Factor xi antibodies and methods of use

Abstract

The present invention relates to monoclonal antibodies and antigen binding fragments thereof that bind to human Factor XI and activated Factor XI (“Factor XIa”), and pharmaceutical compositions and methods of treatment comprising the same.

1 .- 37 . (canceled) 
     
     
         38 . A method of treating a thromboembolic disorder comprising administering to a subject afflicted with or at risk of developing a thromboembolic disorder an effective amount of a pharmaceutical composition comprising an isolated antibody or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment comprises (i) a light chain variable region (VL) comprising complementarity determining regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 39, and (ii) a heavy chain variable region (VH) comprising complementarity determining regions HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 29. 
     
     
         39 . The method of  claim 55 , wherein the subject is afflicted with or at risk of developing venous thromboembolism. 
     
     
         40 . The method of  claim 55 , wherein the subject is afflicted with or at risk of stroke associated with atrial fibrillation or atrial flutter. 
     
     
         41 . The method of  claim 38 , comprising administering to the subject an effective amount of the pharmaceutical composition in combination with a statin therapy. 
     
     
         42 . (canceled) 
     
     
         43 . A nucleic acid coding for an isolated antibody or antigen-binding fragment thereof, wherein the nucleic acid encodes (i) a VH of SEQ ID NO: 9 or 29; (ii) a VL of SEQ ID NO: 19 or 39; (iii) a heavy chain of SEQ ID NO: 11 or 31; or (iv) a light chain of SEQ ID NO: 41 or 21. 
     
     
         44 . An expression vector comprising the nucleic acid according to  claim 43 . 
     
     
         45 . A host cell comprising the expression vector of  claims 44 . 
     
     
         46 .- 52 . (canceled) 
     
     
         53 . The method of  claim 38 , wherein the antibody or antigen-binding fragment thereof comprises:
 i. a heavy chain variable region CDR1 of SEQ ID NO: 23; a heavy chain variable region CDR2 of SEQ ID NO: 24; a heavy chain variable region CDR3 of SEQ ID NO: 25; a light chain variable region CDR1 of SEQ ID NO: 33; a light chain variable region CDR2 of SEQ ID NO: 34; and a light chain variable region CDR3 of SEQ ID NO: 35;   ii. a heavy chain variable region CDR1 of SEQ ID NO: 26; a heavy chain variable region CDR2 of SEQ ID NO: 27; a heavy chain variable region CDR3 of SEQ ID NO: 28; a light chain variable region CDR1 of SEQ ID NO: 36; a light chain variable region CDR2 of SEQ ID NO: 37; and a light chain variable region CDR3 of SEQ ID NO: 38;   iii. a heavy chain variable region CDR1 of SEQ ID NO: 43; a heavy chain variable region CDR2 of SEQ ID NO: 44; a heavy chain variable region CDR3 of SEQ ID NO: 45; a light chain variable region CDR1 of SEQ ID NO: 47; a light chain variable region CDR2 of SEQ ID NO: 37; and a light chain variable region CDR3 of SEQ ID NO: 15; or   iv. a heavy chain variable region CDR1 of SEQ ID NO: 46; a heavy chain variable region CDR2 of SEQ ID NO: 4; a heavy chain variable region CDR3 of SEQ ID NO: 5; a light chain variable region CDR1 of SEQ ID NO: 33; a light chain variable region CDR2 of SEQ ID NO: 14; and a light chain variable region CDR3 of SEQ ID NO: 15.   
     
     
         54 . The method of  claim 38 , wherein the antibody or antigen-binding fragment thereof comprises: (i) an antibody or antigen-binding fragment comprising a heavy chain variable region of SEQ ID NO: 9 and a light chain variable region sequence of SEQ ID NO: 19; or (ii) an antibody or antigen-binding fragment comprising a heavy chain variable region of SEQ ID NO: 29 and a light chain variable region sequence of SEQ ID NO: 39; or
 wherein the antibody comprises (iii) an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 31 and a light chain comprising the amino acid sequence of SEQ ID NO: 41; or (iv) an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 11 and a light chain comprising the amino acid sequence of SEQ ID NO: 21.   
     
     
         55 . The method of  claim 54 , wherein the antibody comprises D265A and P329A substitutions in the Fc domain. 
     
     
         56 . The method of  claim 38 , wherein the subject is afflicted with or at risk of developing a thromboembolic disorder selected from the group consisting of: venous thromboembolism, paroxysmal atrial fibrillation or atrial flutter, stroke associated with atrial fibrillation or atrial flutter, deep vein thrombosis (DVT), cancer, transient ischemic attack, Severe Protein S deficiency, thromboembolic stroke, ischemic stroke, systemic embolism, and myocardial infarction. 
     
     
         57 . The method of  claim 56 , wherein the subject is afflicted with or at risk of developing deep vein thrombosis (DVT). 
     
     
         58 . The method of  claim 39 , the method further comprising measuring efficacy by incidence of DVT occurrence. 
     
     
         59 . The method of  claim 56 , wherein the subject is at high risk for bleeding. 
     
     
         60 . The method of  claim 39 , wherein the subject has undergone a medical procedure selected from the group consisting of knee replacement surgery, hip replacement surgery, orthopedic surgery, pacemaker installation, catheter installation, thoracic surgery, and abdominal surgery. 
     
     
         61 . The method of  claim 60 , wherein the medical procedure is knee. replacement surgery. 
     
     
         62 . The method of  claim 40 , wherein the subject at risk is afflicted with one or more of hypertension, congestive heart failure, left ventricular hypertrophy, and diabetes mellitus. 
     
     
         63 . The method of  claim 40 , wherein the atrial fibrillation or atrial flutter is paroxysmal atrial fibrillation (PAF). 
     
     
         64 . The method of  claim 38 , further comprising evaluating efficacy of the pharmaceutical composition by measuring one or more biomarkers selected from the group consisting of free Factor XI, total Factor XI, Factor XI coagulation activity, activated partial thromboplastin time, and D-dimer. 
     
     
         65 . The method of  claim 38 , further comprising evaluating adverse events to the pharmaceutical composition by measuring bleeding events and/or the presence of anti-drug antibodies. 
     
     
         66 . The method of  claim 65 , further comprising applying one or more of the following to the patient experiencing an adverse event, wherein the adverse event is a bleeding event: (i) fluid replacement using colloids, crystalloids, human plasma or plasma proteins such as albumin; (ii) transfusion with packed red blood or whole blood; or (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. 
     
     
         67 . The host cell of  claim 45 , wherein the host cell is selected from a Pichia, a Chinese Hamster Ovary cell (CHO) or a human cell. 
     
     
         68 . A method of preventing, treating, managing, or reducing the risk of stroke or thromboembolism, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an isolated antibody or an antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment comprises (i) a light chain variable region (VL) comprising complementarity determining regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 39, and (ii) a heavy chain variable region (VH) comprising complementarity determining regions HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 29, wherein the antibody or antigen-binding fragment thereof is administered to the subject at a dose of at least 90 mg. 
     
     
         69 . The method of  claim 68 , wherein a dose of about 150 mg of the antibody or antigen-binding fragment thereof is administered to the subject. 
     
     
         70 . The method of  claim 68 , wherein the antibody or antigen-binding fragment thereof is administered to the subject subcutaneously or intravenously. 
     
     
         71 . The method of  claim 68 , wherein the antibody or antigen-binding fragment thereof is administered to the subject once a month. 
     
     
         72 . The method of  claim 68 , wherein the antibody or antigen-binding fragment thereof is administered to the subject in a pharmaceutical composition further comprising sucrose, a polysorbate, L-histidine, and histidine HCl monohydrate. 
     
     
         73 . The method of  claim 72 , wherein the pharmaceutical composition is at a pH of about 5.5. 
     
     
         74 . The method of  claim 38 , wherein the antibody binds Factor XI and/or activated Factor XI (Factor XIa). 
     
     
         75 . The method of  claim 68 , wherein the antibody binds Factor XI and/or activated Factor XI (Factor XIa).