets.
  • the extent of binding of an antigen-binding molecule to an unrelated target is less than about 10% of the binding of the antigen-binding molecule to the target as measured, e.g., by surface plasmon resonance (SPR), radioimmunoassay (RIA), or Kinetic Exclusion Assay (KinExA®).
  • an antigen-binding molecule that specifically binds to a target has an equilibrium dissociation constant (K D ) of ⁇ 1 pM, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, or ⁇ 0.1 nM.
  • K D equilibrium dissociation constant
  • an antigen-binding molecule specifically binds to an epitope on a protein that is conserved among the protein from different species.
  • specific binding can include, but does not require exclusive binding.
  • antigen-binding molecule refers to a molecule that specifically binds to a target epitope, antigen, ligand, or receptor.
  • Antigen-binding molecules include, but are not limited to, antibodies (e.g., monoclonal, polyclonal, recombinant, humanized, and chimeric antibodies), antibody fragments or portions thereof (e.g., Fab fragments, Fab’2, scFv antibodies, SMIP, domain antibodies, diabodies, minibodies, scFv-Fc, affibodies, nanobodies, and VH and/or VL domains of antibodies), receptors, ligands, aptamers, and other molecules having an identified binding partner.
  • antibodies e.g., monoclonal, polyclonal, recombinant, humanized, and chimeric antibodies
  • antibody fragments or portions thereof e.g., Fab fragments, Fab’2, scFv antibodies, SMIP, domain antibodies, diabo
  • an “affinity matured” antibody refers to an antibody with one or more alterations in one or more complementarity determining regions (CDRs) or hypervariable regions (HVRs), compared to a parent antibody which does not possess such alterations, such alterations resulting in an improvement in the affinity of the antibody for antigen.
  • CDRs complementarity determining regions
  • HVRs hypervariable regions
  • antigen-binding domain refers to a part of a compound or a molecule that specifically binds to a target epitope, antigen, ligand, or receptor.
  • Molecules featuring antigen-binding domains include, but are not limited to, antibodies (e.g., monoclonal, polyclonal, recombinant, humanized, and chimeric antibodies), antibody fragments or portions thereof (e.g., Fab fragments, Fab’2, scFv antibodies, SMIP, domain antibodies, diabodies, minibodies, scFv-Fc, affibodies, nanobodies, and VH and/or VL domains of antibodies), receptors, ligands, aptamers, and other molecules having an identified binding partner.
  • antibodies e.g., monoclonal, polyclonal, recombinant, humanized, and chimeric antibodies
  • antibody fragments or portions thereof e.g., Fab fragments, Fab’2, s
  • 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 desired antigen-binding activity.
  • antibody fragment refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds.
  • 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.
  • a “single-chain variable fragment” or “scFv” is a fusion protein of the variable domains of the heavy (VH) and light chains (VL) of an antibody, connected by a linker.
  • the linker is typically a short polypeptide of 10 to 25 amino acids and is usually rich in glycine for flexibility, as well as serine or threonine for solubility, and can either connect the N-terminus of the VH with the C- terminus of the VL, or vice versa. This protein retains the specificity of the original antibody, despite removal of the constant regions and the introduction of the linker.
  • a “single chain Fab fragment” or “scFab” is a polypeptide 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 said antibody domains and said linker have one of the following orders in 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.
  • said linker is a polypeptide of at least 30 amino acids, preferably between 32 and 50 amino acids.
  • Said single chain Fab fragments are stabilized via the natural disulfide bond between the CL domain and the CH1 domain.
  • these single chain Fab fragments might be further stabilized by generation of interchain disulfide bonds via insertion of cysteine residues (e.g., position 44 in the variable heavy chain and position 100 in the variable light chain according to Kabat numbering).
  • cross-Fab fragment or “xFab fragment” or “crossover Fab fragment” refers to a Fab fragment, wherein either the variable regions or the constant regions of the heavy and light chain are exchanged.
  • a cross-Fab fragment comprises a polypeptide chain composed of the light chain variable region (VL) and the heavy chain constant region 1 (CH1 ), and a polypeptide chain composed of the heavy chain variable region (VH) and the light chain constant region (CL).
  • Asymmetrical Fab arms can also be engineered by introducing charged or non-charged amino acid mutations into domain interfaces to direct correct Fab pairing. See e.g., WO 2016/172485.
  • antigen denotes a proteinaceous or non-proteinaceous molecule to which an antigen-binding molecule (e.g., an antibody) binds.
  • the antigen can include protein, protein fragment, or a hapten.
  • epitope denotes the site on an antigen, either proteinaceous or non-proteinaceous, to which an anti-STEAP1 antigen-binding molecule (e.g., an anti-STEAP1 antibody) binds.
  • Epitopes can be formed both from contiguous amino acid stretches (linear epitope) or comprise non-contiguous amino acids (conformational epitope), e.g., coming in spatial proximity due to the folding of the antigen, i.e., by the tertiary folding of a proteinaceous antigen.
  • Linear epitopes are typically still bound by an anti-STEAP1 antigen-binding molecule after exposure of the proteinaceous antigen to denaturing agents, whereas conformational epitopes are typically destroyed upon treatment with denaturing agents.
  • An epitope comprises at least 3, at least 4, at least 5, at least 6, at least 7, or 8-10 amino acids in a unique spatial conformation.
  • Antigen-binding molecules e.g., antibodies
  • binding to a particular epitope i.e., those binding to the same epitope
  • methods routine in the art such as, e.g., without limitation, alanine scanning, peptide blots (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 Harbor, NY).
  • SAP Antigen Structure-based Antibody Profiling
  • MAP Modification-Assisted Profiling
  • MAP Modification-Assisted Profiling
  • the antibodies in each bin bind to the same epitope which may be a unique epitope either distinctly different from or partially overlapping with epitope represented by another bin.
  • competitive binding can be used to easily determine whether an antigen-binding molecule (e.g., an antibody) binds to the same epitope of STEAP1 as, or competes for binding with, a reference anti-STEAP1 antibody.
  • 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 in a competition assay by 50% or more, and conversely, the reference antibody blocks binding of the antigen-binding molecule to its antigen in a competition assay by 50% or more.
  • 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 removal of the excess of the reference anti- STEAP1 antibody, the ability of an anti-STEAP1 antigen-binding molecule in question to bind to STEAP1 is assessed. If the anti-STEAP1 antigen-binding molecule is able to bind to STEAP1 after saturation binding of the reference anti-STEAP1 antibody, it can be concluded that the anti-STEAP1 antigen-binding molecule in question binds to a different epitope than the reference anti-STEAP1 antibody.
  • the anti-STEAP1 antigen-binding molecule in question may bind to the same epitope as the epitope bound by the reference anti- STEAP1 antibody.
  • routine experimentation can be used (e.g., peptide mutation and binding analyses using ELISA, RIA, surface plasmon resonance, flow cytometry or any other quantitative or qualitative antibody-binding assay available in the art).
  • This assay may be carried out in two set-ups, i.e., with both of the molecules being the saturating antibody. If, in both set-ups, only the first (saturating) antibody is capable of binding to STEAP1 , then it can be concluded that the anti-STEAP1 antigen-binding molecule in question and the reference anti-STEAP1 antibody compete for binding to STEAP1 .
  • 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 variants of STEAP1 , including, for example, splice variants or allelic variants.
  • STEAP1 is a member of the six-transmembrane epithelial antigen of the prostate (STEAP) protein family.
  • the STEAP protein family comprises five members, STEAP1 , STEAP2, STEAP3, STEAP4, and STEAP5.
  • STEAP1 includes, e.g., human STEAP1 (UniProtKB Reference Number: Q9UHE8-1 ; SEQ ID NO:
  • cynomolgus monkey STEAP1 (UniProtKB Reference Number: A0A2K5X1 J3; SEQ ID NO: 66), and orangutan STEAP1 (UniProtKB Reference Number: H2PMZ0; SEQ ID NO: 67).
  • anti-STEAP1 antigen-binding molecule or “antigen-binding molecule that binds STEAP1 ” refer to any molecule that is capable of binding to STEAP1 with sufficient affinity such that the molecule is useful as a diagnostic and/or therapeutic agent in targeting STEAP1 .
  • the extent of binding of an anti-STEAP1 antigen-binding molecule to an unrelated, non- STEAP1 protein is less than about 10% of the binding of the antigen-binding molecule to STEAP1 as measured, e.g., by surface plasmon resonance (SPR), radioimmunoassay (RIA), or Kinetic Exclusion Assay (KinExA®).
  • an anti-STEAP1 antigen-binding molecule has a dissociation constant (K D ) of ⁇ 1 pM, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM (e.g., 10 -8 M or less, e.g., from 10 -8 M to 10 -13 M, e.g., from 10 -9 M to 10 -13 M).
  • K D dissociation constant
  • An antigen-binding molecule is said to “specifically bind” to STEAP1 when the antigen-binding molecule has a K D of 1 pM or less.
  • an anti-STEAP1 antigen-binding molecule binds to an epitope of STEAP1 that is conserved among STEAP from different species.
  • anti-STEAP1 antibody or “an antibody that binds to STEAP1 ” refers to an antibody that is capable of binding to STEAP1 with sufficient affinity such that the molecule is useful as a diagnostic and/or therapeutic agent in targeting STEAP1 .
  • the extent of binding of an anti-STEAP1 antibody to an unrelated, non-STEAP1 protein is less than about 10% of the binding of the antibody to STEAP1 as measured, e.g., by surface plasmon resonance (SPR), radioimmunoassay (RIA), or Kinetic Exclusion Assay (KinExA®).
  • an anti-STEAP1 antibody has a dissociation constant (K D ) of ⁇ 1 ⁇ M, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM (e.g., 10 -8 M or less, e.g., from 10 -8 M to 10 -13 M, e.g., from 10 -9 M to 10 -13 M).
  • K D dissociation constant
  • An antibody is said to “specifically bind” to STEAP1 when the antibody has a K D of 1 pM or less.
  • an anti-STEAP1 antibody binds to an epitope of STEAP1 that is conserved among STEAP from different species.
  • cluster of differentiation 3 refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated, including, for example, CD3 ⁇ , CD3 ⁇ , CD3 ⁇ , and CD3 ⁇ chains.
  • the term encompasses “full-length,” unprocessed CD3 (e.g., unprocessed or unmodified CD3 ⁇ or CD3 ⁇ ), as well as any form of CD3 that results from processing in the cell.
  • the term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants.
  • CD3 includes, for example, human CD3 ⁇ protein (NCBI RefSeq No. NP_000724), which is 207 amino acids in length, and human CD3 ⁇ protein (NCBI RefSeq No. NP_000064), which is 182 amino acids in length.
  • NCBI RefSeq No. NP_000724 human CD3 ⁇ protein
  • NCBI RefSeq No. NP_000064 human CD3 ⁇ protein
  • anti-CD3 antibody and “an antibody that binds to CD3” refer to an antibody that is capable of binding CD3 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting CD3.
  • the extent of binding of an anti-CD3 antibody to an unrelated, non-CD3 protein is less than about 10% of the binding of the antibody to CD3 as measured, e.g., by surface plasmon resonance (SPR), radioimmunoassay (RIA), or Kinetic Exclusion Assay (KinExA®).
  • an antibody that binds to CD3 has a dissociation constant (K D ) of ⁇ 1 pM, ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM (e.g., 10 -8 M or less, e.g., from 10 -8 M to 10 -13 M, e.g., from 10 -9 M to 10 -13 M).
  • K D dissociation constant
  • an anti-CD3 antibody binds to an epitope of CD3 that is conserved among CD3 from different species.
  • the anti-CD3 antibody is described in International Patent Application Publication No.
  • the anti-CD3 antibody is described in U.S. Patent No. 10,174,124, which is incorporated by reference herein in its entirety. In other embodiments, the anti-CD3 antibody is described in International Patent Application No. PCT/US2020/064635, which is incorporated by reference herein in its entirety.
  • the anti-CD3 antibody is 40G5c. In some embodiments, the anti-CD3 antibody is 38E4V1 .MD1 .
  • the SEQ ID NOs for the CDRs and the VH and VL sequences of 40G5c and 38E4V1 .MD1 are listed in Tables 1 and 2.
  • two antibodies are deemed to bind to the same or an overlapping epitope if a 1 -, 5-, 10-, 20- or 100-fold excess of one antibody inhibits binding of the other by at least 50%, at least 75%, at least 90% or even 99% or more as measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. 50 (1990) 1495-1502).
  • two antibodies are deemed to bind to the same epitope if essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody also reduce or eliminate binding of the other.
  • Two antibodies are deemed to have “overlapping epitopes” if only a subset of the amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.
  • 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.
  • the “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain.
  • the antibody is of the IgG 1 isotype.
  • the antibody is of the IgG 1 isotype with the P329G, L234A and L235A mutation to reduce Fc-region effector function.
  • the antibody is of the lgG2 isotype.
  • the antibody is of the lgG4 isotype with the S228P mutation in the hinge region to improve stability of lgG4 antibody.
  • the heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, 8, E, y, and p, respectively.
  • the light chain of an antibody may be assigned to one of two types, called kappa (K) and lambda (A), based on the amino acid sequence of its constant domain.
  • hypervariable region refers to each of the regions of an antibody variable domain which are hypervariable in sequence and which determine antigen binding specificity, for example, “complementarity determining regions” (“CDRs”).
  • CDRs complementarity determining regions
  • antibodies comprise six CDRs: three in the VH (CDR-H1 , CDR-H2, CDR-H3), and three in the VL (CDR-L1 , CDR-L2, CDR-L3).
  • Exemplary CDRs herein include:
  • CDRs are determined according to Kabat et al., supra.
  • CDR designations can also be determined according to Chothia, supra, McCallum, supra, or any other scientifically accepted nomenclature system.
  • variable region refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen.
  • the variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three complementary determining regions (CDRs) or hypervariable regions (HVRs).
  • FRs conserved framework regions
  • CDRs complementary determining regions
  • HVRs hypervariable regions
  • antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880- 887 (1993); Clarkson et al., Nature 352:624-628 (1991 ).
  • a “constant region derived from human origin” or “human constant region” denotes a constant heavy chain region of a human antibody of the subclass IgG 1 , lgG2, lgG3, or lgG4 and/or a constant light chain kappa or lambda region.
  • Such constant regions are well known in the state of the art and e.g., described by Kabat, E.A., et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991 ) (see also e.g., Johnson and Wu, Nucleic Acids Res. 28 (2000) 214-218; Kabat et al., Proc. Natl.
  • EU numbering system also called the EU index of Kabat, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991 ), NIH Publication 91 -3242.
  • Fc region or “Fc domain” are herein used interchangeably to refer to a 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.
  • a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain.
  • the C-terminal lysine (Lys447) of the Fc region may or may not be present.
  • the term encompasses truncated Fc regions, such as those having a C-terminal truncation (e.g., a AGK 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.
  • numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called 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 .
  • a “subunit” of an Fc domain as used herein refers to one of the two polypeptides forming the dimeric Fc domain, i.e., a polypeptide comprising C-terminal constant regions of an immunoglobulin heavy chain, capable of stable self- association.
  • a subunit of an IgG Fc domain comprises an IgG CH2 and an IgG CH3 constant domain.
  • “Framework” or “FR” refers to variable domain residues other than complementary determining regions (CDRs) or hypervariable region (HVR) residues.
  • the FR of a variable domain generally consists of four FR domains: FR1 , FR2, FR3, and FR4. Accordingly, the CDR and FR sequences generally 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.
  • full-length antibody “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region as defined herein.
  • a “human antibody” is one which possesses an amino acid sequence which corresponds to that of an antibody produced by a human or a human cell or derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody 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 ).
  • Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized xenomice (see, e.g., U.S. Pat. Nos.
  • a “human consensus framework” is a framework which represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences.
  • the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences.
  • the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91 -3242, Bethesda MD (1991 ), vols. 1 -3.
  • the subgroup is subgroup kappa I as in Kabat et al., supra.
  • the subgroup is subgroup III as in Kabat et al., supra.
  • a “humanized” antibody refers to a chimeric antibody comprising amino acid residues from non-human CDRs or HVRs and amino acid residues from human FRs.
  • a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDRs or HVRs correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody.
  • 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, e.g., a non-human antibody refers to an antibody that has undergone humanization.
  • the term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts.
  • polyclonal antibody preparations typically include different antibodies directed against different determinants (epitopes)
  • each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.
  • the term “monospecific” refers to an antigen-binding molecule that binds to a single antigen, e.g., STEAP1 .
  • the term “multispecific” refers to an antigen-binding molecule that binds to multiple different antigens, e.g., STEAP1 and CD3.
  • multispecific antibodies are monoclonal antibodies that have binding specificities for at least two different sites, i.e., different epitopes on different antigens or different epitopes on the same antigen.
  • “Native antibodies” refer to naturally occurring immunoglobulin molecules with varying structures.
  • native IgG antibodies are heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light chains and two identical heavy chains that are disulfide- bonded. From N- to C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CH1 , CH2, and CH3). Similarly, from N- to C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain.
  • VH variable heavy domain
  • VL variable region
  • the light chain of an antibody may be assigned to one of two types, called kappa (K) and lambda (A), based on the amino acid sequence of its constant domain.
  • Percent (%) amino acid sequence identity with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity for the purposes of the alignment. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, Clustal W, Megalign (DNASTAR) software or the FASTA program package.
  • the percent identity values can be generated using the sequence comparison computer program ALIGN-2.
  • the ALIGN-2 sequence comparison computer program was authored by Genentech, Inc., and the source code has been filed with user documentation in the U.S. Copyright Office, Washington D.C., 20559, where it is registered under U.S. Copyright Registration No. TXU510087 and is described in WO 2001/007611 .
  • percent amino acid sequence identity values are generated using the ggsearch program of the FASTA package version 36.3.8c or later with a BLOSUM50 comparison matrix.
  • the FASTA program package was authored 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 available from www.fasta.bioch.virginia.edu/fasta_www2/fasta_down.shtml or www.ebi.ac.uk/Tools/ss/fasta.
  • an “isolated” antibody is one which has been separated from a component of its natural environment.
  • an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC) methods.
  • electrophoretic e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis
  • chromatographic e.g., ion exchange or reverse phase HPLC
  • nucleic acid molecule or “polynucleotide” includes any compound and/or substance that comprises a polymer of nucleotides.
  • Each nucleotide is composed of a base, specifically 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.
  • cytosine (C), guanine (G), adenine (A), thymine (T) or uracil (U) a sugar (i.e., deoxyribose or ribose), and a phosphate group.
  • C cytosine
  • G guanine
  • A adenine
  • T thymine
  • U uracil
  • sugar i.e., deoxyribose
  • nucleic acid molecule encompasses deoxyribonucleic acid (DNA) including e.g., complementary DNA (cDNA) and genomic DNA, ribonucleic acid (RNA), in particular messenger RNA (mRNA), synthetic forms of DNA or RNA, and mixed polymers comprising two or more of these molecules.
  • DNA deoxyribonucleic acid
  • cDNA complementary DNA
  • RNA ribonucleic acid
  • mRNA messenger RNA
  • the nucleic acid molecule may be linear or circular.
  • nucleic acid molecule includes both, sense and antisense strands, as well as single stranded and double stranded forms.
  • the herein described nucleic acid molecule can contain naturally occurring or non- naturally occurring nucleotides.
  • nucleic acid molecules also encompass DNA and RNA molecules which are suitable as a vector for direct expression of an antibody of the invention in vitro and/or in vivo, e.g., in a host or patient.
  • DNA e.g., cDNA
  • RNA e.g., mRNA
  • mRNA can be chemically modified to enhance the stability of the RNA vector and/or expression of the encoded molecule so that mRNA can be injected into a subject to generate the antibody in vivo (see e.g., Stadler et al., Nat. Med. 23(7) :815-817, 2017 or EP 2 101 823 B1 ).
  • nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment.
  • An isolated nucleic acid includes a nucleic acid molecule 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.
  • isolated nucleic acid encoding an anti-STEAP1 antibody refers to one or more nucleic acid molecules encoding anti-STEAP1 antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present at one or more locations in a host cell.
  • isolated nucleic acid encoding an anti-CD3 antibody refers to one or more nucleic acid molecules encoding anti-CD3 antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present at one or more locations in a host cell.
  • vector refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked.
  • the term includes the vector as a self-replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced.
  • Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors.”
  • host cell refers 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 therefrom without regard to the number of passages. Progeny may not be completely identical in nucleic acid content to a parent cell, but may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.
  • pharmaceutical formulation refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
  • a “pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, which is nontoxic to a subject.
  • a pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative.
  • administering is meant a method of giving a dosage 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 a composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition including an antigen-binding molecule of the invention) to a subject.
  • a compound e.g., an antigen-binding molecule of the invention or a nucleic acid encoding an antigen-binding molecule of the invention
  • a composition e.g., a pharmaceutical composition, e.g., a pharmaceutical composition including an antigen-binding molecule of the invention
  • compositions utilized in the methods described herein can be administered, for example, intramuscularly, intravenously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subcutaneously, subconjunctivally, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, in cremes, or in lipid compositions.
  • treatment refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include, but are not limited to, preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.
  • antibodies of the invention are used to delay development of a disease or to slow the progression of a disease.
  • “delaying progression” of a disorder or disease means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease or disorder (e.g., a cell proliferative disorder, e.g., cancer).
  • This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated.
  • a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease.
  • a late stage cancer such as development of metastasis, may be delayed.
  • reduce or inhibit is meant the ability to cause an overall decrease, for example, of 20% or greater, of 50% or greater, or of 75%, 85%, 90%, 95%, or greater.
  • reduce or inhibit can refer to the effector function of an antigen-binding molecule that is mediated by the Fc region, such effector functions specifically including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP).
  • CDC complement-dependent cytotoxicity
  • ADCC antibody-dependent cellular cytotoxicity
  • ADCP antibody-dependent cellular phagocytosis
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Included in this definition are benign and malignant cancers.
  • head stage cancer or “early stage tumor” is meant a cancer that is not invasive or metastatic or is classified as a Stage 0, 1 , or 2 cancer.
  • cancer examples 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, stomach cancer, or thyroid cancer; and 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 lymphoid leukemia (CLL), marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), or Waldenstrom macroglobulinemia (WM).
  • BL Burkitt’s lymphoma
  • DLBCL diffuse large B cell lymphoma
  • FL follicular lymphoma
  • MCL mantle cell lymphoma
  • AML
  • tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • cancer refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • cancer refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • STEAP1 -expressing cancer refers to a cancer those cancer cells are characterized with an over-expression of STEAP1 compared to the expression level of STEAP1 in equivalent non-cancerous cells.
  • Examples of STEAP1 -expressing cancer include, but are not limited to, breast cancer, bladder cancer, cervical cancer, colorectal cancer, Ewing sarcoma, lung cancer, ovarian cancer, and prostate cancer.
  • Prostate cancer is one of the most common cancer in men.
  • Prostate cancer types can include adenocarcinomas of the prostate, sarcoma of the prostate, transitional cell carcinoma of the prostate, small cell carcinomas of the prostate, neuroendocrine tumors of the prostate, and castrate- resistant prostate cancer (CRPC).
  • Prostate cancer can also be classified based on molecular signature. For example, prostate cancers can be classified into those with rearrangements in ETS family transcription factors (e.g., ERG, ETV1 , ETV4, and FLU ) and those negative for ETS factors.
  • ETS positive prostate cancer can also include alterations in PI3K and p53 signaling.
  • ETS negative prostate cancers can show recurrent mutations in SPOP, FOXA1 , and IDH1 ; deletions of CHD1 ; and overexpression of SPINK1 .
  • the prostate cancer is a metastatic prostate cancer (e.g., metastatic castrate-resistant prostate cancer).
  • the prostate cancer is a relapsed or refractory prostate cancer.
  • Ewing sarcoma (also referred to as Ewing’s sarcoma or Ewing’s tumor) is a cancer of the bones and soft tissue (e.g., cartilage or nerves).
  • soft tissue e.g., cartilage or nerves.
  • Ewing sarcoma There are several types of Ewing sarcoma, such as Ewing sarcoma of bone, extraosseous Ewing sarcoma, peripheral primitive neuroectodermal tumor (pPNET), and Askin tumor.
  • pPNET peripheral primitive neuroectodermal tumor
  • Askin tumor There is no known cause of Ewing sarcoma. Symptoms include pain and swelling at the site of the tumor.
  • tumor antigen may be understood as those antigens that are presented on tumor cells. These antigens can be presented on the cell surface with an extracellular part, which is often combined with a transmembrane and cytoplasmic part of the molecule. These antigens can sometimes be presented only by tumor cells and never by the normal ones. Tumor antigens can be exclusively expressed on tumor cells or might represent a tumor specific mutation compared to normal cells. In this case, they are called tumor-specific antigens. More common are tumor antigens that are presented by tumor cells and normal cells, and they are called tumor- associated antigens.
  • tumor-associated antigens can be overexpressed compared to normal cells or are accessible for antibody binding in tumor cells due to the less compact structure of the tumor tissue compared to normal tissue.
  • 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 .
  • the 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).
  • the TAA for Ewing sarcoma include HBA-71 , an antigen localized at the cell-surface glycocalyx of tumor cells.
  • T cell receptor refers to a receptor expressed on a T cell.
  • exemplary T cell receptors include, but are not limited to, CD3.
  • an “effective amount” of a compound for example, a bispecific antigen-binding molecule of the invention or a composition (e.g., pharmaceutical composition) thereof, is at least the minimum amount required to achieve the desired therapeutic or prophylactic result, such as a measurable improvement or prevention of a particular disorder (e.g., a cell proliferative disorder, e.g., cancer).
  • An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the individual.
  • An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects.
  • beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
  • beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival.
  • an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e., slow to some extent or desirably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and desirably stop) tumor metastasis; inhibiting to some extent tumor growth; and/or relieving to some extent one or more of the symptoms associated with the disorder.
  • An effective amount can be administered in one or more administrations.
  • an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly.
  • an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.
  • an “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
  • first-line therapy comprises a primary treatment for a subject with a cancer.
  • the cancer is a primary cancer.
  • the cancer is a metastatic or recurrent cancer.
  • the first-line therapy comprises chemotherapy.
  • the first-line treatment comprises radiation therapy.
  • the additional therapeutic agent comprises a second-line therapy, a third-line therapy, a fourth-line therapy, or a fifth-line therapy.
  • a second-line therapy encompasses treatments that are utilized after the primary or first-line treatment stops.
  • a third-line therapy, a fourth-line therapy, or a fifth-line therapy encompass subsequent treatments.
  • a third-line therapy encompass a treatment course upon which a primary and second-line therapy have stopped.
  • mammals include, but are not limited to, domesticated animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats).
  • domesticated animals e.g., cows, sheep, cats, dogs, and horses
  • primates e.g., humans and non-human primates such as monkeys
  • rabbits e.g., mice and rats
  • rodents e.g., mice and rats
  • the invention is based, in part, on antigen-binding molecules (e.g., mono- specific and/or multispecific antigen-binding molecules).
  • the antigen-binding molecules bind to STEAP1 .
  • the antigen-binding molecules are multispecific antigen-binding molecules that bind to STEAP1 and to one or more additional antigens of interest.
  • the multispecific antigen-binding molecules bind to STEAP1 monovalently.
  • Antigen-binding molecules of the invention are useful, e.g., for treating or delaying the progression of a cancer (e.g., STEAP1 -expressing cancer).
  • the invention provides isolated antigen-binding molecules that bind to STEAP1 .
  • an antigen-binding molecule of the present invention comprises at least one, at least two, at least three, at least four, at least five, or all six CDRs as illustrated in Table 1 (Kabat) or Table 2 (Chothia).
  • the antigen-binding molecule comprises a VH and/or a VL as illustrated in Table 1 .
  • the antigen-binding molecule that binds to STEAP1 comprises of 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 SEQ ID NO: 7, 17-25, 30-34, and 38; and/or an anti-STEAP1 light chain variable region (VL) comprising, consisting essentially of, or consisting of CDR-L1 , CDR-L2, and/or CDR-L3 of a VL sequence selected from SEQ ID NO: 8, 26- 29, 39, and 69.
  • VH anti-STEAP1 heavy chain variable region
  • VL anti-STEAP1 light chain variable region
  • At least one, at least two, at least three, at least four, at least five, or all six CDRs are selected from the CDR(s) of the VH sequence selected from SEQ ID NOs: 7, 17- 25, 30-34, 38, and 68 and the VL sequence selected from SEQ ID NO: 8, 26-29, 39, and 69.
  • the six CDRs are defined according to the Kabat numbering (see Table 1 ). In other cases, the six CDRs are defined according to the Chothia numbering (see Table 2). In additional cases, the six CDRs are defined according to the EU numbering.
  • 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: CDR-H1 comprises Xaa 1 Xaa 2 YMA (SEQ ID NO: 35); wherein
  • Xaa 1 is Asp (D) or Asn (N);
  • Xaa 2 is His (H), Tyr (Y), or Phe (F);
  • CDR-H2 comprises YIXaa 3 YDGXaa 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36); wherein
  • Xaa 3 is 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);
  • Xaa 6 is Ser (S) or Tyr (Y);
  • CDR-H3 comprises 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);
  • Xaa 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.
  • 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.
  • 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:
  • CDR-H1 comprises the amino acid sequence of SEQ ID NO: 10, 1 , or 9;
  • CDR-H2 comprises YIXaa 3 YDGXaa 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36); wherein
  • Xaa 3 is 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);
  • Xaa 6 is Ser (S) or Tyr (Y);
  • CDR-H3 comprises 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);
  • Xaa 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/or
  • CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.
  • 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.
  • 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
  • CDR-H1 comprises the amino acid sequence of SEQ ID NO: 10, 1 , or 9;
  • CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, 1 1 , 12, or 13;
  • CDR-H3 comprises 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);
  • Xaa 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/or
  • CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.
  • 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.
  • 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
  • CDR-H1 comprises Xaa 1 Xaa 2 YMA (SEQ ID NO: 35); wherein
  • Xaa 1 is Asp (D) or Asn (N);
  • Xaa 2 is His (H), Tyr (Y), or Phe (F);
  • CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, 11 , 12, or 13;
  • CDR-H3 comprises 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);
  • Xaa 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/or
  • CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.
  • 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.
  • 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
  • CDR-H1 comprises Xaa 1 Xaa 2 YMA (SEQ ID NO: 35); wherein
  • Xaa 1 is Asp (D) or Asn (N);
  • Xaa 2 is His (H), Tyr (Y), or Phe (F);
  • CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, 11 , 12, or 13;
  • CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15;
  • 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.
  • 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.
  • 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
  • CDR-H1 comprises Xaa 1 Xaa 2 YMA (SEQ ID NO: 35); wherein
  • Xaa 1 is Asp (D) or Asn (N);
  • Xaa 2 is His (H), Tyr (Y), or Phe (F);
  • CDR-H2 comprises YIXaa 3 YDGXaa 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36); wherein
  • Xaa 3 is 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);
  • Xaa 6 is Ser (S) or Tyr (Y);
  • CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15;
  • 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.
  • 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.
  • 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
  • VH anti-STEAP1 heavy chain variable region
  • VL anti-STEAP1 light chain variable region
  • CDR-H1 comprises the amino acid sequence of SEQ ID NO: 10, 1 , or 9;
  • CDR-H2 comprises YIXaa 3 YDGXaa 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36); wherein
  • Xaa 3 is 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);
  • Xaa 6 is Ser (S) or Tyr (Y);
  • CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15;
  • 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.
  • 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.
  • 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; in which 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, 1 1 , 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, consists essentially of, or consists of the amino acid sequence of SEQ
  • 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.
  • the antigen-binding molecule comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 1 ; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 2; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the antigen-binding molecule comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 9; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 11 ; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the antigen-binding molecule comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 9; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 12; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the antigen-binding molecule comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 9; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 12; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 14; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the antigen-binding molecule comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 10; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 13; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 15; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the antigen-binding molecule comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 10; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 2; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 16; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • 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 CDR-H1 comprises GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63); wherein
  • Xaa 10 is Asn (N) or Asp (D);
  • Xaa 11 is Tyr (Y), Phe (F), or His (H);
  • CDR-H2 comprises Xaa 12 YDGXaa 13 Xaa 14 (SEQ ID NO: 64); wherein
  • Xaa 12 is Asp (D) or Ser (S);
  • Xaa 13 is Gly (G), Asp (D), or Leu (L);
  • Xaa 14 is Ser (S), Asp (D), or Asn (N);
  • CDR-H3 comprises 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);
  • Xaa 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/or
  • CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.
  • 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.
  • 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
  • VH anti-STEAP1 heavy chain variable region
  • VL anti-STEAP1 light chain variable region
  • CDR-H1 comprises the amino acid sequence of SEQ ID NO: 56, 58, or 59;
  • CDR-H2 comprises Xaa 12 YDGXaa 13 Xaa 14 (SEQ ID NO: 64); wherein
  • Xaa 12 is Asp (D) or Ser (S);
  • Xaa 13 is Gly (G), Asp (D), or Leu (L);
  • Xaa 14 is Ser (S), Asp (D), or Asn (N);
  • CDR-H3 comprises 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);
  • Xaa 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.
  • 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.
  • 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
  • VH anti-STEAP1 heavy chain variable region
  • VL anti-STEAP1 light chain variable region
  • CDR-H1 comprises the amino acid sequence of SEQ ID NO: 56, 58, or 59;
  • CDR-H2 comprises the amino acid sequence of SEQ ID NO: 57, 60, 61 , or 62;
  • CDR-H3 comprises 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);
  • Xaa 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.
  • 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.
  • 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
  • VH anti-STEAP1 heavy chain variable region
  • VL anti-STEAP1 light chain variable region
  • CDR-H1 comprises GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63); wherein
  • Xaa 10 is Asn (N) or Asp (D);
  • Xaa 11 is Tyr (Y), Phe (F), or His (H);
  • CDR-H2 comprises the amino acid sequence of SEQ ID NO: 57, 60, 61 , or 62;
  • CDR-H3 comprises 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);
  • Xaa 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.
  • 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.
  • 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
  • VH anti-STEAP1 heavy chain variable region
  • VL anti-STEAP1 light chain variable region
  • CDR-H1 comprises GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63); wherein
  • Xaa 10 is Asn (N) or Asp (D);
  • Xaa 11 is Tyr (Y), Phe (F), or His (H);
  • CDR-H2 comprises the amino acid sequence of SEQ ID NO: 57, 60, 61 , or 62;
  • CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15;
  • 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.
  • 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.
  • 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 CDR-H1 comprises GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63); wherein
  • Xaa 10 is Asn (N) or Asp (D);
  • Xaa 11 is Tyr (Y), Phe (F), or His (H);
  • CDR-H2 comprises Xaa 12 YDGXaa 13 Xaa 14 (SEQ ID NO: 64); wherein
  • Xaa 12 is Asp (D) or Ser (S);
  • Xaa 13 is Gly (G), Asp (D), or Leu (L);
  • Xaa 14 is Ser (S), Asp (D), or Asn (N);
  • CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15;
  • 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.
  • 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.
  • 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
  • VH anti-STEAP1 heavy chain variable region
  • VL anti-STEAP1 light chain variable region
  • CDR-H1 comprises the amino acid sequence of SEQ ID NO: 56, 58, or 59;
  • CDR-H2 comprises Xaa 12 YDGXaa 13 Xaa 14 (SEQ ID NO: 64); wherein
  • Xaa 12 is Asp (D) or Ser (S);
  • Xaa 13 is Gly (G), Asp (D), or Leu (L);
  • Xaa 14 is Ser (S), Asp (D), or Asn (N);
  • CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15;
  • 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.
  • 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.
  • 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;
  • 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
  • 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.
  • the antigen-binding molecule comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 56; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 57; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the antigen-binding molecule comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 58; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 60; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the antigen-binding molecule comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 58; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 61 ; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the antigen-binding molecule comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 58; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 61 ; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 14; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the antigen-binding molecule comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 59; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 62; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 15; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the antigen-binding molecule comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 59; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 57; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 16; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the antigen-binding molecules of the present invention can be humanized antibodies.
  • an antigen-binding molecule of the present invention comprises a constant region derived from an IgG framework region.
  • the IgG framework region is an IgGi, lgG2, or lgG4 framework region.
  • the IgG framework region is an IgG 1 framework region.
  • the antigen-binding molecule comprises a heavy chain variable region comprising one or more (e.g., 1 , 2, 3, or all 4) of 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; an FR-H2 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; an FR-H3 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; and/or an FR-H4 having at least 80%, 85%, 90%, 91%, 9
  • the antigen-binding molecule comprises a heavy chain variable region comprising an FR-H2 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.
  • the antigen-binding molecule comprises a heavy chain variable region comprising an FR-H2 having the amino acid sequence of SEQ ID NO: 118.
  • the antigen-binding molecule comprises a heavy chain variable region comprising an FR-H2 having the amino acid sequence of SEQ ID NO: 120.
  • the antigen-binding molecule comprises a heavy chain variable region comprising one or more (e.g., 1 , 2, 3, or all 4) of an 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; an FR-H2 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 ; an FR-H3 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; and/or an FR-H4 having at least 80%, 85%, 90%, 91 %, 92%
  • the antigen-binding molecule comprises a light chain variable region comprising one or more (e.g., 1 , 2, 3, or all 4) of 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: 1 14; 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: 1 19; an FR-L3 co 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: 1 16; and/or an FR-L4 having at least 80%, 85%, 90%, 91 %,
  • the antigen-binding molecule comprises a heavy chain variable region comprising 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: 1 19.
  • the antigen-binding molecule comprises a heavy chain variable region comprising an FR-L2 having the amino acid sequence of SEQ ID NO: 1 19.
  • the antigen-binding molecule comprises a heavy chain variable region comprising an FR-L2 having the amino acid sequence of SEQ ID NO: 121 .
  • the antigen-binding molecule comprises a light chain variable region comprising one or more (e.g., 1 , 2, 3, or all 4) of 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: 1 14; 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: 1 15; an FR-L3 co 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: 1 16; and/or an FR-L4 having at least 80%, 85%, 90%, 91 %,
  • the antigen-binding molecule comprises an FR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 1 10; an FR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 1 1 1 ; an FR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 1 12; an FR-H4 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 1 13; an FR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 1 14; an FR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 1 15; an FR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 1 16; and an FR-L4 comprising, consisting, consisting, consisting
  • 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.
  • 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.
  • 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.
  • 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 instances, the heavy chain variable region comprises a VH sequence having at least 99% sequence identity to SEQ ID NO: 7, 17-25, 30-34, 38, or 68. In some instances, the heavy chain variable region comprises a VH sequence having 100% sequence identity to SEQ ID NO: 7, 17-25, 30-34, 38, or 68.
  • a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to SEQ ID NO: 7, 17-25, 30-34, 38, or 68, but an anti-STEAP1 antibody comprising that sequence retains the ability to bind to STEAP1 .
  • 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.
  • substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs).
  • 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.
  • 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.
  • 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.
  • 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 instances, the light chain variable region comprises a VL sequence having at least 99% sequence identity to SEQ ID NO: 8, 26-29, 39, or 69. In some instances, the light chain variable region comprises a VL sequence having 100% sequence identity to SEQ ID NO: 8, 26- 29, 39, or 69.
  • a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to SEQ ID NO: 8, 26-29, 39, or 69, but an anti-STEAP1 antibody comprising that sequence retains the ability to bind to STEAP1 .
  • 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.
  • the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs).
  • the antigen-binding molecule of any of the preceding embodiments features a VH and a VL region, in which 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.
  • CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 9
  • CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 11
  • CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3.
  • 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.
  • 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).
  • 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.
  • 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).
  • the antigen-binding molecule of any of the preceding embodiments features a VH and a VL region, in which 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.
  • CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 9
  • CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 12
  • CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3.
  • 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.
  • 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 ).
  • 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 ).
  • 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.
  • 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).
  • the antigen-binding molecule of any of the preceding embodiments features a VH and a VL region, in which 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.
  • 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.
  • the VH region 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).
  • 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.
  • 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).
  • the antigen-binding molecule of any of the preceding embodiments features a VH and a VL region, in which 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.
  • 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.
  • 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).
  • 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.
  • 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).
  • the antigen-binding molecule of any of the preceding embodiments features a VH and a VL region, in which 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.
  • 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.
  • the VH region 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).
  • 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.
  • 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).
  • the VH region 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
  • 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.
  • 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).
  • 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.
  • the antigen-binding molecule of any of the preceding embodiments features a VH and a VL region, in which 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.
  • CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 35
  • CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 36
  • CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 37.
  • 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.
  • the VH region 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).
  • 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.
  • 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).
  • the antigen-binding molecule binds to an epitope on STEAP1 comprising one or more amino acid residues selected from Seri 01 , His102, G In 103, and Lys281 of STEAP1 .
  • the epitope comprises amino acid residues Seri 01 of ECL1 of
  • the epitope comprises amino acid residues His102 of ECL1 of
  • the epitope comprises amino acid residues Gin 103 of ECL1 of
  • the epitope comprises amino acid residues Lys281 of ECL3 of
  • the epitope comprises Seri 01 , His102, Gl n 103 of ECL1 of STEAP1 , and Lys281 of ECL3 of STEAP1 .
  • the epitope further comprises one or more additional amino acid residues selected from Trp195, Gln198, Gln201 , Gln202, Asn203 and Lys204 of ECL2 of STEAP1 .
  • the epitope does not comprise amino acid residue G In 104 of STEAP1 .
  • the epitope does not comprise amino acid residue Tyr107 of STEAP1 .
  • the epitope does not comprise amino acid residue Asn194 of STEAP1 .
  • the epitope does not comprise amino acid residue Glu205 of STEAP1 .
  • the epitope does not comprise amino acid residues Ala207 of STEAP1 .
  • the antigen-binding molecule binds human STEAP1 with a K D of about 100 nM or lower, as measured by Kinetic Exclusion Assay (KinExA®). In some embodiments, the antigen-binding molecule binds human STEAP1 with a K D of between about 10 pM to about 100 nM. In some embodiments, the antigen-binding molecule binds human STEAP1 with a K D of between about 100 pM to about 50 nM. In some embodiments, the antigen-binding molecule binds human STEAP1 with a K D of between about 1 nM to about 30 nM.
  • the antigen- binding molecule binds cynomolgus STEAP1 with a K D of about 100 nM or lower, as measured by Kinetic Exclusion Assay (KinExA®). In some embodiments, the antigen-binding molecule binds cynomolgus STEAP1 with a K D of between about 10 pM to about 100 nM. In some embodiments, the antigen-binding molecule binds cynomolgus STEAP1 with a K D of between about 100 pM to about 50 nM. In some embodiments, the antigen-binding molecule binds cynomolgus STEAP1 with a K D of between about 1 nM to about 30 nM.
  • the invention provides isolated multispecific antigen-binding molecules that comprises a first antigen-binding domain that binds to STEAP1 as described above. In some instances, the multispecific antigen-binding molecule binds to STEAP1 monovalently. In some instances, the multispecific antigen-binding molecule further comprises a second binding domain that binds to a T cell receptor. In additional instances, the multispecific antigen-binding molecule comprises a third binding domain that binds to an additional antigen (e.g., a tumor-associated antigen).
  • an additional antigen e.g., a tumor-associated antigen
  • a multispecific antigen-binding molecule of the invention is a bispecific antigen-binding molecule (e.g., a bispecific antibody) comprising a first antigen-binding domain that binds to STEAP1 and a second antigen-binding domain that binds to a T cell receptor.
  • T cell receptors include cluster of differentiation 3 (CD3).
  • 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 .
  • the second antigen-binding domain binds to an epitope on CD3 comprising amino acid residue Glu6 of CD3.
  • the epitope further comprises one or more additional amino acid residues selected from Gl n 1 , Asp2, and Met7 of CD3.
  • the epitope comprises amino acid residues Gln1 , Asp2, and Glu6 of CD3. In some embodiments, the epitope comprises amino acid residues Gin 1 , 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 Gl n 1 , 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 cyno CD3 polypeptide.
  • the human CD3 polypeptide or the cyno CD3 polypeptide is a human CD3e polypeptide or a cyno CD3e polypeptide, respectively.
  • the human CD3 polypeptide or the cyno CD3 polypeptide is a human CD3 ⁇ polypeptide or a cyno CD3 ⁇ polypeptide, respectively.
  • the second antigen- binding domain binds the human CD3e polypeptide with a K D of about 100 nM or lower. In some embodiments, the second antigen-binding domain binds the human CD3e polypeptide with a K D of between about 10 pM to about 100 nM.
  • the second antigen-binding domain binds the human CD3e polypeptide with a K D of between about 100 pM to about 50 nM. In some embodiments, the second antigen-binding domain binds the human CD3e polypeptide with a K D of between about 1 nM to about 10 nM.
  • 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 .
  • 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, in which 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:
  • CDR-L1 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:
  • CDR-L2 comprises, consists essentially of, or consists of the amino acid sequence of SEQ ID NO:
  • the second antigen-binding domain comprises a VH sequence comprising at least 80% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 46.
  • the second antigen-binding domain comprises a VL sequence comprising at least 80% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 47.
  • a VH or VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to SEQ ID NO: 46 or 47, but a multispecific antibody comprising that sequence retains the ability to bind to CD3.
  • substitutions e.g., conservative substitutions
  • insertions, or deletions relative to SEQ ID NO: 46 or 47
  • a multispecific antibody comprising that sequence retains the ability to bind to CD3.
  • a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 46 or 47.
  • the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs).
  • 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.
  • 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, in which 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.
  • the second antigen-binding domain comprises a VH sequence comprising 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 comprising at least 80% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 55.
  • a VH or VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (e.g., conservative substitutions), insertions, or deletions relative to SEQ ID NO: 54 or 55, but a multispecific antibody comprising that sequence retains the ability to bind to CD3.
  • substitutions e.g., conservative substitutions
  • insertions, or deletions relative to SEQ ID NO: 54 or 55
  • a multispecific antibody comprising that sequence retains the ability to bind to CD3.
  • a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 54 or 55.
  • the substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs).
  • 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 SEQ ID NO: 7, 17-25, 30-34, 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 NO: 8, 26-29, 39, and 69; and (B) a second antigen-binding domain that binds to a T cell receptor.
  • VH anti-STEAP1 heavy chain variable region
  • VL anti-STEAP1 light chain variable region
  • At least one, at least two, at least three, at least four, at least five, or all six CDRs are selected from the CDR(s) of the VH sequence selected from SEQ ID NO: 7, 17-25, 30-34, 38, and 68 and the VL sequence selected from SEQ ID NO: 8, 26-29, 39, and 69.
  • at least one, at least two, at least three, at least four, at least five, or all six CDRs are selected from the CDR(s) of 40G5c or 38E4v1 .MD1 .
  • the six CDRs are defined according to the Kabat numbering. In other cases, the six CDRs are defined according to the Chothia numbering. In additional cases, the six CDRs are defined according to the EU numbering.
  • 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 Xaa 1 Xaa 2 YMA (SEQ ID NO: 35); wherein
  • Xaa 1 is Asp (D) or Asn (N);
  • Xaa 2 is His (H), Tyr (Y), or Phe (F);
  • CDR-H2 comprises YIXaa 3 YDGXaa 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36); wherein
  • Xaa 3 is 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);
  • Xaa 6 is Ser (S) or Tyr (Y);
  • CDR-H3 comprises 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);
  • 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/or
  • CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6;
  • 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.
  • the second antigen-binding domains binds to CD3.
  • 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 .
  • 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 the amino acid sequence of SEQ ID NO: 10, 1 , or 9;
  • CDR-H2 comprises YIXaa 3 YDGXaa 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36); wherein
  • Xaa 3 is 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);
  • Xaa 6 is Ser (S) or Tyr (Y);
  • CDR-H3 comprises 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);
  • Xaa 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and
  • 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.
  • the second antigen-binding domains binds to CD3.
  • 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 .
  • 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 the amino acid sequence of SEQ ID NO: 10, 1 , or 9
  • CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, 11 , 12, or 13
  • CDR-H3 comprises RSGXaa 7 YHVGYAMXaa 8 Xaa 9 (SEQ ID NO: 37);
  • 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);
  • 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and
  • 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.
  • the second antigen-binding domains binds to CD3.
  • 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 .
  • 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 Xaa 1 Xaa 2 YMA (SEQ ID NO: 35); wherein
  • Xaa 1 is Asp (D) or Asn (N);
  • Xaa 2 is His (H), Tyr (Y), or Phe (F);
  • CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, 11 , 12, or 13;
  • CDR-H3 comprises 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);
  • 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and
  • 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.
  • the second antigen-binding domains binds to CD3.
  • 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 .
  • 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 Xaa 1 Xaa 2 YMA (SEQ ID NO: 35); wherein
  • Xaa 1 is Asp (D) or Asn (N);
  • Xaa 2 is His (H), Tyr (Y), or Phe (F);
  • CDR-H2 comprises the amino acid sequence of SEQ ID NO: 2, 11 , 12, or 13;
  • CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15;
  • 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and
  • 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.
  • the second antigen-binding domains binds to CD3.
  • 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 .
  • 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 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);
  • CDR-H2 comprises YIXaa 3 YDGXaa 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36); wherein
  • Xaa 3 is 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);
  • Xaa 6 is Ser (S) or Tyr (Y);
  • CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15;
  • 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and
  • 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.
  • the second antigen-binding domains binds to CD3.
  • 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 .
  • 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 the amino acid sequence of SEQ ID NO: 10, 1 , or 9;
  • CDR-H2 comprises YIXaa 3 YDGXaa 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36); wherein
  • Xaa 3 is 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);
  • CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15;
  • 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and
  • 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.
  • the second antigen-binding domains binds to CD3.
  • 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 .
  • 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; in which 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, consists essentially of
  • 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.
  • the second antigen-binding domains binds to CD3.
  • 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 .
  • the first antigen-binding domain comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 1 ; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 2; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the first antigen-binding domain comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 9; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 11 ; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the first antigen-binding domain comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 9; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 12; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the first antigen-binding domain comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 9; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 12; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 14; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the first antigen-binding domain comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 10; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 13; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 15; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the first antigen-binding domain comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 10; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 2; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 16; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • 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 GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63); wherein
  • Xaa 10 is Asn (N) or Asp (D);
  • Xaa 11 is Tyr (Y), Phe (F), or His (H);
  • CDR-H2 comprises Xaa 12 YDGXaa 13 Xaa 14 (SEQ ID NO: 64); wherein
  • Xaa 12 is Asp (D) or Ser (S);
  • Xaa 13 is Gly (G), Asp (D), or Leu (L); and Xaa 14 is Ser (S), Asp (D), or Asn (N);
  • CDR-H3 comprises 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);
  • 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and
  • 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.
  • the second antigen-binding domains binds to CD3.
  • 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 .
  • 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 the amino acid sequence of SEQ ID NO: 56, 58, or 59;
  • CDR-H2 comprises Xaa 12 YDGXaa 13 Xaa 14 (SEQ ID NO: 64); wherein
  • Xaa 12 is Asp (D) or Ser (S);
  • Xaa 13 is Gly (G), Asp (D), or Leu (L);
  • Xaa 14 is Ser (S), Asp (D), or Asn (N);
  • CDR-H3 comprises 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);
  • 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and
  • 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.
  • the second antigen-binding domains binds to CD3.
  • 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 .
  • 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 the amino acid sequence of SEQ ID NO: 56, 58, or 59
  • CDR-H2 comprises the amino acid sequence of SEQ ID NO: 57, 60, 61 , or 62;
  • CDR-H3 comprises 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);
  • 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and
  • 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.
  • the second antigen-binding domains binds to CD3.
  • 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 .
  • 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 GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63); wherein
  • Xaa 10 is Asn (N) or Asp (D);
  • Xaa 11 is Tyr (Y), Phe (F), or His (H);
  • CDR-H2 comprises the amino acid sequence of SEQ ID NO: 57, 60, 61 , or 62;
  • CDR-H3 comprises 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);
  • 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and (B) a second antigen-binding domain that binds to a T cell receptor.
  • 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.
  • the second antigen-binding domains binds to CD3.
  • 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 .
  • 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 GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63); wherein
  • Xaa 10 is Asn (N) or Asp (D);
  • Xaa 11 is Tyr (Y), Phe (F), or His (H);
  • CDR-H2 comprises the amino acid sequence of SEQ ID NO: 57, 60, 61 , or 62;
  • CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15;
  • 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/or
  • CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6;
  • 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.
  • the second antigen-binding domains binds to CD3.
  • 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 .
  • 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 GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63); wherein
  • Xaa 10 is Asn (N) or Asp (D);
  • Xaa 11 is Tyr (Y), Phe (F), or His (H);
  • CDR-H2 comprises Xaa 12 YDGXaa 13 Xaa 14 (SEQ ID NO: 64); wherein
  • Xaa 12 is Asp (D) or Ser (S);
  • Xaa 13 is Gly (G), Asp (D), or Leu (L); and Xaa 14 is Ser (S), Asp (D), or Asn (N); CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15; 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and
  • 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.
  • the second antigen-binding domains binds to CD3.
  • 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 .
  • 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 the amino acid sequence of SEQ ID NO: 56, 58, or 59;
  • CDR-H2 comprises Xaa 12 YDGXaa 13 Xaa 14 (SEQ ID NO: 64); wherein
  • Xaa 12 is Asp (D) or Ser (S);
  • Xaa 13 is Gly (G), Asp (D), or Leu (L);
  • Xaa 14 is Ser (S), Asp (D), or Asn (N);
  • CDR-H3 comprises the amino acid sequence of SEQ ID NO: 16, 3, 14, or 15;
  • 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/or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6; and
  • 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.
  • the second antigen-binding domains binds to CD3.
  • 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 .
  • 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; in which 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
  • 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.
  • the second antigen-binding domains binds to CD3.
  • 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 .
  • the first antigen-binding domain comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 56; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 57; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the first antigen-binding domain comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 58; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 60; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the first antigen-binding domain comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 58; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 61 ; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the first antigen-binding domain comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 58; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 61 ; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 14; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the first antigen-binding domain comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 59; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 62; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 15; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the first antigen-binding domain comprises CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 59; CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 57; CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 16; CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 4; CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 5; and CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 6.
  • the multispecific antigen-binding molecules of the present invention can be humanized antibodies.
  • the first antigen-binding domain and/or the second antigen-binding domain each independently comprises a constant region derived from an IgG framework region.
  • the IgG framework region is an IgGi, lgG2, or lgG4 framework region.
  • the IgG framework region is an IgGi framework region.
  • 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 an 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; an FR- H2 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 ; an FR-H3 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; and/or an FR-H4 having at least 80%,
  • 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 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 co 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; and/or an FR-L4 having at least 80%,
  • the multispecific antigen-binding molecule comprises (A) a first antigen-binding domain comprising an FR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 110; an FR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 111 ; an FR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 112; an FR-H4 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 113; an FR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 114; an FR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 115; an FR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:
  • the multispecific antigen-binding molecule comprises (A) a first antigen-binding domain 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; and (B) a second antigen-binding domain that binds to a T cell receptor.
  • 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.
  • 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 instances, 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 instances, 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 instances, 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 domains binds to CD3.
  • the second antigen-binding domain comprises 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: 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.
  • the multispecific antigen-binding molecule comprises (A) a first antigen-binding domain 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; and (B) a second antigen-binding domain that binds to a T cell receptor.
  • the VL sequence comprises at least 90% sequence identity to SEQ ID NO: 8, 26-29, 39, or 69.
  • the VL sequence comprises at least 95% sequence identity to SEQ ID NO: 8, 26-29, 39, or 69.
  • the VL sequence comprises at least 98% sequence identity to SEQ ID NO: 8, 26-29, 39, or 69. In some instances, the VL sequence comprises at least 99% sequence identity to SEQ ID NO: 8, 26-29, 39, or 69. In some instances, the VL sequence comprises 100% sequence identity to SEQ ID NO: 8, 26-29, 39, or 69.
  • the second antigen-binding domains binds to CD3. In some cases, the second antigen-binding domain comprises 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: 47 or 55.
  • 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.
  • a multispecific antigen-binding molecule of the present invention comprises 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 illustrated in Tables 1 or 2.
  • the first antigen-binding domain comprises a VH and/or a VL as illustrated in Table 1 .
  • the multispecific antigen-binding molecule comprises a second antigen-binding domain that binds to a T cell receptor (e.g., CD3).
  • 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 illustrated in Tables 1 or 2. In some instances, the second antigen-binding domain that binds to CD3 comprises a VH and/or a VL as illustrated in Table 1 .
  • 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).
  • a T cell receptor e.g., CD3
  • the first antigen- binding domain features a VH and a VL region, in which 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.
  • CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 9
  • CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 11
  • CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3.
  • 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.
  • 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).
  • 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.
  • 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).
  • the second antigen-binding domain features a VH and a VL region, in which 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: 40 or 48, (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 41 or 49, or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 42 or 50.
  • 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
  • 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 the amino acid sequence of SEQ ID NO: 43 or 51 , (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:44 or 52, or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 45 or 53.
  • 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
  • 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).
  • 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).
  • a T cell receptor e.g., CD3
  • the first antigen- binding domain features a VH and a VL region, in which 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.
  • CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 9
  • CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 12
  • CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 3.
  • 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.
  • 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 ).
  • 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.
  • 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).
  • the second antigen-binding domain features a VH and a VL region, in which 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: 40 or 48, (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 41 or 49, or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 42 or 50.
  • 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
  • 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 the amino acid sequence of SEQ ID NO: 43 or 51 , (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:44 or 52, or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 45 or 53.
  • 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
  • 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).
  • 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).
  • a T cell receptor e.g., CD3
  • the first antigen- binding domain features a VH and a VL region, in which 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.
  • CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 9
  • CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 12
  • CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 14.
  • 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.
  • 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).
  • 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.
  • 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
  • the second antigen-binding domain features a VH and a VL region, in which 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: 40 or 48, (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 41 or 49, or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 42 or 50.
  • CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 40 or 48
  • CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 41 or 49
  • CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 42 or 50.
  • 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).
  • 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).
  • 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 the amino acid sequence of SEQ ID NO: 43 or 51 , (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:44 or 52, or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 45 or 53.
  • CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 43 or 51
  • CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:44 or 52
  • CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 45 or 53.
  • 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).
  • 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).
  • 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).
  • a T cell receptor e.g., CD3
  • the first antigen- binding domain features a VH and a VL region, in which 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.
  • CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 10
  • CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 13
  • CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 15.
  • 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.
  • 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).
  • 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.
  • 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
  • the second antigen-binding domain features a VH and a VL region, in which 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: 40 or 48, (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 41 or 49, or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 42 or 50.
  • CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 40 or 48
  • CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 41 or 49
  • CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 42 or 50.
  • 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).
  • 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).
  • 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 the amino acid sequence of SEQ ID NO: 43 or 51 , (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:44 or 52, or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 45 or 53.
  • CDR-L1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 43 or 51
  • CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:44 or 52
  • CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 45 or 53.
  • 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).
  • 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).
  • 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).
  • a T cell receptor e.g., CD3
  • the first antigen- binding domain features a VH and a VL region, in which 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.
  • CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 10
  • CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 2
  • CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 16.
  • 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.
  • 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).
  • 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.
  • 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
  • the second antigen-binding domain features a VH and a VL region, in which 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: 40 or 48, (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 41 or 49, or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 42 or 50.
  • 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
  • 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 the amino acid sequence of SEQ ID NO: 43 or 51 , (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:44 or 52, or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 45 or 53.
  • 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
  • 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).
  • 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).
  • a T cell receptor e.g., CD3
  • the first antigen- binding domain features a VH and a VL region, in which 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.
  • CDR-H1 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 35
  • CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 36
  • CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 37.
  • 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.
  • 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).
  • 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.
  • 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
  • the second antigen-binding domain features a VH and a VL region, in which 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: 40 or 48, (b) CDR-H2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 41 or 49, or (c) CDR-H3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 42 or 50.
  • 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
  • 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 the amino acid sequence of SEQ ID NO: 43 or 51 , (b) CDR-L2 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO:44 or 52, or (c) CDR-L3 comprising, consisting essentially of, or consisting of the amino acid sequence of SEQ ID NO: 45 or 53.
  • 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
  • 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).
  • 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).
  • a T cell receptor e.g., CD3
  • 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).
  • 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).
  • 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).
  • 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.
  • 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).
  • 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).
  • 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).
  • 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).
  • the multispecific antigen-binding molecule of any of the preceding embodiments comprises an anti-STEAP1 heavy chain constant region 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: 83, and an anti-STEAP1 light chain constant region 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 SEQ ID NO: 82.
  • the multispecific antigen-binding molecule of any of the preceding embodiments comprises an anti-STEAP1 heavy chain constant region 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: 85, and an anti-STEAP1 light chain constant region 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 SEQ ID NO: 84.
  • the multispecific antigen-binding molecule of any of the preceding embodiments comprises an anti-CD3 heavy chain constant region 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: 83, and an anti-CD3 light chain constant region 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 SEQ ID NO: 82.
  • the multispecific antigen-binding molecule of any of the preceding embodiments comprises an anti-CD3 heavy chain constant region 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: 85, and an anti-CD3 light chain constant region 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 SEQ ID NO: 84.
  • the multispecific antigen-binding molecule of any of the preceding embodiments 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 SEQ ID NO: 70.
  • the multispecific antigen-binding molecule of any of the preceding embodiments 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 SEQ ID NO: 72.
  • the multispecific antigen-binding molecule of any of the preceding embodiments 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 SEQ ID NO: 74.
  • the multispecific antigen-binding molecule of any of the preceding embodiments 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 SEQ ID NO: 76.
  • the multispecific antigen-binding molecule of any of the preceding embodiments comprises an anti-STEAP1 heavy chain constant region 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: 122, and an anti-STEAP1 light chain constant region 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 SEQ ID NO: 123.
  • the multispecific antigen-binding molecule of any of the preceding embodiments comprises an anti-STEAP1 heavy chain constant region 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: 126, and an anti-STEAP1 light chain constant region 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 SEQ ID NO: 127.
  • the multispecific antigen-binding molecule of any of the preceding embodiments comprises an anti-STEAP1 heavy chain constant region 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: 130, and an anti-STEAP1 light chain constant region 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 SEQ ID NO: 131.
  • the multispecific antigen-binding molecule of any of the preceding embodiments comprises an anti-STEAP1 heavy chain constant region 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: 134, and an anti-STEAP1 light chain constant region 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 SEQ ID NO: 135.
  • the multispecific antigen-binding molecule of any of the preceding embodiments comprises an anti-STEAP1 heavy chain constant region 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: 138, and an anti-STEAP1 light chain constant region 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 SEQ ID NO: 139.
  • the multispecific antigen-binding molecule of any of the preceding embodiments comprises an anti-STEAP1 heavy chain constant region 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: 142, and an anti-STEAP1 light chain constant region 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 SEQ ID NO: 143.
  • the multispecific antigen-binding molecule of any of the preceding embodiments 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: 79, 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 SEQ ID NO: 78.
  • the multispecific antigen-binding molecule of any of the preceding embodiments 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: 81 , 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 SEQ ID NO: 80.
  • the multispecific antigen-binding molecule of any of the preceding embodiments 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: 124, 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 SEQ ID NO: 125.
  • the multispecific antigen-binding molecule of any of the preceding embodiments 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: 128, 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 SEQ ID NO: 129.
  • the multispecific antigen-binding molecule of any of the preceding embodiments 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: 132, 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 SEQ ID NO: 133.
  • the multispecific antigen-binding molecule of any of the preceding embodiments 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 SEQ ID NO: 137.
  • the multispecific antigen-binding molecule of any of the preceding embodiments 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: 140, 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 SEQ ID NO: 141 .
  • the multispecific antigen-binding molecule of any of the preceding embodiments 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: 144, 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 SEQ ID NO: 145.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 a cell obtained from a solid tumor.
  • the antigen can be expressed on the surface of a cell of prostate cancer, Ewing sarcoma, lung cancer, colorectal cancer, breast cancer, bladder cancer, ovarian cancer, or cervical cancer.
  • the antigen is a tumor-associated antigen (TAA).
  • TAA can be a receptor expressed on the surface of a cell of prostate cancer, Ewing sarcoma, lung cancer, colorectal cancer, breast cancer, bladder cancer, ovarian cancer, or cervical cancer.
  • the TAA is a receptor expressed on the surface of a prostate cancer cell.
  • the TAA is a receptor expressed on an Ewing sarcoma cell.
  • 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 .
  • PSMA prostate-specific membrane antigen
  • PSCA prostate stem cell antigen
  • EpCAM epithelial cell adhesion molecule
  • PSA prostate-specific antigen
  • PAP prostatic acid phosphatase
  • STEAP2 STEAP2
  • HBA-71 HBA-71
  • the multispecific antigen-binding molecule further comprises a third antigen-binding domain that binds to a tumor-associated antigen.
  • the third antigen- binding domain binds to a TAA of prostate cancer, Ewing sarcoma, lung cancer, colorectal cancer, breast cancer, bladder cancer, ovarian cancer, or cervical cancer.
  • 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), prostatic acid phosphatase (PAP), STEAP2, or HBA-71 .
  • PSMA prostate-specific membrane antigen
  • PSCA prostate stem cell antigen
  • EpCAM epithelial cell adhesion molecule
  • PSA prostatic acid phosphatase
  • STEAP2 prostatic acid phosphatase
  • 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 .
  • the multispecific antigen-binding molecule binds to human STEAP1 with a K D 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 lower.
  • multispecific antigen-binding molecule binds to human STEAP1 with a K D 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 5 nM to about 20 nM, about 5 nM to about 10 nM, about 10 nM to about 100 nM, about 10 nM to about 75 nM, about 10 nM to about 50 nM, about 10 nM to about 40 nM, about 1
  • the multispecific antigen-binding molecule binds to human STEAP1 with a K D 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 1 1 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
  • multispecific antigen-binding molecule binds to human STEAP1 with a K D of about 29 nM.
  • the K D is determined using a Kinetic Exclusion Assay (KinExA®), e.g., as described in Example 8.
  • the multispecific antigen-binding molecule binds to cyno STEAP1 with a K D 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 lower.
  • multispecific antigen-binding molecule binds to cyno STEAP1 with a K D 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 5 nM to about 20 nM, about 5 nM to about 10 nM, about 10 nM to about 100 nM, about 10 nM to about 75 nM, about 10 nM to about 50 nM, about 10 nM to about 10 n
  • the multispecific antigen-binding molecule binds to cyno STEAP1 with a K D 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 1 1 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.
  • multispecific antigen-binding molecule binds to cyno STEAP1 with a K D of about 14 nM.
  • the K D is determined using a Kinetic Exclusion Assay (KinExA®), e.g., as described in Example 8.
  • the multispecific antigen-binding molecule has a Cmax of up to or about 15, 20, 25, or 30 ⁇ g/mL. In some instances, the multispecific antigen-binding molecule has a Cmax of about 1 1 , 1 1 .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 ⁇ g/mL.
  • the multispecific antigen-binding molecule has a Cmax of about 10 ⁇ g/mL to about 30 ⁇ g/mL (e.g., about 10 ⁇ g/mL to about 30 ⁇ g/mL, about 10 ⁇ g/mL to about 28 ⁇ g/mL, about 10 ⁇ g/mL to about 26 ⁇ g/mL, about 10 ⁇ g/mL to about 24 ⁇ g/mL, about 10 ⁇ g/mL to about 22 ⁇ g/mL, about 10 ⁇ g/mL to about 20 ⁇ g/mL, about 10 ⁇ g/mL to about 18 ⁇ g/mL, about 10 ⁇ g/mL to about 16 ⁇ g/mL, about 10 ⁇ g/mL to about 14 ⁇ g/mL, about 10 ⁇ g/mL to about 12 ⁇ g/mL, about 12 ⁇ g/mL to about 30 ⁇ g/mL, about 12 ⁇ g/mL to about 28 ⁇
  • the multispecific antigen-binding molecule has a Cmax of about 20 ⁇ g/mL to about 28 ⁇ g/mL (e.g., about 20 ⁇ g/mL, about 21 ⁇ g/mL, about 22 ⁇ g/mL, about 23 ⁇ g/mL, about 24 ⁇ g/mL, about 25 ⁇ g/mL, about 26 ⁇ g/mL, about 27 ⁇ g/mL, or about 28 ⁇ g/mL).
  • the multispecific antigen- binding molecule has a Cmax of about 24 ⁇ g/mL.
  • Cmax may be determined as described in Example 9 (in female SCID mice).
  • Cmax may be determined as described in Example 10 (in cynomolgus monkeys).
  • the multispecific antigen-binding molecule has an EC 50 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 lower. In some cases, the multispecific antigen-binding molecule has an EC 50 of about 0.5 or lower. In some cases, the multispecific antigen-binding molecule has an EC 50 of about 0.4 or lower. In some cases, the multispecific antigen-binding molecule has an EC 50 of about 0.3 or lower. In some cases, the multispecific antigen-binding molecule has an EC 50 of about 0.2 or lower. In some cases, the multispecific antigen-binding molecule has an EC 50 of about 0.1 or lower.
  • the multispecific antigen-binding molecule has an EC 50 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
  • the EC 50 is determined in a cell killing assay at 72 hours with human CD8+ T cells and STEAP1 -expressing LNCaP-X1 .2 cells.
  • the EC 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).
  • the EC 50 is about 0.08 or about 0.3.
  • the EC 50 is about 0.08. In some embodiments, the EC 50 is about 0.3.
  • the EC 50 is determined in a cell killing assay at 72 hours with human CD8+ T cells and STEAP1 -expressing LNCaPXI .2KO3-13 cells.
  • the EC 50 is 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).
  • the EC 50 is about 0.1 or about 0.7.
  • the EC 50 is about 0.1 .
  • the EC 50 is about 0.7.
  • the multispecific antigen-binding molecule binds to STEAP1 monovalently. In other embodiments, the multispecific antigen-binding molecule binds to STEAP1 multivalently (e.g., bivalently).
  • an antibody of the invention comprises a first antigen-binding domain that binds to a STEAP1 protein.
  • the first antigen-binding domain binds to a human STEAP1 protein.
  • the first antigen-binding domain binds to a primate STEAP1 protein, e.g., a STEAP1 protein from cynomolgus monkey or Pongo abelii.
  • 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 the residue positions 101 , 102, 103, 195, 198, 202, and 281 correspond to positions 101 , 102, 103, 195, 198, 202, and 281 set forth in SEQ ID NO: 65.
  • the first antigen-binding domain binds to at least one residue selected from Seri 01 , His102, Gin 103, Trp195, Gln198, Gln202, and Lys281 of SEQ ID NO: 65.
  • a residue from the first antigen-binding domain forms a hydrogen bond with at least one residue selected from Seri 01 , His102, Gin 103, Trp195, G In 198, Gln202, and Lys281 .
  • at least one residue selected from Leu56, Ser73, Asn74, G ly 101 , Tyr103, and Tyr107 of the VH of the first antigen-binding domain forms a hydrogen bond with at least one residue selected from Seri 01 , His102, Gln103, Trp195, Gln198, Gln202, and Lys281 of STEAP1 , wherein the 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.
  • 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 the residue positions 35 and 54 correspond to positions 35 and 54 set forth in SEQ ID NO: 8.
  • residue Asn203 and/or Lys204 of human STEAP1 form van der Waals interactions with one or more VL CDR residues.
  • the residues that form the hydrogen bonds are as illustrated in Table 3. Table 3
  • the antibody of the invention is a monospecific antibody described supra under Section A “antigen-binding molecules that binds to STEAP1
  • the antibody comprises a VH region comprising CDR-H1 , CDR-H2, and CDR-H3 of a VH sequence selected from SEQ ID NOs: 7, 17-25, 30-34, 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, 26-29, 39, and 69.
  • the antibody comprises six CDRs in which:
  • CDR-H1 comprises Xaa 1 Xaa 2 YMA (SEQ ID NO: 35); wherein
  • Xaa 1 is Asp (D) or Asn (N);
  • Xaa 2 is His (H), Tyr (Y), or Phe (F);
  • CDR-H2 comprises YIXaa 3 YDGXaa 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36); wherein
  • Xaa 3 is 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);
  • Xaa 6 is Ser (S) or Tyr (Y);
  • CDR-H3 comprises 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);
  • Xaa 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.
  • the antibody comprises six CDRs, in which:
  • CDR-H1 comprises GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63); wherein
  • Xaa 10 is Asn (N) or Asp (D);
  • Xaa 11 is Tyr (Y), Phe (F), or His (H);
  • CDR-H2 comprises Xaa 12 YDGXaa 13 Xaa 14 (SEQ ID NO: 64); wherein
  • Xaa 12 is Asp (D) or Ser (S);
  • Xaa 13 is Gly (G), Asp (D), or Leu (L);
  • Xaa 14 is Ser (S), Asp (D), or Asn (N);
  • CDR-H3 comprises 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);
  • Xaa 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;
  • CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6.
  • the antibody of the invention is a multispecific antibody described supra under Section B “Multispecific antigen-binding molecules.”
  • 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/or CDR-H3 of a VH sequence selected from SEQ ID NO: 7, 17-25, 30-34, 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 NO: 8, 26-29, 39, and 69; and (B) a second antigen-binding domain that binds to a T cell receptor (e.g., CD3).
  • a T cell receptor e.g., CD3
  • 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; wherein
  • CDR-H1 comprises Xaa 1 Xaa 2 YMA (SEQ ID NO: 35); wherein
  • Xaa 1 is Asp (D) or Asn (N);
  • Xaa 2 is His (H), Tyr (Y), or Phe (F);
  • CDR-H2 comprises YIXaa 3 YDGXaa 4 Xaa 5 TXaa 6 YGDSVKG (SEQ ID NO: 36); wherein
  • Xaa 3 is 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);
  • Xaa 6 is Ser (S) or Tyr (Y);
  • CDR-H3 comprises 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);
  • 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/or
  • CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6;
  • (B) a second antigen-binding domain that binds to a T cell receptor (e.g., CD3).
  • a T cell receptor e.g., CD3
  • 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; wherein
  • CDR-H1 comprises GFTFSXaa 10 Xaa 11 (SEQ ID NO: 63); wherein
  • Xaa 10 is Asn (N) or Asp (D);
  • Xaa 11 is Tyr (Y), Phe (F), or His (H);
  • CDR-H2 comprises Xaa 12 YDGXaa 13 Xaa 14 (SEQ ID NO: 64); wherein
  • Xaa 12 is Asp (D) or Ser (S);
  • Xaa 13 is Gly (G), Asp (D), or Leu (L);
  • Xaa 14 is Ser (S), Asp (D), or Asn (N);
  • CDR-H3 comprises 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);
  • Xaa 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/or
  • CDR-L3 comprises the amino acid sequence of SEQ ID NO: 6;
  • (B) a second antigen-binding domain that binds to a T cell receptor (e.g., CD3).
  • a T cell receptor e.g., CD3
  • a multispecific antigen-binding molecule e.g., a bispecific or trispecific antigen-binding molecule
  • a multispecific antigen-binding molecule features a structure wherein the C-terminus of the first antigen-binding domain is fused to the N-terminus of the second antigen-binding domain via a peptide linker.
  • the peptide linker can be 5-20 amino acids in length (e.g., 5-10, 10-15, or 15-20, e.g., 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids in length).
  • the peptide linker comprises the natural amino acid sequence of the variable heavy chain hinge region (e.g., DKTHT).
  • the peptide linker comprises a (Gly4Ser) n linker (or (G4S) n linker), in which n is from 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 instances, n is 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • the peptide linker comprises a G4SG2 linker. In some embodiments, the peptide linker comprises the G4SG2 linker and the hinge region (e.g., DKTHT). In some embodiments, the peptide linker comprises a plurality of glycines, alanines, or a combination thereof.
  • Antigen-binding molecules e.g., monospecific and/or multispecific antigen-binding molecules such as bispecific or trispecific antigen-binding molecules
  • the Fc domain may feature an Fc domain.
  • the Fc domain may be an IgG Fc domain (e.g., an IgGi, lgG2, or lgG4 Fc domain).
  • the Fc domain can be a human Fc domain.
  • the Fc domain comprises one or more amino acid substitution(s) that reduces binding to an Fc receptor and/or effector function.
  • the one or more amino acid substitutions that reduces binding to an Fc receptor and/or effector function is at one or more position selected from the group of L234, L235, and P329 (e.g., wherein the first Fc subunit and the second Fc subunit each comprises the amino acid substitutions of L234A, L235A and P329G).
  • the Fc receptor may be, for example, an Fey receptor.
  • the antigen-binding molecules e.g., monospecific and/or multispecific antigen- binding molecules such as bispecific or trispecific antigen-binding molecules
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • the Fc domain comprises a modification configured to promote the association of the first Fc subunit with the second Fc subunit.
  • “Knob-in-hole” engineering of bispecific antibodies may be utilized to generate a first arm containing a knob and a second arm containing the hole into which the knob of the first arm may bind.
  • the knob of the multispecific antigen-binding molecules of the invention may be an anti-STEAP1 arm in one embodiment.
  • the knob of the multispecific antigen-binding molecules of the invention may be an anti-CD3 arm.
  • the hole of the multispecific antigen-binding molecules of the invention may be an anti-STEAP1 arm in one embodiment.
  • the hole of the multispecific antigen-binding molecules of the invention may be an anti-CD3 arm.
  • Multispecific antigen-binding molecules such as bispecific antibodies may also be engineered using immunoglobulin crossover (also known as Fab domain exchange or CrossMab format) technology (see e.g., W02009/080253; Schaefer et al., Proc. Natl. Acad. Sci. USA, 108:11187-11192 (2011 )). Multispecific antibodies may also be made by engineering electrostatic steering effects for making antibody Fc-heterodimeric molecules (WO 2009/089004A1 ); cross-linking two or more antibodies or fragments (see, e.g., US Patent No.
  • An amino acid residue in the CH3 domain of the second Fc subunit may be replaced with an amino acid residue having a larger side chain volume, thereby generating a protuberance (e.g., a knob) within the CH3 domain of the second Fc subunit which is positionable in a cavity (e.g., a hole) within the CH3 domain of the first Fc subunit, and an amino acid residue in the CH3 domain of the first Fc subunit may be replaced with an amino acid residue having a smaller side chain volume, thereby generating a cavity (e.g., a hole) within the CH3 domain of the first Fc subunit within which the protuberance (e.g., a knob) within the CH3 domain of the second Fc subunit may be positionable.
  • a protuberance e.g., a knob
  • the CH3 domain of the second Fc subunit comprises the amino acid substitution of T366, and the CH3 domain of the first Fc subunit comprises amino acid substitutions at one, two, or all three of T366, L368, and/or Y407 (all EU numbering).
  • the CH3 domain of the second Fc subunit comprises the amino acid substitution of T366W
  • the CH3 domain of the first Fc subunit comprises one, two, or all three amino acid substitutions of T366S, L368A, and/or Y407V (all EU numbering).
  • the multispecific antigen-binding molecule described herein comprises 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.
  • the multispecific antigen-binding molecule described herein comprises 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.
  • the multispecific antigen-binding molecule described herein comprises a) a first heavy chain/light chain pair binding to a first antigen which comprises a first heavy chain polypeptide (H1 ) and a first light chain polypeptide (L1 ), and b) a second heavy chain/light chain pair binding to a second antigen which comprises 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 each L1 and L2 comprises a light chain variable domain (VL) and a light chain constant domain (VL), wherein: (i) an amino acid at S183 (EU numbering) in the CH1 domain of H1 is replaced with a positively charged residue, an amino acid at Q39 (Kabat numbering) in the VH domain of H1 is replaced with a negatively charged residue, an amino acid at V133 (EU numbering) in the CL domain of L1
  • the positively charged residue is selected from R and K and the negatively charged residue is selected from D and E.
  • the positively charged residue is R.
  • the positively charged residue is K.
  • the negatively charged residue is D.
  • the negatively charged residue is E.
  • the first antigen is STEAP1 and the second antigen is CD3.
  • the first antigen is CD3 and the second antigen is STEAP1 .
  • the multispecific antigen-binding molecule described herein comprises 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 H1 and H2 comprises a heavy chain variable domain (VH) and a heavy chain constant domain (CH1 ), and each L1 and L2 comprises a light chain variable domain (VL) and a light chain constant domain (VL), wherein: (i) an amino acid at S183 (EU numbering) in the CH1 domain of H1 is replaced with an R or K residue, an amino acid at Q39 (Kabat numbering) in the VH domain of H1 is replaced with a D or E residue, an amino acid at V133 (EU numbering) in the CL domain of L1 is replaced with a D or E residue, and an amino acid at Q38 (Kabat
  • the multispecific antigen-binding molecule described herein comprises 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 H1 and H2 comprises a heavy chain variable domain (VH) and a heavy chain constant domain (CH1 ), and each L1 and L2 comprises a light chain variable domain (VL) and a light chain constant domain (VL), wherein: (i) an amino acid at S183 (EU numbering) in the CH1 domain of H1 is replaced with a K residue, an amino acid at Q39 (Kabat numbering) in the VH domain of H1 is replaced with an E residue, an amino acid at V133 (EU numbering) in the CL domain of L1 is replaced with an E residue, and an amino acid at Q38 (Kabat numbering) in the VL domain of L
  • the multispecific antigen-binding molecule described herein comprises an anti-CD3 arm comprising a first heavy chain polypeptide (H1 ) and a first light chain polypeptide (L1 ), and an anti-STEAP1 arm 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 each L1 and L2 comprises a light chain variable domain (VL) and a light chain constant domain (VL), wherein: (i) an amino acid at S183 (EU numbering) in the CH1 domain of H1 is replaced with an R or K residue, an amino acid at Q39 (Kabat numbering) in the VH domain of H1 is replaced with a D or E residue, an amino acid at V133 (EU numbering) in the CL domain of L1 is replaced with a D or E residue, and an amino acid at Q38 (Kabat
  • the multispecific antigen-binding molecule described herein comprises an anti-CD3 arm comprising a first heavy chain polypeptide (H1 ) and a first light chain polypeptide (L1 ), and an anti-STEAP1 arm 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 each L1 and L2 comprises a light chain variable domain (VL) and a light chain constant domain (VL), wherein: (i) an amino acid at S183 (EU numbering) in the CH1 domain of H1 is replaced with a K residue, an amino acid at Q39 (Kabat numbering) in the VH domain of H1 is replaced with an E residue, an amino acid at V133 (EU numbering) in the CL domain of L1 is replaced with an E residue, and an amino acid at Q38 (Kabat numbering) in the VL domain of L
  • the multispecific antigen-binding molecule described herein comprises an anti-STEAP1 arm comprising Q39K (Kabat numbering) and S183E (EU numbering) substitutions in the heavy chain and Q38E (Kabat numbering) and V133K (EU numbering) substitutions in the light chain; and an anti-CD3 arm comprising a Q39E (Kabat numbering) substitution in the heavy chain and a Q38K (Kabat numbering) substitution in the light chain.
  • the multispecific antigen-binding molecule described herein comprises an anti-CD3 arm comprising Q39K (Kabat numbering) and S183E (EU numbering) substitutions in the heavy chain and Q38E (Kabat numbering) and V133K (EU numbering) substitutions in the light chain; and an anti-STEAP1 arm comprising a Q39E (Kabat numbering) substitution in the heavy chain and a Q38K (Kabat numbering) substitution in the light chain.
  • the multispecific antigen-binding molecule described herein comprises an anti-STEAP1 arm comprising Q39E (Kabat numbering) and S183K (EU numbering) substitutions in the heavy chain and Q38K (Kabat numbering) and V133E (EU numbering) substitutions in the light chain; and an anti-CD3 arm comprising a Q39K (Kabat numbering) substitution in the heavy chain and a Q38E (Kabat numbering) substitution in the light chain.
  • the multispecific antigen-binding molecule described herein comprises an anti-CD3 arm comprising Q39E (Kabat numbering) and S183K (EU numbering) substitutions in the heavy chain and Q38K (Kabat numbering) and V133E (EU numbering) substitutions in the light chain; and an anti-STEAP1 arm comprising a Q39K (Kabat numbering) substitution in the heavy chain and a Q38E (Kabat numbering) substitution in the light chain.
  • the multispecific antigen-binding molecule described herein comprises a) a first heavy chain/light chain pair binding to a first antigen which comprises a first heavy chain polypeptide (H1 ) and a first light chain polypeptide (L1 ), and b) a second heavy chain/light chain pair binding to a second antigen which comprises 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 each L1 and L2 comprises a light chain variable domain (VL) and a light chain constant domain (VL), wherein: (i) an amino acid at S183 (EU numbering) in the CH1 domain of H1 is replaced with a positively charged residue, an amino acid at Q39 (Kabat numbering) in the VH domain of H1 is replaced with a negatively charged residue, an amino acid at V133 (EU numbering) in the CL domain of L1
  • the positively charged residue is selected from R and K and the negatively charged residue is selected from D and E.
  • the positively charged residue is R.
  • the positively charged residue is K.
  • the negatively charged residue is D.
  • the negatively charged residue is E.
  • the first antigen is STEAP1 and the second antigen is CD3.
  • the first antigen is CD3 and the second antigen is STEAP1 .
  • the multispecific antigen-binding molecule described herein comprises 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 H1 and H2 comprises a heavy chain variable domain (VH) and a heavy chain constant domain (CH1 ), and each L1 and L2 comprises a light chain variable domain (VL) and a light chain constant domain (VL), wherein: (i) an amino acid at S183 (EU numbering) in the CH1 domain of H1 is replaced with an R or K residue, an amino acid at Q39 (Kabat numbering) in the VH domain of H1 is replaced with a D or E residue, an amino acid at V133 (EU numbering) in the CL domain of L1 is replaced with a D or E residue, an amino acid at Q38 (Kabat number
  • the multispecific antigen-binding molecule described herein comprises 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 H1 and H2 comprises a heavy chain variable domain (VH) and a heavy chain constant domain (CH1 ), and each L1 and L2 comprises a light chain variable domain (VL) and a light chain constant domain (VL), wherein: (i) an amino acid at S183 (EU numbering) in the CH1 domain of H1 is replaced with a K residue, an amino acid at Q39 (Kabat numbering) in the VH domain of H1 is replaced with an E residue, an amino acid at V133 (EU numbering) in the CL domain of L1 is replaced with an E residue, an amino acid at Q38 (Kabat numbering) in the VL domain
  • the multispecific antigen-binding molecule described herein comprises an anti-CD3 arm comprising a first heavy chain polypeptide (H1 ) and a first light chain polypeptide (L1 ), and an anti-STEAP1 arm 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 each L1 and L2 comprises a light chain variable domain (VL) and a light chain constant domain (VL), wherein: (i) an amino acid at S183 (EU numbering) in the CH1 domain of H1 is replaced with an R or K residue, an amino acid at Q39 (Kabat numbering) in the VH domain of H1 is replaced with a D or E residue, an amino acid at V133 (EU numbering) in the CL domain of L1 is replaced with a D or E residue, an amino acid at Q38 (Kabat
  • the multispecific antigen-binding molecule described herein comprises an anti-CD3 arm comprising a first heavy chain polypeptide (H1 ) and a first light chain polypeptide (L1 ), and an anti-STEAP1 arm 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 each L1 and L2 comprises a light chain variable domain (VL) and a light chain constant domain (VL), wherein: (i) an amino acid at S183 (EU numbering) in the CH1 domain of H1 is replaced with a K residue, an amino acid at Q39 (Kabat numbering) in the VH domain of H1 is replaced with an E residue, an amino acid at V133 (EU numbering) in the CL domain of L1 is replaced with an E residue, an amino acid at Q38 (Kabat numbering) in the VL domain
  • the multispecific antigen-binding molecule described herein comprises an anti-STEAP1 arm comprising Q39K (Kabat numbering) and S183E (EU numbering) substitutions in the heavy chain and Q38E (Kabat numbering) and V133K (EU numbering) substitutions in the light chain; and an anti-CD3 arm comprising a Q39E (Kabat numbering) substitution and an S183K (EU numbering) substitution in the heavy chain and a Q38K (Kabat numbering) substitution and a V133E (EU numbering) substitution in the light chain.
  • the multispecific antigen-binding molecule described herein comprises an anti-CD3 arm comprising Q39K (Kabat numbering) and S183E (EU numbering) substitutions in the heavy chain and Q38E (Kabat numbering) and V133K (EU numbering) substitutions in the light chain; and an anti-STEAP1 arm comprising a Q39E (Kabat numbering) substitution and an S183K (EU numbering) substitution in the heavy chain and a Q38K (Kabat numbering) substitution and a V133E (EU numbering) substitution in the light chain.
  • the multispecific antigen-binding molecule described herein comprises an anti-STEAP1 arm comprising Q39E (Kabat numbering) and S183K (EU numbering) substitutions in the heavy chain and Q38K (Kabat numbering) and V133E (EU numbering) substitutions in the light chain; and an anti-CD3 arm comprising a Q39K (Kabat numbering) substitution and an S183E (EU numbering) substitution in the heavy chain and a Q38E (Kabat numbering) substitution and a V133K (EU numbering) substitution in the light chain.
  • the multispecific antigen-binding molecule described herein comprises an anti-CD3 arm comprising Q39E (Kabat numbering) and S183K (EU numbering) substitutions in the heavy chain and Q38K (Kabat numbering) and V133E (EU numbering) substitutions in the light chain; and an anti-STEAP1 arm comprising a Q39K (Kabat numbering) substitution and an S183E (EU numbering) substitution in the heavy chain and a Q38E (Kabat numbering) substitution and a V133K (EU numbering) substitution in the light chain.
  • the multispecific antigen-binding molecule described herein comprises an anti-STEAP1 arm comprising S183K (EU numbering), N297G (EU numbering) and T366W (EU numbering) substitutions in the heavy chain constant region and V133E (EU numbering) substitution in the light chain constant region, and an anti-CD3 arm comprising S183E (EU numbering), N297G (EU numbering), T366S (EU numbering), L368A (EU numbering), and Y407V (EU numbering) substitutions in the heavy chain constant region and V133K (EU numbering) substitution in the light chain constant region.
  • an anti-STEAP1 arm comprising S183K (EU numbering), N297G (EU numbering) and T366W (EU numbering) substitutions in the heavy chain constant region and V133E (EU numbering) substitution in the light chain constant region
  • an anti-CD3 arm comprising S183E (EU numbering), N297G (EU numbering), T366S (EU numbering), L
  • the multispecific antigen-binding molecule described herein comprises an anti-STEAP1 arm comprising S183E (EU numbering), N297G (EU numbering), T366S (EU numbering), L368A (EU numbering), and Y407V (EU numbering) substitutions in the heavy chain constant region and V133K (EU numbering) substitution in the light chain constant region, and an anti-CD3 arm comprising S183K (EU numbering), N297G (EU numbering) and T366W (EU numbering) substitutions in the heavy chain constant region and V133E (EU numbering) substitution in the light chain constant region.
  • an anti-STEAP1 arm comprising S183E (EU numbering), N297G (EU numbering), T366S (EU numbering), L368A (EU numbering), and Y407V (EU numbering) substitutions in the heavy chain constant region and V133K (EU numbering) substitution in the light chain constant region
  • an anti-CD3 arm comprising S183K (EU numbering),
  • the multispecific antigen-binding molecule described herein comprises an anti-STEAP1 arm comprising Q39E (Kabat numbering), S183K (EU numbering), N297G (EU numbering) and T366W (EU numbering) substitutions in the heavy chain and Q38K (Kabat numbering) and V133E (EU numbering) substitutions in the light chain, and an anti-CD3 arm comprising Q39K (Kabat numbering), S183E (EU numbering), N297G (EU numbering), T366S (EU numbering), L368A (EU numbering), and Y407V (EU numbering) substitutions in the heavy chain and Q38E (Kabat numbering) and V133K (EU numbering) substitutions in the light chain.
  • the multispecific antigen-binding molecule described herein comprises an anti-STEAP1 arm comprising Q39K (Kabat numbering), S183E (EU numbering), N297G (EU numbering), T366S (EU numbering), L368A (EU numbering), and Y407V (EU numbering) substitutions in the heavy chain and Q38E (Kabat numbering) and V133K (EU numbering) substitutions in the light chain, and an anti- CD3 arm comprising Q39E (Kabat numbering), S183K (EU numbering), N297G (EU numbering) and T366W (EU numbering) substitutions in the heavy chain and Q38K (Kabat numbering) and V133E (EU numbering) substitutions in the light chain.
  • an anti-STEAP1 arm comprising Q39K (Kabat numbering), S183E (EU numbering), N297G (EU numbering), T366S (EU numbering), L368A (EU numbering), and Y407V (
  • antigen-binding molecules described herein for use in any of the instances enumerated herein may have any of the features, singly or in combination, described in Sections 1 -6 below.
  • an antigen-binding molecule e.g., monospecific and/or multispecific antigen-binding molecules such as bispecific or trispecific antigen-binding molecules
  • K D equilibrium dissociation constant
  • ⁇ 1 ⁇ M ⁇ 100 nM, ⁇ 10 nM, ⁇ 1 nM, ⁇ 0.1 nM, ⁇ 0.01 nM, or ⁇ 0.001 nM (e.g., 10 -8 M or less, e.g., from 10 -8 M to 10 -13 M, e.g., from 10 -9 M to 10 -13 M).
  • K D is measured by a radiolabeled antigen binding assay (RIA).
  • RIA radiolabeled antigen binding assay
  • an RIA is performed with the Fab version of an antigen-binding molecule of interest and its antigen.
  • solution binding affinity of Fabs for antigen is measured by equilibrating Fab with a minimal concentration of ( 125 l)-labeled antigen in the presence of a titration series of unlabeled antigen, then capturing bound antigen with an anti-Fab antibody-coated plate (see, e.g., Chen et al., J. Mol. Biol. 293:865-881 (1999)).
  • MICROTITER® multi-well plates (Thermo Scientific) are coated overnight with 5 pg/ml of a capturing anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and subsequently blocked with 2% (w/v) bovine serum albumin in PBS for two to five hours at room temperature (about 23°C).
  • a non-adsorbent plate (Nunc #269620) 100 pM or 26 pM [ 125 l]-antigen are mixed with serial dilutions of a Fab of interest (e.g., consistent with assessment of the anti-VEGF antibody, Fab-12, in Presta et al., Cancer Res.
  • the Fab of interest is then incubated overnight; however, the incubation may continue for a longer period (e.g., about 65 hours) to ensure that equilibrium is reached. Thereafter, the mixtures are transferred to the capture plate for incubation at room temperature (e.g., for one hour). The solution is then removed and the plate washed eight times with 0.1% polysorbate 20 (TWEEN-20®) in PBS. When the plates have dried, 150 pl/well of scintillant (MICROSCINT-20TM; Packard) is added, and the plates are counted on a TOPCOUNTTM gamma counter (Packard) for ten minutes. Concentrations of each Fab that give less than or equal to 20% of maximal binding are chosen for use in competitive binding assays.
  • K D is measured using a BIACORE® surface plasmon resonance assay.
  • a BIACORE®-2000 or a BIACORE®-3000 BIACORE®, Inc., Piscataway, NJ
  • CM5 chips immobilized antigen CM5 chips at ⁇ 10 response units (RU).
  • CM5 chips carboxymethylated dextran biosensor chips (CM5, BIACORE®, Inc.) are activated with A/-ethyl-A/-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N- hydroxysuccinimide (NHS) according to the supplier’s instructions.
  • EDC A/-ethyl-A/-(3-dimethylaminopropyl)-carbodiimide hydrochloride
  • NHS N- hydroxysuccinimide
  • Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 pg/ml ( ⁇ 0.2 pM) before injection at a flow rate of 5 pl/minute to achieve about 10 response units (RU) of coupled protein. Following the injection of antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetics measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% polysorbate 20 (TWEEN-20TM) surfactant (PBST) at 25°C at a flow rate of about 25 pl/min.
  • TWEEN-20TM polysorbate 20
  • association rates (k on ) and dissociation rates (k off ) are calculated using a simple one-to-one Langmuir binding model (BIACORE® Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams.
  • the equilibrium dissociation constant (K D ) is calculated as the ratio koff/k on . See, for example, Chen et al., J. Mol. Biol. 293:865-881 (1999).
  • K D is measured by Kinetic Exclusion Assay (KinExA®), which can be performed by Sapidyne Instruments.
  • KinExA® Kinetic Exclusion Assay
  • the Kinetic Exclusion Assay (KinExA®) measures the equilibrium binding affinity and kinetics in solution.
  • the K D is measured with human STEAP1 .
  • the K D is measured with cynomolgus STEAP1 .
  • an anti- STEAP1/CD3 TDB described herein has a K D for human STEAP1 of 0.01 -1 nM, or 1 -10 nM, or I Q- 100 nM, or 100-1 ,000 nM.
  • an anti-STEAP1/CD3 TDB described herein has a K D for cynomolgus STEAP1 of 0.01 -1 nM, or 1 -10 nM, or 10-100 nM, or 100-1 ,000 nM.
  • an anti-STEAP1/CD3 TDB described herein has a k a for human STEAP1 of 100-1 ,000 M- 1 S 1 , or 1 ,000-10,000 M -1 S 1 , or 10,000-100,000 M -1 S 1 , or 100,000-1 ,000,000 M -1 S -1 .
  • an anti-STEAP1/CD3 TDB described herein has a k a for cynomolgus STEAP1 of 100- 1 ,000 M- 1 S 1 , or 1 ,000-10,000 M -1 S 1 , or 10,000-100,000 M -1 S 1 , or 100,000-1 ,000,000 M -1 S -1 .
  • an anti-STEAP1/CD3 TDB described herein has a kd for human STEAP1 of 0.0001 - 0.001 S -1 , 0.001 -0.01 S -1 , or 0.01 -0.1 S -1 , or 0.1 -1 S -1 .
  • an anti-STEAP1/CD3 TDB described herein has a kd for cynomolgus STEAP1 of 0.0001 -0.001 S -1 , 0.001 -0.01 S -1 , or 0.01 - 0.1 S -1 , or 0.1 -1 S -1 .
  • an antigen-binding molecule provided herein includes one or more antibody fragments.
  • Antibody fragments include, but are not limited to, Fab, Fab’, Fab’-SH, F(ab’) 2 , Fv, Fd, single-chain Fv (scFv), single-chain Fab fragment (scFab), trispecific (Fabs), bispecific (Fab2), diabody ((VL-VH) 2 or (VH-VL) 2 ), triabody (trivalent), tetrabody (tetravalent), minibody ((SCFV-CH) 2 ), bispecific single-chain Fv (Bis-scFv), lgGdeltaCH2, scFv-Fc, or (scFv) 2 -Fc, and other fragments described below.
  • an antigen-binding molecule provided herein includes a multispecific antigen-binding molecule.
  • a multispecific antigen-binding molecule provided herein is a multispecific antibody, e.g., a bispecific antibody or a trispecific antibody. “In certain aspects, the multispecific antibody is a bispecific antibody. In certain aspects, the multispecific antibody has three or more binding specificities. In certain aspects, one of the binding specificities is for STEAP1 and the other specificity is for any other antigen (e.g., CD3).
  • Multispecific (e.g., bispecific or trispecific) antibodies may also be used to localize cytotoxic agents or cells to cells which express STEAP1 . Multispecific antibodies may be prepared as full length antibodies or antibody fragments.
  • a multispecific antibody described herein is a bispecific antibody, designed to simultaneously bind to a surface antigen on a target cell, e.g., a tumor cell, and to an activating, invariant component of the T cell receptor (TCR) complex, such as CD3, for retargeting of T cells to kill target cells.
  • TCR T cell receptor
  • an antibody provided herein is a multispecific antibody, particularly a bispecific antibody, wherein one of the binding specificities is for STEAP1 and the other is for CD3.
  • bispecific antibody formats examples include, but are not limited to, the so-called “BiTE” (bispecific T cell engager) molecules wherein two scFv molecules are fused by a flexible linker (see, e.g., WO 2004/106381 , WO 2005/061547, WO 2007/042261 , and WO 2008/119567, Nagorsen and Bauerle, Exp. Cell Res. 317, 1255-1260 (2011 )); diabodies (Holliger et al., Prot. Eng. 9, 299-305 (1996)) and derivatives thereof, such as tandem diabodies (“TandAb”; Kipriyanov et al., J. Mol. Biol.
  • Additional multispecific antibody formats include diabodies, antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993/01161 ; Hudson et al. Nat. Med. 9:129-134 (2003); and Hollinger et al. Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al. Nat. Med. 9:129-134 (2003).
  • Multispecific antibodies may also be provided in an asymmetric form with a domain crossover in one or more binding arms of the same antigen specificity, i.e., by exchanging the VH/VL domains (see e.g., WO 2009/080252 and WO 2015/150447), the CH1/CL domains (see e.g., WO 2009/080253) or the complete Fab arms (see e.g., WO 2009/080251 , WO 2016/016299, also see Schaefer et al., Proc. Natl. Acad. Sci. USA 108: 1187-1191 (2011 ), and Klein et al., MAbs 8:1010-20 (2016)).
  • the multispecific antibody comprises a cross-Fab fragment.
  • Engineered antibodies with three or more antigen binding sites including for example, “Octopus antibodies,” or DVD-lg are also included herein (see, e.g., WO 2001/77342 and WO 2008/024715).
  • Other examples of multispecific antibodies with three or more antigen binding sites can be found in WO 2010/1 15589, WO 2010/1 12193, WO 2010/136172, WO 2010/145792, and WO 2013/026831 .
  • the bispecific antibody or antigen binding fragment thereof also includes a “Dual Acting FAb” or “DAF” comprising an antigen binding site that binds to STEAP1 as well as another different antigen, e.g., to CD3 (see, e.g., US 2008/0069820 and WO 2015/095539).
  • Multispecific antibodies include, but are not limited to, recombinant co- expression of two immunoglobulin heavy chain-light chain pairs having different specificities (see Milstein and Cuello, Nature 305:537 (1983)) and “knob-in-hole” engineering (see, e.g., U.S. Patent No. 5,731 ,168, and Atwell et al., J. Mol. Biol. 270:26 (1997)).
  • Multi-specific antibodies may also be made by engineering electrostatic steering effects for making antibody Fc-heterodimeric molecules (see, e.g., WO 2009/089004); cross-linking two or more antibodies or fragments (see, e.g., U.S. Patent No.
  • an antigen-binding molecule provided herein is a chimeric antibody.
  • Certain chimeric antibodies are described, e.g., in U.S. Patent No. 4,816,567; and Morrison et al. Proc. Natl. Acad. Sci. USA, 81 :6851 -6855 (1984)).
  • a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region.
  • a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.
  • a chimeric antibody is a humanized antibody.
  • a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody.
  • a humanized antibody comprises one or more variable domains in which HVRs, e.g., CDRs, (or portions thereof) are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences.
  • HVRs e.g., CDRs, (or portions thereof) are derived from a non-human antibody
  • FRs or portions thereof
  • a humanized antibody optionally will also comprise at least a portion of a human constant region.
  • some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the CDR/HVR residues are derived), e.g., to restore or improve antibody specificity or affinity.
  • a non-human antibody e.g., the antibody from which the CDR/HVR residues are derived
  • Human framework regions that may be used for humanization include but are not limited to: framework regions selected using the “best-fit” method (see, e.g., Sims et al. J. Immunol. 151 :2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151 :2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci.
  • an antigen-binding molecule provided herein is a human antibody.
  • Human antibodies can be produced using various techniques known in the art. Human antibodies are described generally in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001 ) and Lonberg, Curr. Opin. Immunol. 20:450-459 (2008).
  • Human antibodies may be prepared by administering an immunogen to a transgenic animal that has been modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigenic challenge.
  • Such animals typically contain all or a portion of the human immunoglobulin loci, which replace the endogenous immunoglobulin loci, or which are present extrachromosomally or integrated randomly into the animal’s chromosomes.
  • the endogenous immunoglobulin loci have generally been inactivated.
  • Human antibodies may also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.
  • an antigen-binding molecule provided herein may include antibodies derived from a library.
  • Antibodies of the invention may be isolated by screening combinatorial libraries for antibodies with the desired activity or activities. Methods for screening combinatorial libraries are reviewed, e.g., in Lerner et al., Nature Reviews 16:498-508 (2016). For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies possessing the desired binding characteristics.
  • repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR) and recombined randomly in phage libraries, which can then be screened for antigen-binding phage as described in Winter et al., Ann. Rev. Immunol. 12: 433-455 (1994).
  • Phage typically display antibody fragments, either as single-chain Fv (scFv) fragments or as Fab fragments.
  • scFv single-chain Fv
  • Libraries from immunized sources provide high-affinity antibodies to the immunogen without the requirement of constructing hybridomas.
  • naive repertoire can be cloned (e.g., from human) to provide a single source of antibodies to a wide range of non-self and also self antigens without any immunization as described by Griffiths et al., EMBO Journal 12: 725-734 (1993).
  • naive libraries can also be made synthetically by cloning unrearranged V-gene segments from stem cells, and using PCR primers containing random sequence to encode the highly variable CDR3 regions and to accomplish rearrangement in vitro, as described by Hoogenboom and Winter, J. Mol. Biol. 227: 381 -388 (1992).
  • Patent publications describing human antibody phage libraries include, for example: U.S. Patent Nos. 5,750,373; 7,985,840; 7,785,903 and 8,679,490 as well as U.S. Patent Publication Nos. 2005/0079574, 2007/0117126, 2007/0237764 and 2007/0292936.
  • yeast surface display is reviewed, e.g., in Scholler et al., Methods Mol. Biol. 503:135-56 (2012) and in Cherf et al. in Methods Mol. Biol. 1319:155-175 (2015) as well as in Zhao et al., Methods Mol. Biol. 889:73-84 (2012).
  • Antibodies or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.
  • amino acid sequence variants of the antigen-binding molecules e.g., monospecific and/or multispecific antigen-binding molecules such as bispecific or trispecific antigen- binding molecules
  • amino acid sequence variants of an antigen-binding molecule may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antigen-binding molecule, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antigen-binding molecule. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, for example, antigen-binding.
  • an antigen-binding molecule e.g., monospecific and/or multispecific antigen-binding molecules such as bispecific or trispecific antigen-binding molecules
  • an antigen-binding molecule comprises one or more modifications in the VH/VL region and/or CH1/CL region to facilitate correct heavy/light chain pairing.
  • an antigen-binding molecule e.g., monospecific and/or multispecific antigen-binding molecules such as bispecific or trispecific antigen-binding molecules
  • modifications in the VH/VL region, CH1/CL region, and/or FC region are described in International Patent Publication No. WO 2016/172485, which is herein incorporated by reference in its entirety.
  • antigen-binding domain variants having one or more amino acid substitutions are provided.
  • Sites of interest for substitutional mutagenesis include the CDRs and FRs.
  • Conservative substitutions are shown in Table 4 under the heading of “preferred substitutions.” More substantial changes are provided in Table 4 under the heading of “exemplary substitutions,” and as further described below in reference to amino acid side chain classes.
  • Amino acid substitutions may be introduced into an antigen-binding molecule of interest and the products screened for a desired activity, for example, retained/improved antigen binding, decreased immunogenicity, or improved Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) or Complement Dependent Cytotoxicity (CDC).
  • ADCC Antibody-Dependent Cell-Mediated Cytotoxicity
  • CDC Complement Dependent Cytotoxicity
  • Amino acids may be grouped according to common side-chain properties:
  • substitutional variant involves substituting one or more hypervariable region residues of a parent antigen-binding molecule (e.g., a humanized or human antibody).
  • a parent antigen-binding molecule e.g., a humanized or human antibody.
  • the resulting variant(s) selected for further study will have modifications (e.g., improvements) in certain biological properties (e.g., increased affinity and/or reduced immunogenicity) relative to the parent antigen-binding molecule and/or will have substantially retained certain biological properties of the parent antigen-binding molecule.
  • An exemplary substitutional variant is an affinity matured antibody, which may be conveniently generated, for example, using phage display-based affinity maturation techniques such as those described herein. Briefly, one or more CDR/HVR residues are mutated and the variant antibodies displayed on phage and screened for a particular biological activity (e.g., binding affinity).
  • Alterations may be made in CDRs/HVRs, e.g., to improve antibody affinity.
  • Such alterations may be made in CDR/HVR “hotspots,” i.e., residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or residues that contact antigen, with the resulting variant VH or VL being tested for binding affinity.
  • Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al., Methods Mol. Biol.
  • affinity maturation diversity is introduced into the variable genes chosen for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis).
  • a secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity.
  • Another method to introduce diversity involves CDR/HVR-directed approaches, in which several CDR/HVR residues (e.g., 4-6 residues at a time) are randomized.
  • CDR/HVR residues involved in antigen binding may be specifically identified, e.g., using alanine scanning mutagenesis or modeling.
  • CDR-H3 and CDR-L3 in particular are often targeted.
  • substitutions, insertions, or deletions may occur within one or more CDRs/HVRs so long as such alterations do not substantially reduce the ability of the antigen-binding molecule to bind antigen.
  • conservative alterations e.g., conservative substitutions as provided herein
  • Such alterations may, for example, be outside of antigen-contacting residues in the CDRs/HVRs.
  • each CDRs/HVR either is unaltered, or contains no more than one, two or three amino acid substitutions.
  • a useful method for identification of residues or regions of an antigen-binding molecule that may be targeted for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells Science, 244:1081 -1085 (1989).
  • a residue or group of target residues e.g., charged residues such as Arg, Asp, His, Lys, and Glu
  • a neutral or negatively charged amino acid e.g., alanine or polyalanine
  • a crystal structure of an antigen- antigen-binding molecule complex to identify contact points between the antigen-binding molecule and antigen.
  • Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution.
  • Variants may be screened to determine whether they contain the desired properties.
  • Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antigen-binding molecule with an N-terminal methionyl residue.
  • insertional variants of the antigen-binding molecule include the fusion to the N- or C-terminus of the antigen-binding molecule to an enzyme (e.g., for ADEPT) or a polypeptide which increases the serum half-life of the antigen-binding molecule.
  • an enzyme e.g., for ADEPT
  • a polypeptide which increases the serum half-life of the antigen-binding molecule.

Abstract

La présente invention concerne des molécules de liaison à l'antigène monospécifiques et multispécifiques et des compositions de celles-ci. L'invention concerne également des méthodes de traitement d'une maladie ou d'un trouble, tel que le cancer, des procédés d'inhibition de la croissance tumorale, ainsi que des kits destinés à être utilisés avec la ou les méthodes.
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