Dosing regimens for factor XI / XIa antibodies

Abstract

The present disclosure relates to anti-factor XI and / or activated factor XI (factor XIa) antibodies or antigen-binding fragments thereof, pharmaceutical formulations comprising the same, and dosing regimens of the pharmaceutical formulations for use in treating thromboembolic disorders or related conditions. Pharmaceutical formulations of anti-factor XI and / or activated factor XI (factor XIa) antibodies or antigen-binding fragments thereof are also provided. Methods of treating patients with thrombocytopenia with anti-factor XI and / or activated factor XI (factor XIa) antibodies or antigen-binding fragments thereof are also provided.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and U.S. priority to U.S. Provisional Patent Application No. 63 / 281,024, filed November 18, 2021, U.S. Provisional Patent Application No. 63 / 287,633, filed December 9, 2021, and U.S. Provisional Patent Application No. 63 / 355,314, filed June 24, 2022, the entire disclosures of each of which are incorporated herein by reference for all purposes.

[0002] Sequence Listing This application has been submitted electronically and contains a Sequence Listing XML, which is incorporated herein by reference in its entirety. The Sequence Listing SML was created on October 24, 2022, is named ATD-011WO_SL.XML, and is 52,029 bytes in size.

[0003] Field of the Disclosure The present disclosure relates to anti-factor XI and / or activated factor XI (factor XIa) antibodies or antigen-binding fragments thereof, pharmaceutical formulations comprising same, and dosing regimens of pharmaceutical formulations for use in treating thromboembolic disorders or related conditions. Pharmaceutical formulations of anti-factor XI and / or activated factor XI (factor XIa) antibodies or antigen-binding fragments thereof are also provided. [Background technology]

[0004] background There is a large unmet medical need for safer therapies with similar or improved efficacy to that shown by existing therapies and with a lower risk of bleeding to reduce thromboembolic complications, such as stroke, systemic embolism, cognitive decline and mortality. Factor XI (FXI) is a serine protease that functions in both the intrinsic and extrinsic coagulation pathways. Factor XI exists as a homodimer in a zymogen form; cleavage of the peptide bond at R369-I370 activates factor XI (factor XIa, FXIa). FXI plays a minor role in normal hemostasis in a high tissue factor environment, but plays a key role in thrombosis. Genetic factor XI deficiency is associated with a reduced incidence of ischemic stroke and venous thromboembolic events (Salomon et al. (2008); Salomon, et al. (2011) Thromb Haemost.; 105: 269-73). Hemorrhagic manifestations in subjects with factor XI deficiency are infrequent, often mild, result from injury or trauma, and very rarely affect vital organs (Salomon et al. (2011)). Antibodies that bind to factor XI and / or factor XIa have been studied. For example, WO2016 / 207858 describes one such anti-factor XI and / or factor XIa antibody, which is disclosed as antibody 1 in table 1 herein. The present disclosure adds to these developments and provides additional clinical methods, including dosing regimens, to treat patients with certain thromboembolic disorders with desired safety and efficacy. Furthermore, the present disclosure adds to previous developments in the art by providing pharmaceutical formulations that include such FXI and / or FXIa antibodies that are sufficiently stable and suitable for administration to patients. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2016 / 207858 [Non-patent literature]

[0006] [Non-Patent Document 1] Salomon, et al. (2011) Thromb Haemost.; 105: 269-73 Summary of the Invention [Means for solving the problem]

[0007] overview The present disclosure provides dosing regimens for anti-factor XI and / or factor XIa antibodies or antigen-binding fragments thereof, or pharmaceutical formulations comprising same.

[0008] Thus, in one aspect, provided herein is a method of treating a disease or disorder in a subject in need thereof, comprising the steps of intravenously administering to the subject a first dose of about 150 mg of an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or antigen-binding fragment thereof, and subcutaneously administering to the subject a second dose of the isolated anti-FXI and / or anti-FXIa antibody or antigen-binding fragment thereof.

[0009] In some embodiments, the second dose comprises about 150 mg of isolated anti-FXI and / or anti-FXIa antibody or antigen-binding fragment thereof. In some embodiments, the first dose of isolated anti-FXI and / or anti-FXIa antibody or antigen-binding fragment thereof is formulated as an intravenous drug delivery formulation comprising about 150 mg of antibody or antigen-binding fragment thereof. In some embodiments, the second dose of isolated anti-FXI and / or anti-FXIa antibody or antigen-binding fragment thereof is formulated as a subcutaneous drug delivery formulation comprising about 150 mg of antibody or antigen-binding fragment thereof.

[0010] In some embodiments, the antibody is a human monoclonal antibody. In some embodiments, the antibody is a human IgG1 isotype. In some embodiments, the antibody comprises a D265A substitution and a P329A substitution in the Fc domain.

[0011] In some embodiments, the antibody or antigen-binding fragment thereof is administered in a drug delivery formulation comprising a histidine buffer at a concentration of about 20 mM. In some embodiments, the antibody or antigen-binding fragment thereof is administered in a drug delivery formulation comprising sucrose at a concentration of about 220 mM. In some embodiments, the antibody or antigen-binding fragment thereof is administered in a drug delivery formulation comprising polysorbate 20 at a concentration of about 0.04%. In some embodiments, the antibody or antigen-binding fragment thereof is administered in a drug delivery formulation at pH 5.5. In some embodiments, the antibody or antigen-binding fragment thereof is administered in an intravenous drug delivery formulation, and the intravenous drug delivery formulation further comprises about 5% glucose.

[0012] In some embodiments, the subject has cancer. In certain embodiments, the subject has active cancer. In certain embodiments, the subject has cancer selected from the group consisting of gastrointestinal cancer and genitourinary cancer. In some embodiments, the subject is at high risk of venous thromboembolism. In some embodiments, the subject has one or more previous venous thromboembolism.

[0013] In some embodiments, the method further comprises one or more additional subcutaneous doses of the antibody or antigen-binding fragment thereof. In some embodiments, the method comprises administering five subcutaneous doses of the antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously about once a month. In some embodiments, the antibody or antigen-binding fragment thereof is administered intravenously on day 1, and subcutaneously on days 31, 61, 91, 121, and 151. In some embodiments, the subject is treated for about 6 months.

[0014] In another aspect, provided herein is a method of treating a subject having cancer, comprising administering to a subject in need thereof a drug delivery formulation comprising about 150 mg of an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or antigen-binding fragment thereof, wherein the drug delivery formulation is administered intravenously once and then subcutaneously about once a month to treat the subject for about 6 months.

[0015] In some embodiments, the cancer is selected from the group consisting of gastrointestinal cancer and genitourinary cancer.

[0016] In another aspect, a method of treating a primate subject at risk for thrombosis comprises administering to the primate subject: (a) a therapeutically effective amount of an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or antigen-binding fragment thereof in a concentration of about 150 mg; (b) a histidine buffer at a concentration of about 20 mM; (c) sucrose at a concentration of about 220 mM; and (d) polysorbate 20 at a concentration of about 0.04% (v / v); (e) a diluent comprising glucose; administering a single dose of a drug delivery formulation having a pH of 5.5 comprising Including, The administering step is before or during the formation of a blood clot. Methods are provided herein.

[0017] In some embodiments, the primate subject is a baboon. In some embodiments, the primate subject is a human. In some embodiments, the thrombosis is experimentally induced thrombosis. In some embodiments, the primate subject is at risk for vascular graft thrombosis. In some embodiments, the single dose is administered to prevent thrombosis. In some embodiments, the single dose is administered to treat thrombosis. In some embodiments, the single dose is parenteral or intravenous. In certain embodiments, the single dose is followed by a subsequent dose. In certain embodiments, the subsequent dose is parenteral.

[0018] In some embodiments, the therapeutically effective amount of an anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or antigen-binding fragment thereof for administration to a primate subject is about 1 mg / kg. In some embodiments, the therapeutically effective amount of an anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or antigen-binding fragment thereof for administration to a primate subject is about 150 mg.

[0019] In another aspect, provided herein is a method of treating a subject having thrombocytopenia, wherein the thrombocytopenia is selected from the group consisting of chemotherapy-induced thrombocytopenia, congenital thrombocytopenia, thrombocytopenia associated with infection, and idiopathic thrombocytopenia, the method comprising administering a therapeutically effective amount of a factor XI and / or factor XIa antibody or antigen-binding fragment thereof to a subject in need thereof.

[0020] In some embodiments, the subject with thrombocytopenia has cancer.

[0021] In some embodiments, the subject with thrombocytopenia has cirrhosis.

[0022] In some embodiments, the subject with thrombocytopenia has idiopathic thrombocytopenic purpura (ITP).

[0023] In another aspect, provided herein is a method of treating a cancer subject with chemotherapy-induced thrombocytopenia, the method comprising administering a therapeutically effective amount of a factor XI and / or factor XIa antibody, or antigen-binding fragment thereof, to a cancer subject in need thereof.

[0024] In some embodiments, the subject or cancer subject is suffering from or at risk of developing a thromboembolic disorder.

[0025] In some embodiments of the above aspects, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising complementarity determining regions HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 9 or 29; and a light chain variable region (VL) comprising complementarity determining regions LCDR1, LCDR2, LCDR3 in SEQ ID NO: 19 or 39.

[0026] In some embodiments of the above aspects, the antibody or antigen-binding fragment thereof comprises: i. heavy chain variable region CDR1 of SEQ ID NO:23; heavy chain variable region CDR2 of SEQ ID NO:24; heavy chain variable region CDR3 of SEQ ID NO:25; light chain variable region CDR1 of SEQ ID NO:33; light chain variable region CDR2 of SEQ ID NO:34; and 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 that is KNY; 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 that is KNY; and a light chain variable region CDR3 of SEQ ID NO: 15; or iv. Heavy chain variable region CDR1 of SEQ ID NO: 46; heavy chain variable region CDR2 of SEQ ID NO: 4; heavy chain variable region CDR3 of SEQ ID NO: 5; light chain variable region CDR1 of SEQ ID NO: 33; light chain variable region CDR2 of SEQ ID NO: 14; and light chain variable region CDR3 of SEQ ID NO: 15. Includes.

[0027] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) selected from the group consisting of SEQ ID NO: 9, 29, and a VL selected from the group consisting of a light chain variable region (VL) having 90% identity thereto.

[0028] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) selected from the group consisting of SEQ ID NOs: 9 and 29; and a light chain variable region (VL) selected from the group consisting of SEQ ID NOs: 19 and 39. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 31, 11, and a heavy chain having 90% identity thereto; and a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41, 21, and a light chain having 90% identity thereto. In some embodiments, the antibody comprises 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.

[0029] In some embodiments, the antibody is a human monoclonal antibody. In some embodiments, the antibody is a human IgG1 isotype. In certain embodiments, the antibody comprises a D265A substitution and a P329A substitution in the Fc domain.

[0030] In some embodiments, administering the antibody or antigen-binding fragment thereof has no effect on platelet aggregation in the subject compared to platelet aggregation before administration. In certain embodiments, platelet aggregation is measured by impedance aggregometry. In certain embodiments, platelet aggregation is induced by collagen, adenosine 5'-diphosphate (ADP), or thrombin receptor activating peptide-6 (TRAP-6). In certain embodiments, platelet aggregation is determined ex vivo or in vitro.

[0031] In some embodiments, the antibody or antigen-binding fragment thereof is administered intravenously.

[0032] In some embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0033] In some embodiments, a first dose of the antibody or antigen-binding fragment thereof is administered intravenously and a second dose of the antibody or antigen-binding fragment thereof is administered subcutaneously. In certain embodiments, the method further comprises administering one or more additional doses of the antibody or antigen-binding fragment thereof subcutaneously after administering the second dose.

[0034] In some embodiments, the antibody or antigen-binding fragment thereof is administered once a month.

[0035] Other embodiments and details of the present disclosure are described herein below. [Brief description of the drawings]

[0036] [Figure 1] FIG. 1 shows a line graph depicting the time course of activated partial thromboplastin time (aPTT) following intravenous administration of Antibody 1 at 1 mg / kg in four baboons.

[0037] [Diagram 2] Figures 2A-2B show the bleeding time (Figure 2A) and bleeding volume (Figure 2B) before and during each arteriovenous (AV) shunt experiment.

[0038] [Diagram 3] Figures 3A-3B show platelet deposition in the tail segment of an AV shunt for collagen coating (Figure 3A) or collagen + tissue factor (TF) coating (Figure 3B). The vertical dotted line indicates the time of administration of Antibody 1 and the arrow indicates the inflection point where platelet deposition stopped. The time between the vertical dotted line and the arrow measures the time between drug administration and the time when the platelet deposition rate became negative.

[0039] [Figure 4] Figures 4A-4F show platelet deposition in the caudal segments of AV shunts for three treated baboons: Figures 4A, 4B, and 4C show collagen coatings, and Figures 4D, 4E, and 4F show collagen+TF coatings.

[0040] [Diagram 5] 5A-5B show platelet deposition in collagen-coated (FIG. 5A) or collagen+TF-coated (FIG. 5B) segments of the AV shunt. Data are the average of three baboons.

[0041] [Figure 6] Figures 6A-6D show the fibrin content of thrombi in collagen-coated grafts (Figure 6A), collagen + TF-coated grafts (Figure 6B), the downstream tail segment of the collagen-coated graft (Figure 6C), and the downstream tail segment of the collagen + TF-coated graft (Figure 6D).

[0042] [Figure 7] 7A-7B show in vitro platelet aggregation in donor whole blood supplemented with vehicle, antibody 1, or abciximab following induction with collagen (FIG. 7A) or TRAP-6 (FIG. 7B). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] Detailed Description definition To facilitate the understanding of this invention, a number of terms and phrases are defined below.

[0044] The terms "a" and "an" as used herein mean "one or more" and include the plural unless the context requires otherwise.

[0045] As used herein, the terms "FXI protein", "FXI antigen", and "FXI" are used interchangeably to refer to factor XI protein in different species. Factor XI is the mammalian plasma coagulation factor XI, a glycoprotein that exists as a zymogen at a concentration of 25-30 nM in human plasma and, when converted by limited proteolysis to an active serine protease, participates in the intrinsic pathway of blood coagulation.

[0046] The terms "FXIa protein", "FXIa antigen" and "FXIa" are used interchangeably and refer to activated FXI protein in different species. Zymogen factor XI is converted to its activated form, coagulation factor XIa (FXIa), either through the contact phase of blood clotting or through thrombin-mediated activation on the platelet surface. During this activation of factor XI, an internal peptide bond in each of the two chains is cleaved, resulting in activated factor Xla, a serine protease composed of two heavy chains and two light chains held together by disulfide bonds. This serine protease FXIa converts coagulation factor IX to IXa, which then activates coagulation factor X (Xa). Xa can then mediate coagulation factor II / thrombin activation. For example, human FXI has the sequence set out in Table 1 (SEQ ID NO:1) and has been previously reported and described in the literature (Mandle RJ Jr, et al. (1979) Blood; 54 (4): 850; NCBI Reference Sequence: AAA51985).

[0047] For the purposes of the present disclosure, the terms "FXI" and "FXIa" (and the like) include mutants and variants of the native FXI and FXIa proteins, respectively, having substantially the same amino acid sequence as the native primary structure (amino acid sequence) described in the above reports.

[0048] The terms "catalytic domain," "serine protease catalytic domain," and similar terms, as used herein, refer to amino acids Ile370-Val607, counting from Glu1 at the N-terminus of the mature protein present in circulation. This can also be described as residues 388-625 at the C-terminus of FXI. As used herein, the term "active site" refers to the catalytic triad composed of amino acids His413, Asp462, and Ser557 (Bane and Gailani (2014) Drug Disc. 19 (9)).

[0049] The term "antibody" as used herein means whole antibodies and any antigen-binding fragments (e.g., "antigen-binding portions") or single chains thereof. Whole antibodies are glycoproteins composed of at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is composed of three domains, CH1, CH2 and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is composed of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), and more conserved regions, termed framework regions (FRs), interspersed therebetween. Each VH and VL is composed of three CDRs and four FRs, which are arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant regions of the antibody may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. In some specific embodiments, the antibody may be a monoclonal antibody, a human antibody, a humanized antibody, a camelid antibody, or a chimeric antibody. The antibody may be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass.

[0050] The CDRs of an antigen-binding site can be determined by the methods described in Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of proteins of immunological interest. (1991), Chothia et al., J. Mol. Biol. 196: 901-917 (1987), and MacCallum et al., J. Mol. Biol. 262: 732-745 (1996). CDRs determined under these definitions generally contain overlapping or subsets of amino acid residues when compared with each other. In certain embodiments, the term "CDR" refers to the CDRs defined by MacCallum et al., J. Mol. Biol. 262: 732-745 (1996) and Martin A., Protein Sequence and Structure Analysis of Antibody Variable Domains, in Antibody Engineering, Kontermann and Dubel, eds., Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001). In certain embodiments, the term "CDR" refers to the CDRs defined by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of proteins of immunological interest. (1991). In certain embodiments, the heavy and light chain CDRs of an antibody are defined using different conventions. For example, in certain embodiments, the heavy chain CDRs are defined according to MacCallum (supra) and the light chain CDRs are defined according to Kabat (supra). CDRH1, CDRH2 and CDRH3 represent the heavy chain CDRs, and CDRL1, CDRL2 and CDRL3 represent the light chain CDRs.

[0051] As used herein, the term "drug delivery formulation" or "intravenous drug delivery formulation" refers to a pharmaceutical formulation that includes a combination of an active agent with an inert or active carrier, making it into a composition particularly suitable for in vivo or ex vivo diagnostic or therapeutic use.

[0052] As used herein, the terms "subject" and "patient" refer to an organism treated by the methods and compositions described herein. Such organisms preferably include, but are not limited to, mammals (e.g., murine, simian, equine, bovine, porcine, primates, canine, feline, etc.), and more preferably, humans. In certain embodiments, the subject is a human. As used herein, "primate subject" encompasses both human and non-human primates. In certain embodiments, the subject is a baboon model of thrombosis, as described, for example, in Gruber et al. Blood, 1989 Feb 15; 73(3): 639-42 and Crosby et al. Arterioscler Thromb Vasc Biol, 2013 Jul; 33 (7): 1670-8.

[0053] "Thromboembolic disorder" or similar terms, as used herein, refer to a number of conditions or diseases in which intrinsic and / or common coagulation pathways are abnormally activated or not naturally deactivated (e.g., without therapeutic measures). These conditions include, but are not limited to, thromboembolic stroke and other types of stroke of ischemic origin, atrial fibrillation, prevention of stroke in atrial fibrillation (SPAF), deep vein thrombosis, venous thromboembolism, and pulmonary embolism. These also include prevention and treatment of catheter-related thrombosis (e.g., Hickman catheter in tumor patients), in which clots are formed by the catheter, and extracorporeal membrane oxygenation (ECMO), in which clots are formed by the tube and oxygenation membrane.

[0054] "Thromboembolic disorder" or similar term, as used herein, can also refer to any number of the following, which can be prevented or treated using the anti-FXI and / or FXIa antibodies, or antigen-binding fragments thereof, of the present disclosure: Thromboembolism in subjects with suspected or confirmed cardiac arrhythmias, such as paroxysmal, persistent or permanent atrial fibrillation or atrial flutter; -Prevention of Stroke in Atrial Fibrillation (SPAF), this subpopulation is AF patients undergoing percutaneous coronary intervention (PCI); -Treatment of acute venous thromboembolic events (VTE) and prevention of long-term secondary VTE in patients at high risk of bleeding; - Venous thromboembolism (pediatric VTE) in pediatric subjects; - Prevention of cerebral and cardiovascular events during secondary prevention after transient ischemic attack (TIA) or non-disabling stroke, and prevention of thromboembolic events in heart failure with sinus rhythm; - Hemorrhagic stroke; - Thromboembolism in subjects undergoing electrical cardioversion for clot formation in the left atrium and cardiac arrhythmias; - Thrombosis before, during, and after ablation procedures for cardiac arrhythmias; - venous thrombosis, including, but not exclusively, the treatment and secondary prevention of deep or superficial vein thrombosis in the lower or upper members, thrombosis in the abdominal and thoracic veins, sinus thrombosis and thrombosis of the jugular vein; - Thrombosis in any artificial surface in a vein or artery, such as catheters, pacemaker wires, synthetic arterial grafts; mechanical or biological heart valves or left ventricular assist devices; - Pulmonary embolism in patients with or without venous thrombosis; -Chronic Thromboembolic Pulmonary Hypertension (CTEPH); - arterial thrombosis in ruptured atherosclerotic plaques, thrombosis in intra-arterial prostheses or catheters and thrombosis in apparently normal arteries, including but not limited to acute coronary syndromes, ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, unstable angina, stent thrombosis, thrombosis of any artificial surface within the arterial system and thrombosis of the pulmonary artery in subjects with or without pulmonary hypertension; - Thrombosis and thromboembolism in patients undergoing percutaneous coronary intervention (PCI); - Cardiogenic stroke and cryptogenic stroke; -Non-CNS systemic embolism (non-CNS systemic embolism); -Thrombosis in patients with invasive and non-invasive cancer malignancies (e.g. CAT); - Thrombosis on the indwelling catheter; - Thrombosis and thromboembolism in critically ill patients; -cardiac thrombosis and thromboembolism, including but not limited to, cardiac thrombosis following myocardial infarction, ventricular aneurysms, myocardial fibrosis, cardiac enlargement and failure, myocarditis and cardiac prosthesis; - Thromboembolism in patients with valvular heart disease with or without atrial fibrillation; - Thromboembolism on a mechanical or biological prosthetic valve; Thromboembolism in patients with native or artificial cardiac patches, arterial or venous conduits after cardiac repair of simple or complex cardiac anomalies; - venous thrombosis and thromboembolism after knee replacement, hip replacement, and orthopedic, thoracic or abdominal surgery; - Arterial or venous thrombosis after neurosurgery, including intracranial and spinal interventions; - congenital or acquired thrombophilias, including, but not exclusively, factor V Leiden, prothrombin mutations, antithrombin III, protein C and protein S deficiency, factor XIII mutations, familial dysfibrinogenemia, congenital plasminogen deficiency, elevated levels of factor XI, sickle cell disease, antiphospholipid syndrome, autoimmune diseases, chronic intestinal diseases, nephrotic syndrome, hemolytic uremia, myeloproliferative disorders, disseminated intravascular coagulation, paroxysmal nocturnal hemoglobinuria and heparin-induced thrombocytopenia; - Thrombosis and thromboembolism in chronic kidney disease; and -Thrombosis and thromboembolism in patients undergoing hemodialysis and in patients undergoing extracorporeal membrane oxygenation.

[0055] As used herein, the term "trough" or "trough level" refers to the lowest concentration of a drug reached before the next dose of the drug is administered. In certain embodiments, the inhibition of factor XI / factor XIa at the trough is greater than about 50% (e.g., greater than about 60%, greater than about 70%, greater than about 80%, or greater than about 90%). In certain embodiments, the inhibition of factor XI / factor XIa at the trough is greater than about 80%. In certain embodiments, the inhibition of factor XI / factor XIa at the trough is greater than about 90%.

[0056] The terms "treat", "treating" or "treatment" and other grammatical equivalents as used in this disclosure are intended to encompass alleviating, relieving, reversing or preventing a disease, condition or symptom, preventing additional symptoms, reversing or preventing the underlying metabolic cause of a symptom, inhibiting a disease or condition, e.g., arresting the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, relieving a condition caused by a disease or condition, or arresting the symptoms of a disease or condition, and include prophylaxis. The term further encompasses achieving therapeutic and / or prophylactic benefit. "Therapeutic benefit" refers to the eradication or reversal of the underlying disorder being treated. Therapeutic benefit is also achieved with the eradication or reversal of one or more of the physiological symptoms associated with the underlying disorder, such that an improvement is observed in the patient, even though the patient may still be afflicted by the underlying disorder.

[0057] In certain embodiments of the methods described herein, the subject is treatment naive, i.e., has not received any form of anticoagulant therapy prior to treatment with an anti-factor XI / XIa antibody described herein, e.g., antibody 1. In certain embodiments of the methods described herein, the subject has received stable treatment, e.g., with a recommended dose of a novel oral anticoagulant (NOAC), prior to treatment with an anti-factor XI / XIa antibody described herein, e.g., antibody 1. In certain embodiments, the subject has received, e.g., a direct oral anticoagulant (DOAC), prior to treatment with an anti-factor XI / XIa antibody described herein, e.g., antibody 1. In certain embodiments, the subject has received, e.g., a vitamin K antagonist (VKA), prior to treatment with an anti-factor XI / XIa antibody described herein, e.g., antibody 1.

[0058] As used herein, the term "vial" refers to a container that holds a drug. In some embodiments, the vial can be a vial, a bag, a pen, or a syringe. In some embodiments, the vial can be a vial, for example, a glass vial.

[0059] As used herein, the term "agent" refers to an anti-factor XI / XIa antibody described herein, such as antibody 1 disclosed in Table 1, and excipients, such as histidine buffer, sugars, and polysorbates.

[0060] The term "about" refers to any minimal change in concentration or amount of an agent that does not alter the effectiveness of the agent in preparing a formulation and in treating a disease or disorder. In certain embodiments, the term "about" can encompass ±5%, ±10%, or ±15% of a specified numerical value or data point.

[0061] Ranges may be expressed in this disclosure as "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes from one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations by use of the antecedent "about," it is understood that the particular value forms another embodiment. It is further understood that the endpoints for each of the ranges are meant both in relation to the other endpoint and independently of the other endpoint. It is also understood that a number of values ​​are disclosed in this disclosure, and that each value is also disclosed as "about" that particular value, in addition to the value itself. It is also understood that throughout this application, data is presented in a number of different formats, and that this data represents a range of endpoints and starting points, and any combination of data points. For example, if a particular data point "10" and a particular data point "15" are disclosed, it is understood that not only between 10 and 15, but also greater than or equal to 10 and 15, less than 10 and 15, less than or equal to 10 and 15, and equal to 10 and 15 are considered to be disclosed. It is also understood that each unit between two particular units is disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0062] Throughout this description, where compositions are described as having, comprising, or consisting of particular components, or where processes and methods are described as having, comprising, or consisting of particular steps, it is further intended that there are compositions of the invention that consist essentially of or consist of the recited components, and that there are processes and methods according to the invention that consist essentially of or consist of the recited process steps.

[0063] As a general matter, compositions in which percentages are specified are percentages by weight unless otherwise specified. Further, if no definition is associated with a variable, the preceding definition for that variable is governed. Anti-factor XI and / or activated factor XI (factor XIa) antibodies

[0064] In some embodiments, the disclosure provides a pharmaceutical formulation comprising an antibody that binds to FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa), the antibody comprising a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, the formulation comprising a histidine buffer; a sugar or sugar alcohol; and a polysorbate, and wherein the pH of the formulation is pH 5.0-6.0. In certain embodiments, the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 29.

[0065] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising an antibody or antigen-binding fragment thereof that binds to FXI and / or FXIa protein, the pharmaceutical formulation being contained in a vial, the pharmaceutical formulation comprising an overfill volume in the vial such that the formulation can fully extract a therapeutically effective amount of anti-FXI and / or anti-FXIa antibody or antigen-binding fragment thereof. In certain embodiments, the vial contains a pharmaceutical formulation comprising about 150 mg of an antibody that binds to FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa) and has a heavy chain variable domain (VH) having an amino acid sequence of SEQ ID NO: 9 or 29; a histidine buffer at a concentration of about 20 mM; sucrose at a concentration of about 220 mM; and polysorbate 20 at a concentration of about 0.04% (v / v), the pH of the formulation being about pH 5.5.

[0066] In several embodiments, the present disclosure provides an intravenous delivery pharmaceutical formulation comprising about 1.5 mg of an antibody or antigen-binding fragment thereof that binds to a FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa), the antibody or antigen-binding fragment having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29; a histidine buffer at a concentration of about 0.20 mM; sucrose at a concentration of about 2.20 mM; polysorbate 20 at a concentration of about 0.0004% (v / v); and a diluent (e.g., 5% dextrose in water (D5W)), wherein the pH of the formulation is about pH 5.5.

[0067] The present disclosure also provides a pharmaceutical formulation of an antibody that specifically binds to FXI and / or FXIa protein, the antibody comprising a VH CDR having any one of the amino acid sequences of the VH CDRs listed in Table 1 below, the pharmaceutical formulation comprising a histidine buffer; a sugar or sugar alcohol; and a polysorbate, and the pH of the formulation is between pH 5.0 and 6.0. In particular, the disclosure provides a pharmaceutical formulation of an antibody that specifically binds to FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa), the antibody comprising (or consisting of) one, two, three or more VH CDRs having the amino acid sequence of any of the VH CDRs listed in Table 1 below, comprising a histidine buffer; a sugar or sugar alcohol; and a polysorbate, wherein the pH of the formulation is pH 5.0-6.0 (see PCT International Patent Application No. PCT / IB2016 / 053790, filed June 24, 2016, published as WO2016 / 207858, which is incorporated herein by reference in its entirety).

[0068] In some embodiments, the disclosure provides a pharmaceutical formulation of an antibody that specifically binds to a FXI / FXIa protein, the antibody comprising a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39, for use in a method described herein (e.g., a method for treating a subject suffering from or at risk of developing a thromboembolic disorder), the formulation comprising a histidine buffer; a sugar or sugar alcohol; and a polysorbate, wherein the pH of the formulation is pH 5.0-6.0. In certain embodiments, the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 39.

[0069] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising an antibody or antigen-binding fragment thereof that binds to FXI and / or FXIa protein, the pharmaceutical formulation being contained in a vial, the pharmaceutical formulation comprising an overfill volume in the vial such that the formulation can fully extract a therapeutically effective amount of anti-FXI and / or anti-FXIa antibody or antigen-binding fragment thereof. In certain embodiments, the vial contains a pharmaceutical formulation comprising about 150 mg of an antibody that binds to FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa) and has a light chain variable domain (VL) having an amino acid sequence of SEQ ID NO: 19 or 39; a histidine buffer at a concentration of about 20 mM; sucrose at a concentration of about 220 mM; and polysorbate 20 at a concentration of about 0.04% (v / v), the pH of the formulation being about pH 5.5.

[0070] In several embodiments, the present disclosure provides an intravenous delivery pharmaceutical formulation comprising about 1.5 mg of an antibody or antigen-binding fragment thereof that binds to a FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa), and has a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39; a histidine buffer at a concentration of about 0.20 mM; sucrose at a concentration of about 2.20 mM; polysorbate 20 at a concentration of about 0.0004% (v / v); and a diluent (e.g., 5% dextrose in water (D5W)), wherein the pH of the formulation is about pH 5.5.

[0071] The disclosure also provides pharmaceutical formulations of antibodies that specifically bind to FXI and / or FXIa proteins (e.g., human, rabbit, cynomolgus, and baboon FXI and / or FXIa) for use in the methods described herein (e.g., methods for treating a subject suffering from or at risk of developing a thromboembolic disorder), the antibodies comprising a VL CDR having the amino acid sequence of any one of the VL CDRs listed in Table 1 below, the pharmaceutical formulations comprising a histidine buffer; a sugar or sugar alcohol; and a polysorbate, and the pH of the formulation is pH 5.0-6.0. Antibodies that specifically bind to FXIa proteins (e.g., human, rabbit, cynomolgus, and baboon FXI and / or FXIa) may comprise (or consist of) one, two, three, or more VL CDRs having the amino acid sequence of any one of the VL CDRs listed in Table 1 below.

[0072] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising an antibody or antigen-binding fragment thereof that binds to FXI and / or FXIa protein, the pharmaceutical formulation being contained in a vial, the pharmaceutical formulation comprising an overfill volume in the vial such that the formulation can fully extract a therapeutically effective amount of anti-FXI and / or anti-FXIa antibody or antigen-binding fragment thereof. In certain embodiments, the vial contains a pharmaceutical formulation comprising about 150 mg of an antibody that binds to FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa), the antibody having a heavy chain variable domain (VH) having an amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having an amino acid sequence of SEQ ID NO: 19 or 39; a histidine buffer at a concentration of about 20 mM; sucrose at a concentration of about 220 mM; and polysorbate 20 at a concentration of about 0.04% (v / v), the pH of the formulation being about pH 5.5.

[0073] In several embodiments, the disclosure provides an intravenous delivery pharmaceutical formulation comprising about 1.5 mg of an antibody or antigen-binding fragment thereof that binds to a FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa), the antibody or antigen-binding fragment having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39; a histidine buffer at a concentration of about 0.20 mM; sucrose at a concentration of about 2.20 mM; polysorbate 20 at a concentration of about 0.0004% (v / v); and a diluent (e.g., 5% dextrose in water (D5W)), wherein the pH of the formulation is about pH 5.5.

[0074] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising an antibody or antigen-binding fragment thereof that binds to FXI and / or FXIa protein, the pharmaceutical formulation being contained in a vial, the pharmaceutical formulation comprising an overfill volume in the vial such that the formulation can fully extract a therapeutically effective amount of anti-FXI and / or anti-FXIa antibody or antigen-binding fragment thereof. In certain embodiments, the vial contains a pharmaceutical formulation comprising about 150 mg of an antibody that binds to FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa), the antibody having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO:29 and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO:39; a histidine buffer at a concentration of about 20 mM; sucrose at a concentration of about 220 mM; and polysorbate 20 at a concentration of about 0.04% (v / v), the pH of the formulation being about pH 5.5.

[0075] In several embodiments, the disclosure provides an intravenous delivery pharmaceutical formulation comprising about 1.5 mg of an antibody or antigen-binding fragment thereof that binds to a FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa), the antibody or antigen-binding fragment having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 29, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 39; a histidine buffer at a concentration of about 0.20 mM; sucrose at a concentration of about 2.20 mM; polysorbate 20 at a concentration of about 0.0004% (v / v); and a diluent (e.g., 5% dextrose in water (D5W)), wherein the pH of the formulation is about pH 5.5.

[0076] In some embodiments, other antibodies for use in the methods described herein (e.g., methods for treating a subject suffering from or at risk of developing a thromboembolic disorder) comprise amino acids that are mutated but still have at least 60, 70, 80, 85, 90 or 95 percent CDR region identity to the CDR regions set forth in the sequences set forth in Table 1. In some embodiments, the antibodies comprise mutated amino acid sequences in which no more than one, no more than two, no more than three, no more than four or no more than five amino acids in the CDR regions are mutated compared to the CDR regions set forth in the sequences in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0077] In some embodiments, other antibodies for use in the methods or formulations described herein (e.g., methods for treating a subject suffering from or at risk of developing a thromboembolic disorder) include antibodies in which the amino acids or nucleic acids encoding the amino acids have been mutated but still have at least 60, 65, 70, 75, 80, 85, 90, or 95 percent identity to the sequences set forth in Table 1. Some embodiments include mutated amino acid sequences in which no more than one, no more than two, no more than three, no more than four, or no more than five amino acids in the variable regions have been mutated compared to the variable regions set forth in the sequences set forth in Table 1, while retaining substantially the same antigen binding activity.

[0078] Since each of these antibodies can bind to FXI and / or FXIa, the VH, VL, full-length light chain, and full-length heavy chain sequences (amino acid sequences and nucleotide sequences encoding the amino acid sequences) can be "mixed and matched" to create other FXI and / or FXIa binding antibodies of the present disclosure. Such "mixed and matched" FXI and / or FXIa binding antibodies can be tested using binding assays known in the art (e.g., ELISA and other assays described in the Examples section). When mixing and matching these chains, the VH sequence from a particular VH / VL pairing should be replaced with a structurally similar VH sequence. Similarly, the full-length heavy chain sequence from a particular full-length heavy chain / full-length light chain pairing should be replaced with a structurally similar full-length heavy chain sequence. Similarly, the VL sequence from a particular VH / VL pairing should be replaced with a structurally similar VL sequence. Similarly, the full-length light chain sequence from a particular full-length heavy chain / full-length light chain pairing should be replaced with a structurally similar full-length light chain sequence.

[0079] Thus, in one aspect, for use in the methods described herein (e.g., methods for treating a subject suffering from or at risk of developing a thromboembolic disorder), the disclosure provides an isolated antibody, or antigen-binding region thereof, having a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 and 29, and a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19 and 39, which specifically binds to FXI and / or FXIa (e.g., human, rabbit, cynomolgus monkey, and baboon FXIa). In another aspect, for use in the formulations described herein (e.g., vial formulations, intravenous drug delivery formulations), the disclosure provides an isolated antibody or antigen-binding region thereof having a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 and 29, and a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19 and 39, which specifically binds to FXI and / or FXIa (e.g., human, rabbit, cynomolgus monkey, and baboon FXIa).

[0080] More specifically, in certain aspects, the present disclosure provides an isolated antibody or antigen-binding fragment thereof having a heavy chain variable domain and a light chain variable domain comprising an amino acid sequence selected from SEQ ID NOs: 9 and 29; or 19 and 39, respectively.

[0081] In certain embodiments for use in the methods described herein (e.g., methods for treating a subject suffering from or at risk of developing a thromboembolic disorder), an antibody or antigen-binding fragment thereof presented herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:19. In certain embodiments for use in the formulations described herein (e.g., vial formulations, intravenous drug delivery formulations), an antibody or antigen-binding fragment thereof presented herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:19.

[0082] In certain embodiments for use in the methods described herein (e.g., methods for treating a subject suffering from or at risk of developing a thromboembolic disorder), an antibody or antigen-binding fragment thereof presented herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:29, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:39. In certain embodiments for use in the formulations described herein (e.g., vial formulations, intravenous drug delivery formulations), an antibody or antigen-binding fragment thereof presented herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:29, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:39.

[0083] In another aspect for use in the methods described herein, the disclosure provides (i) an isolated antibody having a full-length heavy chain comprising an amino acid sequence optimized for expression in a mammalian cell selected from the group consisting of SEQ ID NO: 11 or 31, and a full-length light chain comprising an amino acid sequence optimized for expression in a mammalian cell selected from the group consisting of SEQ ID NO: 21 or 41; or (ii) a functional protein comprising an antigen-binding portion thereof. More specifically, in certain aspects, the disclosure provides an isolated antibody or antigen-binding region thereof having heavy and light chains comprising amino acid sequences selected from SEQ ID NO: 11 and 31; or 21 and 41, respectively. In another aspect, the disclosure provides (i) an isolated antibody having a full-length heavy chain comprising an amino acid sequence optimized for expression in a mammalian cell selected from the group consisting of SEQ ID NO: 11 or 31, and a full-length light chain comprising an amino acid sequence optimized for expression in a mammalian cell selected from the group consisting of SEQ ID NO: 21 or 41; or (ii) a functional protein comprising an antigen-binding portion thereof, for use in the formulations described herein. More specifically, in certain aspects, the disclosure provides an isolated antibody or antigen-binding region thereof having heavy and light chains comprising amino acid sequences selected from SEQ ID NOs: 11 and 31; or 21 and 41, respectively.

[0084] In certain embodiments for use in the methods described herein, an antibody or antigen-binding fragment thereof provided herein that specifically binds to human FXI and / or FXIa comprises 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. In certain embodiments, an antibody or antigen-binding fragment thereof provided herein that specifically binds to human FXI and / or FXIa for use in the formulations described herein comprises 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.

[0085] In certain embodiments for use in the methods described herein, an antibody or antigen-binding fragment thereof provided herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 31, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 41. In certain embodiments, an antibody or antigen-binding fragment thereof provided herein that specifically binds to human FXI and / or FXIa for use in the formulations described herein comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 31, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 41.

[0086] The terms "complementarity determining region" and "CDR" as used herein refer to the sequence of amino acids in an antibody variable region that confers antigen specificity and binding affinity. Generally, there are three CDRs (HCDR1, HCDR2, HCDR3) in each heavy chain variable region, and three CDRs (LCDR1, LCDR2, LCDR3) in each light chain variable region.

[0087] The exact amino acid sequence boundaries of a given CDR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (the "Kabat" numbering scheme), Al-Lazikani et al., (1997) JMB 273,927-948 (the "Chothia" numbering scheme), Lefranc et al., (2003) Dev. Comp. Immunol., 27, 55-77 (the "IMGT" numbering scheme), or a "combinatorial" system.

[0088] For example, under Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) of antibody 2 are numbered 31-35 (HCDR1), 50-66 (HCDR2), and 99-111 (HCDR3), and the CDR amino acid residues in the light chain variable domain (VL) are numbered 22-35 (LCDR1), 51-57 (LCDR2), and 90-100 (LCDR3). Under Chothia, the CDR amino acids in the VH are numbered 26-32 (HCDR1), 52-57 (HCDR2), and 99-111 (HCDR3), and the amino acid residues in the VL are numbered 25-33 (LCDR1), 51-53 (LCDR2), and 92-99 (LCDR3). By combining both Kabat and Chothia CDR definitions, the CDRs consist of amino acid residues 26-35 (HCDR1), 50-66 (HCDR2), and 99-111 (HCDR3) in human VH, and amino acid residues 22-35 (LCDR1), 51-57 (LCDR2), and 90-100 (LCDR3) in human VL. By combining both Kabat and Chothia CDR definitions, the "combined" CDRs consist of amino acid residues 26-35 (HCDR1), 50-66 (HCDR2), and 99-108 (HCDR3) in human VH, and amino acid residues 24-38 (LCDR1), 54-60 (LCDR2), and 93-101 (LCDR3) in human VL. As another example, under IMGT, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 26-33 (HCDR1), 51-58 (HCDR2), and 97-108 (HCDR3), and the CDR amino acid residues in the light chain variable domain (VL) are numbered 27-36 (LCDR1), 54-56 (LCDR2), and 93-101 (LCDR3). Table 1 provides exemplary Kabat, Chothia, combination, and IMGT HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 for anti-FXI / FXIa antibodies, such as antibody 2 and antibody 1. In another aspect, the disclosure provides FXIa-binding antibodies comprising the heavy and light chain CDR1, CDR2, and CDR3, or combinations thereof, set forth in Table 1.The amino acid sequences of the VH CDR1 of the antibody are shown in SEQ ID NOs: 3 and 23. The amino acid sequences of the VH CDR2 of the antibody are shown in SEQ ID NOs: 4 and 24. The amino acid sequences of the VH CDR3 of the antibody are shown in SEQ ID NOs: 5 and 25. The amino acid sequences of the VL CDR1 of the antibody are shown in SEQ ID NOs: 13 and 33. The amino acid sequences of the VL CDR2 of the antibody are shown in SEQ ID NOs: 14 and 34. The amino acid sequences of the VL CDR3 of the antibody are shown in SEQ ID NOs: 15 and 35. These CDR regions were delineated using the Kabat system.

[0089] Alternatively, when defined using the Chothia system (Al-Lazikani et al., (1997) JMB 273,927-948), the amino acid sequence of the VH CDR1 of the antibody is shown in SEQ ID NOs:6 and 26. The amino acid sequence of the VH CDR2 of the antibody is shown in SEQ ID NOs:7 and 27. The amino acid sequence of the VH CDR3 of the antibody is shown in SEQ ID NOs:8 and 28. The amino acid sequence of the VL CDR1 of the antibody is shown in SEQ ID NOs:16 and 36. The amino acid sequence of the VL CDR2 of the antibody is KNY. The amino acid sequence of the VL CDR3 of the antibody is shown in SEQ ID NOs:18 and 38.

[0090] Alternatively, when defined using the combinatorial system, the amino acid sequence of the VH CDR1 of the antibody is shown in SEQ ID NO: 46. The amino acid sequence of the VH CDR2 of the antibody is shown in SEQ ID NO: 4. The amino acid sequence of the VH CDR3 of the antibody is shown in SEQ ID NO: 5. The amino acid sequence of the VL CDR1 of the antibody is shown in SEQ ID NO: 33. The amino acid sequence of the VL CDR2 of the antibody is shown in SEQ ID NO: 14. The amino acid sequence of the VL CDR3 of the antibody is shown in SEQ ID NO: 15.

[0091] Alternatively, as defined using the IMGT numbering scheme, the amino acid sequence of the VH CDR1 of the antibody is set forth in SEQ ID NO: 43. The amino acid sequence of the VH CDR2 of the antibody is set forth in SEQ ID NO: 44. The amino acid sequence of the VH CDR3 of the antibody is set forth in SEQ ID NO: 45. The amino acid sequence of the VL CDR1 of the antibody is set forth in SEQ ID NO: 47. The amino acid sequence of the VL CDR2 of the antibody is KNY. The amino acid sequence of the VL CDR3 of the antibody is set forth in SEQ ID NO: 15.

[0092] Given that each of these antibodies can bind to FXI and / or FXIa, and that antigen-binding specificity is primarily provided by the CDR1, 2 and 3 regions, the VH CDR1, 2 and 3 sequences and the VL CDR1, 2 and 3 sequences can be "mixed and matched" (e.g., CDRs from different antibodies can be mixed and matched to create other FXI and / or FXIa binding molecules of the disclosure, but preferably each antibody contains VH CDR1, 2 and 3 and VL CDR1, 2 and 3). Such "mixed and matched" FXI and / or FXIa binding antibodies can be tested using binding assays known in the art and those described in the Examples (e.g., ELISA, SET, BIACORE™ assays). When mixing and matching VH CDR sequences, the CDR1, CDR2 and / or CDR3 sequences from a particular VH sequence should be replaced with a structurally similar CDR sequence(s). Similarly, when mixing and matching VL CDR sequences, the CDR1, CDR2 and / or CDR3 sequences from a particular VL sequence should be replaced with a structurally similar CDR sequence(s). It will be readily apparent to one of skill in the art that new VH and VL sequences can be created by replacing one or more VH and / or VL CDR region sequences with structurally similar sequences from the CDR sequences shown herein for the monoclonal antibodies of the present disclosure. In addition to the above, in one embodiment, the antigen-binding fragment of the antibody described herein can include VH CDR1, 2, and 3, or VL CDR1, 2, and 3, where the fragment binds to FXI and / or FXIa as a single variable domain. Note that the CDR sequences of Antibody 1 and Antibody 2 are identical.

[0093] In certain embodiments of the present disclosure, the antibody or antigen-binding fragment thereof may have the heavy and light chain sequences of the Fabs set forth in Table 1. More particularly, the antibody or antigen-binding fragment thereof may have the heavy and light chain sequences of Antibody 2 and Antibody 1.

[0094] In other embodiments of the disclosure, an antibody or antigen-binding fragment that specifically binds to FXI and / or FXIa comprises a heavy chain variable region CDR1, a heavy chain variable region CDR2, a heavy chain variable region CDR3, a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 as defined by Kabat and set forth in Table 1. In yet other embodiments of the disclosure, an antibody or antigen-binding fragment that specifically binds to FXI and / or FXIa comprises a heavy chain variable region CDR1, a heavy chain variable region CDR2, a heavy chain variable region CDR3, a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 as defined by Chothia and set forth in Table 1. In other embodiments, antibodies or antigen-binding fragments that specifically bind to FXI and / or FXIa comprise heavy chain variable region CDR1, heavy chain variable region CDR2, heavy chain variable region CDR3, light chain variable region CDR1, light chain variable region CDR2, and light chain variable region CDR3 as defined by the combinatorial system and set forth in Table 1. In yet other embodiments of the present disclosure, antibodies or antigen-binding fragments that specifically bind to FXI and / or FXIa comprise heavy chain variable region CDR1, heavy chain variable region CDR2, heavy chain variable region CDR3, light chain variable region CDR1, light chain variable region CDR2, and light chain variable region CDR3 as defined by IMGT and set forth in Table 1.

[0095] In certain embodiments for use in the methods described herein, the disclosure encompasses an antibody that specifically binds to FXI and / or FXIa, comprising a heavy chain variable region CDR1 of SEQ ID NO: 3; 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: 13; a light chain variable region CDR2 of SEQ ID NO: 14; and a light chain variable region CDR3 of SEQ ID NO: 15.

[0096] In certain embodiments, the disclosure encompasses an antibody that specifically binds to FXI and / or FXIa, comprising 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.

[0097] In certain embodiments, the disclosure encompasses an antibody that specifically binds to FXI and / or FXIa, comprising a heavy chain variable region CDR1 of SEQ ID NO: 6; a heavy chain variable region CDR2 of SEQ ID NO: 7; a heavy chain variable region CDR3 of SEQ ID NO: 8; a light chain variable region CDR1 of SEQ ID NO: 16; a light chain variable region CDR2 that is KNY; and a light chain variable region CDR3 of SEQ ID NO: 18.

[0098] In certain embodiments, the disclosure encompasses an antibody that specifically binds to FXI and / or FXIa, comprising 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 that is KNY; and a light chain variable region CDR3 of SEQ ID NO: 38.

[0099] In certain embodiments, provided herein is an antibody that specifically binds to FXI and / or FXIa, comprising 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 that is KNY, and a light chain variable region CDR3 of SEQ ID NO: 15.

[0100] In a particular embodiment, the present invention provides an antibody that specifically binds to FXI and / or FXIa, comprising 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.

[0101] In certain embodiments, the present disclosure encompasses antibodies or antigen-binding fragments that specifically bind FXI and / or FXIa, as set forth in Table 1. In certain embodiments for use in the methods described herein, the antibodies or antigen-binding fragments that bind FXI and / or FXIa are Antibody 2 and Antibody 1.

[0102] As used herein, a human antibody includes a heavy or light chain variable region or full-length heavy or light chain that is "the product of" or "derived from" a particular germline sequence if the variable region or full-length chain of the antibody is obtained from a system that uses human germline immunoglobulin genes. Such systems include immunizing a transgenic mouse carrying human immunoglobulin genes with the antigen of interest, or screening a phage-displayed human immunoglobulin gene library with the antigen of interest. A human antibody that is "the product of" or "derived from" a human germline immunoglobulin sequence can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequences of human germline immunoglobulins and selecting the human germline immunoglobulin sequence that is closest in sequence to the sequence of the human antibody (i.e., has the highest % identity).

[0103] A human antibody that is "the product of" or "derived from" a particular human germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence, for example, due to the deliberate introduction of naturally occurring somatic mutations or site-specific mutations. However, in the VH or VL framework regions, the selected human antibody will generally contain amino acid residues whose amino acid sequence is at least 90% identical to the amino acid sequence encoded by a human germline immunoglobulin gene, thereby identifying the human antibody as human when compared to the germline immunoglobulin amino acid sequence of another species (e.g., a mouse germline sequence). In certain cases, the human antibody may be at least 60%, 70%, 80%, 90%, or at least 95%, or even at least 96%, 97%, 98%, or 99% identical to the amino acid sequence encoded by a germline immunoglobulin gene.

[0104] In general, recombinant human antibodies show 10 or less amino acid differences from the amino acid sequence encoded by human germline immunoglobulin genes in the VH or VL framework regions. In certain cases, human antibodies may show 5 or less, or even 4 or less, 3 or less, 2 or less, or 1 or less amino acid differences from the amino acid sequence encoded by germline immunoglobulin genes. Examples of human germline immunoglobulin genes include, but are not limited to, the variable domain germline fragments described below, as well as DP47 and DPK9.

[0105] Homologous antibodies In yet other embodiments for use in the methods described herein (e.g., methods for treating a subject suffering from or at risk of developing a thromboembolic disorder), the present disclosure provides antibodies or antigen-binding fragments thereof comprising an amino acid sequence homologous to a sequence set forth in Table 1 (e.g., SEQ ID NOs: 29, 31, 39, or 41), which bind to FXI and / or FXIa proteins (e.g., human, rabbit, cynomolgus monkey, and baboon FXIa) and retain the desired functional properties of the antibodies set forth in Table 1, such as Antibody 2 and Antibody 1. In certain aspects, such homologous antibodies retain the CDR amino acid sequences set forth in Table 1 (e.g., Kabat CDRs, Chothia CDRs, IMGT CDRs, or combined CDRs).

[0106] For example, in some embodiments, the disclosure provides an isolated antibody or functional antigen-binding fragment thereof comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence that is at least 80%, at least 90%, or at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 and 29, and the light chain variable domain comprises an amino acid sequence that is at least 80%, at least 90%, or at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 19 and 39, and wherein the antibody specifically binds to FXI and / or FXIa (e.g., human, rabbit, cynomolgus monkey, and baboon FXIa). In one embodiment, the isolated antibody or functional antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence that is at least 80%, at least 90%, or at least 95% identical to the amino acid sequence of SEQ ID NO: 9, and the light chain variable domain comprises an amino acid sequence that is at least 80%, at least 90%, or at least 95% identical to the amino acid sequence of SEQ ID NO: 19, and the antibody specifically binds to FXI and / or FXIa (e.g., human, rabbit, cynomolgus monkey, and baboon FXIa). In one embodiment, the isolated antibody or functional antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence that is at least 80%, at least 90%, or at least 95% identical to the amino acid sequence of SEQ ID NO: 29, and the light chain variable domain comprises an amino acid sequence that is at least 80%, at least 90%, or at least 95% identical to the amino acid sequence of SEQ ID NO: 39, and the antibody specifically binds to FXI and / or FXIa (e.g., human, rabbit, cynomolgus monkey, and baboon FXIa). In certain aspects of the disclosure, the heavy and light chain sequences further comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences as defined by Kabat, e.g., SEQ ID NOs: 3, 4, 5, 13, 14, and 15, respectively.In certain other embodiments of the present disclosure, the heavy and light chain sequences further comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences defined by Chothia, e.g., SEQ ID NOs: 6, 7, 8, 16, KNY, and 18, respectively. In certain other embodiments, the heavy and light chain sequences further comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences defined by the combinatorial system, e.g., SEQ ID NOs: 46, 4, 5, 33, 14, and 15, respectively. In certain other embodiments, the heavy and light chain sequences further comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences defined by IMGT, e.g., SEQ ID NOs: 43, 44, 45, 47, KNY, and 15, respectively.

[0107] In other embodiments for use in the methods described herein, the VH and / or VL amino acid sequences can be 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to a sequence set forth in Table 1. In other embodiments for use in the formulations described herein, the VH and / or VL amino acid sequences can be 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to a sequence set forth in Table 1. In other embodiments, the VH and / or VL amino acid sequences can be identical except for amino acid substitutions at no more than one, no more than two, no more than three, no more than four or no more than five amino acid positions. Antibodies having VH and VL regions with high (i.e., 80% or greater) identity to the VH and VL regions of those set forth in Table 1 can be obtained by mutagenesis (e.g., site-directed or PCR-mediated mutagenesis) of nucleic acid molecules encoding SEQ ID NOs: 10 or 30 and SEQ ID NOs: 20 and 40, respectively, and then testing the encoded altered antibodies for retention of function using the functional assays described herein.

[0108] In other embodiments for use in the methods described herein, the full-length heavy and / or full-length light chain amino acid sequences can be 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to a sequence set forth in Table 1 (e.g., SEQ ID NOs: 11 and / or 21, or 31 and / or 41). In other embodiments for use in the formulations described herein, the full-length heavy and / or full-length light chain amino acid sequences can be 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to a sequence set forth in Table 1 (e.g., SEQ ID NOs: 11 and / or 21, or 31 and / or 41). Antibodies having full-length heavy chains and full-length light chains with high (e.g., 80% or greater) identity to the full-length heavy chain of either SEQ ID NO: 11 or 31, and the full-length light chain of either SEQ ID NO: 21 or 41 can be obtained by mutagenesis (e.g., site-directed or PCR-mediated mutagenesis) of a nucleic acid molecule encoding such a polypeptide, and then testing the encoded altered antibody for retention of function using the functional assays described herein.

[0109] In one aspect, the present invention provides an isolated antibody or functional antigen-binding fragment thereof comprising a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence that is at least 80%, at least 90%, or at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 11 and 31, and the light chain comprises an amino acid sequence that is at least 80%, at least 90%, or at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 21 and 41, and wherein the antibody specifically binds to FXI and / or FXIa (e.g., human, rabbit, cynomolgus monkey, and baboon FXIa). In one embodiment, the isolated antibody or functional antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence that is at least 80%, at least 90%, or at least 95% identical to the amino acid sequence of SEQ ID NO: 11, and the light chain comprises an amino acid sequence that is at least 80%, at least 90%, or at least 95% identical to the amino acid sequence of SEQ ID NO: 21, and the antibody specifically binds to FXI and / or FXIa (e.g., human, rabbit, cynomolgus monkey, and baboon FXIa). In one embodiment, the isolated antibody or functional antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence that is at least 80%, at least 90%, or at least 95% identical to the amino acid sequence of SEQ ID NO: 31, and the light chain comprises an amino acid sequence that is at least 80%, at least 90%, or at least 95% identical to the amino acid sequence of SEQ ID NO: 41, and the antibody specifically binds to FXI and / or FXIa (e.g., human, rabbit, cynomolgus monkey, and baboon FXIa). In certain embodiments of the disclosure, the heavy and light chain sequences further comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences as defined by Kabat, e.g., SEQ ID NOs: 3, 4, 5, 13, 14, and 15, respectively. In certain other embodiments of the disclosure, the heavy and light chain sequences further comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences as defined by Chothia, e.g., SEQ ID NOs: 6, 7, 8, 16, KNY, and 18, respectively.In certain other embodiments, the heavy and light chain sequences further comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences defined by the combinatorial system, e.g., SEQ ID NOs: 46, 4, 5, 33, 14, and 15, respectively. In certain other embodiments, the heavy and light chain sequences further comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences defined by IMGT, e.g., SEQ ID NOs: 43, 44, 45, 47, KNY, and 15, respectively.

[0110] In other embodiments for use in the methods described herein, the full length heavy chain and / or full length light chain nucleotide sequences can be 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to the sequences set forth in Table 1 (e.g., SEQ ID NOs: 12 and / or 22, or 32 and / or 42).

[0111] In other embodiments for use in the methods described herein, the nucleotide sequence of the heavy chain variable region and / or the light chain variable region can be 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to a sequence set forth in Table 1 (e.g., SEQ ID NOs: 10 and / or 20, or 30 and / or 40). In other embodiments for use in the formulations described herein, the heavy chain variable region and / or the light chain variable region nucleotide sequence can be 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to a sequence set forth in Table 1 (e.g., SEQ ID NOs: 10 and / or 20, or 30 and / or 40).

[0112] As used herein, the percent identity between two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps and the length of each gap that must be introduced to optimally align the two sequences (i.e., % identity equals the number of identical positions / total number of positions x 100). The comparison of sequences and determination of the percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the non-limiting examples below.

[0113] The isolated anti-FXI and / or FXIa antibodies or antigen-binding fragments thereof described herein may be monoclonal antibodies, human or humanized antibodies, chimeric antibodies, single chain antibodies, Fab fragments, Fv fragments, F(ab')2 fragments, or scFv fragments, and / or IgG isotypes (e.g., IgG1, such as human IgG1). In certain embodiments, the anti-FXI and / or anti-FXIa antibodies described herein are recombinant human antibodies. In certain embodiments, the anti-FXI and / or anti-FXIa antibodies described herein are human IgG1 / lambda (lambda) antibodies. In certain embodiments, the anti-FXI and / or anti-FXIa antibodies described herein are human IgG1 / lambda (lambda) antibodies that include an Fc domain engineered to reduce effector function (e.g., ADCC and / or CDC) potential, e.g., a human Fc domain that includes a D265A and / or P329A substitution.

[0114] Additionally or alternatively, a search of public databases can be performed, e.g., to identify related sequences, using the protein sequences of the present disclosure as a "query sequence." For example, such searches can be performed using the BLAST program (version 2.0) of Altschul, et al., 1990 J. Mol. Biol. 215: 403-10.

[0115] Antibodies with conservative modifications In certain other embodiments, an antibody of the disclosure for use in the methods described herein (e.g., methods for treating a subject suffering from or at risk of developing a thromboembolic disorder) has a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences, where one or more of these CDR sequences have a particular amino acid sequence based on an antibody described herein or a conservative modification thereof, and the antibody retains the desired functional properties of a FXIa-binding antibody of the disclosure. In certain other embodiments, an antibody of the disclosure for use in the formulations described herein (e.g., vial formulations, intravenous drug delivery formulations) has a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences, where one or more of these CDR sequences have a particular amino acid sequence based on an antibody described herein or a conservative modification thereof, and the antibody retains the desired functional properties of a FXIa-binding antibody of the disclosure.

[0116] Thus, for use in the methods described herein, in some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof consisting of a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences, wherein the heavy chain variable region CDR1 amino acid sequence is selected from the group consisting of SEQ ID NOs: 3 and 23, and conservative modifications thereof, the heavy chain variable region CDR2 amino acid sequence is selected from the group consisting of SEQ ID NOs: 4 and 24, and conservative modifications thereof, and the heavy chain variable region CDR3 amino acid sequence is selected from the group consisting of SEQ ID NOs: 5 and 6, and conservative modifications thereof. is selected from the group consisting of SEQ ID NO:5 and 25, and conservative modifications thereof; the light chain variable region CDR1 amino acid sequence is selected from the group consisting of SEQ ID NO:13 and 33, and conservative modifications thereof; the light chain variable region CDR2 amino acid sequence is selected from the group consisting of SEQ ID NO:14 and 34, and conservative modifications thereof; and the light chain variable region CDR3 amino acid sequence is selected from the group consisting of SEQ ID NO:15 and 35, and conservative modifications thereof; and the antibody or antigen-binding fragment thereof specifically binds to FXIa.

[0117] For use in the formulations described herein, in some embodiments, the disclosure provides an isolated antibody or antigen-binding fragment thereof consisting of a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences, wherein the heavy chain variable region CDR1 amino acid sequence is selected from the group consisting of SEQ ID NO: 3 and 23, and conservative modifications thereof, the heavy chain variable region CDR2 amino acid sequence is selected from the group consisting of SEQ ID NO: 4 and 24, and conservative modifications thereof, and the heavy chain variable region CDR3 amino acid sequence is selected from the group consisting of SEQ ID NO: 5 and 6, and conservative modifications thereof, The present invention provides an isolated antibody or antigen-binding fragment thereof, wherein the light chain variable region CDR1 amino acid sequence is selected from the group consisting of SEQ ID NOs: 13 and 33 and conservative modifications thereof, the light chain variable region CDR2 amino acid sequence is selected from the group consisting of SEQ ID NOs: 14 and 34 and conservative modifications thereof, and the light chain variable region CDR3 amino acid sequence is selected from the group consisting of SEQ ID NOs: 15 and 35 and conservative modifications thereof, and the antibody or antigen-binding fragment thereof specifically binds to FXIa.

[0118] In one aspect, the present invention provides an isolated antibody or antigen-binding fragment thereof consisting of a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences, wherein the heavy chain variable region CDR1 amino acid sequence is selected from the group consisting of those listed in Table 1 and conservative modifications thereof, the heavy chain variable region CDR2 amino acid sequence is selected from the group consisting of those listed in Table 1 and conservative modifications thereof, the heavy chain variable region CDR3 amino acid sequence is selected from the group consisting of those listed in Table 1 and conservative modifications thereof, the light chain variable region CDR1 amino acid sequence is selected from the group consisting of those listed in Table 1 and conservative modifications thereof, the light chain variable region CDR2 amino acid sequence is selected from the group consisting of those listed in Table 1 and conservative modifications thereof, and the light chain variable region CDR3 amino acid sequence is selected from the group consisting of those listed in Table 1 and conservative modifications thereof, and the antibody or antigen-binding fragment thereof specifically binds to FXIa.

[0119] In other embodiments for use in the methods described herein, the antibodies of the disclosure are optimized for expression in mammalian cells and have full-length heavy and light chain sequences, where one or more of these sequences have a particular amino acid sequence based on an antibody described herein or a conservative modification thereof, and the antibody retains the desired functional properties of the FXIa-binding antibodies of the disclosure. In other embodiments for use in the formulations described herein, the antibodies of the disclosure are optimized for expression in mammalian cells and have full-length heavy and light chain sequences, where one or more of these sequences have a particular amino acid sequence based on an antibody described herein or a conservative modification thereof, and the antibody retains the desired functional properties of the FXIa-binding antibodies of the disclosure. Thus, the present disclosure provides an isolated antibody consisting of a full-length heavy chain and a full-length light chain optimized for expression in a mammalian cell, wherein the full-length heavy chain has an amino acid sequence selected from the group of SEQ ID NO: 11 or 31, and conservative modifications thereof, and the full-length light chain has an amino acid sequence selected from the group of SEQ ID NO: 21 or 41, and conservative modifications thereof, and wherein the antibody specifically binds to FXI and / or FXIa (e.g., human, rabbit, cynomolgus monkey, and baboon FXIa).

[0120] Antibodies that bind to the same epitope In some embodiments, the present disclosure provides antibodies that compete for the same epitope as the FXI and / or FXIa binding antibodies described in Table 1 for use in the methods described herein (e.g., methods for treating a subject suffering from or at risk of developing a thromboembolic disorder). In some embodiments, the present disclosure provides antibodies that compete for the same epitope as the FXI and / or FXIa binding antibodies described in Table 1 for use in the formulations described herein (e.g., vial formulations, intravenous drug delivery formulations). Accordingly, additional antibodies can be identified based on their ability to compete (e.g., competitively inhibit binding, in a statistically significant manner, by binding to the same or overlapping epitope) with other antibodies of the disclosure in FXI and / or FXIa binding assays (such as those described in the Examples section). The ability of the test antibody to inhibit the antibody of the present disclosure from binding to FXI and / or FXIa protein demonstrates that the test antibody can compete with that antibody for binding to FXI and / or FXIa; such an antibody may bind to the same or related (e.g., structurally similar or spatially proximal) epitope on FXI and / or FXIa protein as the antibody it competes with, according to non-limiting theory. In certain embodiments, the antibody that binds to the same epitope on FXI and / or FXIa as the antibody of the present disclosure is a human monoclonal antibody. Such a human monoclonal antibody can be prepared and isolated as described herein.

[0121] As used herein, an antibody "competes" for binding if the competing antibody binds to the same FXI and / or FXIa epitope as an antibody or antigen-binding fragment of the disclosure (e.g., antibody 1 or antibody 2) when present at equimolar concentrations and inhibits binding of an antibody or antigen-binding fragment of the disclosure to FXI and / or FXIa by greater than 50% (e.g., 80%, 85%, 90%, 95%, 98% or 99%). This can be determined by any of the methods well known to those of skill in the art, for example, in a competitive binding assay.

[0122] As used herein, an antibody or antigen-binding fragment thereof does not "compete" with a FXI and / or FXIa antibody or antigen-binding fragment of the present disclosure (e.g., Antibody 1 or Antibody 2) unless the competing antibody or antigen-binding fragment thereof binds to the same FXI and / or FXIa epitope as an antibody or antigen-binding fragment of the present disclosure, or to an overlapping FXI and / or FXIa epitope. As used herein, a competing antibody or antigen-binding fragment thereof does not include (i) one that sterically blocks the binding of an antibody or antigen-binding fragment of the present disclosure to its target (e.g., where the competing antibody binds to a nearby, non-overlapping FXI and / or FXIa epitope and physically prevents the binding of an antibody or antigen-binding fragment of the present disclosure to its target); and / or (ii) one that binds to a different, non-overlapping FXI and / or FXIa epitope and induces a conformational change in the FXI and / or FXIa protein such that the FXI and / or FXIa antibody or antigen-binding fragment of the present disclosure can no longer bind to the protein as would occur in the absence of said conformational change.

[0123] Engineered and Modified Antibodies In some embodiments, the antibodies of the present disclosure for use in the methods described herein can be further prepared using an antibody having one or more of the VH and / or VL sequences shown herein as starting materials for engineering modified antibodies, where the modified antibodies can have altered properties from the starting antibody. In some embodiments, the antibodies of the present disclosure for use in the formulations described herein can be further prepared using an antibody having one or more of the VH and / or VL sequences shown herein as starting materials for engineering modified antibodies, where the modified antibodies can have altered properties from the starting antibody. The antibodies can be engineered by modifying one or more residues within one or both of the variable regions (i.e., VH and / or VL), e.g., within one or more CDR regions and / or within one or more framework regions. Additionally or alternatively, the antibodies can be engineered by modifying residues within the constant region(s), e.g., to alter the effector function(s) of the antibody.

[0124] One type of variable region engineering that can be performed is CDR grafting. Antibodies predominantly interact with target antigens through amino acid residues located in the six heavy and light chain complementarity determining regions (CDRs). For this reason, the amino acid sequences within the CDRs are more diverse between individual antibodies than sequences outside the CDRs. Because CDR sequences are involved in the majority of antibody-antigen interactions, it is possible to express recombinant antibodies that mimic the properties of a particular naturally occurring antibody by constructing expression vectors that contain the CDR sequences of that particular naturally occurring antibody grafted onto framework sequences from a different antibody with different properties (see, e.g., Riechmann, L. et al., 1998 Nature 332: 323-327; Jones, P. et al., 1986 Nature 321: 522-525; Queen, C. et al., 1989 Proc. Natl. Acad., USA 86: 10029-10033; U.S. Pat. No. 5,225,539 to Winter, and U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and 6,180,370 to Queen et al.).

[0125] Thus, another embodiment of the present disclosure relates to an isolated antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising an amino acid sequence CDR1 sequence selected from the group consisting of SEQ ID NOs: 3 and 23, an amino acid sequence CDR2 sequence selected from the group consisting of SEQ ID NOs: 4 and 24, an amino acid sequence CDR3 sequence selected from the group consisting of SEQ ID NOs: 5 and 25, and a light chain variable region having an amino acid sequence CDR1 sequence selected from the group consisting of SEQ ID NOs: 13 and 33, an amino acid sequence CDR2 sequence selected from the group consisting of SEQ ID NOs: 14 and 34, and a CDR3 sequence consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 and 35. Thus, such antibodies contain the VH and VL CDR sequences of monoclonal antibodies, but may nevertheless contain framework sequences that differ from these antibodies.

[0126] Such framework sequences can be obtained from public DNA databases or published references that contain germline antibody gene sequences. For example, germline DNA sequences of human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database, as well as Kabat, EA, et al., 1991 Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242; Tomlinson, IM, et al., 1992 J. Mol. Biol. 227: 776-798; and Cox, JPL et al., 1994 Eur. J Immunol. 24: 827-836, the contents of each of which are expressly incorporated herein by reference.

[0127] The example of framework sequence for use in the antibody of the present disclosure is structurally similar to the framework sequence used by the selected antibody of the present disclosure, for example, the consensus sequence and / or framework sequence used by the monoclonal antibody of the present disclosure.VH CDR1, 2 and 3 sequences and VL CDR1, 2 and 3 sequences can be grafted to framework regions with the same sequence found in the germline immunoglobulin gene from which the framework sequence is derived, or CDR sequences can be grafted to framework regions that contain one or more mutations compared to the germline sequence.For example, it has been found that in certain cases, it is beneficial to mutate the residues in framework regions so that the antigen binding ability of antibody is maintained or enhanced (see, for example, U.S. Patent Nos. 5,530,101; 5,585,089; 5,693,762 and 6,180,370 to Queen et al.). Frameworks that can be utilized as scaffolds to construct the antibodies and antigen-binding fragments described herein include, but are not limited to, VH1A, VH1B, VH3, Vk1, Vl2, and Vk2.

[0128] Thus, another embodiment of the present disclosure, for use in the methods described herein, relates to an isolated FXIa-binding antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 and 29, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions within the framework regions of such a sequence, and further comprising a light chain variable region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 19 and 39, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions within the framework regions of such a sequence.

[0129] Thus, another embodiment of the present disclosure, for use in the formulations described herein, relates to an isolated FXIa-binding antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 and 29, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions within the framework regions of such a sequence, and further comprising a light chain variable region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 19 and 39, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions within the framework regions of such a sequence.

[0130] Another type of variable region modification is to mutate amino acid residues in the VH and / or VL CDR1, CDR2 and / or CDR3 regions to thereby improve one or more binding properties (e.g., affinity) of the antibody of interest, which is known as "affinity maturation". Site-directed mutagenesis or PCR-mediated mutagenesis can be performed to introduce the mutation(s), and the effect on antibody binding or other functional properties of interest can be evaluated in in vitro or in vivo assays described herein and presented in the Examples section. Conservative modifications (as described above) can be introduced. Mutations can be amino acid substitutions, additions or deletions. Moreover, generally, no more than one, no more than two, no more than three, no more than four or no more than five residues in the CDR regions are changed.

[0131] Thus, in another embodiment for use in the methods described herein, the disclosure provides a heavy chain variable region having a VH CDR1 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 3 and 23, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 3 and 23; a VH CDR2 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 4 and 24, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 4 and 24; a VH CDR3 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5 and 25, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 5 and 25; a VL CDR4 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 13 and 33, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 13 and 33; The present invention provides an isolated FXIa-binding antibody or antigen-binding fragment thereof, comprising: a CDR1 region; a VL CDR2 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 14 and 34, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 14 and 34; and a VL CDR3 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 and 35, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 15 and 35.

[0132] Thus, in another embodiment for use in the methods described herein, the disclosure provides a heavy chain variable region having a VH CDR1 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 6 and 26, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 6 and 26; a VH CDR2 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 7 and 27, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 7 and 27; a VH CDR3 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 8 and 28, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 8 and 28; a VL CDR4 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 16 and 36, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 16 and 36; The present invention provides an isolated FXIa-binding antibody or antigen-binding fragment thereof, comprising: a CDR1 region; a VL CDR2 region having an amino acid sequence of KNY or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to KNY; and a VL CDR3 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 18 and 38 or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 18 and 38.

[0133] Thus, in another embodiment for use in the formulations described herein, the disclosure provides a heavy chain variable region having a VH CDR1 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 3 and 23, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 3 and 23; a VH CDR2 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 4 and 24, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 4 and 24; a VH CDR3 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 5 and 25, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 5 and 25; a VL CDR4 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 13 and 33, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 13 and 33; The present invention provides an isolated FXIa-binding antibody or antigen-binding fragment thereof, comprising: a CDR1 region; a VL CDR2 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 14 and 34, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 14 and 34; and a VL CDR3 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 15 and 35, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 15 and 35.

[0134] Thus, in another embodiment for use in the formulations described herein, the disclosure provides a heavy chain variable region having a VH CDR1 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 6 and 26, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 6 and 26; a VH CDR2 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 7 and 27, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 7 and 27; a VH CDR3 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 8 and 28, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 8 and 28; a VL CDR4 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 16 and 36, or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 16 and 36; The present invention provides an isolated FXIa-binding antibody or antigen-binding fragment thereof, comprising: a CDR1 region; a VL CDR2 region having an amino acid sequence of KNY or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to KNY; and a VL CDR3 region having an amino acid sequence selected from the group consisting of SEQ ID NOs: 18 and 38 or an amino acid sequence having one, two, three, four or five amino acid substitutions, deletions or additions compared to SEQ ID NOs: 18 and 38.

[0135] Antibodies with extended half-lives In some embodiments, the disclosure provides antibodies that specifically bind to FXIa proteins with extended in vivo half-life for use in the methods or formulations described herein.

[0136] Many factors can affect the half-life of a protein in vivo, such as kidney filtration, metabolism in the liver, degradation by proteolytic enzymes (proteases), and immunogenic responses (e.g., protein neutralization by antibodies and uptake by macrophages and dendritic cells). Various strategies can be used to extend the half-life of the antibodies of the present disclosure, such as by chemical linkage with polyethylene glycol (PEG), reCODE PEG, antibody scaffolds, polysialic acid (PSA), hydroxyethyl starch (HES), albumin binding ligands, and carbohydrate shields; by genetic fusion and transfer with proteins that bind serum proteins such as albumin, IgG, FcRn; by coupling (genetically or chemically) with other binding moieties that bind serum proteins, such as nanobodies, Fabs, DARPins, avimers, affibodies, and anticalins; by genetic fusion with rPEG, albumin, domains of albumin, albumin binding proteins, and Fc; or by incorporation into nanocarriers, slow release formulations, or medical devices.

[0137] To prolong the in vivo serum circulation of antibodies, inert polymer molecules such as high molecular weight PEG can be attached to antibodies or fragments thereof, either through site-specific conjugation of PEG to the N-terminus or C-terminus of the antibody, with or without a multifunctional linker, or via epsilon amino groups present on lysine residues. To pegylate an antibody, the antibody or fragment thereof is generally reacted with polyethylene glycol (PEG), such as a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups are attached to the antibody or antibody fragment. PEGylation can be carried out by an acylation reaction or an alkylation reaction with a reactive PEG molecule (or a similar reactive water-soluble polymer). As used herein, the term "polyethylene glycol" is intended to encompass any form of PEG that has been used to derivatize other proteins, such as mono (C1-C10) alkoxy- or aryloxy-polyethylene glycol or polyethylene glycol-maleimide. In certain embodiments, the antibody to be pegylated is a non-glycosylated antibody. Linear or branched polymer derivatization that results in minimal loss of biological activity is used. Conjugation can be closely monitored by SDS-PAGE and mass spectrometry to ensure proper conjugation of PEG molecules to the antibody. Unreacted PEG can be separated from the antibody-PEG conjugate by size exclusion or ion exchange chromatography. PEG-derivatized antibodies can be tested for binding activity and in vivo efficacy using methods well known to those skilled in the art, for example, by immunoassays described herein. Methods for PEGylating proteins are known in the art and can be applied to the antibodies of the present disclosure. See, for example, EP 0 154 316 by Nishimura et al. and EP 0 401 384 by Ishikawa et al.

[0138] Other modified PEGylation technologies include Recoded Chemical Orthogonal Directed Engineering Technology (ReCODE PEG), which incorporates chemically specified side chains into biosynthetic proteins via a reconstituted system containing tRNA synthetase and tRNA. This technology allows the incorporation of more than 30 new amino acids into biosynthetic proteins in E. coli, yeast, and mammalian cells. The non-native amino acid is incorporated by the tRNA wherever an amber codon is located, and the amber is converted from a stop codon to a codon that signals the incorporation of the chemically specified amino acid.

[0139] Recombinant PEGylation technology (rPEG) can also be used to extend serum half-life. This technology involves genetic fusion of an unstructured protein tail of 300-600 amino acids to an existing pharmaceutical protein. Since the apparent molecular weight of such an unstructured protein chain is about 15 times its actual molecular weight, the serum half-life of the protein is significantly increased. In contrast to conventional PEGylation, which requires chemical conjugation and repurification, the manufacturing process is significantly simplified and the product is homogeneous.

[0140] Another technique is polysialylation, which uses the natural polymer polysialic acid (PSA) to extend the active life and improve the stability of therapeutic peptides and proteins. PSA is a polymer of sialic acid (sugar). When used for protein and therapeutic peptide drug delivery, polysialic acid provides a protective microenvironment for conjugation. This increases the active life of the therapeutic protein in circulation and also prevents the therapeutic protein from being recognized by the immune system. PSA polymers are found naturally in the human body. They were utilized by certain bacteria that evolved over millions of years to coat their walls. As a result, these naturally polysialylated bacteria were able to foil the body's defense system through molecular mimicry. PSA, the ultimate stealth technology of nature, can be easily produced by such bacteria in large quantities and with defined physical characteristics. Bacterial PSA is chemically identical to PSA in the human body and is therefore completely non-immunogenic even when coupled to proteins.

[0141] Another technique involves the use of hydroxyethyl starch ("HES") derivatives linked to antibodies. HES is a modified natural polymer derived from waxy corn starch and can be metabolized by the body's enzymes. HES solutions are usually administered to replenish deficient blood volume and improve blood hydrodynamic properties. HESylation of antibodies allows for increased circulation half-life by increasing the stability of the molecule as well as by reducing renal clearance, resulting in increased biological activity. A wide range of HES antibody conjugates can be customized by varying various parameters such as the molecular weight of HES.

[0142] Antibodies with increased in vivo half-lives can also be generated by introducing one or more amino acid modifications (i.e., substitutions, insertions, or deletions) into an IgG constant domain or an FcRn-binding fragment thereof (preferably an Fc or hinge-Fc domain fragment). See, e.g., International Publication Nos. WO 98 / 23289; WO 97 / 34631; and U.S. Patent No. 6,277,375.

[0143] Furthermore, antibody can be conjugated with albumin (e.g., human serum albumin; HSA) to make the antibody or antibody fragment more stable in vivo or longer half-life in vivo.This technique is well known in the art.See, for example, International Patent Publication Nos. WO93 / 15199, WO93 / 15200 and WO01 / 77137; and European Patent Publication No. EP 413,622.Furthermore, for the above bispecific antibody, the specificity of antibody can be designed such that one binding domain of antibody binds to FXIa, while the second binding domain of antibody binds to serum albumin, preferably HSA.

[0144] Strategies for increasing half-life are particularly useful for nanobodies, fibronectin-based binding agents, and other antibodies or proteins for which increased half-life in vivo is desired.

[0145] Antibody conjugates In some embodiments, the present disclosure provides an antibody or fragment thereof that specifically binds to FXIa protein for use in the methods or formulations described herein, recombinantly fused or chemically conjugated (including both covalent and non-covalent conjugation) to a heterologous protein or polypeptide (or a fragment thereof, preferably a polypeptide of at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90 or at least 100 amino acids) to generate a fusion protein. In particular, the present disclosure provides a fusion protein comprising an antigen-binding fragment of an antibody described herein (e.g., a Fab fragment, an Fd fragment, an Fv fragment, an F(ab)2 fragment, a VH domain, a VH CDR, a VL domain or a VL CDR) and a heterologous protein, polypeptide or peptide. Methods for fusing or conjugating a protein, polypeptide or peptide to an antibody or antibody fragment are known in the art. See, e.g., U.S. Pat. Nos. 5,336,603, 5,622,929, 5,359,046, 5,349,053, 5,447,851, and 5,112,946; European Patent Nos. EP 307,434 and EP 367,166; International Publication Nos. WO 96 / 04388 and WO 91 / 06570; Ashkenazi et al., 1991, Proc. Natl. Acad. Sci. USA 88: 10535-10539; Zheng et al., 1995, J. Immunol. 154: 5590-5600; and Vil et al., 1992, Proc. Natl. Acad. Sci. USA 89: Please see 11337-11341.

[0146] Additional fusion proteins can be generated by the techniques of gene shuffling, motif shuffling, exon shuffling, and / or codon shuffling (collectively referred to as "DNA shuffling"). DNA shuffling can be used to alter the activity of an antibody or fragment thereof of the present disclosure (e.g., an antibody or fragment thereof with higher affinity and slower off-rates). See generally U.S. Patent Nos. 5,605,793, 5,811,238, 5,830,721, 5,834,252, and 5,837,458; Patten et al., 1997, Curr. Opinion Biotechnol. 8: 724-33; Harayama, 1998, Trends Biotechnol. 16 (2): 76-82; Hansson, et al., 1999, J. Mol. Biol. 287: 265-76; and Lorenzo and Blasco, 1998, Biotechniques 24 (2): 308-313, each of which is hereby incorporated by reference in its entirety. The antibody or fragment thereof, or the encoded antibody or fragment thereof, can be altered by subjecting it to random mutagenesis by error-prone PCR, random nucleotide insertion or other methods prior to recombination. A polynucleotide encoding an antibody or fragment thereof that specifically binds to an FXIa protein can be recombined with one or more components, motifs, segments, portions, domains, fragments, etc., of one or more heterologous molecules.

[0147] Furthermore, the antibody or fragment thereof can be fused to a marker sequence, such as a peptide, to facilitate purification. In certain embodiments, the marker amino acid sequence is a hexa-histidine peptide (SEQ ID NO: 48), such as the tag provided in the pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, CA, 91311), among others, many of which are commercially available. For example, hexa-histidine (SEQ ID NO: 48) provides convenient purification of the fusion protein, as described in Gentz ​​et al., 1989, Proc. Natl. Acad. Sci. USA 86: 821-824. Other peptide tags useful for purification include, but are not limited to, the hemagglutinin ("HA") tag, which corresponds to an epitope derived from the influenza hemagglutinin protein (Wilson et al., 1984, Cell 37: 767), and the "flag" tag.

[0148] In other embodiments, the antibodies or fragments thereof of the present disclosure are conjugated to a diagnostic or detectable agent. Such antibodies may be useful for monitoring or prognosing the onset, development, progression and / or severity of a disease or disorder, for example, as part of a clinical trial procedure, such as determining the efficacy of a particular treatment. Such diagnosis and detection may involve the use of antibodies, including but not limited to, various enzymes, such as, but not limited to, horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; prosthetic groups, such as, but not limited to, streptavidin / biotin and avidin / biotin; fluorescent materials, such as, but not limited to, umbelliferone, fluorescein, fluorescein isothiocynate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, or phycoerythrin; luminescent materials, such as, but not limited to, luminol; bioluminescent materials, such as, but not limited to, luciferase, luciferin, and aequorin; radioactive materials, such as, but not limited to, iodine ( 131 I, 125 I, 123 I, and 121 I), Carbon ( 14 C), sulfur ( 35 S), tritium ( 3 H), Indium ( 115 In, 113 In, 112 In, and 111 In), Technetium ( 99 Tc), thallium ( 201 Ti), Gallium ( 68 Ga, 67 Ga), palladium ( 103 Pd), Molybdenum ( 99 Mo), Xenon ( 133 Xe), fluorine ( 18 F), 153 Sm, 177 Lu, 159 Gd, 149 Pm, 140 La,175 Yb, 166 Ho, 90 Y, 47 Sc, 186 Re, 188 Re, 142 Pr, 105 Rh, 97 Ru, 68 Ge, 57 Co, 65 Zn, 85 Sr, 32 P, 153 Gd, 169 Yb, 51 Cr, 54 Mn, 75 Se, 113 Sn, and 117 This can be achieved by coupling to a detectable substance, including positron-emitting metals used in various positron emission tomography methods, and non-radioactive paramagnetic metal ions.

[0149] In some embodiments, the present disclosure further encompasses the use of antibodies or fragments thereof conjugated to therapeutic moieties.Antibodies or fragments thereof can be conjugated to therapeutic moieties, such as cytotoxins, e.g., cytostatic or cytocidal agents, therapeutic agents or radioactive metal ions, e.g., alpha emitters.Cytotoxins or cytotoxic agents include any agent that is harmful to cells.

[0150] Furthermore, the antibody or fragment thereof can be conjugated with a therapeutic or drug moiety that modifies a given biological response. The therapeutic or drug moiety is not intended to be limited to classical chemical therapeutic agents. For example, the drug moiety can be a protein, peptide, or polypeptide with a desired biological activity. Such proteins can include, for example, toxins such as abrin, ricin A, pseudomonas exotoxin, cholera toxin, or diphtheria toxin; proteins such as tumor necrosis factor, α-interferon, β-interferon, nerve growth factor, platelet-derived growth factor, tissue plasminogen activator, apoptotic agents, antiangiogenic agents, and the like; or biological response modifiers such as lymphokines.

[0151] Additionally, antibodies can be used to treat, for example, but not limited to, 131 In, 131 Lu, 131 Y, 131 Ho, 131 Radioactive metal ions useful for conjugating polypeptides, including Sm, e.g., alpha emitters, e.g., 213 The antibody can be conjugated to a therapeutic moiety such as a Bi or macrocyclic chelator. In certain embodiments, the macrocyclic chelator is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), which can be attached to the antibody via a linker molecule. Such linker molecules are generally known in the art and are described in Denardo et al., 1998, Clin Cancer Res. 4 (10): 2483-90; Peterson et al., 1999, Bioconjug. Chem. 10 (4): 553-7; and Zimmerman et al., 1999, Nucl. Med. Biol. 26 (8): 943-50, each of which is incorporated by reference in its entirety.

[0152] Techniques for conjugating therapeutic moieties to antibodies are well known. For example, Arnon et al., “Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy”, in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery”, in Controlled Drug Delivery (2nd Ed.), Robinson et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, “Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review”, in Monoclonal Antibodies 84: Biological And Clinical Applications, Pinchera et al. (eds.), pp. 475-506 (1985); “Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer See, for example, "Monoclonal Antibodies For Cancer Detection And Therapy", Baldwin et al. (eds.), pp. 303-16 (Academic Press 1985), and Thorpe et al., 1982, Immunol. Rev. 62: 119-58.

[0153] Antibodies can also be attached to solid supports, which are particularly useful for immunoassays or purification of the target antigen. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene.

[0154] Pharmaceutical preparations In some embodiments, the present disclosure also provides a pharmaceutical formulation containing a therapeutically effective amount of a factor XI and / or factor XIa antibody (e.g., antibody 1) disclosed herein. The pharmaceutical formulation includes one or more excipients and is maintained at a certain pH. As used herein, non-limiting examples of "excipients" include any non-therapeutic agent added to the formulation to provide desired physical or chemical properties, such as pH, osmolality, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption, or permeation.

[0155] drug substance Antibody 1 is a high affinity anti-human factor XI monoclonal antibody. It is expressed in Chinese hamster ovary cell line (CHO-C8TD). In some embodiments, the antibody 1 drug substance is fully formulated for subcutaneous administration (i.e., no additional excipients are added), and is therefore identical in composition to the antibody 1 drug. In some embodiments, the antibody 1 drug is further diluted in a suitable carrier for intravenous administration. In some embodiments, the antibody 1 drug is diluted in a solution containing glucose, for example, 5% glucose in water (D5W).

[0156] Excipients and pH In some embodiments, the excipients contained in the antibody 1 drug are pharmacopoeia grade excipients. In some embodiments, the excipients in the antibody 1 drug include histidine, histidine salts, sugars, and polysorbates. In some embodiments, the excipients in the antibody 1 drug include L-histidine and L-histidine hydrochloride monohydrate (histidine buffer), sucrose, and polysorbate 20. The excipients can be selected for compatibility with intravenous and subcutaneous administration and provide the necessary stabilizing capacity, buffering capacity, and tonicity. The formulation can maximize the stability of the monoclonal antibody product and can also provide a sterile solution suitable for subcutaneous or intravenous administration. In some embodiments, sugars (e.g., sucrose) act as stabilizers. In some embodiments, histidine (e.g., L-histidine, L-histidine HCl monohydrate) acts as a buffering agent. In some embodiments, polysorbates (e.g., polysorbate 20) act as stabilizers. In some embodiments, the formulation is made up to final volume with water for injection (WFI).

[0157] One or more excipients in the pharmaceutical formulation of the present invention include buffering agent.The term "buffering agent" as used herein refers to one or more components that, when added to an aqueous solution, can protect the solution from pH fluctuations when acid or alkali is added or when diluted with a solvent.In addition to phosphate buffer, glycine, carbonate, citrate, histidine buffer, etc. can be used, in which sodium, potassium or ammonium ion can function as counterion.

[0158] In certain embodiments, the buffer or buffer system includes at least one buffer having a buffer range that overlaps completely or partially with the pH range of 5.0 to 7.4. In certain embodiments, the pH of the buffer is about 5.5±0.5. In certain embodiments, the buffer includes a histidine buffer. In certain embodiments, the histidine buffer is 0.05 to 10 mM, 0.1 to 10 mM, 0.2 to 10 mM, 0.5 to 10 mM, 1 to 10 mM, 5 to 10 mM, 5 to 100 mM, 10 to 100 mM, 15 to 100 mM, 20 to 100 mM, 30 to 100 mM, 40 to 100 mM, 50 to 100 mM, 60 to 100 mM, 70 to 100 mM, 80 to 100 mM, In certain embodiments, histidine is present at a concentration of about 0.1 mM, 0.2 mM, 0.5 mM, 1 mM, 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 50 ... In certain embodiments, the histidine buffer is present at a concentration of about 20 mM. In certain embodiments, the histidine buffer is present at a concentration of about 0.20 mM. In certain embodiments, the pH of the histidine buffer is about 5.0, about 5.5, about 6.0, about 6.5, or about 7.0. In certain embodiments, the pH of the histidine buffer is about 5.5.

[0159] The pharmaceutical formulation of the present invention may have a pH of 5.0 to 6.0. For example, in certain embodiments, the pH of the pharmaceutical formulation is 5.0 to 6.0 (i.e., 5.5±0.5), 5.1 to 5.9 (i.e., 5.5±0.4), 5.2 to 5.8 (i.e., 5.5±0.3), 5.3 to 5.7 (i.e., 5.5±0.2), 5.4 to 5.6 (i.e., 5.5±0.1), or 5.45 to 5.55 (i.e., 5.5±0.05). In certain embodiments, the pH of the pharmaceutical formulation is about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, or about 6.5. In certain embodiments, the pH of the pharmaceutical formulation is about 5.5. Under scientific rounding rules, a pH greater than or equal to 5.45 and less than or equal to 5.55 is rounded to 5.5.

[0160] In certain embodiments, the buffer system of the pharmaceutical formulation comprises 10-30 mM histidine at pH 5.5±0.2. In certain embodiments, the buffer system of the pharmaceutical formulation comprises about 20 mM histidine at pH 5.5±0.2. In certain embodiments, the buffer system of the pharmaceutical formulation comprises 10-30 mM histidine at pH 5.5±0.05. In certain embodiments, the buffer system of the pharmaceutical formulation comprises about 20 mM histidine at pH 5.5±0.05.

[0161] In certain embodiments, the buffer system of the pharmaceutical formulation comprises histidine at 0.10-0.30 mM, pH 5.5±0.2. In certain embodiments, the buffer system of the pharmaceutical formulation comprises histidine at about 0.20 mM, pH 5.5±0.2. In certain embodiments, the buffer system of the pharmaceutical formulation comprises histidine at 0.10-0.30 mM, pH 5.5±0.05. In certain embodiments, the buffer system of the pharmaceutical formulation comprises histidine at about 0.20 mM, pH 5.5±0.05.

[0162] One or more excipients in the pharmaceutical formulation of the present invention further comprises a sugar or sugar alcohol. Sugars and sugar alcohols are useful as heat stabilizers in pharmaceutical formulations. In certain embodiments, the pharmaceutical formulation comprises a sugar, such as a monosaccharide (glucose, xylose, or erythritol), a disaccharide (e.g., sucrose, trehalose, maltose, or galactose), or an oligosaccharide (e.g., stachyose). In certain embodiments, the pharmaceutical formulation comprises sucrose. In certain embodiments, the pharmaceutical composition comprises a sugar alcohol, such as a sugar alcohol derived from a monosaccharide (e.g., mannitol, sorbitol, or xylitol), a sugar alcohol derived from a disaccharide (e.g., lactitol or maltitol), or a sugar alcohol derived from an oligosaccharide. In certain embodiments, the pharmaceutical formulation comprises sucrose.

[0163] The amount of sugar or sugar alcohol contained in the formulation may vary depending on the particular situation and intended purpose in which the formulation is used. In certain embodiments, the pharmaceutical formulation contains 50-300 mM, 50-250 mM, 100-300 mM, 100-250 mM, 150-300 mM, 150-250 mM, 200-300 mM, 200-250 mM, or 250-300 mM of sugar or sugar alcohol. In certain embodiments, the pharmaceutical formulation contains about 50 mM, about 75 mM, about 100 mM, about 125 mM, about 150 mM, about 200 mM, about 220 mM, about 250 mM, or about 300 mM of sugar or sugar alcohol. In certain embodiments, the pharmaceutical formulation contains about 220 mM of sugar or sugar alcohol (e.g., sucrose).

[0164] The amount of sugar or sugar alcohol contained in the formulation may vary depending on the particular situation and intended purpose in which the formulation is used. In certain embodiments, the pharmaceutical formulation contains 0.50-3.00 mM, 0.50-2.50 mM, 1.00-3.00 mM, 1.00-2.50 mM, 1.50-3.00 mM, 1.50-2.50 mM, 2.00-3.00 mM, 2.00-2.50 mM, or 2.50-3.00 mM of sugar or sugar alcohol. In certain embodiments, the pharmaceutical formulation contains about 0.50 mM, about 0.75 mM, about 1.00 mM, about 1.25 mM, about 1.50 mM, about 2.00 mM, about 2.20 mM, about 2.50 mM, or about 3.00 mM of sugar or sugar alcohol. In certain embodiments, the pharmaceutical formulation comprises about 2.20 mM sugar or sugar alcohol (eg, sucrose).

[0165] One or more excipients in the pharmaceutical formulation disclosed herein further comprise a surfactant. The term "surfactant" as used herein refers to a surface-active molecule that contains both a hydrophobic portion (e.g., an alkyl chain) and a hydrophilic portion (e.g., a carboxyl and a carboxylate group). Surfactants are useful for reducing aggregation of therapeutic proteins in pharmaceutical formulations. Surfactants suitable for use in pharmaceutical formulations are generally non-ionic surfactants, including but not limited to polysorbates (e.g., polysorbate 20 or 80); poloxamers (e.g., poloxamer 188); sorbitan esters and derivatives; Triton®; sodium lauryl sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetadine ... -sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauramidopropyl-cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl betaine (e.g., lauroamidopropyl); myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; sodium cocoyl methyl taurate or disodium oleyl methyl taurate; and MONAQUAT™ series (Mona Industries, Inc., Paterson, NJ), polyethylene glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (e.g., Pluronics®, PF68, etc.). In certain embodiments, the surfactant is a polysorbate. In certain embodiments, the surfactant is polysorbate 20.

[0166] The amount of non-ionic surfactant contained in the pharmaceutical formulation of the present invention may vary depending on the desired specific properties of the formulation, as well as the specific situation and purpose for which the formulation is intended to be used. In certain embodiments, the pharmaceutical formulation contains 0.02% to 0.06%, 0.03% to 0.05%, or 0.035% to 0.045% of a non-ionic surfactant (e.g., polysorbate 20). In certain embodiments, the pharmaceutical formulation contains about 0.005%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, or about 0.1% of a non-ionic surfactant (e.g., polysorbate 20).

[0167] The amount of non-ionic surfactant contained in the pharmaceutical formulation of the present invention may vary depending on the desired specific properties of the formulation, as well as the specific situation and purpose for which the formulation is intended to be used. In certain embodiments, the pharmaceutical formulation contains 0.0002% to 0.0006%, 0.0003% to 0.0005%, or 0.00035% to 0.00045% of a non-ionic surfactant (e.g., polysorbate 20). In certain embodiments, the pharmaceutical formulation contains about 0.00005%, about 0.0001%, about 0.0002%, about 0.0003%, about 0.0004%, about 0.0005%, about 0.0006%, about 0.0007%, about 0.0008%, about 0.0009%, or about 0.001% of a non-ionic surfactant (e.g., polysorbate 20).

[0168] In certain embodiments, the drug is diluted in an aqueous carrier suitable for the route of administration, for example, intravenous administration.Exemplary carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), pH buffer (e.g., phosphate buffered saline), sterile saline solution, Ringer's solution, or dextrose solution.In one embodiment, when the pharmaceutical formulation is prepared for intravenous administration, the pharmaceutical formulation can be diluted in 5% dextrose solution (D5W).

[0169] Exemplary Formulations In certain embodiments, a pharmaceutical formulation of the invention comprises a factor XI and / or factor XIa antibody (e.g., an antibody having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39), a histidine buffer, a sugar or sugar alcohol (e.g., sucrose), and a polysorbate (e.g., polysorbate 20), and has a pH of 5.5 to 6.5.

[0170] In certain embodiments, the pharmaceutical formulation comprises 100-200 mg / mL of factor XI and / or factor XIa antibody (e.g., an antibody having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39), 10-30 mM histidine buffer, 200-300 mM sugar or sugar alcohol (e.g., sucrose), and 0.02%-0.06% polysorbate (e.g., polysorbate 20), at a pH of 5.0-6.0. In certain embodiments, the pharmaceutical formulation comprises 100-200 mg / mL of a factor XI and / or factor XIa antibody (e.g., an antibody having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39), about 20 mM histidine buffer, about 220 mM sugar or sugar alcohol (e.g., sucrose), and about 0.04% polysorbate (e.g., polysorbate 20), at a pH of 5.0-6.0. In certain embodiments, the pharmaceutical formulation comprises 100-200 mg / mL of a factor XI and / or factor XIa antibody, about 20 mM histidine buffer, about 220 mM sugar or sugar alcohol (e.g., sucrose), and about 0.04% polysorbate (e.g., polysorbate 20), at a pH of 5.2-5.8. In certain embodiments, the pharmaceutical formulation comprises 100-200 mg / mL of factor XI and / or factor XIa antibody (e.g., an antibody having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39), about 20 mM histidine buffer, about 220 mM sugar or sugar alcohol (e.g., sucrose), and about 0.04% polysorbate (e.g., polysorbate 20), at a pH of 5.45-5.55.

[0171] In certain embodiments, the pharmaceutical formulation comprises 1.00-2.00 mg / mL of factor XI and / or factor XIa antibody (e.g., an antibody having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39), 0.10-0.30 mM histidine buffer, 2.00-3.00 mM sugar or sugar alcohol (e.g., sucrose), and 0.0002%-0.0006% polysorbate (e.g., polysorbate 20), at a pH of 5.0-6.0. In certain embodiments, the pharmaceutical formulation comprises 1.00-2.00 mg / mL of factor XI and / or factor XIa antibody (e.g., an antibody having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39), about 0.20 mM histidine buffer, about 2.20 mM sugar or sugar alcohol (e.g., sucrose), and about 0.0004% polysorbate (e.g., polysorbate 20), at a pH of 5.0-6.0. In certain embodiments, the pharmaceutical formulation comprises 1.00-2.00 mg / mL of factor XI and / or factor XIa antibody (e.g., an antibody having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39), about 0.20 mM histidine buffer, about 2.20 mM sugar or sugar alcohol (e.g., sucrose), and about 0.0004% polysorbate (e.g., polysorbate 20), at a pH of 5.2-5.8. In certain embodiments, the pharmaceutical formulation comprises 1.00 to 2.00 mg / mL of factor XI and / or factor XIa antibody (e.g., an antibody having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39), about 0.20 mM histidine buffer, about 2.20 mM sugar or sugar alcohol (e.g., sucrose), and about 0.0004% polysorbate (e.g., polysorbate 20), at a pH of 5.45 to 5.55.

[0172] In certain embodiments, the pharmaceutical formulation comprises 100-200 mg / mL of factor XI and / or factor XIa antibody (e.g., an antibody having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39), 10-30 mM histidine buffer, 200-300 mM sucrose, and 0.02%-0.06% polysorbate 20, at a pH of 5.0-6.0. In certain embodiments, the pharmaceutical formulation comprises 100-200 mg / mL of factor XI and / or factor XIa antibody, about 20 mM histidine buffer, about 220 mM sucrose, and about 0.04% polysorbate 20, at a pH of 5.0-6.0. In certain embodiments, the pharmaceutical formulation comprises 100-200 mg / mL of factor XI and / or factor XIa antibody (e.g., an antibody having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39), about 20 mM histidine buffer, about 220 mM sucrose, and about 0.04% polysorbate 20, at a pH of 5.3-5.7. In certain embodiments, the pharmaceutical formulation comprises 100-200 mg / mL of factor XI and / or factor XIa antibody (e.g., an antibody having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39), about 20 mM histidine buffer, about 220 mM sucrose, and about 0.04% polysorbate 20, at a pH of 5.45-5.55.

[0173] In certain embodiments, the pharmaceutical formulation comprises 1.00-2.00 mg / mL of factor XI and / or factor XIa antibody (e.g., an antibody having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39), 0.10-0.30 mM histidine buffer, 2.00-3.00 mM sucrose, and 0.0002%-0.0006% polysorbate 20, at a pH of 5.0-6.0. In certain embodiments, the pharmaceutical formulation comprises 1.00-2.00 mg / mL of factor XI and / or factor XIa antibody (e.g., an antibody having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39), about 0.20 mM histidine buffer, about 2.20 mM sucrose, and about 0.0004% polysorbate 20, at a pH of 5.0-6.0. In certain embodiments, the pharmaceutical formulation comprises 1.00-2.00 mg / mL of factor XI and / or factor XIa antibody, 20 mM histidine buffer, about 2.20 mM sucrose, and about 0.0004% polysorbate 20, at a pH of 5.3-5.7. In certain embodiments, the pharmaceutical formulation comprises 1.00-2.00 mg / mL of factor XI and / or factor XIa antibody (e.g., an antibody having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39), about 0.20 mM histidine buffer, about 2.20 mM sucrose, and about 0.0004% polysorbate 20, at a pH of 5.45-5.55.

[0174] In some embodiments, the present disclosure provides a pharmaceutical formulation comprising an antibody or antigen-binding fragment thereof that binds to FXI and / or FXIa protein, the pharmaceutical formulation being contained in a vial, the pharmaceutical formulation comprising an overfill volume in the vial such that the therapeutically effective amount of anti-FXI and / or anti-FXIa antibody or antigen-binding fragment thereof can be fully withdrawn. In certain embodiments, the vial contains about 150 mg of an antibody that binds to FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa), the antibody having a heavy chain variable domain (VH) having an amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having an amino acid sequence of SEQ ID NO: 19 or 39; a histidine buffer at a concentration of about 20 mM; sucrose at a concentration of about 220 mM; and polysorbate 20 at a concentration of about 0.04% (v / v), the pH of the formulation being about pH 5.5.

[0175] In several embodiments, the disclosure provides a pharmaceutical formulation for intravenous delivery comprising about 1.5 mg of an antibody or antigen-binding fragment thereof that binds to a FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa), the antibody or antigen-binding fragment having a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39; a histidine buffer at a concentration of about 0.20 mM; sucrose at a concentration of about 2.20 mM; polysorbate 20 at a concentration of about 0.0004% (v / v); and a diluent (e.g., 5% dextrose in water (D5W)), wherein the pH of the formulation is about pH 5.5.

[0176] Stability of Factor XI and / or Factor XIa Antibodies The pharmaceutical formulations of the present invention exhibit a high level of stability. A pharmaceutical formulation is stable if the Factor XI and / or Factor XIa antibodies in the formulation retain an acceptable degree of physical properties, chemical structure, and / or biological function after storage under defined conditions.

[0177] Exemplary methods for determining the stability of factor XI and / or factor XIa antibodies in pharmaceutical formulations are described in Example 1 of the present disclosure. Additionally, protein stability can be assessed by measuring the binding affinity of factor XI and / or factor XIa antibodies to their targets or the biological activity of factor XI and / or factor XIa antibodies in certain in vitro assays, such as the aPTT and FXI activity assays described in WO2016 / 207858.

[0178] The pharmaceutical formulation can be prepared and stored as a liquid formulation. In certain embodiments, the pharmaceutical formulation is a liquid formulation for storage at 2-8° C. (e.g., 4° C.). In certain embodiments, the pharmaceutical formulation is a liquid formulation for storage at 4° C., protected from light.

[0179] Stability testing has found that the 150 mg / mL concentrate of antibody 1 for injection solution is compatible with its excipients and primary packaging materials. The 150 mg / mL concentrate of antibody 1 for injection is suitable for subcutaneous administration using a disposable syringe, either without dilution or with dilution in a carrier buffer, such as 5% glucose (D5W). The concentrate for injection using a commercially available disposable syringe has been demonstrated for a dose range from 0.5 mg / subject to 600 mg / subject. Materials found to be compatible with antibody 1 include injection syringes made of polypropylene or polycarbonate, and injection needles made of stainless steel. Compatibility of the antibody 1 concentrate for injection solution has been demonstrated using a 1 mL syringe for antibody 1 concentrations from 0.5 mg / mL to 150 mg / mL. The suitability of the Antibody 1 concentrate into an injectable solution has been demonstrated using a 3 mL syringe filled to approximately 2 mL for an Antibody 1 concentration of 150 mg / mL, encompassing a total dose range of 0.5 mg up to 150 mg per injection for a 1 mL syringe, and approximately 300 mg for a 3 mL syringe (filled to approximately 2 mL).

[0180] Dosage form Before use as a pharmaceutical product, the pharmaceutical preparation can be diluted in an aqueous carrier if suitable for the route of administration. For intravenous administration, suitable carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), pH buffer (e.g., phosphate buffered saline), sterile saline solution, Ringer's solution, or dextrose solution. For example, when the pharmaceutical preparation is prepared for intravenous administration, the pharmaceutical preparation comprises 5% dextrose solution (D5W). In certain embodiments, the diluted pharmaceutical preparation is isotonic and suitable for administration by intravenous infusion, e.g., D5W. In certain embodiments, the preparation is diluted in about 50mL of D5W, 100mL of D5W, 150mL of D5W, 200mL of D5W, 250mL of D5W, 300mL of D5W, 350mL of D5W, 400mL of D5W, 450mL of D5W, 500mL of D5W, or 1L of D5W.

[0181] The pharmaceutical formulation comprises factor XI and / or factor XIa antibodies at a concentration suitable for storage. In certain embodiments, the pharmaceutical formulation comprises factor XI and / or factor XIa antibodies at a concentration of 100-200 mg / mL, 100-190 mg / mL, 100-180 mg / mL, 100-170 mg / mL, 100-160 mg / mL, 110-150 mg / mL, 120-150 mg / mL, 130-150 mg / mL, 140-150 mg / mL, 140-160 mg / mL, 140-170 mg / mL, 140-180 mg / mL, 140-190 mg / mL, 150-190 mg / mL, 150-180 mg / mL, 150-170 mg / mL, or 150-160 mg / mL. In certain embodiments, the pharmaceutical formulation comprises a factor XI and / or factor XIa antibody at a concentration of about 10 mg / mL, about 15 mg / mL, about 25 mg / mL, about 50 mg / mL, about 75 mg / mL, about 100 mg / mL, about 120 mg / mL, about 125 mg / mL, about 130 mg / mL, about 135 mg / mL, about 140 mg / mL, about 145 mg / mL, about 150 mg / mL, about 155 mg / mL, about 160 mg / mL, about 165 mg / mL, about 170 mg / mL, about 175 mg / mL, about 180 mg / mL, about 185 mg / mL, about 190 mg / mL, about 195 mg / mL, or about 200 mg / mL.

[0182] The pharmaceutical formulation comprises Factor XI and / or Factor XIa antibodies in a concentration suitable for storage. In certain embodiments, the pharmaceutical formulation comprises factor XI and / or factor XIa antibodies at a concentration of 1.00-2.00 mg / mL, 1.00-1.90 mg / mL, 1.00-1.80 mg / mL, 1.00-1.70 mg / mL, 1.00-1.60 mg / mL, 1.10-1.50 mg / mL, 1.20-1.50 mg / mL, 1.30-1.50 mg / mL, 1.40-1.50 mg / mL, 1.40-1.60 mg / mL, 1.40-1.70 mg / mL, 1.40-1.80 mg / mL, 1.40-1.90 mg / mL, 1.50-1.90 mg / mL, 1.50-1.80 mg / mL, 1.50-1.70 mg / mL, or 1.50-1.60 mg / mL. In certain embodiments, the pharmaceutical formulation comprises a factor XI and / or factor XIa antibody at a concentration of about 0.10 mg / mL, about 0.15 mg / mL, about 0.25 mg / mL, about 0.50 mg / mL, about 0.75 mg / mL, about 1.00 mg / mL, about 1.20 mg / mL, about 1.25 mg / mL, about 1.30 mg / mL, about 1.35 mg / mL, about 1.40 mg / mL, about 1.45 mg / mL, about 1.50 mg / mL, about 1.55 mg / mL, about 1.60 mg / mL, about 1.65 mg / mL, about 1.70 mg / mL, about 1.75 mg / mL, about 1.80 mg / mL, about 1.85 mg / mL, about 1.90 mg / mL, about 1.95 mg / mL, or about 2.00 mg / mL.

[0183] In certain embodiments, the pharmaceutical formulation is packaged in a vial (e.g., a vial, bag, pen, or syringe). In certain embodiments, the vial includes an overfill to allow for complete removal of the intended dose. In certain embodiments, the vial includes an overfill of 5-35%, 10-30%, 15-25%, or 10-20%. In certain embodiments, the vial includes an overfill of about 20%.

[0184] In certain embodiments, the formulation may be a liquid formulation. In certain embodiments, the amount of factor XI and / or factor XIa antibody in the container is suitable for administration as a single dose. In certain embodiments, the amount of factor XI and / or factor XIa antibody in the container is suitable for administration in multiple doses. In certain embodiments, the pharmaceutical formulation comprises factor XI and / or factor XIa antibody in an amount of 0.1-200 mg. In certain embodiments, the pharmaceutical formulation comprises factor XI and / or factor XIa antibodies at 1-200 mg, 10-200 mg, 20-200 mg, 50-200 mg, 100-200 mg, 200-200 mg, 500-2000 mg, 1000-2000 mg, 0.1-1000 mg, 1-1000 mg, 10-1000 mg, 20-1000 mg, 50-1000 mg, 100-1000 mg, 200-1000 mg, 500-1000 mg, 0.1-500 mg, 1-500 mg, 10-500 mg , 20-500mg, 50-500mg, 100-500mg, 200-500mg, 0.1-200mg, 1-200mg, 10-200mg, 20-200mg, 50-200mg, 100-200mg, 0.1-100mg, 1-100mg, 10-100mg, 20-100mg, 50-100mg, 0.1-50mg, 1-50mg, 10-50mg, 20-50mg, 0.1-20mg, 1-20mg, 10-20mg, 0.1-10mg, 1-10mg, or 0.1-1mg. In certain embodiments, the pharmaceutical formulation comprises a therapeutically effective amount of factor XI and / or factor XIa antibody in an amount of about 0.1 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1500 mg, or about 2000 mg.

[0185] Dosage Regimens and Therapeutic Use In another aspect, the disclosure provides a method for treating a thromboembolic disease, comprising administering to a subject in need thereof a factor XI and / or factor XIa antibody (e.g., antibody 1) disclosed herein once a month.

[0186] In certain embodiments, the method further comprises administering to the subject, after the first treatment cycle, one or more monthly treatment cycles of factor XI and / or factor XIa antibodies, for example, over a period of three months, where factor XI and / or factor XIa antibodies are administered on days 1, 31, and 61. Subsequent treatment cycles in which the subject receives monthly administration of factor XI and / or factor XIa antibodies are designed to maintain a certain level of factor XI and / or factor XIa antibodies in the subject. In certain embodiments, the subject receives at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 subsequent treatment cycles. In some embodiments, the subject continues to receive treatment for life.

[0187] In some embodiments, the method comprises treating a disease or disorder, e.g., a thromboembolic disease, in a subject in need thereof, and comprises administering a first dose of an anti-FXI / FXIa antibody or antigen-binding fragment thereof (e.g., antibody 1) intravenously, and administering a second dose of an anti-FXI / FXIa antibody or antigen-binding fragment thereof (e.g., antibody 1) subcutaneously. In some embodiments, the method further comprises administering a third dose subcutaneously. In some embodiments, the method further comprises administering a fourth dose subcutaneously. In some embodiments, the method further comprises administering a fifth dose subcutaneously. In some embodiments, the method further comprises administering a sixth dose subcutaneously. In some embodiments, the method further comprises administering a seventh dose subcutaneously. In some embodiments, the method further comprises administering an eighth dose subcutaneously. In some embodiments, the method further comprises administering a ninth dose subcutaneously. In some embodiments, the method further comprises administering a ninth dose subcutaneously. In some embodiments, the method further comprises administering a tenth dose subcutaneously. In some embodiments, the method further comprises administering an eleventh dose subcutaneously. In certain embodiments, the method comprises administering a first dose intravenously, and administering the following 5 doses subcutaneously.In certain embodiments, the duration of treatment is about 6 months.In certain embodiments, the method comprises administering a first dose intravenously, and administering the following 11 doses subcutaneously.In certain embodiments, the duration of treatment is about 1 year.In certain embodiments, the method comprises administering a first dose intravenously, and then administering subcutaneous doses every month until the disease or disorder in the subject resolves, or for the life of the subject.

[0188] In some embodiments, the intravenous drug delivery formulation is administered to a subject suffering from or at risk of developing a thromboembolic disorder and undergoing a surgical procedure on the same day as the surgical procedure. In some embodiments, the intravenous drug delivery formulation is administered between 2 and 10 hours after the surgical procedure. In some embodiments, the intravenous drug delivery formulation is administered between 4 and 8 hours after the surgical procedure. In some embodiments, the intravenous drug delivery formulation is administered about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, or about 10 hours after the surgical procedure.

[0189] In certain embodiments, one or more doses in the initial treatment cycle and in subsequent treatment cycles comprise a factor XI and / or factor XIa antibody at about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4.0 mg / kg, about 4.1 mg / kg, about 4.2 mg / kg, about 4.3 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, about 4.6 mg / kg, about 4.7 mg / kg, about 4.8 mg / kg, about 4.9 mg / kg, about 5.0 mg / kg, about 5.1 mg / kg, about 5.2 mg / kg, about 5.3 mg / kg, The present invention includes administering the compound or compounds subcutaneously at a dose of about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4.0 mg / kg, about 4.1 mg / kg, about 4.2 mg / kg, about 4.3 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, about 4.6 mg / kg, about 4.7 mg / kg, about 4.8 mg / kg, about 4.9 mg / kg, or about 5.0 mg / kg.

[0190] In certain embodiments, one or more doses in the initial treatment cycle and subsequent treatment cycles comprise subcutaneous administration of a factor XI and / or factor XIa antibody (e.g., antibody 1) at a dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, or about 200 mg. In some embodiments, the factor XI and / or factor XIa antibody is administered subcutaneously at a dose of about 90 mg. In some embodiments, the Factor XI and / or Factor XIa antibody is administered subcutaneously at a dose of about 120 mg. In some embodiments, the Factor XI and / or Factor XIa antibody is administered subcutaneously at a dose of about 150 mg. In some embodiments, the Factor XI and / or Factor XIa antibody is administered subcutaneously at a dose of about 180 mg. In any of the above embodiments, the Factor XI and / or Factor XIa antibody is administered subcutaneously monthly.

[0191] In some embodiments, the therapeutically effective dose range of factor XI and / or factor XIa antibodies (e.g., antibody 1) following subcutaneous administration is about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg to about 155 mg, or about 90 mg to about 160 mg. In certain embodiments, the therapeutically effective dose range of factor XI and / or factor XIa antibodies (e.g., antibody 1) following subcutaneous administration is about 90 mg to about 160 mg.

[0192] In certain embodiments, one or more doses in the initial treatment cycle and in subsequent treatment cycles comprise administering to the patient at least one of about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, In some embodiments, the compound is administered intravenously at a dose of about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4.0 mg / kg, about 4.1 mg / kg, about 4.2 mg / kg, about 4.3 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, about 4.6 mg / kg, about 4.7 mg / kg, about 4.8 mg / kg, about 4.9 mg / kg, or about 5.0 mg / kg.

[0193] In certain embodiments, one or more doses in the initial treatment cycle and in subsequent treatment cycles comprise about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, In some embodiments, the Factor XI and / or Factor XIa antibody is administered intravenously at a dose of about 85 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, about 1000 mg, about 1250 mg, about 1500 mg, or about 2000 mg. In some embodiments, the Factor XI and / or Factor XIa antibody is administered intravenously at a dose of about 30 mg. In some embodiments, the Factor XI and / or Factor XIa antibody is administered intravenously at a dose of about 60 mg. In some embodiments, the Factor XI and / or Factor XIa antibody is administered intravenously at a dose of about 75 mg. In some embodiments, the factor XI and / or factor XIa antibody is administered intravenously in a dose of about 150 mg. In some embodiments, the factor XI and / or factor XIa antibody is administered intravenously in a single dose. In some embodiments, the FXI / FXIa antibody (e.g., antibody 1) is administered in a single dose of about 150 mg. In some embodiments, the FXI / FXIa antibody (e.g., antibody 1) is administered in a single dose of about 1000 mg. In some embodiments, the FXI / FXIa antibody (e.g., antibody 1) is administered in a single dose of about 1500 mg. In some embodiments, the FXI / FXIa antibody (e.g., antibody 1) is administered in a single dose of about 2000 mg.

[0194] In some embodiments, a first dose of FXI / FXIa antibody (e.g., antibody 1) is administered in one dose and a second dose of FXI / FXIa antibody (e.g., antibody 1) is administered in a second dose. In certain embodiments, the first and second doses are the same (e.g., 150 mg). In certain embodiments, the first dose is greater than the second dose (e.g., the first dose is about 1000 mg and the second dose is 150 mg). In certain embodiments, the method further comprises administering the subsequent dose at the same dosage as the second dose.

[0195] In certain embodiments, administration of a single dose of a FXI / FXIa antibody (e.g., antibody 1) extends the activated partial thromboplastin time (aPTT) by 400 hours or more, e.g., 400 hours or more, 500 hours or more, or 600 hours or more. In certain embodiments, administration of a single dose of a FXI / FXIa antibody (e.g., antibody 1) extends the activated partial thromboplastin time (aPTT) by about 600 hours.

[0196] A physician may begin the dosage of the antibody of the present disclosure (e.g., antibody 1) used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. In general, the effective dosage of the composition of the present disclosure for treating the thromboembolic disorders described herein will vary depending on many different factors, including the means of administration, the target site, the physiological state of the patient, other drugs administered, and whether the treatment is prophylactic or therapeutic. Treatment dosages can be titrated to optimize safety and efficacy. For systemic administration of the antibody, dosages range from about 0.01 mg to 15 mg per kg of host body weight. For administration of the antibody (e.g., subcutaneous or intravenous), dosages can range from 0.1 mg to 5 mg, or from 1 mg to 600 mg. For example, an anti-FXI / FXIa antibody described herein (e.g., Antibody 1) may be administered at about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0.8 mg / kg, about 0.9 mg / kg, about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4.0 mg / kg, about 4.1 mg / kg, about 4.2 mg / kg, about 4.3 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, about 4.6 mg / kg, about 4.7 mg / kg, about 4.8 mg / kg, about 4.9 mg / kg, about 5.0 mg / kg, about 5.1 mg / kg, about 5.2 mg / kg, about 5.3 mg / kg, about 5. The compound may be administered at a dose of about 0.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8 mg / kg, about 2.9 mg / kg, about 3.0 mg / kg, about 3.1 mg / kg, about 3.2 mg / kg, about 3.3 mg / kg, about 3.4 mg / kg, about 3.5 mg / kg, about 3.6 mg / kg, about 3.7 mg / kg, about 3.8 mg / kg, about 3.9 mg / kg, about 4.0 mg / kg, about 4.1 mg / kg, about 4.2 mg / kg, about 4.3 mg / kg, about 4.4 mg / kg, about 4.5 mg / kg, about 4.6 mg / kg, about 4.7 mg / kg, about 4.8 mg / kg, about 4.9 mg / kg, or about 5.0 mg / kg.

[0197] In certain embodiments, the Factor XI and / or Factor XIa antibodies are administered intravenously. For example, in certain embodiments, the Factor XI and / or Factor XIa antibodies are administered by intravenous infusion, for example, using a pre-filled bag, a pre-filled pen, or a pre-filled syringe. In certain embodiments, the Factor XI and / or Factor XIa antibodies are diluted in a pharmaceutical formulation disclosed herein prior to administration. For example, in certain embodiments, the pharmaceutical formulation is diluted in 5% dextrose in water (D5W) and administered intravenously from a bag. The intravenous infusion can last for about 1 hour (e.g., 50-80 minutes). In certain embodiments, the bag is connected to a channel that includes a tube and / or a needle.

[0198] In certain embodiments, the Factor XI and / or Factor XIa antibodies are administered parenterally. In certain embodiments, the Factor XI and / or Factor XIa antibodies are administered parenterally in one or more doses.

[0199] The types of thromboembolic disorders that can be treated with the factor XI and / or factor XIa antibodies or pharmaceutical formulations disclosed herein include, but are not limited to, "thromboembolic" or similar terms as used herein, and can also refer to any of the following that can be prevented or treated using the anti-FXI and / or FXIa antibodies or antigen-binding fragments thereof disclosed herein: thromboembolism in subjects with suspected or confirmed cardiac arrhythmias, such as paroxysmal, persistent or permanent atrial fibrillation or atrial flutter; prevention of stroke in atrial fibrillation (SPAF), a subpopulation of AF patients undergoing percutaneous coronary intervention (PCI); treatment of acute venous thromboembolic events (VTE) and prevention of long-term secondary VTE in patients at high risk of bleeding; cerebral and cardiovascular events during secondary prevention after a transient ischemic attack (TIA) or non-disabling stroke; prevention of thromboembolic events in stroke and heart failure with sinus rhythm; venous thromboembolism in pediatric subjects (pediatric VTE); thromboembolism in subjects undergoing electrical cardioversion for clot formation in the left atrium and cardiac arrhythmias; thrombosis before, during, and after ablation procedures for cardiac arrhythmias; venous thrombosis, including, but not exclusively, treatment and secondary prevention of deep or superficial venous thrombosis in the lower or upper members, thrombosis in abdominal and thoracic veins, sinus thrombosis, and thrombosis of the jugular vein; any artificial surfaces within a vein or artery, such as catheters, pacemaker wires, synthetic arterial grafts, arteriovenous (AV) shunts; mechanical or biological heart valves or left ventricular assist devices; pulmonary embolism in patients with or without venous thrombosis; chronic thromboembolic pulmonary hypertension (CTEPH); arterial thrombosis in ruptured atherosclerotic plaques, thrombosis in intra-arterial prostheses or catheters and thrombosis in apparently normal arteries, including but not limited to acute coronary syndromes, ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, unstable angina, stent thrombosis, thrombosis of any artificial surface within the arterial system and thrombosis of the pulmonary artery in subjects with or without pulmonary hypertension;Thrombosis and thromboembolism in patients undergoing percutaneous coronary intervention (PCI);cardiogenic and cryptogenic stroke;non-central neurosystemic embolism (non-CNS systemic embolism);hemorrhagic stroke;thrombosis in patients with invasive and non-invasive cancer malignancies (e.g., gastrointestinal and genitourinary cancers);thrombosis on indwelling catheters;thrombosis and thromboembolism in critically ill patients;cardiac thrombosis and thromboembolism, which includes, but is not exclusive to, cardiac thrombosis after myocardial infarction, cardiac thrombosis associated with conditions such as ventricular aneurysms, myocardial fibrosis, cardiac enlargement and failure, myocarditis and artificial heart surfaces;thromboembolism in patients with valvular heart disease with or without atrial fibrillation;thromboembolism on mechanical or biological artificial heart valves;thromboembolism in patients with native or artificial heart patches, arterial or venous conduits after cardiac repair of simple or complex cardiac anomalies; venous thrombosis and thromboembolism after knee replacement, hip replacement, and orthopedic, thoracic or abdominal surgery; arterial or venous thrombosis after neurosurgery, including intracranial and spinal interventions; congenital or acquired thrombophilias, including, but not exclusively, factor V Leiden, prothrombin mutations, antithrombin III, protein C and protein S deficiencies, factor XIII mutations, familial dysfibrinogenemia, congenital plasminogen deficiency, elevated levels of factor XI, sickle cell disease, antiphospholipid syndrome, autoimmune diseases, chronic bowel disease, nephrotic syndrome, hemolytic uremia, myeloproliferative disorders, disseminated intravascular coagulation, paroxysmal nocturnal hemoglobinuria and heparin-induced thrombocytopenia; thrombosis and thromboembolism in chronic kidney disease; and thrombosis and thromboembolism in patients undergoing hemodialysis and in patients undergoing extracorporeal membrane oxygenation. In certain embodiments, the subject to be treated with a factor XI and / or factor XIa antibody or pharmaceutical formulation disclosed herein is obese (e.g., severely obese, e.g., a body mass index (BMI) of ≥ 35 kg / m; 2). In certain embodiments, the subject treated with the factor XI and / or factor XIa antibody or pharmaceutical formulation disclosed herein is not obese. In certain embodiments, the obese subject is associated with a lower exposure after administration of the same dose of factor XI and / or factor XIa antibody (e.g., antibody 1) as a non-obese subject. In certain embodiments, for an obese subject, the exposure after administration of the same dose of factor XI and / or factor XIa antibody (e.g., antibody 1) as a non-obese subject is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% less. In certain embodiments, the obese subject is associated with a shorter duration of aPTT prolongation after administration of the same dose of factor XI and / or factor XIa antibody (e.g., antibody 1) as a non-obese subject. In certain embodiments, for obese subjects, the aPTT prolongation following administration of the same dose of factor XI and / or factor XIa antibody (e.g., Antibody 1) is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% shorter than in non-obese subjects.

[0200] In certain embodiments, an anti-FXI / FXIa antibody or antigen-binding fragment (e.g., antibody 1) described herein is administered to a patient with thrombocytopenia. "Thrombocytopenia" refers to a condition in which a subject has lower than normal platelet levels, e.g., lower than the average physiological platelet level in a particular population. In some embodiments, a patient with thrombocytopenia has a platelet count of 150×10 9The platelet count is less than 100 / L or about 2.5 percentile of normal platelet count distribution. Patients with thrombocytopenia are at increased bleeding risk, but may nevertheless be at risk for thromboembolic disorders (e.g., venous thromboembolism (VTE) or stroke). Treating patients with thrombocytopenia with existing anticoagulant therapy can be clinically challenging, as one must balance the increased bleeding risk with the need to treat, prevent, or reduce the risk of thromboembolic disorders. In certain embodiments, the risk of bleeding from administering an anti-FXI / FXIa antibody or antigen-binding fragment (e.g., antibody 1) described herein to a patient with thrombocytopenia is lower than the administration of another anticoagulant therapy. In some embodiments, administration of an antibody or antigen-binding fragment (e.g., antibody 1) described herein does not affect platelet aggregation in a subject compared to platelet aggregation prior to administration. Platelet aggregation can be determined, for example, but not limited to, by impedance platelet aggregometry and other suitable methods known in the art.

[0201] In some embodiments, thrombocytopenia is associated with cirrhosis. In cirrhosis, the production of both procoagulant and anticoagulant factors is decreased, which may increase the risk of bleeding and / or thrombosis in patients with cirrhosis. As previously demonstrated using the low molecular weight heparin (LMWH) enoxaparin, inhibition of factor XI (e.g., by antibody 1) can prevent the occurrence of portal vein thrombosis and reduce hepatic decompensation events (Villa et al. (2012). Gastroenterology. 143 (5): 1253-1260). However, the use of LMWH for cirrhosis is limited by the risk of user compliance (e.g., daily administration) and the fact that advanced cirrhosis is often complicated by renal failure, and administration of heparin is not recommended. In some embodiments, administering an anti-FXI / FXIa antibody or antigen-binding fragment (e.g., antibody 1) described herein to a patient with cirrhosis slows the progression of cirrhosis. In some embodiments, administering an anti-FXI / FXIa antibody or antigen-binding fragment (e.g., antibody 1) described herein to a patient with cirrhosis prevents or reduces the incidence of intrahepatic microthrombi. In some embodiments, administering an anti-FXI / FXIa antibody or antigen-binding fragment (e.g., antibody 1) described herein to a patient with cirrhosis reduces the incidence of hepatic ischemia and / or fibrosis. In some embodiments, administering an anti-FXI / FXIa antibody or antigen-binding fragment (e.g., antibody 1) described herein to a patient with cirrhosis prevents or reduces the risk of portal vein thrombosis. In some embodiments, administration of an anti-FXI / FXIa antibody or antigen-binding fragment described herein (e.g., Antibody 1) to a patient with cirrhosis reduces the incidence of cirrhosis sequelae (e.g., esophageal varices and variceal bleeding), e.g., compared to the incidence of cirrhosis sequelae in the patient prior to administration.In some embodiments, administration of an anti-FXI / FXIa antibody or antigen-binding fragment (e.g., Antibody 1) described herein to a patient with cirrhosis reduces the number of hepatic decompensation events, for example compared to the number of hepatic decompensation events in the patient prior to administration.

[0202] In some embodiments, the thrombocytopenia is associated with an infection. In certain embodiments, the thrombocytopenia is associated with human immunodeficiency virus (HIV) or hepatitis C virus. In some embodiments, the thrombocytopenia is congenital. In certain embodiments, the congenital thrombocytopenia is Wiskott-Aldrich syndrome, thrombocytopenia-absent radii syndrome, Bernard-Soulier, gray platelet syndrome, familial-thrombocytopenia-leukemia syndrome, MYH9-associated disorder, Fanconi anemia, congenital amegakaryocytic thrombocytopenia, or dyskeratosis congenita. In some embodiments, the thrombocytopenia is idiopathic. In some embodiments, the idiopathic thrombocytopenia is idiopathic thrombocytopenia purpura (ITP).

[0203] In certain embodiments, a factor XI and / or factor XIa antibody (e.g., antibody 1) is administered to a subject having cancer. Venous thromboembolism (VTE) affects 1%-8% of all cancer patients and is estimated to be the second leading cause of death in outpatients undergoing chemotherapy. Treatment of such VTE in cancer patients is complicated by thrombocytopenia, which is widespread in cancer patients undergoing chemotherapy (Bannow et al. (2019). Res. Pract. Thrrom. Haemost., 2: 664-669). In some embodiments, the subject, e.g., a cancer subject, has thrombocytopenia. As used herein, a "cancer subject" or a "subject having cancer" is a subject, e.g., a human subject, diagnosed with cancer. In certain embodiments, the cancer subject is undergoing treatment for said cancer, e.g., chemotherapy. In some embodiments, the thrombocytopenia is associated with chemotherapy. In some embodiments, the thrombocytopenia is induced by chemotherapy.

[0204] In certain embodiments, the cancer is a solid tumor. In certain other embodiments, the cancer is brain cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, leukemia, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, gastric cancer, testicular cancer, or uterine cancer. In still other embodiments, the cancer is an vascularized tumor, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, melanoma, glioma, neuroblastoma, sarcoma (e.g., angiosarcoma or chondrosarcoma), laryngeal cancer, parotid cancer, cholangiocarcinoma, thyroid cancer, acral lentigo melanoma, actinic keratosis, acute lymphocytic leukemia, acute myeloid leukemia, adenoid cystic carcinoma, adenoma, adenosarcoma, adenosquamous carcinoma, anal canal cancer, anal cancer, anorectal cancer, astrocytic tumors, or endothelial tumors. tumor), Bartholin's gland carcinoma, basal cell carcinoma, bile duct cancer, bone cancer, bone marrow cancer, bronchial cancer, bronchial adenocarcinoma, carcinoid, bile duct carcinoma, chondrosarcoma, choroid plexus papilloma / carcinoma, chronic lymphocytic leukemia, chronic myeloid leukemia, clear cell carcinoma, connective tissue cancer, cystadenoma, digestive system cancer, duodenal cancer, endocrine system cancer, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, endothelial cell carcinoma, ependymal carcinoma, epithelial cell carcinoma, Ewing's sarcoma , cancer of the eye and orbit, cancer of the female genital tract, focal nodular hyperplasia, cancer of the gallbladder, cancer of the pyloric antrum, cancer of the fundus of the stomach, gastrinoma, glioblastoma, glucagonoma, cancer of the heart, hemangioblastoma, hemangioendothelioma, hemangioma, hepatic adenoma, hepatic adenomatosis, hepatobiliary cancer, hepatocellular carcinoma, Hodgkin's disease, cancer of the ileum, insulinoma, intraepithelial neoplasia, intraepithelial squamous cell neoplasia, intrahepatic cholangiocarcinoma, invasive squamous cell carcinoma, cancer of the jejunum, cancer of the joints, Kaposi's sarcoma, pelvic cancer cancer, large cell carcinoma, colorectal cancer, leiomyosarcoma, lentigo maligna melanoma, lymphoma, cancer of the male genital tract, malignant melanoma, malignant mesothelioma, medulloblastoma, medulloepithelioma, meningeal cancer, mesothelial carcinoma, metastatic cancer, oral cancer, mucoepidermoid carcinoma, multiple myeloma, cancer of the muscle, cancer of the nasal cavity, cancer of the nervous system, neuroepithelial adenocarcinoma, nodular melanoma, non-epithelial skin cancer, non-Hodgkin's lymphoma, oat cell carcinoma, oligodendroglial carcinoma, oral cavity cancercancer, osteosarcoma, papillary serous adenocarcinoma, penile cancer, pharyngeal cancer, pituitary tumor, plasmacytoma, pseudosarcoma, pulmonary blastoma, rectal cancer, renal cell carcinoma, respiratory system cancer, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, sinus cancer, skin cancer, small cell carcinoma, small intestine cancer, smooth muscle carcinoma, soft tissue cancer, somatostatin-secreting tumor, spinal cancer, squamous cell carcinoma, rhabdomyosarcoma, submesothelial cancer, superficial spreading melanoma, T-cell leukemia, tongue cancer, undifferentiated carcinoma, ureteral cancer, urethral cancer, urinary bladder cancer, urinary system cancer, cervical cancer, uterine cancer, uveal melanoma, vaginal cancer, verrucous carcinoma, VIP-producing tumor, vulvar cancer, well-differentiated carcinoma, or Wilms' tumor. In certain embodiments, the cancer is selected from the group consisting of gastrointestinal cancer and genitourinary cancer.

[0205] In some embodiments, an anti-FXI / FXIa antibody or antigen-binding fragment (e.g., antibody 1) described herein is administered prophylactically, e.g., to prevent clotting in a subject at risk for thrombosis. In some embodiments, an anti-FXI / FXIa antibody or antigen-binding fragment (e.g., antibody 1) described herein is administered therapeutically, e.g., to treat blood clots in a subject at risk for thrombosis.

[0206] In some embodiments, an anti-FXI / FXIa antibody or antigen-binding fragment thereof (e.g., antibody 1) is administered to a subject with cancer-associated thrombosis (CAT). In certain embodiments, the subject with cancer-associated thrombosis has a pre-existing blood clot. In certain embodiments, the subject has microclots. In certain embodiments, the subject has microthrombosis associated with CAT.

[0207] The CHA2DS2-VASc risk score is a validated and widely used stratification tool for predicting thromboembolic risk in AF patients and for identifying patients who should benefit from anticoagulant therapy (LIP 2011; Camm, et al. (2012) Eur Heart J 2012; 33: 2719-2747); accumulating evidence indicates that CHA2DS2-VASc is at least as accurate, or in some cases better, than scores such as CHADS2 in identifying patients who will develop stroke and thromboembolism, and is definitely better at identifying AF patients who are "truly at low risk". CHA2DS2-VASc risk scores range from 0 to a maximum score of 9. In certain embodiments, the CHA2DS2-VASc risk score for subjects treated with the factor XI and / or factor XIa antibodies or pharmaceutical preparations disclosed herein is 0-1 for men and 1-2 for women. In certain embodiments, subjects treated with a Factor XI and / or Factor XIa antibody or pharmaceutical preparation disclosed herein have a CHA2DS2-VASc risk score of >2 for men and >3 for women. In certain embodiments, subjects treated with a Factor XI and / or Factor XIa antibody or pharmaceutical preparation disclosed herein have a CHA2DS2-VASc risk score of >4 or >3 and at least one of a concomitant antiplatelet drug (e.g., aspirin and / or P2Y12 inhibitor) regimen or a CrCl <50 ml / min by Cockcroft-Gault equation.

[0208] The factor XI and / or factor XIa antibodies (e.g., antibody 1) disclosed herein can be used as a monotherapy or in combination with one or more therapies. Such combination therapy can be useful for treating thromboembolic disorders such as ischemic stroke (cardioembolic, thrombotic) or systemic embolism, AF, prevention of stroke due to AF (SPAF), deep vein thrombosis, venous thromboembolism, pulmonary embolism, acute coronary syndrome (ACS), acute limb ischemia, chronic thromboembolic pulmonary hypertension, or systemic embolism). In certain embodiments, factor XI and / or factor XIa antibodies are used as a monotherapy according to the dosing regimen disclosed herein. In other embodiments, factor XI and / or factor XIa antibodies are used in combination with one or more therapies, where factor XI and / or factor XIa antibodies are administered according to the dosing regimen disclosed herein, and one or more therapies are administered according to a dosing regimen known to be suitable for treating a particular subject with a particular disorder.

[0209] In some embodiments, statin therapy may be used in combination with the FXI / FXIa antibodies and antigen-binding fragments described herein, or formulations comprising said FXI / FXIa antibodies and antigen-binding fragments (e.g., Antibody 1), to treat patients with thrombotic and / or thromboembolic disorders. In certain embodiments, non-limiting examples of therapeutically active agents suitable for use in combination with the anti-FXI / FXIa antibodies (e.g., Antibody 1) described herein include thromboxane inhibitors (e.g., aspirin), adenosine diphosphate receptor antagonists (or P2Y12 inhibitors) such as thienopyridines (e.g., clopidogrel and prasugrel) and non-thienopyridines (e.g., ticagrelor and cangrelor), protease-activated receptor-1 (PAR1) antagonists (e.g., vorapaxar and atopaxar), and proton pump inhibitors (PPIs) (e.g., omeprazole, diazepam, phenytoin, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole, esomeprazole, and naproxen). The use of PPI in combination therapy may be appropriate when the subject has GI disorder or history of GI disorder, such as previous GI bleeding or prodromal symptoms of peptic ulcer. In one aspect, the subject is undergoing treatment with a nonsteroidal anti-inflammatory drug (NSAID) and is administered anti-FXI / FXIa antibody (e.g., antibody 1) described herein in combination with a proton pump inhibitor (e.g., omeprazole, diazepam, phenytoin, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole, esomeprazole, and naproxen). In certain embodiments, the subject undergoing treatment with FXI / FXIa antibody and antigen-binding fragment, or a formulation comprising said FXI / FXIa antibody and antigen-binding fragment (e.g., antibody 1), is administered a direct oral anticoagulant (DOAC) after the duration of treatment (e.g., the same day as the end of treatment).In certain embodiments, a vitamin K antagonist (VKA) is administered to a subject undergoing treatment with FXI / FXIa antibodies and antigen-binding fragments, or formulations containing the FXI / FXIa antibodies and antigen-binding fragments (e.g., Antibody 1), following the duration of treatment (e.g., about 5 days prior to the end of treatment, or about 3 days prior to the end of treatment).

[0210] In certain embodiments, the treatment methods disclosed herein result in improved disease response or survival of the subject or patient. For example, in certain embodiments, the disease response is complete response, partial response, or stable disease. In certain embodiments, the improved survival is improved progression-free survival (PFS) or overall survival. The improvement (e.g., improved PFS) can be determined relative to the period before the treatment of the present disclosure is started. Methods for determining disease response (e.g., complete response, partial response, or stable disease) and patient survival (e.g., PFS, overall survival) to the treatment of BTC (e.g., advanced BTC, metastatic BTC) or bile duct tumors are routine in the art and are contemplated by the present invention. In some embodiments, disease response is evaluated according to RECIST 1.1 after the treated patient is subjected to contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the affected area (e.g., chest / abdomen and pelvis extending from the upper area of ​​the thoracic rim to the pubic symphysis). Enumeration of embodiments 1. A method for treating a disease or disorder in a subject in need thereof, comprising the steps of intravenously administering to the subject a first dose of about 150 mg of an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or antigen-binding fragment thereof, and subcutaneously administering to the subject a second dose of the isolated anti-FXI and / or anti-FXIa antibody or antigen-binding fragment thereof. 2. The method of embodiment 1, wherein the second dose comprises about 150 mg of isolated anti-FXI and / or anti-FXIa antibody or antigen-binding fragment thereof. 3. The method of embodiment 1 or 2, wherein the first dose of the isolated anti-FXI and / or anti-FXIa antibody or antigen-binding fragment thereof is formulated as an intravenous drug delivery formulation comprising about 150 mg of the antibody or antigen-binding fragment thereof. 4. The method of any one of embodiments 1 to 3, wherein the second dose of the isolated anti-FXI and / or anti-FXIa antibody or antigen-binding fragment thereof is formulated as a subcutaneous drug delivery formulation comprising about 150 mg of the antibody or antigen-binding fragment thereof. 5. The method of any one of embodiments 1 to 4, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising complementarity determining regions HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 9 or 29; and a light chain variable region (VL) comprising complementarity determining regions LCDR1, LCDR2, LCDR3 in SEQ ID NO: 19 or 39. 6. The antibody or antigen-binding fragment thereof i. heavy chain variable region CDR1 of SEQ ID NO:23; heavy chain variable region CDR2 of SEQ ID NO:24; heavy chain variable region CDR3 of SEQ ID NO:25; light chain variable region CDR1 of SEQ ID NO:33; light chain variable region CDR2 of SEQ ID NO:34; and 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 that is KNY 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 that is KNY; and a light chain variable region CDR3 of SEQ ID NO: 15; or iv. Heavy chain variable region CDR1 of SEQ ID NO: 46; heavy chain variable region CDR2 of SEQ ID NO: 4; heavy chain variable region CDR3 of SEQ ID NO: 5; light chain variable region CDR1 of SEQ ID NO: 33; light chain variable region CDR2 of SEQ ID NO: 14; and light chain variable region CDR3 of SEQ ID NO: 15. 6. The method of any one of embodiments 1 to 5, comprising: 7. The method of any one of embodiments 1 to 6, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) selected from the group consisting of SEQ ID NOs: 9, 29 and having 90% identity thereto; and a light chain variable region (VL) selected from the group consisting of SEQ ID NOs: 19, 39 and having 90% identity thereto. 8. The method of any one of embodiments 1 to 7, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) selected from the group consisting of SEQ ID NOs: 9 and 29; and a light chain variable region (VL) selected from the group consisting of SEQ ID NOs: 19 and 39. 9. The method of any one of embodiments 1 to 8, wherein the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 31, 11 and a heavy chain having 90% identity thereto; and a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41, 21 and a light chain having 90% identity thereto. 10. The method of any one of embodiments 1 to 9, wherein the antibody comprises 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. 11. The method of any one of embodiments 1 to 10, wherein the antibody is a human monoclonal antibody. 12. The method of embodiment 11, wherein the antibody is of the human IgG1 isotype. 13. The method of embodiment 11 or 12, wherein the antibody comprises a D265A substitution and a P329A substitution in the Fc domain. 14. The method of any one of embodiments 1 to 13, wherein the antibody or antigen-binding fragment thereof is administered in a drug delivery formulation comprising a histidine buffer at a concentration of about 20 mM. 15. The method of any one of embodiments 1 to 14, wherein the antibody or antigen-binding fragment thereof is administered in a drug delivery formulation comprising sucrose at a concentration of about 220 mM. 16. The method of any one of embodiments 1 to 15, wherein the antibody or antigen-binding fragment thereof is administered in a drug delivery formulation comprising polysorbate 20 at a concentration of about 0.04%. 17. The method of any one of embodiments 1 to 16, wherein the antibody or antigen-binding fragment thereof is administered in a drug delivery formulation at pH 5.5. 18. The method of any one of embodiments 1 to 17, wherein when the antibody or antigen-binding fragment thereof is administered in an intravenous drug delivery formulation, the intravenous drug delivery formulation further comprises about 5% glucose. 19. The method of any one of embodiments 1 to 18, wherein the subject has cancer. 20. The method of any one of embodiments 1 to 19, wherein the subject has a cancer selected from the group consisting of gastrointestinal cancer and genitourinary cancer. 21. The method of any one of embodiments 1 to 20, wherein the subject is at high risk of venous thromboembolism. 22. The method of any one of embodiments 1 to 21, wherein the subject has one or more prior venous thromboembolism events. 23. The method of any one of embodiments 1 to 22, further comprising one or more additional subcutaneous doses of the antibody or antigen-binding fragment thereof. 24. The method of any one of embodiments 1 to 23, comprising administering five subcutaneous doses of the antibody or antigen-binding fragment thereof. 25. The method of any one of embodiments 1 to 24, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously about once a month. 26. The method of any one of embodiments 1 to 25, wherein the antibody or antigen-binding fragment thereof is administered intravenously on day 1, and subcutaneously on days 31, 61, 91, 121, and 151. 27. The method of any one of embodiments 1 to 26, wherein the subject is treated for about 6 months. 28. A method for treating a subject having cancer, comprising administering to a subject in need thereof a drug delivery formulation comprising about 150 mg of an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or antigen-binding fragment thereof, wherein the drug delivery formulation is administered intravenously once and then subcutaneously about once a month, treating the subject for about 6 months. 29. The method of embodiment 28, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising the complementarity determining regions HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 9 or 29; and a light chain variable region (VL) comprising the complementarity determining regions LCDR1, LCDR2, LCDR3 in SEQ ID NO: 19 or 39. 30. The antibody or antigen-binding fragment thereof, i. heavy chain variable region CDR1 of SEQ ID NO:23; heavy chain variable region CDR2 of SEQ ID NO:24; heavy chain variable region CDR3 of SEQ ID NO:25; light chain variable region CDR1 of SEQ ID NO:33; light chain variable region CDR2 of SEQ ID NO:34; and 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 that is KNY; 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 that is KNY; and a light chain variable region CDR3 of SEQ ID NO: 15; or iv. Heavy chain variable region CDR1 of SEQ ID NO: 46; heavy chain variable region CDR2 of SEQ ID NO: 4; heavy chain variable region CDR3 of SEQ ID NO: 5; light chain variable region CDR1 of SEQ ID NO: 33; light chain variable region CDR2 of SEQ ID NO: 14; and light chain variable region CDR3 of SEQ ID NO: 15. 30. The method of any one of embodiments 28 to 29, comprising: 31. The method of any one of embodiments 28 to 30, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) selected from the group consisting of SEQ ID NOs: 9, 29 and 90% identity thereto; and a light chain variable region (VL) selected from the group consisting of SEQ ID NOs: 19, 39 and 90% identity thereto. 32. The method of any one of embodiments 28 to 31, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) selected from the group consisting of SEQ ID NOs: 9 and 29; and a light chain variable region (VL) selected from the group consisting of SEQ ID NOs: 19 and 39. 33. The method of any one of embodiments 28 to 32, wherein the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 31, 11 and a heavy chain having 90% identity thereto; and a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41, 21 and a light chain having 90% identity thereto. 34. The method of any one of embodiments 28 to 33, wherein the antibody comprises 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. 35. The method of any one of embodiments 28 to 34, wherein the antibody is a human monoclonal antibody. 36. The method of embodiment 35, wherein the antibody is of the human IgG1 isotype. 37. The method of embodiment 35 or 36, wherein the antibody comprises a D265A substitution and a P329A substitution in the Fc domain. 38. The method of any one of embodiments 28 to 37, wherein the cancer is selected from the group consisting of gastrointestinal cancer and genitourinary cancer. 39. A method of treating a primate subject at risk for thrombosis, comprising administering to the primate subject: (a) a therapeutically effective amount of an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or antigen-binding fragment thereof in a concentration of about 150 mg; (b) a histidine buffer at a concentration of about 20 mM; (c) sucrose at a concentration of about 220 mM; and (d) polysorbate 20 at a concentration of about 0.04% (v / v); (e) a diluent containing glucose administering a single dose of a drug delivery formulation having a pH of 5.5, comprising: The administering step is before or during the formation of a blood clot. method. 40. The method of embodiment 39, wherein the primate subject is a baboon. 41. The method of embodiment 39, wherein the primate subject is a human. 42. The method of embodiment 39 or 40, wherein the thrombosis is experimentally induced thrombosis. 43. The method of any one of embodiments 39 to 42, wherein the primate subject is at risk for vascular graft thrombosis. 44. The method of any one of embodiments 39 to 43, wherein a single dose is administered to prevent thrombosis. 45. The method of any one of embodiments 39 to 43, wherein a single dose is administered to treat thrombosis. 46. ​​The method of any one of embodiments 39 to 45, wherein the single dose is parenteral or intravenous. 47. The method of any one of embodiments 39 to 46, wherein the single dose is parenteral. 48. The method of any one of embodiments 39 to 47, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising the complementarity determining regions HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 9 or 29; and a light chain variable region (VL) comprising the complementarity determining regions LCDR1, LCDR2, LCDR3 in SEQ ID NO: 19 or 39. 49. The antibody or antigen-binding fragment thereof i. heavy chain variable region CDR1 of SEQ ID NO:23; heavy chain variable region CDR2 of SEQ ID NO:24; heavy chain variable region CDR3 of SEQ ID NO:25; light chain variable region CDR1 of SEQ ID NO:33; light chain variable region CDR2 of SEQ ID NO:34; and 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 that is KNY 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 that is KNY and a light chain variable region CDR3 of SEQ ID NO: 15; or iv. Heavy chain variable region CDR1 of SEQ ID NO: 46; heavy chain variable region CDR2 of SEQ ID NO: 4; heavy chain variable region CDR3 of SEQ ID NO: 5; light chain variable region CDR1 of SEQ ID NO: 33; light chain variable region CDR2 of SEQ ID NO: 14; and light chain variable region CDR3 of SEQ ID NO: 15. 49. The method of any one of embodiments 39 to 48, comprising: 50. The method of any one of embodiments 39 to 49, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) selected from the group consisting of SEQ ID NOs: 9, 29 and 90% identity thereto; and a light chain variable region (VL) selected from the group consisting of SEQ ID NOs: 19, 39 and 90% identity thereto. 51. The method of any one of embodiments 39 to 50, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) selected from the group consisting of SEQ ID NOs: 9 and 29; and a light chain variable region (VL) selected from the group consisting of SEQ ID NOs: 19 and 39. 52. The method of any one of embodiments 39 to 51, wherein the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 31, 11 and a heavy chain having 90% identity thereto; and a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41, 21 and a light chain having 90% identity thereto. 53. The method of any one of embodiments 39 to 52, wherein the antibody comprises 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. 54. The method of any one of embodiments 39 to 53, wherein the antibody is a human monoclonal antibody. 55. The method of embodiment 54, wherein the antibody is of the human IgG1 isotype. 56. The method of embodiment 54 or 55, wherein the antibody comprises a D265A substitution and a P329A substitution in the Fc domain. 57. The method of any one of embodiments 39 to 40 or 42 to 56, wherein, for administration to a primate subject, the therapeutically effective amount of the anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or antigen-binding fragment thereof is about 1 mg / kg. 58. The method of any one of embodiments 39, 41, or 43 to 56, wherein, for administration to a primate subject, the therapeutically effective amount of the anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or antigen-binding fragment thereof is about 150 mg. 59. A method of treating a subject having thrombocytopenia, wherein the thrombocytopenia is selected from the group consisting of chemotherapy-induced thrombocytopenia, congenital thrombocytopenia, thrombocytopenia associated with infection, and idiopathic thrombocytopenia, the method comprising administering a therapeutically effective amount of a factor XI and / or factor XIa antibody or antigen-binding fragment thereof to a subject in need thereof. 60. The method of embodiment 59, wherein the subject with thrombocytopenia has cancer. 61. The method of embodiment 59 or 60, wherein the subject with thrombocytopenia has cirrhosis. 62. The method of embodiment 59 or 60, wherein the subject with thrombocytopenia has idiopathic thrombocytopenic purpura (ITP). 63. A method for treating a cancer subject with chemotherapy-induced thrombocytopenia, comprising administering a therapeutically effective amount of a factor XI and / or factor XIa antibody or antigen-binding fragment thereof to a cancer subject in need thereof. 64. The method of any one of embodiments 59 to 63, wherein the subject or cancer subject is suffering from or at risk of developing a thromboembolic disorder. 65. The method of any one of embodiments 59 to 64, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising the complementarity determining regions HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 9 or 29; and a light chain variable region (VL) comprising the complementarity determining regions LCDR1, LCDR2, LCDR3 in SEQ ID NO: 19 or 39. 66. The antibody or antigen-binding fragment thereof i. heavy chain variable region CDR1 of SEQ ID NO:23; heavy chain variable region CDR2 of SEQ ID NO:24; heavy chain variable region CDR3 of SEQ ID NO:25; light chain variable region CDR1 of SEQ ID NO:33; light chain variable region CDR2 of SEQ ID NO:34; and 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 that is KNY; 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 that is KNY; and a light chain variable region CDR3 of SEQ ID NO: 15; or iv. Heavy chain variable region CDR1 of SEQ ID NO: 46; heavy chain variable region CDR2 of SEQ ID NO: 4; heavy chain variable region CDR3 of SEQ ID NO: 5; light chain variable region CDR1 of SEQ ID NO: 33; light chain variable region CDR2 of SEQ ID NO: 14; and light chain variable region CDR3 of SEQ ID NO: 15. 66. The method of any one of embodiments 59 to 65, comprising: 67. The method of any one of embodiments 59 to 66, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) selected from the group consisting of SEQ ID NOs: 9, 29 and 90% identity thereto; and a light chain variable region (VL) selected from the group consisting of SEQ ID NOs: 19, 39 and 90% identity thereto. 68. The method of any one of embodiments 59 to 67, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) selected from the group consisting of SEQ ID NOs: 9 and 29; and a light chain variable region (VL) selected from the group consisting of SEQ ID NOs: 19 and 39. 69. The method of any one of embodiments 59 to 68, wherein the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 31, 11 and a heavy chain having 90% identity thereto; and a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41, 21 and a light chain having 90% identity thereto. 70. The method of any one of embodiments 59 to 69, wherein the antibody comprises 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. 71. The method of any one of embodiments 59 to 70, wherein the antibody is a human monoclonal antibody. 72. The method of embodiment 71, wherein the antibody is of the human IgG1 isotype. 73. The method of embodiment 71 or 72, wherein the antibody comprises a D265A substitution and a P329A substitution in the Fc domain. 74. The method of any one of embodiments 59 to 73, wherein administration of the antibody or antigen-binding fragment thereof does not affect platelet aggregation in the subject compared to platelet aggregation prior to administration. 75. The method of embodiment 74, wherein platelet aggregation is measured by impedance aggregometry. 76. The method of embodiment 75, wherein platelet aggregation is induced by collagen, adenosine 5'-diphosphate (ADP), or thrombin receptor-activating peptide-6 (TRAP-6). 77. The method of any one of embodiments 74 to 76, wherein platelet aggregation is determined ex vivo or in vitro. 78. The method of any one of embodiments 59 to 77, wherein the antibody or antigen-binding fragment thereof is administered intravenously. 79. The method of any one of embodiments 59 to 78, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously. 80. The method of any one of embodiments 59 to 78, wherein a first dose of the antibody or antigen-binding fragment thereof is administered intravenously, and a second dose of the antibody or antigen-binding fragment thereof is administered subcutaneously. 81. The method of embodiment 80, further comprising one or more additional doses of the antibody or antigen-binding fragment thereof administered subcutaneously after administering the second dose. 82. The method of any one of embodiments 59 to 81, wherein the antibody or antigen-binding fragment thereof is administered once a month. EXAMPLES

[0211] The disclosure, having been generally described, will now be more readily understood by reference to the following examples, which are included solely for the purpose of illustrating certain aspects and embodiments of the disclosure, and are not intended to limit the scope of the disclosure in any way.

[0212] Example 1 Treatment with Antibody 1 Compared to Apixaban in Patients with Cancer-Associated Thromboembolism Objectives and Rationale The objective of this study is to evaluate whether monthly treatment with Antibody 1 is non-inferior to oral apixaban twice daily (bid) in preventing recurrent venous thromboembolism (VTE) but superior in terms of bleeding rates in patients with cancer and recently diagnosed VTE. This study supports the global registration of Antibody 1 for the treatment of cancer-associated VTE. CAT occurs in an estimated 20% of cancer patients and is the second leading cause of death in patients with malignant disease. Current treatments inhibit one or more factors in the coagulation cascade, which effectively prevent or treat thrombosis, but also interfere with hemostasis, resulting in an increased risk of bleeding. Fear of bleeding and lack of tolerability of available treatments lead to significant undertreatment and poor outcomes.

[0213] The two most common treatments currently available are low molecular weight heparins (LMWHs) and direct acting oral anticoagulants (DOACs), each with their own limitations. LMWHs are the SoC in the majority of parts of the world, but require daily injections over a 6-month period. Unfortunately, patients treated with LMWHs are less likely to persist with therapy compared to other orally administered treatments. DOACs are administered orally and are considered a more tolerated alternative, but some cancer patients have difficulty swallowing or experience vomiting, which leads to poor adherence.

[0214] The goal of developing new treatments for CAT, especially for patients with CAT who are at high risk for bleeding, is to reduce bleeding and improve tolerability while maintaining the same level of efficacy as current agents.

[0215] Objectives and Evaluation Items The primary objective of this study was to evaluate whether Antibody 1 was non-inferior to apixaban in preventing VTE recurrence through 6 months after randomization in patients with cancer and recently diagnosed VTE, with the endpoint being time to first event of centrally adjudicated VTE recurrence through 6 months.

[0216] Secondary objectives of this study are to: To evaluate whether antibody 1 is superior to apixaban in preventing the occurrence of a composite of major or clinically relevant non-major (CRNM) bleeding events through 6 months after randomization. The endpoint is time to first major or CRNM bleeding event as determined by the International Society on Thrombosis and Haemostasis (ISTH) through 6 months. To evaluate whether antibody 1 is superior to apixaban in terms of net clinical benefit defined as survival without VTE recurrence or major or CRNM bleeding events through 6 months after randomization. Endpoints are time to first event of VTE recurrence, ISTH-defined major bleeding event or ISTH-defined CRNM bleeding event through 6 months. To evaluate whether antibody 1 is superior to apixaban in preventing recurrent VTE at 6 months after randomization. The outcome measure is time to first event of recurrent VTE as determined by a central laboratory through 6 months. To evaluate whether antibody 1 is superior to apixaban in terms of permanent non-death discontinuation rates through 6 months post-randomization. The endpoint is time to permanent non-death discontinuation event. To evaluate whether antibody 1 is superior to apixaban in preventing the occurrence of CRNM bleeding events through 6 months after randomization. The outcome measure is time to first CRNM bleeding event as determined by ISTH through 6 months. To evaluate whether antibody 1 is superior to apixaban in preventing the occurrence of major bleeding events through 6 months after randomization. The outcome measure is time to first major bleeding event as determined by ISTH through 6 months. To evaluate whether antibody 1 is superior to apixaban in preventing the occurrence of a composite of GI major bleeding and GI CRNM bleeding through 6 months after randomization. Endpoints are time to first GI ISTH-determined major bleeding event and CRNM bleeding event through 6 months. To evaluate the safety and tolerability of Antibody 1 compared to dalteparin through 6 months post-randomization, and to evaluate the incidence of injection site reactions, hypersensitivity reactions, and immunogenicity in patients treated with Antibody 1. Endpoints include all-cause death, vascular death, serious adverse events, adverse events leading to drug discontinuation, other adverse events, and abnormal laboratory tests, expressed as rates per 100 patient-years. Additional endpoints for patients treated with Antibody 1 include: Percentage of patients with injection site reactions Percentage of patients with injection site reactions by severity status Percentage of patients with hypersensitivity reactions Percentage of patients with hypersensitivity reactions by severity level Percentage of patients with ADA formation Percentage of patients with persistent ADA formation o The percentage of patients with neutralizing antibody (NAb) formation.

[0217] The exploratory objectives of this study are to: To evaluate the effect of Antibody 1 compared to apixaban on a composite of VTE recurrence, major bleeding events or death from any cause. The endpoint is time to first event of a composite endpoint of VTE recurrence, major bleeding or death from any cause. To evaluate the effect of antibody 1 compared to apixaban on arterial thromboembolic events (e.g. stroke, myocardial infarction, arterial embolic events). The endpoint is time to first event of ischemic stroke, or a composite endpoint of myocardial infarction or arterial embolic events. To evaluate the effect of antibody 1 compared to apixaban on venous thromboembolic events other than those qualifying as VTE recurrence (e.g., lower extremity distal DVT, upper extremity DVT, thoracic vein, intracranial or extracranial cerebral vein, visceral DVT and central venous catheter-related thrombosis). Endpoints will be time to first event of DVT recurrence or other venous thromboembolic events and the composite endpoint of time to first event of the following venous thromboembolic events: lower extremity distal DVT, upper extremity DVT, thoracic vein, intracranial or extracranial cerebral vein, visceral DVT or central venous catheter-related thrombosis. To evaluate the effect of antibody 1 compared to apixaban on the number and duration of temporary treatment interruptions not due to procedures or bleeding events. Endpoints will be the number of temporary treatment interruptions not due to procedures or bleeding events and the total duration of temporary treatment interruptions not due to procedures or bleeding events. To evaluate the efficacy and safety of Antibody 1 compared to apixaban in predefined patient subgroups (e.g., sex, age, BMI, ethnicity, cancer location, incident vs symptomatic VTE, presence or absence of PE, days on SoC prior to randomization, ECOG). Endpoints are time to first event of central laboratory-determined VTE recurrence through 6 months in predefined patient subgroups and time to first event of ISTH-defined major bleeding events and CRNM bleeding events through 6 months in predefined patient subgroups. To evaluate the effect of Antibody 1 compared to apixaban on health-related quality of life (HRQoL) at 3 and 6 months, and to evaluate the change over time in EQ-5D-5L in patients presenting with suspected VTE recurrence and suspected bleeding events. ○EQ-5D-5L questionnaire ○EORTC QLQ C30 Questionnaire ○TSQM II Questionnaire The objectives of the study were to assess the change from baseline in scores by domain of EQ-5D-5L, as well as the serial change over time in the EQ-5D-5L questionnaire after suspected VTE recurrence and bleeding events. To evaluate the PK of Antibody 1 in a subset of patients. Endpoints include random, peak and trough plasma concentrations of Antibody 1. To evaluate the PD of Antibody 1 (free and total FXI, FXI:C, aPTT) in a subset of patients. Endpoints include free and total FXI, FXI:C and aPTT at the time points indicated. To evaluate the effect of Antibody 1 compared to apixaban on exploratory biomarkers of hypercoagulable states (potentially including but not limited to d-dimer, F1.2, TAT) in a subset of patients. Endpoints will be change from baseline in biomarkers of hypercoagulable states, which may include d-dimer, F1.2 and TAT, across treatment arms. Cost-effectiveness analysis of VTE (e.g. hospitalizations, transfusions, procedures to stop bleeding or manage VTE, outpatient visits). The outcome measure is resource utilization. DNA evaluation to explore whether individual genetic variations in genes related to the drug target pathway or other relevant genetic pathways confer differential response to Antibody 1. Endpoints will be an exploratory evaluation of associations between genetic polymorphisms and safety, efficacy, PK, and PD responses.

[0218] Test Design This is a randomized, open-label, blinded endpoint evaluation (PROBE), active controlled study comparing the effect of Antibody 1 with apixaban on VTE recurrence in patients with cancer.

[0219] Patients with cancer confirmed by histology and / or valid imaging modalities and newly diagnosed, objectively confirmed symptomatic or incidental proximal lower extremity acute DVT or symptomatic pulmonary embolism (PE), or incidentally detected PE in the segmental pulmonary artery or more proximal pulmonary arteries, will be eligible for study entry within 72 hours of VTE diagnosis.

[0220] After presentation, patients who consent to study participation should undergo a screening / run-in period of up to 72 hours for confirmation of eligibility criteria. During the screening / run-in period, SoC treatment for VTE (e.g., direct-acting oral anticoagulants [DOACs] at recommended doses, unfractionated heparin [UFH], LMWH, or fondaparinux) should be administered. Patients who continue to meet all inclusion / exclusion criteria will be randomized 1:1 to antibody 1 or apixaban. Patients will be stratified by study region, cancer location (GI / GU vs. other), and symptomatic vs. incident VTE. Patients assigned to antibody 1 will receive antibody 1, 150 mg intravenously (iv) on day 1, followed by 150 mg subcutaneous (sc) dosing once a month for an additional 5 months, starting approximately 30 days (± 5 days) after the iv dose (total of 6 treatments). Patients assigned to apixaban will receive apixaban 10 mg orally (po) twice daily (bid) for 7 days starting immediately after randomization, then 5 mg po bid for a total duration of treatment of 6 months. If a patient is receiving apixaban at a dose of 10 mg bid without interruption during screening and is randomized to the apixaban treatment arm, the duration of treatment during study participation with the 10 mg bid dose will be shortened so that no patient receives apixaban at a dose of 10 mg bid for more than 7 days total.

[0221] First-time VTE events, suspected recurrent VTE events, deaths, bleeding events, arterial thromboembolic events, and other venous thromboembolic events will be reviewed by a Clinical Event Committee (CEC). CEC members will be blinded to treatment assignment. Adjudication of the above events occurring through the end of study visit will be made for all randomized patients.

[0222] Patients who complete 6 months of treatment or who prematurely discontinue study treatment will enter a follow-up period of up to 70 days.

[0223] Group Adult male or female subjects with confirmed (histology, valid imaging modality) unresectable GI or GU cancer and acute symptomatic VTE (within 72 hours of diagnosis of qualifying VTE) prior to randomization and a demonstrated need for long-term treatment with LMWH will be eligible for study participation; approximately 1020 patients are expected to be randomized in the study.

[0224] Selection Criteria Inclusion / exclusion criteria must be verified at screening and baseline; patients must meet all of the following criteria at both visits to be eligible for inclusion in the study: Key eligibility criteria include the following (all of the following must be met at the screening and randomization visits): · Male or female, aged 18 or older, or another legal age of maturity depending on your country of residence A confirmed diagnosis of cancer other than exclusively basal or squamous cell carcinoma of the skin (by histology or a valid imaging modality) with one of the following: Active cancer at the time of randomization, defined as either locally active, locally invasive, or metastatic cancer, and / or Currently receiving or have received within the past 6 months any anti-cancer treatment (radiotherapy, chemotherapy, hormonal therapy, any type of targeted therapy, or any other anti-cancer treatment) Confirmed symptomatic or incident acute proximal lower extremity DVT (i.e., venous thrombosis of the popliteal, femoral, iliac, and / or inferior vena cava) and / or confirmed symptomatic or incident PE in the segmental or larger pulmonary arteries. Patients are eligible within 72 hours of diagnosis of a qualifying VTE. - The need for anticoagulant therapy with a therapeutic dose of DOAC for at least 6 months has been demonstrated. -Ability to provide written informed consent

[0225] Exclusion criteria Patients meeting any of the following criteria were ineligible for inclusion in the study: Thrombectomy, insertion of a vena cava filter, or use of fibrinolysin to treat a current (first) episode of DVT and / or PE >72 hours after conditioning with therapeutic doses of UFH, LMWH, fondaparinux, DOAC, or other anticoagulants - Indicated need for continued treatment with therapeutic doses of anticoagulants other than those used for VTE treatment prior to randomization (e.g., atrial fibrillation, mechanical heart valve, previous VTE) Platelet count 50,000 / mm 3 If less than PE resulting in unstable hemodynamics (systolic blood pressure [BP] < 90 mmHg or shock) Acute ischemic or hemorrhagic stroke or intracranial hemorrhage within 4 weeks prior to screening Brain trauma or cerebral or spinal surgery within 4 weeks prior to screening -requiring aspirin in doses greater than 100 mg per day, or any other antiplatelet agent, alone or in combination with aspirin Primary brain cancer or untreated intracranial metastases Acute myeloid or lymphocytic leukemia Bleeding requiring medical attention at or within 4 weeks prior to randomization - If major surgery is planned at baseline Eastern Cooperative Oncology Group (ECOG) performance status of 3 or 4 at screening - Life expectancy at the time of randomization is less than 3 months -Calculated creatinine clearance (CrCl) is less than 30 mL per minute If your hemoglobin level is less than 8g / dL Acute hepatitis, chronic active hepatitis, cirrhosis; or an alanine aminotransferase level three times or higher than the upper limit of the normal range and / or a bilirubin level two times or higher than the upper limit of the normal range without clinical explanation Uncontrolled hypertension (systolic BP>180mm Hg or diastolic BP>100mm Hg despite antihypertensive treatment) Women of childbearing potential (WOCBP) who are unwilling or unable to use highly effective contraception for the duration of the study from screening through 3 days after the last treatment with apixaban or 100 days after administration of antibody 1 Sexually active men with sexual partners of childbearing potential must agree to use condoms or other reliable contraception until 3 days after their last treatment with apixaban or 100 days after administration of antibody 1. Pregnant or breastfeeding women Patients known to be receiving strong dual inducers or inhibitors of both CYP3A4 and P-gp History of hypersensitivity to the study drug (including apixaban) or any of its excipients, to drugs in a similar chemical class, or to any contraindication listed in the labeling for apixaban Subjects who, in the opinion of the investigator, have any condition that places them at high risk of harm if they participate in the study Use of other investigational (non-registered) medications within 5 half-lives prior to enrollment or until predicted pharmacodynamic effects have returned to baseline, whichever is longer. Participation in academic non-interventional or interventional trials, including testing different strategies or different combinations of registered medications, is acceptable.

[0226] Dosage and Administration On Day 1, patients will be randomized in a 1:1 ratio to one of the following treatment arms: Antibody 1, 150 mg iv, followed by monthly 150 mg sc injections for 5 months (total duration of treatment is 6 months) Apixaban 10 mg po bid for 7 days, then 5 mg po bid for 5.75 months (total duration of treatment is 6 months)

[0227] Randomization to treatment groups will be stratified by region, cancer location (GI / GU vs other location), and VTE episodes (symptomatic vs incident).

[0228] Once a subject has been stratified and randomized, the subject will remain in his or her original stratum and randomized treatment group for analysis purposes, even if the subject's treatment or administered dose is subsequently adjusted.

[0229] Distribution of study drugs antibody 1 Each study site will be supplied with Antibody 1 in single-use vials. A unique kit number will be printed on the label of the vial corresponding to the Antibody 1 treatment arm. The study drug vial used for a patient will be identified by study staff contacting the IxRS to obtain the kit number that contains that vial.

[0230] At the Day 1 visit, patients will receive Antibody 1 via 60-minute iv infusion by qualified medical personnel at the study center. For this first dose, patients must remain at the study center for at least 1 hour after administration of study drug to monitor for any infusion reactions, hypersensitivity reactions, or other AEs. Beginning with the second dose (first sc dose), patients will return to the study center monthly to receive sc doses of study drug and to complete the visit procedures.

[0231] Apixaban Each study site will be provided with a carton of apixaban 5 mg tablets. On Day 1, patients assigned to apixaban will receive their supply of apixaban and will be instructed to take two 10 mg doses approximately 12 hours apart on that day. Patients will take 10 mg bid for 7 days, then 5 mg bid for the remainder of the treatment period. If patients were taking apixaban during the screening period, the total number of days they take 10 mg bid should not exceed 7 days. Throughout the study, apixaban will be distributed at appropriate intervals to ensure that patients have an adequate supply of study medication between study visits. Treatment compliance will be monitored throughout the study.

[0232] safety Physical Examination The physical examination should include evaluation of the general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, musculoskeletal, vascular, and neurological.

[0233] Vital signs Vital signs include collection of oral temperature (°C), BP, and pulse.

[0234] Laboratory Evaluation Hemoglobin, hematocrit, red blood cell (RBC) count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), white blood cell (WBC) count with differential, and platelet count will be measured.

[0235] Measure sodium, potassium, creatinine, BUN / urea, uric acid, chloride, albumin, calcium, alkaline phosphatase, total bilirubin, bicarbonate / HCO3, AST, ALT, glucose, total cholesterol, and triglycerides. If total bilirubin is >2×ULN, direct and indirect reacting bilirubin should be differentiated.

[0236] Standard aPTT and prothrombin time / international normalized ratio (PT / INR) samples will be collected at the visits outlined in the evaluation schedule shown in Table 2.

[0237] Obtain a urine dipstick test for specific gravity, protein, glucose, and blood. If the urine dipstick test is abnormal, also evaluate microscopy, WBC, RBC, and sediment.

[0238] The primary safety variable will be for bleeding, defined as a secondary endpoint of the study and determined by the CEC. Bleeding events will be classified according to ISTH guidelines into major, CRNM, and other bleeding. These determined bleeding events will be summarized as part of the evaluation of the secondary objectives.

[0239] These bleeding events will also be included in the listing and analysis of all adverse effects, regardless of decision. All available information on adverse events (AEs) will be presented by treatment group and patient. AEs may also be presented for on-treatment and post-treatment periods. AEs will be presented as rates per 100 patient-years.

[0240] Electrocardiogram (ECG) ECGs will be performed at Screening, Baseline, EoT, and EoS visits. ECGs must be collected locally by a qualified physician at the study site, interpreted, appropriately signed, and archived at the study site.

[0241] Clinical events Effectiveness An independent and blinded CEC will adjudicate and classify the following events: Death from any cause All episodes of suspected DVT and recurrent PE Other suspected arterial thromboembolic events (e.g., ischemic stroke, TIA, arterial embolic events, myocardial infarction [MI]) and other VTE such as distal lower extremity DVT, upper extremity DVT, thoracic veins, large intracranial or extracranial veins, visceral DVT and central venous catheter-related thrombosis

[0242] The primary outcome of the study (recurrent VTE) consisted of a composite of confirmed (as determined by the CEC) VTE: Confirmed new symptomatic or incident proximal DVT of the lower extremities, iliac veins and / or IVC Confirmed new symptomatic PE Confirmed new incidental PE located in the segmental or more proximal pulmonary artery Fatal PE (including unexplained deaths where PE cannot be excluded)

[0243] Confirmed arterial thromboembolic events (e.g., stroke, TIA, acute MI, and arterial embolic events) and confirmed other VTE (e.g., new distal lower extremity DVT, upper extremity DVT, thoracic vein, intracranial or extracranial vein, visceral DVT, and central venous catheter-related thrombosis) will be analyzed as exploratory endpoints of the study.

[0244] Incidental DVT or PE is a thrombus detected during an imaging study (e.g., CT for cancer staging) that is not performed for suspected DVT or PE but for other reasons. A new thrombus detected incidentally in the IVC or iliac veins during abdominal or pelvic CT is considered valid for establishing a diagnosis of DVT recurrence. However, a new thrombus detected incidentally in the common femoral vein or more distal veins may qualify for DVT recurrence only if confirmed by CUS or venography.

[0245] bleeding All suspected bleeding events, whether reported by the subject or observed by the investigator, should be recorded.

[0246] Details of all reported bleeding events will be submitted to the CEC as described in the endpoint reporting guidelines. These details may include, but are not limited to, the following: ·Bleeding location Duration of bleeding Treatment for the bleeding event, including a note or summary of recommendations from the medical professional providing medical treatment, such as an ENT consultation for ear, nose, or throat bleeding; a urological consultation for hematuria or genitourinary tract bleeding; a surgical consultation for skin, soft tissue, or internal bleeding; a gynecological consultation for uterine or vaginal bleeding; a neurological or neurosurgical consultation for intracranial bleeding; or an ophthalmological consultation for eye bleeding. Number of blood product transfusions The size of the bleeding (e.g., the size if it is a cutaneous or subcutaneous hematoma) Hemoglobin levels at the time of the bleeding event, at the nadir, before and after transfusion, and after resolution of the bleeding event Any diagnostic tests performed to evaluate bleeding, such as endoscopy for GI bleeding Any diagnostic imaging performed to evaluate bleeding, e.g., X-ray, CT, MRI, or ultrasound

[0247] Serious bleeding events A major bleeding event was defined as meeting at least one of the following: a) Fatal hemorrhage b) Symptomatic bleeding in vital areas or organs such as: Intracranial (epidural, subdural, subarachnoid, intracerebral, undetermined). ·Intraocular Intraspinal Intra-articular Intramuscular with compartment syndrome Pericardium ·Retroperitoneum c) Clinically significant bleeding events Associated with a decrease in hemoglobin of 2.0 g / dL (>1.24 mMol / L) or greater; or - Transfusion of 2 or more units of packed red blood cells or whole blood

[0248] Clinically relevant non-serious bleeding events A bleeding event was defined as any event that was present with any sign or symptom of bleeding (e.g., bleeding more than would be expected in the clinical setting, including bleeding detected by imaging alone) but did not meet the criteria for the definition of major bleeding, including any of the following: - Medical intervention by a medical professional is required Leading to hospitalization or increased level of care Facilitate face-to-face (i.e., not just phone or electronic communication) assessments If at least one of the following conditions is met, the event is classified as a CRNM bleeding event.

[0249] Minor (clinically non-relevant) bleeding events Other overt bleeding events that do not meet the criteria for either major or CRNM bleeding events will be classified as minor bleeding events.

[0250] No bleeding All other suspected bleeding events (eg, a decrease in hemoglobin without overt bleeding or an incidental finding on imaging without further action, as described above) will be classified as "no bleeding."

[0251] Other evaluations Pharmacokinetics Blood samples for PK will be collected from a subset of patients assigned to Antibody 1 prior to administration of study drug and during select study visits as specified in the assessment schedule. Additional PK samples may be obtained during scheduled outpatient visits or during hospitalization for outcome events (VTE recurrence and bleeding events). Plasma concentrations of total Antibody 1 (i.e., bound or unbound to FXI) will be determined by a validated (LCMS / MS) method.

[0252] Pharmacodynamic evaluation Blood samples for PD assessment will be collected for a subset of patients at the time points defined in the assessment schedule. Additional PD samples can be obtained during scheduled outpatient visits or during hospitalization for outcome events (VTE recurrence and bleeding events).

[0253] PD biomarkers are tested, including but not limited to: Free FXI - Measures FXI not bound to antibody 1 in plasma Total FXI - measures FXI bound to antibody 1 or free in plasma aPTT

[0254] Additionally, FXI:C may be measured for a subset of patients at selected centers based on the availability of suitable -70° C. / -80° C. refrigeration equipment at the center. FXI:C is measured in plasma.

[0255] immunogenicity Immunoassay-based methods are used to detect Antibody 1 ADA. Samples for ADA assessment will be collected prior to administration of study drug and at study visits as specified in the evaluation schedule. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8]

[0256] Additional biomarkers (blood) Additional blood samples will be collected at defined time points in the evaluation schedule and stored for potential future exploratory analyses.

[0257] Additional biomarkers may include, but are not necessarily limited to, the following: D-dimer, F1.2, TAT

[0258] It is recognized that more relevant or novel biomarkers may be discovered during the conduct of the study, so this list may be modified or further expanded, which may be performed in a subset of patients.

[0259] Health-Related Quality of Life (HRQOL) In countries and sites where participation is possible, HRQoL will be measured using three patient-reported outcome (PRO) instruments: · The EQ-5D-5L questionnaire is used to collect information about the impact of the disease and its treatment on the patient's physical, emotional, and social well-being. The EQ-5D-5L is a self-administered, validated instrument that measures general HRQoL across five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. There are five levels of response for each dimension. Furthermore, the instrument contains a visual analog scale (VAS) scale that measures the respondent's overall health on a scale of 0 to 100 points. This instrument is widely used in clinical trials, across various clinical conditions, and among the general population (Berg et al. 2010). The EORTC QLQ-C30 is a questionnaire developed to assess quality of life in cancer patients. It is a 30-item questionnaire with 28 items on a 4-point Likert scale and 2 items on a 7-point Likert scale. The EORTC QLQ-C30 is a validated instrument to measure HRQoL. The instrument is available in over 100 languages ​​(Farge et al. 2018). · The TSQM II measures patient satisfaction with the care provided. It consists of 11 items, each on a 5-point Likert scale, measuring effectiveness of the care, side effects related to the care, convenience of the care, and satisfaction with the care. The instrument is available in over 100 languages ​​(Atkinson et al. 2004).

[0260] All PRO measures will be administered electronically at times as outlined in the assessment schedule. PROs will be administered in a subset of patients. In addition, EQ-D-5L will be recorded at subsequent visits after suspected VTE recurrence and suspected bleeding events, whenever possible.

[0261] Exploratory DNA (genetic) samples For patients who give informed consent for this optional study, blood samples for exploratory DNA will be obtained on Day 1 or any time after informed consent is obtained. Genetic sample collection is only applicable for countries where this test has been approved by health authorities.

[0262] Potential risks associated with SARS-COV2 (COVID-19) The study treatment is not expected to alter natural defense mechanisms against COVID-19 or generate immunity against it. Anticoagulant therapy may have beneficial effects in preventing thromboembolic complications of COVID-19. Patients enrolled in the study must apply social distancing and all other protective measures during the study; in case of COVID-19, the patient should be managed according to usual medical practice. COVID-19 should be recorded in the AE eCRF.

[0263] If the COVID-19 pandemic prevents patients from attending a scheduled clinic or outpatient visit, they should contact the study investigator. Every effort should be made to prevent interruptions in treatment and to report study outcomes. Virtual and home visits may be considered options, if necessary.

[0264] Vaccination against COVID-19 during the study is permissible.

[0265] Study completion and discontinuation Guidelines recommend 6 months of anticoagulation treatment in CAT (Streiff et al. 2018, Key et al. 2019, Khorana et al. 2018, Carrier et al.2018, NCCN Guidelines 2020). The intended duration of treatment in this study is 6 months. Investigators should conduct an EoT visit evaluation at 6 months after randomization or earlier in case of PSDD. All patients will enter a follow-up period of approximately 70 days after the EoT visit to continue reporting of outcome events, other AEs and SAEs, and to continue collecting blood samples to evaluate ADA and PD studies.

[0266] Anticoagulation therapy may need to be followed up or restarted during the follow-up period for some patients. Table 3 provides guidance regarding initiation of non-study anticoagulants during the follow-up period. [Table 3]

[0267] The EoS visit will occur approximately 70 days after the EoT visit and will include the collection of blood samples to assess the patient's overall health and safety prior to concluding their participation in the study.

[0268] Discontinuation of study treatment Discontinuation of study treatment for a patient occurs when the study drug is permanently stopped prior to the protocol-planned duration. Discontinuation of study drug may be initiated by either the patient or the investigator.

[0269] Study treatment should be discontinued by any of the following: Patient demand The investigator's judgment that continuing treatment with the study drug is not in the patient's best interest ·pregnancy - have taken prohibited medication and / or have demonstrated a need to continue prohibited medication

[0270] If a patient has anything that would be expected to result in PSDD, the patient should complete the EoT visit procedure.

[0271] After discontinuation of study treatment, the following data should be collected at a minimum during an informal visit, either during a clinic visit or via telephone / video call visit: Signs and symptoms suggestive of DVT, PE, bleeding, or other thromboembolic events New / concomitant treatments ·AE / SAE

[0272] Example 2 Treatment of Patients with Gastrointestinal or Genitourinary Cancer-Associated Thromboembolism with Antibody 1 Compared to Dalteparin Objectives and Rationale The objective of this study is to evaluate whether monthly treatment with Antibody 1 is non-inferior to daily dalteparin in preventing VTE recurrence but superior in terms of bleeding rates in patients with gastrointestinal (GI) / genitourinary (GU) cancer and recently diagnosed VTE. This study will support the global registration of Antibody 1 for the treatment of CA VTE.

[0273] CAT occurs in an estimated 20% of cancer patients and is the second leading cause of death in patients with malignant disease. Current treatments inhibit one or more factors in the coagulation cascade, which effectively prevent or treat thrombosis, but also interfere with hemostasis, resulting in an increased risk of bleeding. The fear of bleeding and lack of tolerability of available therapies lead to significant undertreatment and poor outcomes.

[0274] These issues are particularly challenging for patients with GI and GU cancers who are at increased risk for bleeding. In fact, current guidelines recommend caution when using DOACs in patients with GI cancers due to the increased risk of bleeding with DOACs compared to LMWHs. LMWHs are the standard of care for treating CAT in patients with GI and GU tumors, but this type of treatment requires daily injections for up to six months, making patients treated with LMWHs less likely to persist with treatment.

[0275] The goal of developing new treatments for CAT, especially for patients with CAT who are at high risk for bleeding, is to reduce bleeding and improve tolerability while maintaining the same level of efficacy as current agents.

[0276] Objectives and Evaluation Items The primary objective of this study was to evaluate whether Antibody 1 was non-inferior to dalteparin in preventing VTE recurrence through 6 months after randomization in patients with GI or GU cancer and recently diagnosed VTE. The outcome measure was time to first event of VTE recurrence as determined by a central laboratory through 6 months.

[0277] Secondary objectives of this study are to: To evaluate whether antibody 1 is superior to dalteparin in preventing the composite of major or CRNM bleeding through 6 months after randomization. The outcome measure is time to first event of VTE recurrence as determined by a central laboratory through 6 months. To evaluate whether antibody 1 is superior to dalteparin with respect to net clinical benefit defined as survival without VTE recurrence or major or CRNM bleeding events through 6 months after randomization. Endpoints are time to first event of VTE recurrence, ISTH-defined major bleeding event, or ISTH-defined CRNM bleeding event through 6 months. To evaluate whether antibody 1 is superior to dalteparin in preventing recurrent VTE through 6 months after randomization. The outcome measure is time to first event of recurrent VTE as determined by a central laboratory through 6 months. To evaluate whether Antibody 1 is superior to dalteparin in terms of permanent discontinuation rate not due to death through 6 months after randomization.The endpoint is to evaluate whether Antibody 1 is superior to dalteparin in terms of permanent discontinuation rate not due to death through 6 months after randomization. To evaluate whether antibody 1 is superior to dalteparin in preventing the occurrence of CRNM bleeding events through 6 months after randomization. The outcome measure is time to first CRNM bleeding event as determined by ISTH through 6 months. To evaluate whether antibody 1 is superior to dalteparin in preventing the occurrence of major bleeding events through 6 months after randomization. The outcome measure is time to first major bleeding event as determined by ISTH through 6 months. To evaluate whether antibody 1 is superior to dalteparin in preventing the occurrence of a composite of GI major bleeding and GI CRNM bleeding through 6 months after randomization. Endpoints are time to first GI ISTH-determined major bleeding event and GI CRNM bleeding event through 6 months. To evaluate the safety and tolerability of Antibody 1 compared to dalteparin through 6 months post-randomization, and to evaluate the incidence of injection site reactions, hypersensitivity reactions, and immunogenicity in patients treated with Antibody 1. Endpoints include death from any cause, vascular-related death, serious adverse events, adverse events leading to drug discontinuation, other adverse events, and abnormal laboratory tests, expressed as rates per 100 patient-years; and, for patients treated with Antibody 1, Percentage of patients with injection site reactions Percentage of patients with injection site reactions by severity status Percentage of patients with hypersensitivity reactions Percentage of patients with hypersensitivity reactions by severity level Percentage of patients with ADA formation Percentage of patients with persistent ADA formation Percentage of patients with neutralizing antibody (NAb) formation It is.

[0278] The exploratory objectives of this study are to: To evaluate the effect of antibody 1 compared to dalteparin on a composite of VTE recurrence, major bleeding events or death from any cause. The endpoint is time to first event of a composite endpoint of VTE recurrence, major bleeding or death from any cause. To evaluate the effect of antibody 1 compared to dalteparin on arterial thromboembolic events (e.g. stroke, myocardial infarction, arterial embolic events). The endpoint is time to first event of ischemic stroke, or a composite endpoint of myocardial infarction or arterial embolic events. To evaluate the effect of Antibody 1 compared to dalteparin on venous thromboembolic events other than those qualifying as VTE recurrence (e.g., lower extremity distal DVT, upper extremity DVT, thoracic vein, intracranial or extracranial cerebral vein, visceral DVT, and central venous catheter-related thrombosis). Endpoints will be time to first event of DVT recurrence or other venous thromboembolic events and the composite endpoint of time to first event of any of the following venous thromboembolic events: lower extremity distal DVT, upper extremity DVT, thoracic vein, intracranial or extracranial cerebral vein, visceral DVT, or central venous catheter-related thrombosis. To evaluate the effect of Antibody 1 compared to dalteparin on the number and duration of temporary treatment interruptions not due to procedures or bleeding events. Endpoints are the number of temporary treatment interruptions not due to procedures or bleeding and the total duration of temporary treatment interruptions not due to procedures or bleeding. To evaluate the efficacy and safety of Antibody 1 compared to dalteparin in predefined patient subgroups (e.g., sex, age, BMI, ethnicity, cancer location, incident vs symptomatic VTE, presence or absence of PE, days on SoC prior to randomization, ECOG performance status). Endpoints are time to first event of central laboratory-determined VTE recurrence through 6 months in predefined patient subgroups and time to first event of ISTH-defined major bleeding events and CRNM bleeding events through 6 months in predefined patient subgroups. To evaluate the effect of Antibody 1 versus dalteparin on HRQoL at 3 and 6 months, and on the change in EQ-5D-5L over time versus dalteparin in patients presenting with suspected VTE recurrence and suspected bleeding events. Endpoints included change from baseline in the total score and scores by domain of the EQ-5D-5L questionnaire, the EORTC QLQ C30 questionnaire, and the TSQM II questionnaire; and serial change over time in the EQ-5D-5L questionnaire after suspected VTE recurrence and bleeding events. To evaluate the PK of Antibody 1 in a subset of patients. Endpoints include random, peak and trough plasma concentrations of Antibody 1. To evaluate the pharmacodynamics (free and total FXI, FXI:C, aPTT) of Antibody 1 in a subset of patients. Endpoints include free and total FXI, FXI:C and aPTT at the time points indicated. To evaluate the effect of Antibody 1 versus dalteparin on exploratory biomarkers of hypercoagulable states (potentially including but not limited to d-dimer, F1.2, TAT) in a subset of patients. Endpoints will be change from baseline in biomarkers of hypercoagulable states, which may include d-dimer, F1.2 and TAT, across treatment arms. Cost-effectiveness analysis of VTE (e.g. hospitalizations, transfusions, procedures to stop bleeding or manage VTE, outpatient visits). The outcome measure is resource utilization. DNA evaluation to explore whether individual genetic variations in genes related to the drug target pathway or other relevant genetic pathways confer differential response to Antibody 1. Endpoints will be an exploratory evaluation of associations between genetic polymorphisms and safety, efficacy, PK, and PD responses.

[0279] Test Design This is a randomized, open-label, blinded endpoint-assessed, phase 3 study comparing the effect of antibody 1 with dalteparin on VTE recurrence in patients with GI or GU cancer.

[0280] Randomization to treatment groups will be stratified by region, cancer location (GI vs. GU cancer), and symptomatic vs. incident thromboembolic events.

[0281] The study consists of 3 periods: 1) screening (up to 3 days [72 hours]), 2) a treatment period with the study drug until the end of treatment (EoT) visit, and 3) a follow-up period until the end of study (EoS) visit.

[0282] Group Adult male or female subjects with confirmed (histology, valid imaging modality) unresectable GI or GU cancer and acute symptomatic VTE (within 72 hours of diagnosis of qualifying VTE) prior to randomization and a demonstrated need for long-term treatment with LMWH will be eligible for study participation; approximately 1020 patients are expected to be randomized in the study.

[0283] Selection Criteria Inclusion and exclusion criteria must be verified at screening and baseline; patients eligible for inclusion in the study must meet all of the following criteria at both visits: · Male or female, aged 18 or older or of other legal age of majority depending on your country of residence Patients with confirmed GI cancer (colorectal, pancreatic, gastric, esophageal, gastroesophageal junction, or hepatobiliary) or confirmed GU cancer (kidney, ureter, bladder, prostate, or urethral cancer) prior to randomization who: ○ Unresectable, locally advanced, metastatic, or non-metastatic GI / GU cancer, and No curative surgery is intended during the study period. Confirmed symptomatic or incident acute proximal lower extremity DVT (i.e., popliteal, femoral, iliac, and / or inferior vena cava [IVC] thrombosis) and / or confirmed symptomatic or incident PE in the segmental or larger pulmonary arteries and / or confirmed symptomatic or incident PE in the segmental or larger pulmonary arteries. Patients are eligible within 72 hours of diagnosis of a qualifying VTE. - The need for anticoagulant therapy with LMWH for at least 6 months has been demonstrated. -Ability to provide written informed consent

[0284] Exclusion criteria Patients meeting any of the following criteria were ineligible for inclusion in the study: Thrombectomy, insertion of a vena cava filter, or use of fibrinolysin to treat current (initial) DVT and / or PE >72 hours after conditioning with therapeutic doses of UFH, LMWH, or other anticoagulants -Indicated need to continue treatment with therapeutic doses of anticoagulants other than those used to treat VTE prior to randomization (e.g., AF, prosthetic heart valve, previous VTE) PE resulting in unstable hemodynamics (blood pressure [BP] < 90 mmHg or shock) Acute ischemic or hemorrhagic stroke or intracranial hemorrhage within 4 weeks of screening Brain trauma or cerebral or spinal surgery within 4 weeks of screening - If you require aspirin in a dosage of >100 mg per day or any other antiplatelet agent, alone or in combination with aspirin Bleeding requiring medical attention at or within 4 weeks prior to randomization - If major surgery is planned at baseline History of heparin-induced thrombocytopenia Primary brain cancer or untreated intracranial metastases -ECOG performance status of 3 or 4 at screening - Life expectancy at the time of randomization is less than 3 months - Calculated creatinine clearance (CrCl) is less than 30 mL per minute (Cockcroft-Gault formula) Platelet count 50,000 / mm 3 If less than If your hemoglobin level is less than 8g / dL Acute hepatitis, chronic active hepatitis, cirrhosis; or alanine aminotransferase (ALT) ≥ 3 x ULN and / or bilirubin ≥ 2 x ULN in the absence of clinical explanation Uncontrolled hypertension despite antihypertensive treatment (systolic BP>180mm Hg or diastolic BP>100mm Hg) Women of childbearing potential (WOCBP) who are unwilling or unable to use highly effective contraception for the duration of the study from screening through up to 3 days after the last treatment with dalteparin or 100 days after administration of Antibody 1 Sexually active men with sexual partners of childbearing potential must agree to use condoms or other reliable contraception up to 3 days after their last treatment with dalteparin or 100 days after administration of Antibody 1. Pregnant or breastfeeding women History of hypersensitivity to the study drug (including dalteparin) or any of its excipients, to drugs in a similar chemical class, or any contraindication listed in the dalteparin label Subjects who, in the opinion of the investigator, have any condition that places them at high risk of harm if they participate in the study Use of other investigational (non-registered) medications within 5 half-lives prior to enrollment or until return of predicted PD effects to baseline, whichever is longer. Participation in academic non-interventional or interventional trials testing different strategies or different combinations of registered medications is acceptable.

[0285] Dosage and Administration On Day 1, patients will be randomized in a 1:1 ratio to one of the following treatment arms: Antibody 1, 150 mg iv, followed by monthly 150 mg sc injections for 5 months (total duration of treatment is 6 months) Dalteparin 200 IU / kg / day sc for 1 month, then 150 IU / kg / day sc for 5 months. The maximum daily dose allowed for dalteparin is 18,000 IU (total duration of treatment is 6 months).

[0286] Randomization to treatment groups will be stratified by region, cancer location (GI vs GU), and VTE presentation (symptomatic vs incident).

[0287] Once a subject has been stratified and randomized, the subject will remain in his or her original stratum and randomized treatment group for analysis purposes, even if the subject's treatment or administered dose is subsequently adjusted.

[0288] safety Physical Examination The physical examination should include evaluation of the general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, musculoskeletal, vascular, and neurological.

[0289] Vital signs Vital signs include collection of oral temperature (°C), BP, and pulse.

[0290] Laboratory Evaluation Hemoglobin, hematocrit, red blood cell (RBC) count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red cell distribution width (RDW), white blood cell (WBC) count with differential, and platelet count will be measured.

[0291] Measure sodium, potassium, creatinine, BUN / urea, uric acid, chloride, albumin, calcium, alkaline phosphatase, total bilirubin, bicarbonate / HCO3, AST, ALT, glucose, total cholesterol, and triglycerides. If total bilirubin is >2×ULN, direct and indirect reacting bilirubin should be differentiated.

[0292] Standard aPTT and prothrombin time / international normalized ratio (PT / INR) samples will be collected at visits as outlined in the evaluation schedule.

[0293] Obtain a urine dipstick test for specific gravity, protein, glucose, and blood. If the urine dipstick test is abnormal, also evaluate microscopy, WBC, RBC, and sediment.

[0294] Electrocardiogram (ECG) ECGs will be performed at Screening, Baseline, EoT, and EoS visits. ECGs must be collected locally by a qualified physician at the study site, interpreted, appropriately signed, and archived at the study site.

[0295] Clinical endpoints Effectiveness An independent and blinded CEC will adjudicate and classify the following events: Death from any cause All episodes of suspected DVT and recurrent PE Other suspected arterial thromboembolic events (e.g., ischemic stroke, TIA, arterial embolic events, myocardial infarction [MI]), and other VTE such as distal lower extremity DVT, upper extremity DVT, thoracic veins, large intracranial or extracranial veins, visceral DVT, and central venous catheter-related thrombosis

[0296] The primary outcome of the study (VTE recurrence) consisted of a composite of the following confirmed (as determined by the CEC) VTE events: Confirmed new symptomatic or incident proximal DVT of the lower extremities, iliac veins and / or IVC Confirmed new symptomatic PE Confirmed new incidental PE located in the segmental or more proximal pulmonary artery Fatal PE (including unexplained deaths where PE cannot be excluded)

[0297] Confirmed arterial thromboembolic events (e.g., stroke, TIA, acute MI, and arterial embolic events) and confirmed other VTE (e.g., new distal lower extremity DVT, upper extremity DVT, thoracic vein, intracranial or extracranial vein, visceral DVT, and central venous catheter-related thrombosis) will be analyzed as exploratory endpoints of the study.

[0298] Incidental DVT or PE is a thrombus detected during an imaging study (e.g., CT for cancer staging) that is not performed for suspected DVT or PE but for other reasons. A new thrombus detected incidentally in the IVC or iliac veins during abdominal or pelvic CT is considered valid for establishing the diagnosis of DVT recurrence. However, a new thrombus detected incidentally in the common femoral vein or more distal veins may qualify for DVT recurrence only if confirmed by CUS or venography.

[0299] Outcome events occurring up to index VTE and EoS visit will be determined in all randomized patients.

[0300] bleeding All suspected bleeding events, whether reported by the subject or observed by the investigator, should be recorded.

[0301] Details of all reported bleeding events will be submitted to the CEC as described in the endpoint reporting guidelines. These details may include, but are not limited to: ·Bleeding location Duration of bleeding Treatment for the bleeding event, including a note or summary of recommendations from the medical professional providing medical treatment, such as an ENT consultation for ear, nose, or throat bleeding; a urological consultation for hematuria or genitourinary tract bleeding; a surgical consultation for skin, soft tissue, or internal bleeding; a gynecological consultation for uterine or vaginal bleeding; a neurological or neurosurgical consultation for intracranial bleeding; or an ophthalmological consultation for eye bleeding. Number of blood product transfusions The size of the bleeding (e.g., the size if it is a cutaneous or subcutaneous hematoma) Hemoglobin levels at the time of the bleeding event, at the nadir, before and after transfusion, and after resolution of the bleeding event Any diagnostic tests performed to evaluate bleeding, such as endoscopy for GI bleeding Any diagnostic imaging performed to evaluate bleeding, e.g., X-ray, CT, MRI, or ultrasound Any other information that may be useful in determining bleeding events by CEC may be included.

[0302] Overt bleeding events are determined by the CEC at a central laboratory. The CEC classifies bleeding events according to the International Society on Thrombosis and Haemostasis (ISTH) definitions and guidance (Kaatz et al. 2015):

[0303] Serious bleeding events A major bleeding event was defined as meeting at least one of the following: a) Fatal hemorrhage b) Symptomatic bleeding in vital areas or organs such as: Intracranial (epidural, subdural, subarachnoid, intracerebral, undetermined) ·Intraocular Intraspinal Intra-articular Intramuscular with compartment syndrome Pericardium ·Retroperitoneum c) Clinically significant bleeding events Associated with a decrease in hemoglobin of ≥ 2.0 g / dL (≥ 1.24 mMol / L), or - Transfusion of 2 or more units of packed red blood cells or whole blood

[0304] Clinically relevant non-serious bleeding events A bleeding event was defined as the presence of any signs or symptoms of bleeding (e.g., bleeding more than would be expected in the clinical setting, including bleeding detected by imaging alone) but not meeting the criteria for the definition of major bleeding, including any of the following criteria: - Medical intervention by a medical professional is required. Leading to hospitalization or increased level of care Facilitate face-to-face (i.e., not just phone or electronic communication) assessments If at least one of the following conditions is met, the event is classified as a CRNM bleeding event.

[0305] Minor (clinically non-relevant) bleeding events Other overt bleeding events that do not meet the criteria for either major or CRNM bleeding events will be classified as minor bleeding events.

[0306] No bleeding All other suspected bleeding events (eg, a decrease in hemoglobin without overt bleeding or an incidental finding on imaging without further action, as described above) will be classified as "no bleeding."

[0307] Other evaluations Pharmacokinetics Blood samples for PK will be collected from a subset of patients assigned to Antibody 1 prior to administration of study drug and during select study visits as specified in the assessment schedule. Additional PK samples may be obtained during scheduled outpatient visits or during hospitalization for outcome events (VTE recurrence and bleeding events). Plasma concentrations of total Antibody 1 (i.e., bound or unbound to FXI) will be determined by a validated LCMS / MS method.

[0308] Pharmacodynamic evaluation Blood samples for PD assessment will be collected for a subset of patients at the time points defined in the assessment schedule. Additional PD samples can be obtained during scheduled outpatient visits or during hospitalization for outcome events (VTE recurrence and bleeding events).

[0309] PD biomarkers are tested, including but not limited to: Free FXI - Measures FXI not bound to antibody 1 in plasma Total FXI - measures FXI bound to antibody 1 or free in plasma aPTT

[0310] Additionally, FXI:C may be measured for a subset of patients at selected centers based on the availability of suitable -70° C. / -80° C. refrigeration equipment at the center. FXI:C is measured in plasma.

[0311] immunogenicity Immunoassay-based methods will be used to detect Antibody 1 ADA. Blood samples for IG will be collected prior to administration of study drug and at study visits as specified in the evaluation schedule shown in Table 4. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8]

[0312] Additional biomarkers (blood) Additional blood samples will be collected at defined time points in the evaluation schedule and stored for potential future exploratory analyses.

[0313] Additional biomarkers may include, but are not necessarily limited to, the following: D-dimer, F1.2, TAT

[0314] It is recognized that more relevant or novel biomarkers may be discovered during the conduct of the study, so this list may be modified or further expanded, which may be performed in a subset of patients.

[0315] Health-Related Quality of Life (HRQOL) In countries and sites where participation is possible, HRQoL will be measured using three patient-reported outcome (PRO) instruments: · The EQ-5D-5L questionnaire is used to collect information about the impact of the disease and its treatment on the patient's physical, emotional, and social well-being. The EQ-5D-5L is a self-administered, validated instrument that measures general HRQoL across five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. There are five levels of response for each dimension. Furthermore, the instrument contains a visual analog scale (VAS) scale that measures the respondent's overall health on a scale of 0 to 100 points. This instrument is widely used in clinical trials, across a variety of clinical conditions, and among the general population (Berg et al. 2010). The EORTC QLQ-C30 is a questionnaire developed to assess quality of life in cancer patients. It is a 30-item questionnaire with 28 items on a 4-point Likert scale and 2 items on a 7-point Likert scale. The EORTC QLQ-C30 is a validated instrument to measure HRQoL. The instrument is available in over 100 languages ​​(Farge et al. 2018). · The TSQM II measures patient satisfaction with the treatment provided. It consists of 11 items on a 5-point Likert scale measuring effectiveness of the treatment, side effects related to the treatment, convenience of the treatment, and satisfaction with the treatment. The instrument is available in over 100 languages ​​(Atkinson et al. 2004).

[0316] All PROs will be administered electronically at times as outlined in the assessment schedule. PROs will be performed in a subset of patients. In addition, EQ-D-5L will be recorded at subsequent visits after suspected VTE recurrence and suspected bleeding events, whenever possible.

[0317] Exploratory DNA (genetic) samples For patients who give informed consent for this optional study, blood samples for exploratory DNA will be obtained on Day 1 or any time after informed consent is obtained. Genetic sample collection is only applicable in countries where this test has been approved by health authorities.

[0318] Potential risks associated with SARS-COV2 (COVID-19) The study treatment is not expected to alter natural defense mechanisms against COVID-19 or generate immunity against it. Anticoagulant therapy may have beneficial effects in preventing thromboembolic complications of COVID-19. Patients enrolled in the study must apply social distancing and all other protective measures during the study; in case of COVID-19, the patient should be managed according to usual medical practice. COVID-19 should be recorded in the AE eCRF.

[0319] If the COVID-19 pandemic prevents a patient from attending a scheduled clinic or outpatient visit, the patient should contact the study investigator. Every effort should be made to prevent interruptions in treatment and ensure reporting of study outcomes. Virtual and home visits may be considered options, if necessary.

[0320] Vaccination against COVID-19 during the study is permissible.

[0321] Study completion and discontinuation Study Completion and Post-Study Procedures Guidelines recommend 6 months of anticoagulation treatment in CAT (Streiff et al. 2018, Key et al. 2019, Khorana et al. 2018, Carrier et al. 2018, NCCN Guidelines 2020). The intended duration of treatment in this study is 6 months. Investigators should conduct an EoT visit evaluation at 6 months after randomization or earlier in case of PSDD. All patients will enter a follow-up period of approximately 70 days after the EoT visit to continue reporting of outcome events, other AEs, and SAEs, and to continue collecting blood samples to evaluate ADA and PD studies.

[0322] It may be necessary to initiate or restart anticoagulant therapy during the follow-up period for some patients. Table 5 provides guidance regarding initiation of non-study anticoagulants during the follow-up period. [Table 5]

[0323] The EoS visit will occur approximately 70 days after the EoT visit and will include the collection of blood samples to assess the patient's overall health and safety prior to concluding their participation in the study.

[0324] Discontinuation of study treatment Discontinuation of study treatment for a patient occurs when the study drug is permanently stopped prior to the protocol-planned duration. Discontinuation of study drug may be initiated by either the patient or the investigator.

[0325] Study treatment should be discontinued by any of the following: Patient demand The investigator's judgment that continuing treatment with the study drug is not in the patient's best interest ·pregnancy - have taken prohibited medication and / or have demonstrated a need to continue prohibited medication

[0326] If a patient exhibits any of the symptoms that would suggest PSDD, they should complete EoT.

[0327] After discontinuation of study treatment, the following data should be collected at a minimum during an informal visit, either during a clinic visit or via telephone / video call visit: Signs and symptoms suggestive of DVT, PE, bleeding, or other thromboembolic events New / concomitant treatments ·AE / SAE If a patient is unable or unwilling to attend any visit(s), study site staff should maintain regular telephone contact with the patient, or a person designated by the patient.

[0328] Example 3 Antibody 1 in a baboon model of vascular graft thrombosis This example is aimed at testing whether Antibody 1 is effective in arresting clot formation and downstream growth when administered prior to or during active clot formation in an established baboon femoral arteriovenous (AV) shunt model. The baboon model is described, for example, in Gruber et al. Blood, 1989 Feb 15; 73 (3): 639-42 and Crosby et al. Arterioscler Thromb Vasc Biol, 2013 Jul;33 (7): 1670-8.

[0329] Young male baboons (weight 8-10 kg) had chronic femoral AV shunts placed in place. Three animals were tested for pharmacodynamics and for AV shunt experiments; one animal was tested for pharmacodynamics only. Seven experiments: two untreated controls, one treatment with antibody 1 administered intravenously at 1 mg / kg 30 minutes after clot initiation, one prevention 24 hours after antibody 1, one prevention 48 hours after antibody 1, and two preventions 144-216 hours after antibody 1.

[0330] Platelet and fibrin deposition was measured on the medial and distal sides of collagen-coated or collagen plus tissue factor (TF)-coated vascular grafts. 111 Indium-labeled platelets and 125 Iodinated fibrinogen was administered to the baboons prior to the experiment. The perfused collagen-coated grafts, the region of interest for measuring the effect of Antibody 1 on thrombus growth, developed a progressively growing distal thrombus within the shunt (tail segment). The collagen + TF-coated grafts are the region of interest for measuring the effect of Antibody 1 on hemostasis. In addition, real-time gamma camera imaging of radioactivity within the thrombogenic device was performed to determine the amount and rate of platelet deposition. After 120 min of perfusion, the grafts were removed and later 111 After indium decay 125 The tissue was stored for measurement of iodine radioactivity to determine fibrin deposition.

[0331] In addition, activated partial thromboplastin time (aPTT) and prothrombin time (PT) were measured before and during the thrombosis experiment and followed until they returned to baseline levels. Bleeding time (BT) and bleeding volume (BV) were assessed using a method approved by the FDA for use in patients (Surgicutt® device, International Technidyne, Piscataway, NJ). Two BT / BV measurements were taken before and during each thrombosis experiment.

[0332] Antibody 1 at a 1 mg / kg iv dose immediately produced an approximately 2- to 2.5-fold prolongation of the aPTT from baseline levels. The prolongation of the aPTT persisted for up to 600 hours after drug administration and then slowly returned to baseline (Figure 1). No changes in PT were observed after antibody 1 administration.

[0333] A small increase of approximately 10%-15% in mean bleeding time (Figure 2A) and bleeding volume (Figure 2B) was observed following administration of Antibody 1. This increase is not considered clinically relevant due to existing clinical trial safety data for Antibody 1.

[0334] Administration of Antibody 1 halted platelet deposition in the tail segments when it was administered 30 minutes after the initiation of thrombosis. The antithrombotic effect of Antibody 1 appears to have begun within 20 minutes of administration, as shown in FIG. 3A for the collagen-coated segments and in FIG. 3B for the collagen+TF-coated segments. Antibody 1 abolished platelet deposition when thrombosis was induced after the initiation of treatment with Antibody 1. Platelet deposition in collagen-coated segments for each of the three baboons is shown in FIG. 4A, FIG. 4B, and FIG. 4C, and platelet deposition in collagen+TF-coated segments for each of the three baboons is shown in FIG. 4D, FIG. 4E, and FIG. 4F. The effect of Antibody 1 in halting the downstream increase in platelet deposition in the three baboons was consistently observed. The effect of Antibody 1 on platelet deposition was small in the coated graft segments (collagen only in FIG. 5A), especially after thrombosis was induced with collagen+TF (FIG. 5B) to mimic the induction of a wound. The lack of effect of Antibody 1 on platelet deposition in collagen+TF coated segments is consistent with the hemostasis sparing potential of Antibody 1.

[0335] Antibody 1 also reduced fibrin deposition in the tail segment, demonstrating antithrombotic efficacy whether administered prior to thrombosis or 30 min after the initiation of thrombosis (Figures 6C, 6D). Fibrin deposition was unaltered in the graft segments, again demonstrating the hemostatic sparing potential of Antibody 1 (Figures 6A, 6B).

[0336] Administration of intravenous antibody 1 30 min after thrombus induction halted downstream thrombus growth and platelet deposition augmentation within 20 min after drug administration. Intravenous antibody 1 was highly effective in preventing downstream thrombus augmentation when administered before the initiation of thrombosis, which is consistent with clinical data. The data on collagen + TF coated grafts support the concept of a hemostatic sparing effect of targeting FXI, thus making antibody 1 suitable for the safe treatment and / or prevention of acute thrombosis. In conclusion, the above studies demonstrate the potential therapeutic benefit of targeting FXI / FXIa with intravenous antibody 1 in both therapeutic and preventive settings.

[0337] Example 4 Treatment of Patients with Vascular Graft Thrombosis Objectives and Rationale This study is designed to test whether Antibody 1 is effective in halting clot formation and downstream growth when administered prior to or during active clot formation in human subjects treated with AV shunts.

[0338] method Patients undergoing treatment with an AV shunt are treated with a single dose of antibody 1, 150 mg, intravenously (iv) or control at the appropriate dosing regimen. Pharmacodynamic effects are measured by activated partial thromboplastin time (aPTT).

[0339] result Consistent with Antibody 1's half-life of 20-30 days, a single 150 mg IV dose of Antibody 1 can result in long-lasting aPTT prolongation.

[0340] These data suggest that Antibody 1 has the potential to slow thrombus growth and reduce thrombus size when administered before a clot is induced. Such data also indicate therapeutic benefit of targeting FXI in both treatment and prevention settings.

[0341] Example 5 Treatment of Patients with Vascular Graft Thrombosis Objectives and Rationale This study was designed to test the effect of increasing concentrations of Antibody 1 on platelet aggregation following stimulation with collagen or thrombin receptor-activating peptide-6 (TRAP-6) compared to vehicle and active control (abciximab, anti-GP2b3a) and to determine the effect of both agents on thrombin generation.

[0342] method Whole blood was obtained (six healthy donors) in EDTA and citrate tubes. Samples were spiked with vehicle, Antibody 1 (250 nM, 500 nM, or 1000 nM), or Abciximab (50 nM). After induction with collagen (1 μg / mL) or TRAP-6 (8 μM), platelet aggregation was recorded using a multiplate impedance aggregometer. The area under the curve (AUC) for platelet aggregation was determined at any aggregation*time (AU*min). Thrombin generation was also measured using a Thrombinoscope CAT (Calibrated Automated Thrombogram; Stago CH SA) and tissue factor reagent (1 pM) in platelet-rich plasma at the above concentrations of Antibody 1 and Abciximab; fluorescence was measured by an automated plate reader fluorometer.

[0343] result Antibody 1 showed no inhibitory or stimulatory effect on collagen (FIG. 7A) or TRAP-6 (FIG. 7B)-induced platelet aggregation. In contrast, a significant reduction in collagen-induced platelet aggregation was observed with abciximab. Antibody 1 caused a significant delay in the lag time of thrombin generation and the time to peak concentration of thrombin generation; abciximab had no effect on thrombin generation.

[0344] Importantly, these results demonstrate that targeting FXI / FXIa with Antibody 1 inhibits thrombin generation while leaving platelet aggregation unaffected.

Claims

1. 1. A pharmaceutical formulation for use in a method of treating a disease or disorder in a subject in need thereof, comprising: The pharmaceutical formulation comprises an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or antigen-binding fragment thereof; The method includes the steps of intravenously administering to the subject a first dose of about 150 mg of an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or its antigen-binding fragment, and subcutaneously administering to the subject a second dose of the isolated anti-FXI and / or anti-FXIa antibody or its antigen-binding fragment, a pharmaceutical formulation.

2. 2. The pharmaceutical formulation of claim 1, wherein the second dose comprises about 150 mg of the isolated anti-FXI and / or anti-FXIa antibody or antigen-binding fragment thereof.

3. The pharmaceutical preparation of claim 1 , wherein the subject has cancer.

4. 4. The pharmaceutical formulation of claim 3, wherein the subject has a cancer selected from the group consisting of gastrointestinal cancer and genitourinary cancer.

5. 5. The pharmaceutical formulation of any one of claims 1 to 4, wherein the subject is at high risk of venous thromboembolism or has had one or more previous venous thromboembolism events.

6. The pharmaceutical formulation of claim 5, wherein the method further comprises one or more additional subcutaneous doses of the antibody or antigen-binding fragment thereof.

7. The pharmaceutical formulation of claim 6, wherein the method comprises administering five subcutaneous doses of the antibody or antigen-binding fragment thereof.

8. The pharmaceutical formulation of claim 7, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously about once a month.

9. 9. The pharmaceutical formulation of claim 8, wherein the antibody or antigen-binding fragment thereof is administered intravenously on day 1 and subcutaneously on days 31, 61, 91, 121, and 151.

10. 10. The pharmaceutical formulation of claim 9, wherein the subject is treated for about 6 months.

11. 1. A drug delivery formulation for use in a method of treating a subject having cancer, comprising: The drug delivery formulation comprises an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or antigen-binding fragment thereof; The method includes administering to the subject in need thereof a drug delivery formulation comprising approximately 150 mg of an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or its antigen-binding fragment, wherein the drug delivery formulation is administered intravenously once and then subcutaneously approximately once a month to treat the subject for approximately six months.

12. The drug delivery formulation of claim 11, wherein the cancer is selected from the group consisting of gastrointestinal cancer and genitourinary cancer.

13. 1. A drug delivery formulation for use in a method of treating a primate subject at risk for thrombosis, comprising: The method comprises administering to the primate subject: (a) a therapeutically effective amount of an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or antigen-binding fragment thereof at a concentration of about 150 mg; (b) a histidine buffer at a concentration of about 20 mM; (c) sucrose at a concentration of about 220 mM; and (d) polysorbate 20 at a concentration of about 0.04% (v / v); (e) a diluent containing glucose administering a single dose of a drug delivery formulation at pH 5.5 comprising: The drug delivery formulation, wherein the administering step is before or during the formation of a blood clot.

14. 1. A pharmaceutical formulation for use in a method of treating a subject having thrombocytopenia, comprising: the pharmaceutical formulation comprises a factor XI and / or factor XIa antibody or antigen-binding fragment thereof; the thrombocytopenia is selected from the group consisting of chemotherapy-induced thrombocytopenia, congenital thrombocytopenia, thrombocytopenia associated with infection, and idiopathic thrombocytopenia; The method comprises administering to the subject in need thereof a therapeutically effective amount of a factor XI and / or factor XIa antibody or antigen-binding fragment thereof.

15. 15. The pharmaceutical preparation of claim 14, wherein the subject with thrombocytopenia has cancer.

16. 16. The pharmaceutical preparation of claim 14 or 15, wherein the subject with thrombocytopenia has cirrhosis or has idiopathic thrombocytopenic purpura (ITP).

17. The pharmaceutical formulation of claim 14, wherein the subject is suffering from or at risk of developing a thromboembolic disorder.

18. 1. A pharmaceutical formulation for use in a method of treating a cancer subject with chemotherapy-induced thrombocytopenia, comprising: the pharmaceutical formulation comprises a factor XI and / or factor XIa antibody or antigen-binding fragment thereof; The method comprises administering to the cancer subject in need thereof a therapeutically effective amount of a factor XI and / or factor XIa antibody or antigen-binding fragment thereof, a pharmaceutical formulation.

19. The pharmaceutical formulation of claim 18, wherein the cancer subject is suffering from or at risk of developing a thromboembolic disorder.

20. A pharmaceutical formulation described in any one of claims 1, 14 and 18 or a drug delivery formulation described in claim 11 or 13, wherein the antibody or its antigen-binding fragment comprises a heavy chain variable region (VH) comprising complementarity-determining regions HCDR1, HCDR2, and HCDR3 in SEQ ID NO: 9 or 29; and a light chain variable region (VL) comprising complementarity-determining regions LCDR1, LCDR2, LCDR3 in SEQ ID NO: 19 or 39.

21. the antibody or antigen-binding fragment thereof 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 that is KNY; 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 that is KNY; 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 21. The pharmaceutical or drug delivery formulation of claim 20, comprising:

22. 22. The pharmaceutical or drug delivery formulation of claim 21, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) selected from the group consisting of SEQ ID NOs: 9, 29 and VH having at least 90% identity thereto; and a light chain variable region (VL) selected from the group consisting of SEQ ID NOs: 19, 39 and VL having at least 90% identity thereto.

23. 23. The pharmaceutical or drug delivery formulation of claim 22, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) selected from the group consisting of SEQ ID NOs: 9 and 29; and a light chain variable region (VL) selected from the group consisting of SEQ ID NOs: 19 and 39.

24. 24. The pharmaceutical or drug delivery formulation of claim 23, wherein the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 31, 11 and heavy chains having at least 90% identity thereto; and a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 41, 21 and light chains having at least 90% identity thereto.

25. The pharmaceutical formulation of any one of claims 1, 14 and 18 or the drug delivery formulation of claim 11 or 13, wherein the antibody comprises 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.

26. The pharmaceutical formulation of any one of claims 1, 14 and 18 or the drug delivery formulation of claim 11 or 13, wherein the administration of the antibody or its antigen-binding fragment does not affect platelet aggregation in the subject compared to platelet aggregation before the administration.

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