Anti-erbb2 antibody-drug conjugate and composition thereof, preparation method therefor, and application thereof

Abstract

The present invention provides an anti-ErbB2 antibody-drug conjugate, a composition comprising the conjugate, a method for preparing the conjugate, use of the conjugate.

1 . An antibody-drug conjugate of Formula (I), or a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing, 
       
         
           
           
               
               
           
         
         wherein: 
         A is an anti-ErbB2 antibody or an active fragment or variant thereof; 
         X is N; 
         Y N or CR 1 , and R 1  is H or C 1 -C 10  alkyl; 
         L is a divalent linker; 
         D is a cytotoxic agent group; and 
         a is an integer selected from the group consisting of 2-10. 
       
     
     
         2 . The antibody-drug conjugate, or pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or solvate of the foregoing according to  claim 1 , wherein the anti-ErbB2 antibody is an anti-human ErbB2 antibody, and preferably, the CDR1, CDR2 and/or CDR3 of the heavy and light chains of the anti-human ErbB2 antibody are CDR1, CDR2 and/or CDR3 of the heavy and light chains of Trastuzumab, respectively. 
     
     
         3 . The antibody-drug conjugate, or pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or solvate of the foregoing according to  claim 2 , wherein the anti-ErbB2 antibody is a humanized antibody or a fully human antibody, preferably Trastuzumab. 
     
     
         4 . The antibody-drug conjugate, or pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or solvate of the foregoing according to  claim 1 , wherein Y is CR 1 . 
     
     
         5 . The antibody-drug conjugate, or pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or solvate of the foregoing according to  claim 1 , wherein R 1  is H. 
     
     
         6 . The antibody-drug conjugate, or pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or solvate of the foregoing according to  claim 1 , wherein a is 2, 3 or 4. 
     
     
         7 . The antibody-drug conjugate, or pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or solvate of the foregoing according to  claim 1 , wherein L is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each of m and n is an integer selected from the group consisting of 1-10, preferably 1, 2, 3, 4, 5 or 6 at each occurrence. 
       
     
     
         8 . The antibody-drug conjugate, or pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or solvate of the foregoing according to  claim 1 , wherein the cytotoxic agent group is derived from a compound of Formula (D1) or (D2) or a stereoisomer thereof: 
       
         
           
           
               
               
           
         
         wherein:
 R 2  is selected from the group consisting of —CH 2 N 3 , —CONHSO 2 (cyclopropyl), thiazol-2-yl, —CH 3  and —COOH; 
 R 3  is selected from the group consisting of H and —OH; and 
 R 4  is selected from the group consisting of H, —NH 2 , Cl, Br, I, —OS(O) 2 R 6 , wherein R 6  is H, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl or C 6 -C 14  aryl, and the alkyl, cycloalkyl and aryl are each optionally substituted with one or more (e.g., 1, 2, 3, 4 or 5) substituents selected from halogens such as F; 
 
       
       
         
           
           
               
               
           
         
         wherein R 5  is selected from the group consisting of —C(CH 3 )N(CH 3 )C(O)CH 2 CH 2 SH and —C(CH 3 )N(CH 3 )C(O)CH 2 C(CH 3 ) 2 SH. 
       
     
     
         9 . The antibody-drug conjugates, pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or solvate of the foregoing according to  claim 8 , wherein the antibody-drug conjugate is selected from the group consisting of I-1, I-2 and I-3: 
       
         
           
           
               
               
           
         
         wherein A is Trastuzumab. 
       
     
     
         10 . A preparation method of the antibody-drug conjugate according to  claim 1 , comprising the steps of:
 (1). preparing a compound of Formula (I-A):   
       
         
           
           
               
               
           
         
       
       wherein D, L, X and Y are as defined in  claim 1  for Formula (I);
 (2). obtaining a compound of Formula (I-A-G) by activating the compound of Formula (I-A) from step (1) 
 
       
         
           
           
               
               
           
         
       
       wherein G is selected from the group consisting of —F, —Cl, —Br, —I, —N 3 , —OR, —SR, —ONRR′, RC(O)O—, —OP(O)RR′, RSO 2 —O— and 
       
         
           
           
               
               
           
         
       
       wherein each of R and R′ at each occurrence is independently C 1 -C 10  alkyl, C 6 -C 14  aryl, heterocyclyl having 5 to 10 ring members, or phenoxy, and each of the alkyl, aryl, heterocyclyl and phenoxy is unsubstituted or independently substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 3 -C 8  cycloalkyl, heterocyclyl having 5 to 8 ring members, C 6 -C 10  aryl or heteroaryl having 5 to 10 ring members; preferably, G is selected from the group consisting of —ONRR′ and —OP(O)RR′, wherein each of R and R at each occurrence is independently phenoxy;
 (3) obtaining a mixture of a variety of antibody-drug conjugates having different a values by conjugating the compound of Formula (I-A-G) from step (2) with the anti-ErbB2 antibody or active fragment or variant thereof; and 
 (4) obtaining the antibody-drug conjugate by purifying the mixture from step (3) with one or more chromatographic methods selected from the group consisting of ion exchange chromatography, hydrophobic chromatography, reverse phase chromatography and affinity chromatography. 
 
     
     
         11 . The preparation method according to  claim 10 , wherein the compound of Formula (I-A-G) in step (2) is a compound of Formula (I-B) formed by reacting the compound of Formula (I-A) with pentafluorophenol: 
       
         
           
           
               
               
           
         
         wherein D, L, X and Y are as defined in  claim 1  for Formula (I), and the reaction is performed preferably using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, N-hydroxysuccinimide and/or dichloromethane. 
       
     
     
         12 . A pharmaceutical composition comprising the antibody-drug conjugate or pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or solvate of the foregoing according to  claim 1 , and a pharmaceutically acceptable carrier, and the pharmaceutical composition optionally further comprises one or more other anti-cancer agents, such as chemotherapeutic agents and/or antibodies. 
     
     
         13 . A method for the prophylaxis or treatment of cancer, comprising administering to a patient in need thereof the antibody-drug conjugate or pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or solvate of the foregoing according to  claim 1 . 
     
     
         14 . The method according to  claim 13 , wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, liver cancer, endometrial cancer, salivary gland cancer, kidney cancer, colon cancer, thyroid cancer, pancreas cancer or bladder cancer, especially breast cancer, such as ErbB2-overexpressing breast cancer. 
     
     
         15 . A pharmaceutical preparation comprising the antibody-drug conjugate or pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or solvate of the foregoing according to  claim 1 , preferably in the form of a solid preparation, semi-solid preparation, liquid preparation or gas preparation, such as lyophilized powder. 
     
     
         16 . A method for the prophylaxis or treatment of cancer, comprising administering to a patient in need thereof the pharmaceutical composition according to  claim 12 , wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, liver cancer, endometrial cancer, salivary gland cancer, kidney cancer, colon cancer, thyroid cancer, pancreas cancer or bladder cancer, especially breast cancer, such as ErbB2-overexpressing breast cancer. 
     
     
         17 . A method for the prophylaxis or treatment of cancer, comprising administering to a patient in need thereof the pharmaceutical preparation according to  claim 15 , wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, liver cancer, endometrial cancer, salivary gland cancer, kidney cancer, colon cancer, thyroid cancer, pancreas cancer or bladder cancer, especially breast cancer, such as ErbB2-overexpressing breast cancer. 
     
     
         18 . A pharmaceutical composition comprising the antibody-drug conjugate or pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or solvate of the foregoing according to  claim 8 , and a pharmaceutically acceptable carrier, and the pharmaceutical composition optionally further comprises one or more other anti-cancer agents, such as chemotherapeutic agents and/or antibodies. 
     
     
         19 . A method for the prophylaxis or treatment of cancer, comprising administering to a patient in need thereof the antibody-drug conjugate or pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or solvate of the foregoing according to  claim 8 , wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, liver cancer, endometrial cancer, salivary gland cancer, kidney cancer, colon cancer, thyroid cancer, pancreas cancer or bladder cancer, especially breast cancer, such as ErbB2-overexpressing breast cancer. 
     
     
         20 . A pharmaceutical preparation comprising the antibody-drug conjugate or pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or solvate of the foregoing according to  claim 8 , preferably in the form of a solid preparation, semi-solid preparation, liquid preparation or gas preparation, such as lyophilized powder. 
     
     
         21 . A method for the prophylaxis or treatment of cancer, comprising administering to a patient in need thereof the pharmaceutical composition according to  claim 18 , wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, liver cancer, endometrial cancer, salivary gland cancer, kidney cancer, colon cancer, thyroid cancer, pancreas cancer or bladder cancer, especially breast cancer, such as ErbB2-overexpressing breast cancer. 
     
     
         22 . A method for the prophylaxis or treatment of cancer, comprising administering to a patient in need thereof the pharmaceutical preparation according to  claim 20 , wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, liver cancer, endometrial cancer, salivary gland cancer, kidney cancer, colon cancer, thyroid cancer, pancreas cancer or bladder cancer, especially breast cancer, such as ErbB2-overexpressing breast cancer. 
     
     
         23 . A pharmaceutical composition comprising the antibody-drug conjugate or pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or solvate of the foregoing according to  claim 9 , and a pharmaceutically acceptable carrier, and the pharmaceutical composition optionally further comprises one or more other anti-cancer agents, such as chemotherapeutic agents and/or antibodies. 
     
     
         24 . A method for the prophylaxis or treatment of cancer, comprising administering to a patient in need thereof the antibody-drug conjugate or pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or solvate of the foregoing according to  claim 9 , wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, liver cancer, endometrial cancer, salivary gland cancer, kidney cancer, colon cancer, thyroid cancer, pancreas cancer or bladder cancer, especially breast cancer, such as ErbB2-overexpressing breast cancer. 
     
     
         25 . A pharmaceutical preparation comprising the antibody-drug conjugate or pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or solvate of the foregoing according to  claim 9 , preferably in the form of a solid preparation, semi-solid preparation, liquid preparation or gas preparation, such as lyophilized powder. 
     
     
         26 . A method for the prophylaxis or treatment of cancer, comprising administering to a patient in need thereof the pharmaceutical composition according to  claim 23 , wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, liver cancer, endometrial cancer, salivary gland cancer, kidney cancer, colon cancer, thyroid cancer, pancreas cancer or bladder cancer, especially breast cancer, such as ErbB2-overexpressing breast cancer. 
     
     
         27 . A method for the prophylaxis or treatment of cancer, comprising administering to a patient in need thereof the pharmaceutical composition according to  claim 25 , wherein the cancer is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, liver cancer, endometrial cancer, salivary gland cancer, kidney cancer, colon cancer, thyroid cancer, pancreas cancer or bladder cancer, especially breast cancer, such as ErbB2-overexpressing breast cancer.