Anti-efna4 antibody-drug conjugates

Abstract

The present invention provides for anti-EFNA4 antibody-drug conjugates and methods for preparing and using the same.

1 .- 69 . (canceled) 
     
     
         70 . An antibody-drug conjugate of the formula: Ab-(L-D), wherein:
 (a) Ab is an antibody, or antigen-binding fragment thereof, that binds to EFNA4 and comprises:
 (i) a heavy chain variable region comprising three CDRs set forth as SEQ ID NOs: 15, 19, and 23 and a light chain variable region comprising three CDRs set forth as SEQ ID NOs: 29, 33, and 35; or 
 (ii) a heavy chain variable region comprising three CDRs set forth as SEQ ID NOs: 41, 45, and 49 and a light chain variable region comprising three CDRs set forth as SEQ ID NOs: 55, 59, and 61; and 
   (b) L-D is a linker-drug moiety, wherein L is a linker and D is a DNA-damaging agent.   
     
     
         71 . The antibody-drug conjugate of  claim 70 , wherein the Ab comprises:
 (i) a heavy chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 13 and a light chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 27; or   (ii) a heavy chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 39 and a light chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 53.   
     
     
         72 . The antibody-drug conjugate of  claim 71 , wherein the Ab comprises:
 (i) a heavy chain variable region set forth as SEQ ID NO: 13 and a light chain variable region set forth as SEQ ID NO: 27; or   (ii) a heavy chain variable region set forth as SEQ ID NO: 39 and a light chain variable region set forth as SEQ ID NO: 53.   
     
     
         73 . The antibody-drug conjugate of  claim 72 , wherein the Ab comprises a IgG1 heavy chain constant region. 
     
     
         74 . The antibody-drug conjugate of  claim 73 , wherein the Ab comprises:
 (i) a heavy chain set forth as SEQ ID NO: 25; or   (ii) a heavy chain set forth as SEQ ID NO: 51.   
     
     
         75 . The antibody-drug conjugate of  claim 72 , wherein the Ab comprises a kappa light chain constant region. 
     
     
         76 . The antibody-drug conjugate of  claim 75 , wherein the Ab comprises:
 (i) a light chain set forth as SEQ ID NO: 37; or   (ii) a light chain set forth as SEQ ID NO: 63.   
     
     
         77 . The antibody-drug conjugate of  claim 72 , wherein the Ab comprises:
 (i) a heavy chain set forth as SEQ ID NO: 25 and a light chain set forth as SEQ ID NO: 37; or   (ii) a heavy chain set forth as SEQ ID NO: 51 and a light chain set forth as SEQ ID NO: 63.   
     
     
         78 . The antibody-drug conjugate of claim  1 , having a drug-antibody ratio (DAR) from 1 to 12. 
     
     
         79 . An antibody-drug conjugate of the formula: Ab-(L-D), wherein:
 (a) Ab is an antibody, or antigen-binding fragment thereof, comprising
 (i) a heavy chain set forth as SEQ ID NO: 25 and a light chain set forth as SEQ ID NO: 37; or 
 (ii) a heavy chain set forth as SEQ ID NO: 51 and a light chain set forth as SEQ ID NO: 63; and 
   (b) L-D is a linker-drug moiety, wherein L is a linker and D is a DNA-damaging agent.   
     
     
         80 . A composition comprising a plurality of antibody-drug conjugates of the formula: Ab-(L-D), and optionally a pharmaceutical carrier, wherein:
 (a) Ab is an antibody, or antigen-binding fragment thereof, that binds to EFNA4 and comprises
 (i) a heavy chain variable region comprising three CDRs set forth as SEQ ID NOs: 15, 19, and 23 and a light chain variable region comprising three CDRs set forth as SEQ ID NOs: 29, 33, and 35; or 
 (ii) a heavy chain variable region comprising three CDRs set forth as SEQ ID NOs: 41, 45, and 49 and a light chain variable region comprising three CDRs set forth as SEQ ID NOs: 55, 59, and 61; and 
   (b) L-D is a linker-drug moiety, wherein L is a linker and D is a DNA-damaging agent; and   wherein the composition has an average DAR from 1 to 12.   
     
     
         81 . The composition of  claim 80 , wherein the composition has an average DAR within the range of 3 to 5. 
     
     
         82 . The composition of  claim 81 , wherein the composition has an average DAR within the range of 3 to 4. 
     
     
         83 . The composition of  claim 82 , wherein the composition has an average DAR within the range of 4 to 5. 
     
     
         84 . The composition of  claim 83 , wherein the composition has an average DAR of about 4. 
     
     
         85 . The composition of  claim 80 , wherein at least 50% of the antibody-drug conjugates have a DAR from 3 to 5. 
     
     
         86 . The composition of  claim 85 , wherein at least 60% of the antibody-drug conjugates have a DAR from 3 to 5. 
     
     
         87 . The composition of  claim 86 , wherein at least 70% of the antibody-drug conjugates have a DAR from 3 to 5. 
     
     
         88 . The composition of  claim 87 , wherein the composition has at least 75% antibody-drug conjugates having a DAR from 3 to 5. 
     
     
         89 . The composition of  claim 86 , wherein the composition has about 70% to 80% antibody-drug conjugates having a DAR from 3 to 5.