REVERSAL BINDING AGENTS FOR ANTI-FACTOR XI/XIa ANTIBODIES AND USES THEREOF

Abstract

The present disclosure relates to reversal agents, which specifically bind to anti-Factor XI and/or anti-Factor XIa antibodies, and reverse one or more anticoagulant effects of the anti-Factor XI and/or anti-Factor XIa antibodies, as well as to methods of use thereof, such as methods for reversing anticoagulant effects of such anti-Factor XI and/or anti-Factor XIa antibodies, and to related methods for managing bleeding or bleeding risks.

1 - 30 . (canceled) 
     
     
         31 . A polynucleotide encoding a binding agent which specifically binds a target antibody that binds human Factor XI (FXI) and/or Factor XIa (FXIa) within the catalytic domain, wherein the target antibody comprises (i) a heavy chain variable region (VH) comprising complementarity determining regions HCDR1, HCDR2 and HCDR3 of a VH comprising the amino acid sequence of SEQ ID NO: 12 and (ii) a light chain variable region (VL) comprising complementarity determining regions LCDR1, LCDR2, and LCDR3 of a VL comprising the amino acid sequence of SEQ ID NO: 23,
 and wherein the binding agent is an antibody or antigen-binding fragment thereof comprising a VH comprising HCDR1, HCDR2, and HCDR3 and a VL comprising LCDR1, LCDR2, and LCDR3, wherein:   a) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 91, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 92, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 93, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 107, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 108, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 109;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 94, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 95, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 96, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 110, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 111, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 112; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 97, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 98, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 99, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 113, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 114, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 115; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 100, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 101, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 102, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 116, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 117, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 118; 
   b) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 27, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 28, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 29, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 43, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 44, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 45;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 30, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 31, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 32, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 46, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 47, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 48; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 33, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 34, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 35, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 49, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 50, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 51; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 36, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 37, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 38, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 52, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 53, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 54; 
   c) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 59, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 60, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 61, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 75, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 76, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 77;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 62, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 63, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 64, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 78, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 79, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 80; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 65, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 66, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 67, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 81, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 82, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 83; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 68, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 69, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 70, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 84, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 85, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 86; 
   d) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 123, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 124, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 125, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 139, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 140, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 141;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 126, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 127, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 128, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 142, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 143, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 144; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 129, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 130, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 131, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 145, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 146, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 147; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 132, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 133, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 134, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 148, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 149, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 150; 
   e) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 155, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 156, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 157, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 171, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 172, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 173;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 158, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 159, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 160, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 174, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 175, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 176; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 161, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 162, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 163, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 177, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 178, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 179; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 164, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 165, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 166, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 180, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 181, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 182; 
   f) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 187, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 188, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 189, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 203, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 204, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 205;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 190, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 191, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 192, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 206, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 207, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 208; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 193, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 194, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 195, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 209, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 210, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 211; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 196, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 197, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 198, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 212, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 213, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 214; 
   p) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 219, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 220, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 221, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 235, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 236, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 237;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 222, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 223, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 224, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 238, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 239, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 240; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 225, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 226, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 227, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 241, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 242, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 243; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 228, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 229, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 230, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 244, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 245, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 246; 
   h) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 251, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 252, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 253, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 267, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 268, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 269;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 254, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 255, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 256, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 270, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 271, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 272; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 257, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 258, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 259, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 273, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 274, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 275; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 260, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 261, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 262, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 276, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 277, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 278; 
   i) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 283, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 284, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 285, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 299, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 300, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 301;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 286, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 287, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 288, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 302, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 303, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 304; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 289, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 290, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 291, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 305, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 306, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 307; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 292, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 293, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 294, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 308, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 309, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 310; or 
   j) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 315, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 316, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 317, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 331, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 332, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 333;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 318, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 319, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 320, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 334, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 335, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 336; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 321, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 322, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 323, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 337, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 338, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 339; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 324, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 325, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 326, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 340, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 341, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 342. 
   
     
     
         32 . A vector comprising the polynucleotide of  claim 31 . 
     
     
         33 . A host cell comprising the polynucleotide of  claim 31 . 
     
     
         34 . A host cell comprising the vector of  claim 32 . 
     
     
         35 . A method of producing a binding agent, wherein said method comprises culturing the host cell of  claim 33  under suitable conditions for expression of the binding agent or a portion thereof, wherein the method optionally comprises purifying the binding agent. 
     
     
         36 - 71 . (canceled) 
     
     
         72 . The polynucleotide of  claim 31 , wherein the binding agent comprises:
 a) a VH comprising the amino acid sequence of SEQ ID NO: 103 and a VL comprising the amino acid sequence of SEQ ID NO: 119;   b) a VH comprising the amino acid sequence of SEQ ID NO: 39 and a VL comprising the amino acid sequence of SEQ ID NO: 55;   c) a VH comprising the amino acid sequence of SEQ ID NO: 71 and a VL comprising the amino acid sequence of SEQ ID NO: 87;   d) a VH comprising the amino acid sequence of SEQ ID NO: 135 and a VL comprising the amino acid sequence of SEQ ID NO: 151;   e) a VH comprising the amino acid sequence of SEQ ID NO: 167 and a VL comprising the amino acid sequence of SEQ ID NO: 183;   f) a VH comprising the amino acid sequence of SEQ ID NO: 199 and a VL comprising the amino acid sequence of SEQ ID NO: 215;   g) a VH comprising the amino acid sequence of SEQ ID NO: 231 and a VL comprising the amino acid sequence of SEQ ID NO: 247;   h) a VH comprising the amino acid sequence of SEQ ID NO: 263 and a VL comprising the amino acid sequence of SEQ ID NO: 279;   i) a VH comprising the amino acid sequence of SEQ ID NO: 295 and a VL comprising the amino acid sequence of SEQ ID NO: 311; or   j) a VH comprising the amino acid sequence of SEQ ID NO: 327 and a VL comprising the amino acid sequence of SEQ ID NO: 343.   
     
     
         73 . The polynucleotide of  claim 31 , wherein the binding agent comprises:
 a) a VH comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 103 and a VL comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 119;   b) a VH comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 39 and a VL comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 55;   c) a VH comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 71 and a VL comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 87;   d) a VH comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 135 and a VL comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 151;   e) a VH comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 167 and a VL comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 183;   f) a VH comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 199 and a VL comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 215;   g) a VH comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 231 and a VL comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 247;   h) a VH comprising amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 263 and a VL comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 279;   i) a VH comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 295 and a VL comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 311; or   j) a VH comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 327 and a VL comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 343.   
     
     
         74 . The polynucleotide of  claim 31 , wherein the binding agent is an antibody comprising a heavy chain and a light chain, and wherein:
 a) the heavy chain comprises the amino acid sequence of SEQ ID NO: 105 and the light chain comprises the amino acid sequence of SEQ ID NO: 121;   b) the heavy chain comprises the amino acid sequence of SEQ ID NO: 41 and the light chain comprises the amino acid sequence of SEQ ID NO: 57;   c) the heavy chain comprises the amino acid sequence of SEQ ID NO: 73 and the light chain comprises the amino acid sequence of SEQ ID NO: 89;   d) the heavy chain comprises the amino acid sequence of SEQ ID NO: 137 and the light chain comprises the amino acid sequence of SEQ ID NO: 153;   e) the heavy chain comprises the amino acid sequence of SEQ ID NO: 169 and the light chain comprises the amino acid sequence of SEQ ID NO: 185;   f) the heavy chain comprises the amino acid sequence of SEQ ID NO: 201 and the light chain comprises the amino acid sequence of SEQ ID NO: 217;   g) the heavy chain comprises the amino acid sequence of SEQ ID NO: 233 and the light chain comprises the amino acid sequence of SEQ ID NO: 249;   h) the heavy chain comprises the amino acid sequence of SEQ ID NO: 265 and the light chain comprises the amino acid sequence of SEQ ID NO: 281;   i) the heavy chain comprises the amino acid sequence of SEQ ID NO: 297 and the light chain comprises the amino acid sequence of SEQ ID NO: 313; or   j) the heavy chain comprises the amino acid sequence of SEQ ID NO: 329 and the light chain comprises the amino acid sequence of SEQ ID NO: 345.   
     
     
         75 . The polynucleotide of  claim 31 , wherein the binding agent is an antibody Fab fragment. 
     
     
         76 . The polynucleotide of  claim 31 , wherein the binding agent is a monoclonal human antibody. 
     
     
         77 . A method of producing a binding agent, wherein said method comprises culturing the host cell of  claim 34  under suitable conditions for expression of the binding agent or a portion thereof, wherein the method optionally comprises purifying the binding agent. 
     
     
         78 . A pharmaceutical composition comprising the binding agent produced by the method of  claim 35  and a pharmaceutically acceptable carrier. 
     
     
         79 . A pharmaceutical composition comprising the binding agent produced by the method of  claim 77  and a pharmaceutically acceptable carrier. 
     
     
         80 . A method for reversing the anticoagulant effect of an anti-FXI/FXIa antibody or antigen-binding fragment thereof in a patient being treated with said anti-FXI/FXIa antibody or antigen-binding fragment thereof, wherein the method comprises administering an effective amount of a binding agent which specifically binds the anti-FXI/FXIa antibody, wherein the anti-FXI/FXIa antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising complementarity determining regions HCDR1, HCDR2 and HCDR3 of a VH comprising the amino acid sequence of SEQ ID NO: 12 and a light chain variable region (VL) comprising complementarity determining regions LCDR1, LCDR2, and LCDR3 of a VL comprising the amino acid sequence of SEQ ID NO: 23,
 and wherein the binding agent is an antibody or antigen-binding fragment thereof wherein:   a) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 27, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 28, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 29, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 43, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 44, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 45;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 30, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 31, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 32, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 46, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 47, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 48; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 33, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 34, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 35, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 49, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 50, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 51; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 36, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 37, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 38, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 52, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 53, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 54; 
   b) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 59, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 60, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 61, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 75, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 76, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 77;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 62, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 63, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 64, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 78, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 79, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 80; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 65, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 66, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 67, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 81, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 82, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 83; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 68, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 69, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 70, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 84, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 85, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 86; 
   c) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 123, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 124, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 125, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 139, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 140, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 141;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 126, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 127, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 128, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 142, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 143, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 144; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 129, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 130, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 131, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 145, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 146, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 147; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 132, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 133, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 134, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 148, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 149, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 150; 
   d) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 155, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 156, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 157, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 171, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 172, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 173;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 158, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 159, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 160, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 174, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 175, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 176; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 161, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 162, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 163, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 177, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 178, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 179; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 164, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 165, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 166, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 180, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 181, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 182; 
   e) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 187, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 188, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 189, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 203, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 204, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 205;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 190, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 191, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 192, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 206, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 207, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 208; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 193, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 194, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 195, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 209, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 210, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 211; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 196, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 197, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 198, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 212, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 213, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 214; 
   f) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 219, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 220, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 221, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 235, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 236, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 237;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 222, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 223, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 224, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 238, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 239, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 240; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 225, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 226, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 227, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 241, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 242, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 243; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 228, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 229, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 230, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 244, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 245, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 246; 
   g) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 251, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 252, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 253, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 267, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 268, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 269;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 254, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 255, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 256, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 270, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 271, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 272; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 257, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 258, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 259, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 273, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 274, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 275; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 260, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 261, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 262, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 276, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 277, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 278; 
   h) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 283, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 284, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 285, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 299, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 300, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 301;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 286, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 287, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 288, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 302, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 303, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 304; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 289, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 290, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 291, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 305, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 306, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 307; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 292, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 293, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 294, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 308, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 309, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 310; or 
   i) i) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 315, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 316, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 317, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 331, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 332, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 333;
 ii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 318, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 319, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 320, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 334, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 335, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 336; 
 iii) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 321, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 322, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 323, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 337, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 338, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 339; or 
 iv) the HCDR1 comprises the amino acid sequence of SEQ ID NO: 324, the HCDR2 comprises the amino acid sequence of SEQ ID NO: 325, the HCDR3 comprises the amino acid sequence of SEQ ID NO: 326, the LCDR1 comprises the amino acid sequence of SEQ ID NO: 340, the LCDR2 comprises the amino acid sequence of SEQ ID NO: 341, and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 342; and wherein the binding agent is isolated from a host cell comprising a polynucleotide encoding said binding agent. 
   
     
     
         81 . The method of  claim 80 , wherein the anti-FXI/FXIa antibody or antigen-binding fragment thereof comprises:
 a) a VH comprising complementarity determining regions HCDR1, HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 4, and SEQ ID NO: 5, respectively; and a VL comprising complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18, respectively;   b) a VH comprising complementarity determining regions HCDR1, HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NO: 7, SEQ ID NO: 8, and SEQ ID NO: 5, respectively; and a VL comprising complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 19, SEQ ID NO: 20, and SEQ ID NO: 21, respectively;   c) a VH comprising complementarity determining regions HCDR1, HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11, respectively; and (ii) a VL comprising complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 22, SEQ ID NO: 20, and SEQ ID NO: 18, respectively; or   d) a VH comprising complementarity determining regions HCDR1, HCDR2, and HCDR3 comprising the amino acid sequences of SEQ ID NO: 3, SEQ ID NO: 4, and SEQ ID NO: 5, respectively; and (ii) a VL comprising complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18, respectively.   
     
     
         82 . The method of  claim 80 , wherein the anti-FXI/FXIa antibody or antigen-binding fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 12 and a VL comprising the amino acid sequence of SEQ ID NO: 23. 
     
     
         83 . The method of  claim 80 , wherein the anti-FXI/FXIa antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 14 and a light chain comprising the amino acid sequence of SEQ ID NO: 25. 
     
     
         84 . The method of  claim 80 , wherein the binding agent comprises:
 a) a VH comprising the amino acid sequence of SEQ ID NO: 39 and a VL comprising the amino acid sequence of SEQ ID NO: 55;   b) a VH comprising the amino acid sequence of SEQ ID NO: 71 and a VL comprising the amino acid sequence of SEQ ID NO: 87;   c) a VH comprising the amino acid sequence of SEQ ID NO: 135 and a VL comprising the amino acid sequence of SEQ ID NO: 151;   d) a VH comprising the amino acid sequence of SEQ ID NO: 167 and a VL comprising the amino acid sequence of SEQ ID NO: 183;   e) a VH comprising the amino acid sequence of SEQ ID NO: 199 and a VL comprising the amino acid sequence of SEQ ID NO: 215;   f) a VH comprising the amino acid sequence of SEQ ID NO: 231 and a VL comprising the amino acid sequence of SEQ ID NO: 247;   g) a VH comprising the amino acid sequence of SEQ ID NO: 263 and a VL comprising the amino acid sequence of SEQ ID NO: 279;   h) a VH comprising the amino acid sequence of SEQ ID NO: 295 and a VL comprising the amino acid sequence of SEQ ID NO: 311; or   i) a VH comprising the amino acid sequence of SEQ ID NO: 327 and a VL comprising the amino acid sequence of SEQ ID NO: 343.   
     
     
         85 . The method of  claim 80 , wherein the binding agent is an antibody comprising a heavy chain and a light chain, and wherein:
 a) the heavy chain comprises the amino acid sequence of SEQ ID NO: 41 and the light chain comprises the amino acid sequence of SEQ ID NO: 57;   b) the heavy chain comprises the amino acid sequence of SEQ ID NO: 73 and the light chain comprises the amino acid sequence of SEQ ID NO: 89;   c) the heavy chain comprises the amino acid sequence of SEQ ID NO: 137 and the light chain comprises the amino acid sequence of SEQ ID NO: 153;   d) the heavy chain comprises the amino acid sequence of SEQ ID NO: 169 and the light chain comprises the amino acid sequence of SEQ ID NO: 185;   e) the heavy chain comprises the amino acid sequence of SEQ ID NO: 201 and the light chain comprises the amino acid sequence of SEQ ID NO: 217;   f) the heavy chain comprises the amino acid sequence of SEQ ID NO: 233 and the light chain comprises the amino acid sequence of SEQ ID NO: 249;   g) the heavy chain comprises the amino acid sequence of SEQ ID NO: 265 and the light chain comprises the amino acid sequence of SEQ ID NO: 281;   h) the heavy chain comprises the amino acid sequence of SEQ ID NO: 297 and the light chain comprises the amino acid sequence of SEQ ID NO: 313; or   i) the heavy chain comprises the amino acid sequence of SEQ ID NO: 329 and the light chain comprises the amino acid sequence of SEQ ID NO: 345.   
     
     
         86 . The method of  claim 80 , wherein the method further comprises applying one or more of the following to the patient: (i) fluid replacement using colloids, crystalloids, human plasma or plasma proteins such as albumin; (ii) transfusion with packed red blood or whole blood; and (iii) administration of fresh frozen plasma (FFP), prothrombin complex concentrates (PCC), activated PCC (APCC) such as factor VIII inhibitor, and/or recombinant, activated factor VII.