Anti-trop2 antibody-drug conjugate

Abstract

It is intended to provide an antitumor drug having an excellent therapeutic effect, which is excellent in terms of antitumor effect and safety. There is provided an antibody-drug conjugate in which an antitumor compound represented by the following formula is conjugated to an anti-TROP2 antibody via a linker having a structure represented by the following formula: -L1-L2-LP-NH—(CH2)n1-La-(CH2)n2-C(═O)— wherein the anti-TROP2 antibody is connected to the terminal of L1, and the antitumor compound is connected to the carbonyl group of the —(CH2)n2-C(═O)— moiety with the nitrogen atom of the amino group at position 1 as a connecting position.

1 . An anti-TROP2 antibody comprising CDRH1 consisting of the amino acid sequence of SEQ ID NO: 23, CDRH2 consisting of the amino acid sequence of SEQ ID NO: 24 and CDRH3 consisting of the amino acid sequence of SEQ ID NO: 25 in its heavy chain variable region and CDRL1 consisting of the amino acid sequence of SEQ ID NO: 26, CDRL2 consisting of the amino acid sequence of SEQ ID NO: 27 and CDRL3 consisting of the amino acid sequence of SEQ ID NO: 28 in its light chain variable region. 
     
     
         2 . The anti-TROP2 antibody according to  claim 1 , wherein the anti-TROP2 antibody comprises a heavy chain variable region and a light chain variable region selected from the group:
 the heavy chain variable region comprising amino acids 20 to 140 of SEQ ID NO: 12 and the light chain variable region comprising amino acids 21 to 129 of SEQ ID NO: 18,   the heavy chain variable region comprising amino acids 20 to 140 of SEQ ID NO: 14 and the light chain variable region comprising amino acids 21 to 129 of SEQ ID NO: 18,   the heavy chain variable region comprising amino acids 20 to 140 of SEQ ID NO: 14 and the light chain variable region comprising amino acids 21 to 129 of SEQ ID NO: 20, and   the heavy chain variable region comprising amino acids SEQ ID NO: 16 and the light chain variable region comprising amino acids 21 to 129 of SEQ ID NO: 22.   
     
     
         3 . The anti-TROP2 antibody according to  claim 1 , wherein the anti-TROP2 antibody comprises a heavy chain and a light chain selected from the group;
 the heavy chain comprising amino acids 20 to 470 of SEQ ID NO: 12 and the light chain comprising amino acids 21 to 234 of SEQ ID NO: 18,   the heavy chain comprising amino acids 20 to 470 of SEQ ID NO: 14 and the light chain comprising amino acids 21 to 234 of SEQ ID NO: 18,   the heavy chain comprising amino acids 20 to 470 of SEQ ID NO: 14 and the light chain comprising amino acids 21 to 234 of SEQ ID NO: 20, and   the heavy chain comprising amino acids 20 to 470 of SEQ ID NO: 16 and the light chain comprising amino acids 21 to 234 of SEQ ID NO: 22.   
     
     
         4 . The anti-TROP2 antibody according to  claim 1 , wherein the anti-TROP2 antibody comprises a heavy chain variable region consisting of the amino acid sequence of positions 20 to 140 of SEQ ID NO: 12 and a light chain variable region consisting of the amino acid sequence of positions 21 to 129 of SEQ ID NO: 18. 
     
     
         5 . The anti-TROP2 antibody according to  claim 1 , wherein the anti-TROP2 antibody comprises a heavy chain consisting of the amino acid sequence of positions 20 to 470 of SEQ ID NO: 12 and a light chain consisting of the amino acid sequence of positions 21 to 234 of SEQ ID NO: 18. 
     
     
         6 . The anti-TROP2 antibody according to  claim 1 , wherein the anti-TROP2 antibody comprises a heavy chain and a light chain selected from the group;
 the heavy chain consisting of amino acids 20 to 469 of SEQ ID NO: 12 and the light chain consisting of amino acids 21 to 234 of SEQ ID NO: 18,   the heavy chain consisting of amino acids 20 to 469 of SEQ ID NO: 14 and the light chain consisting of amino acids 21 to 234 of SEQ ID NO: 18,   the heavy chain consisting of amino acids 20 to 469 of SEQ ID NO: 14 and the light chain consisting of amino acids 21 to 234 of SEQ ID NO: 20, and   the heavy chain consisting of amino acids 20 to 469 of SEQ ID NO: 16 and the light chain consisting of amino acids 21 to 234 of SEQ ID NO: 22.   
     
     
         7 . The anti-TROP2 antibody according to  claim 5 , wherein the anti-TROP2 antibody comprises a heavy chain consisting of amino acids 20 to 469 of SEQ ID NO: 12 and a light chain consisting of amino acids 21 to 234 of SEQ ID NO: 18. 
     
     
         8 . A functional fragment of the anti-TROP2 antibody according to  claim 1 . 
     
     
         9 . A modified variant of the anti-TROP2 antibody according to  claim 1 . 
     
     
         10 . A polynucleotide encoding the anti-TROP2 antibody according to  claim 1 . 
     
     
         11 . A vector comprising the polynucleotide according to  claim 10 . 
     
     
         12 . A transformed host cell comprising the polynucleotide according to  claim 10 . 
     
     
         13 . A transformed host cell comprising the vector according to  claim 11 . 
     
     
         14 . A method for producing the anti-TROP2 antibody according to  claim 1 , a functional fragment thereof, or a modified variant thereof, comprising: culturing a transformed host cell comprising a polynucleotide or vector encoding the anti-TROP2 antibody according to  claim 1 ; and then purifying an anti-TROP2 antibody from a cultured product obtained during culturing. 
     
     
         15 . An antibody-drug conjugate comprising an antitumor compound that is conjugated to the anti-TROP2 antibody according to  claim 1 , a functional fragment thereof, or a modified variant thereof. 
     
     
         16 . A method of delivering an antitumor compound selectively to a cancer cell, comprising administering to a subject with cancer an antibody-drug conjugate comprising the anti-TROP2 antibody according to  claim 1  conjugated to an antitumor compound, wherein the caner expresses TROP2. 
     
     
         17 . A method of delivering an antitumor compound selectively to a cancer cell, comprising administering to a subject with cancer an antibody-drug conjugate comprising the functional fragment according to  claim 8  conjugated to an antitumor compound, wherein the caner expresses TROP2. 
     
     
         18 . A method of delivering an antitumor compound selectively to a cancer cell, comprising administering to a subject with cancer an antibody-drug conjugate comprising the modified variant according to  claim 9  conjugated to an antitumor compound, wherein the caner expresses TROP2.