Human antibody drug conjugates against tissue factor

Abstract

Antibody drug conjugates against tissue factor. Also disclosed are pharmaceutical compositions comprising the antibodies and antibody drug conjugates, and therapeutic and diagnostic methods for using the antibodies and antibody drug conjugates.

1 - 26 . (canceled) 
     
     
         27 . A method of producing an antibody drug conjugate which binds to tissue factor (TF), the method comprising
 (a) providing an antibody which binds to TF, wherein the antibody comprises:
 (i) a VH region comprising a CDR1 region having the amino acid sequence set forth in SEQ ID NO:6, a CDR2 region having the amino acid sequence set forth in SEQ ID NO: 7, and a CDR3 region having the amino acid sequence set forth in SEQ ID NO: 8, and a VL region comprising a CDR1 region having the amino acid sequence set forth in SEQ ID NO:46, a CDR2 region having the amino acid sequence set forth in SEQ ID NO: 47, and a CDR3 region having the amino acid sequence set forth in SEQ ID NO: 48, 
 (ii) a VH region comprising a CDR1 region having the amino acid sequence set forth in SEQ ID NO:34, a CDR2 region having the amino acid sequence set forth in SEQ ID NO: 35, and a CDR3 region having the amino acid sequence set forth in SEQ ID NO: 36, and a VL region comprising a CDR1 region having the amino acid sequence set forth in SEQ ID NO:74, a CDR2 region having the amino acid sequence set forth in SEQ ID NO: 75, and a CDR3 region having the amino acid sequence set forth in SEQ ID NO: 76, 
 (iii) a VH region comprising a CDR1 region having the amino acid sequence set forth in SEQ ID NO:38, a CDR2 region having the amino acid sequence set forth in SEQ ID NO: 39, and a CDR3 region having the amino acid sequence set forth in SEQ ID NO: 40, and a VL region comprising a CDR1 region having the amino acid sequence set forth in SEQ ID NO:78, a CDR2 region having the amino acid sequence set forth in SEQ ID NO: 79, and a CDR3 region having the amino acid sequence set forth in SEQ ID NO: 80, or 
 (iv) a VH region comprising a CDR1 region having the amino acid sequence set forth in SEQ ID NO:2, a CDR2 region having the amino acid sequence set forth in SEQ ID NO: 3, and a CDR3 region having the amino acid sequence set forth in SEQ ID NO: 4, and a VL region comprising a CDR1 region having the amino acid sequence set forth in SEQ ID NO: 42, a CDR2 region having the amino acid sequence set forth in SEQ ID NO: 43, and a CDR3 region having the amino acid sequence set forth in SEQ ID NO: 44; 
   (b) mixing the antibody with a drug under conditions that promote formation of the antibody drug conjugate; and   (c) isolating the antibody drug conjugate from unconjugated antibody and unconjugated drug.   
     
     
         28 . The method of  claim 27 , wherein the antibody comprises:
 (i) a VH region comprising an amino acid sequence of SEQ ID NO: 5 and a VL region comprising an amino acid sequence of SEQ ID NO: 45,   (ii) a VH region comprising an amino acid sequence of SEQ ID NO: 33 and a VL region comprising an amino acid sequence of SEQ ID NO: 73,   (iii) a VH region comprising an amino acid sequence of SEQ ID NO: 37 and a VL region comprising an amino acid sequence of SEQ ID NO: 77, or   (iv) a VH region comprising an amino acid sequence of SEQ ID NO: 1 and a VL region comprising an amino acid sequence of SEQ ID NO: 41.   
     
     
         29 . The method of  claim 27 , wherein the antibody is a full length antibody. 
     
     
         30 . The method of  claim 27 , wherein the antibody is a human monoclonal IgG1 antibody. 
     
     
         31 . The method of  claim 27 , wherein the drug is selected from the group consisting of a cytotoxin, a chemotherapeutic drug, a cytokine, an immunosuppressant, or a radioisotype. 
     
     
         32 . The method of  claim 27 , wherein the drug is an auristatin, or a functional peptide analog or derivative thereof. 
     
     
         33 . The method of  claim 32 , wherein the auristatin is monomethyl auristatin E (MMAE): 
       
         
           
           
               
               
           
         
       
     
     
         34 . The method of  claim 32 , wherein the auristatin is monomethyl auristatin F (MMAF): 
       
         
           
           
               
               
           
         
       
     
     
         35 . The method of  claim 27 , wherein the drug is conjugated to the antibody at internal residues or sugars. 
     
     
         36 . The method of  claim 27 , wherein the drug is conjugated to the antibody via a linker. 
     
     
         37 . The method of  claim 36 , wherein the linker is attached to sulphydryl residues of the antibody obtained by partial reduction of the antibody. 
     
     
         38 . The method of  claim 36 , wherein the linker is an uncleavable linker. 
     
     
         39 . The method of  claim 36 , wherein the linker is a cleavable linker. 
     
     
         40 . The method of  claim 36 , wherein the linker is a peptidyl linker. 
     
     
         41 . The method of  claim 40 , wherein the peptidyl linker is at least two amino acids long. 
     
     
         42 . The method of  claim 41 , wherein the linker is a Val-Cit (vc) linker or a Phe-Lys linker. 
     
     
         43 . The method of  claim 36 , wherein the linker-drug is vcMMAF or vcMMAE: 
       
         
           
           
               
               
           
         
         wherein p denotes a number of from 1 to 8, S represents a sulphydryl residue of the antibody, and Ab designates the antibody. 
       
     
     
         44 . The method of  claim 43 , wherein p is 4. 
     
     
         45 . The method of  claim 36 , wherein the linker-drug is mcMMAF: 
       
         
           
           
               
               
           
         
         wherein p denotes a number of from 1 to 8, S represents a sulphydryl residue of the antibody, and Ab designates the antibody. 
       
     
     
         46 . The method of  claim 45 , wherein p is 4.