Antibodies against clostridium difficile toxins and uses thereof

Abstract

Antibodies that specifically bind to toxins of C. difficile , antigen binding portions thereof, and methods of making and using the antibodies and antigen binding portions thereof are provided herein.

What is claimed is: 
     
         1 . An isolated monoclonal antibody that binds to  Clostridium difficile  ( C. difficile ) toxin A, or an antigen binding portion thereof, wherein the antibody, or antigen binding portion thereof, comprises:
 (i) a heavy chain variable region CDR1 comprising SEQ ID NO: 7;   a heavy chain variable region CDR2 comprising SEQ ID NO: 8;   a heavy chain variable region CDR3 comprising SEQ ID NO: 9;   a light chain variable region CDR1 comprising SEQ ID NO: 16;   a light chain variable region CDR2 comprising SEQ ID NO: 17; and   a light chain variable region CDR3 comprising SEQ ID NO: 18;   (ii) a heavy chain variable region CDR1 comprising SEQ ID NO: 10;   a heavy chain variable region CDR2 comprising SEQ ID NO: 11;   a heavy chain variable region CDR3 comprising SEQ ID NO: 12;   a light chain variable region CDR1 comprising SEQ ID NO: 19;   a light chain variable region CDR2 comprising SEQ ID NO: 20; and   a light chain variable region CDR3 comprising SEQ ID NO: 21; or   (iii) a heavy chain variable region CDR1 comprising SEQ ID NO: 13;   a heavy chain variable region CDR2 comprising SEQ ID NO: 14;   a heavy chain variable region CDR3 comprising SEQ ID NO: 15;   a light chain variable region CDR1 comprising SEQ ID NO: 22;   a light chain variable region CDR2 comprising SEQ ID NO: 23; and   a light chain variable region CDR3 comprising SEQ ID NO: 24.   
     
     
         2 . The isolated monoclonal antibody, or an antigen binding portion thereof, of  claim 1 , wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region CDR1 comprising SEQ ID NO: 7, a heavy chain variable region CDR2 comprising SEQ ID NO: 8, a heavy chain variable region CDR3 comprising SEQ ID NO: 9, a light chain variable region CDR1 comprising SEQ ID NO: 16, a light chain variable region CDR2 comprising SEQ ID NO: 17, and a light chain variable region CDR3 comprising SEQ ID NO: 18. 
     
     
         3 . The isolated monoclonal antibody, or an antigen binding portion thereof, of  claim 1 , wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region CDR1 comprising SEQ ID NO: 10, a heavy chain variable region CDR2 comprising SEQ ID NO: 11, a heavy chain variable region CDR3 comprising SEQ ID NO: 12, a light chain variable region CDR1 comprising SEQ ID NO: 19, a light chain variable region CDR2 comprising SEQ ID NO: 20, and a light chain variable region CDR3 comprising SEQ ID NO: 21. 
     
     
         4 . The isolated monoclonal antibody, or an antigen binding portion thereof, of  claim 1 , wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region CDR1 comprising SEQ ID NO: 13, a heavy chain variable region CDR2 comprising SEQ ID NO: 14, a heavy chain variable region CDR3 comprising SEQ ID NO: 15, a light chain variable region CDR1 comprising SEQ ID NO: 22, a light chain variable region CDR2 comprising SEQ ID NO: 23, and a light chain variable region CDR3 comprising SEQ ID NO: 24. 
     
     
         5 . An isolated monoclonal antibody that binds to  Clostridium difficile  ( C. difficile ) toxin A, or an antigen binding portion thereof, wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3 and/or a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6. 
     
     
         6 . The isolated monoclonal antibody, or an antigen binding portion thereof, of  claim 5 , wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 1. 
     
     
         7 . The isolated monoclonal antibody, or an antigen binding portion thereof, of  claim 5 , wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 2. 
     
     
         8 . The isolated monoclonal antibody, or an antigen binding portion thereof, of  claim 5 , wherein the antibody, or antigen binding portion thereof, comprises a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 3. 
     
     
         9 . The isolated monoclonal antibody, or an antigen binding portion thereof, of  claim 5 , wherein the antibody, or antigen binding portion thereof, comprises a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 4. 
     
     
         10 . The isolated monoclonal antibody, or an antigen binding portion thereof, of  claim 5 , wherein the antibody, or antigen binding portion thereof, comprises a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 5. 
     
     
         11 . The isolated monoclonal antibody, or an antigen binding portion thereof, of  claim 5 , wherein the antibody, or antigen binding portion thereof, comprises a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence set forth in SEQ ID NO: 6. 
     
     
         12 . The isolated monoclonal antibody, or an antigen binding portion thereof, of  claim 5 , wherein the antibody, or antigen binding portion thereof, comprises heavy and light chain variable regions comprising amino acid sequences at least 95% identical to the amino acid sequences set forth in SEQ ID NOs: 1 and 4, respectively. 
     
     
         13 . The isolated monoclonal antibody, or an antigen binding portion thereof, of  claim 5 , wherein the antibody, or antigen binding portion thereof, comprises heavy and light chain variable regions comprising amino acid sequences at least 95% identical to the amino acid sequences set forth in SEQ ID NOs: 2 and 5, respectively. 
     
     
         14 . The isolated monoclonal antibody, or an antigen binding portion thereof, of  claim 5 , wherein the antibody, or antigen binding portion thereof, comprises heavy and light chain variable regions comprising amino acid sequences at least 95% identical to the amino acid sequences set forth in SEQ ID NOs: 3 and 6, respectively. 
     
     
         15 . The isolated monoclonal antibody, or antigen binding portion thereof, of  claim 1 , wherein the antibody is a human antibody, a humanized antibody or a chimeric antibody. 
     
     
         16 . The antigen binding portion of  claim 1 , wherein the antigen binding portion is a Fab, Fab′2, ScFv, Fd, Fv or dAb. 
     
     
         17 . The isolated monoclonal antibody of  claim 1 , wherein the antibody is an IgG1 or IgG3 isotype. 
     
     
         18 . The isolated monoclonal antibody, or antigen binding portion thereof, of  claim 1 , wherein the K D  of the antibody, or antigen binding portion thereof, is less than 20×10 −6  M. 
     
     
         19 . The isolated monoclonal antibody, or antigen binding portion thereof, of  claim 1 , wherein the antibody, or antigen binding portion thereof, neutralizes toxin A in vitro or in vivo.