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 to  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. 
     
     
         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 of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         12 . The antibody drug conjugate of  claim 1  for use as a medicament. 
     
     
         13 . The antibody drug conjugate of  claim 1  for use in the treatment of cancer. 
     
     
         14 . The antibody drug conjugate of  claim 13  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. 
     
     
         15 - 20 . (canceled) 
     
     
         21 . The antibody drug conjugate according to  claim 12 , wherein the medicament is for the treatment of cancer in combination with one or more further therapeutic agents, such as a chemotherapeutic agent. 
     
     
         22 . Use of the antibody drug conjugate of  claim 1  for the manufacture of a medicament for the treatment of cancer. 
     
     
         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 . A method of treating cancer by administration to an individual in need thereof, an effective amount of the antibody drug conjugate of  claim 1 . 
     
     
         26 . The method according to  claim 25 , wherein the antibody drug conjugate is administered in combination with one or more further therapeutic agents, such as a chemotherapeutic agent.