Antibodies and uses thereof

Abstract

The present disclosure relates to anti-PTK7 (Protein Tyrosine Kinase 7), its associated antigen binding fragments, antibody drug conjugates (ADCs) derived therefrom; an anti-TROP2 (trophoblast cell surface antigen 2) antibody, a related antigen binding fragment thereof, an antibody drug conjugate (ADC) derived therefrom; and anti-PTK7 / TROP2 (e.g., multispecific or bispecific) antibodies or antigen binding fragments thereof and antibody drug conjugates (ADCs) derived therefrom and uses thereof.

Description

[0001] CLAIM OF PRIORITY

[0002] This application claims priority to PCT / CN2023 / 083324 filed on March 23, 2023, PCT / CN2023 / 113943 filed on August 21, 2023, and PCT / CN2023 / 125451 filed on October 19, 2023, the entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0003] The present disclosure relates to antibodies, antigen-binding fragments thereof, and antibody drug conjugates (ADCs) derived therefrom. BACKGROUND

[0004] Cancer is currently one of the diseases that causes the highest mortality rate in humans. According to the statistics of the World Health Organization, in 2012, the global cancer incidence and death cases reached 14 million and 8.2 million, respectively. In China, the newly diagnosed cancer cases were 3.07 million, and the death number was 2.2 million. The recent success of anti-cancer antibodies in the clinic and in commerce has caused great interest in antibody-based therapeutic drugs.

[0005] Therefore, there is a need to develop antibodies for various antibody-based therapies to treat cancer. SUMMARY

[0006] The present disclosure relates to anti-PTK7, anti-TROP2, and / or anti-PTK7 / TROP2 antibodies, antigen-binding fragments thereof, and uses thereof.

[0007] In one aspect, the present disclosure relates to an antibody or antigen-binding fragment thereof that binds PTK7 (protein tyrosine kinase 7), comprising:

[0008] a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, wherein the VH CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR1 amino acid sequence, the VH CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR2 amino acid sequence, and the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR3 amino acid sequence; and

[0009] The system comprises light chain variable regions (VLs) including CDR1, 2, and 3, wherein the VL CDR1 region contains an amino acid sequence having at least 80% identity with a selected VL CDR1 amino acid sequence, the VL CDR2 region contains an amino acid sequence having at least 80% identity with a selected VL CDR2 amino acid sequence, and the VL CDR3 region contains an amino acid sequence having at least 80% identity with a selected VL CDR3 amino acid sequence.

[0010] The selected VH CDR1, 2, and 3 amino acid sequences and the selected VL CDR1, 2, and 3 amino acid sequences are one of the following:

[0011] (1) The selected VH CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NO:4-6, and the selected VLCDR1, 2, and 3 amino acid sequences are shown in SEQ ID NO:1-3, respectively;

[0012] (2) The selected VH CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NO:7-9, and the selected VLCDR1, 2, and 3 amino acid sequences are shown in SEQ ID NO:1-3, respectively;

[0013] (3) The selected VH CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NO:10-12, and the selected VLCDR1, 2, and 3 amino acid sequences are shown in SEQ ID NO:1-3, respectively;

[0014] (4) The selected VH CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NO:13-15, and the selected VLCDR1, 2, and 3 amino acid sequences are shown in SEQ ID NO:1-3, respectively.

[0015] (5) The selected VH CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NO:16-18, and the selected VLCDR1, 2, and 3 amino acid sequences are shown in SEQ ID NO:1-3, respectively.

[0016] (6) The selected VH CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NO:19-21, and the selected VLCDR1, 2, and 3 amino acid sequences are shown in SEQ ID NO:1-3, respectively.

[0017] (7) The selected VH CDR1, 2, and 3 amino acid sequences are shown in SEQ ID NO:22-24, and the selected VLCDR1, 2, and 3 amino acid sequences are shown in SEQ ID NO:1-3, respectively;

[0018] (8) the selected VH CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 25-27, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 1-3, respectively;

[0019] (9) the selected VH CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 28-30, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 1-3, respectively;

[0020] (10) the selected VH CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 31-33, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 1-3, respectively;

[0021] (11) the selected VH CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 34-36, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 1-3, respectively;

[0022] (12) the selected VH CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 37-39, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 1-3, respectively;

[0023] (13) the selected VH CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 40-42, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 1-3, respectively;

[0024] (14) the selected VH CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 43-45, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 1-3, respectively;

[0025] (15) the selected VH CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 86-88, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 1-3, respectively; and

[0026] (16) the selected VH CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 89-91, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are identified as SEQ ID NOs: 1-3, respectively.

[0027] In some embodiments, the VH comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 4-6, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

[0028] In some embodiments, the VH comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 7-9, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

[0029] In some embodiments, the VH comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 10-12, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

[0030] In some embodiments, the VH comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 13-15, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

[0031] In some embodiments, the VH comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 16-18, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

[0032] In some embodiments, the VH comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 19-21, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

[0033] In some embodiments, the VH comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 22-24, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

[0034] In some embodiments, the VH includes CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 86-88, respectively, and the VL includes CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

[0035] In some embodiments, the VH includes CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 25-27, respectively, and the VL includes CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Chothia definition.

[0036] In some embodiments, the VH includes CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 28-30, respectively, and the VL includes CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Chothia definition.

[0037] In some embodiments, the VH includes CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 31-33, respectively, and the VL includes CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Chothia definition.

[0038] In some embodiments, the VH includes CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 34-36, respectively, and the VL includes CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Chothia definition.

[0039] In some embodiments, the VH includes CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 37-39, respectively, and the VL includes CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Chothia definition.

[0040] In some embodiments, the VH includes CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 40-42, respectively, and the VL includes CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Chothia definition.

[0041] In some embodiments, the VH comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 43-45, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Chothia definition.

[0042] In some embodiments, the VH comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 89-91, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Chothia definition.

[0043] In some embodiments, the antibody or antigen-binding fragment thereof specifically binds human, monkey, or dog PTK7.

[0044] In some embodiments, the antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment thereof, a single chain variable fragment (scFv), a one-armed antibody, and / or a multi-specific antibody (e.g., a bispecific antibody).

[0045] In some embodiments, the antibody or antigen-binding fragment is a human IgGl antibody or antigen-binding fragment thereof, a human IgG2 antibody or antigen-binding fragment thereof, or a human IgG4 antibody or antigen-binding fragment thereof.

[0046] In one aspect, the disclosure relates to a nucleic acid comprising a polynucleotide encoding a polypeptide comprising:

[0047] (1) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 having the amino acid sequences set forth in SEQ ID NOs: 4-6, respectively, and wherein the VH binds PTK7 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53;

[0048] (2) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 having the amino acid sequences set forth in SEQ ID NOs: 25-27, respectively, and wherein the VH binds PTK7 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53;

[0049] (3) an immunoglobulin light chain or fragment thereof comprising a VL comprising complementarity determining regions (CDRs) 1, 2, and 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, and wherein the VL binds PTK7 when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 46;

[0050] (4) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 7-9, and wherein said VH binds PTK7 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53;

[0051] (5) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 28-30, and wherein said VH binds PTK7 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53;

[0052] (6) an immunoglobulin light chain or fragment thereof comprising a VL comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3, and wherein said VL binds PTK7 when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 47;

[0053] (7) an immunoglobulin heavy chain or fragment thereof comprising a VH comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 10-12, and wherein said VH binds PTK7 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53;

[0054] (8) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 31-33, and wherein said VH binds PTK7 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53;

[0055] (9) an immunoglobulin light chain or fragment thereof comprising a VL comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3, and wherein said VL binds PTK7 when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 48;

[0056] (10) an immunoglobulin heavy chain or fragment thereof comprising a VH comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences as set forth in SEQ ID NOs: 13-15, and wherein the VH binds to PTK7 when paired with a light chain variable region (VL) comprising an amino acid sequence as set forth in SEQ ID NO: 53;

[0057] (11) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences as set forth in SEQ ID NOs: 34-36, and wherein the VH binds to PTK7 when paired with a light chain variable region (VL) comprising an amino acid sequence as set forth in SEQ ID NO: 53;

[0058] (12) an immunoglobulin light chain or fragment thereof comprising a VL comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences as set forth in SEQ ID NOs: 1-3, and wherein the VL binds to PTK7 when paired with a VH comprising an amino acid sequence as set forth in SEQ ID NO: 49;

[0059] (13) an immunoglobulin heavy chain or fragment thereof comprising a VH comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences as set forth in SEQ ID NOs: 16-18, and wherein the VH binds to PTK7 when paired with a light chain variable region (VL) comprising an amino acid sequence as set forth in SEQ ID NO: 53;

[0060] (14) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences as set forth in SEQ ID NOs: 37-39, and wherein the VH binds to PTK7 when paired with a light chain variable region (VL) comprising an amino acid sequence as set forth in SEQ ID NO: 53;

[0061] (15) an immunoglobulin light chain or fragment thereof comprising a VL comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences as set forth in SEQ ID NOs: 1-3, and wherein the VL binds to PTK7 when paired with a VH comprising an amino acid sequence as set forth in SEQ ID NO: 50;

[0062] (16) an immunoglobulin heavy chain or fragment thereof comprising a VH comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences as set forth in SEQ ID NOs: 19-21, and wherein the VH binds to PTK7 when paired with a light chain variable region (VL) comprising an amino acid sequence as set forth in SEQ ID NO: 53;

[0063] (17) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 40-42, and wherein said VH pairs with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53 to bind PTK7;

[0064] (18) an immunoglobulin light chain or fragment thereof comprising a VL comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3, and wherein said VL pairs with a VH comprising the amino acid sequence set forth in SEQ ID NO: 51 to bind PTK7;

[0065] (19) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 22-24, and wherein said VH pairs with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53 to bind PTK7;

[0066] (20) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 43-45, and wherein said VH pairs with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53 to bind PTK7;

[0067] (21) an immunoglobulin light chain or fragment thereof comprising a VL comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3, and wherein said VL pairs with a VH comprising the amino acid sequence set forth in SEQ ID NO: 52 to bind PTK7;

[0068] (22) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 86-88, and wherein said VH pairs with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53 to bind PTK7;

[0069] (23) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 89-91, and wherein the VH pairs with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53 when binding to PTK7; and

[0070] (24) an immunoglobulin light chain or fragment thereof comprising a VL comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3, and wherein the VL pairs with a VH comprising the amino acid sequence set forth in SEQ ID NO: 92 when binding to PTK7.

[0071] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin light chain or fragment thereof comprising a VL comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3.

[0072] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 4-6.

[0073] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 7-9.

[0074] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 10-12.

[0075] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 13-15.

[0076] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 16-18.

[0077] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VHcomprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 19-21, respectively.

[0078] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VHcomprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 22-24, respectively.

[0079] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VHcomprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 25-27, respectively.

[0080] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VHcomprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 28-30, respectively.

[0081] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VHcomprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 31-33, respectively.

[0082] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VHcomprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 34-36, respectively.

[0083] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VHcomprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 37-39, respectively.

[0084] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VHcomprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 40-42, respectively.

[0085] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VHcomprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 43-45, respectively.

[0086] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VHcomprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 86-88, respectively.

[0087] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VHcomprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 89-91, respectively.

[0088] In some embodiments, the VH, when paired with a VL, or the VL, when paired with a VH, specifically binds human, monkey, or dog PTK7.

[0089] In some embodiments, the immunoglobulin heavy chain or fragment thereof is a human immunoglobulin heavy chain or fragment thereof (e.g., a human IgGl heavy chain or fragment thereof, a human IgG2 heavy chain or fragment thereof, or a human IgG4 heavy chain or fragment thereof), and the immunoglobulin light chain or fragment thereof is a human immunoglobulin light chain or fragment thereof.

[0090] In some embodiments, the nucleic acid encodes a single-chain variable fragment (scFv), a one-armed antibody, a multi-specific antibody (e.g., a bispecific antibody), or a chimeric antigen receptor (CAR).

[0091] In some embodiments, the nucleic acid is a cDNA.

[0092] In an aspect, the disclosure relates to a vector comprising one or more nucleic acids described herein.

[0093] In an aspect, the disclosure relates to a vector comprising two nucleic acids described herein, wherein the vector encodes a VL region and a VH region that collectively bind PTK7.

[0094] In an aspect, the disclosure relates to a pair of vectors, wherein each vector comprises a nucleic acid described herein, the pair of vectors collectively encoding a VL region and a VH region that collectively bind PTK7.

[0095] In an aspect, the disclosure relates to a cell comprising a vector described herein, or a pair of vectors described herein.

[0096] In some embodiments, the cell is a CHO cell.

[0097] In one aspect, the disclosure relates to a cell comprising one or more nucleic acids described herein.

[0098] In one aspect, the disclosure relates to a cell comprising two nucleic acids described herein.

[0099] In some embodiments, the two nucleic acids collectively encode a VL region and a VH region that collectively bind PTK7.

[0100] In one aspect, the disclosure relates to a method of producing an antibody or antigen binding fragment thereof, the method comprising

[0101] (a) culturing a cell described herein under conditions sufficient for the cell to produce the antibody or antigen binding fragment; and

[0102] (b) collecting the antibody or antigen binding fragment produced by the cell.

[0103] In one aspect, the disclosure relates to an antibody or antigen binding fragment thereof that binds PTK7, the antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90% identical to a selected VH sequence; and a light chain variable region (VL) comprising an amino acid sequence that is at least 90% identical to a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of:

[0104] (1) the selected VH sequence is SEQ ID NO: 46 and the selected VL sequence is SEQ ID NO: 53;

[0105] (2) the selected VH sequence is SEQ ID NO: 47 and the selected VL sequence is SEQ ID NO: 53;

[0106] (3) the selected VH sequence is SEQ ID NO: 48 and the selected VL sequence is SEQ ID NO: 53;

[0107] (4) the selected VH sequence is SEQ ID NO: 49 and the selected VL sequence is SEQ ID NO: 53;

[0108] (5) the selected VH sequence is SEQ ID NO: 50 and the selected VL sequence is SEQ ID NO: 53;

[0109] (6) the selected VH sequence is SEQ ID NO: 51, and the selected VL sequence is SEQ ID NO: 53;

[0110] (7) the selected VH sequence is SEQ ID NO: 52, and the selected VL sequence is SEQ ID NO: 53; and

[0111] (8) the selected VH sequence is SEQ ID NO: 92, and the selected VL sequence is SEQ ID NO: 53.

[0112] In some embodiments, the VH comprises the sequence of SEQ ID NO: 46, and the VL comprises the sequence of SEQ ID NO: 53.

[0113] In some embodiments, the VH comprises the sequence of SEQ ID NO: 47, and the VL comprises the sequence of SEQ ID NO: 53.

[0114] In some embodiments, the VH comprises the sequence of SEQ ID NO: 48, and the VL comprises the sequence of SEQ ID NO: 53.

[0115] In some embodiments, the VH comprises the sequence of SEQ ID NO: 49, and the VL comprises the sequence of SEQ ID NO: 53.

[0116] In some embodiments, the VH comprises the sequence of SEQ ID NO: 50, and the VL comprises the sequence of SEQ ID NO: 53.

[0117] In some embodiments, the VH comprises the sequence of SEQ ID NO: 51, and the VL comprises the sequence of SEQ ID NO: 53.

[0118] In some embodiments, the VH comprises the sequence of SEQ ID NO: 52, and the VL comprises the sequence of SEQ ID NO: 53.

[0119] In some embodiments, the VH comprises the sequence of SEQ ID NO: 92, and the VL comprises the sequence of SEQ ID NO: 53.

[0120] In an aspect, the present disclosure relates to an antibody or antigen-binding fragment thereof that binds PTK7, the antibody or antigen-binding fragment thereof comprising a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3 identical to the VH CDR1, VH CDR2, and VH CDR3 of a selected VH sequence; and a light chain variable region (VL) comprising a VL CDR1, a VL CDR2, and a VL CDR3 identical to the VL CDR1, VL CDR2, and VL CDR3 of a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following:

[0121] (1) the selected VH sequence is SEQ ID NO: 46, and the selected VL sequence is SEQ ID NO: 53;

[0122] (2) the selected VH sequence is SEQ ID NO: 47, and the selected VL sequence is SEQ ID NO: 53;

[0123] (3) the selected VH sequence is SEQ ID NO: 48, and the selected VL sequence is SEQ ID NO: 53;

[0124] (4) the selected VH sequence is SEQ ID NO: 49, and the selected VL sequence is SEQ ID NO: 53;

[0125] (5) the selected VH sequence is SEQ ID NO: 50, and the selected VL sequence is SEQ ID NO: 53;

[0126] (6) the selected VH sequence is SEQ ID NO: 51, and the selected VL sequence is SEQ ID NO: 53;

[0127] (7) the selected VH sequence is SEQ ID NO: 52, and the selected VL sequence is SEQ ID NO: 53; and

[0128] (8) the selected VH sequence is SEQ ID NO: 92, and the selected VL sequence is SEQ ID NO: 53.

[0129] In some embodiments, the antibody or antigen-binding fragment thereof specifically binds human, monkey, or dog PTK7.

[0130] In some embodiments, the antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment thereof, a single chain variable fragment (scFv), a one-armed antibody, and / or a multi-specific antibody (e.g., a bispecific antibody).

[0131] In some embodiments, the antibody or antigen-binding fragment is a human IgGl antibody or antigen-binding fragment thereof, a human IgG2 antibody or antigen-binding fragment thereof, or a human IgG4 antibody or antigen-binding fragment thereof.

[0132] In one aspect, the present disclosure relates to an antibody or antigen-binding fragment thereof that binds TROP2 (trophoblast cell-surface antigen 2), the antibody or antigen-binding fragment thereof comprising:

[0133] a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, wherein the VH CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR1 amino acid sequence, the VH CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR2 amino acid sequence, and the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR3 amino acid sequence; and

[0134] a light chain variable region (VL) comprising CDRs 1, 2, and 3, wherein the VL CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR1 amino acid sequence, the VL CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR2 amino acid sequence, and the VL CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR3 amino acid sequence,

[0135] wherein the selected VH CDR1, 2, and 3 amino acid sequences and the selected VL CDR1, 2, and 3 amino acid sequences are one of the following:

[0136] (1) the selected VH CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 57-59, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0137] (2) the selected VH CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 60-62, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0138] (3) the selected VH CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 66-68, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; and

[0139] (4) the selected VH CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 69-71, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively.

[0140] In some embodiments, the VH comprises CDRs 1, 2, 3, respectively, of the amino acid sequences set forth in SEQ ID NOs: 57-59, respectively, and the VL comprises CDRs 1, 2, 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

[0141] In some embodiments, the VH comprises CDRs 1, 2, 3, respectively, of the amino acid sequences set forth in SEQ ID NOs: 60-62, respectively, and the VL comprises CDRs 1, 2, 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

[0142] In some embodiments, the VH comprises CDRs 1, 2, 3, respectively, of the amino acid sequences set forth in SEQ ID NOs: 66-68, respectively, and the VL comprises CDRs 1, 2, 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Chothia definition.

[0143] In some embodiments, the VH comprises CDRs 1, 2, 3, respectively, of the amino acid sequences set forth in SEQ ID NOs: 69-71, respectively, and the VL comprises CDRs 1, 2, 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Chothia definition.

[0144] In some embodiments, the antibody or antigen-binding fragment thereof specifically binds human, monkey, or dog TROP2.

[0145] In some embodiments, the antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment thereof, a single chain variable fragment (scFv), a one-armed antibody, and / or a multi-specific antibody (e.g., a bispecific antibody).

[0146] In some embodiments, the antibody or antigen-binding fragment is a human IgGl antibody or antigen-binding fragment thereof, a human IgG2 antibody or antigen-binding fragment thereof, or a human IgG4 antibody or antigen-binding fragment thereof.

[0147] In one aspect, the disclosure relates to a nucleic acid comprising a polynucleotide encoding a polypeptide comprising:

[0148] (1) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 57-59, and wherein said VH binds TROP2 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53;

[0149] (2) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 66-68, and wherein said VH binds TROP2 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53;

[0150] (3) an immunoglobulin light chain or fragment thereof comprising a VL comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3, and wherein said VL binds TROP2 when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 73;

[0151] (4) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 60-62, and wherein said VH binds TROP2 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53;

[0152] (5) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 69-71, and wherein said VH binds TROP2 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53; and

[0153] (6) an immunoglobulin light chain or fragment thereof comprising a VL comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3, and wherein said VL binds TROP2 when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 74.

[0154] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin light chain or fragment thereof comprising a VL comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3.

[0155] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VHcomprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 57-59, respectively.

[0156] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VHcomprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 60-62, respectively.

[0157] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VHcomprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 66-68, respectively.

[0158] In some embodiments, the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VHcomprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 69-71, respectively.

[0159] In some embodiments, the VHspecifically binds to human, monkey, or dog TROP2 when paired with a VL, or the VLspecifically binds to human, monkey, or dog TROP2 when paired with a VH.

[0160] In some embodiments, the immunoglobulin heavy chain or fragment thereof is a human immunoglobulin heavy chain or fragment thereof (e.g., a human IgGl heavy chain or fragment thereof, a human IgG2 heavy chain or fragment thereof, or a human IgG4 heavy chain or fragment thereof), and the immunoglobulin light chain or fragment thereof is a human immunoglobulin light chain or fragment thereof.

[0161] In some embodiments, the nucleic acid encodes a single-chain variable fragment (scFv), a one-armed antibody, a multi-specific antibody (e.g., a bispecific antibody), or a chimeric antigen receptor (CAR).

[0162] In some embodiments, the nucleic acid is a cDNA.

[0163] In an aspect, the present disclosure relates to a vector comprising one or more nucleic acids described herein.

[0164] In an aspect, the present disclosure relates to a vector comprising two nucleic acids described herein, wherein the vector encodes a VLregion and a VHregion that collectively bind to TROP2.

[0165] In an aspect, the present disclosure relates to a pair of vectors, wherein each vector comprises a nucleic acid described herein, the pair of vectors collectively encoding a VL region and a VH region that collectively bind TROP2.

[0166] In an aspect, the present disclosure relates to a cell comprising a vector described herein, or a pair of vectors described herein.

[0167] In some embodiments, the cell is a CHO cell.

[0168] In an aspect, the present disclosure relates to a cell comprising one or more nucleic acids described herein.

[0169] In an aspect, the present disclosure relates to a cell comprising two nucleic acids described herein.

[0170] In some embodiments, the two nucleic acids collectively encode a VL region and a VH region that collectively bind TROP2.

[0171] In an aspect, the present disclosure relates to a method of producing an antibody or antigen binding fragment thereof, the method comprising

[0172] (c) culturing the cell under conditions sufficient for the cell to produce the antibody or antigen binding fragment described herein; and

[0173] (d) collecting the antibody or antigen binding fragment produced by the cell.

[0174] In an aspect, the present disclosure relates to an antibody or antigen binding fragment thereof that binds TROP2, the antibody or antigen binding fragment thereof comprising a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90% identical to a selected VH sequence; and a light chain variable region (VL) comprising an amino acid sequence that is at least 90% identical to a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of:

[0175] (1) the selected VH sequence is SEQ ID NO: 73, and the selected VL sequence is SEQ ID NO: 53; and

[0176] (2) the selected VH sequence is SEQ ID NO: 74, and the selected VL sequence is SEQ ID NO: 53.

[0177] In some embodiments, the VH comprises the sequence of SEQ ID NO: 73, and the VL comprises the sequence of SEQ ID NO: 53.

[0178] In some embodiments, the VH comprises the sequence of SEQ ID NO: 74, and the VL comprises the sequence of SEQ ID NO: 53.

[0179] In one aspect, the present disclosure relates to an antibody or antigen-binding fragment thereof that binds TROP2, comprising a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3 identical to a VH CDR1, a VH CDR2, and a VH CDR3 of a selected VH sequence; and a light chain variable region (VL) comprising a VL CDR1, a VL CDR2, and a VL CDR3 identical to a VL CDR1, a VL CDR2, and a VL CDR3 of a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following:

[0180] (1) the selected VH sequence is SEQ ID NO: 73, and the selected VL sequence is SEQ ID NO: 53; and

[0181] (2) the selected VH sequence is SEQ ID NO: 74, and the selected VL sequence is SEQ ID NO: 53.

[0182] In some embodiments, the antibody or antigen-binding fragment thereof specifically binds human, monkey, or dog TROP2.

[0183] In some embodiments, the antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment thereof, a single chain variable fragment (scFv), a one-armed antibody, and / or a multi-specific antibody (e.g., a bispecific antibody).

[0184] In some embodiments, the antibody or antigen-binding fragment is a human IgGl antibody or antigen-binding fragment thereof, a human IgG2 antibody or antigen-binding fragment thereof, or a human IgG4 antibody or antigen-binding fragment thereof.

[0185] In one aspect, the present disclosure relates to an anti-PTK7 / TROP2 antibody (e.g., a bispecific antibody) or antigen-binding fragment thereof, comprising: a first antigen-binding domain that specifically binds a PTK7 epitope and a second antigen-binding domain that specifically binds a TROP2 epitope.

[0186] In some embodiments, the first antigen-binding domain comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1); and the second antigen-binding domain comprises a second heavy chain variable region (VH2) and a second light chain variable region (VL2).

[0187] In some embodiments, the first heavy chain variable region (VH1) comprises complementarity determining regions (CDRs) 1, 2, and 3, wherein the VH1 CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VH1 CDR1 amino acid sequence, the VH1 CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH1 CDR2 amino acid sequence, and the VH1 CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH1 CDR3 amino acid sequence; and the first light chain variable region (VL1) comprises CDRs 1, 2, and 3, wherein the VL1 CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VL1 CDR1 amino acid sequence, the VL1 CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL1 CDR2 amino acid sequence, and the VL1 CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL1 CDR3 amino acid sequence, wherein the selected VH1 CDR1, 2, and 3 amino acid sequences and the selected VL1 CDR1, 2, and 3 amino acid sequences are one of the following:

[0188] (1) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 4-6, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0189] (2) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 7-9, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0190] (3) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 10-12, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0191] (4) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 13-15, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0192] (5) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 16-18, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0193] (6) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 19-21, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 1-3, respectively;

[0194] (7) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 22-24, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 1-3, respectively;

[0195] (8) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 25-27, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 1-3, respectively;

[0196] (9) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 28-30, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 1-3, respectively;

[0197] (10) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 31-33, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 1-3, respectively;

[0198] (11) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 34-36, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 1-3, respectively;

[0199] (12) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 37-39, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 1-3, respectively;

[0200] (13) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 40-42, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 1-3, respectively;

[0201] (14) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 43-45, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 1-3, respectively;

[0202] (15) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 86-88, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 1-3, respectively; and

[0203] (16) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 89-91, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 1-3, respectively.

[0204] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 4-6, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 1-3, respectively.

[0205] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 7-9, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 1-3, respectively.

[0206] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 10-12, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 1-3, respectively.

[0207] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 13-15, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 1-3, respectively.

[0208] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 16-18, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 1-3, respectively.

[0209] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 19-21, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOS: 1-3, respectively.

[0210] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 22-24, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0211] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 25-27, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0212] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 28-30, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0213] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 31-33, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0214] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 34-36, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0215] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 37-39, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0216] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 40-42, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0217] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 43-45, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0218] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 86-88, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0219] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 89-91, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0220] In some embodiments, the second heavy chain variable region (VH2) comprises CDRs 1, 2, and 3, wherein the VH2 CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VH2 CDR1 amino acid sequence, the VH2 CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH2 CDR2 amino acid sequence, and the VH2 CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH2 CDR3 amino acid sequence; and the second light chain variable region (VL2) comprises CDRs 1, 2, and 3, wherein the VL2 CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VL2 CDR1 amino acid sequence, the VL2 CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL2 CDR2 amino acid sequence, and the VL2 CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL2 CDR3 amino acid sequence, wherein the selected VH2 CDR1, 2, and 3 amino acid sequences and the selected VL2 CDR1, 2, and 3 amino acid sequences are one of the following:

[0221] (1) the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 54-56, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0222] (2) the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 63-65, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0223] (3) the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 57-59, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0224] (4) the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0225] (5) the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 66-68, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively; and

[0226] (6) the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 69-71, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively.

[0227] In some embodiments, the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 54-56, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively.

[0228] In some embodiments, the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 57-59, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively.

[0229] In some embodiments, the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively.

[0230] In some embodiments, the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 63-65, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively.

[0231] In some embodiments, the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 66-68, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively.

[0232] In some embodiments, the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 69-71, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0233] In some embodiments:

[0234] (1) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 4-6, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 54-56, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0235] (2) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 7-9, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 54-56, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0236] (3) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 10-12, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 54-56, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0237] (4) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 13-15, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 54-56, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0238] (5) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 16-18, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 54-56, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0239] (6) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 19-21, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 54-56, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0240] (7) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 22-24, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 54-56, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0241] (8) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 4-6, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 57-59, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0242] (9) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 7-9, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 57-59, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0243] (10) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 10-12, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 57-59, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0244] (11) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 13-15, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 57-59, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0245] (12) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 16-18, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 57-59, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0246] (13) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 19-21, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 57-59, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0247] (14) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 22-24, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 57-59, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0248] (15) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 4-6, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0249] (16) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 7-9, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0250] (17) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 10-12, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0251] (18) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 13-15, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0252] (19) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 16-18, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0253] (20) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 19-21, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 60-62, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0254] (21) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 22-24, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 60-62, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0255] (22) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 25-27, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 63-65, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0256] (23) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 28-30, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 63-65, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0257] (24) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 31-33, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 63-65, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0258] (25) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 34-36, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 63-65, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0259] (26) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 37-39, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 63-65, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0260] (27) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 40-42, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 63-65, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0261] (28) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 43-45, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 63-65, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0262] (29) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 25-27, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 66-68, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0263] (30) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 28-30, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 66-68, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0264] (31) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 31-33, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 66-68, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0265] (32) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 34-36, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 66-68, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0266] (33) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 37-39, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 66-68, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0267] (34) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 40-42, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 66-68, the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3;

[0268] (35) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 43-45, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 66-68, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0269] (36) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 25-27, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 69-71, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0270] (37) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 28-30, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 69-71, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0271] (38) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 31-33, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 69-71, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0272] (39) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 34-36, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 69-71, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0273] (40) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 37-39, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 69-71, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0274] (41) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 40-42, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 69-71, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0275] (42) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 43-45, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 69-71, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0276] (43) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 86-88, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 54-56, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0277] (44) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 89-91, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 63-65, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively;

[0278] (45) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 86-88, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 57-59, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively; and

[0279] (46) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 89-91, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 66-68, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively.

[0280] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 46, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0281] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 47, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0282] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 48, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0283] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 49, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0284] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 50, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0285] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 51, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0286] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 52, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0287] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 46, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0288] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 47, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0289] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 48, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0290] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 49, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0291] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 50, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0292] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 51, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0293] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 52, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0294] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 46, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0295] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 47, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0296] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 48, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0297] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 49, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0298] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 50, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0299] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 51, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0300] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 52, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0301] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 92, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0302] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 92, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0303] In some embodiments, the VH1 comprises an amino acid sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to a selected VH sequence and the VL1 comprises an amino acid sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following:

[0304] (1) the selected VH sequence is SEQ ID NO:46, and the selected VL sequence is SEQ ID NO:53;

[0305] (2) the selected VH sequence is SEQ ID NO:47, and the selected VL sequence is SEQ ID NO:53;

[0306] (3) the selected VH sequence is SEQ ID NO:48, and the selected VL sequence is SEQ ID NO:53;

[0307] (4) the selected VH sequence is SEQ ID NO:49, and the selected VL sequence is SEQ ID NO:53;

[0308] (5) the selected VH sequence is SEQ ID NO:50, and the selected VL sequence is SEQ ID NO:53;

[0309] (6) the selected VH sequence is SEQ ID NO:51, and the selected VL sequence is SEQ ID NO:53;

[0310] (7) the selected VH sequence is SEQ ID NO:52, and the selected VL sequence is SEQ ID NO:53; and

[0311] (8) the selected VH sequence is SEQ ID NO:92, and the selected VL sequence is SEQ ID NO:53.

[0312] In some embodiments, the VH2 comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to a selected VH sequence, and the VL2 comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following:

[0313] (1) the selected VH sequence is SEQ ID NO:72, and the selected VL sequence is SEQ ID NO:53;

[0314] (2) the selected VH sequence is SEQ ID NO:73, and the selected VL sequence is SEQ ID NO:53; and

[0315] (3) the selected VH sequence is SEQ ID NO:74, and the selected VL sequence is SEQ ID NO:53.

[0316] In some embodiments, the VH1 comprises a VH1 CDR1, a VH1 CDR2, and a VH1 CDR3 that are identical to a VH CDR1, a VH CDR2, and a VH CDR3 of a selected VH sequence; and the VL1 comprises a VL1 CDR1, a VL1 CDR2, and a VL1 CDR3 that are identical to a VL CDR1, a VL CDR2, and a VL CDR3 of a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following:

[0317] (1) the selected VH sequence is SEQ ID NO: 46, and the selected VL sequence is SEQ ID NO: 53;

[0318] (2) the selected VH sequence is SEQ ID NO: 47, and the selected VL sequence is SEQ ID NO: 53;

[0319] (3) the selected VH sequence is SEQ ID NO: 48, and the selected VL sequence is SEQ ID NO: 53;

[0320] (4) the selected VH sequence is SEQ ID NO: 49, and the selected VL sequence is SEQ ID NO: 53;

[0321] (5) the selected VH sequence is SEQ ID NO: 50, and the selected VL sequence is SEQ ID NO: 53;

[0322] (6) the selected VH sequence is SEQ ID NO: 51, and the selected VL sequence is SEQ ID NO: 53;

[0323] (7) the selected VH sequence is SEQ ID NO: 52, and the selected VL sequence is SEQ ID NO: 53; and

[0324] (8) the selected VH sequence is SEQ ID NO: 92, and the selected VL sequence is SEQ ID NO: 53.

[0325] In some embodiments, the VH2 comprises a VH2 CDR1, a VH2 CDR2, and a VH2 CDR3 that are identical to a VH CDR1, a VH CDR2, and a VH CDR3 of a selected VH sequence; and the VL2 comprises a VL2 CDR1, a VL2 CDR2, and a VL2 CDR3 that are identical to a VL CDR1, a VL CDR2, and a VL CDR3 of a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following:

[0326] (1) the selected VH sequence is SEQ ID NO: 72, and the selected VL sequence is SEQ ID NO: 53;

[0327] (2) the selected VH sequence is SEQ ID NO: 73, and the selected VL sequence is SEQ ID NO: 53; and

[0328] (3) the selected VH sequence is SEQ ID NO: 74, and the selected VL sequence is SEQ ID NO: 53.

[0329] In some embodiments, the first antigen binding domain specifically binds human, monkey, or dog PTK7, and / or the second antigen binding domain specifically binds human, monkey, or dog TROP2.

[0330] In some embodiments, the first antigen binding domain is a human or humanized antigen binding domain, and / or the second antigen binding domain is a human or humanized antigen binding domain.

[0331] In some embodiments, the first antigen binding domain is a single chain variable fragment (scFv), and / or the second antigen binding domain is a scFv.

[0332] In some embodiments, the first light chain variable region is identical to the second light chain variable region.

[0333] In one aspect, the present disclosure relates to an antibody or antigen binding fragment thereof that cross-competes with an antibody or antigen binding fragment thereof described herein.

[0334] In some embodiments, the antibody or antigen binding fragment thereof comprises a fragment crystallizable region (Fc region).

[0335] In some embodiments, the Fc region has enhanced complement dependent cytotoxicity (CDC) or antibody dependent cellular cytotoxicity (ADCC).

[0336] In one aspect, the present disclosure relates to a chimeric antigen receptor (CAR) comprising any antibody or antigen binding fragment thereof described herein.

[0337] In one aspect, the present disclosure relates to an antibody drug conjugate comprising any antibody or antigen binding fragment thereof described herein covalently bound to a therapeutic agent.

[0338] In some embodiments, the therapeutic agent is a cytotoxic or cytostatic agent.

[0339] In some embodiments, the therapeutic agent is MMAE or MMAF.

[0340] In some embodiments, the therapeutic agent is selected from

[0341]

[0342] In some embodiments, the therapeutic agent is linked to the antibody or antigen binding fragment thereof via a linker. In some embodiments, the linker has the following structure:

[0343]

[0344] In some embodiments, the antibody drug conjugate has the following structure:

[0345]

[0346] In some embodiments, n = 1, 2, 3, 4, 5, 6, 7, or 8; in some embodiments, "Ab" represents an antibody or antigen binding fragment thereof described herein.

[0347] In one aspect, the disclosure relates to a method of treating a subject having a cancer, the method comprising administering to the subject a therapeutically effective amount of a composition comprising any antibody or antigen binding fragment thereof described herein, any CAR described herein, or any antibody drug conjugate described herein.

[0348] In some embodiments, the subject has a solid tumor.

[0349] In some embodiments, the cancer is colon cancer, triple negative breast cancer (TNBC), lung cancer, non-small cell lung cancer (NSCLC), esophageal cancer, pancreatic cancer, colorectal cancer, ovarian cancer (OVCA), or bladder cancer.

[0350] In some embodiments, the subject is further treated with an effective amount of an anti-4-1BB antibody, an anti-OX40 antibody, an anti-PD-1 antibody, an anti-CTLA4 antibody, an anti-CD40 antibody, or an anti-PD-L1 antibody.

[0351] In one aspect, the disclosure relates to a method of reducing the growth rate of a tumor, the method comprising contacting a tumor cell with an effective amount of a composition comprising any antibody or antigen binding fragment thereof described herein, any CAR described herein, or any antibody drug conjugate described herein.

[0352] In one aspect, the disclosure relates to a method of killing a tumor cell, the method comprising contacting the tumor cell with an effective amount of a composition comprising any antibody or antigen binding fragment thereof described herein, any CAR described herein, or any antibody drug conjugate described herein.

[0353] In one aspect, the present disclosure relates to a method of increasing an immune response in a subject, the method comprising: administering to the subject an effective amount of a composition comprising any of the antibodies or antigen-binding fragments thereof described herein, any of the CARs described herein, or any of the antibody drug conjugates described herein.

[0354] In one aspect, the present disclosure relates to a pharmaceutical composition comprising any of the antibodies or antigen-binding fragments thereof described herein and a pharmaceutically acceptable carrier.

[0355] In one aspect, the present disclosure relates to a pharmaceutical composition comprising any of the antibody drug conjugates described herein and a pharmaceutically acceptable carrier.

[0356] In some embodiments, the drug antibody ratio (DAR) is about 4 or 8.

[0357] As used herein, the term "cancer" refers to cells having the ability to grow autonomously. Examples of such cells include cells having an abnormal state or condition characterized by rapidly proliferating cell growth. The term is intended to include cancerous growths (e.g., tumors), cancerous processes, metastatic tissue, and malignant transformed cells, tissues, or organs, regardless of histopathological type or stage of invasiveness. Also included are malignancies of various organ systems, such as the respiratory system, cardiovascular system, renal system, reproductive system, hematological system, nervous system, hepatic system, gastrointestinal system, and endocrine system; and adenocarcinomas, which include malignancies such as most colon cancers, renal cell carcinomas, prostate cancers, and / or testicular tumors, non-small cell lung cancer, and small bowel cancer. A "naturally occurring" cancer includes any cancer that is not experimentally induced by implanting cancer cells into a subject, and includes, for example, a cancer that occurs spontaneously, a cancer that results from a patient's exposure to a carcinogen, a cancer that results from insertion of a transgenic oncogenic gene or knock-out of a tumor suppressor gene, and a cancer that results from infection (e.g., viral infection). The term "carcinoma" is art-recognized and refers to a malignant tumor of epithelial or endocrine tissue. The term also includes carcinosarcomas, which include malignant tumors composed of both carcinoma and sarcoma tissues. An "adenocarcinoma" refers to a carcinoma that originates in glandular tissue, or in which the tumor cells form recognizable glandular structures. The term "sarcoma" is art-recognized and refers to a malignant tumor of mesenchymal derivation. The term "hematopoietic neoplastic disease" includes diseases involving proliferating / neoplastic cells of hematopoietic origin. Hematopoietic neoplastic diseases can be caused by myeloid cells, lymphocytes, or erythroid cells, or their precursor cells.

[0358] As used herein, the term“antibody” refers to any antigen-binding molecule containing at least one (e.g., one, two, three, four, five, or six) complementarity determining region (CDR) (e.g., any of the three CDRs from an immunoglobulin light chain or any of the three CDRs from an immunoglobulin heavy chain) and capable of specifically binding an epitope. Non-limiting examples of antibodies include monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), single-chain antibodies, chimeric antibodies, human antibodies, and humanized antibodies. In some embodiments, an antibody can contain an Fc region of a human antibody. The term antibody also includes derivatives such as bispecific antibodies, single-chain antibodies, diabodies, linear antibodies, and multispecific antibodies formed from antibody fragments.

[0359] As used herein, the term“antigen-binding fragment” refers to a portion of a full-length antibody, wherein the portion of the antibody is capable of specifically binding to an antigen. In some embodiments, an antigen-binding fragment contains at least one variable domain (e.g., a heavy chain variable domain or a light chain variable domain). Non-limiting examples of antibody fragments include, e.g., Fab, Fab’, F(ab’)2, and Fv fragments.

[0360] As used herein, the term“human antibody” refers to an antibody encoded by an endogenous nucleic acid present in a human (e.g., a rearranged human immunoglobulin heavy or light chain locus). In some embodiments, a human antibody is collected from a human or produced in a human cell culture (e.g., a human hybridoma cell). In some embodiments, a human antibody is produced in a non-human cell (e.g., a mouse or hamster cell line). In some embodiments, a human antibody is produced in a bacterial or yeast cell. In some embodiments, a human antibody is produced in a transgenic non-human animal (e.g., a cow) containing an unrearranged or rearranged human immunoglobulin locus (e.g., a heavy chain or light chain human immunoglobulin locus).

[0361] As used herein, the term“chimeric antibody” refers to an antibody containing sequences present in at least two different antibodies (e.g., antibodies from two different mammalian species, such as a human and a mouse antibody). A non-limiting example of a chimeric antibody is an antibody containing variable domain sequences (e.g., all or a portion of a light chain and / or heavy chain variable domain sequence) of a non-human (e.g., mouse) antibody and constant domains of a human antibody. Other examples of chimeric antibodies are described herein and are known in the art.

[0362] As used herein, the term “humanized antibody” refers to a non-human antibody that contains minimal sequence derived from a non-human (e.g., mouse) immunoglobulin and contains sequences derived from human immunoglobulin. In non-limiting examples, a humanized antibody is a human antibody (recipient antibody) in which residues from a hypervariable region (e.g., CDR) of the recipient antibody are replaced by residues from a hypervariable region (e.g., CDR) of a non-human antibody (e.g., donor antibody) such as a mouse, rat, or rabbit antibody that have the desired specificity, affinity, and capacity. In some embodiments, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human (e.g., mouse) immunoglobulin residues. In some embodiments, a humanized antibody can contain residues that are not found in the recipient antibody or donor antibody. These modifications can be made to further improve antibody performance. In some embodiments, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops (CDRs) correspond to those of a non-human (e.g., mouse) immunoglobulin, and all or substantially all of the framework regions are those of a human immunoglobulin. A humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. Humanized antibodies can be produced using methods known in the art of molecular biology. Non-limiting examples of methods for producing humanized antibodies are described herein.

[0363] As used herein, the term “single-chain antibody” refers to a single polypeptide that contains at least two immunoglobulin variable domains (e.g., variable domains of a mammalian immunoglobulin heavy or light chain) that are capable of specific binding to an antigen. Non-limiting examples of single-chain antibodies are described herein.

[0364] As used herein, the term “multimeric antibody” refers to an antibody that contains four or more (e.g., six, eight, or ten) immunoglobulin variable domains.

[0365] As used herein, the terms “subject” and “patient” are used interchangeably throughout the specification and describe an animal (human or non-human) for which treatment according to the present application is desired. Veterinary and non-veterinary applications are contemplated by the present application. A human patient can be an adult or a juvenile (e.g., a person under the age of 18). In addition to humans, patients include, but are not limited to, mice, rats, hamsters, guinea pigs, rabbits, ferrets, cats, dogs, and primates. Included are, for example, non-human primates (e.g., monkeys, chimpanzees, gorillas, etc.), rodents (e.g., rats, mice, hamsters, gerbils, ferrets, rabbits), lagomorphs, swine (e.g., pigs, mini-pigs), equines, canines, felines, bovines, and other domestic, farm, and zoo animals.

[0366] As used herein, the phrases "specifically binds" and "specifically binds to," when referring to an antibody, means that the antibody preferentially interacts with its target molecule (e.g., PTK7) as compared to other molecules because the interaction depends on the presence of a particular structure (i.e., an antigenic determinant or epitope) on the target molecule; in other words, the agent recognizes and binds to a molecule comprising the particular structure, rather than to all molecules generally. An antibody that specifically binds to a target molecule can be referred to as a target-specific antibody. For example, an antibody that specifically binds to a PTK7 molecule can be referred to as a PTK7-specific antibody or an anti-PTK7 antibody. Similarly, an antibody that specifically binds to both PTK7 and TROP2 molecules can be referred to as an anti-PTK7 / TROP2 antibody.

[0367] As used herein, the term "bispecific antibody" refers to an antibody that binds to two different epitopes. The epitopes can be on the same antigen or on different antigens.

[0368] As used herein, the term "multispecific antibody" refers to an antibody that is capable of binding to two or more different epitopes. These epitopes can be located on the same antigen or on different antigens. A multispecific antibody can be, for example, a bispecific antibody or a trispecific antibody. In some embodiments, a multispecific antibody can bind to two, three, four, five, or six different epitopes.

[0369] As used herein, the terms "polypeptide," "peptide," and "protein" are used interchangeably to refer to an amino acid polymer of any length that comprises at least two amino acids.

[0370] As used herein, the terms "polynucleotide," "nucleic acid molecule," and "nucleic acid sequence" are used interchangeably herein to refer to a nucleotide polymer of any length that comprises at least two nucleotides, and includes, but is not limited to, DNA, RNA, DNA / RNA hybrids, and modifications thereof.

[0371] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Methods and materials are described herein for use of the present application; other suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0372] Other features and advantages of the present application will be apparent from the detailed description of the application and the accompanying drawings, which are as follows: BRIEF DESCRIPTION OF DRAWINGS

[0373] Figure 1A Kabat CDR sequences of anti-PTK7 antibodies are listed.

[0374] Figure 1B Kabat CDR sequences of anti-TROP2 antibodies are listed.

[0375] Figure 2A Chothia CDR sequences of anti-PTK7 antibodies are listed.

[0376] Figure 2B Chothia CDR sequences of anti-TROP2 antibodies are listed.

[0377] Figure 3 Sequences of heavy and light variable regions of anti-PTK7 antibodies and anti-TROP2 antibodies or antigen-binding fragments thereof are listed.

[0378] Figure 4 Amino acid sequences discussed in the present disclosure are listed.

[0379] Figure 5 Tumor volumes of different groups of mice xenografted with MDA-MB-468 cells and treated with ADCs are shown. Gantenermin and hu24-ADC were used as positive controls.

[0380] Figure 6 Tumor volumes of different groups of mice xenografted with patient-derived breast tumor fragments and treated with ADCs are shown.

[0381] Figure 7 Tumor volumes of different groups of mice xenografted with patient-derived lung tumor fragments and treated with ADCs are shown.

[0382] Figure 8 Tumor volumes of different groups of mice xenografted with patient-derived pancreatic tumor fragments and treated with ADCs are shown.

[0383] Figure 9 Tumor volumes of different groups of mice xenografted with patient-derived colorectal tumor fragments and treated with ADCs are shown.

[0384] Figure 10 Tumor volumes of different groups of mice xenografted with patient-derived colorectal tumor fragments and treated with ADCs are shown.

[0385] Figure 11 Binding activity of antibodies in NCI-H1975 cells (A) and NUGC-4 cells (B) is shown.

[0386] Figure 12The in vitro killing activity of ADC in NCI-H1975 cells (A) and NUGC-4 cells (B) is shown. DETAILED DESCRIPTION

[0387] A bispecific antibody or antigen-binding fragment thereof is an artificial protein that can bind to two different epitopes (e.g., on two different antigens) simultaneously. In some embodiments, a bispecific antibody or antigen-binding fragment thereof can have two arms. Each arm has one heavy chain variable region and one light chain variable region, forming an antigen-binding domain (or antigen-binding region). In some embodiments, the bispecific antibody has a common light chain.

[0388] The present disclosure provides exemplary antibodies, antigen-binding fragments thereof, and antibody drug conjugates derived from these antibodies that bind to PTK7, TROP2, and / or both PTK7 and TROP2 (PTK7 / TROP2). The present disclosure also relates to anti-PTK7 / TROP2 antibodies (e.g., bispecific antibodies or antigen-binding fragments thereof) that specifically bind to PTK7 and TROP2, and antibody drug conjugates derived from these anti-PTK7 / TROP2 antibodies.

[0389] PTK7 and TROP2

[0390] Tyrosine-protein kinase 7 (PTK7) is a highly conserved member of the receptor tyrosine kinase pseudokinase family. Observable loss of kinase activity across species can be due to substitution of a residue that is typically conserved within the kinase domain. Genetic and biochemical studies have shown that PTK7 has a critical function in non-canonical Wnt signaling and PTK7 null embryos exhibit severe defects in planar cell polarity development. There is also evidence that PTK7 has other potentially context-dependent functions in vascular endothelial growth factor (VEGF), axon guidance proteins / plexins, and the canonical Wnt signaling pathway. Oncogenic functions of PTK7 have been documented in colon, lung, and esophageal cancers, and in acute myeloid leukemia, PTK7 promotes cell survival and chemoresistance.

[0391] PTK7 is highly expressed in breast cancer, associated with poor prognosis, and is associated with tumor metastasis and progression in triple-negative breast cancer (TNBC). Co-expression analysis and gain or loss of function studies of PTK7 in TNBC cell lines showed that PTK7 is involved in EGFR / Akt signaling modulation and is associated with extracellular matrix organization and migration genes in breast cancer, including COL1A1, FN1, WNT5B, MMP11, MMP14, and SDC1. Gain or loss of function experiments of PTK7 showed that PTK7 promotes proliferation and migration of TNBC cell lines. PTK7 knockdown mouse models further demonstrated that PTK7 deficiency inhibits tumor progression of TNBC in vivo.

[0392] For a detailed review of PTK7 and its functions, see Damelin M, et al., A PTK7-targeted antibody-drug conjugate reduces tumor-initiating cells and induces sustained tumor regressions. Sci Transl Med. 2017 Jan 11;9(372):eaag2611. doi: 10.1126 / scitranslmed.aag2611. PMID: 28077676; Xiang et al., Biomater Res. 2022 Dec 5;26(1):74. doi: 10.1186 / s40824-022-00328-9; Cui et al., Front. Oncol., 22 July 2021, Sec. Breast Cancer, Volume 11-2021; and Kim et al., Int J Mol Sci. 2022 Oct 13;23(20):12195. doi: 10.3390 / ijms232012195, which are incorporated herein by reference in their entirety.

[0393] Trophoblast cell surface antigen 2 (TROP2) is a glycoprotein that spans the epithelial cell membrane surface and plays a role in cell self-renewal, proliferation, and transformation. TROP2 is a 35 kDa protein encoded by the TACSTD2 gene, consisting of a large extracellular domain, a single transmembrane domain, and a short intracellular tail that is the functional dominant part of the protein.

[0394] Under physiological conditions, TROP2 plays a crucial role in embryonic development, placental tissue formation, embryonic implantation, stem cell proliferation, and organ development. Low basal expression levels of TROP2 are found on the surface of various normal epithelial tissues, including skin and oral mucosa. TROP2 can promote tumor growth, and its overexpression is commonly found in many types of malignant epithelial tumors.

[0395] Expression of Trop2 is regulated by several oncogenic transcription factors, such as CREB1, nuclear factor NFκB, and HOXA 10 Due to the inactivation of certain transcription factors, such as HNF4A, TP63 / TP53L, ERG, HNF1A / TCF-1, and FOXP3, Trop2 expression can be upregulated. TROP2 overexpression can accelerate the cancer cell cycle and drive cancer growth. Knocking out the TACSTD2 gene disrupts tumor cell proliferation, further confirming the role of TROP2 in tumorigenesis.

[0396] TROP2 is elucidated as an intracellular calcium signal transducer and is known to play a role in multiple cell signaling pathways associated with tumorigenesis. TROP2 expression as a calcium signal transducer results in the release of calcium ions from internal stores. Increased intracellular calcium levels activate MAPK, which in turn increases the phosphorylation levels of ERK1 and ERK2. ERK1 and ERK2 are important mediators of cell cycle progression, angiogenesis, cell proliferation, cell invasion, and metastasis. Intracellular calcium also activates the NFKB pathway, which is involved in stimulating cell growth, and the RAF pathway is critical for upregulation of FOXM1, one of the most commonly overexpressed genes in human solid tumors.

[0397] In addition to stimulating calcium release and MAPK signaling, TROP2 is involved in other pro-cancer signaling pathways that lead to the growth and proliferation of tumor cells. Activation of cyclin E and D further promotes cell cycle progression. Alterations in the Notch, Hedgehog, and Wnt pathways can impede proper stem cell proliferation and differentiation. Studies have shown that TROP2 signaling is also dependent on β-catenin. Direct interaction between β-catenin and the intracellular domain of TROP2 (through β-catenin signaling) enhances the cancer cell's stem-like properties (e.g., self-renewal and transformation). Attenuation of TROP2 on IGF-1 receptor signaling promotes cancer growth and malignancy, particularly in lung cancer.

[0398] For a detailed review of TROP2 and its functions, see Zaman S, Jadid H, Denson AC, Gray JE. Targeting Trop-2 in solid tumors: future prospects. Onco Targets Ther. 2019;12:1781-1790. doi: 10.2147 / OTT.S162447; Shvartsur A, Bonavida B. Trop2 and its overexpression in cancers: regulation and clinical / therapeutic implications. Genes Cancer. 2015;6(3-4):84-105. doi: 10.18632 / genesandcancer.40; Strop P, Tran TT, Dorywalska M, et al. RN927C, a site-specific Trop-2 antibody-drug conjugate (ADC) with enhanced stability, is highly efficacious in preclinical solid tumor models. Mol Cancer Ther. 2016;15(11):2698-2708. doi: 10.1158 / 1535-7163.MCT-16-0431; and Goldenberg DM, Stein R, Sharkey RM. The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. Oncotarget. 2018;9(48):28989-29006. doi: 10.18632 / oncotarget.25615; the entire contents of which are incorporated herein by reference.

[0399] The present disclosure provides certain anti-PTK7, anti-TROP2, and anti-PTK7 / TROP2 (e.g., multispecific or bispecific) antibodies, antigen-binding fragments thereof, and methods of using these anti-PTK7, anti-TROP2, and / or anti-PTK7 / TROP2 antibodies and antigen-binding fragments to inhibit tumor growth, treat cancer, and autoimmune diseases.

[0400] Anti-PTK7 antibodies and antigen-binding fragments

[0401] The present disclosure provides antibodies and antigen-binding fragments thereof that specifically bind PTK7 (e.g., human PTK7, monkey PTK7, or dog PTK7). The antibodies and antigen-binding fragments described herein are capable of binding PTK7. These antibodies can be agonists or antagonists. In some embodiments, these antibodies can enhance an immune response. In some embodiments, these antibodies can block PTK7 activity, e.g., reduce the frequency of tumor initiating cells (TICs) or inhibit angiogenesis and immune cell stimulation.

[0402] The present disclosure provides, e.g., anti-PTK7 antibodies 1A7, 1A11, 1F2, 2A5, 2D11, 2F5, 3C4, 3E6, chimeric antibodies thereof, and human or humanized antibodies thereof.

[0403] The CDR sequences of 1A7 and 1A7-derived antibodies (e.g., human or humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 4, 5, 6) and the CDRs of the light chain variable domain (SEQ ID NOs: 1, 2, 3) as determined by the Rabat definition. The CDRs can also be determined by the Chothia definition. According to the Chothia definition, the CDR sequences of the heavy chain variable domain are set forth in SEQ ID NOs: 25, 26, 27, and the CDR sequences of the light chain variable domain are set forth in SEQ ID NOs: 1, 2, 3.

[0404] The CDR sequences of 1A11 and 1A11-derived antibodies (e.g., human or humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 86, 87, 88) and the CDRs of the light chain variable domain (SEQ ID NOs: 1, 2, 3) as determined by the Rabat definition. The CDRs can also be determined by the Chothia definition. According to the Chothia definition, the CDR sequences of the heavy chain variable domain are set forth in SEQ ID NOs: 89, 90, 91, and the CDR sequences of the light chain variable domain are set forth in SEQ ID NOs: 1, 2, 3.

[0405] The CDR sequences of 1F2 and 1F2-derived antibodies (e.g., human or humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 7, 8, 9) and the CDRs of the light chain variable domain (SEQ ID NOs: 1, 2, 3) as determined by the Rabat definition. The CDRs can also be determined by the Chothia definition. According to the Chothia definition, the CDR sequences of the heavy chain variable domain are set forth in SEQ ID NOs: 28, 29, 30, and the CDR sequences of the light chain variable domain are set forth in SEQ ID NOs: 1, 2, 3.

[0406] 2A5 and 2A5 -derived antibodies (e.g., human or humanized antibodies) include CDR sequences of the heavy chain variable domain (SEQ ID NOs: 10, 11, 12) and CDR sequences of the light chain variable domain (SEQ ID NOs: 1, 2, 3) as determined by the Rabat definition. CDRs can also be determined by the Chothia definition. According to the Chothia definition, the CDR sequences of the heavy chain variable domain are set forth in SEQ ID NOs: 31, 32, 33, and the CDR sequences of the light chain variable domain are set forth in SEQ ID NOs: 1, 2, 3.

[0407] 2D11 and 2D11 -derived antibodies (e.g., human or humanized antibodies) include CDR sequences of the heavy chain variable domain (SEQ ID NOs: 13, 14, 15) and CDR sequences of the light chain variable domain (SEQ ID NOs: 1, 2, 3) as determined by the Rabat definition. CDRs can also be determined by the Chothia definition. According to the Chothia definition, the CDR sequences of the heavy chain variable domain are set forth in SEQ ID NOs: 34, 35, 36, and the CDR sequences of the light chain variable domain are set forth in SEQ ID NOs: 1, 2, 3.

[0408] 2F5 and 2F5 -derived antibodies (e.g., human or humanized antibodies) include CDR sequences of the heavy chain variable domain (SEQ ID NOs: 16, 17, 18) and CDR sequences of the light chain variable domain (SEQ ID NOs: 1, 2, 3) as determined by the Rabat definition. CDRs can also be determined by the Chothia definition. According to the Chothia definition, the CDR sequences of the heavy chain variable domain are set forth in SEQ ID NOs: 37, 38, 39, and the CDR sequences of the light chain variable domain are set forth in SEQ ID NOs: 1, 2, 3.

[0409] 3C4 and 3C4 -derived antibodies (e.g., human or humanized antibodies) include CDR sequences of the heavy chain variable domain (SEQ ID NOs: 19, 20, 21) and CDR sequences of the light chain variable domain (SEQ ID NOs: 1, 2, 3) as determined by the Rabat definition. CDRs can also be determined by the Chothia definition. According to the Chothia definition, the CDR sequences of the heavy chain variable domain are set forth in SEQ ID NOs: 40, 41, 42, and the CDR sequences of the light chain variable domain are set forth in SEQ ID NOs: 1, 2, 3.

[0410] The CDR sequences of 3E6 and 3E6-derived antibodies (e.g., human or humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 22, 23, 24) and the CDRs of the light chain variable domain (SEQ ID NOs: 1, 2, 3) as determined by the Rabat definition. The CDRs can also be determined by the Chothia definition. According to the Chothia definition, the CDR sequences of the heavy chain variable domain are set forth in SEQ ID NOs: 43, 44, 45, and the CDR sequences of the light chain variable domain are set forth in SEQ ID NOs: 1, 2, 3.

[0411] The amino acid sequence of the heavy chain variable region of the 1A7 antibody is set forth in SEQ ID NO: 46. The amino acid sequence of the light chain variable region of the 1A7 antibody is set forth in SEQ ID NO: 53.

[0412] The amino acid sequence of the heavy chain variable region of the 1A11 antibody is set forth in SEQ ID NO: 92. The amino acid sequence of the light chain variable region of the 1A11 antibody is set forth in SEQ ID NO: 53.

[0413] The amino acid sequence of the heavy chain variable region of the 1F2 antibody is set forth in SEQ ID NO: 47. The amino acid sequence of the light chain variable region of the 1F2 antibody is set forth in SEQ ID NO: 53.

[0414] The amino acid sequence of the heavy chain variable region of the 2A5 antibody is set forth in SEQ ID NO: 48. The amino acid sequence of the light chain variable region of the 2A5 antibody is set forth in SEQ ID NO: 53.

[0415] The amino acid sequence of the heavy chain variable region of the 2D11 antibody is set forth in SEQ ID NO: 49. The amino acid sequence of the light chain variable region of the 2D11 antibody is set forth in SEQ ID NO: 53.

[0416] The amino acid sequence of the heavy chain variable region of the 2F5 antibody is set forth in SEQ ID NO: 50. The amino acid sequence of the light chain variable region of the 2F5 antibody is set forth in SEQ ID NO: 53.

[0417] The amino acid sequence of the heavy chain variable region of the 3C4 antibody is set forth in SEQ ID NO: 51. The amino acid sequence of the light chain variable region of the 3C4 antibody is set forth in SEQ ID NO: 53.

[0418] The amino acid sequence of the heavy chain variable region of the 3E6 antibody is set forth in SEQ ID NO: 52. The amino acid sequence of the light chain variable region of the 3E6 antibody is set forth in SEQ ID NO: 53.

[0419] Amino acid sequences of the modified heavy chain variable region and light chain variable region of the antibodies are also provided. In some embodiments, the heavy chain variable region has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to any one of SEQ ID NOs: 46-52 and 92. In some embodiments, the light chain variable region has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 53. The heavy chain variable region sequences can be paired with the corresponding light chain variable region sequences, and they collectively bind PTK7.

[0420] Percent humanization means the percent identity of a heavy or light chain variable region sequence compared to a human antibody sequence in the international immunogenetics information system (IMGT) database. In some embodiments, the percent humanization is greater than 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95%. Detailed descriptions of how to determine percent humanization and how to determine optimal alignment are known in the art and described in, e.g., Jones et al., “The INNs and outs of antibody nonproprietary names.” MAbs. Vol. 8. No. 1. Taylor & Francis, 2016, which is incorporated by reference herein in its entirety. A high percent humanization often has various advantages, e.g., is safer and more effective in humans, is more likely to be tolerated by human subjects, and / or is less likely to have side effects. In some embodiments, the variable region is fully human, e.g., derived from human heavy chain immunoglobulin locus sequences (e.g., recombination of human IGHV, human IGHD, and human IGHJ genes), and / or human kappa chain immunoglobulin locus sequences (e.g., recombination of human IGKV and human IGKJ genes).

[0421] Further, in some embodiments, the antibodies or antigen-binding fragments thereof described herein can also contain one, two, or three heavy chain variable region CDRs selected from the group consisting of SEQ ID NOs: 4-6, 7-9, 10-12, 13-15, 16-18, 19-21, 22-24, 25-27, 28-30, 31-33, 34-36, 37-39, 40-42, 43-45, 86-88, 89-91; and / or one, two, or three light chain variable region CDRs selected from the group consisting of SEQ ID NOs: 1-3.

[0422] In some embodiments, the antibody can have a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, 3, wherein the CDR1 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VH CDR1 amino acid sequence, the CDR2 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VH CDR2 amino acid sequence, and the CDR3 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VH CDR3 amino acid sequence. In some embodiments, the antibody can have a light chain variable region (VL) comprising CDRs 1, 2, 3, wherein the CDR1 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VL CDR1 amino acid sequence, the CDR2 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VL CDR2 amino acid sequence, and the CDR3 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VL CDR3 amino acid sequence. The selected VH CDR1, 2, 3 amino acid sequences and the selected VL CDR1, 2, 3 amino acid sequences are set forth in Table 1. Figure 1A (Kabat CDR) and Figure 2A (Chothia CDR).

[0423] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 4 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 5 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 6 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0424] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 7 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 8 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 9 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0425] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 10 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 11 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 12 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0426] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 13 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 14 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 15 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0427] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 16 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 17 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 18 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0428] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 19 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 20 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 21 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0429] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 22 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 23 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 24 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0430] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 25 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 26 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 27 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0431] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 28 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 29 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 30 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0432] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 31 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 32 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 33 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0433] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 34 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 35 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 36 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0434] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 37 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 38 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 39 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0435] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 40 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 41 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 42 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0436] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 43 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 44 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 45 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0437] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 86 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 87 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 88 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0438] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 89 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 90 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 91 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0439] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 89 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 90 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 91 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0440] Insertions, deletions, and substitutions can be within a CDR sequence, or at one or both ends of a CDR sequence. In some embodiments, the CDRs are determined based on the Kabat numbering scheme. In some embodiments, the CDRs are determined based on the Chothia numbering scheme. In some embodiments, the CDRs are determined based on a combination of the Kabat and Chothia numbering schemes.

[0441] The present disclosure also provides antibodies or antigen-binding fragments thereof that bind PTK7. The antibodies or antigen-binding fragments thereof contain a heavy chain variable region (VH) comprising or consisting of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VH sequence; and a light chain variable region (VL) comprising or consisting of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VL sequence. In some embodiments, the selected VH sequence is SEQ ID NO: 46 and the selected VL sequence is SEQ ID NO: 53. In some embodiments, the selected VH sequence is SEQ ID NO: 47 and the selected VL sequence is SEQ ID NO: 53. In some embodiments, the selected VH sequence is SEQ ID NO: 48 and the selected VL sequence is SEQ ID NO: 53. In some embodiments, the selected VH sequence is SEQ ID NO: 49 and the selected VL sequence is SEQ ID NO: 53. In some embodiments, the selected VH sequence is SEQ ID NO: 50 and the selected VL sequence is SEQ ID NO: 53. In some embodiments, the selected VH sequence is SEQ ID NO: 51 and the selected VL sequence is SEQ ID NO: 53. In some embodiments, the selected VH sequence is SEQ ID NO: 52 and the selected VL sequence is SEQ ID NO: 53. In some embodiments, the selected VH sequence is SEQ ID NO: 92 and the selected VL sequence is SEQ ID NO: 53.

[0442] The present disclosure also provides antibodies or antigen-binding fragments thereof that can compete with the antibodies described herein. In some aspects, the antibodies or antigen-binding fragments can bind to the same epitope as the antibodies described herein.

[0443] The present disclosure also provides nucleic acids comprising a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or an immunoglobulin light chain. The immunoglobulin heavy chain or the immunoglobulin light chain comprises a CDR as shown in Figure 1A or Figure 2A having a sequence as shown in Figure 3 When the polypeptide is paired with a corresponding polypeptide (e.g., a corresponding heavy chain variable region or a corresponding light chain variable region), the paired polypeptides bind PTK7 (e.g., human PTK7).

[0444] The anti-PTK7 antibodies and antigen-binding fragments can also be antibody variants (including derivatives and conjugates) of antibodies or antibody fragments and multispecific (e.g., bispecific) antibodies or antibody fragments. Other antibodies provided herein are polyclonal antibodies, monoclonal antibodies, multispecific (multimeric, e.g., bispecific) antibodies, human antibodies, chimeric antibodies (e.g., human-mouse chimeras), single-chain antibodies, intracellularly produced antibodies (i.e., intrabodies), and antigen-binding fragments thereof. The antibodies or antigen-binding fragments thereof can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. In some embodiments, the antibodies or antigen-binding fragments thereof are IgG antibodies or antigen-binding fragments thereof.

[0445] Antibody fragments that retain the desired affinity and specificity of full-length antibodies are useful in the provided methods. Thus, antibody fragments that bind PTK7 will retain the ability to bind PTK7. Fv fragments are the smallest unit of an antibody that contains a complete antigen recognition and binding site. This region consists of a dimer of one heavy chain variable domain and one light chain variable domain, connected by a "knob-in-hole" interaction that can be covalent, such as in scFv. In this configuration, it is the three CDRs of each variable domain that interact to define the antigen binding site on the surface of the VH-VL dimer. Collectively, the six CDRs, or subsets thereof, confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv that includes only the three CDRs specific to an antigen) has the ability to recognize and bind antigen, although usually at a lower affinity than the entire binding site.

[0446] In some embodiments, the antibodies or antigen-binding fragments thereof described herein recognize endogenous PTK7 or recombinant PTK7. In some embodiments, the antibodies or antigen-binding fragments thereof described herein recognize human PTK7. In some embodiments, the antibodies or antigen-binding fragments thereof described herein recognize monkey PTK7. In some embodiments, the antibodies or antigen-binding fragments thereof described herein recognize dog PTK7.

[0447] Anti-TROP2 antibodies and antigen-binding fragments

[0448] The present disclosure also provides antibodies and antigen-binding fragments thereof that specifically bind to TROP2 (e.g., human TROP2, monkey TROP2, or dog TROP2). The antibodies and antigen-binding fragments described herein are capable of binding to TROP2. These antibodies can be agonists or antagonists. In some embodiments, these antibodies can enhance an immune response. In some embodiments, these antibodies can block TROP2 activity, such as stimulating calcium release and activating the MAPK signaling pathway.

[0449] The present disclosure provides, for example, anti-TROP2 antibodies 18E9, 18F12, 6F7, chimeric antibodies thereof, and human or humanized antibodies thereof.

[0450] The CDR sequences of 18E9 and 18E9-derived antibodies (e.g., human or humanized antibodies) include the CDRs of the heavy chain variable domain (SEQ ID NOs: 57, 58, 59) and the CDRs of the light chain variable domain (SEQ ID NOs: 1, 2, 3) as determined by the Rabat definition. The CDRs can also be determined by the Chothia definition. According to the Chothia definition, the CDR sequences of the heavy chain variable domain are set forth in SEQ ID NOs: 66, 67, 68, and the CDR sequences of the light chain variable domain are set forth in SEQ ID NOs: 1, 2, 3.

[0451] Similarly, the CDR sequences of 18F12 and 18F12-derived antibodies include the CDRs of the heavy chain variable domain (SEQ ID NOs: 60, 61, 62) and the CDRs of the light chain variable domain (SEQ ID NOs: 1, 2, 3) as determined by the Rabat definition. According to the Chothia definition, the CDR sequences of the heavy chain variable domain are set forth in SEQ ID NOs: 69, 70, 71, and the CDR sequences of the light chain variable domain are set forth in SEQ ID NOs: 1, 2, 3.

[0452] The CDR sequences of 6F7 and 6F7-derived antibodies include the CDRs of the heavy chain variable domain (SEQ ID NOs: 54, 55, 56) and the CDRs of the light chain variable domain (SEQ ID NOs: 1, 2, 3) as determined by the Rabat definition. According to the Chothia definition, the CDR sequences of the heavy chain variable domain are set forth in SEQ ID NOs: 63, 64, 65, and the CDR sequences of the light chain variable domain are set forth in SEQ ID NOs: 1, 2, 3.

[0453] The amino acid sequence of the heavy chain variable region of the 18E9 antibody is set forth in SEQ ID NO: 73. The amino acid sequence of the light chain variable region of the 18E9 antibody is set forth in SEQ ID NO: 53.

[0454] The amino acid sequence of the heavy chain variable region of the 18F12 antibody is set forth in SEQ ID NO: 74. The amino acid sequence of the light chain variable region of the 18F12 antibody is set forth in SEQ ID NO: 53.

[0455] The amino acid sequence of the heavy chain variable region of the 6F7 antibody is set forth in SEQ ID NO: 72. The amino acid sequence of the light chain variable region of the 6F7 antibody is set forth in SEQ ID NO: 53.

[0456] Amino acid sequences of the modified heavy chain variable region and light chain variable region of the antibody are also provided. In some embodiments, the heavy chain variable region has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to any one of SEQ ID NOs: 73 and 74. In some embodiments, the light chain variable region has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 53. The heavy chain variable region sequence can be paired with a corresponding light chain variable region sequence, and they collectively bind TROP2.

[0457] Percent humanization means the percent identity of a heavy chain or light chain variable region sequence compared to a human antibody sequence in the international immunogenetics information system (IMGT) database. In some embodiments, the percent humanization is greater than 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95%. Detailed descriptions of how to determine percent humanization and how to determine optimal alignment are known in the art and described in, e.g., Jones et al., “The INNs and outs of antibody nonproprietary names.” MAbs. Vol. 8. No. 1. Taylor & Francis, 2016, which is incorporated by reference herein in its entirety. A high percent humanization often has various advantages, e.g., is safer and more effective in humans, is more likely to be tolerated by human subjects, and / or is less likely to have side effects. In some embodiments, the variable region is fully human, e.g., derived from human heavy chain immunoglobulin locus sequences (e.g., recombination of human IGHV, human IGHD, and human IGHJ genes), and / or human kappa chain immunoglobulin locus sequences (e.g., recombination of human IGKV and human IGKJ genes).

[0458] Further, in some embodiments, the antibodies or antigen-binding fragments thereof described herein can also contain one, two, or three heavy chain variable region CDRs selected from the group consisting of SEQ ID NOs: 54-56, 57-59, 60-62, 63-65, 66-68, 69-71; and / or one, two, or three light chain variable region CDRs selected from the group consisting of SEQ ID NOs: 1-3.

[0459] In some embodiments, an antibody can have a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, 3, wherein the CDR1 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VH CDR1 amino acid sequence, the CDR2 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VH CDR2 amino acid sequence, and the CDR3 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VH CDR3 amino acid sequence. In some embodiments, an antibody can have a light chain variable region (VL) comprising CDRs 1, 2, 3, wherein the CDR1 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VL CDR1 amino acid sequence, the CDR2 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VL CDR2 amino acid sequence, and the CDR3 region comprises or consists of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VL CDR3 amino acid sequence. Selected VH CDR1, 2, 3 amino acid sequences and selected VL CDR1, 2, 3 amino acid sequences are set forth in Table 1. Figure 1B (Kabat CDR) and Figure 2B (Chothia CDR).

[0460] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: a CDR of SEQ ID NO: 54 with zero, one, or two amino acid insertions, deletions, or substitutions; a CDR of SEQ ID NO: 55 with zero, one, or two amino acid insertions, deletions, or substitutions; a CDR of SEQ ID NO: 56 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0461] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: a CDR of SEQ ID NO: 63 with zero, one, or two amino acid insertions, deletions, or substitutions; a CDR of SEQ ID NO: 64 with zero, one, or two amino acid insertions, deletions, or substitutions; a CDR of SEQ ID NO: 65 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0462] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 57 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 58 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 59 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0463] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 60 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 61 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 62 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0464] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 66 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 67 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 68 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0465] In some embodiments, an antibody or antigen-binding fragment described herein can include a heavy chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 69 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 70 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 71 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0466] In some embodiments, an antibody or antigen-binding fragment described herein can include a light chain variable domain that includes one, two, or three of the following CDRs: CDRs of SEQ ID NO: 1 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 2 with zero, one, or two amino acid insertions, deletions, or substitutions; CDRs of SEQ ID NO: 3 with zero, one, or two amino acid insertions, deletions, or substitutions.

[0467] Insertions, deletions, and substitutions can be within under one or both terminal ends of a CDR sequence. In some embodiments, the CDRs are determined based on the Kabat numbering scheme. In some embodiments, the CDRs are determined based on the Chothia numbering scheme. In some embodiments, the CDRs are determined based on a combination of the Kabat and Chothia numbering schemes.

[0468] The present disclosure also provides an antibody or antigen-binding fragment thereof that binds TROP2. The antibody or antigen-binding fragment thereof comprises: a heavy chain variable region (VH) comprising or consisting of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VH sequence; and a light chain variable region (VL) comprising or consisting of an amino acid sequence that is at least 80%, 85%, 90%, or 95% identical to a selected VL sequence. In some embodiments, the selected VH sequence is SEQ ID NO: 72 and the selected VL sequence is SEQ ID NO: 53. In some embodiments, the selected VH sequence is SEQ ID NO: 73 and the selected VL sequence is SEQ ID NO: 53. In some embodiments, the selected VH sequence is SEQ ID NO: 74 and the selected VL sequence is SEQ ID NO: 53.

[0469] The present disclosure also provides an antibody or antigen-binding fragment thereof that can compete with an antibody described herein. In some aspects, the antibody or antigen-binding fragment can bind to the same epitope as an antibody described herein.

[0470] The present disclosure also provides a nucleic acid comprising a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or an immunoglobulin light chain. The immunoglobulin heavy chain or the immunoglobulin light chain comprises a CDR as shown in Figure 1B or Figure 2B or has a sequence as shown in Figure 3 When the polypeptide is paired with a corresponding polypeptide (e.g., a corresponding heavy chain variable region or a corresponding light chain variable region), the paired polypeptides bind TROP2 (e.g., human TROP2, monkey TROP2, or dog TROP2).

[0471] The anti-TROP2 antibodies and antigen-binding fragments can also be antibody variants (including derivatives and conjugates) of antibodies or antibody fragments and multispecific (e.g., bispecific) antibodies or antibody fragments. Other antibodies provided herein are polyclonal antibodies, monoclonal antibodies, multispecific (multimeric, e.g., bispecific) antibodies, human antibodies, chimeric antibodies (e.g., human-mouse chimeras), single-chain antibodies, intracellularly produced antibodies (i.e., intrabodies), and antigen-binding fragments thereof. The antibodies or antigen-binding fragments thereof can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. In some embodiments, the antibodies or antigen-binding fragments thereof are IgG antibodies or antigen-binding fragments thereof.

[0472] Antibody fragments that retain the desired affinity and specificity of full-length antibodies are useful in the provided methods. Thus, antibody fragments that bind TROP2 will retain the ability to bind TROP2. Fv fragments are the smallest unit of an antibody that contains a complete antigen recognition and binding site. This region consists of a dimer of one heavy chain variable domain and one light chain variable domain, which can be held together by noncovalent forces, such as scFv. In this configuration, it is the three CDRs of each variable domain that interact to define the antigen binding site on the surface of the VH-VL dimer. Collectively, the six CDRs, or a subset thereof, confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv that includes only three CDRs specific to an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.

[0473] In some embodiments, the antibodies or antigen-binding fragments thereof described herein recognize endogenous TROP2 or recombinant TROP2. In some embodiments, the antibodies or antigen-binding fragments thereof described herein recognize human TROP2. In some embodiments, the antibodies or antigen-binding fragments thereof described herein recognize monkey TROP2. In some embodiments, the antibodies or antigen-binding fragments thereof described herein recognize dog TROP2.

[0474] Anti-PTK7 / TROP2 multispecific antibodies and antigen-binding fragments

[0475] The present disclosure provides anti-PTK7 / TROP2 multispecific (e.g., bispecific) antibodies and antigen-binding fragments thereof. In one aspect, the present disclosure provides an anti-PTK7 / TROP2 multispecific (e.g., bispecific) antibody or antigen-binding fragment thereof, comprising: a first antigen-binding domain that specifically binds PTK7; and a second antigen-binding domain that specifically binds TROP2.

[0476] In some embodiments, the first antigen binding domain comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1); and the second antigen binding domain comprises a second heavy chain variable region (VH2) and a second light chain variable region (VL2).

[0477] In some embodiments, the first heavy chain variable region (VH1) comprises complementarity determining regions (CDRs) 1, 2, and 3, wherein the VH1 CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VH1 CDR1 amino acid sequence, the VH1 CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH1 CDR2 amino acid sequence, and the VH1 CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH1 CDR3 amino acid sequence; and

[0478] the first light chain variable region (VL1) comprises CDRs 1, 2, and 3, wherein the VL1 CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VL1 CDR1 amino acid sequence, the VL1 CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL1 CDR2 amino acid sequence, and the VL1 CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL1 CDR3 amino acid sequence,

[0479] wherein the selected VH1 CDR1, 2, and 3 amino acid sequences and the selected VL1 CDR1, 2, and 3 amino acid sequences are one of:

[0480] (1) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 4-6, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0481] (2) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 7-9, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0482] (3) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 10-12, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0483] (4) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 13-15, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively;

[0484] (5) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 16-18, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively;

[0485] (6) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 19-21, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively;

[0486] (7) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 22-24, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively;

[0487] (8) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 25-27, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively;

[0488] (9) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 28-30, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively;

[0489] (10) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 31-33, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively;

[0490] (11) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 34-36, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively;

[0491] (12) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 37-39, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively;

[0492] (13) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 40-42, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0493] (14) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 43-45, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively;

[0494] (15) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 86-88, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; and

[0495] (16) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 89-91, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0496] In some embodiments, the second heavy chain variable region (VH2) comprises CDRs 1, 2, and 3, wherein the VH2 CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VH2 CDR1 amino acid sequence, the VH2 CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH2 CDR2 amino acid sequence, and the VH2 CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH2 CDR3 amino acid sequence; and

[0497] the second light chain variable region (VL2) comprises CDRs 1, 2, and 3, wherein the VL2 CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VL2 CDR1 amino acid sequence, the VL2 CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL2 CDR2 amino acid sequence, and the VL2 CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL2 CDR3 amino acid sequence,

[0498] wherein the selected VH2 CDR1, 2, and 3 amino acid sequences and the selected VL2 CDR1, 2, and 3 amino acid sequences are one of the following:

[0499] (1) the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 54-56, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively;

[0500] (2) the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 57-59, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively;

[0501] (3) the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively;

[0502] (4) the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 63-65, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively;

[0503] (5) the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 66-68, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; and

[0504] (6) the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 69-71, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively.

[0505] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 4-6, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 54-56, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively.

[0506] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 7-9, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 54-56, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0507] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 10-12, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 54-56, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0508] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 13-15, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 54-56, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0509] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 16-18, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 54-56, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0510] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 19-21, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 54-56, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0511] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 22-24, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 54-56, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0512] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 25-27, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 63-65, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0513] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 28-30, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 63-65, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0514] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 31-33, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 63-65, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0515] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 34-36, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 63-65, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0516] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 37-39, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 63-65, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0517] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 40-42, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 63-65, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0518] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 43-45, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 63-65, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0519] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 4-6, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 57-59, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0520] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 7-9, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 57-59, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0521] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 10-12, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 57-59, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0522] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 13-15, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 57-59, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0523] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 16-18, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 57-59, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0524] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 19-21, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 57-59, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0525] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 22-24, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 57-59, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0526] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 25-27, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 66-68, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0527] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 28-30, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 66-68, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0528] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 31-33, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 66-68, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0529] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 34-36, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 66-68, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0530] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 37-39, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 66-68, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0531] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 40-42, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 66-68, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0532] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 43-45, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 66-68, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0533] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 4-6, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs:, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0534] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 7-9, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0535] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 10-12, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0536] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 13-15, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 60-62, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0537] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 16-18, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 60-62, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0538] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 19-21, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 60-62, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0539] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 22-24, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 60-62, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0540] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 25-27, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 69-71, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0541] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 28-30, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 69-71, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0542] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 31-33, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 69-71, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0543] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 34-36, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 69-71, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0544] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 37-39, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 69-71, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0545] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 40-42, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 69-71, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0546] In some embodiments, the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 43-45, respectively, the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 69-71, respectively, the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

[0547] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 46, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0548] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 47, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0549] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 48, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53. In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 46, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0550] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 49, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0551] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 50, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0552] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 51, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0553] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 52, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0554] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 46, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0555] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 47, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0556] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 48, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0557] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 49, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0558] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 50, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0559] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 51, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0560] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 52, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0561] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 46, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0562] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 47, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0563] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 48, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0564] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 49, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0565] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 50, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0566] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 51, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0567] In some embodiments, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 52, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0568] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 92, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0569] In some embodiments, the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 92, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53.

[0570] In some embodiments, the VH1 comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to a selected VH sequence and the VL1 comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following:

[0571] (1) the selected VH sequence is SEQ ID NO: 46 and the selected VL sequence is SEQ ID NO: 53;

[0572] (2) the selected VH sequence is SEQ ID NO: 47 and the selected VL sequence is SEQ ID NO: 53;

[0573] (3) the selected VH sequence is SEQ ID NO: 48 and the selected VL sequence is SEQ ID NO: 53;

[0574] (4) the selected VH sequence is SEQ ID NO: 49 and the selected VL sequence is SEQ ID NO: 53;

[0575] (5) the selected VH sequence is SEQ ID NO:50, and the selected VL sequence is SEQ ID NO:53;

[0576] (6) the selected VH sequence is SEQ ID NO:51, and the selected VL sequence is SEQ ID NO:53;

[0577] (7) the selected VH sequence is SEQ ID NO:52, and the selected VL sequence is SEQ ID NO:53; and

[0578] (8) the selected VH sequence is SEQ ID NO:92, and the selected VL sequence is SEQ ID NO:53.

[0579] In some embodiments, the VH2 comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to a selected VH sequence, and the VL2 comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following:

[0580] (1) the selected VH sequence is SEQ ID NO:72, and the selected VL sequence is SEQ ID NO:53;

[0581] (2) the selected VH sequence is SEQ ID NO:73, and the selected VL sequence is SEQ ID NO:53; and

[0582] (3) the selected VH sequence is SEQ ID NO:74, and the selected VL sequence is SEQ ID NO:53.

[0583] In some embodiments, the VH1 comprises a VH1 CDR1, a VH1 CDR2, and a VH1 CDR3 that are identical to a VH CDR1, a VH CDR2, and a VH CDR3 of a selected VH sequence; and the VL1 comprises a VL1 CDR1, a VL1 CDR2, and a VL1 CDR3 that are identical to a VL CDR1, a VL CDR2, and a VL CDR3 of a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following:

[0584] (1) the selected VH sequence is SEQ ID NO:46, and the selected VL sequence is SEQ ID NO:53;

[0585] (2) the selected VH sequence is SEQ ID NO:47, and the selected VL sequence is SEQ ID NO:53;

[0586] (3) the selected VH sequence is SEQ ID NO:48, and the selected VL sequence is SEQ ID NO:53;

[0587] (4) the selected VH sequence is SEQ ID NO:49, and the selected VL sequence is SEQ ID NO:53;

[0588] (5) the selected VH sequence is SEQ ID NO:50, and the selected VL sequence is SEQ ID NO:53;

[0589] (6) the selected VH sequence is SEQ ID NO:51, and the selected VL sequence is SEQ ID NO:53;

[0590] (7) the selected VH sequence is SEQ ID NO:52, and the selected VL sequence is SEQ ID NO:53; and

[0591] (8) the selected VH sequence is SEQ ID NO:92, and the selected VL sequence is SEQ ID NO:53.

[0592] In some embodiments, the VH2 comprises a VH2 CDR1, a VH2 CDR2, and a VH2 CDR3 that are identical to a VH CDR1, a VH CDR2, and a VH CDR3 of a selected VH sequence; and the VL2 comprises a VL2 CDR1, a VL2 CDR2, and a VL2 CDR3 that are identical to a VL CDR1, a VL CDR2, and a VL CDR3 of a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following:

[0593] (1) the selected VH sequence is SEQ ID NO:72, and the selected VL sequence is SEQ ID NO:53;

[0594] (2) the selected VH sequence is SEQ ID NO:73, and the selected VL sequence is SEQ ID NO:53; and

[0595] (3) the selected VH sequence is SEQ ID NO:74, and the selected VL sequence is SEQ ID NO:53.

[0596] In some embodiments, the first antigen binding domain specifically binds human, mouse, monkey, or dog PTK7; and / or the second antigen binding domain specifically binds human, mouse, monkey, or dog TROP2.

[0597] In some embodiments, the first antigen binding domain is a human or humanized antigen binding domain; and / or the second antigen binding domain is a human or humanized antigen binding domain.

[0598] In some embodiments, the first antigen binding domain is a single chain variable fragment (scFv); and / or the second antigen binding domain is a scFv.

[0599] In some embodiments, the first light chain variable region and the second light chain variable region are identical.

[0600] In some embodiments, a knob-into-hole mutation is introduced in the Fc region of the bispecific antibody to reduce the chance of mispairing between two heavy chains. Exemplary bispecific antibodies obtained include: 3C4-6F7, 3C4-18E9, 3C4-18F12, 3E6-6F7, 3E6-18E9, and 3E6-18F12. Figure 5 The human IgGl constant region sequence with knob mutation is set forth in SEQ ID NO: 85.

[0601] In some embodiments, the anti-PTK7 / TROP2 antibody or antibody fragment thereof comprises Figures 1A-3 a combination of anti-PTK7 and anti-TROP2 antigen binding domains set forth.

[0602] In some embodiments, 1A7-6F7 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 1A7 and a second anti-TROP2 antigen binding domain derived from 6F7. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 1A7. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 6F7. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 1A7. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 6F7.

[0603] In some embodiments, 1A11-6F7 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 1A11 and a second anti-TROP2 antigen binding domain derived from 6F7. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 1A11. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 6F7. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 1A11. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 6F7.

[0604] In some embodiments, 1F2-6F7 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 1F2 and a second anti-TROP2 antigen binding domain derived from 6F7. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 1F2. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 6F7. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 1F2. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 6F7.

[0605] In some embodiments, 2A5-6F7 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 2A5 and a second anti-TROP2 antigen binding domain derived from 6F7. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 2A5. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 6F7. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 2A5. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 6F7.

[0606] In some embodiments, 2D11-6F7 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 2D11 and a second anti-TROP2 antigen binding domain derived from 6F7. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 2D11. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 6F7. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 2D11. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 6F7.

[0607] In some embodiments, 2F5-6F7 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 2F5 and a second anti-TROP2 antigen binding domain derived from 6F7. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 2F5. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 6F7. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 2F5. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 6F7.

[0608] In some embodiments, 3C4-6F7 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 3C4 and a second anti-TROP2 antigen binding domain derived from 6F7. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 3C4. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 6F7. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 3C4. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 6F7.

[0609] In some embodiments, 3E6-6F7 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 3E6 and a second anti-TROP2 antigen binding domain derived from 6F7. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 3E6. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 6F7. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 3E6. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 6F7.

[0610] In some embodiments, 1A7-18E9 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 1A7 and a second anti-TROP2 antigen binding domain derived from 18E9. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 1A7. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 18E9. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 1A7. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 18E9.

[0611] In some embodiments, 1A11-18E9 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 1A11 and a second anti-TROP2 antigen binding domain derived from 18E9. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 1A11. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 18E9. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 1A11. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 18E9.

[0612] In some embodiments, 1F2-18E9 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 1F2 and a second anti-TROP2 antigen binding domain derived from 18E9. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 1F2. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 18E9. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 1F2. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 18E9.

[0613] In some embodiments, 2A5-18E9 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 2A5 and a second anti-TROP2 antigen binding domain derived from 18E9. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 2A5. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 18E9. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 2A5. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 18E9.

[0614] In some embodiments, 2D11-18E9 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 2D11 and a second anti-TROP2 antigen binding domain derived from 18E9. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 2D11. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 18E9. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 2D11. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 18E9.

[0615] In some embodiments, 2F5-18E9 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 2F5 and a second anti-TROP2 antigen binding domain derived from 18E9. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 2F5. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 18E9. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 2F5. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 18E9.

[0616] In some embodiments, 3C4-18E9 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 3C4 and a second anti-TROP2 antigen binding domain derived from 18E9. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 3C4. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 18E9. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 3C4. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 18E9.

[0617] In some embodiments, 3E6-18E9 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 3E6 and a second anti-TROP2 antigen binding domain derived from 18E9. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 3E6. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 18E9. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 3E6. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 18E9.

[0618] In some embodiments, 1A7-18F12 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 1A7 and a second anti-TROP2 antigen binding domain derived from 18F12. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 1A7. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 18F12. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 1A7. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 18F12.

[0619] In some embodiments, 1F2-18F12 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 1F2 and a second anti-TROP2 antigen binding domain derived from 18F12. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 1F2. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 18F12. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 1F2. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 18F12.

[0620] In some embodiments, 2A5-18F12 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 2A5 and a second anti-TROP2 antigen binding domain derived from 18F12. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 2A5. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 18F12. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 2A5. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 18F12.

[0621] In some embodiments, 2D11-18F12 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 2D11 and a second anti-TROP2 antigen binding domain derived from 18F12. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 2D11. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 18F12. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 2D11. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 18F12.

[0622] In some embodiments, 2F5-18F12 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 2F5 and a second anti-TROP2 antigen binding domain derived from 18F12. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 2F5. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 18F12. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 2F5. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 18F12.

[0623] In some embodiments, 3C4-18F12 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 3C4 and a second anti-TROP2 antigen binding domain derived from 18F12. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 3C4. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 18F12. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 3C4. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 18F12.

[0624] In some embodiments, 3E6-18F12 refers to an anti-PTK7 / TROP2 antibody comprising a first anti-PTK7 antigen binding domain derived from 3E6 and a second anti-TROP2 antigen binding domain derived from 18F12. In some embodiments, the first anti-PTK7 antigen binding domain comprises the CDRs of 3E6. In some embodiments, the second anti-TROP2 antigen binding domain comprises the CDRs of 18F12. In some embodiments, the first anti-PTK7 antigen binding domain comprises the VH and VL of 3E6. In some embodiments, the second anti-TROP2 antigen binding domain comprises the VH and VL of 18F12.

[0625] In some embodiments, in 3C4-6F7, the heavy chain constant region of 3C4 comprises a knob mutation and the heavy chain constant region of 6F7 comprises a hole mutation. In some embodiments, the sequence of the light chain constant region is set forth in SEQ ID NO: 83; the human IgGl constant region with a knob mutation is set forth in SEQ ID NO: 84; the human IgGl constant region with a hole mutation is set forth in SEQ ID NO: 85

[0626] In some embodiments, the anti-PTK7 / TROP2 antibody is a bispecific antibody. Bispecific antibodies can be produced by engineering the interface between a pair of antibody molecules to maximize the percentage of heterodimers recovered from recombinant cell culture. For example, the interface can include at least a portion of the CH3 domain of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g., tyrosine or tryptophan). Compensatory “cavities” of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g., alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted side products such as homodimers. This method is described in, e.g., WO 96 / 27011, which is incorporated herein by reference in its entirety.

[0627] Any of the anti-PTK7 / TROP2 antibodies or antigen binding fragments described herein can be conjugated to a stabilizing molecule (e.g., a molecule that increases the half-life of the antibody or antigen binding fragment thereof in a subject or in solution). Non-limiting examples of stabilizing molecules include: a polymer (e.g., polyethylene glycol) or a protein (e.g., serum albumin, such as human serum albumin). Conjugation of a stabilizing molecule can increase the half-life or prolong the biological activity of the anti-PTK7 / TROP2 antibody or antigen binding fragment in vitro (e.g., in tissue culture or when stored as a pharmaceutical composition) or in vivo (e.g., in a human).

[0628] Anti-PTK7 / TROP2 antibodies, antigen-binding fragments thereof, can also have various formats. Many different formats of bispecific antibodies or antigen-binding fragments thereof are known in the art and described, for example, in Suurs et al. “A review of bispecific antibodies and antibody constructs in oncology and clinical challenges,” Pharmacology & therapeutics (2019), which is incorporated by reference herein in its entirety.

[0629] In some embodiments, the anti-PTK7 / TROP2 antibody is a BiTe, (scFv)2, Nanobody, Nanobody-HSA, DART, TandAb, scDiabody, scDiabody-CH3, scFv-CH-CL-scFv, HSAbody, scDiabody-HAS, or tandem scFv. In some embodiments, the anti-PTK7 / TROP2 antibody is a VHH-scAb, VHH-Fab, dual scFab, F(ab’)2, diabody, crossMab, DAF (two-in-one), DAF (four-in-one), DutaMab, DT-IgG, knob-in-hole common light chain, knob-in-hole assembly, charge pair, Fab arm exchange, SEEDbody, LUZ-Y, Fcab, kappa lambda-body, orthogonal Fab, DVD-IgG, IgG(H)-scFv, scFv-(H)IgG, IgG(L)-scFv, scFv-(L)IgG, IgG(L,H)-Fv, IgG(H)-V, V(H)-IgG, IgG(L)-V, V(L)-IgG, KIH IgG-scFab, 2scFv-IgG, IgG-2scFv, scFv4-Ig, Zybody, DVI-IgG, diabody-CH3, triple body, miniantibody, minibody, TriBi minibody, scFv-CH3 KIH, Fab-scFv, F(ab’)2-scFv2, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scdiabody-Fc, diabody-Fc, tandem scFv-Fc, intrabody, dock and lock, lmmTAC, IgG-IgG conjugate, Cov-X-Body, or scFv1-PEG-scFv2.

[0630] In some embodiments, the anti-PTK7 / TROP2 antibody can be a TrioMab. In TrioMabs, two heavy chains are from different species, where different sequences limit heavy chain-light chain pairing.

[0631] In some embodiments, the anti-PTK7 / TROP2 antibody has two different heavy chains and one common light chain. The heterodimerization of the heavy chains can be based on a knob-into-hole structure or some other heavy chain pairing technology.

[0632] In some embodiments, bispecific anti-PTK7 / TROP2 antibodies can be generated using CrossMAb technology. CrossMAb technology can be used to achieve correct light chain binding in bispecific heterodimeric IgG antibodies, which allows the generation of various bispecific antibody formats, including bis-(1+1), tri-(2+1), and tetra-(2+2) valent bispecific antibodies, as well as non-Fc-tandem antigen binding fragment (Fab)-based antibodies. These formats can be derived from any existing antibody pair using domain crossover, without the need to identify a common light chain, post-translational processing / in vitro chemical assembly, or the introduction of a set of mutations that enable correct light chain binding. This method is described in Klein et al., "The use of CrossMAb technology for the generation of bi- and multispecific antibodies." MAbs. Vol. 8. No. 6. Taylor & Francis, 2016, which is incorporated by reference herein in its entirety. In some embodiments, the CH1 domain in the heavy chain and the CL domain in the light chain are exchanged.

[0633] The anti-PTK7 / TROP2 antibody can be a Duobody. A naturally occurring Fab exchange mechanism in IgG4 antibodies is similar to the controlled material in IgG1 antibodies, which is referred to as controlled Fab exchange. This format ensures specific pairing between heavy and light chains.

[0634] In a dual variable domain antibody (DVD-Ig), additional VH and variable light (VL) domains are added to each N-terminus for bispecific targeting. This format is similar to IgG-scFv, but the added binding domains bind to their respective N-termini individually, rather than scFv binding to each heavy chain N-terminus.

[0635] In scFv-IgG, two scFvs are connected to the C-terminus of the heavy chain (CH3). The scFv-IgG format has two different bivalent binding sites, and is therefore also referred to as tetravalent. The scFv-IgG does not have heavy and light chain pairing issues.

[0636] In some embodiments, the anti-PTK7 / TROP2 antibody can have an IgG-IgG format. Two intact IgG antibodies are conjugated by chemically linking the C-terminus of the heavy chains.

[0637] The anti-PTK7 / TROP2 antibody can also have a Fab-scFv-Fc format. In the Fab-scFv-Fc format, a light chain, a heavy chain, and a third chain containing an Fc region and an scFv are assembled. This format can ensure efficient production and purification.

[0638] In some embodiments, the anti-PTK7 / TROP2 antibody can be a TF. Three Fab fragments are linked by disulfide bridges. Two fragments target tumor-associated antigens (TAAs), and one fragment targets a hapten. The TF format does not have an Fc region.

[0639] ADAPTIR has two scFvs bound to both sides of an Fc region. This format abandons an intact IgG as the basis of its construct, but retains the Fc region to extend the half-life and facilitate purification.

[0640] Dual-affinity retargeting (DART) antibodies have two peptide chains that link opposite fragments, i.e., VLA and VHB and VLB and VHA, and have a sulfur bond at their C-terminus that fuses them together. In DART, the sulfur bond can improve its stability compared to BiTE.

[0641] In DART-Fc, an Fc region is linked to the DART structure. It can be produced by assembling three chains, where two chains are linked by a disulfide bond, as in DART. One chain contains half of the Fc region, which will dimerize with a third chain that expresses only the Fc region. The addition of the Fc region improves the half-life, thereby extending the effective concentration and avoiding continuous intravenous (IV) administration.

[0642] Tetravalent DART consists of four peptide chains. Basically, two DART molecules have half of the Fc region and will dimerize. This format is a tetravalent molecule because it has a bivalent binding to both targets.

[0643] Tandem diabody (TandAb) includes two diabodies. Each diabody consists of VHA and VLB fragments, and the VHA and VLB fragments are covalently bound. The two diabodies are linked to a peptide chain. Compared to a diabody consisting of two scFvs, its stability is improved. It has two bivalent binding sites.

[0644] ScFv-scFv-toxin includes a toxin and two scFvs with a stabilizing linker. It can be used to specifically deliver a payload.

[0645] In some embodiments, the anti-PTK7 / TROP2 antibody is a bispecific antibody. In some embodiments, the bispecific antibody of the present disclosure is designed as 1+1 (monovalent for each target) and has an IgGl subtype structure. This can reduce avidity to PTK7 and TROP2 cells that are low expressers and increase avidity to cells that co-express PTK7 and TROP2 to achieve enhanced targeting function.

[0646] TROP2 cells, and increase avidity to cells that co-express PTK7 and TROP2 to achieve enhanced targeting function.

[0647] In some embodiments, the anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof has a light chain constant region having at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 83, and a heavy chain constant region having at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to any one of SEQ ID NOs: 84 and 85.

[0648] In some embodiments, the anti-PTK7 / TROP2 antibody includes a KIH mutation. In some embodiments, the anti-PTK7 / TROP2 antibody includes a first antigen binding domain that specifically binds PTK7 and a second antigen binding domain that specifically binds TROP2. In some embodiments, the first antigen binding domain includes a heavy chain that includes one or more knob mutations (knob heavy chain), and the second antigen binding domain includes a heavy chain that includes one or more hole mutations (hole heavy chain). In some embodiments, the first antigen binding domain includes a heavy chain that includes one or more hole mutations (hole heavy chain), and the second antigen binding domain includes a heavy chain that includes one or more knob mutations (knob heavy chain). In some embodiments, the anti-PTK7 / TROP2 antibody includes a knob heavy chain that includes a constant region having at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 84. In some embodiments, the anti-PTK7 / TROP2 antibody includes a hole heavy chain that includes a constant region having at least 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to SEQ ID NO: 85.

[0649] Antibodies and antigen-binding fragments

[0650] The present disclosure provides anti-PTK7, anti-TROP2, and / or anti-PTK7 / TROP2 antibodies and antigen-binding fragments thereof.

[0651] Generally, antibodies (also referred to as immunoglobulins) are composed of two classes of polypeptide chains, i.e., light and heavy chains. Non-limiting antibodies of the present disclosure can be intact, four immunoglobulin chain antibodies that include two heavy chains and two light chains. The heavy chain of an antibody can be of any isotype (including IgM, IgG, IgE, IgA, or IgD) or subisotype (including IgGl, IgG2, IgG2a, IgG2b, IgG3, IgG4, IgEl, IgE2, etc.). The light chain can be a kappa light chain or a lambda light chain. An antibody can include two identical copies of a light chain and two identical copies of a heavy chain. The heavy chains, each containing one variable domain (or variable region, VH) and multiple constant domains (or constant regions), are joined to one another by disulfide bonds within their constant domains to form the “backbone” of the antibody. The light chains, each containing one variable domain (or variable region, VL) and one constant domain (or constant region), are each joined to one heavy chain by disulfide bonds. The variable region of each light chain is aligned with the variable region of the heavy chain to which it is joined. The variable regions of both light and heavy chains contain three hypervariable regions, which are sandwiched between more conserved framework regions (FRs).

[0652] These hypervariable regions, known as complementarity determining regions (CDRs), form loops that comprise the majority of the antibody’s primary antigen-binding surface. The four framework regions mostly adopt beta-sheet conformations, while the CDRs form loops that connect and in some cases form part of the beta-sheet structure. The CDRs in each chain are held together and in correct orientation by the framework regions and, together with the CDRs from the other chain, contribute to the formation of the antigen-binding region.

[0653] Methods for identifying the CDR regions of an antibody by analyzing the amino acid sequence of the antibody are well known and generally use a number of definitions of CDRs. The Kabat definition is based on sequence variability and the Chothia definition is based on the location of the structural loop regions. These methods and definitions are described in, for example, Martin, “Protein sequence and structure analysis of antibody variable domains”, Antibody engineering, Springer Berlin Heidelberg, 2001, 422-439; Abhinandan et al., “Analysis and improvements to Kabat and structurally correct numbering of antibody variable domains”, Molecular immunology 45.14 (2008): 3832-3839; Wu, T.T. and Kabat, E.A. (1970) J. Exp. Med., 132: 211-250; Martin et al., Methods Enzymol. 203: 121-153 (1991); Morea et al., Biophys Chem. 68(1-3): 9-16 (Oct. 1997); Morea et al., J Mol Biol. 275(2): 269-294 (Jan. 1998); Chothia et al., Nature 342(6252): 877-883 (Dec. 1989); Ponomarenko and Bourne, BMC Structural Biology 7:64 (2007), all of which are incorporated herein by reference in their entirety.

[0654] CDRs are important for recognizing an epitope of an antigen. As used herein, an “epitope” is the smallest portion of a target molecule that is capable of being specifically bound by an antigen binding domain of an antibody. The minimum size of an epitope can be about three, four, five, six, or seven amino acids, but these amino acids need not be in a contiguous linear sequence of the primary structure of the antigen, as an epitope can depend on the three-dimensional configuration of the antigen based on the secondary and tertiary structure of the antigen.

[0655] In some embodiments, the antibody is an intact immunoglobulin molecule (e.g., IgGl, IgG2a, IgG2b, IgG3, IgM, IgD, IgE, IgA). IgG subclasses (IgGl, IgG2, IgG3, and IgG4) are highly conserved, but differ in their constant regions, particularly the hinge and upper CH2 domains. Sequences and differences of IgG subclasses are known in the art and described in, e.g., Vidarsson et al., "IgG subclasses and allotypes: from structure to effector functions." Frontiers in immunology 5 (2014); Irani et al., "Molecular properties of human IgG subclasses and their implications for designing therapeutic monoclonal antibodies against infectious diseases." Molecular immunology 67.2 (2015): 171-182; Shakib, Farouk, ed. "The human IgG subclasses: molecular analysis of structure, function and regulation." Elsevier, 2016, each of which is incorporated by reference herein in its entirety.

[0656] Antibodies can also be immunoglobulin molecules derived from any species (e.g., human, rodent, mouse, camelid). Antibodies disclosed herein also include, but are not limited to, polyclonal antibodies, monoclonal antibodies, monospecific antibodies, multispecific antibodies, and chimeric antibodies comprising an immunoglobulin binding domain fused to another polypeptide. The term “antigen binding domain” or “antigen binding fragment” is a portion of an antibody that retains the specific binding activity of the intact antibody, i.e., any portion of an antibody that is capable of specifically binding to an epitope on a target molecule of the intact antibody. It includes, for example, Fab, Fab’, F(ab’)2, and variants of these fragments. Thus, in some embodiments, an antibody or antigen binding fragment thereof can be, for example, a scFv, Fv, Fd, dAb, bispecific antibody, bispecific scFv, diabody, linear antibody, single-chain antibody molecule, multispecific antibody formed from antibody fragments, and any polypeptide comprising an antibody binding domain or a binding domain homologous thereto. Non-limiting examples of antigen binding domains include, for example, a heavy and / or light chain CDR of an intact antibody, a heavy and / or light chain variable region of an intact antibody, a full-length heavy or light chain of an intact antibody, or a single CDR from a heavy or light chain of an intact antibody.

[0657] In some embodiments, the antigen binding fragment can form part of a chimeric antigen receptor (CAR). In some embodiments, the chimeric antigen receptor is a fusion of a single-chain variable fragment (scFv) as described herein fused to a CD3-zeta transmembrane domain and an intracellular domain. In some embodiments, the chimeric antigen receptor further includes intracellular signaling domains from various costimulatory protein receptors (e.g., CD28, 41BB, ICOS). In some embodiments, the chimeric antigen receptor includes multiple signaling domains, e.g., CD3z-CD28-41BB or CD3z-CD28-OX40, to increase potency. Thus, in one aspect, the present disclosure also provides a cell (e.g., a T cell) expressing a chimeric antigen receptor as described herein.

[0658] In some embodiments, the scFv has one heavy chain variable domain and one light chain variable domain. In some embodiments, the scFv has two heavy chain variable domains and two light chain variable domains.

[0659] A single-chain Fv (scFv) or antibody fragment comprises the VH and VL domains (or regions) of an antibody, wherein these domains are present in a single polypeptide chain. Generally, the scFv polypeptide also includes a polypeptide linker between the VH and VL domains, which enables the scFv to form the desired structure for antigen binding.

[0660] Fab fragments contain the variable domain and the constant domain of the light chain and the variable domain and the first constant domain (CH1) of the heavy chain. F(ab')2 antibody fragments comprise a pair of Fab fragments which are generally covalently linked near their carboxy termini by hinge cysteines between them. Other chemical couplings of antibody fragments are also known in the art.

[0661] Diabodies are small antibody fragments with two antigen-binding sites, which fragments comprise VHand VLconnected to the same polypeptide chain. By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites.

[0662] Linear antibodies include a pair of tandem Fd segments (VH-CH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen binding regions. Linear antibodies can be bispecific or monospecific.

[0663] One-arm antibodies can have a heavy chain and a light chain, and a heavy chain fragment that includes CH2 and CH3 domains of an IgG. In some embodiments, a one-arm antibody is an antibody that has only one of the two antigen-binding arms of a typical antibody. In some embodiments, a one-arm antibody includes one antigen-binding arm (e.g., VH+CH1 and VL+CL) and an Fc region.

[0664] Antibodies and antibody fragments of the present disclosure can be modified in the Fc region to provide a desired effector function or serum half-life. In some embodiments, the Fc region can be modified to silence or reduce complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC). In some embodiments, the Fc region can be modified to enhance complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC).

[0665] Polymerization of antibodies can be achieved by natural aggregation of antibodies or by chemical or recombinant linkage techniques known in the art. For example, a certain percentage of purified antibody preparations (e.g., purified IgG1 molecules) spontaneously form protein aggregates containing antibody homodimers and other higher order antibody polymers.

[0666] Alternatively, antibody homodimers can be formed by chemical linkage techniques known in the art. For example, heterobifunctional cross-linking reagents including, but not limited to, SMCC (succinimidyl 4-(maleimidomethyl) cyclohexane-l-carboxylate) and SATA (N-succinimidyl S-acetylthioacetate) can be used to form antibody multimers. An exemplary protocol for forming antibody homodimers is described in Ghetie et al. (Proc. Natl. Acad. Sci. U.S.A. 94:7509-7514, 1997). By pepsin digestion, antibody homodimers can be converted to Fab'2 homodimers. Another method of forming antibody homodimers is by use of the autophilic T15 peptide, which is described in Zhao et al. (J. Immunol. 25:396-404, 2002).

[0667] In some embodiments, the multispecific antibody is a bispecific antibody. Bispecific antibodies can be produced by engineering the interface between a pair of antibody molecules to maximize the recovery of heterodimers from recombinant cell culture. For example, the interface can include at least a portion of the CH3 domain of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g., tyrosine or tryptophan). Compensatory “cavities” of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g., alanine or threonine). This provides a mechanism for maximizing yield of the desired heterodimers and a concomitant reduction in the yield of other unwanted species such as homodimers. This method is described in, for example, WO 96 / 27011, which is incorporated herein by reference in its entirety.

[0668] Bispecific antibodies include cross-linked or “heteroconjugate” antibodies. For example, one of the antibodies in a heteroconjugate can be coupled to avidin, the other to biotin. Heteroconjugate antibodies can be made using any convenient cross-linking methods. Suitable cross-linking agents and cross-linking techniques are well known in the art and are disclosed in U.S. Patent No. 4,676,980, which is incorporated herein by reference in its entirety.

[0669] Methods of generating bispecific antibodies from antibody fragments are also known in the art. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al. (Science 229:81, 1985) describe a method in which intact antibodies are cleaved by a proteolytic enzyme to generate F(ab')2 fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The resulting Fab' fragments are then converted to thioester derivatives. One of the Fab' thioester derivatives is then converted to a Fab' thiol by reduction with mercaptoethylamine, and mixed with an equimolar amount of the other Fab' thioester derivative to form the bispecific antibody.

[0670] In some embodiments, the sequences (e.g., CDR or VH / VL sequences) of the antibodies or antigen-binding fragments thereof described herein can be used to generate a bispecific antibody that targets PTK7 and TROP2.

[0671] Any of the antibodies or antigen-binding fragments described herein can be conjugated to a stabilizing molecule (e.g., a molecule that increases the half-life of the antibody or antigen-binding fragment thereof in a subject or in solution). Non-limiting examples of stabilizing molecules include: a polymer (e.g., polyethylene glycol) or a protein (e.g., serum albumin, such as human serum albumin). Conjugation to a stabilizing molecule can increase the half-life or prolong the biological activity of the antibody or antigen-binding fragment in vitro (e.g., in tissue culture or when stored as a pharmaceutical composition) or in vivo (e.g., in a human).

[0672] The present disclosure also provides antibodies or antigen-binding fragments thereof that cross-compete with any of the antibodies or antigen-binding fragments as described herein. Cross-competition assays are known in the art and described, for example, in Moore et al., "Antibody cross-competition analysis of the human immunodeficiency virus type 1 gp120 exterior envelope glycoprotein." Journal of virology, 70.3 (1996): 1863-1872, which is incorporated by reference herein in its entirety. In an aspect, the present disclosure also provides antibodies or antigen-binding fragments thereof that bind to the same epitope or region as any of the antibodies or antigen-binding fragments as described herein. Epitope binning assays are known in the art and described, for example, in Estep et al., "High throughput solution-based measurement of antibody-antigen affinity and epitope binning." MAbs. Vol. 5. No. 2. Taylor & Francis, 2013, which is incorporated by reference herein in its entirety.

[0673] To determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and second amino acid or nucleic acid sequence for optimal alignment and non homologous sequences can be disregarded for comparison purposes). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using, for example, a Blossum 62 scoring matrix, wherein the gap penalty is 12, the gap extension penalty is 4, and the frameshift gap penalty is 5.

[0674] Antibody drug conjugates (ADCs)

[0675] In some embodiments, the antibody, antigen-binding fragment thereof, or multispecific antibody (e.g., bispecific antibody) can be conjugated to a therapeutic agent, optionally through a linker, to form an antibody drug conjugate. The antibody drug conjugate comprising the antibody or antigen-binding fragment thereof can covalently or noncovalently bind the therapeutic agent. In some embodiments, the therapeutic agent is a cytotoxic or cytostatic agent (e.g., monomethyl auristatin E, monomethyl auristatin F, camptothecin, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, teniposide, vincristine, vinblastine, colchicin, doxorubicin, daunorubicin, dihydroxy anthracin dione, maytansinoid (such as DM-1 and DM-4), diketopiperazine, mitoxantrone, actinomycin, dactinomycin, 1-dehydrotestosterone, glucocorticoid, procaine, tetracaine, lidocaine, propranolol, puromycin, epirubicin, and cyclophosphamide and analogs). In some embodiments, the therapeutic agent is MMAE or MMAF.

[0676] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this application, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional group definitions can be found in, e.g., Riddick, Organic Functional Group

[0677] All ranges recited herein are inclusive. When listing ranges, it is intended to encompass each value and sub-range within the range. For example, "Ci-6" is intended to encompass Ci, C2, C3, C4, C5, C6, Ci-6, Ci-5, Ci-4, Ci-3, Ci-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6.

[0678] The compounds of the present disclosure or any depicted and described formula of a compound can have one or more chiral (asymmetric) centers. The present invention includes all stereoisomer forms of the compounds described herein or any depicted and described formula of a compound. Asymmetric centers present in the compounds of the present invention or any depicted and described formula of a compound can independently have the (R) or (S) configuration. When the bond to a chiral carbon is depicted in the structural formula as a straight line, or when a (R) or (S) configuration designation for a chiral carbon is absent in a compound name, it is understood that both the (R) and (S) configurations of each chiral carbon are included in the formula or name, thus encompassing each enantiomer or diastereomer and mixtures thereof.

[0679] The present disclosure includes all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomers, for example, mixtures of enantiomers and / or diastereomers in various proportions. Thus, enantiomers of the present disclosure include enantiomerically pure, levorotatory enantiomers and dextrorotatory enantiomers, racemates, and mixtures of enantiomers in various proportions. If cis / trans isomers, then both cis and trans, and mixtures in various proportions are included. If desired, individual stereoisomers can be prepared by the separation of a mixture of such isomers by ordinary techniques, for example, chromatography or crystallization techniques, by synthesis from a stereospecifically pure starting material, or by stereoselective synthesis. Optionally, derivatization can be performed following the separation of the stereoisomers. The separation of mixtures of stereoisomers can be performed as an intermediate step in the synthesis of the compound or on the final racemic product. The absolute stereochemistry can be determined by X-ray crystallographic analysis of a crystalline product or crystalline intermediate which has been derivatized, if necessary, to introduce a chiral center of known absolute configuration. Alternatively, the absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectroscopy analysis.

[0680] Unless otherwise stated, structures depicted herein are also meant to include only compounds which differ only in the presence of one or more isotopically enriched atoms. In other words, compounds which differ only in the presence of one or more non-naturally occurring atoms, for example deuterium (2H or D), carbon-13 (13C), carbon-14 (14C), nitrogen-15 (15N), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P), and sulfur-35 (35S) are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, as reference standards in bioassays, or as therapeutic agents in animal studies. Examples of suitable isotopes include, but are not limited to,2H (i.e., D),3H,11C,13C,14C,13N,15N,17O,18O,18F,123I,125I,32P, and35S. Certain isotopic variations of the compounds of the disclosure or any of the depicted and described formulae of the compounds, for example, those incorporating a radioactive isotope, can be useful in drug and / or substrate tissue distribution studies. In particular, compounds having the structures described, differing only in the placement of a heavier isotope, such as deuterium (2H or D) for hydrogen, can provide certain therapeutic advantages, for example, greater metabolic stability, longer half-life in vivo, or reduced dosage requirements, and thus, can be used in certain particular circumstances. Isotopic variations of the compounds of the disclosure or any of the depicted and described formulae of the compounds can generally be prepared by techniques known to those skilled in the art, or by processes analogous to those described in the accompanying Examples, and synthesized using appropriate isotopically-labeled reagents in place of the non-labeled reagents previously employed.

[0681] The compounds provided herein are described in terms of general formulae and specific compounds. In addition, the compounds of the disclosure can exist in a variety of different forms or derivatives, all of which are within the scope of the disclosure. These include, for example, pharmaceutically acceptable salts, tautomers, stereoisomers, racemic mixtures, regioisomers, prodrugs, solvated forms, different crystal or polymorphic forms, and active metabolites, among others.

[0682] As used herein, unless otherwise noted, the term "pharmaceutically acceptable salt" includes salts that retain the biological effectiveness and non-antagonistic of the free acids and bases forms of the particular compound and that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts can include salts with inorganic or organic bases and acids. In cases where the compounds of the present disclosure contain one or more acidic or basic groups, the present disclosure also includes the corresponding pharmaceutically acceptable salts thereof. Thus, compounds of the present disclosure containing an acidic group, such as a carboxyl group, can exist as salts and can be used in accordance with the present disclosure, for example, alkali metal salts, alkaline earth metal salts, aluminum salts, or ammonium salts. Further non-limiting examples of such salts include lithium, sodium, potassium, calcium, magnesium, barium, or salts with ammonia or organic amines such as ethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, N-methylglutamine, or amino acids. These salts are readily obtained by, for example, reacting a compound having an acidic group with a suitable base (e.g., lithium hydroxide, sodium hydroxide, sodium propoxide, potassium hydroxide, potassium ethoxide, magnesium hydroxide, calcium hydroxide, or barium hydroxide). Other base salts of the compounds of the present disclosure include, but are not limited to, copper (I), copper (II), iron (II), iron (III), manganese (II), and zinc salts. Compounds of the present disclosure containing one or more basic groups, such as protonatable groups, can exist as salts and can be used in accordance with the present disclosure in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, sulfosalicylic acid, trifluoroacetic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, carbonic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, pamoic acid, mandelic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid, or aspartic acid, and other acids known to those skilled in the art. Salts formed include hydrochlorides, chlorides, hydrobromides, bromides, iodides, sulfates, phosphates, methanesulfonates (mesylates), toluenesulfonates, carbonates, bicarbonates, formates, acetates, sulfosalicylates, trifluoromethanesulfonates, oxalates, malonates, maleates, succinates, tartrates, malates, pamoates, mandelates, fumarates, lactates, citrates, glutarates, stearates, aspartates, and glutamates. In addition, the stoichiometric ratios of the salts formed from the compounds of the present disclosure can be whole or non- whole number multiples of one.

[0683] Compounds containing basic nitrogen-containing groups in the present disclosure can be quaternized with dialkyl sulfates such as dimethyl, diethyl, and diamyl sulfate; with long chain alkyl halides such as decyl, lauryl, myristyl, and stearyl chlorides; and with arylalkyl halides such as benzyl and benzhydryl bromides. The compounds of the present disclosure can be formulated into pharmaceutical compositions and administered in a variety of dosage forms. The compounds of the present disclosure can be administered by oral, parenteral (including subcutaneous, intravenous, intramuscular, intraarterial, intrathecal, and intraperitoneal), by inhalation, or rectally, and in the form of compositions such as tablets, capsules, patches, powders, granules, creams, suppositories, liquids, or injections. The compounds of the present disclosure can also be administered topically, in the form of solutions, suspensions, lotions, gels, creams, ointments, aerosols, or patches. The compounds of the present disclosure can also be administered in the form of sterile solid compositions suitable for solution in, or suspension in, sterile water, or other sterile injectable medium, immediately before use. The compounds of the present disclosure can also be administered in the form of sterile solids or powders intended for reconstitution with water or other suitable medium immediately before use.

[0684] If the compounds of the present disclosure contain both acidic and basic moieties within the molecule, in addition to the salt forms mentioned above, the present disclosure also includes the zwitterions or betaines. The corresponding salts can be obtained in customary manner by contacting these salts with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present disclosure also includes all salts of the compounds of the present disclosure which, due to low physiological compatibility, are not suitable for direct use in medicine, but can be used as, for example, intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. For an overview of more suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002).

[0685] The compounds of the present disclosure or any formula depicting and describing the compounds and pharmaceutically acceptable salts thereof can exist in unsolvated and solvated forms. The term “solvate” as used herein refers to a molecular complex comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules. For example, the term “hydrate” is used when the solvent is water.

[0686] Pharmaceutically acceptable solvates according to the present disclosure can include those wherein the solvent can be isotopically substituted, such as D2O, d6-acetone, d6-DMSO.

[0687] Linker (linker compound)

[0688] In some embodiments, the therapeutic agent is conjugated via a linker (or linker compound). As used herein, the term “linker” or “linker compound” refers to a compound that can react with the groups of a ligand compound and a therapeutic agent compound, respectively, via, for example, a coupling reaction, to link the ligand (such as an antibody, antigen-binding fragment thereof, or antigen-binding protein construct (e.g., bispecific antibody) as described herein and the therapeutic agent (such as any therapeutic agent as described herein) together to form a ligand-drug conjugate.

[0689] In some embodiments, the linker described herein is a compound having the following formula:

[0690] Q-L Formula (I),

[0691] or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, wherein Q represents a linking moiety capable of coupling to a ligand through a bond selected from a carbonyl, thioether, amide, disulfide, and hydrazone bond; L represents a linker moiety capable of linking Q to a therapeutic agent.

[0692] In some embodiments, the linking moiety (Q in Formula (I)) has the following structure:

[0693]

[0694] In some embodiments, the linking moiety (L in Formula (I)) has the following structure:

[0695]

[0696] wherein L1is a polypeptide residue consisting of 3 to 8 amino acid residues, the polypeptide residue including at least one amino acid residue bearing a side chain carboxyl group, such as a glutamic acid residue or an aspartic acid residue, wherein “-COOH” represents the carboxyl group of the C-terminal amino acid residue of the polypeptide residue;

[0697] L2is absent or a monodentate, bidentate, or tridentate hydrophilic group attached to the side chain carboxyl group of an amino acid residue of the polypeptide residue L1, and L2has the structure of NHC(R L2a )(R L2b )(R L2c ), wherein R L2a , R L2b , and R L2c are each independently selected from the group consisting of H, -(CH2O)(CH2CH2O) m (CH2) p C(O)OH, and -(CH2O)(CH2CH2O) m (CH2) p C(O)NHR L2d , wherein R L2d is H or C 1-6 alkyl optionally substituted with 1 to 6 hydroxyl groups, each m is independently an integer from 0 to 10, preferably 0 to 4, such as 0, 1, 2, 3, or 4, with m being particularly preferably 0, each p is independently an integer from 1 to 4, such as 1, 2, 3, or 4; and

[0698] represents the N-terminal side of the polypeptide residue covalently linked to the linking moiety Q.

[0699] In some embodiments, polypeptide residue LI is NH-glutamic acid-valine-alanine-COOH. In some embodiments, hydrophilic group L2 has the following structure:

[0700]

[0701] wherein “*” indicates the site of covalent attachment to polypeptide residue LI, such as the side chain of the glutamic acid residue in NH-glutamic acid-valine-alanine-COOH.

[0702] In some embodiments, the linker described herein is a compound having the following structure:

[0703]

[0704] In some embodiments, the linker is a VC linker. For detailed information on linkers used in ADCs, see Su, Z, et al., “Antibody-drug conjugates: Recent advances in linker chemistry.” Acta Pharmaceutica Sinica B (2021), which is incorporated by reference herein in its entirety.

[0705] Therapeutic agent

[0706] In some embodiments, the therapeutic agent conjugated to an antibody, antigen binding fragment thereof, or multispecific antibody (e.g., bispecific antibody) described herein is discussed below.

[0707] In some embodiments, the therapeutic agent described herein is a cytotoxic agent. In some embodiments, the cytotoxic agent is a camptothecin compound, an analog or derivative thereof. In some preferred embodiments, the camptothecin compound is a compound having the following structure:

[0708]

[0709] wherein X is selected from the group consisting of -CH2-, O, and S; Y is selected from the group consisting of H, D, and F.

[0710] In some embodiments, the therapeutic agent is (S)-4-amino-9-ethyl-9-hydroxy-1,9,12,15- tetrahydro-13H-pyrano[3',4':6,7]indolizino[1,2-b]thiopyrano[4,3,2-de]quinoline-10,13(2H)- dione (CPT-1). The structure of CPT-1 is shown below:

[0711]

[0712] In some embodiments, the therapeutic agent is (S)-4-amino-9-ethyl-9-hydroxy- 1,9,12,15-tetrahydro-13H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline- 10,13(2H)-dione (CPT-2). The structure of CPT-2 is shown below:

[0713]

[0714] In some embodiments, the therapeutic agent is CPT3. The structure of CPT-3 is shown below:

[0715]

[0716] In some embodiments, the therapeutic agent is (S)-4-amino-9-ethyl-5-fluoro-9- hydroxy-1,9,12,15-tetrahydro-13H-pyrano[4,3,2-de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline- 10,13(2H)-dione (CPT-4). The structure of CPT-4 is shown below:

[0717]

[0718] In some embodiments, the therapeutic agent is an auristatin, such as auristatin E (also known in the art as a derivative of dolastatin-10) or a derivative thereof. For example, the auristatin can be an ester formed between auristatin E and a keto acid. For example, auristatin E can react with p-acetylbenzoic acid or benzoylvaleric acid to form AEB and AEVB, respectively. Other exemplary auristatins include AFP, MMAF, and MMAE. Synthesis and structures of exemplary auristatins are described in U.S. Patent Application Publication No. 2003-0083263, International Patent Publication No. WO 04 / 010957, International Patent Publication No. WO 02 / 088172, and U.S. Patent Nos. 7,498,298; 6,884,869; 6,323,315; 6,239,104; 6,034,065; 5,780,588; 5,665,860; 5,663,149; 5,635,483; 5,599,902; 5,554,725; 5,530,097; 5,521,284; 5,504,191; 5,410,024; 5,138,036; 5,076,973; 4,986,988; 4,978,744; 4,879,278; 4,816,444; and 4,486,414, which are incorporated by reference in their entireties and for all purposes.

[0719] Studies have shown that auristatins can interfere with microtubule dynamics as well as nuclear and cell division and have anti-cancer activity. Auristatins bind to tubulin and can produce cytotoxic or cytostatic effects on cancer cells. There are a number of different assays known in the art that can be used to determine whether an auristatin or an antibody-drug conjugate produced therefrom produces cytostatic or cytotoxic effects on the desired cells.

[0720] In some embodiments, the therapeutic agent is a chemotherapeutic agent. Examples of chemotherapeutic agents include alkylating agents (such as thiotepa and cyclosphosphamide (CYTOXAN®)), alkyl sulfonates, aziridines, ethylenimines, methylmelamines, nitrogen mustards, nitrosoureas, platinum compounds, and tetrahydrofurans. TMalkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as aclacinomycin, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalarnycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine;Pentostatin; Pheanamet; Pirarubicin; Podophyllin; 2-Ethylhydrazide; Procarbazine; PSK7; Razosen; Cizonan; Germanium spiroamine; Alternaria solanilic acid; Triaminoquinone; 2',2',2'-Trichlorotriethylamine; Ethyl carbamate; Vinpocetine; Dacarbazine; Mannomustine; Dibromomannitol; Dibromoeugenol; Piperobromide; Gacytosine; Arabinoside (“Ara-C”); Cyclophosphamide; Taxanes (e.g., paclitaxel); Bristol-Myers Squibb Oncology, Princeton, NJ) and Dorcetasi ( Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6-thioguanine; platinum analogs (such as cisplatin and carboplatin); vincristine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; mitoxantrone; teniposide; donomycin; aminopterin; Xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoic acid; esperapycin; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing substances. This definition also includes anti-hormonal agents that regulate or inhibit the effects of hormones on tumors, such as anti-estrogens, including, for example, tamoxifen, raloxifene, aromatase-inhibiting 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, raloxifene, LY117018, onanasone, and toremifene (Falletone); and anti-androgens, such as flutamide, nilumid, bicalutamide, leuprorelin, and goserelin; and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing substances. A detailed description of chemotherapeutic agents can be found, for example, in US20180193477A1, the entire text of which is incorporated herein by reference.

[0721] Linker-therapeutic compound

[0722] In some implementations, a linker (as described herein) and a therapeutic agent (as described herein) may be linked to form a "linker-therapeutic agent" compound.

[0723] In some embodiments, the linker-therapeutic compound has the following structure:

[0724]

[0725] In some embodiments, a linker-therapeutic compound has the following structure:

[0726]

[0727] In some embodiments, an antibody ("Ab"), such as any antibody, antigen-binding fragment or antigen-binding protein construct (e.g., bispecific antibody) described herein, can be linked to a linker-therapeutic compound, such as any linker-therapeutic compound described herein, to generate an antibody-drug conjugate. In some embodiments, an antibody-drug conjugate has the following structure:

[0728]

[0729] wherein n = 1, 2, 3, 4, 5, 6, 7, or 8.

[0730] Drug loading is represented by the number of drug moieties per antibody in the ADC molecule. For some antibody drug conjugates, drug loading can be limited by the number of attachment sites on the antibody. For example, when cysteine thiols are attached, as in certain exemplary embodiments described herein, drug loading can range from 0 to 8 drug moieties per antibody. In certain embodiments, higher drug loading, e.g., p > 5, can cause aggregation, insolubility, toxicity, or loss of cell permeability of certain antibody drug conjugates. In certain embodiments, the average drug loading of an antibody drug conjugate ranges from 1 to about 8; from about 2 to about 6; or from about 3 to about 5. Indeed, for certain antibody drug conjugates, it has been demonstrated that the optimal ratio of drug moieties per antibody can be about 4. In some embodiments, the drug antibody ratio (DAR) of an ADC described herein is about 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, or 9.0. In some embodiments, the DAR of an ADC described herein is about 3.5 to about 4.5, about 3.6 to about 4.5, about 3.7 to about 4.5, about 3.8 to about 4.5, about 3.9 to about 4.5, about 4.0 to about 4.5, about 4.1 to about 4.5, about 4.2 to about 4.5, about 4.3 to about 4.5, about 4.4 to about 4.5, about 3.5 to about 4.4, about 3.6 to about 4.4, about 3.7 to about 4.4, about 3.8 to about 4.4, about 3.9 to about 4.4, about 4.0 to about 4.4, about 4.1 to about 4.4, about 4.2 to about 4.4, about 4.3 to about 4.4, about 3.5 to about 4.3, about 3.6 to about 4.3, about 3.7 to about 4.3, about 3.8 to about 4.3, about 3.9 to about 4.3, about 4.0 to about 4.3, about 4.1 to about 4.3, about 4.2 to about 4.3, about 3.5 to about 4.2, about 3.6 to about 4.2, about 3.7 to about 4.2, about 3.8 to about 4.2, about 3.9 to about 4.2, about 4.0 to about 4.2, about 4.1 to about 4.2, about 3.5 to about 4.1, about 3.6 to about 4.1, about 3.7 to about 4.1, about 3.8 to about 4.1, about 3.9 to about 4.1, about 4.0 to about 4.1, about 3.5 to about 4.0, about 3.6 to about 4.0, about 3.7 to about 4.0, about 3.8 to about 4.0, about 3.9 to about 4.0, about 3.5 to about 3.9, about 3.6 to about 3.9, about 3.7 to about 3.9, about 3.8 to about 3.9, about 3.5 to about 3.8, about 3.6 to about 3.8, about 3.7 to about 3.8, about 3.5 to about 3.7, about 3.6 to about 3.7, or about 3.5 to about 3.6. In some embodiments, the average DAR in a composition is about 1 to about 2, about 2 to about 3, about 3 to about 4, about 3 to about 5, about 4 to about 5, about 5 to about 6, about 6 to about 7, or about 7 to about 8.

[0731] In some embodiments, the DAR of the ADCs described herein is about 7.5 to about 8.5, about 7.6 to about 8.5, about 7.7 to about 8.5, about 7.8 to about 8.5, about 7.9 to about 8.5, about 8.0 to about 8.5, about 8.1 to about 8.5, about 8.2 to about 8.5, about 8.3 to about 8.5, about 8.4 to about 8.5, about 7.5 to about 8.4, about 7.6 to about 8.4, about 7.7 to about 8.4, about 7.8 to about 8.4, about 7.9 to about 8.4, about 8.0 to about 8.4, about 8.1 to about 8.4, about 8.2 to about 8.4, about 8.3 to about 8.4, about 7.5 to about 8.3, about 7.6 to about 8.3, about 7.7 to about 8.3, about 7.8 to about 8.3, about 7.9 to about 8.3, about 8.0 to about 8.3, about 8.1 to about 8.3, about 8.2 to about 8.3, about 7.5 to about 8.2, about 7.6 to about 8.2, about 7.7 to about 8.2, about 7.8 to about 8.2, about 7.9 to about 8.2, about 8.0 to about 8.2, about 8.1 to about 8.2, about 7.5 to about 8.1, about 7.6 to about 8.1, about 7.7 to about 8.1, about 7.8 to about 8.1, about 7.9 to about 8.1, about 8.0 to about 8.1, about 7.5 to about 8.0, about 7.6 to about 8.0, about 7.7 to about 8.0, about 7.8 to about 8.0, about 7.9 to about 8.0, about 7.5 to about 7.9, about 7.6 to about 7.9, about 7.7 to about 7.9, about 7.8 to about 7.9, about 7.5 to about 7.8, about 7.6 to about 7.8, about 7.7 to about 7.8, about 7.5 to about 7.7, about 7.6 to about 7.7, or about 7.5 to about 7.6.

[0732] In some embodiments, the anti-PTK7, anti-TROP2, and / or anti-PTK7 / TROP2 ADCs described herein can effectively inhibit in vitro cancer cell growth at a concentration of less than 10 pg / mL, less than 3.33 pg / mL, less than 1.11 pg / mL, less than 0.37 pg / mL, less than 0.12 pg / mL, less than 0.04 pg / mL, or less than 0.01 pg / mL. In some embodiments, the anti-PTK7, anti-TROP2, and / or anti-PTK7 / TROP2 ADCs described herein can effectively inhibit in vitro cancer cell growth at a concentration of less than 10 pg / mL, less than 3.33 pg / mL, less than 1.11 pg / mL, less than 0.37 pg / mL, less than 0.12 pg / mL, less than 0.04 pg / mL, or less than 0.01 pg / mL.

[0733] The anti-PTK7, anti-TROP2, and / or anti-PTK7 / TROP2 ADCs can inhibit in vivo cancer cell growth (e.g., lung cancer, gastric cancer, or skin cancer) in a xenograft mouse model at a dose level of less than 10 mg / kg, 9 mg / kg, 8 mg / kg, 7 mg / kg, 6 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1.5 mg / kg, or 1 mg / kg.

[0734] Antibody and ADC Characteristics

[0735] The antibodies described herein, or their antigen-binding fragments, or ADCs derived therefrom, can block the binding between PTK7 and its ligand (e.g., Wnt ligand). In some embodiments, the antibodies described herein, or their antigen-binding fragments, or ADCs derived therefrom, can block the binding between TROP2 and its ligand (e.g., ErbB3 ligand neuroregulatory protein-1). In some embodiments, the antibodies described herein, or their antigen-binding fragments, or ADCs derived therefrom, can simultaneously block the binding between PTK7 and its ligand, as well as the binding between TROP2 and its ligand.

[0736] The antibodies or antigen-binding fragments thereof, or ADCs derived therefrom, described herein can be agonists or antagonists. In some embodiments, antibodies inhibit the PTK7 signaling pathway by binding to PTK7. In some embodiments, antibodies inhibit the TROP2 signaling pathway by binding to TROP2. In some embodiments, antibodies inhibit both the PTK7 and TROP2 pathways by simultaneously binding to both. In some embodiments, antibodies upregulate or downregulate the immune response.

[0737] In some implementations, the antibody (or its antigen-binding fragment) or an ADC derived therefrom delivers an antibody at a speed of less than 0.1 s. -1 Less than 0.01s -1 Less than 0.001s -1 Less than 0.0001s -1 Less than 0.00001s -1 Less than 0.000001s -1 or less than 0.0000001s -1 The dissociation rate (koff) specifically binds to PTK7 (e.g., human PTK7, monkey PTK7 (e.g., rhesus macaques, cynomolgus monkeys), dog PTK7, mouse PTK7). In some embodiments, the dissociation rate (koff) is greater than 0.01 s. -1 Greater than 0.001s -1 Greater than 0.0001s -1 Greater than 0.00001s -1 Greater than 0.000001s -1 Greater than 0.0000001s -1 or greater than 0.00000001s -1 .

[0738] In some implementations, the antibody (or its antigen-binding fragment) or an ADC derived therefrom delivers an antibody at a speed of less than 0.1 s. -1 Less than 0.01s -1less than 0.0001 s -1 less than 0.00001 s -1 less than 0.000001 s -1 less than 0.0000001 s -1 or less than 0.00000001 s -1 specifically binds TROP2 (e.g., human TROP2, monkey TROP2 (e.g., rhesus macaques, Macaca fascicularis), dog TROP2, mouse TROP2) with an off-rate (koff) of greater than 0.01 s -1 greater than 0.001 s -1 greater than 0.0001 s -1 greater than 0.00001 s -1 greater than 0.000001 s -1 greater than 0.0000001 s -1 or greater than 0.00000001 s -1 .

[0739] In some embodiments, the on-rate (kon) for PTK7 or TROP2 is greater than 1 x 10 2 Ms, greater than 1 x 10 3 Ms, greater than 1 x 10 4 Ms, greater than 1 x 10 5 Ms, or greater than 1 x 10 6 Ms. In some embodiments, the on-rate (kon) is less than 1 x 10 5 Ms, less than 1 x 10 6 Ms, or less than 1 x 10 7 Ms.

[0740] The affinity can be derived from the quotient of the kinetic rate constants (KD = koff / kon). In some embodiments, the KD for PTK7 or TROP2 is less than 1 x 10 -6 M, less than 1 x 10 -7 M, less than 1 x 10 -8 M, less than 1 x 10 -9 M, less than 1 x 10 -10 M, less than 1 x 10 -11 M, less than 1 x 10 -12 M, less than 1 x 10 -13 M, or less than 1 x 10 -14M. In some implementations, KD is less than 50 nM, 30 nM, 20 nM, 15 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM. In some implementations, KD is greater than 1 × 10⁻⁶. -7 M, greater than 1×10 -8 M, greater than 1×10 -9 M, greater than 1×10 -10 M, greater than 1×10 -11 M, greater than 1×10 -12 M, greater than 1×10 -13 M, greater than 1×10 -14 M.

[0741] Common techniques for measuring antibody affinity for antigens include, for example, ELISA, RIA, and surface plasmon resonance (SPR). In some embodiments, the antibody binds to human PTK7 (SEQ ID NO:75), monkey PTK7, dog PTK7 (SEQ ID NO:76), and / or mouse PTK7. In some embodiments, the antibody does not bind to human PTK7, monkey PTK7, dog PTK7, and / or mouse PTK7.

[0742] In some embodiments, the antibody binds to human TROP2, monkey TROP2, dog TROP2, and / or mouse TROP2. In some embodiments, the antibody does not bind to human TROP2, monkey TROP2, dog TROP2, and / or mouse TROP2.

[0743] In some embodiments, the antibody binds to human PTK7 and TROP2 (PTK7 / TROP2), monkey PTK7 / TROP2, dog PTK7 / TROP2, and / or mouse PTK7 / TROP2. In some embodiments, the antibody does not bind to human PTK7 / TROP2, monkey PTK7 / TROP2, dog PTK7 / TROP2, and / or mouse PTK7 / TROP2.

[0744] In some embodiments, an antibody or antigen-binding fragment thereof described herein or an ADC derived therefrom is added to NUGC-4 cells (e.g., Cobioer, Cat#: CBP60493) or LN229 cells (ATCC, Cat#: CRL-2611) to test endocytosis rate. In some embodiments, an antibody or antigen-binding fragment thereof described herein or an ADC derived therefrom has an endocytosis rate of greater than 5%, greater than 10%, greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 91%, greater than 92%, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, or greater than 98%.

[0745] In some embodiments, thermal stability is determined. An antibody or antigen-binding fragment thereof described herein or an ADC derived therefrom can have a Tm of greater than 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, or 95 °C. In some embodiments, the Tm is less than 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, or 95 °C.

[0746] In some embodiments, an antibody or antigen-binding fragment thereof as described herein or an ADC derived therefrom can bind the same epitope of PTK7, TROP2, and / or PTK7 / TROP2. In some embodiments, an antibody or antigen-binding fragment thereof as described herein or an ADC derived therefrom can bind different epitopes of PTK7, TROP2, and / or PTK7 / TROP2.

[0747] In some embodiments, an ADC described herein has an average drug antibody ratio (DAR) of greater than 3, greater than 3.2, greater than 3.4, greater than 3.6, greater than 3.8, greater than 4, greater than 4.2, greater than 4.4, or greater than 4.6, as determined by HPLC. In some embodiments, an ADC described herein has an average DAR of less than 3, less than 3.2, less than 3.4, less than 3.6, less than 3.8, less than 4, less than 4.2, less than 4.4, or less than 4.6, as determined by HPLC.

[0748] In some embodiments, an antibody or antigen-binding fragment thereof as described herein, or an ADC derived therefrom, has a tumor growth inhibition percentage (TGI%) of greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%. In some embodiments, an antibody or antigen-binding fragment thereof as described herein, or an ADC derived therefrom, has a tumor growth inhibition percentage of less than 60%, 70%, 80%, 90%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%. The TGI% can be determined, for example, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days after the start of treatment, or 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months after the start of treatment. As used herein, the tumor growth inhibition percentage (TGI%) is calculated using the following formula:

[0749] TGI (%) = [1 - (Ti - To) / (Vi - Vo)] x 100

[0750] Ti is the average tumor volume in the treatment group on day i. To is the average tumor volume in the treatment group on day zero. Vi is the average tumor volume in the control group on day i. Vo is the average tumor volume in the control group on day zero.

[0751] In some embodiments, an antibody or antigen-binding fragment thereof as described herein, or an ADC derived therefrom, is a PTK7 antagonist. In some embodiments, an antibody or antigen-binding fragment thereof as described herein, or an ADC derived therefrom, reduces PTK7 signaling in a target cell expressing PTK7.

[0752] In some embodiments, an antibody or antigen-binding fragment thereof as described herein, or an ADC derived therefrom, is a TROP2 antagonist. In some embodiments, an antibody or antigen-binding fragment thereof as described herein, or an ADC derived therefrom, reduces TROP2 signaling in a target cell expressing TROP2.

[0753] In some embodiments, the antibody or antigen-binding fragment thereof or ADC derived therefrom as described herein is a PTK7 and TROP2 (PTK7 / TROP2) antagonist. In some embodiments, the antibody or antigen-binding fragment thereof or ADC derived therefrom as described herein reduces PTK7 and TROP2 (PTK7 / TROP2) signaling in target cells expressing PTK7 and TROP2 (PTK7 / TROP2).

[0754] In some embodiments, the antibody or antigen-binding fragment thereof or ADC derived therefrom described herein can enhance APC (e.g., DC cell) function, e.g., induce surface expression of costimulatory and MHC molecules, induce production of proinflammatory cytokines, and / or enhance T cell priming function.

[0755] In some embodiments, the antibody or antigen-binding fragment thereof or ADC derived therefrom described herein can bind to tumor cells expressing PTK7. In some embodiments, the antibody or antigen-binding fragment thereof or ADC derived therefrom described herein can bind to tumor cells expressing TROP2. In some embodiments, the antibody or antigen-binding fragment thereof or ADC derived therefrom described herein can bind to tumor cells expressing both PTK7 and TROP2. In some embodiments, the antibody or antigen-binding fragment thereof or ADC derived therefrom described herein can induce complement-dependent cytotoxicity (CDC) and / or antibody-dependent cellular cytotoxicity (ADCC) and kill tumor cells.

[0756] In some embodiments, the antibody or antigen-binding fragment thereof or ADC derived therefrom described herein has a functional Fc region. In some embodiments, the effector function of the functional Fc region is antibody-dependent cell-mediated cytotoxicity (ADCC). In some embodiments, the effector function of the functional Fc region is phagocytosis. In some embodiments, the effector function of the functional Fc region is ADCC and phagocytosis.

[0757] In some embodiments, the antibody or antigen-binding fragment thereof or ADC derived therefrom described herein can induce complement-dependent cytotoxicity (CDC).

[0758] In some embodiments, the Fc region is human IgGl, human IgG2, human IgG3, or human IgG4. In some embodiments, the antibody is a human IgGl antibody, optionally with SI mutations, LALA mutations, N297A mutations, YTE mutations, and / or FLAA mutations. In some embodiments, the antibody is a human IgG4 antibody, optionally with SI mutations, LALA mutations, N297A mutations, YTE mutations, and / or FLAA mutations.

[0759] In some embodiments, the antibody or antigen-binding fragment thereof described herein, or the ADC derived therefrom, does not have a functional Fc region. For example, the antibody or antigen-binding fragment is a Fab, Fab', F(ab')2, and Fv fragment. In some embodiments, the Fc region has LALA mutations (L234A and L235A mutations according to EU numbering), or LALA-PG mutations (L234A, L235A, P329G mutations according to EU numbering). In some embodiments, the Fc region has FLAA mutations (F234A and L235A according to EU numbering). In some embodiments, the Fc has SI mutations (S239D and I332E mutations according to EU numbering). In some embodiments, the Fc has N297A mutation according to EU numbering. In some embodiments, the Fc has YTE mutations (M252Y, S254T, and T256E according to EU numbering).

[0760] Methods of making anti-PTK7, anti-TROP2, and / or anti-PTK7 / TROP2 antibodies

[0761] Antibodies can be produced using standard techniques for polyclonal and monoclonal antibody production using isolated human PTK7 and / or TROP2 fragments as immunogens. Polyclonal antibodies can be produced in animals by multiple injections (e.g., subcutaneous or intraperitoneal injections) of the antigenic peptide or protein. In some embodiments, the antigenic peptide or protein is injected with at least one adjuvant. In some embodiments, the antigenic peptide or protein can be conjugated to an agent that is immunogenic in the species to be immunized. The animal can be injected more than once (e.g., twice, three times, or four times) with the antigenic peptide or protein.

[0762] Full-length polypeptides or proteins, or antigenic peptide fragments thereof, can be used as immunogens. Antigenic peptides of a protein include at least 8 (e.g., at least 10, 15, 20, or 30) amino acid residues of the amino acid sequence of PTK7, TROP2, and encompass an epitope of the protein such that an antibody raised against the peptide forms a specific immunological complex with the protein. As noted above, the full-length sequence of human PTK7 (SEQ ID NO: 75) and TROP2 are known in the art. In some embodiments, human PTK7 or TROP2 proteins with an Fc tag or a His tag are used as immunogens.

[0763] Immunogens are typically used to prepare antibodies by immunizing a suitable subject (e.g., a human or transgenic animal that expresses at least one human immunoglobulin locus). An appropriate immunogenic preparation can contain, for example, a recombinantly expressed or chemically synthesized polypeptide (e.g., a fragment of human PTK7 or TROP2). The preparation can also include an adjuvant (such as Freund’s complete or incomplete adjuvant) or similar immunostimulatory agent.

[0764] Polyclonal antibodies can be prepared as described above by immunizing a suitable subject with a PTK7 or TROP2 polypeptide or an antigenic peptide thereof (e.g., a portion of PTK7 or TROP2) as an immunogen. Antibody titers in immunized subjects can be monitored over time by standard techniques, such as with an enzyme-linked immunoadsorbent assay (ELISA) using immobilized PTK7 or TROP2 polypeptides or peptides. If desired, antibody molecules can be isolated from the mammal (e.g., from the blood) and further purified by well-known techniques, such as protein A or protein G chromatography, to obtain the IgG fraction. At an appropriate time after immunization, e.g., when specific antibody titers are highest, antibody-producing cells can be obtained from the subject and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique first described by Kohler et al. (Nature 256:495-497, 1975), the human B-cell hybridoma technique (Kozbor et al., Immunol. Today 4:72, 1983), the EBV-hybridoma technique (Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96, 1985), or the trioma technique. Techniques for producing hybridomas are well known (see generally "Current Protocols in Immunology", 1994, Coligan et al. (Eds.), John Wiley & Sons, Inc., New York, NY). Hybridoma cells that produce a monoclonal antibody are detected by screening the hybridoma culture supernatants for antibodies that bind the polypeptide or epitope of interest, e.g., using a standard ELISA assay.

[0765] Variants of the antibodies or antigen-binding fragments described herein can be prepared by introducing appropriate nucleotide changes into the DNA encoding a human, humanized, or chimeric antibody or antigen-binding fragment thereof described herein, or by peptide synthesis. Such variants include, for example, deletions from, insertions into, or substitutions of residues within the amino acid sequence of an antigen-binding site comprising an antibody or antigen-binding domain. Within a population of such variants, some antibodies or antigen-binding fragments will have increased affinity for the target protein (e.g., PTK7 or TROP2). Any combination of deletion, insertion, and / or substitution can be made to obtain an antibody or antigen-binding fragment thereof having increased binding affinity for the target. Introducing amino acid changes to an antibody or antigen-binding fragment can also alter or introduce new post-translational modifications into the antibody or antigen-binding fragment, such as changing (e.g., increasing or decreasing) the number of glycosylation sites, changing the type of glycosylation site (e.g., changing the amino acid sequence such that a different sugar is attached by enzymes present in the cell), or introducing new glycosylation sites.

[0766] The antibodies disclosed herein can be derived from any species of animal, including mammals. Non-limiting examples of native antibodies include antibodies derived from humans, primates (e.g., monkeys and apes), bovines, porcines, equines, ovines, camelids (e.g., camels and llamas), chickens, goats, and rodents (e.g., rats, mice, hamsters, and rabbits, including transgenic rodents genetically engineered to produce human antibodies).

[0767] Human and humanized antibodies include antibodies having variable and constant regions derived from (or identical to) human germline immunoglobulin sequences. Human antibodies can include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by in vitro random or site-specific mutagenesis or in vivo somatic mutation), for example, in the CDRs.

[0768] Humanized antibodies are typically grafted with non-human CDRs onto a human framework (FR). Thus, a humanized antibody has one or more amino acid sequences introduced into it from a non-human source. These non-human amino acid residues are typically referred to as “import” residues, which are typically taken from an “import” variable domain. Humanization can be essentially performed, for example, by substituting individual rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. These methods are described, for example, in Jones et al., Nature, 321 :522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988); the entire disclosures of which are incorporated herein by reference. Accordingly, a “humanized” antibody is a chimeric antibody that contains small portions of the entire human V domain replaced by corresponding sequences from a non-human species. In practice, humanized antibodies are typically mouse antibodies in which some CDR residues and some FR residues are substituted by residues from analogous sites in human antibodies.

[0769] The selection of human VHand VLdomains for use in making humanized antibodies is important to reduce immunogenicity. According to the so-called “best-fit” method, the V domain sequence of a mouse antibody is screened against the entire library of known human domain sequences. The human sequence which is closest to that of the mouse is then accepted as the human FR for the humanized antibody (Sims et al., J. Immunol., 151 :2296 (1993); Chothia et al., J. Mol. Biol., 196:901 (1987)).

[0770] More importantly, the antibody is humanized while retaining high specificity and affinity for the antigen and other favorable biological properties. To achieve this goal, a humanized antibody can be produced by a process that analyzes the parent sequence and various conceptual humanized products using three-dimensional models of the parent and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen. By this method, FR residues can be selected and combined from the recipient and import sequences so that the desired antibody characteristics, such as increased affinity for the target antigen, are achieved.

[0771] Generally, an amino acid sequence variant of a human, humanized, or chimeric anti-PTK7, anti-TROP2, or anti-PTK7 / TROP2 antibody will contain an amino acid sequence that has at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% percent identity to the sequence found in the original antibody light or heavy chain.

[0772] In some embodiments, the antibody is produced using a mouse having a humanized heavy chain immunoglobulin locus and a humanized kappa chain immunoglobulin locus (e.g., a RenMab® mouse TM The heavy chain immunoglobulin locus is the region of a chromosome that contains the antibody heavy chain genes. This locus can include, for example, human IGHV (variable) genes, human IGHD (diversity) genes, human IGHJ (joining) genes, and mouse heavy chain constant domain genes. The kappa chain immunoglobulin locus is the region of a chromosome that contains the genes encoding antibody light chains (kappa chain). The kappa chain immunoglobulin locus can include, for example, human IGKV (variable) genes, human IGKJ (joining) genes, and mouse light chain constant domain genes. A detailed description of the RenMab® mouse can be found in PCT / CN2020 / 075698 or US20200390073A1, which are incorporated herein by reference in their entirety. TM The heavy chain immunoglobulin locus is the region of a chromosome that contains the antibody heavy chain genes. This locus can include, for example, human IGHV (variable) genes, human IGHD (diversity) genes, human IGHJ (joining) genes, and mouse heavy chain constant domain genes. The kappa chain immunoglobulin locus is the region of a chromosome that contains the genes encoding antibody light chains (kappa chain). The kappa chain immunoglobulin locus can include, for example, human IGKV (variable) genes, human IGKJ (joining) genes, and mouse light chain constant domain genes. A detailed description of the RenMab® mouse can be found in PCT / CN2020 / 075698 or US20200390073A1, which are incorporated herein by reference in their entirety.

[0773] In some embodiments, the antibody is produced using a mouse having a humanized heavy chain immunoglobulin locus and a humanized kappa chain immunoglobulin locus (e.g., a RenLite TMThe heavy chain immunoglobulin locus is the region of a chromosome that contains the genes for antibody heavy chains. This locus can include, for example, human IGHV (variable) genes, human IGHD (diversity) genes, human IGHJ (joining) genes, and mouse heavy chain constant domain genes. The kappa chain immunoglobulin locus is the region of a chromosome that contains the genes for common light chains. The kappa chain immunoglobulin locus can include, for example, human IGKV (variable) genes, human IGKJ (joining) genes, and mouse light chain constant domain genes. For RenLite TM A detailed description of the mouse can be found in PCT / CN2021 / 097652, which is incorporated by reference herein in its entirety.

[0774] Antibodies produced by the mouse have a complete human VH, a complete human VL, and mouse constant regions. In some embodiments, the human VH and the human VL are linked to a human IgG constant region (e.g., IgGl, IgG2, IgG3, and IgG4).

[0775] Identity or homology to the original sequence is typically the percentage of amino acid residues in the candidate sequence that have a identical with the sequence that occurs in the human, humanized, or chimeric anti-PTK7, anti-TROP2, or anti-PTK7 / TROP2 antibody or fragment after aligning the candidate sequence with the original sequence and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity.

[0776] Additional modifications can be made to the anti-PTK7, anti-TROP2, or anti-PTK7 / TROP2 antibody or antigen-binding fragment. For example, cysteine residues can be introduced into the Fc region, thereby allowing interchain disulfide bonds to form in this region. The homodimeric antibodies thus produced can have increased in vitro and / or in vivo half-lives. Homodimeric antibodies with increased in vitro and / or in vivo half-lives can also be prepared using heterobifunctional cross-linkers, as described in, for example, Wolff et al. (Cancer Res. 53:2560-2565, 1993). Alternatively, the antibodies can be engineered to have dual Fc regions (see, e.g., Stevenson et al., Anti-Cancer Drug Design, 3:219-230, 1989).

[0777] In some embodiments, the anti-PTK7, anti-TROP2, or anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof can be covalently modified. These covalent modifications can be made by either chemical or enzymatic synthesis, or by enzymatic or chemical cleavage. Other types of covalent modifications of the antibody or fragment are introduced into the molecule by reacting targeted amino acid residues of the antibody or fragment with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C-terminal residues.

[0778] In some embodiments, antibody variants are provided having a carbohydrate structure that lacks (directly or indirectly) fucose attached to the Fc region. For example, the amount of fucose in such antibodies can be 1-80%, 1-65%, 5-65%, or 20-40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297 relative to the total sum of all glycostructures attached to Asn297 (e.g., complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry (as described in WO 2008 / 077546). Asn297 refers to the asparagine residue located at about position 297 in the Fc region (Eu numbering of Fc region residues; or position 314 in Kabat numbering); however, Asn297 can also be located about ±3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants can have improved ADCC function. In some embodiments, to reduce glycan heterogeneity, the Fc region of an antibody can be further engineered to replace the asparagine at position 297 with an alanine (N297A).

[0779] In some embodiments, to promote production efficiency by avoiding Fab arm exchange, the Fc region of an antibody is further engineered to replace the serine at position 228 (EU numbering) of IgG4 with proline (S228P). See, e.g., Silva et al., "The S228P mutation prevents in vivo and in vitro IgG4 Fab-arm exchange as demonstrated using a combination of novel quantitative immunoassays and physiological matrix preparation." Journal of Biological Chemistry 290.9 (2015): 5462-5469, which is incorporated by reference in its entirety.

[0780] Recombinant vectors

[0781] The present disclosure also provides recombinant vectors (e.g., expression vectors) comprising the isolated polynucleotides disclosed herein (e.g., polynucleotides encoding the polypeptides disclosed herein), host cells into which these recombinant vectors have been introduced (i.e., such that the host cells contain the polynucleotides and / or the vectors comprising the polynucleotides), and recombinant antibody polypeptides or fragments thereof produced by recombinant techniques.

[0782] As used herein, a “vector” is any construct that, when introduced into a host cell, is capable of delivering one or more polynucleotides of interest to that host cell. An “expression vector” is capable of delivering and expressing one or more polynucleotides of interest as encoded polypeptides in a host cell into which the expression vector has been introduced. Thus, in an expression vector, a polynucleotide of interest is positioned to be expressed in the vector by being operably linked with regulatory elements such as promoters, enhancers, and / or poly-A tails within the vector or in the genome of the host cell at or near or flanking the site of integration of the polynucleotide of interest, such that the polynucleotide of interest will be translated in a host cell into which the expression vector is introduced.

[0783] Vectors can be introduced into host cells by methods known in the art, such as electroporation, chemical transfection (e.g., DEAE-dextran), transformation, transfection, and infection and / or transduction (e.g., with recombinant viruses). Thus, non-limiting examples of vectors include viral vectors (which can be used to produce recombinant viruses), naked DNA or RNA, plasmids, cosmids, phage vectors, and DNA or RNA expression vectors associated with cationic condensing agents.

[0784] In some embodiments, the polynucleotides disclosed herein (e.g., polynucleotides encoding the polypeptides disclosed herein) are introduced using a viral expression system (e.g., vaccinia or other poxvirus, retrovirus, or adenovirus), which can involve the use of a nonpathogenic (defective), replication-competent virus, or a replication-defective virus can be used. In the latter case, viral propagation generally occurs only in complementing virus packaging cells. Suitable systems are disclosed, for example, in Fisher-Hoch et al., 1989, Proc. Natl. Acad. Sci. USA 86:317-321; Flexner et al., 1989, Ann. N.Y. Acad Sci. 569:86-103; Flexner et al., 1990, Vaccine, 8:17-21; U.S. Patent Nos. 4,603,112, 4,769,330, and 5,017,487; WO 89 / 01973; U.S. Patent No. 4,777,127; GB 2,200,651; EP 0,345,242; WO 91 / 02805; Berkner-Biotechniques, 6:616-627, 1988; Rosenfeld et al., 1991, Science, 252:431-434; Kolls et al., 1994, Proc. Natl. Acad. Sci. USA, 91:215-219; Kass-Eisler et al., 1993, Proc. Natl. Acad. Sci. USA, 90:11498-11502; Guzman et al., 1993, Circulation, 88:2838-2848; and Guzman et al., 1993, Cir. Res., 73:1202-1207. Techniques for integrating DNA into such expression systems are well known to those of ordinary skill in the art. DNA can also be “naked,” as described in, for example, Ulmer et al., 1993, Science, 259:1745-1749, and Cohen, 1993, Science, 259:1691-1692. Uptake of naked DNA can be increased by coating the DNA on biodegradable beads that are efficiently transported into cells.

[0785] For expression, the DNA including the polynucleotide encoding the antibody or polypeptide disclosed herein can be inserted into a suitable vector in operable connection to a suitable promoter (e.g., a heterologous promoter), such as the bacteriophage lambda PL promoter, the E. coli lac, trp, and tac promoters, the SV40 early and late promoters, and promoters of retroviral LTRs, among others. Other suitable promoters are known to those skilled in the art. The expression construct can also contain a transcription initiation, termination site, and in the case of transcription into mRNA, a ribosome binding site in the transcribed region. The coding portion of the mature transcript expressed by the construct can include a translation initiation codon at the start of the polypeptide to be translated and a termination codon (UAA, UGA, or UAG) in proper reading frame, at the end of the polypeptide to be translated.

[0786] As noted above, the expression vector can include at least one selectable marker. Such markers include dihydrofolate reductase genes for eukaryotic cell culture selection of transfectants or neomycin resistance genes for selection in both E. coli and other bacteria. Representative examples of suitable hosts include, but are not limited to, bacterial cells, such as E. coli, Streptomyces, and Salmonella typhimurium cells; fungal cells, such as yeast cells; insect cells, such as Drosophila S2 and Spodoptera Sf9 cells; animal cells, such as CHO, COS, Bowes melanoma, and HK 293 cells; and plant cells. Suitable media and conditions for the cultivation of host cells useful in the present disclosure are known in the art.

[0787] Introduction of the construct into the host cell can be effected by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection or other methods. These procedures are described in many standard laboratory manuals, such as Davis et al., Basic Methods In Molecular Biology (1986), which is incorporated herein by reference in its entirety.

[0788] Transcription of DNA encoding the antibodies of the present disclosure by higher eukaryotes can be increased by inserting an enhancer sequence into the vector. Enhancers are cis-acting elements of DNA, usually about from 10 to 300 bp that act to increase transcriptional activity of a promoter in a given host cell type. Examples of enhancers include the SV40 enhancer, which is in the late side of the replication origin, the cytomegalovirus early promoter enhancer, the polyoma enhancer, and adenovirus enhancers.

[0789] To allow secretion of the translated protein into the endoplasmic reticulum lumen, periplasmic space, or extracellular environment, an appropriate secretion signal can be incorporated into the expressed polypeptide. The signal can be an endogenous signal of the polypeptide or a heterologous signal.

[0790] Polypeptides (e.g., antibodies) can be expressed in modified form, such as a fusion protein (e.g., a GST fusion protein) or with a histidine tag, and can include not only a secretion signal but also additional heterologous functional regions. For example, regions of additional amino acids, particularly charged amino acids, can be added to the N-terminus of the polypeptide to improve stability and persistence in the host cel...

Claims

1. An antibody or antigen-binding fragment thereof that binds PTK7 (protein tyrosine kinase 7), the antibody or antigen-binding fragment thereof comprising: a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, wherein the VH CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR1 amino acid sequence, the VH CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR2 amino acid sequence, and the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR3 amino acid sequence; and a light chain variable region (VL) comprising CDRs 1, 2, and 3, wherein the VL CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR1 amino acid sequence, the VL CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR2 amino acid sequence, and the VL CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR3 amino acid sequence, wherein the selected VH CDR1, 2, and 3 amino acid sequences and the selected VL CDR1, 2, and 3 amino acid sequences are one of: (1) the selected VH CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 4-6, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; (2) the selected VH CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 7-9, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; (3) the selected VH CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 10-12, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; (4) the selected VH CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 13-15, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; (5) the selected VH CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 16-18, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; (6) the selected VH CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 19-21, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; (7) the selected VH CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 22-24, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; (8) the selected VH CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 25-27, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively; (9) the selected VH CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 28-30, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively; (10) the selected VH CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 31-33, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively; (11) the selected VH CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 34-36, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively; (12) the selected VH CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 37-39, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively; (13) the selected VH CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 40-42, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively; (14) the selected VH CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 43-45, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively; (15) the selected VH CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 86-88, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively; and (16) the selected VH CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 89-91, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively.

2. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 4-6, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

3. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 7-9, respectively, and the VL comprises CDR1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

4. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 10-12, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

5. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 13-15, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

6. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 16-18, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

7. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 19-21, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

8. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 22-24, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

9. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 86-88, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

10. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 25-27, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 1-3, respectively, according to the Chothia definition.

11. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 28-30, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 1-3, respectively, according to the Chothia definition.

12. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 31-33, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 1-3, respectively, according to the Chothia definition.

13. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 34-36, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 1-3, respectively, according to the Chothia definition.

14. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 37-39, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 1-3, respectively, according to the Chothia definition.

15. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 40-42, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 1-3, respectively, according to the Chothia definition.

16. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 43-45, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 1-3, respectively, according to the Chothia definition.

17. The antibody or antigen-binding fragment thereof of claim 1, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 89-91, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences of SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

18. The antibody or antigen-binding fragment thereof of any one of claims 1-17, wherein the antibody or antigen-binding fragment thereof specifically binds human, monkey, or dog PTK7.

19. The antibody or antigen-binding fragment thereof of any one of claims 1-18, wherein the antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment thereof, a single chain variable fragment (scFv), a one-armed antibody, and / or a multispecific antibody (e.g., a bispecific antibody).

20. The antibody or antigen-binding fragment thereof of any one of claims 1-19, wherein the antibody or antigen-binding fragment thereof is a human IgGl antibody or antigen-binding fragment thereof, a human IgG2 antibody or antigen-binding fragment thereof, or a human IgG4 antibody or antigen-binding fragment thereof.

21. A nucleic acid comprising a polynucleotide encoding a polypeptide, the polypeptide comprising: (1) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 4-6, respectively, and wherein the VH pairs with a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 53 to bind PTK7; (2) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 25-27, respectively, and wherein the VH pairs with a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 53 to bind PTK7; (3) an immunoglobulin light chain or fragment thereof comprising a VL comprising complementarity determining regions (CDRs) 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 1-3, respectively, and wherein the VL pairs with a VH comprising an amino acid sequence of SEQ ID NO: 46 to bind PTK7; (4) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 7-9, respectively, and wherein the VH pairs with a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 53 to bind PTK7; (5) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 28-30, respectively, and wherein the VH pairs with a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 53 to bind PTK7; (6) an immunoglobulin light chain or fragment thereof comprising a VL comprising complementarity determining regions (CDRs) 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 1-3, respectively, and wherein the VL pairs with a VH comprising an amino acid sequence of SEQ ID NO: 47 to bind PTK7; (7) an immunoglobulin heavy chain or fragment thereof comprising a VH comprising complementarity determining regions (CDRs) 1, 2, and 3 having the amino acid sequences of SEQ ID NOs: 10-12, respectively, and wherein the VH pairs with a light chain variable region (VL) comprising an amino acid sequence of SEQ ID NO: 53 to bind PTK7; (8) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 31-33, and wherein said VH pairs with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53 to bind PTK7; (9) an immunoglobulin light chain or fragment thereof comprising a VL comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3, and wherein said VL pairs with a VH comprising the amino acid sequence set forth in SEQ ID NO: 48 to bind PTK7; (10) an immunoglobulin heavy chain or fragment thereof comprising a VH comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 13-15, and wherein said VH pairs with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53 to bind PTK7; (11) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 34-36, and wherein said VH pairs with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53 to bind PTK7; (12) an immunoglobulin light chain or fragment thereof comprising a VL comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3, and wherein said VL pairs with a VH comprising the amino acid sequence set forth in SEQ ID NO: 49 to bind PTK7; (13) an immunoglobulin heavy chain or fragment thereof comprising a VH comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 16-18, and wherein said VH pairs with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53 to bind PTK7; (14) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 37-39, and wherein said VH pairs with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53 to bind PTK7; (15) an immunoglobulin light chain or fragment thereof comprising a VL comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3, and wherein said VL pairs with a VH comprising the amino acid sequence set forth in SEQ ID NO: 50 to bind PTK7; ​ ​ (16) an immunoglobulin heavy chain or fragment thereof comprising a VH comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 19-21, and wherein said VH binds PTK7 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53; (17) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 40-42, and wherein said VH binds PTK7 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53; (18) an immunoglobulin light chain or fragment thereof comprising a VL comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3, and wherein said VL binds PTK7 when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 51; (19) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 22-24, and wherein said VH binds PTK7 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53; (20) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 43-45, and wherein said VH binds PTK7 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53; (21) an immunoglobulin light chain or fragment thereof comprising a VL comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3, and wherein said VL binds PTK7 when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 52; (22) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 86-88, and wherein said VH binds PTK7 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53; (23) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 89-91, and wherein said VH binds PTK7 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53; and ​ ​ ​ ​ ​ (24) an immunoglobulin light chain or fragment thereof comprising a VL comprising complementarity determining regions (CDRs) 1, 2, and 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, and wherein the VL pairs with a VH comprising the amino acid sequence set forth in SEQ ID NO: 92 to bind PTK7.

22. The nucleic acid of claim 21, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin light chain or fragment thereof comprising a VL comprising CDRs 1, 2, and 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively.

23. The nucleic acid of claim 21, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDRs 1, 2, and 3 having the amino acid sequences set forth in SEQ ID NOs: 4-6, respectively.

24. The nucleic acid of claim 21, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDRs 1, 2, and 3 having the amino acid sequences set forth in SEQ ID NOs: 7-9, respectively.

25. The nucleic acid of claim 21, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDRs 1, 2, and 3 having the amino acid sequences set forth in SEQ ID NOs: 10-12, respectively.

26. The nucleic acid of claim 21, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDRs 1, 2, and 3 having the amino acid sequences set forth in SEQ ID NOs: 13-15, respectively.

27. The nucleic acid of claim 21, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDRs 1, 2, and 3 having the amino acid sequences set forth in SEQ ID NOs: 16-18, respectively.

28. The nucleic acid of claim 21, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDRs 1, 2, and 3 having the amino acid sequences set forth in SEQ ID NOs: 19-21, respectively.

29. The nucleic acid of claim 21, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDRs 1, 2, and 3 having the amino acid sequences set forth in SEQ ID NOs: 22-24, respectively.

30. The nucleic acid of claim 21, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain comprising a VH or fragment thereof, the VH comprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOS: 25-27, respectively.

31. The nucleic acid of claim 21, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain comprising a VH or fragment thereof, the VH comprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOS: 28-30, respectively.

32. The nucleic acid of claim 21, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain comprising a VH or fragment thereof, the VH comprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOS: 31-33, respectively.

33. The nucleic acid of claim 21, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain comprising a VH or fragment thereof, the VH comprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOS: 34-36, respectively.

34. The nucleic acid of claim 21, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain comprising a VH or fragment thereof, the VH comprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOS: 37-39, respectively.

35. The nucleic acid of claim 21, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain comprising a VH or fragment thereof, the VH comprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOS: 40-42, respectively.

36. The nucleic acid of claim 21, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain comprising a VH or fragment thereof, the VH comprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOS: 43-45, respectively.

37. The nucleic acid of claim 21, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain comprising a VH or fragment thereof, the VH comprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOS: 86-88, respectively.

38. The nucleic acid of claim 21, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain comprising a VH or fragment thereof, the VH comprising CDRs 1, 2, and 3 having the amino acid sequences of SEQ ID NOS: 89-91, respectively.

39. The nucleic acid of any one of claims 21-38, wherein the VH specifically binds human, monkey, or dog PTK7 when paired with a VL, or the VL specifically binds human, monkey, or dog PTK7 when paired with a VH.

40. The nucleic acid of any one of claims 21-39, wherein the immunoglobulin heavy chain or fragment thereof is a human immunoglobulin heavy chain or fragment thereof (e.g., a human IgGl heavy chain or fragment thereof, a human IgG2 heavy chain or fragment thereof, or a human IgG4 heavy chain or fragment thereof), and the immunoglobulin light chain or fragment thereof is a human immunoglobulin light chain or fragment thereof.

41. The nucleic acid of any one of claims 21-40, wherein the nucleic acid encodes a single chain variable fragment (scFv), a one-armed antibody, a multi-specific antibody (e.g., a bispecific antibody), or a chimeric antigen receptor (CAR).

42. The nucleic acid of any one of claims 21-41, wherein the nucleic acid is a cDNA.

43. A vector comprising one or more nucleic acids of any one of claims 21-42.

44. A vector comprising two nucleic acids of any one of claims 21-42, wherein the vector encodes a VL region and a VH region that collectively bind PTK7.

45. A pair of vectors, wherein each vector comprises a nucleic acid of any one of claims 21-42, wherein the pair of vectors collectively encodes a VL region and a VH region that collectively bind PTK7.

46. A cell comprising the vector of claim 43 or 44, or the pair of vectors of claim 45.

47. The cell of claim 46, wherein the cell is a CHO cell.

48. A cell comprising one or more nucleic acids of any one of claims 21-42.

49. A cell comprising two nucleic acids of any one of claims 21-42.

50. The cell of claim 49, wherein the two nucleic acids collectively encode a VL region and a VH region that collectively bind PTK7.

51. A method of producing an antibody or antigen-binding fragment thereof, the method comprising (a) culturing the cell of any one of claims 46-50 under conditions sufficient for the cell to produce an antibody or antigen-binding fragment; and (b) collecting the antibody or antigen-binding fragment produced by the cell.

52. An antibody or antigen-binding fragment thereof that binds PTK7, the antibody or antigen-binding fragment thereof comprising: a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90% identical to a selected VH sequence; and a light chain variable region (VL) comprising an amino acid sequence that is at least 90% identical to a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of: (1) the selected VH sequence is SEQ ID NO: 46 and the selected VL sequence is SEQ ID NO: 53; (2) the selected VH sequence is SEQ ID NO: 47 and the selected VL sequence is SEQ ID NO: 53; (3) the selected VH sequence is SEQ ID NO:48, and the selected VL sequence is SEQ ID NO:53; (4) the selected VH sequence is SEQ ID NO:49, and the selected VL sequence is SEQ ID NO:53; (5) the selected VH sequence is SEQ ID NO:50, and the selected VL sequence is SEQ ID NO:53; (6) the selected VH sequence is SEQ ID NO:51, and the selected VL sequence is SEQ ID NO:53; (7) the selected VH sequence is SEQ ID NO:52, and the selected VL sequence is SEQ ID NO:53; and (8) the selected VH sequence is SEQ ID NO:92, and the selected VL sequence is SEQ ID NO:

53.

53. The antibody or antigen-binding fragment thereof of claim 52, wherein the VH comprises the sequence of SEQ ID NO:46, and the VL comprises the sequence of SEQ ID NO:

53.

54. The antibody or antigen-binding fragment thereof of claim 52, wherein the VH comprises the sequence of SEQ ID NO:47, and the VL comprises the sequence of SEQ ID NO:

53.

55. The antibody or antigen-binding fragment thereof of claim 52, wherein the VH comprises the sequence of SEQ ID NO:48, and the VL comprises the sequence of SEQ ID NO:

53.

56. The antibody or antigen-binding fragment thereof of claim 52, wherein the VH comprises the sequence of SEQ ID NO:49, and the VL comprises the sequence of SEQ ID NO:

53.

57. The antibody or antigen-binding fragment thereof of claim 52, wherein the VH comprises the sequence of SEQ ID NO:50, and the VL comprises the sequence of SEQ ID NO:

53.

58. The antibody or antigen-binding fragment thereof of claim 52, wherein the VH comprises the sequence of SEQ ID NO:51, and the VL comprises the sequence of SEQ ID NO:

53.

59. The antibody or antigen-binding fragment thereof of claim 52, wherein the VH comprises the sequence of SEQ ID NO:52, and the VL comprises the sequence of SEQ ID NO:

53.

60. The antibody or antigen-binding fragment thereof of claim 52, wherein the VH comprises the sequence of SEQ ID NO:92, and the VL comprises the sequence of SEQ ID NO:

53.

61. An antibody or antigen-binding fragment thereof that binds PTK7, comprising: a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3 that are identical to the VH CDR1, the VH CDR2, and the VH CDR3 of a selected VH sequence; and a light chain variable region (VL) comprising a VL CDR1, a VL CDR2, and a VL CDR3 that are identical to the VL CDR1, the VL CDR2, and the VL CDR3 of a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following: (1) the selected VH sequence is SEQ ID NO: 46, and the selected VL sequence is SEQ ID NO: 53; (2) the selected VH sequence is SEQ ID NO: 47, and the selected VL sequence is SEQ ID NO: 53; (3) the selected VH sequence is SEQ ID NO: 48, and the selected VL sequence is SEQ ID NO: 53; (4) the selected VH sequence is SEQ ID NO: 49, and the selected VL sequence is SEQ ID NO: 53; (5) the selected VH sequence is SEQ ID NO: 50, and the selected VL sequence is SEQ ID NO: 53; (6) the selected VH sequence is SEQ ID NO: 51, and the selected VL sequence is SEQ ID NO: 53; (7) the selected VH sequence is SEQ ID NO: 52, and the selected VL sequence is SEQ ID NO: 53; and (8) the selected VH sequence is SEQ ID NO: 92, and the selected VL sequence is SEQ ID NO:

53.

62. The antibody or antigen-binding fragment thereof of any one of claims 52-61, wherein the antibody or antigen-binding fragment thereof specifically binds human, monkey, or dog PTK7.

63. The antibody or antigen-binding fragment thereof of any one of claims 52-62, wherein the antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment thereof, a single chain variable fragment (scFv), a one-armed antibody, and / or a multi-specific antibody (e.g., a bispecific antibody).

64. The antibody or antigen-binding fragment thereof of any one of claims 52-63, wherein the antibody or antigen-binding fragment is a human IgGl antibody or antigen-binding fragment thereof, a human IgG2 antibody or antigen-binding fragment thereof, or a human IgG4 antibody or antigen-binding fragment thereof.

65. An antibody or antigen-binding fragment thereof that binds TROP2 (trophoblast cell surface antigen 2), the antibody or antigen-binding fragment thereof comprising: a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, wherein the VH CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR1 amino acid sequence, the VH CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR2 amino acid sequence, and the VH CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH CDR3 amino acid sequence; and a light chain variable region (VL) comprising CDRs 1, 2, and 3, wherein the VL CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR1 amino acid sequence, the VL CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR2 amino acid sequence, and the VL CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL CDR3 amino acid sequence, wherein the selected VH CDR1, 2, and 3 amino acid sequences and the selected VL CDR1, 2, and 3 amino acid sequences are one of the following: (1) the selected VH CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 57-59, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; (2) the selected VH CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 60-62, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; (3) the selected VH CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 66-68, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; and (4) the selected VH CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 69-71, respectively, and the selected VL CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

66. The antibody or antigen-binding fragment thereof of claim 65, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 57-59, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

67. The antibody or antigen-binding fragment thereof of claim 65, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 60-62, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to the Kabat definition.

68. The antibody or antigen-binding fragment thereof of claim 65, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 66-68, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to Chothia definition.

69. The antibody or antigen-binding fragment thereof of claim 65, wherein the VH comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 69-71, respectively, and the VL comprises CDRs 1, 2, 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, according to Chothia definition.

70. The antibody or antigen-binding fragment thereof of any one of claims 65-69, wherein the antibody or antigen-binding fragment thereof specifically binds human, monkey, or dog TROP2.

71. The antibody or antigen-binding fragment thereof of any one of claims 65-70, wherein the antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment thereof, a single chain variable fragment (scFv), a one-armed antibody, and / or a multi-specific antibody (e.g., a bispecific antibody).

72. The antibody or antigen-binding fragment thereof of any one of claims 65-71, wherein the antibody or antigen-binding fragment thereof is a human IgGl antibody or antigen-binding fragment thereof, a human IgG2 antibody or antigen-binding fragment thereof, or a human IgG4 antibody or antigen-binding fragment thereof.

73. A nucleic acid comprising a polynucleotide encoding a polypeptide, the polypeptide comprising: (1) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 having the amino acid sequences set forth in SEQ ID NOs: 57-59, respectively, and wherein the VH binds TROP2 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53; (2) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 having the amino acid sequences set forth in SEQ ID NOs: 66-68, respectively, and wherein the VH binds TROP2 when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53; (3) an immunoglobulin light chain or fragment thereof comprising a VL comprising complementarity determining regions (CDRs) 1, 2, and 3 having the amino acid sequences set forth in SEQ ID NOs: 1-3, respectively, and wherein the VL binds TROP2 when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 73; (4) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 60-62, and wherein the VH, when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53, binds TROP2; (5) an immunoglobulin heavy chain or fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 69-71, and wherein the VH, when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 53, binds TROP2; and (6) an immunoglobulin light chain or fragment thereof comprising a VL comprising complementarity determining regions (CDRs) 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 74, binds TROP2.

74. The nucleic acid of claim 73, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin light chain or fragment thereof comprising a VL comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 1-3.

75. The nucleic acid of claim 73, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 57-59.

76. The nucleic acid of claim 73, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 60-62.

77. The nucleic acid of claim 73, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 66-68.

78. The nucleic acid of claim 73, wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or fragment thereof comprising a VH comprising CDRs 1, 2, and 3, respectively, having the amino acid sequences set forth in SEQ ID NOs: 69-71.

79. The nucleic acid of any one of claims 73-78, wherein the VH, when paired with a VL, or the VL, when paired with a VH, specifically binds human, monkey, or dog TROP2.

80. The nucleic acid of any one of claims 73-79, wherein the immunoglobulin heavy chain or fragment thereof is a human immunoglobulin heavy chain or fragment thereof (e.g., a human IgGl heavy chain or fragment thereof, a human IgG2 heavy chain or fragment thereof, or a human IgG4 heavy chain or fragment thereof), and the immunoglobulin light chain or fragment thereof is a human immunoglobulin light chain or fragment thereof.

81. The nucleic acid of any one of claims 73-80, wherein the nucleic acid encodes a single chain variable fragment (scFv), a one-armed antibody, a multi-specific antibody (e.g., a bispecific antibody), or a chimeric antigen receptor (CAR).

82. The nucleic acid of any one of claims 73-81, wherein the nucleic acid is a cDNA.

83. A vector comprising one or more nucleic acids of any one of claims 73-82.

84. A vector comprising two nucleic acids of any one of claims 73-82, wherein the vector encodes a VL region and a VH region that collectively bind TROP2.

85. A pair of vectors, wherein each vector comprises a nucleic acid of any one of claims 73-82, wherein the pair of vectors collectively encodes a VL region and a VH region that collectively bind TROP2.

86. A cell comprising the vector of claim 83 or 84, or the pair of vectors of claim 85.

87. The cell of claim 86, wherein the cell is a CHO cell.

88. A cell comprising one or more nucleic acids of any one of claims 73-82.

89. A cell comprising two nucleic acids of any one of claims 73-82.

90. The cell of claim 89, wherein the two nucleic acids collectively encode a VL region and a VH region that collectively bind TROP2.

91. A method of producing an antibody or antigen-binding fragment thereof, the method comprising (a) culturing the cell of any one of claims 86-90 under conditions sufficient for the cell to produce an antibody or antigen-binding fragment; and (b) collecting the antibody or antigen-binding fragment produced by the cell.

92. An antibody or antigen-binding fragment thereof that binds TROP2, the antibody or antigen-binding fragment thereof comprising: a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90% identical to a selected VH sequence; and a light chain variable region (VL) comprising an amino acid sequence that is at least 90% identical to a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of: (1) the selected VH sequence is SEQ ID NO: 73 and the selected VL sequence is SEQ ID NO: 53; and (2) the selected VH sequence is SEQ ID NO: 74 and the selected VL sequence is SEQ ID NO:

53.

93. The antibody or antigen-binding fragment thereof of claim 92, wherein the VH comprises the sequence of SEQ ID NO: 73, and the VL comprises the sequence of SEQ ID NO:

53.

94. The antibody or antigen-binding fragment thereof of claim 92, wherein the VH comprises the sequence of SEQ ID NO: 74, and the VL comprises the sequence of SEQ ID NO:

53.

95. An antibody or antigen-binding fragment thereof that binds TROP2, comprising: a heavy chain variable region (VH) comprising a VH CDR1, a VH CDR2, and a VH CDR3 identical to the VH CDR1, the VH CDR2, and the VH CDR3 of a selected VH sequence; and a light chain variable region (VL) comprising a VL CDR1, a VL CDR2, and a VL CDR3 identical to the VL CDR1, the VL CDR2, and the VL CDR3 of a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of: (1) the selected VH sequence is SEQ ID NO: 73, and the selected VL sequence is SEQ ID NO: 53; and (2) the selected VH sequence is SEQ ID NO: 74, and the selected VL sequence is SEQ ID NO:

53.

96. The antibody or antigen-binding fragment thereof of any one of claims 92-95, wherein the antibody or antigen-binding fragment thereof specifically binds human, monkey, or dog TROP2.

97. The antibody or antigen-binding fragment thereof of any one of claims 92-96, wherein the antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment thereof, a single chain variable fragment (scFv), a one-armed antibody, and / or a multi-specific antibody (e.g., a bispecific antibody).

98. The antibody or antigen-binding fragment thereof of any one of claims 92-97, wherein the antibody or antigen-binding fragment is a human IgGl antibody or antigen-binding fragment thereof, a human IgG2 antibody or antigen-binding fragment thereof, or a human IgG4 antibody or antigen-binding fragment thereof.

99. An anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof, comprising a first antigen-binding domain that specifically binds a PTK7 epitope; and a second antigen-binding domain that specifically binds a TROP2 epitope.

100. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 99, wherein the first antigen-binding domain comprises a first heavy chain variable region (VH1) and a first light chain variable region (VL1); and the second antigen-binding domain comprises a second heavy chain variable region (VH2) and a second light chain variable region (VL2).

101. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 100, wherein the first heavy chain variable region (VH1) comprises complementarity determining regions (CDRs) 1, 2, and 3, wherein the VH1 CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VH1 CDR1 amino acid sequence, the VH1 CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH1 CDR2 amino acid sequence, and the VH1 CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH1 CDR3 amino acid sequence; and the first light chain variable region (VL1) comprises CDRs 1, 2, and 3, wherein the VL1 CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VL1 CDR1 amino acid sequence, the VL1 CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL1 CDR2 amino acid sequence, and the VL1 CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL1 CDR3 amino acid sequence, wherein the selected VH1 CDR1, 2, and 3 amino acid sequences and the selected VL1 CDR1, 2, and 3 amino acid sequences are one of: (1) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 4-6, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; (2) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 7-9, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; (3) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 10-12, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; (4) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 13-15, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; (5) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 16-18, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; (6) the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 19-21, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively; (7) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 22-24, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (8) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 25-27, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (9) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 28-30, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (10) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 31-33, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (11) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 34-36, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (12) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 37-39, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (13) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 40-42, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (14) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 43-45, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (15) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 86-88, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; and (16) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 89-91, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively.

102. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 100 or 101, wherein the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 4-6, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively.

103. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 100 or 101, wherein the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 7-9, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively.

104. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 100 or 101, wherein the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 10-12, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively.

105. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 100 or 101, wherein the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 13-15, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively.

106. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 100 or 101, wherein the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 16-18, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively.

107. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 100 or 101, wherein the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 19-21, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively.

108. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 100 or 101, wherein the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 22-24, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively.

109. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 100 or 101, wherein the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 25-27, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively.

110. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 100 or 101, wherein the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 28-30, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively.

111. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 100 or 101, wherein the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 31-33, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively.

112. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 100 or 101, wherein the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 34-36, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively.

113. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 100 or 101, wherein the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 37-39, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively.

114. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 100 or 101, wherein the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 40-42, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively.

115. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 100 or 101, wherein the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 43-45, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively.

116. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 100 or 101, wherein the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 86-88, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively.

117. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of claim 100 or 101, wherein the selected VH1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 89-91, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively.

118. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-117, wherein the second heavy chain variable region (VH2) comprises CDRs 1, 2, and 3, wherein the VH2 CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VH2 CDR1 amino acid sequence, the VH2 CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VH2 CDR2 amino acid sequence, and the VH2 CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VH2 CDR3 amino acid sequence; and the second light chain variable region (VL2) comprises CDRs 1, 2, and 3, wherein the VL2 CDR1 region comprises an amino acid sequence that is at least 80% identical to a selected VL2 CDR1 amino acid sequence, the VL2 CDR2 region comprises an amino acid sequence that is at least 80% identical to a selected VL2 CDR2 amino acid sequence, and the VL2 CDR3 region comprises an amino acid sequence that is at least 80% identical to a selected VL2 CDR3 amino acid sequence, wherein the selected VH2 CDR1, 2, and 3 amino acid sequences and the selected VL2 CDR1, 2, and 3 amino acid sequences are one of: (1) the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 54-56, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively; (2) the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 63-65, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively; (3) the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 57-59, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively; (4) the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively; (5) the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 66-68, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOS: 1-3, respectively; and (6) the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 69-71, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

119. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-118, wherein the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 54-56, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

120. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-118, wherein the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 57-59, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

121. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-118, wherein the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

122. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-118, wherein the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 63-65, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

123. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-118, wherein the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 66-68, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

124. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-118, wherein the selected VH2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 69-71, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1-3, respectively.

125. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-124, wherein (1) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 4-6, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 54-56, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively; (2) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 7-9, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 54-56, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively; (3) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 10-12, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 54-56, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively; (4) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 13-15, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 54-56, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively; (5) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 16-18, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 54-56, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively; (6) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 19-21, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 54-56, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (7) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 22-24, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 54-56, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (8) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 4-6, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 57-59, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (9) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 7-9, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 57-59, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (10) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 10-12, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 57-59, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (11) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 13-15, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 57-59, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (12) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 16-18, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 57-59, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (13) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 19-21, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 57-59, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (14) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 22-24, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 57-59, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (15) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 4-6, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (16) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 7-9, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (17) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 10-12, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (18) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 13-15, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (19) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 16-18, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (20) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 19-21, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (21) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 22-24, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 60-62, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (22) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 25-27, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 63-65, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (23) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 28-30, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 63-65, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (24) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 31-33, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 63-65, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (25) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 34-36, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 63-65, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (26) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 37-39, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 63-65, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (27) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 40-42, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 63-65, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (28) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 43-45, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 63-65, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (29) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 25-27, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 66-68, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (30) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 28-30, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 66-68, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (31) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 31-33, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 66-68, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (32) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 34-36, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 66-68, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (33) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 37-39, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 66-68, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (34) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 40-42, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 66-68, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (35) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 43-45, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 66-68, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (36) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 25-27, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 69-71, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (37) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 28-30, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 69-71, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (38) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 31-33, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 69-71, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (39) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 34-36, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 69-71, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (40) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 37-39, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 69-71, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (41) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 40-42, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 69-71, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (42) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 43-45, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 69-71, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (43) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 86-88, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 54-56, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (44) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 89-91, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 63-65, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; (45) the selected VH1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 86-88, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 57-59, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set out in SEQ ID NOs: 1-3, respectively; and (46) the selected VH1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 89-91, respectively, and the selected VL1 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively, and the selected VH2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 66-68, respectively, and the selected VL2 CDR1, 2, 3 amino acid sequences are as set forth in SEQ ID NOs: 1-3, respectively.

126. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 46, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

127. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 47, the first light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

128. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 48, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

129. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 49, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

130. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 50, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

131. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 51, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

132. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 52, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

133. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 46, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

134. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 47, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

135. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 48, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

136. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 49, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

137. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 50, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

138. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 51, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

139. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 52, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

140. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 46, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

141. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 47, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

142. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 48, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

143. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 49, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

144. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 50, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

145. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 51, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

146. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 52, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 74, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

147. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, wherein the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 92, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 72, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

148. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-125, the first heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 92, the first light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 53, the second heavy chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 73, and the second light chain variable region comprises a sequence at least 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO:

53.

149. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-148, wherein the VH1 comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to a selected VH sequence and the VL1 comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of: (1) the selected VH sequence is SEQ ID NO: 46 and the selected VL sequence is SEQ ID NO: 53; (2) the selected VH sequence is SEQ ID NO: 47 and the selected VL sequence is SEQ ID NO: 53; (3) the selected VH sequence is SEQ ID NO: 48 and the selected VL sequence is SEQ ID NO: 53; (4) the selected VH sequence is SEQ ID NO: 49 and the selected VL sequence is SEQ ID NO: 53; (5) the selected VH sequence is SEQ ID NO: 50 and the selected VL sequence is SEQ ID NO: 53; (6) the selected VH sequence is SEQ ID NO: 51 and the selected VL sequence is SEQ ID NO: 53; (7) the selected VH sequence is SEQ ID NO: 52 and the selected VL sequence is SEQ ID NO: 53; and (8) the selected VH sequence is SEQ ID NO: 92 and the selected VL sequence is SEQ ID NO:

53.

150. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-149, wherein the VH2 comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to a selected VH sequence and the VL2 comprises an amino acid sequence that is at least 80%, 85%, 90%, 95%, 99%, or 100% identical to a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of: (1) the selected VH sequence is SEQ ID NO: 72 and the selected VL sequence is SEQ ID NO: 53; (2) the selected VH sequence is SEQ ID NO: 73 and the selected VL sequence is SEQ ID NO: 53; and (3) the selected VH sequence is SEQ ID NO: 74 and the selected VL sequence is SEQ ID NO:

53.

151. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-150, wherein the VH1 comprises a VH1 CDR1, a VH1 CDR2, and a VH1 CDR3 that are identical to a VH CDR1, a VH CDR2, and a VH CDR3 of a selected VH sequence; and the VL1 comprises a VL1 CDR1, a VL1 CDR2, and a VL1 CDR3 that are identical to a VL CDR1, a VL CDR2, and a VL CDR3 of a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following: (1) the selected VH sequence is SEQ ID NO: 46 and the selected VL sequence is SEQ ID NO: 53; (2) the selected VH sequence is SEQ ID NO: 47 and the selected VL sequence is SEQ ID NO: 53; (3) the selected VH sequence is SEQ ID NO: 48 and the selected VL sequence is SEQ ID NO: 53; (4) the selected VH sequence is SEQ ID NO: 49 and the selected VL sequence is SEQ ID NO: 53; (5) the selected VH sequence is SEQ ID NO: 50 and the selected VL sequence is SEQ ID NO: 53; (6) the selected VH sequence is SEQ ID NO: 51 and the selected VL sequence is SEQ ID NO: 53; (7) the selected VH sequence is SEQ ID NO: 52 and the selected VL sequence is SEQ ID NO: 53; and (8) the selected VH sequence is SEQ ID NO: 92 and the selected VL sequence is SEQ ID NO:

53.

152. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-151, wherein the VH2 comprises a VH2 CDR1, a VH2 CDR2, and a VH2 CDR3 that are identical to a VH CDR1, a VH CDR2, and a VH CDR3 of a selected VH sequence; and the VL2 comprises a VL2 CDR1, a VL2 CDR2, and a VL2 CDR3 that are identical to a VL CDR1, a VL CDR2, and a VL CDR3 of a selected VL sequence, wherein the selected VH sequence and the selected VL sequence are one of the following: (1) the selected VH sequence is SEQ ID NO: 72 and the selected VL sequence is SEQ ID NO: 53; (2) the selected VH sequence is SEQ ID NO: 73 and the selected VL sequence is SEQ ID NO: 53; and (3) the selected VH sequence is SEQ ID NO: 74 and the selected VL sequence is SEQ ID NO:

53.

153. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-152, wherein the first antigen-binding domain specifically binds human, monkey, or dog PTK7; and / or the second antigen-binding domain specifically binds human, monkey, or dog TROP2.

154. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-153, wherein the first antigen-binding domain is a human or humanized antigen-binding domain; and / or the second antigen-binding domain is a human or humanized antigen-binding domain.

155. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-154, wherein the first antigen-binding domain is a single-chain variable fragment (scFv); and / or the second antigen-binding domain is a scFv.

156. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-155, wherein the first light chain variable region is identical to the second light chain variable region.

157. The anti-PTK7 / TROP2 antibody or antigen-binding fragment thereof of any one of claims 100-156, wherein the antibody or antigen-binding fragment thereof is a bispecific antibody or antigen-binding fragment thereof.

158. An antibody or antigen-binding fragment thereof that cross-competes with the antibody or antigen-binding fragment thereof of any one of claims 1-20, 52-72, and 92-157.

159. The antibody or antigen-binding fragment thereof of any one of claims 1-20, 52-72, and 92-157, wherein the antibody or antigen-binding fragment thereof comprises a fragment crystallizable region (Fc region).

160. The antibody or antigen-binding fragment thereof of claim 159, wherein the Fc region has enhanced complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC).

161. A chimeric antigen receptor (CAR) comprising the antibody or antigen-binding fragment thereof of any one of claims 1-20, 52-72, and 92-157.

162. An antibody drug conjugate comprising the antibody or antigen-binding fragment thereof of any one of claims 1-20, 52-72, and 92-157 covalently bound to a therapeutic agent.

163. The antibody drug conjugate of claim 162, wherein the therapeutic agent is a cytotoxic agent or a cytostatic agent.

164. The antibody drug conjugate of claim 162 or 163, wherein the therapeutic agent is MMAE or MMAF.

165. The antibody drug conjugate of claim 162 or 163, wherein the therapeutic agent is selected from 166. The antibody drug conjugate of claim 162 or 165, wherein the therapeutic agent is linked to the antibody or antigen-binding fragment thereof by a linker.

167. The antibody drug conjugate of any one of claims 162, 165, and 166, wherein the linker has the following structure:

168. The antibody drug conjugate of any one of claims 162, 165-167, wherein the antibody drug conjugate has the following structure: wherein n = 1, 2, 3, 4, 5, 6, 7, or 8; and “Ab” represents the antibody or antigen binding fragment thereof.

169. A method of treating a subject having a cancer, the method comprising: administering to the subject a therapeutically effective amount of a composition comprising the antibody or antigen binding fragment thereof of any one of claims 1-20, 52-72, and 92-157, the CAR of claim 161, or the antibody drug conjugate of any one of claims 162-168.

170. The method of claim 169, wherein the subject has a solid tumor.

171. The method of claim 170, wherein the cancer is colon cancer, triple negative breast cancer (TNBC), lung cancer, non-small cell lung cancer (NSCLC), pancreatic cancer, esophageal cancer, colorectal cancer, ovarian cancer (OVCA), or bladder cancer.

172. The method of any one of claims 169-171, wherein the subject is further treated with an effective amount of an anti-4-1BB antibody, an anti-OX40 antibody, an anti-PD-1 antibody, an anti-CTLA4 antibody, an anti-CD40 antibody, or an anti-PD-L1 antibody.

173. A method of reducing the growth rate of a tumor, the method comprising contacting the tumor cell with an effective amount of a composition comprising the antibody or antigen binding fragment thereof of any one of claims 1-20, 52-72, and 92-157, the CAR of claim 161, or the antibody drug conjugate of any one of claims 162-168.

174. A method of killing a tumor cell, the method comprising contacting the tumor cell with an effective amount of a composition comprising the antibody or antigen binding fragment thereof of any one of claims 1-20, 52-72, and 92-157, the CAR of claim 161, or the antibody drug conjugate of any one of claims 162-168.

175. A method of increasing an immune response in a subject, the method comprising administering to the subject an effective amount of a composition comprising the antibody or antigen binding fragment thereof of any one of claims 1-20, 52-72, and 92-157, the CAR of claim 161, or the antibody drug conjugate of any one of claims 162-168.

176. A pharmaceutical composition comprising the antibody or antigen binding fragment thereof of any one of claims 1-20, 52-72, and 92-157, and a pharmaceutically acceptable carrier.

177. A pharmaceutical composition comprising the antibody drug conjugate of any one of claims 162-168, and a pharmaceutically acceptable carrier.

178. The antibody drug conjugate of any one of claims 162-168, wherein the drug antibody ratio (DAR) is about 4 or 8.

Images