Eribulin-based antibody-drug conjugates and methods of use

Abstract

Linker toxins and antibody-drug conjugates that bind to human oncology antigen targets such as folate receptor alpha and/or provide anti-tubulin drug activity are disclosed. The linker toxins and antibody-drug conjugates comprise an eribulin drug moiety and can be internalized into target antigen-expressing cells. The disclosure further relates to methods and compositions for use in the treatment of cancer by administering the antibody-drug conjugates provided herein.

1 - 183 . (canceled) 
     
     
         184 . An antibody-drug conjugate of Formula (I):
   Ab-(L-D) p   (I)
   
       wherein
 Ab is an internalizing anti-folate receptor alpha antibody or internalizing antigen-binding fragment thereof comprising three heavy chain complementarity determining regions (HCDRs) comprising amino acid sequences of SEQ ID NO:2 (HCDR1), SEQ ID NO:3 (HCDR2), and SEQ ID NO:4 (HCDR3); and three light chain complementarity determining regions (LCDRs) comprising amino acid sequences of SEQ ID NO:7 (LCDR1), SEQ ID NO:8 (LCDR2), and SEQ ID NO:9 (LCDR3), as defined by the Kabat numbering system; or three heavy chain complementarity determining regions (HCDRs) comprising amino acid sequences of SEQ ID NO:13 (HCDR1), SEQ ID NO:14 (HCDR2), and SEQ ID NO:15 (HCDR3); and three light chain complementarity determining regions (LCDRs) comprising amino acid sequences of SEQ ID NO:16 (LCDR1), SEQ ID NO:17 (LCDR2), and SEQ ID NO:18 (LCDR3), as defined by the IMGT numbering system; 
 D is eribulin; 
 L is a cleavable linker comprising an antibody attachment group, a spacer unit comprising at least one polyethylene glycol (PEG) moiety, and a cleavable amino acid unit; and 
 p is an integer from 1 to 8. 
 
     
     
         185 . The antibody-drug conjugate of  claim 184 , wherein the spacer unit comprises -(PEG) m - and m is an integer from 1 to 10. 
     
     
         186 . The antibody-drug conjugate of  claim 185 , wherein m is an integer from 2 to 8. 
     
     
         187 . The antibody-drug conjugate of  claim 185 , wherein m is 2. 
     
     
         188 . The antibody-drug conjugate of  claim 184 , wherein the spacer unit is attached to the antibody or antigen-binding fragment through the antibody attachment group. 
     
     
         189 . The antibody-drug conjugate of  claim 184 , wherein the antibody attachment group comprises a maleimide (Mal). 
     
     
         190 . The antibody-drug conjugate of  claim 184 , wherein the antibody attachment group is attached to a cysteine residue on the antibody or antigen-binding fragment. 
     
     
         191 . The antibody-drug conjugate of  claim 184 , wherein the spacer unit is attached to the cleavable amino acid unit. 
     
     
         192 . The antibody-drug conjugate of  claim 184 , wherein the cleavable amino acid unit comprises valine (Val) attached to citrulline (Cit). 
     
     
         193 . The antibody-drug conjugate of  claim 184 , wherein the cleavable linker comprises the antibody attachment group attached to the spacer unit attached to the cleavable amino acid unit. 
     
     
         194 . The antibody-drug conjugate of  claim 193 , wherein the cleavable linker comprises Mal-spacer unit-Val-Cit. 
     
     
         195 . The antibody-drug conjugate of  claim 193 , wherein the cleavable linker comprises Mal-(PEG) 2 -Val-Cit. 
     
     
         196 . The antibody-drug conjugate of  claim 184 , wherein the cleavable amino acid unit is covalently attached to eribulin directly or through an optional additional spacer unit. 
     
     
         197 . The antibody-drug conjugate of  claim 196 , wherein the additional spacer unit is self-immolative. 
     
     
         198 . The antibody-drug conjugate of  claim 196 , wherein the additional spacer unit comprises a p-aminobenzyloxycarbonyl (pAB). 
     
     
         199 . The antibody-drug conjugate of  claim 184 , wherein the cleavable linker is covalently attached to eribulin via a C-35 amine. 
     
     
         200 . The antibody-drug conjugate of  claim 184 , wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO:23, and a light chain variable region comprising an amino acid sequence of SEQ ID NO:24. 
     
     
         201 . The antibody-drug conjugate of  claim 184 , wherein the antibody or antigen-binding fragment comprises a human IgG1 heavy chain constant domain. 
     
     
         202 . The antibody-drug conjugate of  claim 184 , wherein the antibody or antigen-binding fragment comprises a human Ig kappa light chain constant domain. 
     
     
         203 . The antibody-drug conjugate of  claim 184 , wherein p is 3 or 4. 
     
     
         204 . A composition comprising multiple copies of the antibody-drug conjugate of  claim 184 , wherein the average p of the antibody-drug conjugates in the composition is from about 3.2 to about 4.4. 
     
     
         205 . A pharmaceutical composition comprising the antibody-drug conjugate of  claim 184 , and a pharmaceutically acceptable carrier. 
     
     
         206 . A method of treating a cancer in a patient, comprising administering to the patient a therapeutically effective amount of the antibody-drug conjugate of  claim 184 , wherein the cancer expresses folate receptor alpha. 
     
     
         207 . The method of  claim 206 , wherein the cancer is a gastric cancer, an ovarian cancer, a lung cancer, a colorectal cancer, a breast cancer, an endometrial cancer, or an osteosarcoma. 
     
     
         208 . A method of producing the antibody-drug conjugate of  claim 184 , comprising reacting the antibody or antigen-binding fragment with the cleavable linker and eribulin under conditions that allow conjugation.