Anti-ptk7 antibody-drug conjugates

Abstract

The present invention provides anti-PTK7 antibody-drug conjugates and methods for preparing and using the same.

1 . An antibody-drug conjugate of the formula: Ab-(L-D), wherein:
 (a) Ab is an antibody, or antigen-binding fragment thereof, that binds to human protein tyrosine kinase 7 (PTK7) comprising:   at least one of a heavy chain variable region comprising three CDRs set forth as SEQ ID NOs: 3, 7, and 11 and a light chain variable region comprising three CDRs set forth as SEQ ID NOs: 17, 19, and 21; or   at least one of a heavy chain variable region comprising three CDRs set forth as SEQ ID NOs: 27, 31, and 35 and a light chain variable region comprising three CDRs set forth as SEQ ID NOs: 41, 43, and 45; and   (b) L-D is a linker-drug moiety, wherein L is a linker, and D is a drug comprising a calicheamicin.   
     
     
         2 .- 8 . (canceled) 
     
     
         9 . The antibody-drug conjugate of  claim 1 , wherein the antibody comprises a heavy chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 1 and a light chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 15 or a heavy chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 25 and a light chain variable region having an amino acid sequence that is at least 90% identical to SEQ ID NO: 39. 
     
     
         10 . The antibody-drug conjugate of  claim 9 , wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 1 and a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 15 or a heavy chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 25 and a light chain variable region comprising an amino acid sequence set forth as SEQ ID NO: 39. 
     
     
         11 . The antibody-drug conjugate of  claim 10 , wherein the antibody comprises an IgG heavy chain constant region. 
     
     
         12 . The antibody-drug conjugate of  claim 11 , wherein the antibody comprises a heavy chain comprising an amino acid sequence set forth as SEQ ID NO: 13 or a heavy chain comprising an amino acid sequence set forth as SEQ ID NO: 37. 
     
     
         13 . The antibody-drug conjugate of  claim 10 , wherein the antibody comprises a kappa light chain constant region. 
     
     
         14 . The antibody-drug conjugate of  claim 13 , wherein the antibody comprises a light chain comprising an amino acid sequence set forth as SEQ ID NO: 23 or a light chain comprising an amino acid sequence set forth as SEQ ID NO: 47. 
     
     
         15 . The antibody-drug conjugate of  claim 10 , wherein the antibody comprises a heavy chain comprising an amino acid sequence set forth as SEQ ID NO: 13 and a light chain comprising an amino acid sequence set forth as SEQ ID NO: 23 or a heavy chain comprising an amino acid sequence set forth as SEQ ID NO: 37 and a light chain comprising an amino acid sequence set forth as SEQ ID NO: 47. 
     
     
         16 .- 49 . (canceled) 
     
     
         50 . The antibody-drug conjugate of  claim 1 , wherein the antibody-drug conjugate has a drug-to-antibody ratio (DAR) of 1 to 8. 
     
     
         51 . The antibody-drug conjugate of  claim 1 , wherein the calicheamicin is N-acetyl-γ-calicheamicin. 
     
     
         52 . The antibody-drug conjugate of  claim 1 , wherein the linker is (4 (4′acetylphenoxy)butanoic acid)(AcBut) and wherein the drug is N-acetyl-γ-calicheamicin dimethyl hydrazide (CM). 
     
     
         53 . An antibody-drug conjugate of the formula: Ab-(L-D), wherein:
 (a) Ab is an antibody that binds to human protein tyrosine kinase 7 (PTK7) comprising a heavy chain comprising an amino acid sequence set forth as SEQ ID NO: 13 and a light chain comprising an amino acid sequence set forth as SEQ ID NO: 23 or a heavy chain comprising an amino acid sequence set forth as SEQ ID NO: 37 and a light chain comprising an amino acid sequence set forth as SEQ ID NO: 47; and   (b) L-D is a linker-drug moiety, wherein L is (4 (4 (4′acetylphenoxy)butanoic acid)(AcBut) and wherein the drug is N-acetyl-γ-calicheamicin dimethyl hydrazide (CM); and   wherein the antibody-drug conjugate has a drug-to-antibody ratio (DAR) of 1 to 8.   
     
     
         54 . A pharmaceutical composition comprising the antibody-drug conjugate of  claim 53  and a pharmaceutically acceptable carrier. 
     
     
         55 . A composition comprising a plurality of the antibody-drug conjugate of  claim 53 , and optionally a pharmaceutical carrier, wherein the composition has an average DAR within a range of 1 to 8. 
     
     
         56 . A process for producing the antibody-drug conjugate of  claim 53 , comprising:
 (a) linking AcBut to CM;   (b) conjugating the linker-drug moiety to the antibody; and   (c) purifying the antibody-drug conjugate.   
     
     
         57 . A method of treating a PTK7-associated disorder comprising administering a therapeutically effective amount of a composition comprising the antibody-drug conjugate of  claim 53  to a subject in need thereof. 
     
     
         58 . The method of  claim 57 , wherein the PTK7-associated disorder is a hyperproliferative disorder. 
     
     
         59 . The method of  claim 58 , wherein the hyperproliferative disorder is a neoplastic disorder. 
     
     
         60 . The method of  claim 59 , wherein the neoplastic disorder is a solid tumor. 
     
     
         61 . The method of  claim 60 , wherein the solid tumor is selected from the group consisting of breast cancer, ovarian cancer, colorectal cancer, esophageal cancer, gastric cancer, melanoma, sarcoma, kidney cancer, pancreatic cancer, prostate cancer, liver cancer, and lung cancer. 
     
     
         62 . The method of  claim 61 , wherein the breast cancer is triple-negative breast cancer (TNBC). 
     
     
         63 . The method of  claim 61 , wherein the lung cancer is small cell lung cancer (SCLC). 
     
     
         64 . The method of  claim 61 , wherein the cancer is ovarian cancer.