Antibodies

Abstract

The present invention relates to antibodies binding to B7H4, including bispecific antibodies binding to B7H4 and CD3. The invention further provides pharmaceutical compositions comprising the antibodies and use of the antibodies for therapeutic and diagnostic procedures, in particular in cancer therapy.

1 - 78 . (canceled) 
     
     
         79 . A method of treating cancer comprising tumor cells which express B7H4, the method comprising administering to a subject in need thereof a therapeutically effective amount of an antibody comprising a first antigen-binding region which binds to human B7H4, and a second antigen-binding region which binds to human CD3. 
     
     
         80 . The method of  claim 79 , wherein the first antigen-binding region of the antibody comprises a VH region and a VL region selected from the group consisting of:
 (a) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs: 26, 27, and 28, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 34, the sequence GAS, and SEQ ID NO: 35, respectively;   (b) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs: 26, 30, and 28, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 34, the sequence GAS, and SEQ ID NO: 35, respectively;   (c) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs: 37, 38, and 39, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 41, the sequence DTS, and SEQ ID NO: 42, respectively;   (d) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs: 44, 45, and 46, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 48, the sequence YTS, and SEQ ID NO: 49, respectively;   (e) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs: 51, 52, and 53, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 55, the sequence GAS, and SEQ ID NO: 56, respectively;   (f) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs: 26, 32, and 28, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 34, the sequence GAS, and SEQ ID NO: 35, respectively; and   (g) a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs: 66, 67, and 68, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 70, the sequence GAS, and SEQ ID NO: 71, respectively.   
     
     
         81 . The method of  claim 79 , wherein the first antigen-binding region of the antibody comprises a VH region comprising the CDR1, CDR2 and CDR3 sequences of SEQ ID NOs: 26, 30, and 28, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 34, the sequence GAS, and SEQ ID NO: 35, respectively. 
     
     
         82 . The method of  claim 79 , wherein the second antigen-binding region of the antibody comprises a VH region and a VL region selected from the group consisting of:
 (a) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 18, 19, and 20, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 23, the sequence GTN, and SEQ ID NO: 24, respectively, and   (b) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 18, 19, and 21, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 23, the sequence GTN, and SEQ ID NO: 24, respectively.   
     
     
         83 . The method of  claim 79 , wherein the first antigen-binding region of the antibody comprises a variable heavy chain (VH) region comprising a CDR1 comprising the sequence of SEQ ID NO: 26, a CDR2 comprising the sequence of SEQ ID NO: 30, and a CDR3 comprising the sequence of SEQ ID NO: 28, and a variable light chain (VL) region comprising a CDR1 comprising the sequence of SEQ ID NO: 34, a CDR2 comprising the sequence GAS, and a CDR3 comprising the sequence of SEQ ID NO: 35, and the second antigen-binding region of the antibody comprises a VH region comprising a CDR1 comprising the sequence of SEQ ID NO: 18, a CDR2 comprising the sequence of SEQ ID NO: 19, and a CDR3 comprising the sequence of SEQ ID NO: 21, and a VL region comprising a CDR1 comprising the sequence of SEQ ID NO: 23, a CDR2 comprising the sequence GTN, and a CDR3 comprising the sequence of SEQ ID NO: 24. 
     
     
         84 . The method of  claim 83 , wherein the antibody further comprises a first heavy chain constant region and a second heavy chain constant region which are of an IgG isotype. 
     
     
         85 . The method of  claim 84 , wherein the isotype is IgG1. 
     
     
         86 . The method according to  claim 84 , wherein the amino acid in the position corresponding to K409 in a human IgG1 heavy chain is R in said first heavy chain, and the amino acid in the position corresponding to F405 in a human IgG1 heavy chain is L in said second heavy chain, or vice versa. 
     
     
         87 . The method according to  claim 85 , wherein the amino acid in the position corresponding to K409 in a human IgG1 heavy chain is R in said first heavy chain, and the amino acid in the position corresponding to F405 in a human IgG1 heavy chain is L in said second heavy chain, or vice versa. 
     
     
         88 . The method of  claim 83 , wherein the antibody further comprises a first heavy chain constant region and a second heavy chain constant region, wherein said first heavy chain constant region comprises the sequence of SEQ ID NO: 61 and said second heavy chain constant region comprises the sequence of SEQ ID NO: 60, optionally wherein the c-terminal lysines (K) of SEQ ID NOs: 61 and 60 are deleted. 
     
     
         89 . The method of  claim 88 , wherein the antibody further comprises a first light chain constant region and a second light chain constant region, optionally wherein said first light chain constant region comprises the sequence of SEQ ID NO: 63 and said second light chain constant region comprises the sequence of SEQ ID NO: 64. 
     
     
         90 . The method of  claim 79 , wherein the cancer is selected from the group consisting of: lung cancer, non-small cell lung cancer, stomach cancer, pancreatic cancer, cholangiocarcinoma, bladder cancer, cervical cancer, head and neck cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, renal cancer, and uterine cancer. 
     
     
         91 . The method of  claim 79 , wherein the cancer is selected from the group consisting of: uterine carcinosarcoma, bladder urothelial carcinoma, head and neck adenocarcinoma, head and neck squamous cell carcinoma, pancreatic adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, triple-negative breast cancer, uterine corpus endometrial carcinoma, and ovarian serous cystadenocarcinoma. 
     
     
         92 . The method of  claim 79 , wherein the first antigen-binding region of the antibody comprises a VH region and a VL region selected from the group consisting of:
 (a) a VH region comprising the amino acid sequence of SEQ ID NO: 25, and a VL region comprising the amino acid sequence of SEQ ID NO: 33;   (b) a VH region comprising the amino acid sequence of SEQ ID NO: 29, and a VL region comprising the amino acid sequence of SEQ ID NO: 33;   (c) a VH region comprising the amino acid sequence of SEQ ID NO: 36, and a VL region comprising the amino acid sequence of SEQ ID NO: 40;   (d) a VH region comprising the amino acid sequence of SEQ ID NO: 43, and a VL region comprising the amino acid sequence of SEQ ID NO: 47;   (e) a VH region comprising the amino acid sequence of SEQ ID NO: 50, and a VL region comprising the amino acid sequence of SEQ ID NO: 54;   (f) a VH region comprising the amino acid sequence of SEQ ID NO: 31, and a VL region comprising the amino acid sequence of SEQ ID NO: 33; and   (g) a VH region comprising the amino acid sequence of SEQ ID NO: 65, and a VL region comprising the amino acid sequence of SEQ ID NO: 69.   
     
     
         93 . The method of  claim 79 , wherein the first antigen-binding region of the antibody comprises a VH region comprising the amino acid sequence of SEQ ID NO: 29, and a VL region comprising the amino acid sequence of SEQ ID NO: 33. 
     
     
         94 . The method of  claim 79 , wherein the second antigen-binding region of the antibody comprises a VH region and a VL region selected from the group consisting of:
 (a) a VH region comprising the amino acid sequence of SEQ ID NO: 16 and a VL region comprising the amino acid sequence of SEQ ID NO: 22; and   (b) a VH region comprising the amino acid sequence of SEQ ID NO: 17 and a VL region comprising the amino acid sequence of SEQ ID NO: 22.   
     
     
         95 . The method of  claim 79 , wherein the first antigen-binding region of the antibody comprises a VH region comprising the sequence of SEQ ID NO: 29 and a VL region comprising the sequence of SEQ ID NO: 33, and the second antigen-binding region of the antibody comprises a VH region comprising the sequence of SEQ ID NO: 17 and a VL region comprising the sequence of SEQ ID NO: 22. 
     
     
         96 . The method of  claim 95 , wherein the antibody further comprises a first heavy chain constant region and a second heavy chain constant region which are of an IgG isotype. 
     
     
         97 . The method of  claim 96 , wherein the isotype is IgG1. 
     
     
         98 . The method according to  claim 96 , wherein the amino acid in the position corresponding to K409 in a human IgG1 heavy chain is R in said first heavy chain, and the amino acid in the position corresponding to F405 in a human IgG1 heavy chain is L in said second heavy chain, or vice versa. 
     
     
         99 . The method according to  claim 97 , wherein the amino acid in the position corresponding to K409 in a human IgG1 heavy chain is R in said first heavy chain, and the amino acid in the position corresponding to F405 in a human IgG1 heavy chain is L in said second heavy chain, or vice versa. 
     
     
         100 . The method of  claim 95 , wherein the antibody further comprises a first heavy chain constant region and a second heavy chain constant region, wherein said first heavy chain constant region comprises the sequence of SEQ ID NO: 61 and said second heavy chain constant region comprises the sequence of SEQ ID NO: 60, optionally wherein the c-terminal lysines (K) of SEQ ID NOs: 61 and 60 are deleted. 
     
     
         101 . The method of  claim 100 , wherein the antibody further comprises a first light chain constant region and a second light chain constant region, optionally wherein said first light chain constant region comprises the sequence of SEQ ID NO: 63 and said second light chain constant region comprises the sequence of SEQ ID NO: 64. 
     
     
         102 . The method of  claim 92 , wherein the cancer is selected from the group consisting of: lung cancer, non-small cell lung cancer, stomach cancer, pancreatic cancer, cholangiocarcinoma, bladder cancer, cervical cancer, head and neck cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, renal cancer, and uterine cancer. 
     
     
         103 . The method of  claim 92 , wherein the cancer is selected from the group consisting of: uterine carcinosarcoma, bladder urothelial carcinoma, head and neck adenocarcinoma, head and neck squamous cell carcinoma, pancreatic adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, triple-negative breast cancer, uterine corpus endometrial carcinoma, and ovarian serous cystadenocarcinoma. 
     
     
         104 . A method of treating cancer comprising tumor cells which express B7H4, the method comprising administering to a subject in need thereof a therapeutically effective amount of an antibody comprising a first antigen-binding region which binds to human B7H4, and a second antigen-binding region which binds to human CD3,
 wherein the first antigen-binding region comprises a variable heavy chain (VH) region comprising a CDR1 comprising the sequence of SEQ ID NO: 26, a CDR2 comprising the sequence of SEQ ID NO: 30, and a CDR3 comprising the sequence of SEQ ID NO: 28, and a variable light chain (VL) region comprising a CDR1 comprising the sequence of SEQ ID NO: 34, a CDR2 comprising the sequence GAS, and a CDR3 comprising the sequence of SEQ ID NO: 35,   wherein the second antigen-binding region comprises a VH region comprising a CDR1 comprising the sequence of SEQ ID NO: 18, a CDR2 comprising the sequence of SEQ ID NO: 19, and a CDR3 comprising the sequence of SEQ ID NO: 21, and a VL region comprising a CDR1 comprising the sequence of SEQ ID NO: 23, a CDR2 comprising the sequence GTN, and a CDR3 comprising the sequence of SEQ ID NO: 24, and   wherein the antibody comprises a first heavy chain constant region and a second heavy chain constant region and a first light chain constant region and a second light chain constant region, wherein said first heavy chain constant region comprises the sequence of SEQ ID NO: 61 and said second heavy chain constant region comprises the sequence of SEQ ID NO: 60, and wherein said first light chain constant region comprises the sequence of SEQ ID NO: 63 and said second light chain constant region comprises the sequence of SEQ ID NO: 64, optionally wherein the c-terminal lysines (K) of SEQ ID NOs: 61 and 60 are deleted.   
     
     
         105 . The method of  claim 104 , wherein the cancer is selected from the group consisting of: lung cancer, non-small cell lung cancer, stomach cancer, pancreatic cancer, cholangiocarcinoma, bladder cancer, cervical cancer, head and neck cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, renal cancer, and uterine cancer. 
     
     
         106 . The method of  claim 104 , wherein the cancer is selected from the group consisting of: uterine carcinosarcoma, bladder urothelial carcinoma, head and neck adenocarcinoma, head and neck squamous cell carcinoma, pancreatic adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, triple-negative breast cancer, uterine corpus endometrial carcinoma, and ovarian serous cystadenocarcinoma. 
     
     
         107 . A method of treating cancer comprising tumor cells which express B7H4, the method comprising administering to a subject in need thereof a therapeutically effective amount of an antibody comprising a first antigen-binding region which binds to human B7H4, and a second antigen-binding region which binds to human CD3,
 wherein the first antigen-binding region comprises a variable heavy chain (VH) region comprising the sequence of SEQ ID NO: 29 and a variable light chain (VL) region comprising the sequence of SEQ ID NO: 33, and the second antigen-binding region comprises a VH region comprising the sequence of SEQ ID NO: 17 and a VL region comprising the sequence of SEQ ID NO: 22, and   wherein the antibody comprises a first heavy chain constant region and a second heavy chain constant region and a first light chain constant region and a second light chain constant region, wherein said first heavy chain constant region comprises the sequence of SEQ ID NO: 61 and said second heavy chain constant region comprises the sequence of SEQ ID NO: 60, and wherein said first light chain constant region comprises the sequence of SEQ ID NO: 63 and said second light chain constant region comprises the sequence of SEQ ID NO: 64, optionally wherein the c-terminal lysines (K) of SEQ ID NOs: 61 and 60 are deleted.   
     
     
         108 . The method of  claim 107 , wherein the cancer is selected from the group consisting of: lung cancer, non-small cell lung cancer, stomach cancer, pancreatic cancer, cholangiocarcinoma, bladder cancer, cervical cancer, head and neck cancer, breast cancer, ovarian cancer, cervical cancer, prostate cancer, renal cancer, and uterine cancer. 
     
     
         109 . The method of  claim 107 , wherein the cancer is selected from the group consisting of: uterine carcinosarcoma, bladder urothelial carcinoma, head and neck adenocarcinoma, head and neck squamous cell carcinoma, pancreatic adenocarcinoma, lung squamous cell carcinoma, breast invasive carcinoma, triple-negative breast cancer, uterine corpus endometrial carcinoma, and ovarian serous cystadenocarcinoma.