Alpha5-beta1 antibodies and their uses

Abstract

The present disclosure provides isolated monoclonal antibodies, particularly human monoclonal antibodies, or antigen binding portions thereof, that specifically bind to integrin α5β1 with high affinity. Nucleic acid molecules encoding the antibodies of the disclosure, expression vectors, host cells and methods for expressing the antibodies of the disclosure are also provided. Immunoconjugates, bispecific molecules and pharmaceutical compositions comprising the antibodies or antigen binding portions thereof are also provided. The disclosure also provides methods for treating various cancers using the anti-α5β1 antibodies or antigen binding portions thereof described herein.

1 - 10 . (canceled) 
     
     
         11 . An isolated monoclonal antibody, or an antigen-binding portion thereof, that:
 (a) binds to human integrin α5β1 with a K D  of 1×10 −7  M or less; and   (b) is capable of inducing antibody dependent cellular cytotoxicity (ADCC).   
     
     
         12 . The antibody of  claim 11 , which is a full-length human antibody of subclass IgG1. 
     
     
         13 . The antibody or antigen-binding portion thereof of  claim 11 , wherein said antibody or antigen-binding portion binds to human integrin α5β1 with a K D  of 5×10 −8  M or less. 
     
     
         14 . The antibody of  claim 12 , wherein at least one amino acid in the Fc region of said antibody is mutated, and further wherein said antibody exhibits greater ADCC than an identical antibody wherein said at least one amino acid is not mutated. 
     
     
         15 . The antibody of  claim 14 , wherein the at least one mutation occurs at amino acid position serine 247, alanine 338, or isoleucine 340. 
     
     
         16 . The antibody of  claim 15 , where the at least one mutation is selected from the group consisting of serine 247 to aspartic acid (S247D), alanine 338 to leucine (A338L), and isoleucine 340 to glutamic acid (I340E). 
     
     
         17 . An isolated human full-length IgG1 antibody having at least one Fc region amino acid mutation, exhibiting greater antibody dependent cellular cytotoxicity (ADCC) than an identical antibody without the at least one Fc region amino acid mutation and capable of binding to human integrin α5β1 with a K D  of 1×10 −7  M or less. 
     
     
         18 . The antibody of  claim 17 , wherein said antibody binds to human integrin α5β1 with a K D  of 5×10 −8  M or less. 
     
     
         19 . An isolated monoclonal antibody or antigen-binding portion thereof that binds to human integrin α5β1 with a K D  of 1×10 −7  M or less and comprises a heavy chain variable region that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO:7. 
     
     
         20 . The antibody or antigen-binding portion thereof of  claim 19  further comprising a light chain variable region that is at least 90% identical to the amino acid sequence set forth in SEQ ID NO:8. 
     
     
         21 . A composition comprising the antibody or antigen-binding portion of  claim 11 , and a pharmaceutically acceptable carrier. 
     
     
         22 . An isolated nucleic acid molecule encoding the heavy and/or light chain of the antibody, or antigen-binding portions thereof of  claim 11 . 
     
     
         23 . An expression vector comprising the nucleic acid molecule of  claim 22 . 
     
     
         24 . A host cell comprising the expression vector of  claim 23 . 
     
     
         25 . A method for preparing an anti-α5β1 antibody or antigen-binding portion thereof, comprising expressing the antibody or antigen-binding portion in the host cell of  claim 24 . 
     
     
         26 . A method of inhibiting growth of tumor cells expressing integrin α5β1, comprising contacting the cells with the antibody, or antigen-binding portion thereof, of  claim 11  in an amount effective to inhibit growth of the tumor cells.