Human antibodies against hepatitis c virus (hcv) and uses thereof

Abstract

Isolated human monoclonal antibodies which bind to hepatitis C virus (HCV), and related antibody-based compositions and molecules, are disclosed. The human antibodies can be produced in a transfectoma or in a non-human transgenic animal, e.g., a transgenic mouse, capable of producing multiple isotypes of human monoclonal antibodies by undergoing V-D-J recombination and isotype switching. Also disclosed are pharmaceutical compositions comprising the human antibodies, non-human transgenic animals, and hybridomas which produce the human antibodies, and therapeutic and diagnostic methods for using the human antibodies.

1 .- 66 . (canceled) 
     
     
         67 . An isolated human antibody, or antigen binding portion thereof that competes for binding to an E2 protein of hepatitis C virus (HCV) with a second antibody, or antigen binding portion thereof, said second antibody or antigen binding portion thereof comprising:
 (a) heavy and light chain variable regions comprising the sequences of SEQ ID NOs:1 and 2, SEQ ID NOs: 3 and 4, or SEQ ID NOs: 5 and 6, respectively;   (b) a heavy chain variable region CDR3 sequence comprising the sequence of SEQ ID NO:9, a light chain variable region CDR3 sequence comprising the sequence of SEQ ID NO:18, a heavy chain variable region CDR2 sequence comprising the sequence of SEQ ID NO:8, a light chain variable region CDR2 sequence comprising the sequence of SEQ ID NO:17, a heavy chain variable region CDRI sequence comprising the sequence of SEQ ID NO:7, and a light chain variable region CDRI sequence comprising the sequence of SEQ ID NO:16;   (c) a heavy chain variable region CDR3 sequence comprising the sequence of SEQ ID NO:12, a light chain variable region CDR3 sequence comprising the sequence of SEQ ID NO:21, a heavy chain variable region CDR2 sequence comprising the sequence of SEQ ID NO:11, a light chain variable region CDR2 sequence comprising the sequence of SEQ ID NO:20, a heavy chain variable region CDRI sequence comprising the sequence of SEQ ID NO:10, and a light chain variable region CDRI sequence comprising the sequence of SEQ ID NO:19; or   (d) a heavy chain variable region CDR3 sequence comprising the sequence of SEQ ID NO:15, a light chain variable region CDR3 sequence comprising the sequence of SEQ ID NO:24, a heavy chain variable region CDR2 sequence comprising the sequence of SEQ ID NO:14, a light chain variable region CDR2 sequence comprising the sequence of SEQ ID NO:23, a heavy chain variable region CDRI sequence comprising the sequence of SEQ ID NO:13, and a light chain variable region CDRI sequence comprising the sequence of SEQ ID NO:22.   
     
     
         68 . The isolated human antibody or antigen binding portion of  claim 67 , wherein the second antibody or antigen binding portion comprises heavy and light chain variable regions comprising the sequences of SEQ ID NOs:1 and 2, SEQ ID NOs:3 and 4, or SEQ ID NOs:5 and 6, respectively. 
     
     
         69 . The isolated human antibody, or antigen binding portion thereof of  claim 67 , wherein the second antibody, or antigen binding portion thereof comprises heavy and light chain variable regions comprising the sequences of SEQ ID NOs:1 and 2. 
     
     
         70 . The isolated human antibody of  claim 67 , wherein the antibody is a full-length antibody. 
     
     
         71 . The isolated human antibody, or antigen binding portion thereof of  claim 67 , wherein the antibody or antigen binding portion is selected from the group consisting of an antibody comprising an Fc domain, a single-chain antibody, and a Fab fragment. 
     
     
         72 . The isolated human antibody or antigen binding portion of  claim 67 , wherein the antibody or antigen binding portion inhibits binding of hepatitis C virus (HCV) to mammalian cells. 
     
     
         73 . The isolated human antibody or antigen binding portion of  claim 67 , wherein the antibody or antigen binding portion inhibits binding of an HCV E2 protein to mammalian cells. 
     
     
         74 . The isolated human antibody or antigen binding portion of  claim 67 , which binds to a non-conformational (linear) epitope on the HCV E2 protein and inhibits the ability of the virus to infect cells. 
     
     
         75 . The isolated human antibody or antigen binding portion of  claim 67 , wherein the antibody or antigen binding portion neutralizes HCV in an HCV pseudovirus neutralization assay. 
     
     
         76 . The isolated human antibody or antigen binding portion of  claim 67 , wherein the antibody inhibits HCV infection in vivo in a subject. 
     
     
         77 . The isolated human antibody or antigen binding portion of  claim 67 , wherein the antibody or antigen binding portion thereof, inhibits HCV-mediated hepatocyte pathology in a subject. 
     
     
         78 . The isolated human antibody or antigen binding portion of  claim 67 , wherein the antibody binds to two or more HCV genotypes of an HCV E2 protein or fragment thereof. 
     
     
         79 . The isolated human antibody or antigen binding portion of  claim 67 , wherein the antibody binds an HCV E2 protein from a HCV virus having a genotype selected from the group consisting of 1a, 1b, 2b, 3a, 4a, 5, 5a, 6a, 6g, 6k, and any combination thereof. 
     
     
         80 . The isolated human antibody or antigen binding portion of  claim 67 , wherein the epitope is between amino acid residues 412-464, 412-423, or 413-420 of the E2 protein (SEQ ID NO:93). 
     
     
         81 . The isolated human antibody or antigen binding portion of  claim 67 , wherein the antibody or antigen binding portion thereof specifically binds to an HCV E2 protein, or fragment thereof, with a KD of at least about 1×10 −7  M, 1×10 −8  M, 1×10 −9  M, 1×10 −10  M, 1×10 −11  M, 1×10 −12  M or better. 
     
     
         82 . The isolated human antibody or antigen binding portion of  claim 67 , further comprising a label or a toxin. 
     
     
         83 . A composition comprising the isolated human antibody or antigen binding portion of  claim 67  in a pharmaceutically acceptable carrier. 
     
     
         84 . A composition suitable for treating an HCV-mediated disease or disorder in a mammal, said composition comprising the isolated human antibody or antigen binding portion of  claim 67  in a pharmaceutically acceptable carrier. 
     
     
         85 . A kit comprising the isolated human antibody or antigen binding portion of  claim 67  and instruction for use of said antibody of antigen binding portion in treating an HCV-mediated disease.