US2021403570A1PendingUtilityA1

Anti-pd-1 antibodies and uses thereof

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Assignee: EUCURE BEIJING BIOPHARMA CO LTDPriority: Feb 23, 2018Filed: Sep 17, 2021Published: Dec 30, 2021
Est. expiryFeb 23, 2038(~11.6 yrs left)· nominal 20-yr term from priority
Inventors:Yi Yan YangJingshu XieChunyan DongFang YangChengyuan LuXiaodong ChengYuelei ShenJian NiYanan GuoYunyun Chen
A61P 31/00A61P 37/04C07K 16/28A61P 35/00A61K 47/6801C07K 2317/92A61K 2039/505C07K 16/2818C07K 2317/76C07K 16/2803C07K 2317/33A61K 39/39C07K 2317/24C07K 2317/622C12N 15/85C07K 2317/94A61K 39/395C07K 2317/565
67
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Claims

Abstract

This disclosure relates to anti-PD-1 (Programmed Cell Death Protein 1) antibodies, antigen-binding fragments, and the uses thereof.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . An antibody or antigen-binding fragment thereof that binds to PD-1 (Programmed Cell Death Protein 1) 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 CDRs 1, 2, and 3 amino acid sequences and the selected VL CDRs, 1, 2, and 3 amino acid sequences are one of the following:   (1) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 1, 2, 3, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 4, 5, 6, respectively;   (2) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 7, 8, 9, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 10, 11, 12, respectively;   (3) the selected VH CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 7, 13, 14, respectively, and the selected VL CDRs 1, 2, 3 amino acid sequences are set forth in SEQ ID NOs: 10, 11, 15, respectively.   
     
     
         2 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the VH comprises CDRs 1, 2, 3 with the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3 respectively, and the VL comprises CDRs 1, 2, 3 with the amino acid sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively. 
     
     
         3 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the VH comprises CDRs 1, 2, 3 with the amino acid sequences set forth in SEQ ID NOs: 7, 8, and 9, respectively, and the VL comprises CDRs 1, 2, 3 with the amino acid sequences set forth in SEQ ID NOs: 10, 11, and 12, respectively. 
     
     
         4 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the VH comprises CDRs 1, 2, 3 with the amino acid sequences set forth in SEQ ID NOs: 7, 13, and 14, respectively, and the VL comprises CDRs 1, 2, 3 with the amino acid sequences set forth in SEQ ID NOs: 10, 11, and 15, respectively. 
     
     
         5 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 4 , wherein the antibody or antigen-binding fragment specifically binds to human PD-1. 
     
     
         6 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 5 , wherein the antibody or antigen-binding fragment is a humanized antibody or antigen-binding fragment thereof. 
     
     
         7 . The antibody or antigen-binding fragment thereof of any one of  claims 1 - 6 , wherein the antibody or antigen-binding fragment is a single-chain variable fragment (scFV). 
     
     
         8 . A nucleic acid comprising a polynucleotide encoding a polypeptide comprising:
 (1) an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively, and wherein the VH, when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 29, 30, 31, or 40, binds to PD-1;   (2) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 26, 27, 28, or 39, binds to PD-1;   (3) an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 7, 8, and 9, respectively, and wherein the VH, when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 36, 37, 38 or 42, binds to PD-1;   (4) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 10, 11, and 12, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 32, 33, 34, 35 or 41, binds to PD-1;   (5) an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 7, 13, and 14, respectively, and wherein the VH, when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO: 44 binds to PD-1;   (6) an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 10, 11, and 15, respectively, and wherein the VL, when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO: 43 binds to PD-1.   
     
     
         9 . The nucleic acid of  claim 8 , wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively. 
     
     
         10 . The nucleic acid of  claim 8 , wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively. 
     
     
         11 . The nucleic acid of  claim 8 , wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 7, 8, and 9, respectively. 
     
     
         12 . The nucleic acid of  claim 8 , wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 10, 11, and 12, respectively. 
     
     
         13 . The nucleic acid of  claim 8 , wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 7, 13, and 14, respectively. 
     
     
         14 . The nucleic acid of  claim 8 , wherein the nucleic acid comprises a polynucleotide encoding a polypeptide comprising an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 comprising the amino acid sequences set forth in SEQ ID NOs: 10, 11, and 15, respectively. 
     
     
         15 . The nucleic acid of any one of  claims 8 - 14 , wherein the VH when paired with a VL specifically binds to human PD-1, or the VL when paired with a VH specifically binds to human PD-1. 
     
     
         16 . The nucleic acid of any one of  claims 8 - 15 , wherein the immunoglobulin heavy chain or the fragment thereof is a humanized immunoglobulin heavy chain or a fragment thereof, and the immunoglobulin light chain or the fragment thereof is a humanized immunoglobulin light chain or a fragment thereof. 
     
     
         17 . The nucleic acid of any one of  claims 8 - 16 , wherein the nucleic acid encodes a single-chain variable fragment (scFv). 
     
     
         18 . The nucleic acid of any one of  claims 8 - 17 , wherein the nucleic acid is cDNA. 
     
     
         19 . A vector comprising one or more of the nucleic acids of any one of  claims 8 - 18 . 
     
     
         20 . A vector comprising two of the nucleic acids of any one of  claims 8 - 18 , wherein the vector encodes the VL region and the VH region that together bind to PD-1. 
     
     
         21 . A pair of vectors, wherein each vector comprises one of the nucleic acids of any one of  claims 8 - 18 , wherein together the pair of vectors encodes the VL region and the VH region that together bind to PD-1. 
     
     
         22 . A cell comprising the vector of  claim 19  or  20 , or the pair of vectors of  claim 21 . 
     
     
         23 . The cell of  claim 22 , wherein the cell is a CHO cell. 
     
     
         24 . A cell comprising one or more of the nucleic acids of any one of  claims 8 - 18 . 
     
     
         25 . A cell comprising two of the nucleic acids of any one of  claims 8 - 18 . 
     
     
         26 . The cell of  claim 25 , wherein the two nucleic acids together encode the VL region and the VH region that together bind to PD-1. 
     
     
         27 . A method of producing an antibody or an antigen-binding fragment thereof, the method comprising
 (a) culturing the cell of any one of  claims 22 - 26  under conditions sufficient for the cell to produce the antibody or the antigen-binding fragment; and   (b) collecting the antibody or the antigen-binding fragment produced by the cell.   
     
     
         28 . An antibody or antigen-binding fragment thereof that binds to PD-1 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 the following:   (1) the selected VH sequence is SEQ ID NOs: 26, 27, 28, or 39, and the selected VL sequence is SEQ ID NOs: 29, 30, 31, or 40;   (2) the selected VH sequence is SEQ ID NOs: 32, 33, 34, 35 or 41, and the selected VL sequence is SEQ ID NOs: 36, 37, 38 or 42;   (3) the selected VH sequence is SEQ ID NO: 43, and the selected VL sequence is SEQ ID NO: 44.   
     
     
         29 . The antibody or antigen-binding fragment thereof of  claim 28 , wherein the VH comprises the sequence of SEQ ID NO: 26 and the VL comprises the sequence of SEQ ID NO: 31. 
     
     
         30 . The antibody or antigen-binding fragment thereof of  claim 28 , wherein the VH comprises the sequence of SEQ ID NO: 27 and the VL comprises the sequence of SEQ ID NO: 31. 
     
     
         31 . The antibody or antigen-binding fragment thereof of any one of  claims 28 - 31 , wherein the antibody or antigen-binding fragment specifically binds to human PD-1. 
     
     
         32 . The antibody or antigen-binding fragment thereof of any one of  claims 28 - 32 , wherein the antibody or antigen-binding fragment is a humanized antibody or antigen-binding fragment thereof. 
     
     
         33 . The antibody or antigen-binding fragment thereof of any one of  claims 28 - 30 , wherein the antibody or antigen-binding fragment is a single-chain variable fragment (scFV). 
     
     
         34 . An antibody-drug conjugate comprising the antibody or antigen-binding fragment thereof of any one of  claims 1 - 7  and  28 - 33  covalently bound to a therapeutic agent. 
     
     
         35 . The antibody drug conjugate of  claim 34 , wherein the therapeutic agent is a cytotoxic or cytostatic agent. 
     
     
         36 . A method of treating a subject having cancer, the method comprising administering a therapeutically effective amount of a composition comprising the antibody or antigen-binding fragment thereof of any one of  claims 1 - 7  and  28 - 33 , or the antibody-drug conjugate of  claim 34  or  35 , to the subject. 
     
     
         37 . The method of  claim 36 , wherein the subject has a solid tumor. 
     
     
         38 . The method of  claim 36 , wherein the cancer is unresectable melanoma or metastatic melanoma. 
     
     
         39 . The method of  claim 36 , wherein the cancer is non-small cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), head and neck cancer, renal cell carcinoma (RCC), melanoma, bladder cancer, gastric cancer, urothelial cancer, Merkel-cell carcinoma, triple-negative breast cancer (TNBC), or colorectal carcinoma. 
     
     
         40 . A method of decreasing the rate of tumor growth, the method comprising contacting a tumor cell with an effective amount of a composition comprising an antibody or antigen-binding fragment thereof of any one of  claims 1 - 7  and  28 - 33 , or the antibody-drug conjugate of  claims 34  or  35 . 
     
     
         41 . A method of killing a tumor cell, the method comprising
 contacting a tumor cell with an effective amount of a composition comprising the antibody or antigen-binding fragment thereof of any one of  claims 1 - 7  and  28 - 33 , or the antibody-drug conjugate of  claims 34  or  35 .   
     
     
         42 . A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of any one of  claims 1 - 7  and  28 - 33 , and a pharmaceutically acceptable carrier. 
     
     
         43 . A pharmaceutical composition comprising the antibody drug conjugate of  claim 34  or  35 , and a pharmaceutically acceptable carrier.

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