Anti-HER2 Antibodies and Immunoconjugates

Abstract

The invention provides anti-HER2 antibodies and immunoconjugates and methods of using the same.

1 - 19 . (canceled) 
     
     
         20 . An immunoconjugate comprising an antibody of and a cytotoxic agent, wherein the antibody comprises (i) a heavy chain variable region comprising the sequence of SEQ ID NO: 11 and a light chain variable region comprising the sequence of SEQ ID NO: 10; (ii) a heavy chain comprising the sequence of SEQ ID NO: 19 and a light chain comprising the sequence of SEQ ID NO: 23; or (iii) a heavy chain comprising the sequence of SEQ ID NO: 24 and a light chain comprising the sequence of SEQ ID NO: 18. 
     
     
         21 . An immunoconjugate having the formula Ab-(L-D)p, wherein:
 (a) Ab is an antibody of comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO:15, HVR-H2 comprising the amino acid sequence of SEQ ID NO:16, HVR-H3 comprising the amino acid sequence of SEQ ID NO:17, HVR-L1 comprising the amino acid sequence of SEQ ID NO:12, HVR-L2 comprising the amino acid sequence of SEQ ID NO:13, and HVR-L3 comprising the amino acid sequence of SEQ ID NO:14; (ii) a heavy chain variable region comprising the sequence of SEQ ID NO: 11 and a light chain variable region comprising the sequence of SEQ ID NO: 10; (iii) a heavy chain comprising the sequence of SEQ ID NO: 19 and a light chain comprising the sequence of SEQ ID NO: 23; or (iv) a heavy chain comprising the sequence of SEQ ID NO: 24 and a light chain comprising the sequence of SEQ ID NO: 18;   (b) L is a linker;   (c) D is a cytotoxic agent; and   (d) p ranges from 1-8.   
     
     
         22 . The immunoconjugate of  claim 20 , wherein the cytotoxic agent is selected from an auristatin, a maytansinoid, a calicheamicin, a pyrrolobenzodiazepine, a nemorubicin derivative, and a 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indole (CBI). 
     
     
         23 . The immunoconjugate of  claim 21 , wherein the cytotoxic agent is a pyrrolobenzodiazepine of Formula A: 
       
         
           
           
               
               
           
         
         wherein the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3; 
         R 2  is independently selected from H, OH, ═O, ═CH 2 , CN, R, OR, ═CH—R D , ═C(R D ) 2 , O—SO 2 —R, CO 2 R and COR, and optionally further selected from halo or dihalo, wherein R D  is independently selected from R, CO 2 R, COR, CHO, CO 2 H, and halo; 
         R 6  and R 9  are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, NO 2 , Me 3 Sn and halo; 
         R 7  is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, NO 2 , Me 3 Sn and halo; 
         Q is independently selected from O, S and NH; 
         R 11  is either H or R, or Q is O and R 11  is SO 3 M, where M is a metal cation; 
         R and R′ are each independently selected from optionally substituted C 1-8  alkyl, C 3-8  heterocyclyl and C 5-20  aryl groups, and optionally in relation to the group NRR′, R and R′ together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring; 
         R 12 , R 16 , R 19  and R 17  are as defined for R 2 , R 6 , R 9  and R 7  respectively; 
         R″ is a C 3-12  alkylene group, which chain may be interrupted by one or more heteroatoms and/or aromatic rings that are optionally substituted; and 
         X and X′ are independently selected from O, S and N(H). 
       
     
     
         24 . The immunoconjugate of  claim 23 , wherein D has the structure: 
       
         
           
           
               
               
           
         
         wherein n is 0 or 1. 
       
     
     
         25 . The immunoconjugate of  claim 21 , wherein the cytotoxic agent is a nemorubicin derivative. 
     
     
         26 . The immunoconjugate of  claim 25 , wherein the cytotoxic agent has a structure selected from: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The immunoconjugate of  claim 21 , wherein the cytotoxic agent comprises a 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indole (CBI). 
     
     
         28 . The immunoconjugate of  claim 27 , wherein the cytotoxic agent has the formula: 
       
         
           
           
               
               
           
         
         where 
         R 1  is selected from H, P(O) 3 H 2 , C(O)NR a R b , or a bond to L; 
         R 2  is selected from H, P(O) 3 H 2 , C(O)NR a R b , or a bond to L; 
         R a  and R b  are independently selected from H and C 1 -C 6  alkyl optionally substituted with one or more F, 
         or R a  and R b  form a five or six membered heterocyclyl group; 
         T is a tether group selected from C 3 -C 12  alkylene, Y, (C 1 -C 6  alkylene)-Y—(C 1 -C 6  alkylene), (C 1 -C 6  alkylene)-Y—(C 1 -C 6  alkylene)-Y—(C 1 -C 6  alkylene), (C 2 -C 6  alkenylene)-Y—(C 2 -C 6  alkenylene), and (C 2 -C 6  alkynylene)-Y—(C 2 -C 6  alkynylene); 
         where Y is independently selected from O, S, NR 1 , aryl, and heteroaryl; 
         where alkylene, alkenylene, aryl, and heteroaryl are independently and optionally substituted with F, OH, O(C 1 -C 6  alkyl), NH 2 , NHCH 3 , N(CH 3 ) 2 , OP(O) 3 H 2 , and C 1 -C 6  alkyl, where alkyl is optionally substituted with one or more F; 
         or alkylene, alkenylene, aryl, and heteroaryl are independently and optionally substituted with a bond to L; 
         D′ is a drug moiety selected from: 
       
       
         
           
           
               
               
           
         
         where the wavy line indicates the site of attachment to T; 
         X 1  and X 2  are independently selected from O and NR 3 , where R 3  is selected from H and C 1 -C 6  alkyl optionally substituted with one or more F; 
         R 4  is H, CO 2 R, or a bond to a linker (L), where R is C 1 -C 6  alkyl or benzyl; and 
         R 5  is H or C 1 -C 6  alkyl. 
       
     
     
         29 . The immunoconjugate of  claim 28 , wherein the cytotoxic agent has a structure selected from: 
       
         
           
           
               
               
           
         
       
     
     
         30 . The immunoconjugate of  claim 21 , wherein the linker is cleavable by a protease. 
     
     
         31 . The immunoconjugate of  claim 21 , wherein the linker is acid-labile. 
     
     
         32 . The immunoconjugate of  claim 31 , wherein the linker comprises hydrazone. 
     
     
         33 . The immunoconjugate of  claim 21 , wherein the linker comprises a disulfide. 
     
     
         34 . The immunoconjugate of  claim 21  having a structure selected from: 
       
         
           
           
               
               
           
         
       
     
     
         35 . The immunoconjugate of  claim 21  having a formula selected from: 
       
         
           
           
               
               
           
         
       
     
     
         36 . The immunoconjugate of  claim 21 , having a structure selected from: 
       
         
           
           
               
               
           
         
       
     
     
         37 . The immunoconjugate of  claim 21 , wherein the cytotoxic agent comprises the structure: 
       
         
           
           
               
               
           
         
       
     
     
         38 . The immunoconjugate of  claim 21 , wherein p ranges from 1.3-2 or from 2-5. 
     
     
         39 - 76 . (canceled) 
     
     
         77 . The immunoconjugate of  claim 20 , wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 19 and a light chain comprising the sequence of SEQ ID NO: 23. 
     
     
         78 . The immunoconjugate of  claim 20 , wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 24 and a light chain comprising the sequence of SEQ ID NO: 18. 
     
     
         79 . The immunoconjugate of  claim 21 , wherein the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 11 and a light chain variable region comprising the sequence of SEQ ID NO: 10. 
     
     
         80 . The immunoconjugate of  claim 21 , wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 19 and a light chain comprising the sequence of SEQ ID NO: 23. 
     
     
         81 . The immunoconjugate of  claim 21 , wherein the antibody comprises a heavy chain comprising the sequence of SEQ ID NO: 24 and a light chain comprising the sequence of SEQ ID NO: 18. 
     
     
         82 . The immunoconjugate of  claim 21 , wherein the cytotoxic agent is selected from an auristatin, a maytansinoid, a calicheamicin, a pyrrolobenzodiazepine, a nemorubicin derivative, and a 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indole (CBI).