Antibodies to coagulation factor xia and uses thereof

Abstract

In one aspect, antibodies, or antigen-binding fragments thereof, that specifically bind to activated Factor XI (FXIa) are provided. Also provided are methods of obtaining such antibodies and nucleic acids encoding the same. In another aspect, compositions and therapeutic prevention of thrombotic diseases, disorders or conditions are provided. In another aspect, anti-idiotype antibodies that bind anti-FXIa antibodies of the disclosure, as well as compositions comprising the anti-idiotype antibodies, methods of obtaining the antibodies and nucleic acids encoding the same, are also provided.

1 . An isolated monoclonal antibody, or an antigen-binding portion thereof, that specifically binds the Factor XIa catalytic domain, wherein the antibody or antigen-binding portion thereof has at least one of the following properties:
 (a) prolongs activated partial thromboplastin time (APTT) without significantly increasing prothrombin time (PT);   (b) has an increased dissociation rate from FXIa in the presence of a serine protease inhibitor;   (c) has an increased dissociation rate from FXIa after treatment of the latter with an agent that chemically modifies the active site serine of a serine protease; and   (d) binds to, and has its anticoagulant activity decreased by, a recombinant FXIa protease-domain in which the active site serine is changed to alanine.   
     
     
         2 . The isolated monoclonal antibody of  claim 1 , or an antigen-binding portion thereof, wherein the antibody comprises:
 a) a heavy chain complementarity region (HCDR) 1 comprising the amino acid sequence of SEQ ID NO: 2 or 5;   b) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 3, 6, 94 or 95;   c) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 4;   d) a light chain complementarity region (LCDR)1 comprising the amino acid sequence of SEQ ID NO: 8, 11, 32, or 33;   e) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 9 or 12; and/or   f) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 10 or 13.   
     
     
         3 . The antibody or antigen-binding portion of  claim 2 , wherein the antibody or antigen-binding portion comprises HCDR1-3 and LCDR1-3 comprising the amino acid sequences of:
 a) SEQ ID NOs: 2, 3, 4, 8, 9, and 10, respectively;   b) SEQ ID NOs: 5, 6, 4, 11, 12, and 13, respectively;   c) SEQ ID NOs: 2, 94, 4, 8, 9, and 10, respectively;   d) SEQ ID NOs: 5, 95, 4, 11, 12, and 13, respectively;   e) SEQ ID NOs: 2, 15, 4, 8, 9, and 10, respectively;   f) SEQ ID NOs: 5, 16, 4, 11, 12, and 13, respectively;   g) SEQ ID NOs: 2, 66, 4, 8, 9, and 10, respectively; or   h) SEQ ID NOs: 5, 67, 4, 11, 12, and 13, respectively.   
     
     
         4 . The isolated monoclonal antibody of  claim 2 , or an antigen-binding portion thereof, wherein the antibody comprises: a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 1 and/or a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 7. 
     
     
         5 . The isolated monoclonal antibody of  claim 2 , or an antigen-binding portion thereof, wherein the antibody comprises: a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 65 and/or a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 68. 
     
     
         6 . The isolated monoclonal antibody of  claim 2 , or an antigen-binding portion thereof, wherein the antibody comprises: a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 14 and/or a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 17. 
     
     
         7 . The isolated monoclonal antibody of  claim 2 , or an antigen-binding portion thereof, wherein the antibody comprises:
 a) a heavy chain variable domain (VH) sequence comprising the amino acid sequence of SEQ ID NOs: 1, 14, 18, 22, 24, 26, 28, 34, 38, 40, 43, 47, 51, 55, 59, 63, 65, or 96; and/or   b) a light chain variable domain (VL) sequence comprising the amino acid sequence of SEQ ID NOs: 7, 17, 21, 23, 25, 27, 31, 37, 39, 42, 46, 50, 54, 58, 62, 64, 68, or 97.   
     
     
         8 . The isolated monoclonal antibody of  claim 7 , or an antigen-binding portion thereof, wherein the antibody comprises a heavy chain variable domain and a light chain variable domain comprising the following amino acid sequences, respectively:
 SEQ ID NOs: 18 and 21,   SEQ ID NOs: 22 and 23,   SEQ ID NOs: 24 and 25,   SEQ ID NOs: 26 and 27,   SEQ ID NOs: 28 and 31,   SEQ ID NOs: 34 and 37,   SEQ ID NOs: 38 and 39,   SEQ ID NOs: 40 and 42,   SEQ ID NOs: 43 and 46,   SEQ ID NOs: 47 and 50,   SEQ ID NOs: 51 and 54,   SEQ ID NOs: 55 and 58,   SEQ ID NOs: 59 and 62, or   SEQ ID NOs: 63 and 64.   
     
     
         9 . (canceled) 
     
     
         10 . The isolated monoclonal antibody or antigen-binding portion of  claim 1 , wherein the antibody specifically binds to the active site of the catalytic domain of Factor XIa. 
     
     
         11 . The isolated monoclonal antibody or antigen-binding portion of  claim 1 , wherein the antibody is chimeric, humanized, or human. 
     
     
         12 . The isolated monoclonal antibody or antigen-binding portion of  claim 11 , wherein the antibody comprises a human IgG heavy chain constant region. 
     
     
         13 . The isolated monoclonal antibody or antigen-binding portion of  claim 12 , wherein the antibody comprises a human IgG 1  heavy chain constant region. 
     
     
         14 . The isolated monoclonal antibody or antigen-binding portion of  claim 2 , wherein the antibody comprises a heavy chain constant domain comprising the amino acid sequence of SEQ ID NO: 82 and/or a light chain constant domain comprising the amino acid sequence of SEQ ID NO: 83. 
     
     
         15 . An isolated monoclonal antibody, or an antigen-binding portion thereof, that specifically binds Factor XIa, wherein the antibody comprises: a heavy chain variable domain (VH) comprising the amino acid sequence encoded by the cDNA insert of the plasmid deposited under ATCC accession number PTA-122090 and/or a light chain variable domain (VL) comprising the amino acid sequence encoded by the cDNA insert of the plasmid deposited under ATCC accession number PTA-122091. 
     
     
         16 - 17 . (canceled) 
     
     
         18 . The isolated monoclonal antibody or antigen-binding portion of  claim 2 , wherein the agent that chemically modifies the active site serine of a serine protease is PMSF (phenylmethylsulfonyl fluoride). 
     
     
         19 - 21 . (canceled) 
     
     
         22 . An isolated nucleic acid molecule comprising a nucleotide sequence encoding the isolated monoclonal antibody or antigen-binding portion of  claim 1 . 
     
     
         23 . The isolated nucleic acid molecule of  claim 22 , wherein the nucleic acid molecule comprises:
 a) the nucleotide sequence of SEQ ID NO: 84, 86, or 88;   b) the nucleotide sequence of SEQ ID NO: 85, 87, or 89; or   c) both a) and b).   
     
     
         24 . A vector comprising the nucleic acid molecule of  claim 22 . 
     
     
         25 . An isolated host cell comprising the vector of  claim 24 . 
     
     
         26 . An isolated host cell that produces the antibody or antigen-binding portion of  claim 1 . 
     
     
         27 . A method of producing an antibody or antigen-binding portion thereof, comprising culturing the host cell of  claim 26  under conditions that result in production of the antibody, and isolating the antibody or antigen-binding portion from the host cell or culture. 
     
     
         28 . A method for inhibiting the intrinsic pathway of coagulation in a subject, comprising administering to said subject the isolated monoclonal antibody or antigen-binding portion of  claim 1 . 
     
     
         29 . A method for increasing clotting time in a subject, comprising administering to said subject the isolated monoclonal antibody or antigen-binding portion of  claim 1 , wherein the clotting time is increased compared to the clotting time in the subject prior to administration of the antibody or antigen-binding portion. 
     
     
         30 - 33 . (canceled) 
     
     
         34 . A pharmaceutical composition comprising the isolated monoclonal antibody or antigen-binding portion of  claim 1 , and a pharmaceutically acceptable excipient. 
     
     
         35 . An isolated monoclonal anti-idiotype antibody, or an antigen-binding portion thereof, that specifically binds to the antigen-binding site of an anti-Factor XIa antibody or antigen-binding portion of  claim 1 , wherein the antibody comprises:
 a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 70 or 73;   b) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 71 or 74;   c) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 72;   d) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 76 or 79;   e) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 77 or 80; and/or   f) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 78 or 81.   
     
     
         36 - 38 . (canceled) 
     
     
         39 . The isolated monoclonal anti-idiotype antibody or antigen-binding portion of  claim 35 , wherein the anti-idiotype antibody comprises: a heavy chain variable domain (VH) comprising the amino acid sequence of SEQ ID NO: 69 and/or a light chain variable domain (VL) comprising the amino acid sequence of SEQ ID NO: 75. 
     
     
         40 - 44 . (canceled) 
     
     
         45 . An isolated nucleic acid molecule comprising a nucleotide sequence encoding the isolated monoclonal anti-idiotype antibody or antigen-binding portion of  claim 35 . 
     
     
         46 . The isolated nucleic acid molecule of  claim 45 , wherein the nucleic acid molecule comprises:
 (a) the nucleotide sequence of SEQ ID NO: 90;   (b) the nucleotide sequence of SEQ ID NO: 91; or   (c) both (a) and (b).   
     
     
         47 - 57 . (canceled)