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 . An antibody drug conjugate comprising an antibody which binds to tissue factor and which 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, or   (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, or   (v) a variant of any of said antibodies, wherein said variant preferably has at most 1, 2 or 3 amino-acid modifications, more preferably amino-acid substitutions, such as conservative amino-acid substitutions in said sequences,   wherein the antibody has been conjugated to an auristatin or a functional peptide analog or derivate thereof via a linker.   
     
     
         2 . The antibody drug conjugate according to  claim 1 , 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, or   (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, or   (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.   
     
     
         3 . The antibody drug conjugate according to  claim 1 , wherein the antibody is a full length antibody. 
     
     
         4 . The antibody drug conjugate according to  claim 1 , wherein the antibody is a fully human monoclonal IgG1 antibody, such as an IgG1,κ. 
     
     
         5 . The antibody drug conjugate according too  claim 1 , wherein the auristatin is monomethyl auristatin E (MMAE): 
       
         
           
           
               
               
           
         
         wherein the wavy line indicates the attachment site for the linker. 
       
     
     
         6 . The antibody drug conjugate according to  claim 1 , wherein the auristatin is monomethyl auristatin F (MMAF): 
       
         
           
           
               
               
           
         
         wherein the wavy line indicates the attachment site for the linker. 
       
     
     
         7 . The antibody drug conjugate according to  claim 1 , wherein the linker is attached to sulphydryl residues of the anti-TF antibody obtained by (partial) reduction of the anti-TF antibody. 
     
     
         8 . The antibody drug conjugate according to  claim 1 , wherein the linker-auristatin is vcMMAF or vcMMAE: 
       
         
           
           
               
               
           
         
         wherein p denotes a number of from 1 to 8, S represents a sulphydryl residue of the anti-TF antibody, and Ab designates the anti-TF antibody. 
       
     
     
         9 . The antibody drug conjugate according to  claim 8 , wherein the linker-auristatin is vcMMAE as defined in  claim 8 . 
     
     
         10 . The antibody drug conjugate according to  claim 1 , wherein the linker-conjugate is mcMMAF: 
       
         
           
           
               
               
           
         
         wherein p denotes a number of from 1 to 8, S represents a sulphydryl residue of the anti-TF antibody, and Ab designates the anti-TF antibody. 
       
     
     
         11 . A pharmaceutical composition comprising the antibody drug conjugate as defined in  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         12 - 21 . (canceled) 
     
     
         22 . A method for treating cancer, comprising administering to an individual in need thereof an effective amount of the antibody drug conjugate of  claim 1 . 
     
     
         23 . (canceled) 
     
     
         24 . A method for inducing cell death, or inhibiting growth and/or proliferation of a tumor cell expressing tissue factor, comprising administration, to an individual in need thereof, of an effective amount of the antibody drug conjugate of  claim 1 . 
     
     
         25 - 26 . (canceled) 
     
     
         27 . A method of producing an antibody drug conjugate that binds to tissue factor, the method comprising:
 (a) providing an antibody which binds to TF, wherein the antibody comprises 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;   (b) mixing the antibody with a drug under conditions that promote formation of the antibody drug conjugate, wherein the drug is an auristatin or a functional peptide analog or derivative thereof; and   (c) isolating the antibody drug conjugate from the unconjugated antibody and unconjugated drug.   
     
     
         28 . The method according to  claim 22 , wherein the cancer is selected from the group consisting of tumors of the central nervous system, head and neck cancer, lung cancer. such as NSCLC, breast cancer, specifically triple negative breast cancer, esophageal cancer, gastric or stomach cancer, liver and biliary cancer, pancreatic cancer, colorectal cancer, bladder cancer, kidney cancer, prostate cancer, endometrial cancer, ovarian cancer, malignant melanoma, sarcoma, tumors of unknown primary origin, bone marrow cancer, acute lymphoblastic leukemia, AML, chronic lymphoblastic leukemia and non-Hodgkin lymphoma, skin cancer, glioma, cancer of the brain, uterus, and rectum. 
     
     
         29 . The method according to  claim 22 , further comprising the administration one or more additional therapeutic agents. 
     
     
         30 . The method according to  claim 29 , wherein the therapeutic agents are chemotherapeutic agents.