Anti-cd40 antibodies and uses thereof

Abstract

The present invention encompasses antagonist anti-CD40 antibodies and antigen-binding portions thereof. Specifically, the invention relates to humanized anti-CD40 antibodies. In certain embodiments, antibodies of the invention neutralize human CD40 (hCD40) activity. Antibodies, or antibody portions, of the invention are useful for detecting CD40 and for inhibiting CD40 activity, e.g., in a human subject suffering from a disorder in which CD40 activity is detrimental.

1 . An isolated nucleic acid encoding an antagonist anti-CD40 antibody amino acid sequence comprising
 a) a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 41, and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 40;   b) a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:6, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:42, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:8, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:21, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:11, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:12; or   c) a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 28 and a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 20   
     
     
         2 . A vector comprising the isolated nucleic acid of  claim 1 . 
     
     
         3 . A host cell comprising the vector of  claim 2 . 
     
     
         4 . A method of producing an antagonist anti-CD40 antibody, or antigen binding portion thereof, the method comprising the steps of culturing the host cell of  claim 3  in culture medium under conditions sufficient to produce the antagonist anti-CD40 antibody, or antigen binding portion thereof. 
     
     
         5 . A method reducing human CD40 activity, the method comprising the step of contacting human CD40 with an anti-CD40 antibody, or antigen-binding portion thereof, such that human CD40 activity is reduced, wherein the anti-CD40 antibody is an isolated antibody, or antigen binding portion thereof, that binds an epitope of human CD40 defined by the topographic regions Cys62-Phe67, Gln79-Cys83, Arg90-Thr99, and Thr24-Cys37 of SEQ ID NO:1. 
     
     
         6 . The method of  claim 5 , wherein the antibody, or antigen binding portion thereof, is humanized. 
     
     
         7 . The method of  claim 5 , wherein the antibody, or antigen binding portion thereof, is substantially free of agonist activity. 
     
     
         8 . The method of  claim 5 , wherein the anti-CD40 antibody is an antagonist anti-CD40 antibody, or antigen-binding portion thereof, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:6, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:42, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:8, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:21, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:11, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 12. 
     
     
         9 . The method of  claim 5 , wherein the anti-CD40 antibody is an antagonist anti-CD40 antibody, or antigen-binding portion thereof, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 28 and a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 20. 
     
     
         10 . The method of  claim 5 , wherein the anti-CD40 antibody is an anti-CD40 antibody comprising a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 41, and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 40. 
     
     
         11 . The method of  claim 5 , wherein the method comprises reducing human CD40 activity in a human subject having a disorder in which CD40 activity is detrimental, the method comprising the step of administering to the human subject an anti-CD40 antibody, or antigen binding portion thereof, such that human CD40 activity in the human subject is reduced, wherein the anti-CD40 antibody, or antigen-binding portion thereof, is an isolated antibody, or antigen binding portion thereof, that binds an epitope of human CD40 defined by the topographic regions Cys62-Phe67, Gln79-Cys83, Arg90-Thr99, and Thr24-Cys37 of SEQ ID NO:1. 
     
     
         12 .- 13 . (canceled) 
     
     
         14 . The method of  claim 11 , wherein the anti-CD40 antibody is an antagonist anti-CD40 antibody, or antigen-binding portion thereof, comprising a heavy chain CDR comprising an amino acid sequence as set forth in SEQ ID NO:6, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:42, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:8, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:21, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:11, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 12. 
     
     
         15 . The method of  claim 11 , wherein the anti-CD40 antibody is an antagonist anti-CD40 antibody, or antigen-binding portion thereof, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 28 and a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 20. 
     
     
         16 . The method of  claim 11 , wherein the anti-CD40 antibody is an anti-CD40 antibody comprising a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 41, and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 40. 
     
     
         17 .- 22 . (canceled) 
     
     
         23 . A method of determining the presence of CD40 or fragment thereof in a test sample by an immunoassay, wherein the immunoassay comprises contacting the test sample with at least one anti-CD40 antibody, or antigen-binding portion thereof, and at least one detectable label, wherein the anti-CD40 antibody, or antigen-binding portion thereof, is
 an isolated antibody, or antigen binding portion thereof, that binds an epitope of human CD40 defined by the topographic regions Cys62-Phe67, Gln79-Cys83, Arg90-Thr99, and Thr24-Cys37 of SEQ ID NO:1.   
     
     
         24 . The method of claim  22 , wherein the antibody, or antigen binding portion thereof, is humanized. 
     
     
         25 . The method of claim  22 , wherein the antibody, or antigen binding portion thereof, is substantially free of agonist activity. 
     
     
         26 . The method of claim  22 , wherein the anti-CD40 antibody is an antagonist anti-CD40 antibody, or antigen-binding portion thereof, comprising a heavy chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:6, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:42, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO:8, a light chain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO:21, a light chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:11, and a light chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 12. 
     
     
         27 . The method of claim  22 , wherein the anti-CD40 antibody is an antagonist anti-CD40 antibody, or antigen-binding portion thereof, comprising a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 28 and a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 20. 
     
     
         28 . The method of claim  22 , wherein the anti-CD40 antibody is an anti-CD40 antibody comprising a heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 41, and a light chain comprising an amino acid sequence as set forth in SEQ ID NO: 40.