Anti-factor xi monoclonal antibodies and methods of use thereof

Abstract

Compositions and methods for inhibiting thrombosis without compromising hemostasis are described. Compositions include anti-factor XI monoclonal antibodies (aXIMabs) capable of binding to an epitope on the heavy chain of human FXI, particularly the A3 domain of the heavy chain of human FXI. Compositions also include epitope-binding fragments, variants, and derivatives of the monoclonal antibodies, cell lines producing these antibody compositions, and isolated nucleic acid molecules encoding the amino acid sequences of the antibodies. The disclosure further includes pharmaceutical compositions comprising the disclosed anti-factor XI monoclonal antibodies, or epitope-binding fragments, variants, or derivatives thereof, in a pharmaceutically acceptable carrier. Methods of the disclosure include administering the compositions described above to a subject in need thereof for the purpose of inhibiting thrombosis, reducing a required dose of an antithrombotic agent in the treatment of thrombosis, treating metastatic cancer, or treating an acute inflammatory reaction.

1 . An isolated monoclonal antibody or antigen-binding fragment thereof that specifically binds to an epitope on the heavy chain of human FXI described in SEQ ID NO:1, wherein:
 said antibody is biologically active; and   said epitope comprises amino acids 183 to 197, 203 to 204, 234 to 236, 241 to 243, 252 to 254, and 258 to 260 of SEQ ID NO: 1.   
     
     
         2 . The isolated monoclonal antibody of  claim 1 , wherein the epitope is in the A3 domain of the heavy chain of human FXI, corresponding to amino acid positions 182 to 265 of SEQ ID NO:1. 
     
     
         3 . A conjugate comprising the isolated monoclonal antibody or antigen-binding fragment of  claim 1  and a heterologous polypeptide. 
     
     
         4 . A composition comprising the isolated monoclonal antibody or antigen-binding fragment of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         5 . A method for treating a coagulopathy in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of the composition of  claim 4 . 
     
     
         6 . The method of  claim 5 , wherein the coagulopathy comprises disseminated intravascular coagulation (DIC) or acute respiratory distress syndrome (ARDS). 
     
     
         7 . The method of  claim 6 , wherein the subject has an infection. 
     
     
         8 . The method of  claim 7 , wherein the infection is a viral infection. 
     
     
         9 . The method of  claim 6 , wherein the subject has cancer. 
     
     
         10 . The method of  claim 5 , wherein the subject is human. 
     
     
         11 . An isolated polynucleotide encoding the monoclonal antibody of antigen-binding fragment of  claim 1 . 
     
     
         12 . The isolated polynucleotide of  claim 11 , comprising SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 6, or SEQ ID NO: 8. 
     
     
         13 . A vector comprising the polynucleotide of  claim 11 . 
     
     
         14 . The vector of  claim 13 , wherein the polynucleotide is operably associated with a promoter. 
     
     
         15 . A host cell comprising the vector of  claim 14 .