Combination Therapy with Anti-Factor XI / Factor XIA Antibodies

Abstract

The present disclosure relates to dosing regimens for combination therapies comprising, for example, anti-factor XI and / or activated factor XI (factor XIa) antibodies or antigen-binding fragments thereof for use in the treatment of thrombotic disorders or related conditions. Thus, in one aspect, provided herein is a method of reversing the anticoagulant effect of an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody, or antigen-binding fragment thereof, in a subject, where the subject has been administered the isolated antibody or antigen-binding fragment thereof at a dose of about 150 mg, the method comprising administering to the subject a therapeutically effective amount of recombinant activated factor VII (rFVIIa), thereby reversing the anticoagulant effect.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 355,319, filed on June 24, 2022, the disclosure of which is hereby incorporated by reference in its entirety for all purposes.

[0002] The present disclosure relates to dosing regimens for combination therapies comprising anti - Factor XI and / or activated Factor XI (Factor XIa) antibodies, or antigen - binding fragments thereof, for use, for example, in the treatment of thromboembolic disorders or related conditions.

Background Art

[0003] There is a high unmet medical need for safer therapies to reduce thromboembolic complications such as stroke, systemic embolism, cognitive decline, and death, with comparable or improved efficacy to that shown by existing treatments and a lower risk of bleeding. Factor XI (FXI) is a serine protease that functions in both the intrinsic and extrinsic coagulation pathways. Factor XI exists as a zymogen in the form of a homodimer and is activated (Factor XIa, FXIa) upon cleavage of the peptide bond at R369 - I370. FXI is not important for normal hemostasis in a high - tissue - factor environment but plays an important role in thrombosis. Genetic Factor XI deficiency has been 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). Bleeding symptoms in subjects with Factor XI deficiency are not frequent and are often mild, arising from injury or trauma and rarely affecting 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 in Table 1 herein as antibody 1. In addition to these developments, the present disclosure provides further clinical methods, including combination dosing regimens for treating patients with certain thrombotic disorders with a desired level of safety and efficacy.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Non-Patent Documents

[0005]

Non-Patent Document 1

Summary of the Invention

[0006] The present disclosure provides combination therapies with anti-factor XI and / or factor XIa antibodies or antigen-binding fragments thereof, or pharmaceutical formulations containing the same.

[0007] Thus, in one aspect, provided herein is a method for reversing the anticoagulant effect of an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody, or antigen-binding fragment thereof, in a subject, wherein the subject has been administered the isolated antibody or antigen-binding fragment thereof at a dose of about 150 mg, and the method comprises administering to the subject a therapeutically effective amount of recombinant activated factor VII (rFVIIa), thereby reversing the anticoagulant effect.

[0008] In some embodiments, the therapeutically effective amount of rFVIIa is a low dose. In certain embodiments, the therapeutically effective amount of rFVIIa is from 0.5 to 1 μg / mL. In some embodiments, the therapeutically effective amount of rFVIIa is administered once. In some embodiments, the therapeutically effective amount of rFVIIa is administered two or more times. In some embodiments, the therapeutically effective amount of rFVIIa is administered as needed.

[0009] In some embodiments, administering a therapeutically effective amount of rFVIIa prolongs the clotting time (CT) compared to the CT before administering the therapeutically effective amount. In some embodiments, administering a therapeutically effective amount of rFVIIa prolongs the clot formation time (CFT) compared to the CFT before administering the therapeutically effective amount. In certain embodiments, the CT or CFT is determined by rotational thromboelastometry (ROTEM) in a whole blood assay. In certain embodiments, the whole blood assay is ex vivo or in vitro.

[0010] In certain embodiments, the method further comprises applying one of the following to the subject: (i) fluid replacement using a plasma protein such as a colloid, crystalloid, human plasma, or albumin, (ii) transfusion with packed red blood cells or whole blood, (iii) administration of fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), activated PCC (APCC) such as factor VIII inhibitor, or (iv) an anti-idiotype antibody against an isolated anti-FXI and / or anti-FXIa antibody or an antigen-binding fragment thereof.

[0011] In another aspect, provided herein is a method of doing so in a subject in need of treatment of a disease or disorder, the method comprising administering to the subject an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody, or an antigen-binding fragment thereof, at a dose of about 150 mg, and administering (a) about 1 mg / mL of aspirin or (b) about 3 μM of ticagrelor.

[0012] In some embodiments, aspirin or ticagrelor is administered prior to the administration of the antibody or antigen-binding fragment thereof.

[0013] In some embodiments, aspirin or ticagrelor is administered simultaneously with the administration of the antibody or antigen-binding fragment thereof.

[0014] In some embodiments, aspirin or ticagrelor is administered after the administration of the antibody or antigen-binding fragment thereof.

[0015] In some embodiments, the administration of the antibody or antigen-binding fragment thereof does not affect platelet aggregation in the subject as compared to a subject treated with aspirin or ticagrelor alone. In certain embodiments, platelet aggregation is measured by an impedance platelet aggregation assay. 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 measured ex vivo or in vitro.

[0016] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising complementarity determining regions HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 9 or 29, and a light chain variable region (VL) comprising complementarity determining regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 19 or 39.

[0017] In some embodiments of the above-described aspects, the antibody or antigen-binding fragment thereof comprises: i. CDR1 of the heavy chain variable region of SEQ ID NO: 23, CDR2 of the heavy chain variable region of SEQ ID NO: 24, CDR3 of the heavy chain variable region of SEQ ID NO: 25, CDR1 of the light chain variable region of SEQ ID NO: 33, CDR2 of the light chain variable region of SEQ ID NO: 34, and CDR3 of the light chain variable region of SEQ ID NO: 35, ii. The heavy chain variable region CDR1 of SEQ ID NO: 26, the heavy chain variable region CDR2 of SEQ ID NO: 27, the heavy chain variable region CDR3 of SEQ ID NO: 28, the light chain variable region CDR1 of SEQ ID NO: 36, the light chain variable region CDR2 (or amino acid sequence KNY) of SEQ ID NO: 37, and the light chain variable region CDR3 of SEQ ID NO: 38, iii. The heavy chain variable region CDR1 of SEQ ID NO: 43, the heavy chain variable region CDR2 of SEQ ID NO: 44, the heavy chain variable region CDR3 of SEQ ID NO: 45, the light chain variable region CDR1 of SEQ ID NO: 47, the light chain variable region CDR2 (or amino acid sequence KNY) of SEQ ID NO: 37, and the light chain variable region CDR3 of SEQ ID NO: 15, or iv. The heavy chain variable region CDR1 of SEQ ID NO: 46, the heavy chain variable region CDR2 of SEQ ID NO: 4, the heavy chain variable region CDR3 of SEQ ID NO: 5, the light chain variable region CDR1 of SEQ ID NO: 33, the light chain variable region CDR2 of SEQ ID NO: 14, and the light chain variable region CDR3 of SEQ ID NO: 15.

[0018] 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 VH having 90% identity thereto, and a light chain variable region (VL) selected from the group consisting of SEQ ID NO: 19, 39, and VL having 90% identity thereto.

[0019] 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 and 29, and a light chain variable region (VL) selected from the group consisting of SEQ ID NO: 19 and 39.

[0020] In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 31, 11, and heavy chains having 90% identity thereto, and a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 41, 21, and light chains having 90% identity thereto. In certain 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.

[0021] In some embodiments, the antibody is a human monoclonal antibody.

[0022] In some embodiments, the antibody is of the human IgG1 isotype.

[0023] In some embodiments, the antibody comprises D265A and P329A substitutions in the Fc domain.

[0024] In some embodiments, the antibody or antigen-binding fragment thereof is administered intravenously.

[0025] In some embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously.

[0026] In some embodiments, the antibody or antigen-binding fragment thereof is administered in a drug delivery formulation comprising 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.

[0027] In some embodiments, 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.

[0028] In some embodiments, the subject has or is at risk of developing a thromboembolic disorder. In some embodiments, the thromboembolic disorder is selected from the group consisting of atrial fibrillation or flutter, transient ischemic attack, ischemic stroke, thromboembolic stroke, hemorrhagic stroke, venous thromboembolism (VTE), pediatric VTE, systemic embolism, non-central nervous system systemic embolism, myocardial infarction, deep vein thrombosis, severe protein S deficiency, cerebrovascular disorder, and cancer.

[0029] In some embodiments, a first dose of an antibody or an antigen-binding fragment thereof is administered intravenously and a second dose of the antibody or the antigen-binding fragment is administered subcutaneously. In certain embodiments, the method further comprises one or more additional doses of the antibody or an antigen-binding fragment thereof that are administered subcutaneously following the administration of the second dose.

[0030] In some embodiments, the antibody or an antigen-binding fragment thereof is administered once per month.

[0031] Other embodiments and details of the present disclosure are presented hereinbelow.

Brief Description of the Drawings

[0032]

Figure 1

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Figure 2

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Figure 3

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Figure 4

Mode for Carrying Out the Invention

[0036] Definitions To facilitate the understanding of the present invention, several terms and phrases are defined below.

[0037] As used herein, the terms "a" and "an" mean "one or more" and include plural unless the context is inappropriate.

[0038] As used herein, the terms "FXI protein", "FXI antigen", and "FXI" are used synonymously and refer to factor XI proteins in various species. Factor XI is a mammalian plasma coagulation factor XI, a glycoprotein present in human plasma at a concentration of 25 - 30 nM as zymogen, and this glycoprotein is involved in the intrinsic pathway of blood coagulation when converted to an active serine protease by limited proteolysis.

[0039] The terms "FXIa protein", "FXIa antigen", and "FXIa" are used synonymously and refer to the activated FXI protein in various species. Factor XI zymogen is converted to its active form, coagulation factor Xla (FXIa), either via the contact phase of blood coagulation or by thrombin-mediated activation on the platelet surface. During the activation of factor XI, internal peptide bonds are cleaved in each of the two chains, resulting in the 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 subsequently activates factor X (Xa). Xa can then mediate the activation of coagulation factor II / thrombin. For example, human FXI has the sequence described in Table 1 (SEQ ID NO: 1) and has been described in previous reports and the literature (Mandle RJ Jr, et al. (1979) Blood; 54(4):850; NCBI Reference Sequence: AAA51985).

[0040] In the context of the present disclosure, the terms "FXI" and "FXIa" (and the like) include the respective variants and mutants of the native FXI and FXIa proteins, which have amino acid sequences that are substantially the same as the native primary structure (amino acid sequence) described in the above reports.

[0041] As used herein, the terms "catalytic domain", "serine protease catalytic domain", and similar terms mean amino acids Ile370 - Val607, counted from Glu1 at the N-terminus of the mature protein in circulation. This can also be described as residues 388 - 625 at the C-terminus of FXI. As used herein, the term "active site" means the catalytic triad composed of amino acids His413, Asp462, and Ser557. (Bane and Gilani (2014) Drug Disc. 19(9)).

[0042] As used herein, the term "antibody" means a whole antibody and any antigen-binding fragment thereof (e.g., an "antigen-binding portion") or single chain. A whole antibody is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain consists of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region consists of three domains, CH1, CH2, and CH3. Each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region consists of one domain, CL. The VH and VL regions can be further subdivided into hypervariable regions called complementarity determining regions (CDRs) interspersed with more conserved regions called framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs and is arranged in the following order from amino terminus to carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain the binding domains that interact with an antigen. The constant region of the antibody can 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 of the classical complement system (C1q). In some particular embodiments, the antibody can be a monoclonal antibody, a human antibody, a humanized antibody, a camelid antibody, or a chimeric antibody. The antibody can 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.

[0043] The CDRs of the 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 protein 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). The CDRs determined by these definitions usually contain amino acid residue overlaps or subsets when compared to each other. In certain embodiments, the term "CDR" is the CDR as defined by MacCallum et al., J. Mol. Biol. 262:732-745 (1996) and Martin A. Protein Sequence and Structure Analysis of Antibody Variable Domains, Antibody Engineering, Kontermann and Dubel, eds., Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001). In certain embodiments, the term "CDR" is the CDR as defined by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of protein of immunological interest. (1991). In certain embodiments, the heavy-chain CDRs 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 denote the heavy-chain CDRs, and CDRL1, CDRL2, and CDRL3 denote the light-chain CDRs.

[0044] As used herein, the terms "drug delivery formulation" or "intravenous drug delivery formulation" refer to a pharmaceutical formulation comprising an active agent in combination with an inert or active carrier that renders the composition particularly suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0045] As used herein, the terms "subject" and "patient" refer to an organism to be treated by the methods and compositions described herein. Such organisms preferably include, but are not limited to, mammals (e.g., rodents, monkeys, horses, cows, pigs, primates, dogs, cats, etc.), more preferably humans. In certain embodiments, the subject is a human. As used herein, "primate subject" includes both humans and non-human primates. In certain embodiments, the subject is, for example, a baboon model of thrombosis as described 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.

[0046] As used herein, the term "thromboembolic disorder" or similar terms refer to any number of conditions or diseases in which the intrinsic and / or common coagulation pathways are abnormally activated or not naturally inactivated (e.g., without treatment means). These conditions include, but are not limited to, thromboembolic stroke and other types of stroke of ischemic origin, atrial fibrillation, stroke prevention in atrial fibrillation (SPAF), deep vein thrombosis, venous thromboembolism, and pulmonary embolism. These may also include catheter-related thrombosis in which the catheter thromboses (e.g., Hickman catheter in cancer patients), and prevention and treatment of clot formation on the tubing and oxygenation membrane of extracorporeal membrane oxygenation (ECMO).

[0047] As used herein, the term "thromboembolic disorder" or similar terms can also refer to any 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 suspected or confirmed to have arrhythmias such as paroxysmal, persistent, or permanent atrial fibrillation or atrial flutter; - Stroke prevention in atrial fibrillation (SPAF) (the sub-population is AF patients who have undergone percutaneous coronary intervention (PCI)); - Treatment of acute venous thromboembolic events (VTE) and extended prevention of secondary VTE in patients at high risk of bleeding; - Venous thromboembolism (where the subject is a pediatric subject (pediatric VTE)); - Prevention of cerebral and cardiovascular events in secondary prevention after transient ischemic attack (TIA) or stroke without sequelae, and prevention of thromboembolic events in heart failure with sinus rhythm; - Hemorrhagic stroke; - Thrombosis and thromboembolism in the left atrium in subjects undergoing cardioversion for arrhythmias; - Thrombosis before, during, and after ablation treatment for arrhythmias; - Venous thrombosis (including, but not limited to, treatment and secondary prevention of deep or superficial venous thrombosis of the lower or upper extremities, thrombosis of the abdominal and thoracic veins, venous sinus thrombosis, and thrombosis of the jugular vein); - Thrombosis on any artificial surface in veins or arteries, such as catheters, pacemaker wires, synthetic arterial grafts, etc.; 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 lesions, thrombosis in arterial prostheses or catheters, and thrombosis in macroscopically normal arteries (including, but not limited to, acute coronary syndrome, ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, unstable angina, stent thrombosis, thrombosis on any artificial surface of the arterial system, and thrombosis of the pulmonary artery in subjects regardless of the presence or absence of pulmonary hypertension); - Thrombosis and thromboembolism in patients undergoing percutaneous coronary intervention (PCI); - Cardioembolic stroke and potential stroke; - Non-central nervous system systemic embolism (non-CNS systemic embolism); - Thrombosis in invasive and non-invasive cancer malignancy patients (e.g., CAT); - Thrombosis due to indwelling catheter; - Thrombosis and thromboembolism in critically ill patients; - Cardiac thrombosis and thromboembolism, including but not limited to cardiac thrombosis associated with states such as cardiac thrombosis after myocardial infarction, cardiac aneurysm, myocardial fibrosis, cardiac hypertrophy and dysfunction, myocarditis and artificial surface of the heart; - Thromboembolism in patients with valvular heart disease with or without atrial fibrillation; - Thromboembolism due to mechanical or biological valve prosthesis; - Thromboembolism in patients who had natural or artificial heart patches, ductus arteriosus or venous ducts after cardiac repair of simple or complex congenital heart defects; - Venous thrombosis and thromboembolism after knee replacement, hip replacement, and orthopedic, thoracic or abdominal surgery; - Arterial or venous thrombosis after neurosurgery including intracranial and intraspinal interventions; - Congenital or acquired thrombotic tendencies including but not limited to factor V Leiden, prothrombin mutation, antithrombin III, protein C and protein S deficiency, factor XIII mutation, familial fibrinogenemia, congenital plasminogen deficiency, elevated 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 receiving hemodialysis and patients receiving extracorporeal membrane oxygenation.

[0048] As used herein, the term "trough" or "trough level" refers to the lowest concentration that a drug reaches before the next dose of the drug is administered. In certain embodiments, the inhibition of factor XI / factor XIa at 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 trough is greater than about 80%. In certain embodiments, the inhibition of factor XI / factor XIa at trough is greater than about 90%.

[0049] As used in the present disclosure, the terms "treat", "treating", or "treatment" and other grammatical equivalents thereof are intended to include alleviating, reducing, improving, or preventing a disease, condition, or symptom, preventing additional symptoms, improving or preventing the underlying metabolic cause of a symptom, inhibiting a disease or condition, e.g., preventing the occurrence of a disease or condition, reducing a disease or condition, causing regression of a disease or condition, alleviating a condition caused by a disease or condition, or stopping the symptoms of a disease or condition, including prevention. These terms further include achieving a therapeutic and / or prophylactic effect. A "therapeutic effect" means the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic effect is achieved by the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, where amelioration is observed in the patient, although the patient may still have the underlying disorder.

[0050] In certain embodiments of the methods described herein, the subject is untreated, i.e., has not received any form of anticoagulant therapy prior to treatment with an anti-Factor XI / XIa antibody described herein, such as Antibody 1. In certain embodiments of the methods described herein, the subject has received stable treatment with a recommended dose of a novel oral anticoagulant (NOAC) prior to treatment with an anti-Factor XI / XIa antibody described herein, such as Antibody 1. In certain embodiments, the subject has received a direct oral anticoagulant (DOAC) prior to treatment with an anti-Factor XI / XIa antibody described herein, such as Antibody 1. In certain embodiments, the subject has received a vitamin K antagonist (VKA) prior to treatment with an anti-Factor XI / XIa antibody described herein, such as Antibody 1.

[0051] As used herein, the term "vial" refers to a container that holds a pharmaceutical product. In some embodiments, the vial can be a vial, bag, pen, or syringe. In some embodiments, the vial may be a vial, such as a glass vial.

[0052] As used herein, the term "pharmaceutical product" refers to an anti-Factor XI / XIa antibody described herein, such as Antibody 1 disclosed in Table 1, and excipients such as histidine buffer, sugar, and polysorbate.

[0053] The term "about" refers to any minimal variation in the concentration or amount of a drug that does not change the effectiveness of the drug in the preparation of a formulation and in the treatment of a disease or disorder. In certain embodiments, the term "about" can include ±5%, ±10%, or ±15% of a specified numerical value or data point.

[0054] In the present disclosure, ranges can be presented as "about" one particular value and / or "about" another particular value. When such a range is expressed, another aspect includes from one particular value and / or to another particular value. Similarly, when a value is presented as approximate by use of the preceding "about", it is understood that the particular value forms another aspect. It is further understood that each endpoint of a range is significant, whether related to or independent of the other endpoint. It is also understood that many values are disclosed in the present disclosure, and each value is also disclosed as "about" that particular value in addition to the value itself. Throughout this application, data is provided in several different formats, and this data is understood to represent endpoints and starting points and ranges of 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 greater than 10 and 15, 10 and 15 or greater, 10 and 15 less than, 10 and 15 or less than, 10 and 15 equal to, and between 10 and 15 are disclosed. It is also understood that each unit between two particular units is disclosed. For example, if 10 and 15 are disclosed, 11, 12, 13, and 14 are also disclosed.

[0055] Throughout this description, when a composition is described as having, including, or comprising a particular component, or a process and method are described as having, including, or comprising particular steps, it is contemplated that there are compositions of the invention that consist essentially of or consist of the components described, as well as processes and methods according to the invention that consist essentially of or consist of the process steps described.

[0056] In general, compositions specifying percentages are by weight unless otherwise specified. Further, when a variable element is not accompanied by a definition, the previous definition of that variable element prevails. Anti-factor XI and / or activated factor XI (factor XIa) antibody

[0057] In some embodiments, the present 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 polysorbate, and the pH of the formulation being from pH 5.0 to 6.0. In certain embodiments, the antibody comprises a VH having the amino acid sequence of SEQ ID NO: 29.

[0058] In embodiments, the present disclosure provides a pharmaceutical formulation comprising an antibody that binds to FXI and / or FXIa protein, or an antigen-binding fragment thereof, the pharmaceutical formulation being contained in a vial comprising an overfill volume for completely removing a therapeutically effective amount of the anti-FXI and / or anti-FXIa antibody or an 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: 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), and the pH of the formulation being about pH 5.5.

[0059] In embodiments, the present disclosure provides an intravenous delivery pharmaceutical formulation comprising about 1.5 mg of an antibody that binds to FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa) or an antigen-binding fragment thereof (the antibody 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 aqueous solution (D5W)), and the pH of the formulation being about pH 5.5.

[0060] The present disclosure also provides a pharmaceutical formulation of an antibody that specifically binds to an FXI and / or FXIa protein, the antibody comprising a VH CDR having the amino acid sequence of any one of the VH CDRs listed in Table 1 below, the formulation comprising a histidine buffer, a sugar or sugar alcohol, and polysorbate, and the pH of the formulation being from pH 5.0 to 6.0. In particular, the present disclosure provides a pharmaceutical formulation of an antibody that specifically binds to an FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa), the antibody comprising one, two, three, or more VH CDRs (or consisting of) having the amino acid sequence of any of the VH CDRs listed in Table 1 below, the formulation comprising a histidine buffer, a sugar or sugar alcohol, and polysorbate, and the pH of the formulation being from pH 5.0 to 6.0 (see PCT International Patent Application No. PCT / IB2016 / 053790, filed Jun. 24, 2016 and published as WO2016 / 207858, which is hereby incorporated by reference in its entirety).

[0061] In some embodiments, the present disclosure provides a pharmaceutical formulation of an antibody that specifically binds to an FXI / FXIa protein for use in the methods described herein (e.g., methods for treating a subject suffering from or at risk of developing a thrombotic disorder), the antibody comprising a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39, the formulation comprising a histidine buffer, a sugar or sugar alcohol, and polysorbate, and the pH of the formulation being from pH 5.0 to 6.0. In certain embodiments, the antibody comprises a VL having the amino acid sequence of SEQ ID NO: 39.

[0062] In embodiments, the present disclosure provides a pharmaceutical formulation comprising an antibody that binds to FXI and / or FXIa protein, or an antigen-binding fragment thereof, wherein the pharmaceutical formulation is contained in a vial that includes an overfill volume for completely removing a therapeutically effective amount of the anti-FXI and / or anti-FXIa antibody or its antigen-binding fragment. 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), 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), and the pH of the formulation is about pH 5.5.

[0063] In embodiments, the present disclosure provides an intravenous delivery pharmaceutical formulation comprising about 1.5 mg of an antibody or an antigen-binding fragment thereof that binds to FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa), 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 aqueous solution (D5W)), and the pH of the formulation is about pH 5.5.

[0064] The present disclosure also provides a pharmaceutical formulation of an antibody that specifically binds to an FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, 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 thrombotic disorder). The antibody comprises a VL CDR having an amino acid sequence of any one of the VL CDRs listed in Table 1 below, and the formulation comprises a histidine buffer, a sugar or sugar alcohol, and polysorbate, and the pH of the formulation is from pH 5.0 to 6.0. The antibody that specifically binds to an FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa) may comprise (or consist of) one, two, three, or more VL CDRs having an amino acid sequence of any of the VL CDRs listed in Table 1 below.

[0065] In embodiments, the present disclosure provides a pharmaceutical formulation comprising an antibody that binds to an FXI and / or FXIa protein, or an antigen-binding fragment thereof, wherein the pharmaceutical formulation is contained in a vial that includes an overfill volume for completely removing a therapeutically effective amount of the 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 an 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: 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 20 mM, sucrose at a concentration of about 220 mM, and polysorbate 20 at a concentration of about 0.04% (v / v), and the pH of the formulation is about pH 5.5.

[0066] In embodiments, the present disclosure provides an intravenous delivery pharmaceutical formulation comprising an antibody or antigen-binding fragment thereof that binds to about 1.5 mg of FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa), 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 aqueous solution (D5W)), and the pH of the formulation is about pH 5.5.

[0067] In embodiments, the present disclosure provides a pharmaceutical formulation comprising an antibody that binds to FXI and / or FXIa protein, or an antigen-binding fragment thereof, and the pharmaceutical formulation is contained in a vial that includes an overfill volume for completely removing a therapeutically effective amount of the anti-FXI and / or anti-FXIa antibody or antigen-binding fragment thereof. In certain embodiments, the vial contains a pharmaceutical formulation comprising an antibody of about 150 mg that binds to FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa) (the antibody has 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), and the pH of the formulation is about pH 5.5.

[0068] In an embodiment, the present disclosure provides an intravenous delivery pharmaceutical formulation comprising an antibody or an antigen-binding fragment thereof that binds to about 1.5 mg of FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa), 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 aqueous solution (D5W)), and the pH of the formulation is about pH 5.5.

[0069] In some embodiments, other antibodies for use in the methods described herein (e.g., methods of treating a subject suffering from or at risk of developing a thromboembolic disorder) are mutated but contain amino acids having at least 60, 70, 80, 85, 90, or 95 percent identity to the CDR regions shown in the sequences listed in Table 1 in the CDR regions. In some embodiments, the antibody contains a mutant amino acid sequence in which 1, 2, 3, 4, or 5 or fewer amino acids are mutated compared to the CDR regions shown in the sequences listed in Table 1 in the CDR regions.

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

Table 1-10

[0070] In some embodiments, other antibodies for use in the methods or formulations described herein (e.g., methods of treating a subject having or at risk of developing a thromboembolic disorder) have amino acids or nucleic acids encoding amino acids that are mutated, but 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 variant amino acid sequences that have 1, 2, 3, 4, or 5 or fewer amino acids mutated in the variable region compared to the variable regions shown in the sequences of Table 1, but that maintain substantially the same antigen-binding activity.

[0071] Since each of these antibodies is capable of binding 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 "combined" 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 these chains are combined, it is necessary to replace the VH sequence from a particular VH / VL pairing 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 needs to be replaced with a structurally similar full-length heavy chain sequence. Similarly, the VL sequence from a particular VH / VL pairing needs to 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 needs to be replaced with a structurally similar full-length light chain sequence.

[0072] Accordingly, in one aspect, for use in the methods described herein (e.g., methods of treating a subject suffering from or at risk of developing a thrombotic disorder), the present disclosure provides an isolated antibody or antigen-binding fragment thereof having a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 9 and 29 and a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 19 and 39, wherein the antibody 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., formulations in vials, intravenous drug delivery formulations), the present disclosure provides an isolated antibody or antigen-binding fragment thereof having a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 9 and 29 and a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 19 and 39, wherein the antibody specifically binds to FXI and / or FXIa (e.g., human, rabbit, cynomolgus monkey, and baboon FXIa).

[0073] More specifically, in certain embodiments, 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 amino acid sequences each selected from SEQ ID NO: 9 and 29, or 19 and 39.

[0074] In certain embodiments for use in the methods described herein (e.g., methods of treating a subject having or at risk of developing a thrombotic disorder), 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: 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., formulations in vials, intravenous drug delivery formulations), 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: 9 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19.

[0075] In certain embodiments for use in the methods described herein (e.g., methods of treating a subject having or at risk of developing a thrombotic disorder), 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: 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., formulations in vials, intravenous drug delivery formulations), 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: 29 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 39.

[0076] 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 mammalian cells 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 mammalian cells 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 an antigen-binding fragment 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 for use in the formulations described herein, the disclosure provides (i) an isolated antibody having a full-length heavy chain comprising an amino acid sequence optimized for expression in mammalian cells 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 mammalian cells 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 an antigen-binding fragment thereof having heavy and light chains comprising amino acid sequences selected from SEQ ID NO: 11 and 31, or 21 and 41, respectively.

[0077] In certain embodiments for use in the methods described herein, an antibody or an 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 for use in the formulations described herein, an antibody or an 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.

[0078] In certain embodiments for use in the methods described herein, the antibodies or antigen-binding fragments thereof provided herein that specifically bind to human FXI and / or FXIa comprise 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 for use in the formulations described herein, the antibodies or antigen-binding fragments thereof provided herein that specifically bind to human FXI and / or FXIa comprise 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.

[0079] As used herein, the terms “complementary determining region” and “CDR” refer to the sequences of amino acids within the antibody variable regions that confer 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.

[0080] The exact amino acid sequence boundaries of a given CDR can be readily determined using any of several well-known schemes, including those described below. 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 “composite” system.

[0081] For example, in Kabat, the CDR amino acid residues of antibody 2 in the heavy chain variable domain (VH) are numbered 31 - 35 (HCDR1), 50 - 66 (HCDR2), and 99 - 111 (HCDR3), and the CDR amino acid residues of the light chain variable domain (VL) are numbered 22 - 35 (LCDR1), 51 - 57 (LCDR2), and 90 - 100 (LCDR3). In Chothia, the CDR amino acids of VH are numbered 26 - 32 (HCDR1), 52 - 57 (HCDR2), and 99 - 111 (HCDR3), and the amino acid residues of VL are numbered 25 - 33 (LCDR1), 51 - 53 (LCDR2), and 92 - 99 (LCDR3). When combining the CDR definitions of both Kabat and Chothia, the CDR consists of the amino acid residues 26 - 35 (HCDR1), 50 - 66 (HCDR2), and 99 - 111 (HCDR3) of human VH, and the amino acid residues 22 - 35 (LCDR1), 51 - 57 (LCDR2), and 90 - 100 (LCDR3) of human VL. When combining the CDR definitions of both Kabat and Chothia, the "composite" CDR consists of the amino acid residues 26 - 35 (HCDR1), 50 - 66 (HCDR2), and 99 - 108 (HCDR3) of human VH, and the amino acid residues 24 - 38 (LCDR1), 54 - 60 (LCDR2), and 93 - 101 (LCDR3) of human VL. As another example, in IMGT, the CDR amino acid residues of the heavy chain variable domain (VH) are numbered 26 - 33 (HCDR1), 51 - 58 (HCDR2), and 97 - 108 (HCDR3), and the CDR amino acid residues of the light chain variable domain (VL) are numbered 27 - 36 (LCDR1), 54 - 56 (LCDR2), and 93 - 101 (LCDR3). Table 1 provides exemplary Kabat, Chothia, composite, 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 present disclosure provides an FXIa - binding antibody comprising the heavy and light chain CDR1, CDR2, and CDR3 described in Table 1, or combinations thereof. The amino acid sequence of the VH CDR1 of the antibody is shown in SEQ ID NO: 3 and 23. The amino acid sequence of the VH CDR2 of the antibody is shown in SEQ ID NO: 4 and 24.The amino acid sequences of the VH CDR3 of the antibody are shown in SEQ ID NO: 5 and 25. The amino acid sequences of the VL CDR1 of the antibody are shown in SEQ ID NO: 13 and 33. The amino acid sequences of the VL CDR2 of the antibody are shown in SEQ ID NO: 14 and 34. The amino acid sequences of the VL CDR3 of the antibody are shown in SEQ ID NO: 15 and 35. These CDR regions are delineated using the Kabat system.

[0082] Alternatively, when defined using the Chothia system (Al-Lazikani et al., (1997) JMB 273, 927-948), the amino acid sequences of the VH CDR1 of the antibody are shown in SEQ ID NO: 6 and 26. The amino acid sequences of the VH CDR2 of the antibody are shown in SEQ ID NO: 7 and 27. The amino acid sequences of the VH CDR3 of the antibody are shown in SEQ ID NO: 8 and 28. The amino acid sequences of the VL CDR1 of the antibody are shown in SEQ ID NO: 16 and 36. The amino acid sequences of the VL CDR2 of the antibody are shown in SEQ ID NO: 17 and 37 or have the amino acid sequence KNY. The amino acid sequences of the VL CDR3 of the antibody are shown in SEQ ID NO: 18 and 38.

[0083] Alternatively, when defined using a composite system, the amino acid sequences of the VH CDR1 of the antibody are shown in SEQ ID NO: 46. The amino acid sequences of the VH CDR2 of the antibody are shown in SEQ ID NO: 4. The amino acid sequences of the VH CDR3 of the antibody are shown in SEQ ID NO: 5. The amino acid sequences of the VL CDR1 of the antibody are shown in SEQ ID NO: 33. The amino acid sequences of the VL CDR2 of the antibody are shown in SEQ ID NO: 14. The amino acid sequences of the VL CDR3 of the antibody are shown in SEQ ID NO: 15.

[0084] Alternatively, when defined using the IMGT numbering scheme, the amino acid sequence of the VH CDR1 of the antibody is shown in SEQ ID NO: 43. The amino acid sequence of the VH CDR2 of the antibody is shown in SEQ ID NO: 44. The amino acid sequence of the VH CDR3 of the antibody is shown in SEQ ID NO: 45. The amino acid sequence of the VL CDR1 of the antibody is shown in SEQ ID NO: 47. The amino acid sequence of the VL CDR2 of the antibody is shown in SEQ ID NO: 37 (or the amino acid sequence KNY). The amino acid sequence of the VL CDR3 of the antibody is shown in SEQ ID NO: 15.

[0085] Each of these antibodies can bind to FXI and / or FXIa, and considering that antigen-binding specificity is mainly provided by the CDR1, 2, and 3 regions, the VH CDR1, 2, and 3 sequences, as well as the VL CDR1, 2, and 3 sequences, can be "combined" (e.g., CDRs from different antibodies can be combined, but each antibody preferably contains VH CDR1, 2, and 3 as well as VL CDR1, 2, and 3, creating other FXI and / or FXIa-binding molecules of the present disclosure). Such "combined" FXI and / or FXIa-binding antibodies can be tested using binding assays known in the art and those described in this example (e.g., ELISA, SET, BIACORE™ assay). When VH CDR sequences are combined, it is necessary to replace the CDR1, CDR2, and / or CDR3 sequences from a particular VH sequence with structurally similar CDR sequence(s). Similarly, when VL CDR sequences are combined, it is necessary to replace the CDR1, CDR2, and / or CDR3 sequences from a particular VL sequence with structurally similar CDR sequence(s). It will be readily apparent to those skilled in the art that novel VH and VL sequences can be created by replacing the sequences of one or more VH and / or VL CDR regions with structurally similar sequences derived from the CDR sequences shown herein for the monoclonal antibodies of the present disclosure. In addition to the foregoing, 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, and 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.

[0086] In certain embodiments of the present disclosure, the antibody or its antigen-binding fragment can have the heavy and light chain sequences of the Fab described in Table 1. More specifically, the antibody or its antigen-binding fragment can have the heavy and light chain sequences of antibody 2 and antibody 1.

[0087] In other embodiments of the present 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 still other embodiments of the present 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, 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 a composite system and set forth in Table 1. In still other embodiments of the present 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 IMGT and set forth in Table 1.

[0088] In certain embodiments for use in the methods described herein, the present disclosure includes an antibody that specifically binds to FXI and / or FXIa, the antibody 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.

[0089] In certain embodiments, the present disclosure includes an antibody that specifically binds to FXI and / or FXIa, the antibody 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.

[0090] In certain embodiments, the present disclosure includes antibodies that specifically bind to FXI and / or FXIa and that include 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 (or amino acid sequence KNY) of SEQ ID NO: 17, and a light chain variable region CDR3 of SEQ ID NO: 18.

[0091] In certain embodiments, the present disclosure includes antibodies that specifically bind to FXI and / or FXIa and that include 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 (or amino acid sequence KNY) of SEQ ID NO: 37, and a light chain variable region CDR3 of SEQ ID NO: 38.

[0092] In certain embodiments, provided herein are antibodies that specifically bind to FXI and / or FXIa and that include 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 (or amino acid sequence KNY) of SEQ ID NO: 37, and a light chain variable region CDR3 of SEQ ID NO: 15.

[0093] In certain embodiments, provided herein are antibodies that specifically bind to FXI and / or FXIa and that include 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.

[0094] In certain embodiments, the disclosure includes antibodies or antigen-binding fragments that specifically bind to FXI and / or FXIa as described in Table 1. In certain embodiments for use in the methods described herein, the antibodies or antigen-binding fragments that bind to FXI and / or FXIa are Antibody 2 and Antibody 1.

[0095] As used herein, a human antibody includes a heavy or light chain variable region, or a full-length heavy or light chain, that is a "product of" or "derived from" a particular germline sequence when the variable region or full-length chain of the antibody is obtained from a system using human germline immunoglobulin genes. Such systems include immunizing transgenic mice having human immunoglobulin genes with the antigen of interest or screening a human immunoglobulin gene library displayed on phage with the antigen of interest. A human antibody that is a "product of" or "derived from" a particular human germline immunoglobulin sequence can be identified by comparing the amino acid sequence of the human antibody to the amino acid sequence of human germline immunoglobulins and selecting the human germline immunoglobulin sequence that is most closely related (i.e., has the highest percent identity) to the sequence of the human antibody.

[0096] A human antibody that is a "product of" or "derived from" a particular human germline immunoglobulin sequence can contain amino acid differences compared to the germline sequence, for example, due to naturally occurring somatic mutations or intentional introduction of site-specific mutations. However, in the VH or VL framework region, the selected human antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the human germline immunoglobulin gene and contains amino acid residues that identify the human antibody as human when compared to germline immunoglobulin amino acid sequences of other species (e.g., mouse germline sequences). In certain cases, the human antibody can have an amino acid sequence that is 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 the germline immunoglobulin gene.

[0097] Typically, a recombinant human antibody exhibits no more than 10 amino acid differences from the amino acid sequence encoded by a human germline immunoglobulin gene in the VH or VL framework region. In certain cases, a human antibody may exhibit no more than 5, or even no more than 4, 3, 2, or 1 amino acid differences from the amino acid sequence encoded by a germline immunoglobulin gene. Examples of human germline immunoglobulin genes include, but are not limited to, the variable domain germline segments described below, as well as DP47 and DPK9.

[0098] Homologous antibody In yet other embodiments for use in the methods described herein (e.g., methods of treating a subject suffering from or at risk of developing a thrombotic disorder), the disclosure provides an antibody or antigen-binding fragment thereof comprising an amino acid sequence homologous to the sequences described in Table 1 (e.g., SEQ ID NO: 29, 31, 39, or 41), wherein the antibody binds to an FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXIa) and retains the desired functional properties of the antibodies described in Table 1, such as Antibody 2 and Antibody 1. In certain aspects, such homologous antibodies retain the CDR amino acid sequences described in Table 1 (e.g., Kabat CDR, Chothia CDR, IMGT CDR, or composite CDR).

[0099] For example, in some embodiments, the present disclosure provides an isolated antibody, or a 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 NO: 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 NO: 19 and 39, 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 a 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 a 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 present disclosure, the heavy-chain and light-chain sequences further comprise the 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 aspects of the disclosure, the heavy and light chain sequences further comprise the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences as defined by Chothia, e.g., SEQ ID NOs: 6, 7, 8, 16, 17 (or amino acid sequence KNY), and 18, respectively. In certain other aspects, the heavy and light chain sequences further comprise the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences as defined by a composite system, e.g., SEQ ID NOs: 46, 4, 5, 33, 14, and 15, respectively. In certain other aspects, the heavy and light chain sequences further comprise the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences as defined by IMGT, e.g., SEQ ID NOs: 43, 44, 45, 47, 37 (or amino acid sequence KNY), and 15, respectively.

[0100] 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 the sequences listed in Table 1. In other embodiments for use in the formulations described herein, the VH and / or VL amino acid sequences are 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to the sequences listed in Table 1. In other embodiments, the VH and / or VL amino acid sequences can be identical except for amino acid substitutions at one, two, three, four or five or fewer amino acid positions. Antibodies having VH and VL regions with high (i.e., 80% or greater) identity to the VH and VL regions set forth in Table 1 can be obtained by mutagenesis (e.g., site-directed or PCR-mediated mutagenesis) of the nucleic acid molecules encoding SEQ ID NO: 10 or 30 and SEQ ID NO: 20 and 40, respectively, followed by testing for retention of function of the encoded mutated antibodies using the functional assays described herein.

[0101] In other embodiments for use in the methods described herein, the full-length heavy chain and / or full-length light chain amino acid sequences can be 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to the sequences described in Table 1 (e.g., SEQ ID NO: 11 and / or 21, or 31 and / or 41). In other embodiments for use in the formulations described herein, the full-length heavy chain and / or full-length light chain amino acid sequences can be 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or 99% identical to the sequences described in Table 1 (e.g., SEQ ID NO: 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 either the full-length heavy chain of SEQ ID NO: 11 or 31, and either the full-length light chain of SEQ ID NO: 21 or 41, can be obtained by mutagenesis of the nucleic acid molecule encoding such polypeptide (e.g., site-directed or PCR-mediated mutagenesis), followed by testing for retention of function of the encoded, altered antibody using the functional assays described herein.

[0102] In one aspect, provided herein is an isolated antibody, or a 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 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 a 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 a 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 aspects of the present disclosure, the heavy and light chain sequences further comprise the 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 aspects of the present disclosure, the heavy and light chain sequences further comprise the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences as defined by Chothia, e.g., SEQ ID NOs: 6, 7, 8, 16, 17 (or the amino acid sequence 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 a composite 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, 37 (or amino acid sequence KNY), and 15, respectively.

[0103] In other embodiments for use in the methods described herein, the full-length heavy 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).

[0104] In other embodiments for use in the methods described herein, the nucleotide sequences of the variable region of the heavy chain and / or the variable region of the light chain 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: 10 and / or 20, or 30 and / or 40). In other embodiments for formulating the methods described herein, the nucleotide sequences of the variable region of the heavy chain and / or the variable region of the light chain 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: 10 and / or 20, or 30 and / or 40).

[0105] 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 that need to be introduced for optimal alignment of the two sequences and the length of each gap (i.e., % identity = number of identical positions / total number of positions x 100). Comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm as described in the non-limiting examples below.

[0106] The isolated anti-FXI and / or FXIa antibodies, or antigen-binding fragments thereof, described herein can 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 (λ) antibodies. In certain embodiments, the anti-FXI and / or anti-FXIa antibodies described herein are human IgG1 / lambda (λ) antibodies that include an Fc domain engineered to reduce the potential for effector functions, such as, for example, a human Fc domain that includes D265A and / or P329A substitutions (e.g., ADCC and / or CDC).

[0107] Furthermore, or alternatively, the protein sequences of the present disclosure can also be used as “query sequences” for performing searches against public databases, for example, to identify related sequences. Such searches can be performed, for example, using the BLAST program (version 2.0) of Altschul, et al., 1990 J. Mol. Biol. 215:403-10.

[0108] Antibodies with conservative modifications In certain other embodiments, an antibody of the disclosure for use in the methods described herein (e.g., a method of treating a subject suffering from or at risk of developing a thrombotic 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, wherein one or more of these CDR sequences has a specific amino acid sequence based on the antibodies described herein or a conservative modification thereof, and the antibody retains the desired functional properties of the FXIa-binding antibodies of the disclosure. In certain other embodiments, an antibody of the disclosure for use in the formulations described herein (e.g., a formulation in a vial, an intravenous drug delivery formulation) has a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences, wherein one or more of these CDR sequences has a specific amino acid sequence based on the antibodies described herein or a conservative modification thereof, and the antibody retains the desired functional properties of the FXIa-binding antibodies of the disclosure.

[0109] Thus, in some embodiments, for use in the methods described herein, 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, the heavy chain variable region CDR3 amino acid sequence is selected from the group consisting of SEQ ID NOs: 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 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, 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.

[0110] For use in the formulations described herein, in some embodiments, the present disclosure provides an isolated antibody or antigen-binding fragment thereof comprising 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, the heavy chain variable region CDR3 amino acid sequence 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, 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.

[0111] In one aspect, provided herein is an isolated antibody or antigen-binding fragment thereof comprising 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 the amino acid sequences set forth in Table 1, and conservative modifications thereof, the heavy chain variable region CDR2 amino acid sequence is selected from the group consisting of the amino acid sequences set forth in Table 1, and conservative modifications thereof, the heavy chain variable region CDR3 amino acid sequence is selected from the group consisting of the amino acid sequences set forth in Table 1, and conservative modifications thereof, the light chain variable region CDR1 amino acid sequence is selected from the group consisting of the amino acid sequences set forth in Table 1, and conservative modifications thereof, the light chain variable region CDR2 amino acid sequence is selected from the group consisting of the amino acid sequences set forth in Table 1, and conservative modifications thereof, the light chain variable region CDR3 amino acid sequence is selected from the group consisting of the amino acid sequences set forth in Table 1, and conservative modifications thereof, and the antibody or antigen-binding fragment thereof specifically binds to FXIa.

[0112] In other embodiments for use in the methods described herein, the antibodies of the present disclosure are optimized for expression in mammalian cells and have full-length heavy chain and full-length light chain sequences, one or more of which have a specific amino acid sequence based on the antibodies described herein or a conservative modification thereof, and the antibody retains the desired functional properties of the FXIa-binding antibodies of the present disclosure. In other embodiments for use in the formulations described herein, the antibodies of the present disclosure are optimized for expression in mammalian cells and have full-length heavy chain and full-length light chain sequences, one or more of which have a specific amino acid sequence based on the antibodies described herein or a conservative modification thereof, and the antibody retains the desired functional properties of the FXIa-binding antibodies of the present disclosure. Accordingly, the present disclosure provides an isolated antibody consisting of a full-length heavy chain and a full-length light chain, optimized for expression in mammalian cells, wherein the full-length heavy chain has an amino acid sequence selected from the group consisting 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 consisting of SEQ ID NO: 21 or 41, and conservative modifications thereof, and the antibody specifically binds to FXI and / or FXIa (e.g., human, rabbit, cynomolgus monkey, and baboon FXIa).

[0113] Antibodies that bind to the same epitope In some embodiments, the disclosure provides an antibody that competes 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 of treating a subject suffering from or at risk of developing a thromboembolic disorder). In some embodiments, the disclosure provides an antibody that competes 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., formulations in vials, intravenous drug delivery formulations). Thus, additional antibodies can be identified based on their ability to compete with other antibodies of the disclosure in an FXI and / or FXIa binding assay (e.g., those described in the Examples section) (e.g., by binding to the same or overlapping epitopes and competitively inhibiting binding in a statistically significant manner). The ability of a test antibody to inhibit the binding of an antibody of the disclosure to an FXI and / or FXIa protein indicates that the test antibody can compete with that antibody for binding to FXI and / or FXIa, and such an antibody can, according to non-limiting theory, bind to the same or a related (e.g., structurally similar or spatially proximate) epitope on the FXI and / or FXIa protein as the antibody with which it competes. In certain embodiments, an antibody that binds to the same epitope on FXI and / or FXIa as an antibody of the disclosure is a human monoclonal antibody. Such human monoclonal antibodies can be prepared and isolated as described herein.

[0114] As used herein, an antibody "competes" for binding if a 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) and inhibits the FXI and / or FXIa binding of the antibody or antigen-binding fragment of the disclosure by more than 50% (e.g., 80%, 85%, 90%, 95%, 98% or 99%) in the presence of equimolar concentrations of the competing antibody. This can be determined, for example, in a competitive binding assay by any of the methods well known to those of skill in the art.

[0115] As used herein, an antibody or antigen-binding fragment thereof does not "compete" with the FXI and / or FXIa antibodies or antigen-binding fragments (e.g., Antibody 1 or Antibody 2) of the present disclosure. The antibody binds to the same FXI and / or FXIa epitope as the antibody or antigen-binding fragment of the present disclosure, or overlapping FXI and / or FXIa epitopes. As used herein, a competing antibody or antigen-binding fragment thereof is one that (i) sterically blocks the binding of the antibody or antigen-binding fragment of the present disclosure to its target (e.g., the competing antibody binds to a neighboring non-overlapping FXI and / or FXIa epitope antibody and physically prevents the antibody or antigen-binding fragment of the present disclosure from binding to its target), and / or (ii) binds to a different non-overlapping FXI and / or FXIa epitope and induces a conformational change in the FXI and / or FXIa protein, rendering the protein unable to bind to the FXI and / or FXIa antibody or antigen-binding fragment of the present disclosure that would occur in the absence of such conformational change.

[0116] Engineered and modified antibodies In some embodiments, the antibodies of the present disclosure for use in the methods described herein can further be prepared by using an antibody having one or more of the VH and / or VL sequences shown herein as a starting material for engineering a modified antibody, which may have properties that vary from the starting antibody. In some embodiments, the antibodies of the present disclosure for use in the formulations described herein can further be prepared by using an antibody having one or more of the VH and / or VL sequences shown herein as a starting material for engineering a modified antibody, which may have properties that vary from the starting antibody. The antibody can be engineered by modifying one or more residues within one or both of the variable regions (i.e., VH and / or VL), such as within one or more CDR regions and / or within one or more framework regions. Additionally or alternatively, the antibody can be engineered by modifying residues within the constant region(s), such as to alter the effector function(s) of the antibody.

[0117] One type of practicable variable region manipulation is CDR grafting. Antibodies interact with target antigens mainly via 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 among individual antibodies than the sequences outside the CDRs. Since CDR sequences are involved in most antibody-antigen interactions, recombinant antibodies that mimic the properties of specific naturally occurring antibodies can be expressed by constructing expression vectors containing CDR sequences from specific naturally occurring antibodies grafted onto framework sequences from different antibodies with different properties (see, for example, 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., U.S.A. 86:10029-10033, U.S. Patent No. 5,225,539 by Winter, and U.S. Patent Nos. 5,530,101, 5,585,089, 5,693,762 and 6,180,370 by Queen et al.).

[0118] Accordingly, another embodiment of the present disclosure relates to an isolated antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable region comprising a CDR1 sequence having an amino acid sequence selected from the group consisting of SEQ ID NO: 3 and 23, a CDR2 sequence having an amino acid sequence selected from the group consisting of SEQ ID NO: 4 and 24, and a CDR3 sequence having an amino acid sequence selected from the group consisting of SEQ ID NO: 5 and 25, and a light chain variable region comprising a CDR1 sequence having an amino acid sequence selected from the group consisting of SEQ ID NO: 13 and 33, a CDR2 sequence having an amino acid sequence selected from the group consisting of SEQ ID NO: 14 and 34, and a CDR3 sequence consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 15 and 35. Accordingly, such antibodies contain the VH and VL CDR sequences of monoclonal antibodies, but may contain framework sequences different from those of these antibodies.

[0119] Such framework arrays can be obtained from publicly available DNA databases or published references that contain germline antibody gene sequences. For example, the 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 in Kabat, E.A., et al., 1991 Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242, Tomlinson, I.M., et al., 1992 J. Mol. Biol. 227:776-798, and Cox, J.P.L. et al., 1994 Eur. J Immunol. 24:827-836, the contents of each of which are hereby expressly incorporated by reference.

[0120] Examples of framework sequences for use in the antibodies of the present disclosure are those that are structurally similar to the framework sequences used by the selected antibodies of the present disclosure, such as consensus sequences and / or framework sequences used by the monoclonal antibodies of the present disclosure. The VH CDR1, 2, and 3 sequences, as well as the VL CDR1, 2, and 3 sequences, can be grafted into framework regions having sequences identical to those found in the germline immunoglobulin genes from which the framework sequences are derived, or the CDR sequences can be grafted into framework regions that contain one or more mutations as compared to the germline sequences. For example, in certain cases, it has been found beneficial to mutate residues within the framework region in order to maintain or enhance the antigen-binding ability of the antibody (e.g., U.S. Pat. Nos. 5,530,101, 5,585,089, 5,693,762, and 6,180,370 by Queen et al.). Framework sequences that can be utilized as scaffolds for constructing the antibodies and antigen-binding fragments described herein include, but are not limited to, VH1A, VH1B, VH3, Vk1, Vl2, and Vk2.

[0121] Thus, for use in the methods described herein, another embodiment of the disclosure relates to an isolated FXIa-binding antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 9 and 29, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions in the framework region 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 NO: 19 and 39, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions in the framework region of such a sequence.

[0122] Thus, for use in the formulations described herein, another embodiment of the disclosure relates to an isolated FXIa-binding antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 9 and 29, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions in the framework region 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 NO: 19 and 39, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions in the framework region of such a sequence.

[0123] Another type of variable region modification is a mutation of an amino acid residue within the CDR1, CDR2, and / or CDR3 regions of VH and / or VL, thereby improving one or more binding properties (e.g., affinity) of the antibody of interest, 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 the in vitro or in vivo assays described herein and provided in the Examples section. Conservative modifications (such as those described above) can be introduced. The mutation(s) can be an amino acid substitution, addition, or deletion. Further, usually 1, 2, 3, 4, or 5 or fewer residues within the CDR region are modified.

[0124] Thus, in another embodiment for use in the methods described herein, the disclosure provides an isolated FXIa-binding antibody or an antigen-binding fragment thereof comprising a heavy chain variable region having a VH CDR1 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 3 and 23, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 3 and 23; a VH CDR2 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 4 and 24, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 4 and 24; a VH CDR3 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 5 and 25, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 5 and 25; a VL CDR1 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 13 and 33, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 13 and 33; a VL CDR2 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 14 and 34, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 14 and 34; and a VL CDR3 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 15 and 35, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 15 and 35.

[0125] Accordingly, in another embodiment for use in the methods described herein, the disclosure provides an isolated FXIa-binding antibody or antigen-binding fragment thereof comprising a heavy chain variable region having a VH CDR1 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 6 and 26, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 6 and 26; a VH CDR2 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 7 and 27, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 7 and 27; a VH CDR3 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 8 and 28, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 8 and 28; a VL CDR1 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 16 and 36, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 16 and 36; a VL CDR2 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 17 and 37 or the amino acid sequence KNY, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 17 and 37 or the amino acid sequence KNY; and a VL CDR3 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 18 and 38, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 18 and 38.

[0126] Thus, in another embodiment for use in the formulations described herein, the disclosure provides an isolated FXIa-binding antibody or an antigen-binding fragment thereof comprising a heavy chain variable region having a VH CDR1 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 3 and 23, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 3 and 23; a VH CDR2 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 4 and 24, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 4 and 24; a VH CDR3 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 5 and 25, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 5 and 25; a VL CDR1 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 13 and 33, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 13 and 33; a VL CDR2 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 14 and 34, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 14 and 34; and a VL CDR3 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 15 and 35, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 15 and 35.

[0127] Thus, in another embodiment for use in the formulations described herein, the disclosure provides an isolated FXIa-binding antibody or an antigen-binding fragment thereof comprising a heavy chain variable region having a VH CDR1 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 6 and 26, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 6 and 26; a VH CDR2 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 7 and 27, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 7 and 27; a VH CDR3 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 8 and 28, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 8 and 28; a VL CDR1 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 16 and 36, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 16 and 36; a VL CDR2 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 17 and 37 or the amino acid sequence KNY, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 17 and 37 (or the amino acid sequence KNY); and a VL CDR3 region consisting of an amino acid sequence selected from the group consisting of SEQ ID NO: 18 and 38, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions as compared to SEQ ID NO: 18 and 38.

[0128] Half-life extended antibody In some embodiments, the disclosure provides an antibody that specifically binds to an FXIa protein and has an extended in vivo half-life for use in the methods or formulations described herein.

[0129] Multiple factors can affect the half-life of a protein in vivo. For example, 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. For example, chemical conjugation to polyethylene glycol (PEG), reCODE PEG, antibody scaffolds, polysialic acid (PSA), hydroxyethyl starch (HES), albumin-binding ligands, and carbohydrate shields; gene fusion to proteins that bind to serum proteins such as albumin, IgG, FcRn, and transferrin; (genetic or chemical) coupling to other binding moieties that bind to serum proteins such as nanobodies, Fabs, DARPins, avimers, affibodies, and anticalins; gene fusion to rPEG, albumin, albumin domains, albumin-binding proteins, and Fc; or incorporation into nanocarriers, sustained-release formulations, or medical devices.

[0130] To extend the serum circulation of an antibody in vivo, an inert polymer molecule such as high molecular weight PEG can be attached to an antibody or a fragment thereof, with or without a multifunctional linker, by site-specific conjugation of PEG to the N or C terminus of the antibody, or by either via the epsilon-amino group present in lysine residues. To pegylate an antibody, the antibody, or a fragment thereof, is typically reacted with polyethylene glycol (PEG), for example, a reactive ester or aldehyde derivative of PEG, under conditions such that one or more PEG groups become attached to the antibody or antibody fragment. Pegylation can be carried out by an acylation or 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 an aglycosylated antibody. Linear or branched polymer derivatization is used to minimize loss of biological activity. The degree of conjugation can be carefully monitored by SDS-PAGE and mass spectrometry to ensure proper conjugation of the PEG molecule to the antibody. Unreacted PEG can be separated from the antibody-PEG conjugate by size exclusion or ion exchange chromatography. The PEG-derivatized antibody can be tested for binding activity and in vivo efficacy using methods well known to those of skill in the art, for example, by the 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, EP0154316 by Nishimura et al. and EP0401384 by Ishikawa et al.

[0131] Other modified PEGylation techniques include chemically orthogonal engineering by recombination (ReCODE PEG), which incorporates chemically specified side chains into biosynthetic proteins via a reconstituted system containing tRNA synthetase and tRNA. This technology enables the incorporation of over 30 novel amino acids into biosynthetic proteins in E. coli, yeast, and mammalian cells. The tRNA incorporates unnatural amino acids at any position where the amber codon is located, converting the amber from a stop codon to a codon that signals the incorporation of a chemically specified amino acid.

[0132] Recombinant PEGylation technology (rPEG) can also be used to extend serum half-life. This technology involves genetically fusing 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 approximately 15 times larger than its actual molecular weight, the serum half-life of the protein is significantly extended. In contrast to conventional PEGylation, which requires chemical conjugation and repurification, the manufacturing process is greatly simplified and the product is uniform.

[0133] Polysialylation is another technique that uses the natural polymer polysialic acid (PSA) to extend the active lifespan and improve the stability of therapeutic peptides and proteins. PSA is a polymer of sialic acid (sugar). When used for drug delivery of proteins and therapeutic peptides, polysialic acid provides a protective microenvironment for conjugation. This increases the active lifespan of the therapeutic protein in circulation and prevents the therapeutic protein from being recognized by the immune system. PSA polymers are naturally found in the human body. It is taken up by certain bacteria and has evolved over millions of years to coat the bacterial wall. These naturally polysialylated bacteria were thus able to disable the body's defense system by molecular mimicry. PSA, the ultimate stealth technology in nature, can be easily produced in large quantities with predetermined physical properties from such bacteria. Bacterial PSA is completely non-immunogenic because it is chemically identical to PSA in the human body, even when bound to proteins.

[0134] Another technique involves the use of hydroxyethyl starch (「HES」) derivatives conjugated to antibodies. HES is a modified natural polymer derived from waxy maize starch and can be metabolized by the body's enzymes. HES solutions are typically administered to replace depleted blood volume and improve the rheological properties of blood. Hesylation of antibodies allows for an extended circulation half-life and increased biological activity by increasing the stability of the molecule and reducing renal clearance. By varying various parameters such as the molecular weight of HES, a wide range of HES-antibody conjugates can be customized.

[0135] One can also generate antibodies with an increased half-life in vivo by introducing one or more amino acid modifications (i.e., substitutions, insertions, or deletions) into the IgG constant domain, or an FcRn-binding fragment thereof (preferably, the Fc or hinge-Fc domain fragment). See, for example, International Publication No. WO98 / 23289, International Publication No. WO97 / 34631, and U.S. Patent No. 6,277,375.

[0136] Furthermore, the antibody can be conjugated to albumin (e.g., human serum albumin; HSA) to make the antibody or antibody fragment more stable in vivo or to have a longer half-life in vivo. This technique is well-known in the art; see, for example, International Publication Nos. WO93 / 15199, WO93 / 15200, and WO01 / 77137, and European Patent No. EP413,622. Furthermore, with respect to the bispecific antibodies described above, the specificity of the antibody can be designed such that one binding domain of the antibody binds to FXIa while the second binding domain of the antibody binds to serum albumin, preferably HSA.

[0137] Strategies for increasing the half-life are particularly useful in nanobodies, fibronectin-based binders, and other antibodies or proteins for which an increase in in vivo half-life is desired.

[0138] Antibody complex In some embodiments, the disclosure provides an antibody or fragment thereof that specifically binds to an FXIa protein recombinantly fused or chemically conjugated to a heterologous protein or polypeptide (or 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) for use in the methods or formulations described herein, to produce a fusion protein. In particular, the disclosure provides a fusion protein comprising an antigen-binding fragment of an antibody described herein (e.g., a Fab fragment, Fd fragment, Fv fragment, F(ab)2 fragment, VH domain, VH CDR, VL domain, or VL CDR) and a heterologous protein, polypeptide, or peptide. Methods of fusing or conjugating a protein, polypeptide, or peptide to an antibody or antibody fragment are known in the art. See, for example, U.S. Pat. Nos. 5,336,603, 5,622,929, 5,359,046, 5,349,053, 5,447,851, and 5,112,946, European Patents EP307,434 and EP367,166, International Publications WO96 / 04388 and WO91 / 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 89:11337-11341.

[0139] Additional fusion proteins can be generated by 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 the antibodies or fragments thereof of the present disclosure (e.g., antibodies or fragments thereof having higher affinity and lower dissociation rates). Generally, see 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 these patents and publications is hereby incorporated by reference in its entirety). Antibodies or fragments thereof, or the encoded antibodies or fragments thereof, can be modified by subjecting them to error-prone PCR, random nucleotide insertion, or other methods of random mutagenesis prior to recombination. A polynucleotide encoding an antibody or fragment thereof that specifically binds to the FXIa protein may be recombined using one or more components, motifs, sections, parts, domains, fragments, etc. of one or more heterologous molecules.

[0140] 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 hexahistidine peptide (amino acid sequence: HHHHHH; SEQ ID NO: 48), for example, the pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, CA, 91311), many of which are commercially available. For example, as described in Gentz et al., 1989, Proc. Natl. Acad. Sci. USA 86:821-824, hexahistidine (SEQ ID NO: 48) enables facile purification of the fusion protein. Other peptide tags useful for purification include, but are not limited to, the hemagglutinin ("HA") tag corresponding to an epitope derived from the hemagglutinin protein of influenza (Wilson et al., 1984, Cell 37:767), and the "FLAG" tag.

[0141] In other embodiments, the antibodies or fragments thereof of the present disclosure are conjugated to diagnostic or detectable agents. Such antibodies can be useful for monitoring or predicting the signs, onset, progression, and / or severity of a disease or disorder as part of clinical testing procedures, such as determining the effectiveness of a particular treatment. Such diagnosis and detection can be achieved by binding the antibody to detectable substances including, but not limited to, various enzymes such as horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; bridging molecule families such as streptavidin biotin and avidin / biotin; fluorescent substances such as umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, or phycoerythrin; luminescent substances such as luminol; bioluminescent substances such as luciferase, luciferin, and aequorin; radioactive substances such as iodine (131I, 125I, 123I, and 121I), carbon (14C), sulfur (35S), tritium (3H), indium (115In, 113In, 112In, and 111In), technetium (99Tc), thallium (201Ti), gallium (68Ga, 67Ga), palladium (103Pd), molybdenum (99Mo), xenon (133Xe), fluorine (18F), 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 186Re, 188Re, 142Pr, 105Rh, 97Ru, 68Ge, 57Co, 65Zn, 85Sr, 32P, 153Gd, 169Yb, 51Cr, 54Mn, 75Se, 113Sn, and 117Tin; positron-emitting metals using various positron emission tomography; and detectable substances including, but not limited to, non-radioactive paramagnetic metal ions.

[0142] In some embodiments, the disclosure further encompasses the use of an antibody or fragment thereof conjugated to a therapeutic moiety. The antibody or fragment thereof can be conjugated to a therapeutic moiety, such as a cytotoxin, e.g., a cell growth inhibitor or a cell killing agent, a therapeutic agent, or a radioactively labeled metal ion, e.g., an alpha emitter. Cytotoxins or cytotoxic drugs include any agent that is harmful to cells.

[0143] Furthermore, the antibody or fragment thereof can be conjugated to a therapeutic moiety or drug moiety that modifies a given biological response. The therapeutic moiety or drug moiety should not be construed as being limited to classical chemotherapeutic agents. For example, the drug moiety can be a protein, peptide, or polypeptide having a desired biological activity. Such proteins include, for example, toxins such as abrin, ricin A, Pseudomonas exotoxin, cholera toxin, or diphtheria toxin, tumor necrosis factor, alpha-interferon, beta-interferon, nerve growth factor, platelet-derived growth factor, tissue plasminogen activator, apoptosis agents, anti-angiogenesis agents, or biological response modifiers such as, for example, lymphokines.

[0144] Furthermore, the antibody can be conjugated to a macrocyclic chelating agent useful for conjugating a therapeutic moiety, such as a radioactive metal ion, such as an alpha emitter, such as 213Bi, or a radioactive metal ion including, but not limited to, 131In, 131Lu, 131Y, 131Ho, 131Sm, to the polypeptide. In certain embodiments, the macrocyclic chelating agent 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 herein by reference in its entirety.

[0145] Techniques for conjugating a therapeutic moiety to an antibody are well known, see, 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 Therapy”, in 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.

[0146] The antibody may also be bound to a solid support, which is particularly useful for immunoassay or purification of the target antigen. Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride, or polypropylene.

[0147] Pharmaceutical preparation In some embodiments, the disclosure also provides a pharmaceutical preparation comprising a therapeutically effective amount of a Factor XI and / or Factor XIa antibody disclosed herein (e.g., Antibody 1). The pharmaceutical preparation includes one or more excipients and is maintained at a specific pH. Non-limiting examples of "excipients" as used herein include any non-therapeutic agent added to the formulation to provide desired physical or chemical properties such as pH, osmotic pressure, viscosity, transparency, color, isotonicity, odor, sterility, stability, dissolution rate or release rate, adsorption, or penetration. Exemplary pharmaceutical preparations containing a Factor XI and / or Factor XIa antibody (e.g., Antibody 1) disclosed herein are provided, for example, in International Application Publication No. WO2021 / 127525.

[0148] Active pharmaceutical ingredient Antibody 1 is a high-affinity anti-human Factor XI monoclonal antibody. It is expressed in a Chinese hamster ovary cell line (CHO-C8TD). In some embodiments, the active pharmaceutical ingredient of Antibody 1 is fully formulated for subcutaneous administration (i.e., no further excipients are added), and thus has the same composition as the pharmaceutical product of Antibody 1. In some embodiments, for intravenous administration, the pharmaceutical product of Antibody 1 is further diluted with a suitable carrier. In some embodiments, the pharmaceutical product of Antibody 1 is diluted with a solution containing dextrose (e.g., 5% dextrose aqueous solution (D5W)).

[0149] Excipients and pH In some embodiments, the excipients contained in the pharmaceutical product of Antibody 1 are pharmacopeial grade excipients. In some embodiments, the excipients in the pharmaceutical product of Antibody 1 include histidine, histidine salts, sugars, and polysorbates. In some embodiments, the excipients in the pharmaceutical product of Antibody 1 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 stabilization, buffering capacity, and isotonicity. The formulation can maximize the stability of the monoclonal antibody product and provide a sterile solution suitable for subcutaneous or intravenous administration. In some embodiments, the sugar (e.g., sucrose) acts as a stabilizer. In some embodiments, histidine (e.g., L-histidine, L-histidine HCl monohydrate) acts as a buffer. In some embodiments, polysorbate (e.g., polysorbate 20) acts as a stabilizer. In some embodiments, the formulation is adjusted to the final volume in water for injection (WFI).

[0150] One or more excipients in the pharmaceutical formulation of the present invention include a buffer. The term "buffer" as used herein refers to one or more components that, when added to an aqueous solution, can protect the solution from pH fluctuations when an acid or alkali is added or when diluted with a solvent. In addition to phosphate buffers, glycinate, carbonate, citrate, histidine buffer, etc. can be used, in which case sodium ions, potassium ions, or ammonium ions can function as counterions.

[0151] In certain embodiments, the buffer or buffer system comprises at least one buffer having a buffering range that completely or partially overlaps with a range of pH 5.0 to 7.4. In certain embodiments, the buffer has a pH of about 5.5 ± 0.5. In certain embodiments, the buffer comprises a histidine buffer. In certain embodiments, the histidine buffer is present at a concentration of 0.05 - 10 mM, 0.1 - 10 mM, 0.2 - 10 mM, 0.5 - 10 mM, 1 - 10 mM, 5 - 10 mM, 5 - 100 mM, 10 - 100 mM, 15 - 100 mM, 20 - 100 mM, 30 - 100 mM, 40 - 100 mM, 50 - 100 mM, 60 - 100 mM, 70 - 100 mM, 80 - 100 mM, 90 - 100 mM, 5 - 90 mM, 5 - 80 mM, 5 - 70 mM, 5 - 60 mM, 5 - 50 mM, 5 - 40 mM, 5 - 30 mM, 5 - 20 mM, 10 - 50 mM, 10 - 40 mM, 10 - 30 mM, 10 - 20 mM, 5 - 25 mM, 10 - 25 mM, 15 - 25 mM, 20 - 25 mM, 5 - 20 mM, 10 - 20 mM, or 15 - 20 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, or about 50 mM. 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 histidine buffer has a pH of about 5.0, about 5.5, about 6.0, about 6.5, or about 7.0. In certain embodiments, the histidine buffer has a pH of about 5.5.

[0152] The pharmaceutical preparation of the present invention may have a pH of 5.0 to 6.0. For example, in certain embodiments, the pharmaceutical preparation has a pH of 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 pharmaceutical preparation has a pH of 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 pharmaceutical preparation has a pH of about 5.5. According to the scientific rounding rule, a pH of 5.45 or higher and 5.55 or lower is rounded to 5.5.

[0153] In certain embodiments, the buffer system of the pharmaceutical preparation contains histidine at 10 to 30 mM and pH 5.5 ± 0.2. In certain embodiments, the buffer system of the pharmaceutical preparation contains histidine at about 20 mM and pH 5.5 ± 0.2. In certain embodiments, the buffer system of the pharmaceutical preparation contains histidine at 10 to 30 mM and pH 5.5 ± 0.05. In certain embodiments, the buffer system of the pharmaceutical preparation contains histidine at about 20 mM and pH 5.5 ± 0.05.

[0154] In certain embodiments, the buffer system of the pharmaceutical preparation contains histidine at 0.10 to 0.30 mM and pH 5.5 ± 0.2. In certain embodiments, the buffer system of the pharmaceutical preparation contains histidine at about 0.20 mM and pH 5.5 ± 0.2. In certain embodiments, the buffer system of the pharmaceutical preparation contains histidine at 0.10 to 0.30 mM and pH 5.5 ± 0.05. In certain embodiments, the buffer system of the pharmaceutical preparation contains histidine at about 0.20 mM and pH 5.5 ± 0.05.

[0155] One or more excipients in the pharmaceutical preparation of the present invention further comprise a sugar or a sugar alcohol. Sugars and sugar alcohols are useful as heat stabilizers in pharmaceutical preparations. In certain embodiments, the pharmaceutical preparation 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 a specific embodiment, the pharmaceutical preparation 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 a specific embodiment, the pharmaceutical preparation comprises sucrose.

[0156] The amount of sugar or sugar alcohol included in the preparation can vary depending on the specific circumstances in which the preparation is used and the intended purpose. In certain embodiments, the pharmaceutical preparation comprises 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 mM - 300 mM of sugar or sugar alcohol. In certain embodiments, the pharmaceutical preparation comprises 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 a particular embodiment, the pharmaceutical preparation comprises about 220 mM of sugar or sugar alcohol (e.g., sucrose).

[0157] The amount of sugar or sugar alcohol contained in the formulation can vary depending on the specific circumstances in which the formulation is used and the intended purpose. In certain embodiments, the pharmaceutical formulation contains from 0.50 to 3.00 mM, from 0.50 to 2.50 mM, from 1.00 to 3.00 mM, from 1.00 to 2.50 mM, from 1.50 to 3.00 mM, from 1.50 to 2.50 mM, from 2.00 to 3.00 mM, from 2.00 to 2.50 mM, or from 2.50 mM to 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 specific embodiments, the pharmaceutical formulation contains about 2.20 mM of sugar or sugar alcohol (e.g., sucrose).

[0158] One or more excipients in the pharmaceutical formulations disclosed herein further include a surfactant. As used herein, the term "surfactant" refers to a surfactant molecule containing both a hydrophobic moiety (e.g., an alkyl chain) and a hydrophilic moiety (e.g., a carboxyl group and a carboxylate group). Surfactants are useful for reducing the 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 (R); sodium lauryl sulfate; sodium octyl glucoside; lauryl sulfobetaine, myristyl sulfobetaine, linoleyl sulfobetaine, or stearyl sulfobetaine; lauryl sarcosine, myristyl sarcosine, linoleyl sarcosine, or stearyl sarcosine; linoleyl betaine, myristyl betaine, or cetyl betaine; lauramidopropyl betaine, cocamidopropyl betaine, linoleamidopropyl betaine, myristamidopropyl betaine, palmidopropyl betaine, or isostearamidopropyl betaine (e.g., lauroamidopropyl); myristamidopropyldimethylamine, palmidopropyldimethylamine, or isostearamidopropyldimethylamine; sodium methyl cocoyl taurate, or disodium methyl oleyl taurate; and the MONAQUAT (TM) series (Mona Industries, Inc., Paterson, N.J.), polyethylene glycol, polypropylene glycol, and copolymers of ethylene and propylene glycol (e.g., Pluronics (R), PF68, etc.). In certain embodiments, the surfactant is a polysorbate. In certain embodiments, the surfactant is polysorbate 20.

[0159] The amount of nonionic surfactant contained within the pharmaceutical formulation of the present invention may vary depending on the specific desired characteristics of the formulation, as well as the specific circumstances and purposes for which the formulation is intended to be used. In certain embodiments, the pharmaceutical formulation comprises from 0.02% to 0.06%, from 0.03% to 0.05%, or from 0.035% to 0.045% nonionic surfactant (e.g., polysorbate 20). In certain embodiments, the pharmaceutical formulation comprises 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% nonionic surfactant (e.g., polysorbate 20).

[0160] The amount of nonionic surfactant contained within the pharmaceutical formulation of the present invention may vary depending on the specific desired characteristics of the formulation, as well as the specific circumstances and purposes for which the formulation is intended to be used. In certain embodiments, the pharmaceutical formulation comprises from 0.0002% to 0.0006%, from 0.0003% to 0.0005%, or from 0.00035% to 0.00045% nonionic surfactant (e.g., polysorbate 20). In certain embodiments, the pharmaceutical formulation comprises about 0.00005%, about 0.00001%, about 0.00002%, about 0.00003%, about 0.00004%, about 0.00005%, about 0.00006%, about 0.00007%, about 0.00008%, about 0.00009%, or about 0.001% nonionic surfactant (e.g., polysorbate 20).

[0161] In certain embodiments, the pharmaceutical product is diluted in an aqueous carrier suitable for the route of administration, e.g., intravenous administration. Exemplary carriers include sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), pH buffered solutions (e.g., phosphate buffered saline), sterile saline solutions, Ringer's solution, or dextrose solutions. In one embodiment, when the pharmaceutical formulation is prepared for intravenous administration, the pharmaceutical formulation may be diluted with 5% dextrose solution (D5W).

[0162] Exemplary formulations In certain embodiments, the pharmaceutical formulation of the present invention comprises a factor XI and / or factor XIa antibody (e.g., an antibody having a heavy chain variable domain (VH) with the amino acid sequence of SEQ ID NO: 9 or 29 and a light chain variable domain (VL) with 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.

[0163] In certain embodiments, the pharmaceutical formulation comprises Factor XI and / or Factor XIa antibody at 100 - 200 mg / mL (e.g., an antibody having a heavy chain variable domain (VH) with the amino acid sequence of SEQ ID NO: 9 or 29 and a light chain variable domain (VL) with 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), and has a pH of 5.0 - 6.0. In certain embodiments, the pharmaceutical formulation comprises Factor XI and / or Factor XIa antibody at 100 - 200 mg / mL (e.g., an antibody having a heavy chain variable domain (VH) with the amino acid sequence of SEQ ID NO: 9 or 29 and a light chain variable domain (VL) with the amino acid sequence of SEQ ID NO: 19 or 39), approximately 20 mM histidine buffer, approximately 220 mM sugar or sugar alcohol (e.g., sucrose), and approximately 0.04% polysorbate (e.g., polysorbate 20), and has a pH of 5.0 - 6.0. In certain embodiments, the pharmaceutical formulation comprises Factor XI and / or Factor XIa antibody at 100 - 200 mg / mL, approximately 20 mM histidine buffer, approximately 220 mM sugar or sugar alcohol (e.g., sucrose), and approximately 0.04% polysorbate (e.g., polysorbate 20), and has a pH of 5.2 - 5.8. In certain embodiments, the pharmaceutical formulation comprises Factor XI and / or Factor XIa antibody at 100 - 200 mg / mL (e.g., an antibody having a heavy chain variable domain (VH) with the amino acid sequence of SEQ ID NO: 9 or 29 and a light chain variable domain (VL) with the amino acid sequence of SEQ ID NO: 19 or 39), approximately 20 mM histidine buffer, approximately 220 mM sugar or sugar alcohol (e.g., sucrose), and approximately 0.04% polysorbate (e.g., polysorbate 20), and has a pH of 5.45 - 5.55.

[0164] In certain embodiments, the pharmaceutical formulation comprises Factor XI and / or Factor XIa antibody at 1.00 - 2.00 mg / mL (for example, an antibody having a heavy chain variable domain (VH) with the amino acid sequence of SEQ ID NO: 9 or 29 and a light chain variable domain (VL) with the amino acid sequence of SEQ ID NO: 19 or 39), histidine buffer at 0.10 - 0.30 mM, sugar or sugar alcohol at 2.00 - 3.00 mM (for example, sucrose), and polysorbate at 0.0002% - 0.0006% (for example, polysorbate 20), and has a pH of 5.0 - 6.0. In certain embodiments, the pharmaceutical formulation comprises Factor XI and / or Factor XIa antibody at 1.00 - 2.00 mg / mL (for example, an antibody having a heavy chain variable domain (VH) with the amino acid sequence of SEQ ID NO: 9 or 29 and a light chain variable domain (VL) with the amino acid sequence of SEQ ID NO: 19 or 39), histidine buffer at about 0.20 mM, sugar or sugar alcohol at about 2.20 mM (for example, sucrose), and polysorbate at about 0.0004% (for example, polysorbate 20), and has a pH of 5.0 - 6.0. In certain embodiments, the pharmaceutical formulation comprises Factor XI and / or Factor XIa antibody at 1.00 - 2.00 mg / mL (for example, an antibody having a heavy chain variable domain (VH) with the amino acid sequence of SEQ ID NO: 9 or 29 and a light chain variable domain (VL) with the amino acid sequence of SEQ ID NO: 19 or 39), histidine buffer at about 0.20 mM, sugar or sugar alcohol at about 2.20 mM (for example, sucrose), and polysorbate at about 0.0004% (for example, polysorbate 20), and has a pH of 5.2 - 5.8. In certain embodiments, the pharmaceutical formulation comprises Factor XI and / or Factor XIa antibody at 1.00 - 2.00 mg / mL (for example, an antibody having a heavy chain variable domain (VH) with the amino acid sequence of SEQ ID NO: 9 or 29 and a light chain variable domain (VL) with the amino acid sequence of SEQ ID NO: 19 or 39), histidine buffer at about 0.20 mM, sugar or sugar alcohol at about 2.20 mM (for example, sucrose), and polysorbate at about 0.0004% (for example, polysorbate 20), and has a pH of 5.45 - 5.55.

[0165] In certain embodiments, the pharmaceutical formulation comprises factor XI and / or factor XIa antibody at 100 - 200 mg / mL (for example, an antibody having a heavy chain variable domain (VH) with the amino acid sequence of SEQ ID NO: 9 or 29 and a light chain variable domain (VL) with 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, and has a pH of 5.0 - 6.0. In certain embodiments, the pharmaceutical formulation comprises factor XI and / or factor XIa antibody at 100 - 200 mg / mL, about 20 mM histidine buffer, about 220 mM sucrose, and about 0.04% polysorbate 20, and has a pH of 5.0 - 6.0. In certain embodiments, the pharmaceutical formulation comprises factor XI and / or factor XIa antibody at 100 - 200 mg / mL (for example, an antibody having a heavy chain variable domain (VH) with the amino acid sequence of SEQ ID NO: 9 or 29 and a light chain variable domain (VL) with the amino acid sequence of SEQ ID NO: 19 or 39), about 20 mM histidine buffer, about 220 mM sugar or sugar alcohol (for example, sucrose), and about 0.04% polysorbate (for example, polysorbate 20), and has a pH of 5.3 - 5.7. In certain embodiments, the pharmaceutical formulation comprises factor XI and / or factor XIa antibody at 100 - 200 mg / mL (for example, an antibody having a heavy chain variable domain (VH) with the amino acid sequence of SEQ ID NO: 9 or 29 and a light chain variable domain (VL) with 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 (for example, polysorbate 20), and has a pH of 5.45 - 5.55.

[0166] In certain embodiments, the pharmaceutical formulation comprises Factor XI and / or Factor XIa antibody at 1.00 - 2.00 mg / mL (for example, an antibody having a heavy chain variable domain (VH) with the amino acid sequence of SEQ ID NO: 9 or 29 and a light chain variable domain (VL) with the amino acid sequence of SEQ ID NO: 19 or 39), histidine buffer at 0.10 - 0.30 mM, sucrose at 2.00 - 3.00 mM, and polysorbate 20 at 0.0002% - 0.0006%, and has a pH of 5.0 - 6.0. In certain embodiments, the pharmaceutical formulation comprises Factor XI and / or Factor XIa antibody at 1.00 - 2.00 mg / mL (for example, an antibody having a heavy chain variable domain (VH) with the amino acid sequence of SEQ ID NO: 9 or 29 and a light chain variable domain (VL) with the amino acid sequence of SEQ ID NO: 19 or 39), histidine buffer at about 0.20 mM, sucrose at about 2.20 mM, and polysorbate 20 at about 0.0004%, and has a pH of 5.0 - 6.0. In certain embodiments, the pharmaceutical formulation comprises Factor XI and / or Factor XIa antibody at 1.00 - 2.00 mg / mL, histidine buffer at 20 mM, sucrose at about 2.20 mM, and polysorbate 20 at about 0.0004%, and has a pH of 5.3 - 5.7. In certain embodiments, the pharmaceutical formulation comprises Factor XI and / or Factor XIa antibody at 1.00 - 2.00 mg / mL (for example, an antibody having a heavy chain variable domain (VH) with the amino acid sequence of SEQ ID NO: 9 or 29 and a light chain variable domain (VL) with the amino acid sequence of SEQ ID NO: 19 or 39), histidine buffer at about 0.20 mM, sucrose at about 2.20 mM, and polysorbate 20 at about 0.0004%, and has a pH of 5.45 - 5.55.

[0167] In an embodiment, the present disclosure provides a pharmaceutical formulation comprising an antibody that binds to FXI and / or FXIa protein, or an antigen-binding fragment thereof, wherein the pharmaceutical formulation is contained in a vial that includes an overfill volume for completely removing a therapeutically effective amount of the anti-FXI and / or anti-FXIa antibody or an 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), 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), and the pH of the formulation is about pH 5.5. The antibody has 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.

[0168] In an embodiment, the present disclosure provides an intravenous delivery pharmaceutical formulation comprising about 1.5 mg of an antibody or an antigen-binding fragment thereof that binds to FXI and / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or FXIa), 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 aqueous solution (D5W)), and the pH of the formulation is about pH 5.5. The antibody has 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.

[0169] 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, after storage under defined conditions, the Factor XI and / or Factor XIa antibodies in the formulation retain acceptable physical characteristics, chemical structure, and / or biological function.

[0170] An exemplary method for determining the stability of factor XI and / or factor XIa antibodies in a pharmaceutical formulation is described in Example 1 of the present disclosure. Further, the stability of the protein can be evaluated by measuring the binding affinity of the factor XI and / or factor XIa antibody to its target, or the biological activity of the factor XI and / or factor XIa antibody, in certain in vitro assays, such as the aPTT and FXI activity assays described in WO2016 / 207858.

[0171] The pharmaceutical formulation can be prepared and stored as a liquid formulation. In certain embodiments, the pharmaceutical formulation is a liquid formulation stored at 2 - 8°C (e.g., 4°C). In certain embodiments, the pharmaceutical formulation is a liquid formulation stored protected from light at 4°C.

[0172] As a result of the stability tests, it has been found that a 150 mg / mL concentrate for the injectable solution of antibody 1 is compatible with its excipients and primary packaging materials. The 150 mg / mL injectable concentrate of antibody 1 is suitable for subcutaneous administration using a disposable syringe, either undiluted or diluted with a carrier buffer, such as 5% dextrose (D5W). The injectable concentrate using a commercially available disposable syringe has been demonstrated in a dose range of 0.5 mg / subject to 600 mg / subject. Materials known to be compatible with antibody 1 include injectable syringes composed of polypropylene or polycarbonate, and injectable needles composed of stainless steel. The compatibility of the concentrate for the injectable solution of antibody 1 has been demonstrated with 1 mL syringes for antibody 1 concentrations of 0.5 mg / mL to 150 mg / mL. The compatibility of the concentrate for the injectable solution of antibody 1 has been demonstrated with 3 mL syringes filled up to about 2 mL for a concentration of 150 mg / mL of antibody 1, covering a total dose range of 0.5 mg to 150 mg for 1 mL syringes and a dose of about 300 mg for 3 mL syringes (filled to about 2 mL) per injection.

[0173] Dosage form Before use, the pharmaceutical formulation can be diluted with 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 buffered solutions (e.g., phosphate buffered saline), sterile saline solutions, Ringer's solution, or dextrose solutions. For example, if the pharmaceutical formulation is prepared for intravenous administration, the pharmaceutical formulation contains 5% dextrose solution (D5W). In certain embodiments, the diluted pharmaceutical formulation is isotonic and suitable for intravenous infusion, e.g., administration with D5W. In certain embodiments, the formulation is diluted with about 50 mL of D5W, 100 mL of D5W, 150 mL of D5W, 200 mL of D5W, 250 mL of D5W, 300 mL of D5W, 350 mL of D5W, 400 mL of D5W, 450 mL of D5W, 500 mL of D5W, or 1 L of D5W.

[0174] The pharmaceutical formulation contains factor XI and / or factor XIa antibodies at a concentration suitable for storage. In certain embodiments, the pharmaceutical formulation contains 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 contains factor XI and / or factor XIa antibodies 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.

[0175] The pharmaceutical preparation contains factor XI and / or factor XIa antibodies at a concentration suitable for storage. In certain embodiments, the pharmaceutical preparation contains 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 preparation contains factor XI and / or factor XIa antibodies 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.

[0176] In certain embodiments, the pharmaceutical preparation is contained in a vial (e.g., vial, bag, pen, or syringe). In certain embodiments, the vial contains an overfill that allows for complete removal of the intended dose. In certain embodiments, the vial contains an overfill of 5 - 35%, 10 - 30%, 15 - 25%, or 10 - 20%. In certain embodiments, the vial contains an overfill of about 20%.

[0177] In certain embodiments, the formulation can 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 as multiple doses. In certain embodiments, the pharmaceutical formulation comprises factor XI and / or factor XIa antibody in an amount of 0.1 to 200 mg. In certain embodiments, the pharmaceutical formulation comprises factor XI and / or factor XIa antibody in an amount of 1 to 200 mg, 10 to 200 mg, 20 to 200 mg, 50 to 200 mg, 100 to 200 mg, 200 to 200 mg, 500 to 2000 mg, 1000 to 2000 mg, 0.1 to 1000 mg, 1 to 1000 mg, 10 to 1000 mg, 20 to 1000 mg, 50 to 1000 mg, 100 to 1000 mg, 200 to 1000 mg, 500 to 1000 mg, 0.1 to 500 mg, 1 to 500 mg, 10 to 500 mg, 20 to 500 mg, 50 to 500 mg, 100 to 500 mg, 200 to 500 mg, 0.1 to 200 mg, 1 to 200 mg, 10 to 200 mg, 20 to 200 mg, 50 to 200 mg, 100 to 200 mg, 0.1 to 100 mg, 1 to 100 mg, 10 to 100 mg, 20 to 100 mg, 50 to 100 mg, 0.1 to 50 mg, 1 to 50 mg, 10 to 50 mg, 20 to 50 mg, 0.1 to 20 mg, 1 to 20 mg, 10 to 20 mg, 0.1 to 10 mg, 1 to 10 mg, or 0.1 to 1 mg. In certain embodiments, the pharmaceutical formulation comprises factor XI and / or factor XIa antibody in a therapeutically effective 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.

[0178] Dosage Regimen and Therapeutic Use In another aspect, the present disclosure provides a method for treating a thromboembolic disease, the method 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.

[0179] In certain embodiments, the method further comprises, after an initial treatment cycle, administering to the subject a Factor XI and / or Factor XIa antibody in one or more monthly treatment cycles, e.g., for a period of three months, wherein the Factor XI and / or Factor XIa antibody is administered on Day 1, Day 31, and Day 61. Subsequent treatment cycles in which the subject receives monthly administration of the Factor XI and / or Factor XIa antibody are designed to maintain the Factor XI and / or Factor XIa antibody at a certain level 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 treatment throughout their lifetime.

[0180] In some embodiments, the method comprises treating a disease or disorder (e.g., a thrombotic disorder) in a subject in need of treatment for the disease or disorder, the method comprising administering a first dose of an anti-FXI / FXIa antibody or an antigen-binding fragment thereof (e.g., Antibody 1), wherein the first dose is administered intravenously, and administering a second dose of an anti-FXI / FXIa antibody or an antigen-binding fragment thereof (e.g., Antibody 1), wherein the second dose is administered 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 tenth dose subcutaneously. In some embodiments, the method further comprises administering an eleventh dose subcutaneously. In certain embodiments, the method comprises administering the first dose intravenously and administering the subsequent five doses subcutaneously. In certain embodiments, the treatment period is about six months. In certain embodiments, the method comprises administering the first dose intravenously and administering the subsequent eleven doses subcutaneously. In certain embodiments, the treatment period is about one year. In certain embodiments, the method comprises administering the first dose intravenously and then administering subcutaneous doses monthly until the disease or disorder in the subject resolves or for the lifetime of the subject.

[0181] In some embodiments, a subject suffering from or at risk of developing a thromboembolic disorder and undergoing a surgical procedure is administered an intravenous drug delivery formulation on the same day as the surgical procedure. In some embodiments, the intravenous drug delivery formulation is administered 2 to 10 hours after the surgery. In some embodiments, the intravenous drug delivery formulation is administered 4 to 8 hours after the surgery. 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 surgery.

[0182] In certain embodiments, one or more doses in the first and subsequent treatment cycles are subcutaneously administered at a dose 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, 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, comprising a Factor XI and / or Factor XIa antibody.

[0183] In certain embodiments, one or more doses in the initial and subsequent treatment cycles comprise a Factor XI and / or Factor XIa antibody (e.g., Antibody 1) administered subcutaneously 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.

[0184] In some embodiments, the therapeutically effective dose range of the Factor XI and / or Factor XIa antibody (e.g., Antibody 1) after subcutaneous administration is about 75 mg to about 165 mg, about 80 mg to about 160 mg, about 85 mg to 155 mg, or about 90 mg to about 160 mg. In certain embodiments, the therapeutically effective dose range of the Factor XI and / or Factor XIa antibody (e.g., Antibody 1) after subcutaneous administration is about 90 mg to about 160 mg.

[0185] In certain embodiments, one or more doses in the initial and subsequent treatment cycles are Factor XI and / or Factor XIa antibodies (e.g., Antibody 1) administered intravenously at a dose 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, 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.

[0186] In certain embodiments, one or more doses in the initial and subsequent treatment cycles comprise a Factor XI and / or Factor XIa antibody (e.g., Antibody 1) administered intravenously 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, 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 at a dose of about 150 mg. In some embodiments, the Factor XI and / or Factor XIa antibody is administered intravenously as a single dose. In some embodiments, the FXI / FXIa antibody (e.g., Antibody 1) is administered as a single dose of about 150 mg. In some embodiments, the FXI / FXIa antibody (e.g., Antibody 1) is administered as a single dose of about 1000 mg. In some embodiments, the FXI / FXIa antibody (e.g., Antibody 1) is administered as a single dose of about 1500 mg. In some embodiments, the FXI / FXIa antibody (e.g., Antibody 1) is administered as a single dose of about 2000 mg.

[0187] In some embodiments, the first dose of the FXI / FXIa antibody (e.g., antibody 1) is administered as a single dose and the second dose of the FXI / FXIa antibody (e.g., antibody 1) is administered as 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 more 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 includes administering subsequent doses at the same dose as the second dose.

[0188] In certain embodiments, administration of a single dose of the FXI / FXIa antibody (e.g., antibody 1) prolongs 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 the FXI / FXIa antibody (e.g., antibody 1) prolongs the activated partial thromboplastin time (aPTT) by about 600 hours.

[0189] The physician can start with a dose 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. The dosage of the composition of the present disclosure effective for the treatment of thrombotic disorders described herein varies depending on many different factors including the means of administration, the target site, the physiological state of the patient, other drugs being administered, and whether the treatment is prophylactic or therapeutic. The treatment dosage can be titrated to optimize safety and efficacy. In the case of systemic administration using an antibody, the dosage is in the range of about 0.01 - 15 mg / kg patient body weight. In the case of administration using an antibody (e.g., subcutaneous or intravenous administration), the dosage can be in the range of 0.1 mg - 5 mg or 1 mg - 600 mg. For example, the anti-FXI / FXIa antibody (e.g., Antibody 1) described herein can be administered at a dosage 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, 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.

[0190] In certain embodiments, the Factor XI and / or Factor XIa antibody is administered intravenously. For example, in certain embodiments, the Factor XI and / or Factor XIa antibody is administered by intravenous infusion, e.g., using a prefilled bag, prefilled pen, or prefilled syringe. In certain embodiments, the Factor XI and / or Factor XIa antibody in the pharmaceutical formulations disclosed herein is diluted prior to administration. For example, in certain embodiments, the pharmaceutical formulation is diluted with dextrose 5% in water for injection (D5W) and administered intravenously from a bag. The intravenous infusion can be 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.

[0191] In certain embodiments, the Factor XI and / or Factor XIa antibody is administered parenterally. In certain embodiments, the Factor XI and / or Factor XIa antibody is administered parenterally in one or more doses.

[0192] 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, those that include the term "thromboembolic" or similar terms as used herein, and include any number of the following that can be prevented or treated using the anti-FXI and / or FXIa antibodies or antigen-binding fragments thereof of the present disclosure: thromboembolism in a subject suspected or confirmed to have an arrhythmia, such as paroxysmal, persistent or permanent atrial fibrillation or atrial flutter; prevention of stroke in atrial fibrillation (SPAF) (subpopulations thereof are AF patients undergoing percutaneous coronary intervention (PCI)); treatment of acute venous thromboembolic events (VTE) in patients at high risk of bleeding, and expansion of secondary VTE prevention; prevention of cerebral and cardiovascular events and thromboembolic events in heart failure with sinus rhythm in secondary prevention after transient ischemic attack (TIA) or stroke without sequelae; venous thromboembolism in pediatric subjects (pediatric VTE); thrombus formation and thromboembolism in the left atrium in a subject undergoing cardioversion for an arrhythmia; thrombosis before, during, and after ablation procedures for arrhythmias; venous thrombosis, which includes, but is not limited to, treatment and secondary prevention of deep or superficial venous thrombosis of the lower or upper extremities, thrombosis of the abdominal and thoracic veins, venous sinus thrombosis, and jugular vein thrombosis; thrombosis on any artificial surface in a vein or artery, such as a catheter, pacemaker wire, synthetic arterial graft, etc.; arteriovenous (AV) shunt; mechanical or biological heart valve or left ventricular assist device; pulmonary embolism in patients with or without venous thrombosis; chronic thromboembolic pulmonary hypertension (CTEPH); arterial thrombosis in a ruptured atherosclerotic plaque, thrombosis on an arterial prosthesis or catheter, and thrombosis in an apparently normal artery, which includes, but is not limited to, acute coronary syndrome, ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, unstable angina, stent thrombosis, thrombosis on any artificial surface of the arterial system, and thrombosis of the pulmonary artery in a subject with or without pulmonary hypertension; thrombosis and thromboembolism in patients undergoing percutaneous coronary intervention (PCI); cardiogenic cerebral embolism and potential stroke; non-central nervous system systemic embolism (non-CNS systemic embolism); hemorrhagic stroke;Thrombosis in patients with invasive and non-invasive cancer malignancies (e.g., gastrointestinal cancer and genitourinary cancer); thrombosis due to indwelling catheters; thrombosis and thromboembolism in critically ill patients; cardiac thrombosis and thromboembolism, including but not limited to cardiac thrombosis associated with conditions such as post-myocardial infarction cardiac thrombosis, cardiac aneurysms, cardiomyopathy, cardiac hypertrophy and insufficiency, myocarditis and artificial surfaces of the heart; thromboembolism in patients with valvular heart disease with or without atrial fibrillation; thromboembolism due to mechanical or biological valve prostheses; thromboembolism in patients with natural or artificial heart patches, arterial or venous conduits after cardiac repair of simple or complex cardiac deformities; venous thrombosis and thromboembolism after knee replacement surgery, hip replacement surgery, and orthopedic, thoracic or abdominal surgery; arterial or venous thrombosis after neurosurgery including intracranial and intraspinal interventions; congenital or acquired thrombotic tendencies including but not limited to factor V Leiden, prothrombin mutations, antithrombin III, protein C and protein S deficiencies, factor XIII mutations, familial fibrinogen abnormalities, congenital deficiencies of plasminogen, elevated levels of factor XI, sickle cell disease, antiphospholipid syndrome, autoimmune diseases, chronic bowel 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 patients receiving extracorporeal membrane oxygenation. In certain embodiments, the subject treated with the factor XI and / or factor XIa antibody or pharmaceutical formulation disclosed herein is obese (e.g., severely obese, e.g., body mass index (BMI) of ≧ 35 kg / m; 2)。In certain embodiments, the subject being treated with a Factor XI and / or Factor XIa antibody or pharmaceutical formulation disclosed herein is not obese. In certain embodiments, obese subjects are associated with lower exposure following administration of the same dose of Factor XI and / or Factor XIa antibody (e.g., Antibody 1) as non-obese subjects. In certain embodiments, in obese subjects, following administration of the same dose of Factor XI and / or Factor XIa antibody (e.g., Antibody 1) as non-obese subjects, the exposure is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% less. In certain embodiments, obese subjects are associated with a shorter aPTT prolongation period following administration of the same dose of Factor XI and / or Factor XIa antibody (e.g., Antibody 1) as non-obese subjects. In certain embodiments, in obese subjects, following administration of the same dose of Factor XI and / or Factor XIa antibody (e.g., Antibody 1) as non-obese subjects, the aPTT prolongation is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% shorter.

[0193] In certain embodiments, the Factor XI and / or Factor XIa antibody (e.g., Antibody 1) is administered to a subject having cancer. Venous thromboembolism (VTE) is estimated to affect 1% - 8% of all cancer patients and is furthermore the second most common cause of death in ambulatory cancer patients undergoing chemotherapy. Treatment of such VTE in cancer patients is complicated by thrombocytopenia, which is widespread among cancer patients undergoing chemotherapy (Bannow et al. (2019). Res. Pract. Throm. Haemost., 2:664 - 669).

[0194] In certain embodiments, the cancer is a solid tumor. In certain other aspects, 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, stomach cancer, testicular cancer, or uterine cancer.In still other embodiments, the cancer is an angiogenic tumor, squamous cell carcinoma, adenocarcinoma, small cell carcinoma, melanoma, glioma, neuroblastoma, sarcoma (e.g., angiosarcoma or chondrosarcoma), laryngeal cancer, parotid gland cancer, biliary tract cancer, thyroid cancer, acral lentiginous melanoma, actinic keratosis, acute lymphocytic leukemia, acute myeloid leukemia, adenoid cystic carcinoma, adenoma, adenosarcoma, adenosquamous carcinoma, anal canal cancer, anal cancer, rectal cancer, astrocytic tumor, Bartholin gland adenocarcinoma, basal cell carcinoma, biliary tract cancer, bone cancer, bone marrow cancer, bronchial cancer, bronchial adenocarcinoma, carcinoid, cholangiocarcinoma, 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, endometrial adenocarcinoma, endothelial cell carcinoma, epithelioma, epithelial cell carcinoma, Ewing sarcoma, eye and orbit cancer, female genital cancer, focal nodular hyperplasia, gallbladder cancer, gastric squamous cancer, gastric fundus cancer, gastrinoma, glioblastoma, glucagonoma, heart cancer, hemangioblastoma, hemangioendothelioma, hemangioma, hepatic adenoma, hepatic adenomatosis, hepatobiliary tract cancer, hepatocellular carcinoma, Hodgkin's disease, ileal cancer, insulinoma, intraepithelial neoplasia, intraepithelial squamous neoplasia, intrahepatic bile duct cancer, invasive squamous cell carcinoma, jejunal cancer, joint cancer, Kaposi sarcoma, pelvic cancer, large cell carcinoma, colorectal cancer, leiomyosarcoma, malignant lentigo-derived melanoma, lymphoma, male genital cancer, malignant melanoma, malignant mesothelial tumor, medulloblastoma, medulloepithelioma, meningiocarcinoma, mesothelioma, metastatic cancer, oral cancer, mucoepidermoid carcinoma, multiple myeloma, myosarcoma, nasal cavity cancer, nervous system cancer, neuroepithelial adenocarcinoma, nodular melanoma, non-epithelial skin cancer, non-Hodgkin lymphoma, oat cell carcinoma, oligodendroglioma, oral cancer, osteosarcoma, serous papillary adenocarcinoma, penile cancer, pharyngeal cancer, pituitary tumor, plasmacytoma, pseudosarcoma, pulmonary blastoma, rectal cancer, renal cell carcinoma, respiratory system cancer, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, paranasal sinus cancer, skin cancer, small cell carcinoma, small intestine cancer, leiomyosarcoma, soft tissue cancer, somatostatin-secreting tumor, spinal cancer, squamous cell carcinoma, rhabdomyosarcoma, subcutaneous cancer, superficial spreading melanoma, T cell leukemia, tongue cancer, undifferentiated carcinoma, ureteral cancer, urethral cancer, bladder cancer, urinary system cancer, cervical cancer, uterine body cancer, choroidal melanoma, vaginal cancer, verrucous carcinoma, VIP tumor, vulvar cancer, well-differentiated carcinoma, or Wilms tumor. In certain embodiments, the cancer is selected from the group consisting of gastrointestinal cancer and urogenital cancer.

[0195] In some embodiments, the anti-FXI / FXIa antibodies or antigen-binding fragments described herein (e.g., Antibody 1) are administered prophylactically, for example, to prevent thrombus formation in a subject at risk of thrombosis. In some embodiments, the anti-FXI / FXIa antibodies or antigen-binding fragments described herein (e.g., Antibody 1) are administered therapeutically, for example, to treat thrombus in a subject at risk of thrombosis.

[0196] In some embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof (e.g., Antibody 1) is administered to a subject having cancer-associated thrombosis (CAT). In certain embodiments, the subject having cancer-associated thrombosis has an existing thrombus. In certain embodiments, the subject has a microthrombus. In certain embodiments, the subject has microthrombosis associated with CAT.

[0197] The CHA2DS2-VASc risk score is a validated and widely used stratification tool for predicting the thromboembolic risk in patients with AF and identifying patients who would benefit from anticoagulant therapy (LIP 2011; Camm, et al. (2012) Eur Heart J 2012;33:2719-2747). The accumulated evidence suggests that CHA2DS2-VASc may be at least as accurate as or higher than scores such as CHADS2 in identifying patients who develop stroke and thromboembolism, and has been shown to be determinatively superior in identifying "truly low-risk" patients with AF. The CHA2DS2-VASc risk score ranges from 0 to a maximum score of 9. In certain embodiments, a subject treated with a Factor XI and / or Factor XIa antibody or pharmaceutical formulation disclosed herein has a CHA2DS2-VASc risk score of 0 to 1 for males and 1 to 2 for females. In certain embodiments, a subject treated with a Factor XI and / or Factor XIa antibody or pharmaceutical formulation disclosed herein has a CHA2DS2-VASc risk score of ≧2 for males and ≧3 for females. In certain embodiments, a subject treated with a Factor XI and / or Factor XIa antibody or pharmaceutical formulation disclosed herein has a CHA2DS2-VASc risk score of ≧4 or ≧3 and co-administration of at least one antiplatelet agent is contemplated (e.g., aspirin and / or a P2Y12 inhibitor), or CrCl ≦50 ml / min by the Cockcroft-Gault equation.

[0198] The Factor XI and / or Factor XIa antibodies (e.g., Antibody 1) disclosed herein can be used as monotherapy or in combination with one or more therapies. Such combination therapies can be useful for the treatment of thromboembolic disorders such as ischemic stroke (cardiovascular embolic, thrombotic) or systemic embolism, AF, stroke prevention in AF (SPAF), deep vein thrombosis, venous thromboembolism, pulmonary embolism, acute coronary syndrome (ACS), acute lower limb ischemia, chronic thromboembolic pulmonary hypertension, or systemic embolism. In certain embodiments, the Factor XI and / or Factor XIa antibodies are used as monotherapy according to the dosing regimens disclosed herein. In other embodiments, the Factor XI and / or Factor XIa antibodies are used in combination with one or more therapies, the Factor XI and / or Factor XIa antibodies are administered according to the dosing regimens disclosed herein, and the one or more therapies are administered according to dosing regimens known to be suitable for treating a particular subject having a particular disorder.

[0199] In some embodiments, statin therapy can be used in combination with a formulation comprising an FXI / FXIa antibody and antigen-binding fragment described herein, or the FXI / FXIa antibody and antigen-binding fragment (e.g., Antibody 1) for the treatment of patients with thrombotic and / or thromboembolic disorders. In certain embodiments, non-limiting examples of therapeutic active agents suitable for use in combination with an anti-FXI / FXIa antibody (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 atopaaxar), and proton pump inhibitors (PPI) (e.g., omeprazole, diazepam, phenytoin, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole, esomeprazole, and naproxen). The use of PPI in combination therapy may be appropriate if the subject has or has a history of GI disorders, e.g., a history of GI bleeding or a previous peptic ulcer. In one embodiment, the subject is being treated with a non-steroidal anti-inflammatory drug (NSAID), and an anti-FXI / FXIa antibody (e.g., Antibody 1) described herein is administered in combination with a proton pump inhibitor (e.g., omeprazole, diazepam, phenytoin, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole, esomeprazole, and naproxen). In certain embodiments, a subject treated with a formulation comprising an FXI / FXIa antibody and antigen-binding fragment, or the FXI / FXIa antibody and antigen-binding fragment (e.g., Antibody 1) is administered a direct oral anticoagulant (DOAC) following the treatment period (e.g., on the same day as the end of treatment). In certain embodiments, a subject treated with a formulation comprising an FXI / FXIa antibody and antigen-binding fragment, or the FXI / FXIa antibody and antigen-binding fragment (e.g., Antibody 1) is administered a vitamin K antagonist (VKA) following the treatment period (e.g., about 5 days before the end of treatment, or about 3 days before the end of treatment).

[0200] In certain embodiments, the treatment methods disclosed herein result in disease response or improved survival in a subject or patient. For example, in certain embodiments, disease response is complete response, partial response, or stable disease. In certain embodiments, improved survival is improved progression-free survival (PFS) or overall survival. The improvement (e.g., in PFS) can be determined as compared to the period prior to initiation of the treatment of the present disclosure. Methods for determining disease response (e.g., complete response, partial response, or stable disease) and patient survival (e.g., PFS, overall survival) for BTC (e.g., advanced BTC, metastatic BTC) or biliary tract tumor treatment are routine in the art and are also contemplated herein. In some embodiments, disease response is evaluated according to RECIST 1.1 after subjecting the treated patient to contrast computed tomography (CT) or magnetic resonance imaging (MRI) of the affected area (e.g., the chest / abdomen and pelvis covering the area from above the thoracic inlet to the symphysis pubis).

[0201] Combination therapies and related dosing regimens Combination therapy for reversal of anticoagulant effect In one aspect, provided herein is a method for reversing the anticoagulant effect of an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody, or antigen-binding fragment thereof, in a subject, wherein the subject is administered the isolated antibody or antigen-binding fragment thereof at a dose of about 150 mg, and the method comprises administering to the subject a therapeutically effective amount of recombinant activated factor VII (rFVIIa), thereby reversing the anticoagulant effect. In certain embodiments, such methods are used, for example, in subjects at high risk of bleeding.

[0202] In some embodiments, a temporary reversal or inhibition of one or more of the anticoagulant effects of the anti-FXI / FXIa antibodies or antigen-binding fragments described herein (e.g., Antibody 1) is desirable and / or medically necessary, for example, for subjects at high risk of bleeding. In some embodiments, bleeding is typically associated with, for example, but not limited to, trauma, surgery, menstruation, or postpartum. Thus, under these circumstances, a subject treated with an anti-FXI / FXIa antibody or antigen-binding fragment described herein (e.g., Antibody 1) may require a rapid and effective treatment to reduce bleeding or the risk of bleeding. In certain embodiments, prolonged bleeding can occur after major trauma or surgery, for example, but not limited to, surgery involving organs with highly fibrinolytic regions such as the buccal, nasal, genital, or urinary tract mucosa. Tooth extraction, tonsillectomy, and resection of the uterus or prostate are further non-limiting examples of surgeries associated with a high risk of bleeding. In certain embodiments, the co-administration of antiplatelet agents, other anticoagulants, and fibrinolytic agents can increase the risk of bleeding. In some embodiments, subjects at high risk of bleeding can be identified by a past history of bleeding, for example, bleeding during or after surgery, or bleeding when treated with an anticoagulant (e.g., warfarin). In some embodiments, subjects at high risk of bleeding can be identified by in vitro / ex vivo assays known in the art, for example, but not limited to, assays using the subject's blood or plasma: measurement of aPTT, evaluation of biomarkers of the extrinsic coagulation pathway, measurement of prothrombin time (PT), thrombin time (TT), rotational thromboelastometry (ROTEM®), etc.

[0203] In some embodiments, the anticoagulant effect of the anti-FXI / FXIa antibodies or antigen-binding fragments described herein (e.g., Antibody 1) is achieved by administering a therapeutically effective amount of recombinant activated factor VII (rFVIIa), for example, at a low dose. As used herein, "low dose" of rFVIIa refers to a therapeutically effective amount of rFVIIa less than about 15 μg / kg.

[0204] In certain embodiments, a therapeutically effective amount of rFVIIa is from about 0.5 μg / mL to about 14.5 μg / mL, such as from about 0.5 μg / mL to about 14 μg / mL, from about 0.5 μg / mL to about 13.5 μg / mL, from about 0.5 μg / mL to about 13 μg / mL, from about 0.5 μg / mL to about 12.5 μg / mL, from about 0.5 μg / mL to about 12 μg / mL, from about 0.5 μg / mL to about 11.5 μg / mL, from about 0.5 μg / mL to about 11 μg / mL, from about 0.5 μg / mL to about 10.5 μg / mL, from about 0.5 μg / mL to about 10 μg / mL, from about 0.5 μg / mL to about 9.5 μg / mL, from about 0.5 μg / mL to about 9 μg / mL, from about 0.5 μg / mL to about 8.5 μg / mL, from about 0.5 μg / mL to about 8 μg / mL, from about 0.5 μg / mL to about 7.5 μg / mL, from about 0.5 μg / mL to about 7 μg / mL, from about 0.5 μg / mL to about 6.5 μg / mL, from about 0.5 μg / mL to about 6 μg / mL, from about 0.5 μg / mL to about 5.5 μg / mL, from about 0.5 μg / mL to about 5 μg / mL, from about 0.5 μg / mL and about 4.5 μg / mL, from about 0.5 μg / mL to about 4 μg / mL, from about 0.5 μg / mL to about 3.5 μg / mL, from about 0.5 μg / mL to about 3 μg / mL, from about 0.5 μg / mL to about 2.5 μg / mL, from about 0.5 μg / mL to about 2 μg / mL, from about 0.5 μg / mL to about 1.5 μg / mL, or from 0.5 μg / mL to about 1 μg / mL. In certain embodiments, a therapeutically effective amount of rFVIIa is from about 0.5 to about 1 μg / mL.

[0205] In certain embodiments, a therapeutically effective amount of rFVIIa is about 14.5 μg / mL, about 14 μg / mL, about 13.5 μg / mL, about 13 μg / mL, about 12.5 μg / mL, about 12 μg / mL, about 11.5 μg, about 11 μg / mL, about 10.5 μg / mL, about 10 μg / mL, about 9.5 μg / mL, about 9 μg / mL, about 8.5 μg / mL, about 8 μg / mL, about 7.5 μg / mL, about 7 μg / mL, about 6.5 μg / mL, about 6 μg / mL, about 5.5 μg / mL, about 5 μg / mL, about 4.5 μg / mL, about 4 μg / mL, about 3.5 μg / mL, about 3 μg / mL, about 2.5 μg / mL, about 2 μg / mL, about 1.5 μg / mL, about 1 μg / mL, or about 0.5 μg / mL. In some embodiments, rFVIIa is administered at a dose of about 0.5 μg / mL. In some embodiments, rFVIIa is administered at a dose of about 1 μg / mL.

[0206] In some embodiments, rFVIIa is administered once. In some embodiments, rFVIIa is administered twice. In some embodiments, rFVIIa is administered multiple times, for example, 2, 3, 4, 5, or more times.

[0207] In some embodiments, a therapeutically effective amount of rFVIIa is administered as needed. As used herein, "administered as needed" refers to administering rFVIIa until symptoms, such as bleeding, are treated and / or the risk of bleeding is reduced. In some embodiments, rFVIIa is administered for a particular period, for example, during the time of a surgical procedure. In some embodiments, rFVIIa is administered for a particular period, for example, during the time of a surgical procedure and hospitalization. In some embodiments, rFVIIa is administered when medically necessary, for example, as determined by a physician.

[0208] In some embodiments, rFVIIa is administered hourly. In some embodiments, rFVIIa is administered every two hours. In some embodiments, rFVIIa is administered every four hours. In some embodiments, rFVIIa is administered every six hours. In some embodiments, rFVIIa is administered every eight hours. In some embodiments, rFVIIa is administered twice a day, for example, every twelve hours. In certain embodiments, the frequency of rFVIIa administration decreases as the risk of bleeding decreases, for example, rFVIIa is administered every two hours for a predetermined period (e.g., 24 hours or 48 hours), and then rFVIIa is administered every four hours for a predetermined period (e.g., up to one week).

[0209] In some embodiments, a therapeutically effective amount of recombinant activated factor VII (rFVIIa), for example, a low dose, is administered intravenously to a subject, for example, by intravenous bolus injection.

[0210] In some embodiments, the anticoagulant effect of the anti-FXI / FXIa antibodies or antigen-binding fragments described herein (e.g., Antibody 1) is evaluated using methods known in the art. For example, without limitation, the anticoagulant effect can be confirmed by clotting time (CT), clot formation time (CFT), activated partial thromboplastin time (aPTT), and the like. In certain embodiments, administering a therapeutically effective amount of rFVIIa prolongs the CT in a subject treated with an anti-FXI / FXIa antibody or antigen-binding fragment (e.g., Antibody 1) described herein, resulting in at least a 10%, at least a 20%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least an 80%, or at least a 90% prolongation of CT compared to the CT before administering rFVIIa. In certain embodiments, administering a therapeutically effective amount of rFVIIa prolongs the CFT in a subject treated with an anti-FXI / FXIa antibody or antigen-binding fragment (e.g., Antibody 1) described herein, resulting in at least a 10%, at least a 20%, at least a 30%, at least a 40%, at least a 50%, at least a 60%, at least a 70%, at least an 80%, or at least a 90% prolongation of CFT compared to the CFT before administering rFVIIa.

[0211] In some embodiments, the therapeutically effective amount of recombinant activated factor VII (rFVIIa) described herein may be administered in combination with one or more additional anticoagulation reversal therapies. Non-limiting examples of conventional strategies for reversing the anticoagulant effect include (i) fluid replacement using colloids, crystalloids, human plasma, or plasma proteins such as albumin, or (ii) transfusion with concentrated red blood cells or whole blood. For example, examples of treatments for reversing the effect of anticoagulants in severe emergency situations include, but are not limited to, fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), and activated PCC (APCC), such as hemostasis-promoting blood components such as factor VIII inhibitor bypass activity (FEIBA). In some embodiments, the therapeutically effective amount of rFVIIa is administered in combination with an anticoagulation reversal therapy such as emicizumab (ACE910), tranexamic acid, fresh frozen plasma (FFP), Hemoeleven, prothrombin complex concentrate (PCC), activated PCC, or FEIBA (FVIII inhibitor complex).

[0212] In some embodiments, the therapeutically effective amount of recombinant activated factor VII (rFVIIa) described herein may be administered in combination with an anti-idiotype antibody, or an antigen-binding fragment thereof, to the anti-FXI / FXIa antibody or antigen-binding fragment (e.g., antibody 1) described herein. Methods for producing anti-idiotype antibodies are known in the art.

[0213] Antiplatelet drug combination therapy In one aspect, provided herein is a combination method of treating a subject, the method comprising administering an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or antigen-binding fragment thereof (e.g., antibody 1) described herein at a dose of about 150 mg, and administering a therapeutically effective dose of an oral antiplatelet therapy. In some embodiments, the subject has or is at risk of developing a thrombotic disorder. Exemplary antiplatelet therapies include, but are not limited to, for example, aspirin, clopidogrel, prasugrel, dipyridamole, ticlopidine, eptifibatide, and ticagrelor. In some embodiments, the antiplatelet therapy is aspirin. In some embodiments, the antiplatelet therapy is clopidogrel. In some embodiments, the antiplatelet therapy is prasugrel. In some embodiments, the antiplatelet therapy is dipyridamole. In some embodiments, the antiplatelet therapy is ticlopidine. In some embodiments, the antiplatelet therapy is eptifibatide. In some embodiments, the antiplatelet therapy is ticagrelor.

[0214] In one aspect, provided herein is a combination method for treating a subject, e.g., a subject suffering from or at risk of developing a thromboembolic disorder, the method comprising administering an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody, or an antigen-binding fragment thereof, e.g., Antibody 1, described herein, at a dose of about 125 nM, about 250 nM, or about 500 nM, and administering about 1 mg / mL of aspirin. In another aspect, provided herein is a combination method for treating a subject, e.g., a subject suffering from or at risk of developing a thromboembolic disorder, the method comprising administering an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody, or an antigen-binding fragment thereof, e.g., Antibody 1, described herein, at a dose of about 150 mg, and administering about 100 mg of aspirin. In certain embodiments, aspirin is administered orally, e.g., in the form of a pill or tablet. In certain embodiments, aspirin is low-dose aspirin. In certain embodiments, aspirin is at a dose of about 75 mg, about 81 mg, about 100 mg, about 150 mg, about 162 mg, or about 200 mg. In certain embodiments, aspirin is administered daily. In certain embodiments, aspirin is administered twice daily. In certain embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment (e.g., Antibody 1) described herein is administered intravenously. In certain embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment (e.g., Antibody 1) described herein is administered subcutaneously. In certain embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment (e.g., Antibody 1) described herein is administered intravenously at a first dose and subsequent doses (e.g., a second dose, a third dose, a fourth dose, a fifth dose, a sixth dose, etc.) are administered subcutaneously. In certain embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment (e.g., Antibody 1) described herein is administered monthly.

[0215] In one aspect, provided herein is a combination method for treating a subject, e.g., a subject suffering from or at risk of developing a thromboembolic disorder, the method comprising administering an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody, or an antigen-binding fragment thereof, e.g., antibody 1, described herein, at a dose of about 125 nM, about 250 nM, or about 500 nM, and administering about 3 μM ticagrelor. In another aspect, provided herein is a combination method for treating a subject, e.g., a subject suffering from or at risk of developing a thromboembolic disorder, the method comprising administering an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody, or an antigen-binding fragment thereof, e.g., antibody 1, described herein, at a dose of about 150 mg, and administering about 60 mg ticagrelor. In certain embodiments, ticagrelor is administered orally, e.g., as a pill or tablet. In certain embodiments, ticagrelor is at a dose of about 60 mg, about 90 mg, or about 180 mg. In certain embodiments, ticagrelor is administered as a loading dose (e.g., about 180 mg), and subsequent administrations are maintenance doses (e.g., about 60 mg or about 90 mg). In certain embodiments, ticagrelor is administered daily. In certain embodiments, ticagrelor is administered twice daily. In certain embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment (e.g., antibody 1) described herein is administered intravenously. In certain embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment (e.g., antibody 1) described herein is administered subcutaneously. In certain embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment (e.g., antibody 1) described herein is administered intravenously at a first dose, and subsequent doses (e.g., a second dose, a third dose, a fourth dose, a fifth dose, a sixth dose, etc.) are administered subcutaneously. In certain embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment (e.g., antibody 1) described herein is administered monthly.

[0216] In some embodiments, a subject administered with an anti-FXI / FXIa antibody or antigen-binding fragment described herein (e.g., Antibody 1), e.g., a subject suffering from or at risk of developing a thrombotic disorder, is undergoing dual antiplatelet therapy (DAPT). In certain embodiments, DAPT comprises ticagrelor and aspirin. In some embodiments, the subject is administered about 3 μM ticagrelor, about 1 mg / mL aspirin, and an anti-FXI and / or anti-FXIa antibody described herein, e.g., Antibody 1. In certain embodiments, ticagrelor is administered orally, e.g., in the form of a pill or tablet. In certain embodiments, ticagrelor is administered daily. In certain embodiments, aspirin is administered orally, e.g., in the form of a pill or tablet. In certain embodiments, aspirin is low-dose aspirin. In certain embodiments, aspirin is administered daily. In certain embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment described herein (e.g., Antibody 1) is administered intravenously. In certain embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment described herein (e.g., Antibody 1) is administered subcutaneously. In certain embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment described herein (e.g., Antibody 1) is administered intravenously at a first dose, and subsequent doses (e.g., a second dose, a third dose, a fourth dose, a fifth dose, a sixth dose, etc.) are administered subcutaneously. In certain embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment described herein (e.g., Antibody 1) is administered monthly.

[0217] In some embodiments, administration of an anti-FXI / FXIa antibody or antigen-binding fragment described herein (e.g., Antibody 1) does not affect platelet aggregation in a subject as compared to a subject treated with antiplatelet therapy alone, e.g., aspirin alone or ticagrelor alone. Methods for assessing platelet aggregation are known in the art and include, for example, but are not limited to, impedance platelet aggregation assays.

[0218] In some embodiments, for example, if a subject, such as a subject administered with an anti-FXI / FXIa antibody or antigen-binding fragment (e.g., Antibody 1) described herein, is at high risk of bleeding (e.g., as described above), the subject may discontinue receiving antiplatelet drug therapy and may be administered a therapeutically effective amount of recombinant activated Factor VII (rFVIIa) as discussed above.

Example

[0219] The present disclosure generally described herein will be more readily understood by reference to the following examples, which are included for the purpose of illustration only of certain aspects and embodiments of the present disclosure and are not intended to limit the scope of the present disclosure in any way.

[0220] Example 1 - Treatment of Patients with Vascular Graft Thrombosis Objective and Rationale This study was designed to test the effect of increasing concentrations of Antibody 1 on platelet aggregation after stimulation with collagen or thrombin receptor activating peptide-6 (TRAP-6), compared to vehicle and active drug control (abciximab, anti-GP2b3a), and to determine the effect of both drugs on thrombin generation.

[0221] Methods Whole blood was obtained in EDTA and citrate tubes (6 healthy donors). Samples were spiked with vehicle, Antibody 1 (250, 500, or 1000 nM), or abciximab (50 nM). Platelet aggregation was induced using collagen (1 μg / mL) or TRAP-6 (8 μM) and then recorded using a multiplate impedance platelet aggregometer. The area under the curve (AUC) for platelet aggregation was determined in arbitrary aggregation * time (AU * min). Thrombin generation was also measured in platelet-rich plasma at the above Antibody 1 and abciximab concentrations using a Thrombinoscope CAT (calibrated automated thrombogram, Stago CH S.A. and tissue factor reagent (1 pM), and fluorescence was measured with an automated plate reader fluorometer.

[0222] Results Antibody 1 did not show an inhibitory or stimulatory effect on platelet aggregation induced by collagen (Figure 1A) or TRAP-6 (Figure 1B). In contrast, a significant decrease in collagen-induced platelet aggregation was observed with abciximab. With antibody 1, the lag time and the time to reach the peak concentration of thrombin generation were significantly delayed, and abciximab had no effect on thrombin generation.

[0223] Importantly, these results indicate that targeting of FXI / FXIa by antibody 1 does not affect platelet aggregation while inhibiting thrombin generation.

[0224] Example 2 - Antibody 1 does not affect the effects of two commonly used antiplatelet agents in vitro Objectives and theoretical basis As demonstrated in Example 1 above, antibody 1 did not affect platelet function. The combination of antibody 1 and antiplatelet drugs has not been evaluated previously. Therefore, this study was designed to evaluate the effect of increasing concentrations of antibody 1 on platelet aggregation inhibition by aspirin or ticagrelor.

[0225] Methods Two tests were performed simultaneously. Blood samples were obtained in EDTA and citrate tubes (6 healthy donors for each test). In the first test, whole blood was spiked with vehicle, aspirin (1 mg / mL), or aspirin (1 mg / mL) + antibody 1 (125, 250, and 500 nM). Platelet aggregation was measured by impedance platelet aggregation assay after induction with collagen (3.2 μg / mL) or arachidonic acid (0.5 mM) (Multiplate® analyzer, COLtest and ASPItest reagents; Roche Diagnostics International Ltd, Rotkreuz, Switzerland).

[0226] In the second test, whole blood was spiked with vehicle, ticagrelor (3 μM), or ticagrelor (3 μM) + antibody 1 (125, 250, and 500 nM). Platelet aggregation was measured by the same methodology after induction with ADP (6.4 μM) or thrombin receptor-activating peptide-6 (TRAP-6, 32 μM).

[0227] Results In the presence of aspirin, platelet aggregation induced by collagen (Figure 2A) or arachidonic acid (Figure 2B) was inhibited by 60% and 71%, respectively (p < 0.05). Antibody 1 at 125, 250, and 500 ng / mL did not attenuate or increase the level of inhibition achieved by aspirin alone.

[0228] In the presence of ticagrelor, platelet aggregation induced by ADP (Figure 3A) or TRAP-6 (Figure 3B) was inhibited by 54% and 31%, respectively (p < 0.05). Antibody 1 at 125, 250, and 500 ng / mL did not alter the platelet inhibition achieved by ticagrelor alone.

[0229] Conclusion Clinically relevant concentrations of antibody 1 did not alter the inhibitory effects of aspirin or ticagrelor. These results suggest that there is a low likelihood of a pharmacodynamic interaction between antibody 1 and aspirin or ticagrelor, two commonly used antiplatelet agents.

[0230] Example 3 - Low concentrations of rFVIIa avoid changes in rotational thromboelastometry (ROTEM®) coagulation parameters induced by antibody 1 in vitro Objectives and rationale Low-dose recombinant activated factor VII (rFVIIa) has been used to prevent or stop bleeding in patients with severe factor XI (FXI) deficiency. A similar strategy was hypothesized as a way to circumvent the pharmacodynamic effects of antibody 1. This study was designed to test whether low concentrations of rFVIIa can correct changes in antibody 1-induced coagulation parameters as measured by rotational thromboelastometry (ROTEM) in an in vitro assay with whole blood.

[0231] Methods Blood samples were obtained from six healthy human donors into citrate tubes. Samples were incubated at 37°C for 10 minutes with 15 and 30 μg / mL of antibody 1 or vehicle. Samples were then spiked with 0.5 and 1 μg / mL of rFVIIa or vehicle control. Thrombosis was monitored using a ROTEM® Delta Analyzer and non-activated thromboelastometry (NATEM) test with a recalcification reagent. Coagulation time (CT, in seconds), clot formation time (CFT, in seconds), alpha angle, etc. were measured and compared to the reference ranges provided by the manufacturer (Pentapharm GmbH, Munich, Germany).

[0232] Results Antibody 1 at concentrations of 15 and 30 μg / mL prolonged CT by 61% and 64% respectively, CFT by 37% and 32% respectively, and decreased the alpha angle by 10% and 14% respectively, compared to baseline. When 0.5 and 1.0 μg / mL of rFVIIa were added to samples spiked with antibody 1, CT became shorter by 21% and 38% respectively, CFT became shorter by 33% and 49% respectively, and the alpha angle increased by 29% and 47% respectively. The CT parameters are presented in Figure 4A and the CFT parameters are presented in Figure 4B. When rFVIIa was added, the NATEM parameters remained within the normal reference range.

[0233] Conclusions Low concentrations of rFVIIa (0.5 - 1 μg / mL) were able to correct the effect of antibody 1 when evaluated by rotational thromboelastometry. Furthermore, normalization without over - correcting the ROTEM clotting parameters suggested that the concentrations of rFVIIa tested were unlikely to cause a hypercoagulable state. These data support the use of low - dose rFVIIa for bleeding management in patients treated with antibody 1.

Claims

**Claim 1** A method for reversing the anticoagulant effect of an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody, or an antigen-binding fragment thereof, in a subject, wherein the subject has been administered the isolated antibody or its antigen-binding fragment at a dose of about 150 mg, and the method comprises administering to the subject a therapeutically effective amount of recombinant activated factor VII (rFVIIa) thereby reversing the anticoagulant effect. **Claim 2** The method of claim 1, wherein the therapeutically effective amount of rFVIIa is a low dose. **Claim 3** The method according to claim 1 or 2, wherein the therapeutically effective amount of rFVIIa is 0.5 to 1 μg / mL. **Claim 4** The method according to any one of claims 1 to 3, wherein the therapeutically effective amount of rFVIIa is administered as a single dose. **Claim 5** The method according to any one of claims 1 to 3, wherein the therapeutically effective amount of rFVIIa is administered as needed. **Claim 6** The method according to any one of claims 1 to 5, wherein administering the therapeutically effective amount of rFVIIa extends the clotting time (CT) as compared to the CT before administering the therapeutically effective amount. **Claim 7** The method according to any one of claims 1 to 5, wherein administering the therapeutically effective amount of rFVIIa extends the clot formation time (CFT) as compared to the CFT before administering the therapeutically effective amount. **Claim 8** The method according to claim 6 or 7, wherein the CT or CFT is determined by rotational thromboelastometry (ROTEM) in a whole blood assay. **Claim 9** The method of claim 8, wherein the whole blood assay is ex vivo or in vitro. **Claim 10** The method according to any one of claims 1 to 9, further comprising applying to the subject one of (i) a fluid replacement using a colloid, crystalloid, human plasma, or a plasma protein such as albumin, (ii) a transfusion with concentrated red blood cells or whole blood, (iii) administration of fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), activated PCC (APCC) such as factor VIII inhibitor, or (iv) an anti-idiotype antibody against the isolated anti-FXI and / or anti-FXIa antibody or its antigen-binding fragment. **Claim 11** A method of treating a disease or disorder in a subject in need of treatment for the disease or disorder, the method comprising administering to the subject an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody, or an antigen-binding fragment thereof, at a dose of about 150 mg, and (a) administering about 1 mg / mL of aspirin or (b) administering about 3 μM of ticagrelor.

12. The method according to claim 11, wherein the aspirin or ticagrelor is administered prior to the administration of the antibody or the antigen-binding fragment thereof.

13. The method according to claim 11, wherein the aspirin or ticagrelor is administered simultaneously with the administration of the antibody or the antigen-binding fragment thereof.

14. The method according to claim 11, wherein the aspirin or ticagrelor is administered after the administration of the antibody or the antigen-binding fragment thereof.

15. The method according to any one of claims 11 to 14, wherein the administration of the antibody or the antigen-binding fragment thereof does not affect platelet aggregation in the subject as compared to the subject treated with aspirin or ticagrelor alone.

16. The method according to claim 15, wherein the platelet aggregation is measured by an impedance platelet aggregation assay.

17. The method according to claim 16, wherein the platelet aggregation is induced by collagen, adenosine 5'-diphosphate (ADP), or thrombin receptor activating peptide-6 (TRAP-6).

18. The method according to any one of claims 15 to 17, wherein the platelet aggregation is measured ex vivo or in vitro.

19. The method according to any one of claims 1 to 18, wherein the antibody or the antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising complementarity-determining regions HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 9 or 29, and a light chain variable region (VL) comprising complementarity-determining regions LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 19 or 39.

20. The antibody or the antigen-binding fragment thereof is i. complementarity-determining region CDR1 of the heavy chain variable region of SEQ ID NO: 23, complementarity-determining region CDR2 of the heavy chain variable region of SEQ ID NO: 24, complementarity-determining region CDR3 of the heavy chain variable region of SEQ ID NO: 25, complementarity-determining region CDR1 of the light chain variable region of SEQ ID NO: 33, complementarity-determining region CDR2 of the light chain variable region of SEQ ID NO: 34, and complementarity-determining region CDR3 of the light chain variable region of SEQ ID NO: 35, ii. The CDR1 of the heavy chain variable region of SEQ ID NO: 26, the CDR2 of the heavy chain variable region of SEQ ID NO: 27, the CDR3 of the heavy chain variable region of SEQ ID NO: 28, the CDR1 of the light chain variable region of SEQ ID NO: 36, the CDR2 of the light chain variable region of SEQ ID NO: 37 (or the amino acid sequence KNY), and the CDR3 of the light chain variable region of SEQ ID NO: 38, iii. The CDR1 of the heavy chain variable region of SEQ ID NO: 43, the CDR2 of the heavy chain variable region of SEQ ID NO: 44, the CDR3 of the heavy chain variable region of SEQ ID NO: 45, the CDR1 of the light chain variable region of SEQ ID NO: 47, the CDR2 of the light chain variable region of SEQ ID NO: 37 (or the amino acid sequence KNY), and the CDR3 of the light chain variable region of SEQ ID NO: 15, or iv. The CDR1 of the heavy chain variable region of SEQ ID NO: 46, the CDR2 of the heavy chain variable region of SEQ ID NO: 4, the CDR3 of the heavy chain variable region of SEQ ID NO: 5, the CDR1 of the light chain variable region of SEQ ID NO: 33, the CDR2 of the light chain variable region of SEQ ID NO: 14, and the CDR3 of the light chain variable region of SEQ ID NO: 15, The method according to any one of claims 1 to 19, comprising the same.

21. The method according to any one of claims 1 to 20, wherein 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 VH having 90% identity thereto, and a light chain variable region (VL) selected from the group consisting of SEQ ID NO: 19, 39, and VL having 90% identity thereto.

22. The method according to any one of claims 1 to 21, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) selected from the group consisting of SEQ ID NO: 9 and 29, and a light chain variable region (VL) selected from the group consisting of SEQ ID NO: 19 and 39.

23. The method according to any one of claims 1 to 22, wherein the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 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 NO: 41, 21, and a light chain having 90% identity thereto.

24. The method according to any one of claims 1 to 23, 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.

25. The method according to any one of claims 1 to 24, wherein the antibody is a human monoclonal antibody.

26. The method according to claim 25, wherein the antibody is of the human IgG1 isotype.

27. The method according to claim 25 or 26, wherein the antibody comprises D265A and P329A substitutions in the Fc domain.

28. The method according to any one of claims 1 to 27, wherein the antibody or antigen-binding fragment thereof is administered intravenously.

29. The method according to any one of claims 1 to 28, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously.

30. The method according to any one of claims 1 to 29, 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.

31. The method according to any one of claims 1 to 30, wherein the antibody or antigen-binding fragment thereof is administered in a drug delivery formulation comprising sucrose at a concentration of about 220 mM.

32. The method according to any one of claims 1 to 31, 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%.

33. The method according to any one of claims 1 to 32, wherein the antibody or antigen-binding fragment thereof is administered in a drug delivery formulation at pH 5.

5.

34. The method according to any one of claims 1 to 33, 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.

35. The method according to any one of claims 1 to 34, wherein the subject has or is at risk of developing a thromboembolic disorder.

36. The method according to claim 35, wherein the thromboembolic disorder is selected from the group consisting of atrial fibrillation or flutter, transient ischemic attack, ischemic stroke, thromboembolic stroke, hemorrhagic stroke, venous thromboembolism (VTE), pediatric VTE, systemic embolism, non-central nervous system systemic embolism, myocardial infarction, deep vein thrombosis, severe protein S deficiency, cerebrovascular disorder, and cancer.

37. The method according to any one of claims 1 to 36, 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 is administered subcutaneously.

38. The method according to claim 37, further comprising one or more additional doses of the antibody or antigen-binding fragment thereof administered subcutaneously following the administration of the second dose.

39. The method according to any one of claims 1 to 38, wherein the antibody or antigen-binding fragment thereof is administered about once a month.

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