Pharmaceutical formulations and drug regimens of factor XI / XIa antibodies

Abstract

The present invention relates to pharmaceutical formulations of anti-factor XI and / or activated factor XI (factor XIa) antibodies or antigen-binding fragments thereof, and provides such antibodies or antigen-binding fragments, drug regimens of pharmaceutical formulations containing them, and pharmaceutical formulations for use in the treatment of thromboembolic disorders or related conditions. [Solution] A vial is provided comprising a drug delivery formulation having a pH of 5.0 to 6.0, comprising (a) a therapeutically effective amount of isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or its antigen-binding fragment; (b) a histidine buffer; (c) a sugar or sugar alcohol; and (d) a polysorbate, wherein the vial includes an excess filling to completely extract the therapeutically effective amount of the anti-FXI and / or anti-FXIa antibody or its antigen-binding fragment.

Description

[Technical Field]

[0001] Cross-references to related applications This application, in its entirety, is incorporated herein by reference for any purpose. Benefits and priority of U.S. Provisional Patent Application No. 62 / 951,887 filed December 20, 2019 It asserts a right.

[0002] Sequence List This application has been submitted electronically in ASCII format and is available by reference in its entirety. This specification includes sequence listings. The ASCII copy is from December 2020. Created on the 18th of the month, named ATD-008WO_ST25.txt, size It is 39,163 bytes.

[0003] Areas of this disclosure This disclosure generally refers to anti-factor XI and / or activated factor XI (factor XIa) anti This disclosure relates to pharmaceutical formulations of the body or its antigen-binding fragments. This disclosure also generally relates to such anti Drug regimens for the body or its antigen-binding fragments, or pharmaceutical preparations containing them; and thrombi This also relates to pharmaceutical formulations for use in the treatment of embolic disorders or related conditions. [Background technology]

[0004] background Reduces thromboembolic complications such as stroke, systemic embolism, cognitive decline, and mortality. The effectiveness for this purpose is equivalent to or improved upon that shown by existing treatments, and also, There is a significant, yet unaddressed, medical need for safer treatments with a lower risk of bleeding. exist. Factor XI (FXI) is a serin that functions in both the intrinsic and extrinsic coagulation pathways. It is a rotease. Factor XI exists as a homodimer in its zymogenized form; R36 When the peptide bond of 9-I370 is cleaved, factor XI is activated (factor XIa). FXI (FXIa). FXI plays an important role in normal hemostasis in a high tissue factor environment. However, it plays an important role in thrombosis. Factor XI deficiency is associated with ischemia. A reduction in the incidence of cerebral stroke and venous thromboembolic events is associated with this (Salomon et al. (200 8); Salomon, et al. (2011) Thromb Haemost.; 105: 269-73). Factor XI deficiency In subjects with minimal symptoms, overt bleeding is infrequent and, in most cases, mild, and does not cause injury. It is caused by trauma and, very rarely, affects extremely vital organs (Salomon et al.). (2011). Antibodies that bind to factor XI and / or factor XIa are being studied. For example, W O2016 / 207858 discloses such an antibody X as antibody 1 in Table 1. One of the factor I and / or factor XIa antibodies is described. This disclosure describes these To increase the risk and treat patients with specific thromboembolic disorders with desired safety and efficacy. Therefore, we provide further clinical methods, including medication regimens. Furthermore, this disclosure is intended to help patients Regarding the administration of such FXI and / or FXIa antibodies, which are sufficiently stable and appropriate By providing formulations containing this substance, we aim to enhance previous developments in this field. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] International Publication No. 2016 / 207858

Non-Patent Literature

[0006]

Non-Patent Literature 1

Summary of the Invention

Means for Solving the Problems

[0007] Gist of the Present Disclosure The present disclosure relates to a pharmaceutical preparation of an anti-factor XI and / or activated factor XI (factor XIa) antibody or its antigen-binding fragment. Also provided are dosages of such an antibody or its antigen-binding fragment, and pharmaceutical preparations for use in the treatment of thrombotic and thromboembolic disorders or related conditions.

[0008] Thus, in one aspect, there is provided a vial containing a drug delivery formulation having a pH of 5.0 to 6.0 and comprising: (a) a therapeutically effective amount of an isolated anti-factor XI (FXI) and / or anti-activated factor XI (FXIa) antibody or its antigen-binding fragment; (b) a histidine buffer; (c) a sugar or sugar alcohol; and (d) polysorbate, wherein the vial contains an overfill such that a therapeutically effective amount of the anti-FXI and / or anti-FXIa antibody or its antigen-binding fragment can be completely withdrawn.

[0009] In certain embodiments, the vial contains a therapeutically effective amount of an isolated anti-FXI and / or anti-FXIa antibody or its antigen-binding fragment at a concentration between 120 mg / ml and 180 mg / ml. In certain embodiments, the vial contains a therapeutically effective amount at a concentration of about 150 mg / ml. ​​Therapeutic doses of isolated anti-FXI and / or anti-FXIa antibodies or their antigen-binding decomposition Includes pieces.

[0010] In certain embodiments, the histidine buffer comprises histidine and histidine salts. In certain embodiments, histidine is L-histidine. In this case, the histidine salt is histidine HCl monohydrate. In a particular embodiment, The concentration of the stidine buffer is between 10 mM and 30 mM. In a particular embodiment, The concentration of the histidine buffer is approximately 20 mM.

[0011] In certain embodiments, the sugar or sugar alcohol is a disaccharide. Then, the disaccharide is sucrose. In a particular embodiment, the concentration of sucrose is 17 The concentration is between 0 mM and 270 mM. In a particular embodiment, the concentration of sucrose is approximately 2 It is 20 mM.

[0012] In a particular embodiment, the polysorbate is polysorbate 20. In the embodiment, the concentration of polysorbate 20 is from 0.02% (v / v) to 0.06% (v It is between / v). In a particular embodiment, the concentration of polysorbate 20 is about 0.04 It is %(v / v).

[0013] In certain embodiments, the pH of the drug delivery formulation is 5.3 to 5.7. In this embodiment, the pH of the drug delivery formulation is approximately 5.5.

[0014] In a particular embodiment, the excess filling is 10% (v / v) to 30% of the drug delivery formulation. The (v / v) interval is configured, and if necessary, the vial contains 1.1 mL to 1. Contains 3 mL. In certain embodiments, the excess filling is approximately 20% (v / v) of the drug delivery formulation. ) constitutes the vial, and if necessary, the vial contains approximately 1.2 mL of the drug delivery formulation.

[0015] In another embodiment, (a) A therapeutically effective dose of isolated anti-factor XI (FXI) at a concentration of approximately 150 mg and / or an anti-activated factor XI (FXIa) antibody or its antigen-binding fragment; (b) Histidine buffer at a concentration of approximately 20 mM; (c) Sucrose at a concentration of approximately 220 mM; and (d) Polysorbate 20 at a concentration of approximately 0.04% (v / v) A vial containing a drug delivery formulation with a pH of 5.5, Complete therapeutically effective dose of anti-FXI and / or anti-FXIa antibody or its antigen-binding fragment A vial containing an excess filling portion that can be withdrawn is disclosed herein.

[0016] In another embodiment, (a) a therapeutically effective dose of isolated anti-FXI and / or anti-FXIa antibody or its antigen-binding fragment; (b) histidine buffer; (c) sugar or sugar alcohol; ( d) Polysorbate and (e) Diluent, including intravenous drug delivery at pH 5.0–6.0 This is an intravenous drug delivery formulation in which the diluent is a solution containing a second sugar and water. Provided by invention.

[0017] In certain embodiments, isolated anti-FXI and / or anti-FXIa antibodies or so The therapeutically effective concentration of the antigen-binding fragment is between 1.20 mg / ml and 1.80 mg / ml. In certain embodiments, isolated anti-FXI and / or anti-FXIa antibodies The therapeutically effective concentration of its antigen-binding fragment is approximately 1.50 mg / ml.

[0018] In certain embodiments, the histidine buffer comprises histidine and histidine salts. In certain embodiments, histidine is L-histidine. In this case, the histidine salt is histidine HCl monohydrate. In a particular embodiment, The concentration of the stidine buffer is between 0.10 mM and 0.30 mM. In this state, the concentration of the histidine buffer is approximately 0.20 mM.

[0019] In certain embodiments, the sugar or sugar alcohol is a disaccharide. In this case, the disaccharide is sucrose. In a particular embodiment, the concentration of sucrose is 1. It is between 70 mM and 2.70 mM. In a particular embodiment, the sucrose concentration is It is approximately 2.20 mM.

[0020] In a particular embodiment, the polysorbate is polysorbate 20. In this embodiment, the concentration of polysorbate 20 is less than 0.001% (v / v). In certain embodiments, the concentration of polysorbate 20 is approximately 0.0004% (v / v). .

[0021] In certain embodiments, the pH of the intravenous drug delivery formulation is 5.3 to 5.7. In a particular embodiment, the pH of the intravenous drug delivery formulation is approximately 5.5.

[0022] In certain embodiments, the second sugar in the diluent is a monosaccharide. In certain embodiments, The monosaccharide is glucose. In a particular embodiment, the glucose concentration is 2.5% (v / v ) to 7.5% (v / v). In a particular embodiment, the glucose concentration is approximately 5 It is %(v / v).

[0023] In another embodiment, (a) A therapeutically effective dose of isolated anti-FXI and / or anti-FXI at a concentration of approximately 1.5 mg. Ia antibody or its antigen-binding fragment; (b) Histidine buffer at a concentration of approximately 0.20 mM; (c) Sucrose at a concentration of approximately 2.20 mM; (d) Polysorbate 20 at a concentration of approximately 0.0004% (v / v), and (e) Diluent An intravenous drug delivery preparation with a pH of 5.5 containing, An intravenous drug delivery formulation wherein the diluent is 5% glucose in water (D5W), is described herein. It will be disclosed.

[0024] The following features may be incorporated into any of the above embodiments:

[0025] In a particular embodiment, the antibody or its antigen-binding fragment is linked to SEQ ID NO: 9 or 29. Heavy chain variable region including complementarity determination regions HCDR1, HCDR2, and HCDR3 ( VH); and complementarity determination regions LCDR1, LCDR in sequence number 19 or 39. 2. Includes a light chain variable region (VL) including LCDR3.

[0026] In a particular embodiment, the antibody or its antigen-binding fragment is i. Heavy chain variable region CDR1 of SEQ ID NO: 23; heavy chain variable region CDR2 of SEQ ID NO: 24; distribution Heavy chain variable region CDR3 in column number 25; light chain variable region CDR1 in sequence number 33; sequence number 3 Light chain variable region CDR2 of sequence number 4; and light chain variable region CDR3 of sequence number 35; ii. Heavy chain variable region CDR1 of SEQ ID NO: 26; heavy chain variable region CDR2 of SEQ ID NO: 27; Heavy chain variable region CDR3 of SEQ ID NO: 28; Light chain variable region CDR1 of SEQ ID NO: 36; SEQ ID NO: Light chain variable region CDR2 of sequence number 37; and light chain variable region CDR3 of sequence number 38; iii. Heavy chain variable region CDR1 of SEQ ID NO: 43; Heavy chain variable region CDR2 of SEQ ID NO: 44 ;Heavy chain variable region CDR3 of sequence number 45;Light chain variable region CDR1 of sequence number 47;Sequence number Light chain variable region CDR2 of sequence number 37; and light chain variable region CDR3 of sequence number 15; or iv. Heavy chain variable region CDR1 of SEQ ID NO: 46; Heavy chain variable region CDR2 of SEQ ID NO: 4; Distribution Heavy chain variable region CDR3 of column number 5; light chain variable region CDR1 of sequence number 33; sequence number 14 Light chain variable region CDR2 of sequence number 15; and light chain variable region CDR3 of sequence number 15 Includes.

[0027] In a particular embodiment, the antibody or its antigen-binding fragment is derived from SEQ ID NOs: 9, 29. A heavy chain variable region (VH) selected from the group, and a group having 90% identity with respect to it VH; and a light chain variable region (VL) selected from the group consisting of sequence numbers 19 and 39. and includes a VL having 90% identity thereto. In a particular embodiment, the antibody Alternatively, the antigen-binding fragment is a heavy chain variable selected from the group consisting of SEQ ID NOs: 9 and 29. Region (VH); and light chain variable regions selected from the group consisting of sequence numbers 19 and 39. Includes (VL).

[0028] In a particular embodiment, the antibody or its antigen-binding fragment is derived from SEQ ID NOs. 31, 11 A heavy chain containing an amino acid sequence selected from the group, and having 90% identity thereto A heavy chain; and an amino acid sequence selected from the group consisting of SEQ ID NOs: 41 and 21. Includes a light chain and a light chain having 90% identity with respect to it.

[0029] In a particular embodiment, the antibody or its antigen-binding fragment is the amino acid of SEQ ID NO: 31 It contains a heavy chain containing the sequence and a light chain containing the amino acid sequence of SEQ ID NO: 41.

[0030] In certain embodiments, the antibody is a human monoclonal antibody. In this state, the antibody is a human IgG1 isotype. In a particular embodiment, the antibody is The Fc domain includes D265A substitution and P329A substitution, and if necessary, 120m g-180 mg of the aforementioned anti-factor XI (FXI) and / or anti-factor XI for administration to the target. This is the therapeutically effective amount of activated factor XI (FXIa) antibody or its antigen-binding fragment.

[0031] In another aspect, the person has a thromboembolic disorder or is at risk of developing one. A method for treating a target, wherein the drug delivery preparation or intravenous drug present in the vial A method comprising the step of administering a delivery formulation in a therapeutically effective dose to a subject in need thereof is described herein. It will be provided to.

[0032] In certain embodiments, thromboembolic disorders include atrial fibrillation or atrial flutter, transient ischemia. Seizures, ischemic stroke, thromboembolic stroke, hemorrhagic stroke, venous thromboembolism (VTE), children VTE, systemic embolism, non-central nervous system embolism, myocardial infarction, deep vein thrombosis, severe prostate The group is selected from insulin S deficiency, cerebrovascular accident, and cancer.

[0033] In certain embodiments, drug delivery formulations or intravenous drug delivery formulations present in vials The medication is administered once a month.

[0034] In certain embodiments, drug delivery formulations or intravenous drug delivery formulations present in vials The drug is administered in doses of approximately 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, and 1 The dose is selected from the group consisting of 80 mg. In certain embodiments, vials The drug delivery formulation present inside is administered at a dose of approximately 90 mg. In a particular embodiment, The drug delivery formulation present in the ial is administered at a dose of approximately 120 mg. In a specific embodiment Next, administer the drug delivery formulation contained in the vial at a dose of approximately 150 mg.

[0035] In certain embodiments, the drug delivery formulation present in the vial is administered subcutaneously.

[0036] In certain embodiments, the thromboembolic disorder is atrial fibrillation or atrial flutter. In certain embodiments, atrial fibrillation or atrial flutter is paroxysmal atrial fibrillation (PAF).

[0037] In a particular embodiment, the drug delivery formulation present in the vial is delivered once a month for three months. It is administered over a period of one month.

[0038] In certain embodiments, the subjects are in a state of low stroke risk. Morphologically, the CHA2DS2VASc risk score for the target group is between 0 and 1.

[0039] In a particular embodiment, the subjects are in a state of moderate risk of stroke.

[0040] In certain embodiments, the subjects are those at high risk of stroke. In terms of morphology, the CHA2DS2VASc risk score for the target group was ≥2 for male subjects. For female subjects, the value is ≥3.

[0041] In a particular embodiment, the method determines the effectiveness of a drug delivery formulation present in a vial. Evaluation is performed by measuring the trough inhibition of factor XI after the third dose of the delivered-by-body formulation. The method further includes the step of doing the drug present in the vial. In a particular embodiment, the method includes the step of doing the drug The efficacy of the delivery formulation is measured by free factor XI, total factor XI, factor XI coagulation activity, and activation. Select one from a list consisting of partial thromboplastin time and D-dimer. This further includes a step of evaluation by assessing multiple biomarkers.

[0042] In a particular embodiment, the method involves detecting adverse events of a drug delivery formulation present in a vial. The step further includes evaluating the presence of bleeding events or anti-drug antibodies. In a particular embodiment, the method involves, in a patient experiencing an adverse event, which is a bleeding event, the following: (i) Using colloids, crystalloids, human plasma, or plasma proteins such as albumin (ii) fluid replacement; (ii) transfusion using packed red blood cells or whole blood; or (iii) fresh frozen plasma FFP), concentrated prothrombin complex (PCC), activated PCC (APCC), for example, Administration of factor VIII inhibitors and / or recombinant activated factor VII, among This further includes the step of applying one or more of the following:

[0043] In another aspect, there is a condition of having a thromboembolic disorder or being at risk of developing one. , a method for treating an object to undergo a surgical procedure, and any one of claims 29 to 58 The step includes administering the intravenous drug delivery formulation described in the section to a subject who requires it, This specification provides a method for administering the intravenous drug delivery formulation on the same day as the surgical procedure. To be served.

[0044] In certain embodiments, the surgical procedure is knee replacement (e.g., unilateral total knee replacement). Total knee arthroplasty (TKA), artificial hip replacement, orthopedic surgery, pacemaker implantation, catheter implantation, The procedure is selected from the group consisting of thoracic surgery and abdominal surgery. In a particular embodiment, The surgical procedure is unilateral total knee arthroplasty (TKA).

[0045] In a particular embodiment, the intravenous drug delivery formulation is administered once a month.

[0046] In certain embodiments, the intravenous drug delivery formulation is delivered in doses of approximately 30 mg, approximately 60 mg, and approximately 90 mg. The dose is selected from a group consisting of g, approximately 120 mg, approximately 150 mg, and approximately 180 mg. Administer. In certain embodiments, the intravenous drug delivery formulation is administered at a dose of approximately 30 mg. In certain embodiments, the intravenous drug delivery formulation is administered at a dose of approximately 60 mg. In certain embodiments, the intravenous drug delivery formulation is administered at a dose of approximately 75 mg. In this embodiment, the intravenous drug delivery formulation is administered at a dose of approximately 150 mg.

[0047] In certain embodiments, intravenous drug delivery is administered approximately 4-8 hours after surgery. ru.

[0048] In another aspect, there is a condition of having a thromboembolic disorder or being at risk of developing one. a method for treating subjects receiving nonsteroidal anti-inflammatory drugs (NSAIDs), The drug delivery preparation or intravenous drug delivery present in the ial is delivered in a therapeutically effective amount, protons A method that includes the step of administering a steroid inhibitor in combination with a target that requires it. Provided in the specifications.

[0049] In certain embodiments, drug delivery formulations or intravenous drug delivery formulations present in vials The medication is administered once a month.

[0050] In certain embodiments, drug delivery formulations or intravenous drug delivery formulations present in vials The drug is administered in doses of approximately 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, and 1 The drug will be administered in a dose selected from the group consisting of 80 mg.

[0051] In certain embodiments, the drug delivery formulation present in the vial is administered subcutaneously.

[0052] Other embodiments and details of this disclosure are described below herein. [Brief explanation of the drawing]

[0053] [Figure 1A] Figures 1A and 1B show linear size exclusion high-performance liquid chromatography (SE-HPLC) analyses of drugs containing antibody 1 diluted in glucose (D5W, shown in Figure 1A) or drugs containing aprotinin (APN, shown in Figure 1B). [Figure 1B] Figures 1A and 1B show linear size exclusion high-performance liquid chromatography (SE-HPLC) analyses of drugs containing antibody 1 diluted in glucose (D5W, shown in Figure 1A) or drugs containing aprotinin (APN, shown in Figure 1B).

[0054] [Figure 2A] Figures 2A and 2C show the duration of the effects of antibody 1 on various biomarkers. Figure 2A shows the concentration of antibody 1 in plasma of subjects with atrial fibrillation (AF). Figure 2B shows the free factor XI in plasma of AF subjects treated with antibody 1. Figure 2C demonstrates the effects of multiple doses of antibody 1 on free factor XI. [Figure 2B]Figures 2A and 2C show the duration of the effects of antibody 1 on various biomarkers. Figure 2A shows the concentration of antibody 1 in plasma of subjects with atrial fibrillation (AF). Figure 2B shows the free factor XI in plasma of AF subjects treated with antibody 1. Figure 2C demonstrates the effects of multiple doses of antibody 1 on free factor XI. [Figure 2C] Figures 2A and 2C show the duration of the effects of antibody 1 on various biomarkers. Figure 2A shows the concentration of antibody 1 in plasma of subjects with atrial fibrillation (AF). Figure 2B shows the free factor XI in plasma of AF subjects treated with antibody 1. Figure 2C demonstrates the effects of multiple doses of antibody 1 on free factor XI.

[0055] [Figure 3A] Figures 3A–3C show a safety analysis of experimental antithrombotic treatments based on the number of patients experiencing any venous thromboembolic (VTE) events related to antibody 1 (Figure 3A), and published clinical trials using factor XI antisense oligonucleotides (FXI-ASO) (Figure 3B), and FOXTROT (Figure 3C); in each case, the experimental treatment is shown in comparison to enoxaparin as a control. [Figure 3B] Figures 3A–3C show a safety analysis of experimental antithrombotic treatments based on the number of patients experiencing any venous thromboembolic (VTE) events related to antibody 1 (Figure 3A), and published clinical trials using factor XI antisense oligonucleotides (FXI-ASO) (Figure 3B), and FOXTROT (Figure 3C); in each case, the experimental treatment is shown in comparison to enoxaparin as a control. [Figure 3C] Figures 3A–3C show a safety analysis of experimental antithrombotic treatments based on the number of patients experiencing any venous thromboembolic (VTE) events related to antibody 1 (Figure 3A), and published clinical trials using factor XI antisense oligonucleotides (FXI-ASO) (Figure 3B), and FOXTROT (Figure 3C); in each case, the experimental treatment is shown in comparison to enoxaparin as a control.

[0056] [Figure 4A] Figures 4A and 4B show the duration of the effects of antibody 1 on various biomarkers. Figure 4A shows the concentration of antibody 1 in the plasma of subjects undergoing total knee arthroplasty (TKA). Figure 4B shows the free factor XI in the plasma of TKA subjects treated with antibody 1. [Figure 4B] Figures 4A and 4B show the duration of the effects of antibody 1 on various biomarkers. Figure 4A shows the concentration of antibody 1 in the plasma of subjects undergoing total knee arthroplasty (TKA). Figure 4B shows the free factor XI in the plasma of TKA subjects treated with antibody 1. [Modes for carrying out the invention]

[0057] Detailed explanation definition To facilitate understanding of the present invention, several terms and phrases are defined below.

[0058] The terms “one (a)” and “one (an)” are used herein. It means "one or more," and may not be appropriate in the context. Excluding multiple items, and including multiple items.

[0059] As used herein, "FXI protein," "FXI antigen," and "FXI" are used interchangeably. The term is used interchangeably and refers to factor XI proteins in different species. Factor XI is the mammalian plasma coagulation factor XI, found in human plasma at concentrations of 25-30 nM. It is a glycoprotein that exists as zymogen and is activated by limited protein hydrolysis. When converted to serine proteases, they become involved in the intrinsic pathway of blood coagulation.

[0060] The terms "FXIa protein," "FXIa antigen," and "FXIa" are interchangeable. It is used to refer to the activated FXI protein in different species. Factor XI, in its active form, coagulation factor XIa (FXIa), interacts with the contact phase of blood coagulation. It is converted either by means of or through thrombin-mediated activation on the platelet surface. During the activation of factor XI, the peptide bonds within each of the two chains are cleaved. As a result, two heavy chains and two light chains are held together by disulfide bonds. This produces activated Xla factor, which is a serine protease composed of chains. Lymph protease FXIa converts coagulation factor IX to IXa, which then converts to coagulation factor X Factor (Xa) is activated. Subsequently, Xa can mediate the activation of coagulation factor II / thrombin. For example, human FXI has the sequence listed in Table 1 (Sequence ID 1), and previously reported... As stated in the report and literature (Mandle RJ Jr, et al. (1979) Blood; 54 (4): 850; NCBI Reference Sequence: AAA51985).

[0061] In relation to this disclosure, the terms "FXI" and "FXIa" (etc.) are defined as above, respectively. The native primary structure (amino acid sequence) described in the report is virtually the same as the amino acids. Mutants and variants of the natural FXI and FXIa proteins containing the sequence Includes.

[0062] The terms "catalytic domain," "serine protease catalytic domain," and similar usage When used herein, the term refers to the N-terminal Glu1 of mature proteins present in circulation. This refers to amino acids Ile370~Val607, counting from the beginning. It can also be written as residues 388-625. When used herein, "active site" The term refers to a contact that is composed of amino acids His413, Asp462, and Ser557. This signifies a triple-linked structure of the drug (Bane and Gailani (2014) Drug Disc. 19 (9)).

[0063] When used herein, the term "antibody" refers to the entire antibody and any antigenic antibody. This refers to a disulfide fragment (e.g., "antigen-binding portion") or a single chain. The entire antibody is disulfide. It consists of at least two heavy (H) chains and two light (L) chains interconnected by id bonds. It is a glycoprotein. Each heavy chain has a heavy chain variable region (abbreviated as VH in this specification). It is composed of three domains, CH1, CH2 and It is composed of CH3. Each light chain has a light chain variable region (abbreviated as VL herein) and It consists of a light chain steady region. The light chain steady region consists of one domain, CL. VH region The region and the VL region are a region of hypervariability called the complementarity determination region (CDR), and between them It is further subdivided into more conserved areas called framework areas (FRs), which are scattered throughout. Each VH and VL consists of three CDRs and four FRs, and these The atoms are arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1 FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains are related to the antigen and It contains interacting binding domains. The constant region of the antibody is connected to various immune system cells (for example) For example, effector cells and the first component of the classical complement system (Clq) are included in the host group. It can mediate the binding of immunoglobulins to tissue or factors. In some specific embodiments, antibodies It may be a monoclonal antibody, a human antibody, a humanized antibody, a camelized antibody, or a chimeric antibody. Antibodies can be any isotype (e.g., IgG, IgE, IgM, IgD, IgA and (and IgY), classes (for example, IgG1, IgG2, IgG3, IgG4, IgA1 and It may be IgA2) or a subclass of IgA2.

[0064] The CDR of the antigen-binding site is given by 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 MacC According to the method described in allum et al., J. Mol. Biol. 262: 732-745 (1996) It can be determined that the CDRs determined under these definitions are generally relative to each other. When compared, it includes duplicates or subsets of amino acid residues. In certain embodiments, The term "CDR" is defined in MacCallum et al., J. Mol. Biol. 262: 732-745 (19 96) and Martin A., Protein Sequence and Structure Analysis of Antibody Variable Domains, in Antibody Engineering, Kontermann and Dubel, eds., Defined by Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001) This is a CD-R. In certain embodiments, the term "CDR" is used by Kabat et al. J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of CDR is defined by protein of immunological interest. (1991) In certain embodiments, the heavy chain CDR and light chain CDR of an antibody are defined using different conventions. For example, in a particular embodiment, the heavy chain CDR is determined according to MacCallum (above). The light chain CDR is defined according to Kabat (above). CDRH1, CDRH2 and CDRH3 represents the heavy chain CDR, while CDRL1, CDRL2, and CDRL3 represent the light chain CDR. Represents R

[0065] As used herein, the terms "drug delivery formulation" or "intravenous drug delivery formulation" are used in this specification. The term includes combinations of active agents and inactive or active carriers, in vivo or ex. This refers to a pharmaceutical formulation that is particularly suitable for use in the diagnosis or treatment of life.

[0066] As used herein, the terms “subject” and “patient” are defined as described herein. This refers to organisms treated by the method and composition. Such organisms are not limited to this. It is not defined, but mammals (for example, rodents, apes, equids, and bovines) It is preferable that it includes animals (such as pigs, primates, canids, and felines), and humans It is more preferable to include it. In certain embodiments, the subject is human.

[0067] When used herein, "thromboembolic disorder" or similar terms refer to intrinsic and / or intrinsic / Or the common coagulation pathway is ectopically activated or not naturally deactivated. For example, it refers to any number of conditions or diseases (without treatment). These conditions include This includes, but is not limited to, thromboembolic stroke and other types of ischemic stroke, and atrial fibrillation. , prevention of stroke due to atrial fibrillation (SPAF), deep vein thrombosis, venous thromboembolism, and This includes pulmonary embolism. These include catheter-related conditions in which blood clots are formed by catheters. Thrombosis (e.g., Hickman catheter in tumor patients), as well as tubes and membranes. This also includes the prevention and management of blood clots that form during extracorporeal membrane oxygenation (ECMO) using artificial lungs. .

[0068] When used herein, the term "thromboembolic disorder" or similar terms may be interpreted as any number of, Disclosed anti-FXI and / or FXIa antibodies or their antigen-binding fragments are used to prevent This may also refer to the following things that can be treated: - Suspected cardiac arrhythmias such as paroxysmal, persistent, or permanent atrial fibrillation or atrial flutter. Thromboembolism in subjects with confirmed cardiac arrhythmias; - Prevention of stroke due to atrial fibrillation (SPAF), this subgroup is percutaneous coronary intervention The patient is an AF patient undergoing PCI (percutaneous coronary intervention); - Management and long-term care of acute venous thromboembolic events (VTE) in patients at high risk of bleeding Prevention of secondary VTE; - The target is children; venous thromboembolism (pediatric VTE); - Cerebral and cardiovascular events or incapacity during secondary prevention following transient ischemic attack (TIA). Prevention of strokes that do not result in thromboembolic events, and in heart failure with sinus rhythm; - Hemorrhagic stroke; - For patients undergoing electrical cardioversion for blood clot formation in the left atrium and cardiac arrhythmias. Thromboembolism; - Thrombosis before, during, and after ablation procedures for cardiac arrhythmias; - Venous thrombosis, which is not exclusive, but occurs in the lower or upper members. Deep vein or superficial vein thrombosis, thrombosis in the abdominal and thoracic veins, sinus thrombosis This includes the treatment and secondary prevention of jugular vein thrombosis; - Catheters, pacemaker wires, synthetic arterial grafts; mechanical or biological Blood in any artificial surface within a vein or artery, such as a heart valve or left ventricular assist device. Embolism; - Pulmonary embolism in patients with or without venous thrombosis; - Chronic thromboembolic pulmonary hypertension (CTEPH); - Arterial thrombosis in ruptured arteriosclerotic lesions, intra-arterial prostheses or catheters Thrombosis and thrombosis in seemingly normal arteries, this includes but is not limited to these. However, acute coronary syndrome, ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, unstable angina, steroids Subjects with thrombosis, thrombosis on any artificial surface within the arterial system, and pulmonary hypertension or lung This includes pulmonary thrombosis in patients without hypertension; - Thrombosis and Thromboembolism; - Cardiogenic stroke and cryptogenic stroke; - Non-central nervous system embolism (non-CNS systemic embolism); - Thrombosis in patients with invasive and non-invasive cancerous malignancies; - Thrombosis in an indwelling catheter; - Thrombosis and thromboembolism in critically ill patients; -This list is not limited to, but also includes cardiac thrombosis after myocardial infarction, ventricular aneurysm, myocardial fibrosis, and cardiomegaly. And cardiac thrombosis including heart failure, myocarditis, and conditions such as artificial heart surface. Thrombosis and thromboembolism; - Thromboembolism in patients with or without atrial fibrillation and valvular heart disease; - Thromboembolism of mechanical or biological prosthetic valves; - After cardiac repair of simple or complex cardiac malformations, native or artificial heart patch, movement Thromboembolism in patients who have developed a pulse or venous conduit; - After knee replacement, total hip replacement, and orthopedic surgery, thoracic or abdominal surgery. Venous thrombosis and thromboembolism; - Arterial or venous thrombosis following neurosurgical procedures, including intracranial and spinal cord interventions; - Not mutually exclusive, but factor V Leiden, prothrombin mutation, antithrombin III, Protein C and Protein S deficiency, Factor XIII mutation, Familial abnormalities Fibrinogenemia, congenital plasminogen deficiency, elevated factor XI levels, sickle-shaped morphology Erythrocytosis, antiphospholipid syndrome, autoimmune diseases, chronic bowel disease, nephrotic syndrome, hemolytic urine Poisoning, myeloproliferative disorders, disseminated intravascular coagulation, paroxysmal nocturnal hemoglobinuria, and heparin Congenital or acquired thrombotic tendencies, including causative thrombocytopenia; - Thrombosis and thromboembolism in chronic kidney disease; as well as - Thrombosis in patients undergoing hemodialysis and patients receiving extracorporeal membrane oxygenation (ECMO) therapy. and thromboembolism.

[0069] As used herein, the terms “trough” or “trough level” refer to the drug’s This refers to the lowest concentration of the drug to be reached before the next dose is administered. In certain embodiments, The inhibition of factor XI / factor XIa during the rough phase is greater than approximately 50% (e.g., approximately 60%). Greater than, greater than approximately 70%, greater than approximately 80%, or greater than approximately 90% (Key). In a particular embodiment, inhibition of factor XI / factor XIa at trough is approximately 8 Greater than 0%. In certain embodiments, the inhibition of factor XI / factor XIa at trough. The harm is greater than approximately 90%.

[0070] "To treat," "to treat," or "treatment" The term "(treatment)" and other grammatical equivalents used in this disclosure are used in this disclosure. In such cases, the aim is to alleviate, reduce, or improve a disease, condition, or symptom. To prevent further symptoms, prevent additional symptoms, and improve the underlying metabolic causes of the symptoms. To cause or prevent, to inhibit a disease or condition, for example, a disease or This refers to suppressing the occurrence of a condition, alleviating a disease or condition, or reversing a disease or condition. To cause contraction, to alleviate a condition caused by a disease or illness, It is intended to include stopping the symptoms of a disease or condition, and to include preventive measures. This term further encompasses achieving therapeutic and / or preventive benefits. "Therapeutic benefit" means the eradication or improvement of the underlying disorder being treated. The benefit is realized by the elimination or improvement of one or more physiological symptoms associated with the underlying disorder. This is evident, and therefore, the patient may still be suffering from the underlying disorder. Nevertheless, improvement is observed in the patients.

[0071] In certain embodiments of the methods described herein, the subject is naive with respect to the treatment. That is, treatment using the anti-factor XI / XIa antibody described herein, for example, antibody 1. I have never received any form of anticoagulant therapy before. In certain embodiments, the target is an anti-factor XI / XIa antibody as described herein, for example, antibody 1 Prior to treatment using [the drug], stable treatment with, for example, the recommended dose of a novel oral anticoagulant (NOAC) should be performed. In certain embodiments, the subject is the anti-XI / X described herein. Before treatment with factor Ia antibodies, for example antibody 1, for example, direct oral anticoagulants (DOACs) In certain embodiments, the subject is the anti-XI / X described herein. Before treatment with factor Ia antibodies, for example, antibody 1, for example, vitamin K antagonist (V I have taken the KA exam.

[0072] As used herein, the term "vial" refers to a container for holding a drug. In some embodiments, the vial may be a vial, bag, pen, or syringe. In some embodiments, the vial may be a glass vial, for example.

[0073] As used herein, the term “drug” refers to the anti-XI / XI as described herein. Factor A antibody, for example, antibody 1 disclosed in Table 1, and excipients, for example, histidine This refers to buffers, sugars, and polysorbates.

[0074] The term "approximately" refers to the action of a substance in the preparation of a drug and in the treatment of a disease or disorder. This refers to any minimum change in the concentration or amount of the active substance that does not alter its quality or effectiveness. In a specific embodiment, the term "approximately" means ±5%, ±10% of a specified numerical value or data point. , or may include ±15%.

[0075] The range is defined in this disclosure as being "approximately" from one specific value and / or "approximately" from another specific value. It can be expressed as such. If such a range is expressed, another aspect is one specific value or And / or up to a specific value. Similarly, the value, by the preceding use of "about" When expressed as an approximation, it is understood that a particular value may take on a different form. Furthermore, each endpoint of the range is in relation to the other endpoints, and independently of the other endpoints. It is understood that it can mean either of the following. A large number of values ​​are disclosed in this disclosure. It is also understood that each value is disclosed not only as the value itself, but also "approximately" as that specific value. Throughout this application, the data will be presented in a number of different formats, and This data can also represent a range of any combination of endpoints, start points, and data points. It is understood. For example, if a specific data point "10" and a specific data point "15" are disclosed In this case, not only between 10 and 15, but also greater than 10 and 15, 10 and 15 Greater than or equal to, less than 10 and 15, greater than 10 and 15 It is also disclosed that it is smaller than or equal to it, as well as equal to 10 and 15. It is understood that this will be considered as such. It is also understood that each unit between the two specific units will be disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. It will be shown.

[0076] Throughout this description, compositions are described as having, containing, or being composed of specific components. If it is stated that the process and method have certain steps, If it is stated that it contains or consists of the listed ingredients, then further, There exists a composition of the present invention that is essentially or consists of these, and described A process according to the present invention that is essentially composed of or consists of process steps. And it is intended that methods exist.

[0077] As a general rule, compositions for which a percentage is specified are, unless otherwise specified, heavy This is a percentage of quantity. Furthermore, if a variable does not have a definition attached to it, it relates to that variable. It is governed by the previous definition. Anti-factor XI and / or activated factor XI (factor XIa) antibody

[0078] In some embodiments, this disclosure refers to FXI and / or FXIa proteins (e.g., Antibody binding to humans, rabbits, cynomolgus monkeys, and baboons (FXI and / or FXIa) It is a compound containing a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29. A pharmaceutical preparation containing an antibody, a histidine buffer; sugar or sugar alcohol; and a potency The present invention provides a pharmaceutical formulation containing resorbate, with a pH of 5.0 to 6.0. In a particular embodiment, the antibody comprises VH having the amino acid sequence of SEQ ID NO: 29.

[0079] In some embodiments, the present disclosure relates to binding to FXI and / or FXIa proteins. A pharmaceutical preparation comprising an antibody or an antigen-binding fragment thereof, contained in a vial, In the vial, the formulation contains anti-FXI and / or anti-FXIa antibodies or their antigen-binding fragments. To provide a pharmaceutical formulation that includes an excess volume so that the therapeutically effective amount can be completely extracted. In certain embodiments, the vial contains FXI and / or FXIa proteins (e.g., For example, humans, rabbits, crab-eating macaques, and baboons (FXI and / or FXIa) are bound to this species. An antibody that has a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29. Approximately 150 mg of antibody containing ); approximately 20 mM histidine buffer; approximately 220 mM It contains sucrose at a concentration; and polysorbate 20 at a concentration of approximately 0.04% (v / v). This product contains a pharmaceutical preparation with a pH of approximately 5.5.

[0080] In some embodiments, the present disclosure relates to FXI and / or FXIa proteins (e.g., Antibody binding to humans, rabbits, cynomolgus monkeys, and baboons (FXI and / or FXIa) A heavy chain having the amino acid sequence of SEQ ID NO: 9 or 29, which is a body or its antigen-binding fragment. Approximately 1.5 mg of antibody or its antigen-binding fragment containing a variable domain (VH); approximately 0.2 0 mM histidine buffer; approximately 2.20 mM sucrose; approximately 0.0004 Polysorbate 20 at a concentration of %(v / v), and a diluent (e.g., 5% glucose in water) We provide an intravenous delivery pharmaceutical formulation containing D5W), the pH of which is approximately pH 5.5.

[0081] This disclosure relates to an antibody that specifically binds to the FXI and / or FXIa proteins, It has one of the amino acid sequences listed in Table 1 below (VH CDR). A pharmaceutical formulation of an antibody containing VH CDR, comprising a histidine buffer; sugar or sugar alcohol A pharmaceutical formulation containing ru; and polysorbate, with a pH of 5.0 to 6.0. This disclosure also provides information on FXI and / or FXIa proteins (e.g., human It specifically binds to rabbits, cynomolgus macaques, and baboons (FXI and / or FXIa). It is an antibody that has one of the amino acid combinations of VH CDR listed in Table 1 below. Includes one, two, three, or more VH CDRs having columns (or, A pharmaceutical preparation comprising an antibody (consisting of the same), a histidine buffer; sugar or sugar alcohol; We propose a pharmaceutical formulation containing polysorbate, with a pH of 5.0 to 6.0. Provided (the entire application is incorporated herein by reference, filed on June 24, 2016) This is the PCT international patent application PCT / IB2, published as WO2016 / 207858. (See issue 016 / 053790).

[0082] In some embodiments, this disclosure describes the methods described herein (for example, for thromboembolic disorders) Methods for treating subjects who are suffering from or at risk of developing the disease. An antibody that specifically binds to the FXIa protein for use, and is sequence number 19 or A pharmaceutical formulation of an antibody containing a light chain variable domain (VL) having a sequence of 39 amino acids. The formulation contains a histidine buffer; sugar or sugar alcohol; and polysorbate, and the pH of the formulation. The present invention provides a pharmaceutical formulation having a pH of 5.0 to 6.0. In a particular embodiment, the antibody is It contains VL having the amino acid sequence of SEQ ID NO: 39.

[0083] In some embodiments, the present disclosure relates to binding to FXI and / or FXIa proteins. A pharmaceutical preparation comprising an antibody or an antigen-binding fragment thereof, contained in a vial, In the vial, the formulation contains anti-FXI and / or anti-FXIa antibodies or their antigen-binding fragments. To provide a pharmaceutical formulation that includes an excess volume so that the therapeutically effective amount can be completely extracted. In certain embodiments, the vial contains FXI and / or FXIa proteins (e.g., For example, humans, rabbits, crab-eating macaques, and baboons (FXI and / or FXIa) are bound to this species. An antibody that has a light chain variable domain (V) having the amino acid sequence of SEQ ID NO: 19 or 39. Approximately 150 mg of antibody containing L; approximately 20 mM histidine buffer; approximately 220 mM Contains sucrose at a concentration of 0.04% (v / v) and polysorbate 20 at a concentration of approximately 0.04% (v / v). It contains a pharmaceutical preparation whose pH is approximately 5.5.

[0084] In some embodiments, the present disclosure relates to FXI and / or FXIa proteins (e.g., Antibody binding to humans, rabbits, cynomolgus monkeys, and baboons (FXI and / or FXIa) A body or its antigen-binding fragment having the amino acid sequence of SEQ ID NO: 19 or 39. Approximately 1.5 mg of antibody or its antigen-binding fragment containing a variable chain domain (VL); approximately 0. 20 mM histidine buffer; approximately 2.20 mM sucrose; approximately 0.000 A 4% (v / v) concentration of polysorbate 20, and a diluent (e.g., 5% glucose in water). The present invention provides an intravenous delivery pharmaceutical formulation containing (D5W)) and having a pH of approximately 5.5. .

[0085] This disclosure describes the methods described herein (for example, if you have a thromboembolic disorder or For use in methods for dealing with objects at risk of that occurring, FXI and / or FXIa proteins (e.g., human, rabbit, cynomolgus monkey, and baboon) Antibodies that specifically bind to FXI and / or FXIa) are listed in Table 1 below. Antibody containing a VL CDR having any one amino acid sequence among the VL CDRs A pharmaceutical preparation containing a histidine buffer; sugar or sugar alcohol; and polysorbate. We also provide pharmaceutical formulations that contain and have a pH of 5.0 to 6.0. FXIa Proteins (e.g., human, rabbit, cynomolgus monkey, and baboon FXI and / or F The antibodies that specifically bind to XIa) are among the VL CDRs listed in Table 1 below. One, two, three, or more VL CDs having any of the amino acid sequences It may contain (or be derived from) R.

[0086] In some embodiments, the present disclosure relates to binding to FXI and / or FXIa proteins. A pharmaceutical preparation comprising an antibody or an antigen-binding fragment thereof, contained in a vial, In the vial, the formulation contains anti-FXI and / or anti-FXIa antibodies or their antigen-binding fragments. To provide a pharmaceutical formulation that includes an excess volume so that the therapeutically effective amount can be completely extracted. In certain embodiments, the vial contains FXI and / or FXIa proteins (e.g., For example, humans, rabbits, crab-eating macaques, and baboons (FXI and / or FXIa) are bound to this species. An antibody that 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 Contains approximately 150 mg of antibody; approximately 20 mM concentration of histidine buffer; approximately 220 mM concentration The formulation contains sucrose; and polysorbate 20 at a concentration of approximately 0.04% (v / v). It contains a pharmaceutical preparation with a pH of approximately 5.5.

[0087] In some embodiments, the present disclosure relates to FXI and / or FXIa proteins (e.g., Antibody binding to humans, rabbits, cynomolgus monkeys, and baboons (FXI and / or FXIa) A heavy chain having the amino acid sequence of SEQ ID NO: 9 or 29, which is a body or its antigen-binding fragment. Variable light chain having a variable domain (VH) and the amino acid sequence of SEQ ID NO: 19 or 39. Approximately 1.5 mg of antibody or its antigen-binding fragment containing a domain (VL); approximately 0.20 mg Histidine buffer at a concentration of M; sucrose at a concentration of approximately 2.20 mM; approximately 0.0004% Polysorbate 20 at a concentration of v / v, and a diluent (e.g., 5% glucose in water (D5) The present invention provides an intravenous delivery pharmaceutical formulation containing W)) and having a pH of approximately 5.5.

[0088] In some embodiments, the present disclosure relates to binding to FXI and / or FXIa proteins. A pharmaceutical preparation comprising an antibody or an antigen-binding fragment thereof, contained in a vial, In the vial, the formulation contains anti-FXI and / or anti-FXIa antibodies or their antigen-binding fragments. To provide a pharmaceutical formulation that includes an excess volume so that the therapeutically effective amount can be completely extracted. In certain embodiments, the vial contains FXI and / or FXIa proteins (e.g., For example, humans, rabbits, crab-eating macaques, and baboons (FXI and / or FXIa) are bound to this species. It is an antibody that has a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 29, and Approximately 15 antibodies possess a light chain variable domain (VL) with the amino acid sequence of SEQ ID NO: 39. 0 mg; histidine buffer at a concentration of approximately 20 mM; sucrose at a concentration of approximately 220 mM; It contains approximately 0.04% (v / v) polysorbate 20, and the pH of the formulation is approximately pH 5. It contains a pharmaceutical preparation, which is 5.

[0089] In some embodiments, the present disclosure relates to FXI and / or FXIa proteins (e.g., Antibody binding to humans, rabbits, cynomolgus monkeys, and baboons (FXI and / or FXIa) A body or its antigen-binding fragment, having the amino acid sequence of SEQ ID NO: 29, is a heavy chain variable dormant The in (VH) and the light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 39 Contains approximately 1.5 mg of antibody or its antigen-binding fragment; approximately 0.20 mM histidine Buffering agent; sucrose at a concentration of approximately 2.20 mM; porciniol at a concentration of approximately 0.0004% (v / v) The formulation comprises Resorbate 20 and a diluent (e.g., 5% glucose in water (D5W)). The present invention provides an intravenous delivery pharmaceutical formulation with a pH of approximately 5.5.

[0090] In some embodiments, the methods described herein (for example, for patients suffering from thromboembolic disorders) For use in methods for treating objects that are at risk of such occurrence. Other antibodies have mutated, but still show the CDR region shown in the sequence in Table 1. CDR area of ​​at least 60, 70, 80, 85, 90, or 95 percent of the region It contains amino acids having the same identity. In some embodiments, the antibody is as shown in the sequence in Table 1. Compared to the CDR region, the CDR region has one or fewer, two or fewer, or three or fewer amino acids. , containing mutant amino acid sequences in which four or fewer or five or fewer amino acids have been mutated. [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]

[0091] In some embodiments, the methods or formulations described herein (for example, those suffering from thromboembolic disorders) Methods for treating subjects who are suffering from or at risk of developing the disease. Other antibodies for use have mutated amino acids or nucleic acids that encode amino acids. However, even so, for the sequences listed in Table 1, at least 60, 65, 70, 75, 80, 85 The antibody contains 90 or 95 percent identity. Some embodiments are shown in Table 1. Compared to the variable region shown in the sequence described, one or fewer amino acids in the variable region, 2 While there are one or fewer, three or fewer, four or five or fewer mutations, on the other hand, they are essentially the same It contains a mutant amino acid sequence that retains antigen-binding activity.

[0092] Each of these antibodies can bind to FXI and / or FXIa. To create other FXI and / or FXIa-binding antibodies of the present disclosure, VH, VL, Full-length light chain and full-length heavy chain sequence (amino acid sequence and nucleo encoding the amino acid sequence) It is possible to "mix and harmonize" such "mixed and harmonized" FXI and / or FXIa-binding antibodies can be used in binding assays known in the art (e.g., Test using ELISA and other assays described in the Examples section. This is possible. When these chains are mixed and harmonized, the VH pairing from a specific VH / VL pairing The sequence should be replaced with a structurally similar VH sequence. Similarly, a specific full-length heavy chain / full-length sequence The full-length heavy chain sequences derived from light chain pairings should be replaced with structurally similar full-length heavy chain sequences. Similarly, replace the VL sequence from a specific VH / VL pairing with a structurally similar VL sequence. Similarly, the full-length light chain sequences from a particular full-length heavy chain / full-length light chain pair should be structurally similar. It should be replaced with the full-length light chain sequence.

[0093] Therefore, in one embodiment, the method described herein (for example, when suffering from a thromboembolic disorder) (Used in methods for treating objects that are or are at risk of developing dolphins) To that end, this disclosure includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 and 29. A heavy chain variable domain, and an amino acid selected from the group consisting of SEQ ID NOs: 19 and 39. An isolated antibody having a light chain variable domain containing an acid sequence, or its antigen-binding region. FXI and / or FXIa (for example, humans, rabbits, crab-eating macaques, and baboons) This invention provides an isolated antibody or its antigen-binding region that specifically binds to FXIa). In another embodiment, the formulations described herein (e.g., formulations in vials, intravenous drug delivery) For use in pharmaceutical formulations, this disclosure relates to a selection from the group consisting of SEQ ID NOs: 9 and 29. Select from the group consisting of heavy chain variable domains containing mino acid sequences, and SEQ ID NOs: 19 and 39. An isolated antibody having a light chain variable domain containing a selected amino acid sequence or its antigenic chain in a synthetic domain that specifically binds to FXI and / or FXIa (e.g., human, rabbit, cane rat, and baboon FXIa), an isolated antibody or its antigen-binding region is provided.

[0094] More specifically, in certain embodiments, the disclosure provides a heavy chain variable domain and a light chain variable domain comprising amino acid sequences selected from SEQ ID NOs: 9 and 29; and also 19 and 39, respectively, of an isolated antibody or an antigen-binding fragment thereof. In certain embodiments for use in the methods described herein (e.g., methods for treating a subject suffering from or at risk of developing a thrombotic disorder), an antibody or an antigen-binding fragment thereof presented herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In certain embodiments for use in the formulations described herein (e.g., formulations in vials, intravenous drug delivery formulations), an antibody or an antigen-binding fragment thereof presented herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19.

[0095] In certain embodiments for use in the methods described herein (e.g., methods for treating a subject suffering from or at risk of developing a thrombotic disorder), an antibody or an antigen-binding fragment thereof presented herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In certain embodiments for use in the methods described herein (e.g., methods for treating a subject suffering from or at risk of developing a thrombotic disorder), an antibody or an antigen-binding fragment thereof presented herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In certain embodiments for use in the methods described herein (e.g., methods for treating a subject suffering from or at risk of developing a thrombotic disorder), an antibody or an antigen-binding fragment thereof presented herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In certain embodiments for use in the methods described herein (e.g., methods for treating a subject suffering from or at risk of developing a thrombotic disorder), an antibody or an antigen-binding fragment thereof presented herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In certain embodiments for use in the formulations described herein (e.g., formulations in vials, intravenous drug delivery formulations), an antibody or an antigen-binding fragment thereof presented herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In certain embodiments for use in the formulations described herein (e.g., formulations in vials, intravenous drug delivery formulations), an antibody or an antigen-binding fragment thereof presented herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In certain embodiments for use in the formulations described herein (e.g., formulations in vials, intravenous drug delivery formulations), an antibody or an antigen-binding fragment thereof presented herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In certain embodiments for use in the formulations described herein (e.g., formulations in vials, intravenous drug delivery formulations), an antibody or an antigen-binding fragment thereof presented herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In certain embodiments for use in the formulations described herein (e.g., formulations in vials, intravenous drug delivery formulations), an antibody or an antigen-binding fragment thereof presented herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19.

[0096] In certain embodiments for use in the methods described herein (e.g., methods for treating a subject suffering from or at risk of developing a thrombotic disorder), an antibody or an antigen-binding fragment thereof presented herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19. In certain embodiments for use in the methods described herein (e.g., methods for treating a subject suffering from or at risk of developing a thrombotic disorder), an antibody or an antigen-binding fragment thereof presented herein that specifically binds to human FXI and / or FXIa comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 19.​​​or the antigen-binding fragment thereof 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), the antibody or antigen-binding fragment thereof that specifically binds to human FXI and / or FXIa presented herein 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 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 embodiments, the disclosure provides an isolated antibody or an antigen-binding region thereof having a heavy chain and a light chain 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; human and / or an antibody or antigen-binding fragment thereof presented herein that specifically binds to 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. <>

[0097] <> 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 embodiments, the disclosure provides an isolated antibody or an antigen-binding region thereof having a heavy chain and a light chain 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; optimized for expression in mammalian cells, 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. selected from the group consisting of SEQ ID NO: 21 or 41, and an antigen-binding portion thereof. More specifically, in certain embodiments, the disclosure provides an isolated antibody or an antigen-binding region thereof having a heavy chain and a light chain 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; 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; selected from the group consisting of SEQ ID NO: 11 or 31, optimized for expression in mammalian cells, 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. selected from the group consisting of SEQ ID NO: 21 or 41, ​(ii) provides a functional protein containing its antigen-binding moiety. More specifically, a In certain embodiments, this disclosure refers to Sequence IDs 11 and 31; or 21 and 41, respectively. Isolated antibodies having heavy and light chains containing amino acid sequences selected from or the anti- It provides a region capable of primary bonding.

[0098] In specific embodiments for use in the method described herein, human FXI and / Alternatively, antibodies or antigen-binding cleavage of antibodies presented herein that specifically bind to FXIa. The piece contains a heavy chain containing the amino acid sequence of SEQ ID NO: 11, and the amino acid sequence of SEQ ID NO: 21. Contains light chains. In certain embodiments, human FX for use in the formulations described herein. Antibodies or their anti-Is that specifically bind to I and / or FXIa as presented herein. The primordial fragment contains a heavy chain with the amino acid sequence of SEQ ID NO: 11, and the amino acid sequence of SEQ ID NO: 21. It contains a light chain that includes an acid sequence.

[0099] In specific embodiments for use in the method described herein, human FXI and / Alternatively, antibodies or antigen-binding cleavage of antibodies presented herein that specifically bind to FXIa. The fragment contains the heavy chain variable region with the amino acid sequence of SEQ ID NO: 31, and the amino acids of SEQ ID NO: 41. Includes a light chain variable region containing an array. In certain embodiments, use in the formulations described herein For this purpose, the present invention specifically binds to human FXI and / or FXIa. The antibody or its antigen-binding fragment contains a heavy chain variable region including the amino acid sequence of SEQ ID NO: 31, It also includes a light chain variable region containing the amino acid sequence of sequence number 41.

[0100] The terms “complementarity determination region” and “CDR” are used herein to mean “anti- This refers to the sequence of amino acids within the antibody's variable region that confers specificity and binding affinity. Within each heavy chain variable region, there are three CDRs (HCDR1, HCDR2, HCDR3). Within each light chain variable region, there are three CDRs (LCDR1, LCDR2, LCDR3).

[0101] The precise amino acid sequence boundaries of a given CDR are defined in Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service e, National Institutes of Health, Bethesda, MD ("Kabat" numbered ski Al-Lazikani et al., (1997) JMB 273, 927-948 ("Chothia" number) (Attachment scheme), Lefranc et al., (2003) Dev. Comp. Immunol., 27, 55-77 (" Those described by the "IMGT" numbering scheme, or including "combined" systems. This can be easily determined using one of the many well-known schemes.

[0102] For example, under Kabat, the CDR amino acid residues of antibody 2 are in the heavy chain variable domain (V The items in H) are 31-35 (HCDR1), 50-66 (HCDR2), and 99-1 Numbered 11(HCDR3), it is a CDR amino acid residue within the light chain variable domain (VL). These are 22-35 (LCDR1), 51-57 (LCDR2), and 90-100 (LC It is numbered DR3). Under Chothia, the CDR amino acids in VH are 26 ~32 (HCDR1), 52~57 (HCDR2), and 99~111 (HCDR3) and numbered, and the amino acid residues within VL are numbered 25 - 33 (LCDR1), 51 - 53 (L CDR2), and 92 - 99 (LCDR3). By combining both CDR definitions of Kabat and Chot hia, the CDRs consist of amino acid residues 26 - 35 (HCDR1), 50 - 66 (HCDR2), and 99 - 111 (HC DR3) in human VH, and amino acid residues 22 - 35 (LCDR1), 51 - 57 ( LCDR2), and 90 - 100 (LCDR3) in human VL. By combining both CDR definitions of Kabat and Chothi a, the "combined" CDRs consist of amino acid residues 26 - 35 (HCDR1), 50 - 66 (HCDR2), and 99 - 108 (HCDR3) in human VH, and amino acid residues 24 - 38 (LCDR1), 54 - 60 (LCDR2), and 93 - 101 (LCDR3) in human VL. As another example, under IM GT, the CDR amino acid residues within the heavy chain variable domain (VH) are numbered 26 - 33 (HC DR1), 51 - 58 (HCDR2), and 97 - 108 (HCDR3), and the CDR amino acid residues within the light chain variable domain (VL) are numbered 27 - 36 (LCDR1), 54 - 56 (LCDR2), and 93 - 101 (LCDR3). Table 1 presents exemplary Kabat , Chothia, combined, 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 the heavy and light chain CDR1, CDR2, and CDR3 as set forth in Table 1, or combinations thereof , or combinations thereof , and LCDR1, LCDR2, and LCDR3. In another aspect, the present disclosure provides the heavy and light chain CDR1, CDR2, and CDR3 as set forth in Table 1, or combinations thereof The present invention provides an FXIa-binding antibody containing [the specified component]. The amino acid sequence of the antibody's VH CDR1 is [the specified sequence number]. The amino acid sequences of the antibody's VH CDR2 are shown in 3 and 23. The amino acid sequences of the antibody's VH CDR3 are shown in SEQ ID NOs. 5 and 25. The amino acid sequences of the antibody VL CDR1 are shown in SEQ ID NOs: 13 and 33. The amino acid sequences of CDR2 are shown in SEQ ID NOs: 14 and 34. VL CDR3 of the antibody The amino acid sequences are shown in SEQ ID NOs. 15 and 35. These CDR regions are Kabat It was drawn using a system.

[0103] Or Chothia series (Al-Lazikani et al., (1997) JMB 273, 927-948) When defined using the above, the amino acid sequences of the antibody VH CDR1 are SEQ ID NOs: 6 and 26 The amino acid sequences of the antibody's VH CDR2 are shown in SEQ ID NOs. 7 and 27. The amino acid sequences of the antibody's VH CDR3 are shown in SEQ ID NOs: 8 and 28. The amino acid sequence of CDR1 is shown in SEQ ID NOs: 16 and 36. The VL of the antibody CDR2 The amino acid sequence is shown in SEQ ID NOs. 17 and 37. The amino acid sequence of the antibody VL CDR3 is shown below. The columns are indicated by sequence numbers 18 and 38.

[0104] Alternatively, if defined using a combination system, the amino acid sequence of the antibody's VH CDR1 is This is shown in SEQ ID NO: 46. The amino acid sequence of the antibody's VH CDR2 is shown in SEQ ID NO: 4. The amino acid sequence of the antibody VH CDR3 is shown in SEQ ID NO: 5. The amino acid sequence of the antibody VL CDR1 The amino acid sequence is shown in SEQ ID NO: 33. The amino acid sequence of the antibody VL CDR2 is the sequence It is indicated by number 14. The amino acid sequence of the antibody's VL CDR3 is shown in SEQ ID NO: 15.

[0105] Alternatively, if defined using the IMGT numbering scheme, the VH CDR1 of the antibody The amino acid sequence is shown in SEQ ID NO: 43. The amino acid sequence of the antibody VH CDR2 is the sequence It is indicated by number 44. The amino acid sequence of the antibody's VH CDR3 is shown in sequence number 45. The amino acid sequence of antibody VL CDR1 is shown in SEQ ID NO: 47. The amino acid sequence is shown in SEQ ID NO: 37. The amino acid sequence of the antibody VL CDR3 is the sequence It is indicated by the number 15.

[0106] Each of these antibodies can bind to FXI and / or FXIa. Furthermore, the antigen-binding specificity is mainly provided by the CDR1, 2, and 3 regions. Considering this, VH CDR1, 2, and 3 sequences and VL CDR1, 2, and 3 sequences It can be “mixed and harmonized” (for example, other FXI and / or FX of the Disclosure). To create an Ia-binding molecule, CDRs from different antibodies are mixed and harmonized. It is possible, but each antibody is VH CDR1, 2, and 3 and VL CDR1, 2, and 3 (Preferably contains) such “mixed and harmonized” FXI and / or F XIa-binding antibodies are used in binding assays and examples known in the art. Test using (for example, ELISA, SET, BIACORE® assay) It is possible. When mixing and harmonizing VH CDR sequences, C from a specific VH sequence DR1, CDR2 and / or CDR3 sequences are structurally similar CDR sequences (single or (Multiple) should be replaced. Similarly, when mixing and harmonizing VL CDR sequences , CDR1, CDR2 and / or CDR3 sequences from a specific VL sequence are structurally similar It should be replaced with the following CDR sequence(s) (one or more). One or more VH and The and / or VL CDR region sequence shown herein with respect to the monoclonal antibody of this disclosure By substituting a structurally similar sequence from the existing CDR sequence, a novel VH sequence can be created. It will be readily apparent to those skilled in the art that VL sequences can be created. In addition to the above In one embodiment, the antigen-binding fragment of the antibody described herein is VH CDR1, 2, and 3, or VL CDR1, 2, and 3, where fragments are FXI and It binds to antibody 1 and / or FXIa as a single variable domain. CDR of antibody 1 and antibody 2 Note that the sequences are identical.

[0107] In certain embodiments of this disclosure, the antibody or its antigen-binding fragment is F as described in Table 1. It may have the heavy chain and light chain sequences of ab. More specifically, the antibody or its antigen-binding fragment is It may have the heavy chain and light chain sequences of antibody 2 and antibody 1.

[0108] Other embodiments of this disclosure include antibodies that specifically bind to FXI and / or FXIa. The antigen-binding fragments are defined by Kabat and are listed in Table 1 as heavy chain variable regions. Region CDR1, heavy chain variable region CDR2, heavy chain variable region CDR3, light chain variable region CDR1, light Including a chain variable region CDR2 and a light chain variable region CDR3. Further embodiments of the present disclosure So, an antibody or antigen-binding fragment that specifically binds to FXI and / or FXIa is, Defined by Chothia, the heavy chain variable region CDR1, listed in Table 1, heavy chain variable Variable region CDR2, heavy chain variable region CDR3, light chain variable region CDR1, light chain variable region CDR2 , and light chain variable region CDR3. In other embodiments, FXI and / or FXI The antibody or antigen-binding fragment that specifically binds to a is defined by its combination system, as shown in Table 1. The heavy chain variable region CDR1, heavy chain variable region CDR2, heavy chain variable region CDR3, This includes light chain variable region CDR1, light chain variable region CDR2, and light chain variable region CDR3. In yet another embodiment of the disclosure, an antibody that specifically binds to FXI and / or FXIa. Alternatively, antigen-binding fragments are defined by IMGT and are heavy chain variable regions listed in Table 1. Region CDR1, heavy chain variable region CDR2, heavy chain variable region CDR3, light chain variable region CDR1, light It includes a chain variable region CDR2 and a light chain variable region CDR3.

[0109] In certain embodiments for use in the method described herein, this disclosure is an array of sequences. Heavy chain variable region CDR1 of sequence 3; heavy chain variable region CDR2 of sequence 4; heavy chain variable region of sequence 5 Region CDR3; Light chain variable region CDR1 of sequence number 13; Light chain variable region CD of sequence number 14 R2; and the light chain variable region CDR3 of sequence number 15, FXI and / or FXI It includes an antibody that specifically binds to a.

[0110] In certain embodiments, this disclosure relates to the heavy chain variable region CDR1 of SEQ ID NO: 23; SEQ ID NO: 24 Heavy chain variable region CDR2; heavy chain variable region CDR3 of SEQ ID NO: 25; light chain variable region CDR3 of SEQ ID NO: 33 Variable region CDR1; light chain variable region CDR2 of SEQ ID NO: 34; and light chain variable region of SEQ ID NO: 35 Includes antibodies that specifically bind to FXI and / or FXIa, including region CDR3. .

[0111] In certain embodiments, this disclosure relates to the heavy chain variable region CDR1 of SEQ ID NO: 6; the heavy chain variable region of SEQ ID NO: 7 Chain variable region CDR2; heavy chain variable region CDR3 of SEQ ID NO: 8; light chain variable region of SEQ ID NO: 16 CDR1; Light chain variable region of SEQ ID NO: 17; CDR2; and Light chain variable region C of SEQ ID NO: 18 It includes antibodies that specifically bind to FXI and / or FXIa, including DR3.

[0112] In certain embodiments, this disclosure relates to the heavy chain variable region CDR1 of SEQ ID NO: 26; SEQ ID NO: 27 Heavy chain variable region CDR2; heavy chain variable region CDR3 of SEQ ID NO: 28; light chain variable region CDR3 of SEQ ID NO: 36 Variable region CDR1; light chain variable region CDR2 of SEQ ID NO: 37; and light chain variable region of SEQ ID NO: 38 Includes antibodies that specifically bind to FXI and / or FXIa, including region CDR3. .

[0113] In a specific embodiment, the heavy chain variable region CDR1 of SEQ ID NO: 43; the heavy chain variable region of SEQ ID NO: 44. Region CDR2; Heavy chain variable region of SEQ ID NO: 45; Light chain variable region CD of SEQ ID NO: 47 R1; Light chain variable region CDR2 of SEQ ID NO: 37 and light chain variable region CDR3 of SEQ ID NO: 15 The present invention provides antibodies that specifically bind to FXI and / or FXIa, including the above.

[0114] In a specific embodiment, the heavy chain variable region CDR1 of SEQ ID NO: 46; the heavy chain variable region of SEQ ID NO: 4 Region CDR2; heavy chain variable region CDR3 of SEQ ID NO: 5; light chain variable region CDR1 of SEQ ID NO: 33 Includes light chain variable region CDR2 of SEQ ID NO: 14 and light chain variable region CDR3 of SEQ ID NO: 15 The present invention provides antibodies that specifically bind to FXI and / or FXIa.

[0115] In certain embodiments, this disclosure relates to FXI and / or F as described in Table 1. The method described herein includes an antibody or antigen-binding fragment that specifically binds to XIa. In a particular embodiment for use in, an anti- The bodies or antigen-binding fragments are antibody 2 and antibody 1.

[0116] When used herein, a human antibody is defined as having a variable region or full-length chain that is a human germline. If obtained from a system using cell lineage immunoglobulin genes, specific reproductive cells A heavy chain or light chain variable region or full length that is "a product of" or "derived from" a cellular sequence. It includes heavy or light chains. Such systems are trans-human immunoglobulin genes. Immunizing genic mice with the target antigen, or displaying it on phages. This includes screening a human immunoglobulin gene library for a target antigen. Human antibodies that are "products of" or "derived from" human germline immunoglobulin sequences are The amino acid sequence of human antibodies was compared with the amino acid sequence of human germline immunoglobulins. The human germline with the closest sequence to the human antibody (i.e., with the highest percentage identity) By selecting immunoglobulin sequences, it is possible to identify them as such. ru.

[0117] A product of or derived from a specific human germline immunoglobulin sequence. Antibodies are, for example, intentionally created to counteract naturally occurring somatic mutations or site-directed mutations. Due to the introduction, it may contain amino acid differences compared to the germline sequence. However, V In the H or VL framework region, selected human antibodies generally consist of amino acids. The sequence is similar to the amino acid sequence encoded by the human germline immunoglobulin gene. They are at least 90% identical, and the germline immunoglobulin amino acid sequences of other species (for example, When compared to mouse germline sequences, human antibodies are considered to be human. Therefore, it contains amino acid residues that are identified. In certain cases, human antibodies contain amino acids The sequence is at least the amino acid sequence encoded by the germline immunoglobulin gene. 60%, 70%, 80%, 90%, or at least 95%, or even less They may be 96%, 97%, 98%, or 99% identical.

[0118] Generally, recombinant human antibodies are found within the VH or VL framework region of human germ cells. The amino acid sequence encoded by the lineage immunoglobulin gene and the sequence of 10 or fewer amino acids It shows differences. In certain cases, human antibodies are derived from germline immunoglobulin genes. The amino acid sequence that is coded as follows: 5 or fewer, or even 4 or fewer, 3 or fewer, 2 or fewer The following may show differences of one or fewer amino acids. Human germline immunoglobulin genetics Examples of children include, but are not limited to, the following variable domain germline fragments, Other examples include DP47 and DPK9.

[0119] homologous antibodies The methods described herein (for example, if you have a thromboembolic disorder or if it is occurring) Further implementations for use in methods for treating subjects at risk of [doing something] In this disclosure, the sequences listed in Table 1 (for example, sequence numbers 29, 31, 39, or 41) An antibody or antigen-binding fragment containing an amino acid sequence homologous to ) and FXI and bi / or FXIa protein (e.g., human, rabbit, cynomolgus monkey, and baboon FXIa) It binds to Ia) and retains the desired functional properties of the antibodies listed in Table 1, such as antibody 2 and antibody 1. The present invention provides an antibody or an antigen-binding fragment thereof. In certain embodiments, such homologous antibody The body uses the CDR amino acid sequences listed in Table 1 (e.g., Kabat CDR, Chothia Holds a CD-R, IMGT CD-R, or combined CD-R.

[0120] For example, in some embodiments, the Disclosure relates to heavy chain variable domains and light chain variable domains. The isolated antibody or its functional antigen-binding fragment, wherein the heavy chain variable domain is distributed Amino acid sequences selected from the group consisting of sequence numbers 9 and 29, and at least 80%, less Both contain amino acid sequences that are 90% or at least 95% identical, and have a light chain variable domain. However, at least 80% of the amino acid sequences are selected from the group consisting of SEQ ID NOs: 19 and 39. The antibody contains an amino acid sequence that is at least 90% or at least 95% identical, FXI and / or FXIa (e.g., humans, rabbits, cynomolgus macaques, and baboons) Provides an isolated antibody or a functional antigen-binding fragment that specifically binds to Ia). In one embodiment, the isolated antibody or its functional antigen-binding fragment is a heavy chain variable domain. It includes an amino acid and a light chain variable domain, where the heavy chain variable domain is the amino acid of SEQ ID NO: 9 amino acids that are at least 80%, at least 90%, or at least 95% identical to the sequence. The acid sequence is present, and the light chain variable domain is at least 80% of the amino acid sequence of SEQ ID NO: 19. The antibody contains amino acid sequences that are at least 90% or at least 95% identical, and the antibody is F XI and / or FXIa (e.g., humans, rabbits, cynomolgus macaques, and baboons FXI) a) specifically binds to the isolated antibody or its functional antigen binding The fragment includes a heavy chain variable domain and a light chain variable domain, where the heavy chain variable domain is , the amino acid sequence of SEQ ID NO: 29 is at least 80%, at least 90%, or at least It also contains an amino acid sequence that is 95% identical, and the light chain variable domain is the amino acid of SEQ ID NO: 39 amino acids that are at least 80%, at least 90%, or at least 95% identical to the sequence. The antibody contains an acid sequence and is FXI and / or FXIa (e.g., human, rabbit, cynomolgus). It specifically binds to isal and baboon FXIa). In certain aspects of this disclosure, the heavy chain And the light chain sequences are defined by Kabat as HCDR1, HCDR2, HCDR3 , LCDR1, LCDR2, and LCDR3 sequences, for example, sequence numbers 3, 4, respectively Further including 5, 13, 14, and 15. In certain other aspects of this disclosure, heavy chains and The light chain sequences are HCDR1, HCDR2, and HCDR3 as defined by Chothia. , LCDR1, LCDR2, and LCDR3 sequences, for example, sequence numbers 6, 7, respectively Further including 8, 16, 17, and 18. In certain other embodiments, heavy chain and light chain combinations The columns are defined by the combination system: HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 arrays, for example, arrays 46, 4, 5, 33, and 1 respectively. 4 and 15 further include. In certain other embodiments, the heavy chain and light chain sequences are IMG HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, defined by T and LCDR3 sequences, for example, sequence numbers 43, 44, 45, 47, 37, and It also includes 15.

[0121] In other embodiments for use in the method described herein, VH and / or V The L amino acid sequences are those listed in Table 1 and 50%, 60%, 70%, 80%, 90%, 95%. They may be identical in percentages of %, 96%, 97%, 98%, or 99%. In other embodiments for use, the VH and / or VL amino acid sequences are as shown in Table 1. Columns and 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or They may be 99% identical. In other embodiments, the VH and / or VL amino acid sequences are 1 amino acid positions at one or fewer, two or fewer, three or fewer, four or fewer, or five or fewer amino acid positions Other than the exchange, they may be identical. For the VH and VL regions of those listed in Table 1 VH and VL regions with high (i.e., 80% or greater) identity Antibodies having the region, with SEQ ID NOs. 10 or 30 and SEQ ID NOs. 20 and 40 respectively. Mutagenesis of nucleic acid molecules (e.g., site-directed or PCR-mediated mutagenesis) ) and then the modified antibody encoded herein is used to maintain its function as described herein. This can be obtained by testing using a functional assay.

[0122] Other embodiments for use in the methods described herein include full-length heavy chains and / or The full-length light chain amino acid sequence is the sequence listed in Table 1 (for example, SEQ ID NOs: 11 and / or 2). 1, or 31 and / or 41) and 50%, 60%, 70%, 80%, 90%, 95 They may be identical in percentages of %, 96%, 97%, 98%, or 99%. In other embodiments for use, the full-length heavy chain and / or full-length light chain amino acid sequences are shown in Table 1. The sequence described (for example, sequence numbers 11 and / or 21, or 31 and / or 41) ) and 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98% or They may be 99% identical. The full-length heavy chain of either SEQ ID NO: 11 or 31, and SEQ ID NO: High for either 21 or 41 total length light chains (e.g., 80% or more) (i) An antibody having a full-length heavy chain and a full-length light chain that are identical, such a polypeptide Mutagenesis of nucleic acid molecules encoding (e.g., site-directed or PCR-mediated mutation) Induction is performed, and then the modified antibody encoded herein is used to maintain its function. This can be obtained by testing using the functional assay described.

[0123] In one embodiment, an isolated antibody comprising a heavy chain and a light chain or a functional antigen-binding fragment thereof The heavy chain consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 11 and 31, and a small number of others. Contains amino acid sequences that are identical by at least 80%, at least 90%, or at least 95%. Furthermore, the light chain is an amino acid sequence selected from the group consisting of SEQ ID NOs. 21 and 41, and at least It also contains amino acid sequences that are 80%, at least 90%, or at least 95% identical, Antibodies are FXI and / or FXIa (e.g., human, rabbit, cynomolgus monkey, and An isolated antibody or its functional antigen-binding fragment that specifically binds to baboon FXIa) Provided in the present invention, in one embodiment, an isolated antibody or its functional antigen-binding fragment It includes a heavy chain and a light chain, where the heavy chain has the amino acid sequence of SEQ ID NO: 11 and at least It contains amino acid sequences that are 80%, at least 90%, or at least 95% identical, and The chain is at least 80%, at least 90%, or less than the amino acid sequence of SEQ ID NO: 21. The antibodies contain amino acid sequences that are at least 95% identical, and the antibodies are FXI and / or FXIa. For example, it specifically binds to humans, rabbits, cynomolgus monkeys, and baboons (FXIa). In the application form, the isolated antibody or its functional antigen-binding fragment contains a heavy chain and a light chain. Here, the heavy chain is at least 80% and at least 90% of the amino acid sequence of SEQ ID NO: 31. , or containing an amino acid sequence that is at least 95% identical, the light chain is the amino acid sequence of SEQ ID NO: 41 The ano acid sequence is at least 80%, at least 90%, or at least 95% identical to the a The antibody contains a amino acid sequence and is FXI and / or FXIa (e.g., human, rabbit, ka It specifically binds to carrion macaques and baboons (FXIa). In certain aspects of this disclosure, The heavy and light chain sequences are defined by Kabat as HCDR1, HCDR2, and HCD. R3, LCDR1, LCDR2, and LCDR3 sequences, for example, sequence number 3, Further including 4, 5, 13, 14, and 15. In certain other aspects of this disclosure, heavy chain The light chain sequences are defined by Chothia as HCDR1, HCDR2, and HCD. R3, LCDR1, LCDR2, and LCDR3 sequences, for example, sequence number 6, Further including 7, 8, 16, 17, and 18. In certain other embodiments, heavy chain and light chain. The chain sequences are defined by the combination system: HCDR1, HCDR2, HCDR3, LCDR 1, LCDR2, and LCDR3 sequences, for example, sequence numbers 46, 4, 5, and 33 respectively. , 14, and 15 further include. In certain other embodiments, the heavy chain and light chain sequences are I HCDR1, HCDR2, HCDR3, LCDR1, LCDR 2, and LCDR3 sequences, for example, arrays 43, 44, 45, 47, 37 respectively. and 15 further include.

[0124] Other embodiments for use in the methods described herein include full-length heavy chains and / or The full-length light chain nucleotide sequence is the sequence listed in Table 1 (for example, SEQ ID NO: 12 and / or (22, or 32 and / or 42) and 60%, 70%, 80%, 90%, 95%, They may be 96%, 97%, 98%, or 99% identical.

[0125] In other embodiments for use in the method described herein, the variable region of the heavy chain and / or the nucleotide sequence of the variable region of the light chain is one of the sequences listed in Table 1 (e.g., Sequence ID No. 1) 0 and / or 20, or 30 and / or 40) and 60%, 70%, 80%, 9 They may be 0%, 95%, 96%, 97%, 98%, or 99% identical. In other embodiments for use in pharmaceutical formulations, the variable region of the heavy chain and / or the variable region of the light chain. The nucleotide sequences are those listed in Table 1 (for example, sequence numbers 10 and / or 20, (30 and / or 40) and 60%, 70%, 80%, 90%, 95%, 96%, 9 They may be 7%, 98%, or 99% identical.

[0126] When used herein, the percentage identity between two sequences is the optimal value of the two sequences. Consider the number of gaps that need to be introduced for alignment and the length of each gap. It is a function of the number of identical positions shared by those arrays (i.e., %identity) (This is equal to the number of identical positions / total number of positions × 100). Array comparison and between two arrays The determination of percentage identity is done using a mathematical algorithm, as described in the non-restrictive example below. This can be achieved using M.

[0127] The isolated anti-FXI and / or FXIa antibodies or their antigenic binding described herein. Sex fragments include monoclonal antibodies, human or humanized antibodies, chimeric antibodies, single-chain antibodies, Fa b fragment, Fv fragment, F(ab')2 fragment, or scFv fragment, and / or IgG It may be an isotype (for example, 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 It is an IgG1 / lambda (λ) antibody. In certain embodiments, the anti-FXI described herein is And / or anti-FXIa antibodies have effector functions (e.g., ADCC and / or C Fc domains engineered to reduce the potential of DC, e.g., D265A and / or human IgG1 / lambda (λ) containing a human Fc domain including a P329A substitution It is an antibody.

[0128] In addition, or instead, for example, to identify relevant sequences, the present disclosure The protein sequence is then used as a "query sequence" to search public databases. Such a search can be carried out. For example, see Altschul, et al., 1990 J. M. The procedure was performed using the BLAST program (version 2.0) from ol. Biol. 215: 403-10. It is possible.

[0129] Antibodies with Conservative Modifications In certain other embodiments, the method described herein (for example, for a person suffering from a thromboembolic disorder) (Methods for dealing with objects that are currently doing so or are at risk of doing so) For use, the antibodies of this disclosure are heavy chain variable containing CDR1, CDR2, and CDR3 sequences. It has a region and a light chain variable region including the CDR1, CDR2, and CDR3 sequences, and here One or more of these CDR sequences are antibodies or their reservoirs as described herein. Having a specific amino acid sequence based on a prior modification, the antibody is an FXIa-binding antibody of the present disclosure. It retains the desired functional properties. In certain other embodiments, the formulations described herein (e.g.) For example, the antibodies of this disclosure for use in formulations in vials, intravenous drug delivery formulations, Heavy chain variable region including CDR1, CDR2, and CDR3 sequences, and CDR1, CDR 2, and a light chain variable region containing CDR3 sequences, where among these CDR sequences One or more of these are specific antibodies based on the antibodies or their conservative modifications described herein. Having a no-acid sequence, the antibody retains the desired functional properties of the FXIa-binding antibody of this disclosure.

[0130] Therefore, for use in the methods described herein, in some embodiments, this opening The diagram shows the heavy chain variable region containing the CDR1, CDR2, and CDR3 sequences, and CDR1, An isolated antibody or its anti- A primordial-binding fragment, the heavy chain variable region CDR1 amino acid sequence is such that of SEQ ID NOs. 3 and 23. A selection from the group consisting of both the heavy chain variable region CDR2 amino acid sequence and its conservative modifications is Selected from the group consisting of Sequence IDs 4 and 24, and their conservative modifications, heavy chain variable region The group consists of the CDR3 amino acid sequences of Sequence ID Nos. 5 and 25, and their conservative modifications. Selected from, the light chain variable region CDR1 amino acid sequence is sequence numbers 13 and 33, and From the group consisting of these conservative modifications, the amino acid sequence of the light chain variable region CDR2 is selected, Selected from the group consisting of numbers 14 and 34, and their conservative modifications, the light chain variable region The CDR3 amino acid sequence consists of Sequence ID Nos. 15 and 35, and their conservative modifications. Selected from, an antibody or its antigen-binding fragment specifically binds to FXIa, isolated The present invention provides an antibody or an antigen-binding fragment thereof.

[0131] For use in the formulations described herein, in some embodiments, this disclosure is CDR1, Heavy chain variable region including CDR2 and CDR3 sequences, and CDR1, CDR2, An isolated antibody or its antigen-binding fragment consisting of a light chain variable region containing the CDR3 sequence. The heavy chain variable region CDR1 amino acid sequence is represented in SEQ ID NOs. 3 and 23, and its conservation Selected from a group consisting of modifications, the heavy chain variable region CDR2 amino acid sequence is such that SEQ ID NO: 4 Selected from the group consisting of 24 and its conservative modifications, the heavy chain variable region CDR3 amino The acid sequence was selected from the group consisting of Sequence IDs 5 and 25, and their conservative modifications, The CDR1 amino acid sequence of the chain variable region is used in SEQ ID NOs: 13 and 33, and its conservation modification. Selected from the group consisting of, the light chain variable region CDR2 amino acid sequence is such that SEQ ID NOs. 14 and 3 4. Selected from the group consisting of these and their conservative modifications, the CDR3 amino acids in the light chain variable region. The sequence was selected from the group consisting of sequence numbers 15 and 35, and their conservative modifications, and The body or its antigen-binding fragment specifically binds to FXIa, isolated antibodies or so It provides antigen-binding fragments.

[0132] In one embodiment, the heavy chain variable region includes the CDR1, CDR2, and CDR3 sequences, and C An isolated antibody consisting of a light chain variable region containing DR1, CDR2, and CDR3 sequences, or The antigen-binding fragment is the heavy chain variable region CDR1 amino acid sequence, as shown in Table 1. Selected from the group consisting of those and their conservative modifications, the heavy chain variable region CDR2 ami The no-acid sequence is selected from the group consisting of those listed in Table 1 and their conservative modifications. The heavy chain variable region CDR3 amino acid sequences are those listed in Table 1, and their conserved sequences. Selected from the group consisting of modifications, the light chain variable region CDR1 amino acid sequence is as described in Table 1. Selected from the group consisting of those present and their conservative modifications, the light chain variable region CDR2 amino The acid sequences are selected from the group consisting of those listed in Table 1 and their conservative modifications. The CDR3 amino acid sequences of the light chain variable region are those listed in Table 1, and their conservation A group consisting of modifications is selected, wherein the antibody or its antigen-binding fragment specifically binds to FXIa. The present invention provides isolated antibodies or antigen-binding fragments thereof that can be combined.

[0133] In other embodiments for use in the methods described herein, the antibodies of this disclosure are used in milk It is optimized for expression in animal cells and contains both full-length heavy chain and full-length light chain sequences. Here, one or more of these sequences are antibodies or their conserved forms as described herein. Having a specific amino acid sequence based on the modification, the antibody is a desired FXIa-binding antibody of this disclosure. It retains the functional properties of the formulation described herein. The disclosed antibodies are optimized for expression in mammalian cells, and their full-length heavy chain sequences and It has a full-length light chain sequence, where one or more of these sequences are the anti- The antibody has a specific amino acid sequence based on the body or a conservative modification thereof, and the antibody is FXI of this disclosure. The desired functional properties of the α-binding antibody are preserved. Therefore, this disclosure relates to mammalian cells. An isolated antibody consisting of full-length heavy chains and full-length light chains, optimized for expression. The full-length heavy chain is selected from the group of sequence numbers 11 or 31 and their conservative modifications. Having an acid sequence, the full-length light chain is from the group consisting of SEQ ID NOs. 21 or 41, and their conservative modifications. The antibody has a selected amino acid sequence and is FXI and / or FXIa (e.g., human Isolated antibodies that specifically bind to rabbits, cynomolgus monkeys, and baboons (FXIa) provide.

[0134] The same epitope-binding antibody In some embodiments, this disclosure describes the methods described herein (for example, for thromboembolic disorders) Methods for treating subjects who are suffering from or at risk of developing the disease. For use, use the FXI and / or FXIa-binding antibodies listed in Table 1, and the same epitox. To provide a competing antibody for P. In some embodiments, this disclosure is described herein. Table 1 shows the following for use in pharmaceutical formulations (e.g., formulations in vials, intravenous drug delivery formulations). Antibodies that compete for the same epitopes as the listed FXI and / or FXIa-binding antibodies Therefore, additional antibodies are used in FXI and / or FXIa binding assays. Competing with other antibodies in this disclosure (for example, those described in the Examples section) (For example, by binding to the same or overlapping epitopes, the binding can be statistically significant.) Based on their ability to competitively inhibit, the test antibodies can be identified. Due to the ability of the disclosed antibody to inhibit the binding of FXI and / or FXIa proteins, The test antibody may compete with that antibody for binding to FXI and / or FXIa. This is demonstrated; such an antibody, according to a non-restrictive theory, is the same as the competing antibody. Or related (e.g., structurally similar or spatially proximal) FXI and / or It can bind to an epitope on the FXIa protein. In certain embodiments of this disclosure Antibodies that bind to the same epitopes on FXI and / or FXIa as the antibody are human monoclonal. This is a ronal antibody. Such a human monoclonal antibody is prepared as described herein. It can be done and isolated.

[0135] As used herein, "competing" for binding means that the competing antibody is equivalent to When present in molar concentration, a competing antibody is present in the antibody or antigen-binding fragment of this disclosure (e.g., antibody). 1) or antibody 2) binds to the same FXI and / or FXIa epitope as the present disclosure, and is an antibody of this disclosure. Binding of the body or antigen-binding fragment to FXI and / or FXIa greater than 50% This refers to cases where inhibition occurs by 80%, 85%, 90%, 95%, 98%, or 99%. This is determined, for example, by any method well known to those skilled in the art in a competitive binding assay. It can be determined.

[0136] When used herein, an antibody or its antigen-binding fragment is the same as the competing antibody or The antigen-binding fragment is the same FXI and / or F as the antibody or antigen-binding fragment of this disclosure. Binds to an XIa epitope, or to an overlapping FXI and / or FXIa epitope. Unless otherwise specified, the FXI and / or FXIa antibodies or antigen-binding fragments of this disclosure (e.g., anti- It does not "compete" with body 1 or antibody 2). When used herein, it does not compete with a competing antibody or The antigen-binding fragment (i) establishes the binding of the antibody or antigen-binding fragment of this disclosure to its target. A substance that blocks (for example, the competing antibody is a nearby non-overlapping FXI and / or Binds to the FXIa epitope and allows the antibody or antigen-binding fragment of this disclosure to bind to its target. (ii) if it physically obstructs; and / or (ii) different, non-overlapping FXI and / Alternatively, it binds to the FXIa epitope and controls the FXI and / or FXIa proteins. It induces a change in formation, and as a result, the FXI and / or other components of the present disclosure are used in the protein. Alternatively, if the FXIa antibody or antigen-binding fragment no longer undergoes the aforementioned conformational change This does not include anything that prevents combination, as would occur in certain cases.

[0137] Engineered and modified antibodies In some embodiments, for use in the methods described herein, the antibodies of this disclosure are Furthermore, having one or more of the VH and / or VL sequences shown herein The antibody is prepared using the modified antibody as a starting material for engineering manipulation. This is possible, and here, the modified antibody may have altered properties from the starting antibody. In the embodiments described herein, the antibodies of this disclosure are further described herein for use in the formulations described herein. An antibody having one or more of the VH and / or VL sequences shown in the details. Modified antibodies can be prepared using them as starting materials for engineering manipulation. Here, the modified antibody may have altered properties from the starting antibody. One of the variable regions Or both (i.e., within VH and / or VL), for example, one or more CDs. One or more remaining within the R domain and / or within one or more framework domains Antibodies can be engineered by modifying their base. In addition, or Instead, for example, to modify the effector function (one or more) of an antibody, By modifying residues within the constant region (one or more), antibodies can be engineered and manipulated. It is possible.

[0138] One type of engineering operation that can be performed within a variable domain is CDR grafting. Antibodies are transmitted through amino acid residues located in six heavy and light chain complementarity-determining regions (CDRs). It interacts predominantly with the target antigen. For this reason, the amino acid sequence within the CDR is individual The diversity among antibodies is greater than that of the sequences outside the CDR. The CDR sequence represents the majority of antibody-antigen relationships. Because they are involved in interactions, recombinant antibodies that mimic the properties of specific naturally occurring antibodies are expressed. This can result in different CDR sequences of that particular naturally occurring antibody having different properties. Construct an expression vector containing a grafted antibody-derived framework sequence. This is possible by (for example, Riechmann, L. et al., 1998 Nature 332: 32 3-327; Jones, P. et al., 1986 Nature 321: 522-525; Queen, C. et al ., 1989 Proc. Natl. Acad., USA 86: 10029-10033; US special treatment for winter Patent No. 5,225,539, and U.S. Patent No. 5,530,10 to Queen et al. No. 1; No. 5,585,089; No. 5,693,762 and No. 6,180,3 (See issue 70.)

[0139] Therefore, another embodiment of this disclosure is derived from the group consisting of Sequence ID Nos. 3 and 23, respectively. Selected amino acid sequence CDR1 sequence; selected from the group consisting of SEQ ID NOs: 4 and 24. Amino acid sequence CDR2 sequence; amino acid sequence selected from the group consisting of SEQ ID NOs. 5 and 25 A heavy chain variable region containing the column CDR3 sequence; and consisting of sequence numbers 13 and 33, respectively. amino acid sequence CDR1 sequence selected from the group; selected from the group consisting of SEQ ID NOs: 14 and 34 Selected amino acid sequence CDR2 sequence; and selected from the group consisting of SEQ ID NOs: 15 and 35. An isolated antibody containing a light chain variable region having a CDR3 sequence consisting of the amino acid sequence This relates to its antigen-binding fragment. Therefore, such an antibody is a monoclonal antibody. It contains VH and VL CDR sequences, but nevertheless, these antibodies are different It may contain a framework array.

[0140] Such framework sequences include public DNA sequences containing germline antibody gene sequences. It can be obtained from databases or publicly available references. For example, human heavy chain and The germline DNA sequences of the light chain variable region genes are from the "VBase" human germline DNA sequence. The column database, and the contents of each of them, are explicitly incorporated herein by reference. Kabat, EA, et al., 1991 Sequences of Proteins of Immunological Int. erest, Fifth Edition, US Department of Health and Human Services, NI H Publication No. 91-3242;Tomlinson, IM, et al., 1992 J. Mol. Bio l. 227: 776-798; and Cox, JPL et al., 1994 Eur. J Immunol. 24 This can be found in pages 827-836.

[0141] Examples of framework sequences for use in antibodies of this disclosure are provided for selected antibodies of this disclosure. Therefore, a framework array that is structurally similar to the one used, for example, the monoclear array of this disclosure Consensus sequences and / or framework sequences used by ronal antibodies Yes. The VH CDR1, 2, and 3 sequences, as well as the VL CDR1, 2, and 3 sequences, Although found in germline immunoglobulin genes from which the framework sequence originates, It can be graphed into a framework region having the same sequence as, or The CDR sequence is compared to the germline sequence and contains one or more mutations. It can be grafted onto the homework region. For example, in a particular case, an antibody The residues within the framework region are mutated so that the antigen-binding ability is maintained or enhanced. It has been found that this is beneficial (for example, the US patent against Queen et al.) Nos. 5,530,101; Nos. 5,585,089; Nos. 5,693,762 and See also Patent Nos. 6,180,370). Antibody and antigen binding cleavage described herein. This is not the only framework that can be used as a scaffolding for building a foundation. While not definitively defined, VH1A, VH1B, VH3, Vk1, Vk2, and Vk2 are examples. ru.

[0142] Therefore, another embodiment of the present disclosure for use in the method described herein is: An amino acid sequence selected from the group consisting of SEQ ID NOs: 9 and 29, or such a sequence Substitutions and deletions of one, two, three, four, or five amino acids within the framework region are also possible. It includes a heavy chain variable region containing an amino acid sequence having an addition, and SEQ ID NOs. 19 and 39 An amino acid sequence selected from the following group, or within the framework region of such a sequence Amino acids having one, two, three, four, or five amino acid substitutions, deletions, or additions. An isolated FXIa-conjugated antibody or the light chain variable region having a noacid sequence further comprising Regarding antigen-binding fragments.

[0143] Therefore, another embodiment of this disclosure for use in the formulations described herein is an array An amino acid sequence selected from the group consisting of numbers 9 and 29, or a fraction of such a sequence Substitutions, deletions, or other changes of one, two, three, four, or five amino acids within a hierarchical region. It includes a heavy chain variable region containing an amino acid sequence having additions, and from SEQ ID NOs. 19 and 39 an amino acid sequence selected from the group, or one within the framework region of such a sequence , amino acids having substitutions, deletions, or additions of two, three, four, or five amino acids An isolated FXIa-binding antibody or its antigen further comprising a light chain variable region having a sequence. Regarding binding fragments.

[0144] Another type of variable region modification is VH and / or VL CDR1, CDR2 and / or This involves mutating amino acid residues within the CDR3 region, thereby creating one of the target antibodies. This involves improving multiple binding properties (e.g., affinity), and this is called "affinity maturation". This is publicly known. Site-directed mutagenesis or PCR-mediated mutagenesis is performed. Mutations (one or more) can be introduced, and antibody binding properties or other functional properties for specific purposes can be enhanced. The effects on sex are described herein and presented in the Examples section in vitro or This can be evaluated in an in vivo assay. Conservative modifications (as described above) Mutations can be introduced. Mutations can be amino acid substitutions, additions, or deletions. Generally, this involves one or fewer, two or fewer, three or fewer, four or five residues within the CDR region. The following will be changed.

[0145] Therefore, in another embodiment for use in the method described herein, the disclosure is , an amino acid sequence selected from the group having SEQ ID NOs. 3 and 23 or SEQ ID NOs. 3 and Compared to 23, one, two, three, four, or five amino acid substitutions, deletions, or additions VH CDR1 region consisting of amino acid sequences; from the group consisting of SEQ ID NOs: 4 and 24 One, two, three, or four amino acids compared to the selected amino acid sequence or SEQ ID NOs: 4 and 24. Alternatively, VH CD having an amino acid sequence with five amino acid substitutions, deletions, or additions. R2 region; an amino acid sequence or sequence number selected from the group consisting of SEQ ID NOs. 5 and 25. Compared to numbers 5 and 25, there are one, two, three, four, or five amino acid substitutions or deletions. or a heavy chain variable region having a VH CDR3 region having an amino acid sequence with additions; sequence An amino acid sequence selected from the group consisting of numbers 13 and 33, or sequence number 13 and Compared to 33, one, two, three, four, or five amino acid substitutions, deletions, or additions A group consisting of VL CDR1 regions having the amino acid sequence; SEQ ID NOs: 14 and 34. The selected amino acid sequence, or one, two, or three compared to SEQ ID NOs. 14 and 34 VL having an amino acid sequence with four or five amino acid substitutions, deletions, or additions. CDR2 region; and amino acid sequences selected from the group consisting of SEQ ID NOs. 15 and 35. , or one, two, three, four or five amino acids compared to SEQ ID NOs. 15 and 35 A single VL CDR3 region having an amino acid sequence with acid substitution, deletion, or addition. The present invention provides a detached FXIa-binding antibody or its antigen-binding fragment.

[0146] Therefore, in another embodiment for use in the method described herein, the disclosure is , an amino acid sequence selected from the group having SEQ ID NOs. 6 and 26 or SEQ ID NOs. 6 and Compared to 26, one, two, three, four, or five amino acid substitutions, deletions, or additions VH CDR1 region consisting of amino acid sequences; from the group consisting of SEQ ID NOs: 7 and 27 One, two, three, or four amino acids compared to the selected amino acid sequence or SEQ ID NOs. 7 and 27. Alternatively, VH CD having an amino acid sequence with five amino acid substitutions, deletions, or additions. R2 region; an amino acid sequence or sequence number selected from the group consisting of SEQ ID NOs. 8 and 28. Compared to numbers 8 and 28, there are one, two, three, four, or five amino acid substitutions or deletions. or a heavy chain variable region having a VH CDR3 region having an amino acid sequence with additions; sequence An amino acid sequence selected from the group consisting of numbers 16 and 36, or sequence number 16 and Compared to 36, one, two, three, four, or five amino acid substitutions, deletions, or additions A group consisting of VL CDR1 regions having the amino acid sequence; SEQ ID NOs: 17 and 37. The amino acid sequence selected, or compared to SEQ ID NOs. 17 and 37, one, two, or three. VL having an amino acid sequence with four or five amino acid substitutions, deletions, or additions. CDR2 region; and amino acid sequences selected from the group consisting of SEQ ID NOs. 18 and 38. , or one, two, three, four or five amino acids compared to SEQ ID NOs. 18 and 38 A single VL CDR3 region having an amino acid sequence with acid substitution, deletion, or addition. The present invention provides a detached FXIa-binding antibody or its antigen-binding fragment.

[0147] Therefore, in another embodiment for use in the formulations described herein, this disclosure is distributed Amino acid sequences selected from the group having sequence numbers 3 and 23, or sequence numbers 3 and 23 Compared to [another molecule], it has one, two, three, four, or five amino acid substitutions, deletions, or additions. A VH CDR1 region consisting of the amino acid sequence; selected from the group consisting of SEQ ID NOs: 4 and 24. The amino acid sequence is compared to one, two, three, or four of the sequences in sequence numbers 4 and 24. VH CDR2 has an amino acid sequence with five amino acid substitutions, deletions, or additions. Region; an amino acid sequence selected from the group consisting of SEQ ID NOs. 5 and 25, or SEQ ID NO. 5 and substitutions, deletions, or Heavy chain variable region having a VH CDR3 region with an added amino acid sequence; SEQ ID NO: An amino acid sequence selected from the group consisting of 13 and 33, or SEQ ID NOs: 13 and 33 Compared to [another molecule], it has one, two, three, four, or five amino acid substitutions, deletions, or additions. VL CDR1 region having the amino acid sequence; selected from the group consisting of SEQ ID NOs: 14 and 34 The selected amino acid sequence, or one, two, three, or four amino acids compared to SEQ ID NOs. 14 and 34. VL C has an amino acid sequence with one or five amino acid substitutions, deletions, or additions. DR2 region; and an amino acid sequence selected from the group consisting of SEQ ID NOs. 15 and 35, Or, compared to SEQ ID NOs. 15 and 35, one, two, three, four, or five amino acids Isolated VL CDR3 regions having amino acid sequences with substitutions, deletions, or additions. This invention provides an FXIa-binding antibody or its antigen-binding fragment.

[0148] Therefore, in another embodiment for use in the formulations described herein, this disclosure is distributed Amino acid sequences selected from the group having sequence numbers 6 and 26, or sequence numbers 6 and 26 Compared to [another molecule], it has one, two, three, four, or five amino acid substitutions, deletions, or additions. A VH CDR1 region consisting of the amino acid sequence; selected from the group consisting of SEQ ID NOs: 7 and 27. The amino acid sequence is compared to one, two, three, or four of the sequences in sequence numbers 7 and 27. VH CDR2 has an amino acid sequence with five amino acid substitutions, deletions, or additions. Region; an amino acid sequence selected from the group consisting of SEQ ID NOs: 8 and 28, or SEQ ID NO: 8 and 28, with the substitution, deletion or Heavy chain variable region having a VH CDR3 region with an added amino acid sequence; SEQ ID NO: An amino acid sequence selected from the group consisting of 16 and 36, or SEQ ID NOs. 16 and 36 Compared to [another molecule], it has one, two, three, four, or five amino acid substitutions, deletions, or additions. VL CDR1 regions having the amino acid sequence; selected from the group consisting of SEQ ID NOs: 17 and 37 The selected amino acid sequence, or one, two, three, or four amino acids compared to SEQ ID NOs. 17 and 37. VL C has an amino acid sequence with one or five amino acid substitutions, deletions, or additions. DR2 region; and an amino acid sequence selected from the group consisting of SEQ ID NOs: 18 and 38, Or, compared to SEQ ID NOs. 18 and 38, one, two, three, four, or five amino acids Isolated VL CDR3 regions having amino acid sequences with substitutions, deletions, or additions. This invention provides an FXIa-binding antibody or its antigen-binding fragment.

[0149] Antibodies with extended half-lives In some embodiments, this disclosure is intended for use in the method or formulation described herein. It specifically binds to the FXIa protein, which has an extended half-life in vivo. We provide antibodies.

[0150] Many factors can influence the half-life of a protein in vivo. For example... For example, renal filtration, metabolism in the liver, breakdown by proteases, and immunogenic responses (e.g., antibody-mediated protein neutralization and macrophages and trees) (Uptake by cellular cells). The half-life of the antibodies of this disclosure can be extended using various strategies. Yes, it is possible. For example, polyethylene glycol (PEG), reCODE PEG, antibody scaffolds. Polysialic acid (PSA), hydroxyethyl starch (HES), albumin-binding lycophosphate By chemical linkage with Gand and carbohydrate shields; serum proteins such as albumin By gene fusion and transfer with proteins that bind to blood, such as IgG and FcRn; Other binding sites that bind to clean proteins, e.g., nanobodies, Fab, DARPin, Coupling with avimer, aphibody, and antikalin, etc. (genetically or Chemically; rPEG, albumin, albumin domain, albumin binding By gene fusion with proteins and Fc; or by nanocarriers, slow-release formulations, or By incorporating it into medical devices.

[0151] To prolong the in vivo serum circulation of antibodies, high molecular weight PEGs and other materials are used. Active polymer molecules are added to antibodies or fragments thereof, with or without a multifunctional linker. This is done through site-specific conjugation of PEG to the N-terminus or C-terminus of the antibody. , or by attachment via the epsilon-amino group present in the lysine residue. This can be done. In order to pegyrate an antibody, generally the antibody or a fragment thereof and the reactivity of PEG are used. Polyethylene glycol (PEG), such as an ester or aldehyde derivative, is used in a single or This involves reacting the antibody or antibody fragment under conditions in which multiple PEG groups are attached. Pegylation is a reaction. Acylation or alkylation reaction with a PEG molecule (or a similar reactive water-soluble polymer) This can be carried out by reaction. When used herein, "polyethylene glycol" The term "mono(C1~C10)alkoxy- or aryloxy-polyethylene" Induces other proteins such as polyethylene glycol or polyethylene glycol-maleimide. It is intended to include any form of PEG used for emulation. In certain embodiments, the antibody to be pegylated is an antibody that has not been glycosylated. Use linear or branched polymer derivatization that minimizes loss of physical activity. The process is closely monitored using SDS-PAGE and mass spectrometry to determine the PEG molecule's properties. This ensures proper conjugation of the antibody. Unreacted PEG can be used with the antibody. Separation from PEG conjugates by size exclusion or ion exchange chromatography It is possible to derivatize antibodies with PEG, and in terms of binding activity, as well as in Regarding the efficacy in vivo, using methods well known to those skilled in the art, for example, as described herein It can be tested by the immunoassay described. Method for pegyrating proteins. The law is publicly known in the art and can be applied to the antibodies of this disclosure. For example, Nishimur EP 0 154 316 by a et al. and EP 0 4 by Ishikawa et al. Please refer to 01 384.

[0152] Other modified pegylation techniques include adding chemically specified side chains to biosynthetic proteins. Reconstitution chemicals are incorporated via a reconstituted system containing RNA polymerase and tRNA. One example is the orthogonal directional operation technique (ReCODE PEG). This technique allows Ec Oli, yeast, and mammalian cells biosynthesize more than 30 new amino acids. It becomes possible to incorporate them into proteins. tRNA allows non-native amino acids to be incorporated. The amber codon is incorporated into any position where it is located, and the amber is a terminal codon. The signal is converted from a chemically specified amino acid into a codon that signals the incorporation of that amino acid.

[0153] Recombinant pegylation technology (rPEG) can also be used to extend the serum half-life. The procedure involves modifying the unstructured protein tail of 300-600 amino acids with existing pharmaceutical proteins. This involves fusion with proteins and genes. The appearance of such unstructured protein chains. Since its molecular weight is approximately 15 times its actual molecular weight, the serum half-life of the protein is significantly increased. In contrast to conventional PEGylation, which requires chemical conjugation and repurification, The manufacturing process is significantly simplified, and the product is homogeneous.

[0154] Another technique is polysial oxidation, which uses the natural polymer polysialic acid (PSA). It is used to extend the activity lifespan and improve the stability of therapeutic peptides and proteins. Therefore, PSA is a polymer of sialic acid (sugar). Proteins and therapeutic peptides When used for drug delivery, polysialic acid provides protection to the conjugation. This creates a microenvironment, which increases the active lifespan of therapeutic proteins in circulation. Furthermore, the immune system's recognition of therapeutic proteins is prevented. PSA polymers are used in the human body. It is found naturally within the body. PSA polymers have evolved over millions of years in certain bacteria. It was used to coat the wall. As a result, these naturally polysial oxidized These bacteria, through molecular mimicry, were able to reinforce the body's defense system. PSA, a TELLS technology, uses such bacteria to impart specific physical characteristics to a large quantity of bacteria. It can be easily produced. Bacterial PSA is chemically identical to PSA in the human body. Therefore, even when coupled with a protein, it remains completely non-immunogenic.

[0155] Another technique involves using a hydroxyethyl starch ("HES") derivative linked to an antibody. Uses include: HES is a modified natural polymer derived from waxy corn starch. It is a substance that can be metabolized by enzymes in the body. HES solution usually replenishes the deficient blood volume. It is administered to fill the blood and improve its hydrodynamic properties. By HES conversion of antibodies, molecules By increasing the stability of the circulatory system and by reducing renal clearance, the circulatory system is improved. This allows for extending the ring half-life, which in turn leads to increased biological activity. (HES) By varying various parameters such as molecular weight, a wide range of HES antibody conjugates can be created. The gate can be customized.

[0156] Antibodies with an increased half-life in vivo have an IgG constant domain or its Fc One or more A It can also be produced by introducing mino acid modifications (i.e., substitution, insertion, or deletion). For example For example, International Publication No. WO98 / 23289; International Publication No. WO97 / 34631; and US Please refer to Japanese Patent No. 6,277,375.

[0157] Furthermore, the antibody is conjugated with albumin (e.g., human serum albumin; HSA). Therefore, it is more stable in vivo or has a longer half-life in vivo. This technique can produce longer antibodies or antibody fragments. This technique is well known in the art. For example, International Patent Publication No. WO93 / 15199, WO93 / 15200, and See also WO01 / 77137 and European Patent Publication EP 413,622. Please do so. Furthermore, regarding the bispecific antibodies mentioned above, the specificity of the antibody is determined by one of the antibodies' properties. The binding domain binds to FXIa, while the antibody's second binding domain binds to serum albumin. Preferably, it can be designed to bond to an HSA.

[0158] Strategies to increase half-life include nanobodies, fibronectin-based binding agents, And for other antibodies or proteins for which an increase in half-life in vivo is desired. It is especially useful.

[0159] Antibody conjugate In some embodiments, this disclosure is intended for use in the method or formulation described herein. An antibody or fragment thereof that specifically binds to the FXIa protein, and which is a heterologous protein Quality or polypeptide (or fragments thereof, preferably at least 10, at least 20) At least 30, at least 40, at least 50, at least 60, at least 70, (Polypeptides of at least 80, at least 90, or at least 100 amino acids) They fused by exchange or chemically conjugated (covalent conjugates) It generates fusion proteins (including both conjugations and non-covalent conjugations). This disclosure provides an antibody or a fragment thereof. In particular, this disclosure provides an antigenic fragment of the antibody described herein. Compatibility fragments (e.g., Fab fragment, Fd fragment, Fv fragment, F(ab)2 fragment, VH domain) (VH CDR, VL domain or VL CDR), and heterologous proteins, polypeptides The invention provides a fusion protein containing a protein, polypeptide, or peptide. The method for fusing or conjugating peptides with antibodies or antibody fragments is described in this technology. It is publicly known in the field. For example, U.S. Patent No. 5,336,603 and No. 5,622,929. , No. 5,359,046, No. 5,349,053, No. 5,447,851, and Patent No. 5,112,946; European Patent Nos. EP307,434 and EP36 Publication No. 7,166; International Publication Nos. 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., 19 See 92, Proc. Natl. Acad. Sci. USA 89: 11337–11341.

[0160] Additional fusion proteins are used for gene shuffling, motif shuffling, and exotherapy. DNA shuffling, and / or codon shuffling (collectively referred to as "DNA shuffling") It can be generated using a technique called "DNA shuffling". This can change the activity of the antibody or fragment thereof (for example, if affinity is Antibodies or fragments with higher dissociation rates (or lower dissociation rates). Generally, U.S. Patent No. 5,605 No. 793, No. 5,811,238, No. 5,830,721, No. 5,834,2 Patent No. 52, and Nos. 5,837,458; Patent 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 See Blasco, 1998, Biotechniques 24 (2): 308-313 (these patents and (and publications are incorporated by reference in their entirety.) Antibodies or their cleavage Before recombination, the antibody or fragments to be encoded are subjected to error-prone PCR. By subjecting it to random nucleotide insertion or other methods of random mutagenesis It can be changed to: an antibody or fragment that specifically binds to the FXIa protein. A polynucleotide encoding one or more components of one or more heterologous molecules, Motifs, sections, parts, domains, fragments, etc., can be rearranged.

[0161] Furthermore, to facilitate purification, the antibody or its fragments are treated as marker sequences such as peptides. It can be fused with. In certain embodiments, the marker amino acid sequence is, among other things pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Ch) Hexa-histidine peptides such as tags provided by Atsworth, CA, 91311. This is tide (SEQ ID NO: 48), and most of it is commercially available. Gentz ​​et al., 1989, Pr As described in oc. Natl. Acad. Sci. USA 86: 821-824, for example, hexa- Histidine (SEQ ID NO: 48) allows for the convenient purification of the fusion protein. Other peptide tags useful for purification include, but are not limited to, influenza Egg agglutinin ("HA") tags corresponding to epitopes derived from hemagglutinin protein. (Wilson et al., 1984, Cell 37: 767), and the "flag" tag are cited as examples. .

[0162] In other embodiments, the antibody or fragment thereof is used as a diagnostic or detectable active substance. Conjugate. Such antibodies are involved in the onset, development, progression and / or Or, the severity, for example, part of the clinical trial procedure, such as determining the effectiveness of a particular treatment. It may be useful for monitoring or prognosis. Such diagnosis and testing The source is antibodies, but not limited to these, various enzymes, for example, not limited to these. Horseradish sprouts contain horseradish peroxidase, alkaline phosphatase, and beta-galactosidase. , or acetylcholinesterase, etc.; prosthetic group, for example, not limited to this. However, streptavidin / biotin and avidin / biotin, etc.; fluorescent materials, for example. However, this is not limited to these, but also includes umbelliferone, fluorescein, and fluorescein iso. Isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein Ceine, dansilloride, or phycoerythrin, etc.; luminescent materials, for example, only Examples include, but are not limited to, luminol; bioluminescent materials, for example, but are not limited to, Luciferase, luciferin, and aequorin, etc.; radioactive materials, for example, just this While not limited to these, iodine (131I, 125I, 123I, and 121I), carbon (14C), sulfur (35S), tritium (3H), indium (115In, 113I) n, 112In, and 111In), technetium (99Tc), thallium (201 Ti), gallium (68Ga, 67Ga), palladium (103Pd), molybdenum (9 9Mo), xenon (133Xe), fluorine (18F), 153Sm, 177Lu, 15 9Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y, 47Sc, 186 Re, 188Re, 142Pr, 105Rh, 97Ru, 68Ge, 57Co, 65Zn , 85Sr, 32P, 153Gd, 169Yb, 51Cr, 54Mn, 75Se, 113 Sn and 117Tin, etc.; positron-emitting materials used in various positron emission tomography techniques. It couples with detectable substances, including metals and non-radioactive paramagnetic metal ions. This can be achieved by [method].

[0163] In some embodiments, this disclosure relates to an antibody or fragment conjugated with a therapeutic moiety. This further includes the use of antibodies or fragments thereof as cytotoxic agents, for example, cell proliferation inhibitors. These are cell-destroying agents, therapeutic agents, or radioactive metal ions, such as alpha-emitters. It can be conjugated with the therapeutic portion. Cytotoxic or cytotoxic agents affect cells. Contains any harmful active ingredients.

[0164] Furthermore, antibodies or fragments thereof are used as therapeutic components or drugs to modify a given biological response. It can be conjugated with the substance part. The therapeutic or drug part is classically chemical. It is not interpreted as being limited to therapeutic agents. For example, the drug portion has the desired biological activity. It may be a protein, peptide, or polypeptide. Such a protein is, for example, For example, toxins, such as abrin, lysine A, Pseudomonas exotoxin, cholera toxin, or These include diphtheria toxin; proteins, such as tumor necrosis factor, α-interferon, β - Interferon, nerve growth factor, platelet-derived growth factor, tissue plasminogen acti Beta-agonists, apoptotic agents, anti-angiogenic agents, etc.; or biological reaction modifiers. This could include, for example, lymphokines.

[0165] Furthermore, antibodies, though not limited to these, include 131In, 131LU, 131Y, and 1 Conjugates radioactive metal ions, including 31Ho and 131Sm, to polypeptides. Radioactive metal ions such as alpha-emitters, e.g., 213Bi or large rings It can be conjugated with a chelating agent therapeutic portion. In a particular embodiment, Macrocyclic chelating agents can be attached to antibodies via linker molecules 1,4,7, 10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) Yes, such linker molecules are generally known in the art, and each whole This is incorporated by reference, Denardo et al., 1998, Clin Cancer Res. 4 (10): 2483-90; Peterson et al., 1999, Bioconjug. Chem. 10 (4): 553-7; approximately This is described in Zimmerman et al., 1999, Nucl. Med. Biol. 26 (8): 943-50. ru.

[0166] Techniques for conjugating therapeutic molecules with antibodies are well known. For example, Arnon et al. l., “Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Ther apy”, in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (e ds.), pp. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., “Antibo dies For Drug Delivery”, in Controlled Drug Delivery (2nd Ed.), Robin son et al. (eds.), pp. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, “ Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review”, i n Monoclonal Antibodies 84: Biological And Clinical Applications, Pinch era et al. (eds.), pp. 475-506 (1985); “Analysis, Results, And Futur e Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cance r 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. See also

[0167] Antibodies can also be attached to a solid support, which can be used for immunoassays of target antigens or It is particularly useful for purification. Such solid supports are not limited to these, but include gas Lath, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride, Polypropylene is one example.

[0168] Pharmaceutical preparations In some embodiments, this disclosure relates to a therapeutically effective amount of Factor XI and the information disclosed herein. / Also providing a pharmaceutical formulation containing a factor XIa antibody (e.g., antibody 1). The pharmaceutical formulation is , comprising one or more excipients and maintained at a specific pH. Used herein In some cases, a non-limiting example of an "excipient" is a desired physical or chemical property, for example, pH, volumetric osmolality, viscosity, transparency, color, isotonicity, odor, sterility, stability, solubility or any non-therapeutic agent added to the formulation to cause release rate, adsorption, or permeation It can be listed.

[0169] drug substance Antibody 1 is a high-affinity anti-human factor XI monoclonal antibody. This is a Chinese antibody. It is expressed in the hamster ovary cell line (CHO-C8TD). In some embodiments, The antibody 1 active ingredient is fully formulated for subcutaneous administration (i.e., no further excipients are required). (Not added), therefore, it has the same composition as antibody 1 drug. In some embodiments, static For intravenous administration, the antibody drug is further diluted in a suitable carrier. In some embodiments, the antibody 1. Dilute the drug in a glucose-containing solution, for example, 5% glucose in water (D5W).

[0170] Excipients and pH In some embodiments, the excipients contained in the antibody drug are pharmacopoeia-grade excipients. In some embodiments, the excipients in the antibody drug are histidine, histidine salts, sugars, etc. It also contains polysorbate. In some embodiments, the excipient in the antibody drug is L-hist Din and L-histidine hydrochloride monohydrate (histidine buffer), sucrose, and por Contains Resorbate 20. Excipients were selected with regard to suitability for intravenous and subcutaneous administration. This can provide the necessary stabilization, buffering capacity, and tensile strength. The formulation is monoclonal To maximize the stability of antibody products and provide sterile solutions for subcutaneous or intravenous administration. This can be achieved. In some embodiments, sugars (e.g., sucrose) are used as stabilizers. In some embodiments, histidine (e.g., L-histidine, L-histidine H) is used. Cl monohydrate acts as a buffer. In some embodiments, polysorbate (e.g., Polysorbate 20) acts as a stabilizer. In some embodiments, the formulation is used in water for injection. The final volume is adjusted using (WFI).

[0171] The pharmaceutical formulation of the present invention contains one or more excipients, including a buffering agent. As used herein, the term refers to the addition of an acid or alkali when added to an aqueous solution. When used, or when diluted with a solvent, it can protect the solution from pH fluctuations. This refers to multiple components. In addition to phosphate buffering agents, it includes glycine, carbonic acid, citric acid, and histidine. Buffering agents can be used, in which case sodium, potassium, or ammonium may be used. Ions can function as counterions.

[0172] In certain embodiments, the buffer or buffer system is completely within the pH range of 5.0 to 7.4. or comprising at least one buffer having a partially overlapping buffer range. In the application configuration, the pH of the buffer is approximately 5.5 ± 0.5. In a particular embodiment, buffer The agent contains a histidine buffer. In a particular embodiment, the histidine buffer is 0.05 ~10mM, 0.1~10mM, 0.2~10mM, 0.5~10mM, 1~10mM, 5~10mM, 5~100mM, 10~100mM, 15~100mM, 20~100m M, 30~100mM, 40~100mM, 50~100mM, 60~100mM, 70 ~100mM, 80~100mM, 90~100mM, 5~90mM, 5~80mM, 5 ~70mM, 5~60mM, 5~50mM, 5~40mM, 5~30mM, 5~20mM , 10~50mM, 10~40mM, 10~30mM, 10~20mM, 5~25mM, 10-25 mM, 15-25 mM, 20-25 mM, 5-20 mM, 10-20 mM, It is present at a concentration of 15-20 mM. In certain embodiments, histidine is present at approximately 0 mM. 1mM, 0.2mM, 0.5mM, 1mM, 5mM, about 10mM, about 15mM, about 20m It is present at concentrations of M, approximately 25 mM, or approximately 50 mM. In certain embodiments, hist The din buffer is present at a concentration of approximately 20 mM. In certain embodiments, histidine buffer is used. The agent is present at a concentration of approximately 0.20 mM. In certain embodiments, the histidine buffer is The pH is approximately 5.0, 5.5, 6.0, 6.5, or 7.0. Specific implementation Morphologically, the pH of the histidine buffer is approximately 5.5.

[0173] The pharmaceutical formulation of the present invention may have a pH of 5.0 to 6.0. For example, in a certain embodiment So, what is the pH of pharmaceutical preparations? 5.0-6.0 (i.e., 5.5 ± 0.5), 5.1-5. 9 (i.e., 5.5 ± 0.4), 5.2~5.8 (i.e., 5.5 ± 0.3), 5. 3-5.7 (i.e., 5.5 ± 0.2), 5.4-5.6 (i.e., 5.5 ± 0.1) ), or 5.45 to 5.55 (i.e., 5.5 ± 0.05). A particular implementation In terms of form, the pH of pharmaceutical formulations is approximately 5.5, 5.6, 5.7, 5.8, 5.9, and It is 6.0, approximately 6.1, approximately 6.2, approximately 6.3, approximately 6.4, or approximately 6.5. In this embodiment, the pH of the pharmaceutical formulation is approximately 5.5. Under the rules of scientific rounding, 5. p is greater than or equal to 45 and less than or equal to 5.55 H is rounded up to 5.5.

[0174] In a particular embodiment, the buffering system of the pharmaceutical formulation is 10-30 mM, pH 5.5 ± 0.2 It contains histidine. In certain embodiments, the buffer system of the pharmaceutical formulation is approximately 20 mM, pH It contains 5.5 ± 0.2 histidine. In a particular embodiment, the buffering system of the pharmaceutical formulation is 1 It contains histidine at 0-30 mM and pH 5.5 ± 0.05. In certain embodiments, The buffer system of the drug formulation contains histidine at approximately 20 mM and pH 5.5 ± 0.05.

[0175] In a particular embodiment, the buffering system of the pharmaceutical formulation is 0.10-0.30 mM, pH 5.5 It contains ±0.2 histidine. In certain embodiments, the buffering system of the pharmaceutical formulation is about 0.2 It contains histidine at 0 mM, pH 5.5 ± 0.2. In certain embodiments, the pharmaceutical formulation The buffer system contains histidine at 0.10–0.30 mM and pH 5.5 ± 0.05. In a specific embodiment, the buffer system of the pharmaceutical formulation is approximately 0.20 mM, pH 5.5 ± 0.05. Contains thidine.

[0176] One or more excipients in the pharmaceutical formulation of the present invention further comprise a sugar or a sugar alcohol. Sugars and sugar alcohols are useful as heat stabilizers in pharmaceutical formulations. In terms of application form, pharmaceutical preparations contain sugars, such as monosaccharides (glucose, xylose, or erythritol). (Thor), disaccharides (e.g., sucrose, trehalose, maltose, or galactose) ), or oligosaccharides (e.g., stachyose). In certain embodiments, the pharmaceutical formulation is , containing sucrose. In certain embodiments, the pharmaceutical composition includes sugar alcohols, for example, Sugar alcohols derived from monosaccharides (e.g., mannitol, sorbitol, or xylitol) ), disaccharide-derived sugar alcohols (e.g., lactitol or maltitol), or It contains a sugar alcohol derived from a ligose. In certain embodiments, the pharmaceutical formulation contains sucrose. .

[0177] The amount of sugar or sugar alcohol contained in the formulation depends on the specific circumstances under which the formulation is used and the intention behind its use. It may vary depending on the illustrated purpose. In a particular embodiment, the pharmaceutical formulation is 50 to 300 mM, 50~250mM, 100~300mM, 100~250mM, 150~300m M, 150-250mM, 200-300mM, 200-250mM, or 250-3 Contains 00 mM sugar or sugar alcohol. In certain embodiments, the pharmaceutical formulation contains about 50 mM mM, approx. 75mM, approx. 100mM, approx. 125mM, approx. 150mM, approx. 200mM, approx. 22 Contains 0 mM, approximately 250 mM, or approximately 300 mM of sugar or sugar alcohol. Specific implementation In terms of form, the pharmaceutical preparation contains approximately 220 mM of sugar or sugar alcohol (e.g., sucrose). include.

[0178] The amount of sugar or sugar alcohol contained in the formulation depends on the specific circumstances under which the formulation is used and the intention behind its use. It may vary depending on the illustrated purpose. In a particular embodiment, the pharmaceutical formulation is 0.50 to 3 .00mM, 0.50~2.50mM, 1.00~3.00mM, 1.00~2.50m M, 1.50~3.00mM, 1.50~2.50mM, 2.00~3.00mM, 2. Contains 0.00-2.50 mM or 2.50-3.00 mM of sugar or sugar alcohol. In a particular embodiment, the pharmaceutical formulation is approximately 0.50 mM, approximately 0.75 mM, and approximately 1.00 mM. , about 1.25mM, about 1.50mM, about 2.00mM, about 2.20mM, about 2.50mM , or containing about 3.00 mM of sugar or sugar alcohol. In certain embodiments, a pharmaceutical formulation. It contains approximately 2.20 mM of sugar or sugar alcohol (e.g., sucrose).

[0179] One or more excipients in the pharmaceutical formulations disclosed herein are surfactants further Includes. The term "surfactant" as used herein refers to the hydrophobic portion (e.g., Both the alkyl chain and the hydrophilic moiety (e.g., carboxyl and carboxylate groups) This refers to a surface-active molecule containing [a certain substance]. Surface-active substances are used in pharmaceutical formulations to enhance therapeutic proteins. It is useful for reducing aggregation. Surfactants suitable for use in pharmaceutical formulations are generally non Ionic surfactants, and not limited to these, but also polysorbates (for example, poly Solvate 20 or 80); poloxamer (e.g., poloxamer 188); sorbita Esters and derivatives; Triton®; sodium lauryl sulfate; octane Sodium lauryl glycosides; lauryl-, myristyl-, linoleyl-, or stearyl- Sulfobetadine; lauryl-, myristyl-, linoleyl- or ste Allyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauramycin Dopropyl-cocamidopropyl-,linoleamidopropyl-,myristamidopropyl- , palmidopropyl-, or isostearamidopropyl betaine (e.g., lauroami Dopropyl; myristamidopropyl-, palmidopropyl-, or isostearamide Propyldimethylamine; sodium cocoyl methyl taurate, or oleyl methyl Disodium taurine; and the MONAQUAT® series (Mona Ind Merctories, Inc., Paterson, NJ), polyethylene glycol, Polypropyl glycol, and copolymers of ethylene and propylene glycol (for example, Examples include Pluronics, PF68, etc. In certain embodiments, surfactant The substance is polysorbate. In certain embodiments, the surfactant is polysorbate. It is 20.

[0180] The amount of nonionic surfactant contained in the pharmaceutical formulation of the present invention determines the desired specific properties of the formulation. Furthermore, it may vary depending on the specific circumstances and purposes in which the formulation is intended to be used. In certain embodiments, the pharmaceutical formulation is 0.02%~0.06%, 0.03%~0.0 5%, or 0.035% to 0.045% of nonionic surfactants (e.g., polysorbate) (20) is included. In a particular embodiment, the pharmaceutical formulation is about 0.005%, about 0.01 %, approximately 0.02%, approximately 0.03%, approximately 0.04%, approximately 0.05%, approximately 0.06%, approximately 0. 0.7%, approximately 0.08%, approximately 0.09%, or approximately 0.1% nonionic surfactant (for example) For example, it contains polysorbate (20%).

[0181] The amount of nonionic surfactant contained in the pharmaceutical formulation of the present invention determines the desired specific properties of the formulation. Furthermore, it may vary depending on the specific circumstances and purposes in which the formulation is intended to be used. In certain embodiments, the pharmaceutical formulation is 0.0002% to 0.0006%, 0.000 Nonionic surfactants in concentrations of 3% to 0.0005%, or 0.00035% to 0.00045% It contains a substance (e.g., polysorbate 20). In certain embodiments, the pharmaceutical formulation is about 0.00005%, approximately 0.0001%, approximately 0.0002%, approximately 0.0003%, approximately 0.0 0.004%, approximately 0.0005%, approximately 0.0006%, approximately 0.0007%, approximately 0.0008% Approximately 0.0009%, or approximately 0.001%, of nonionic surfactants (e.g., polysol) Includes Beethoven's 20th Symphony.

[0182] In certain embodiments, the drug is placed in an aqueous carrier suitable for a route of administration, such as intravenous administration. Dilute. Examples of carriers include sterile water for injection (SWFI) and bacteriostatic water for injection (BWFI). ), pH buffer (e.g., phosphate buffer), sterile saline solution, Ringer's solution, or A glucose solution is one example. In one embodiment, when preparing a pharmaceutical preparation for intravenous administration, Pharmaceutical preparations can be diluted in a 5% glucose solution (D5W).

[0183] Exemplary formulations In certain embodiments, the pharmaceutical formulation of the present invention contains factor XI and / or factor XIa. Progenitor antibodies (e.g., heavy chain variable domain having the amino acid sequence of SEQ ID NO: 9 or 29 (VH) ), and a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39 Antibodies), histidine buffer, sugar or sugar alcohol (e.g., sucrose), It contains polysorbate (e.g., polysorbate 20) and has a pH of 5.5 to 6.5. .

[0184] In a particular embodiment, the pharmaceutical formulation contains 100-200 mg / mL of factor XI and / or Factor XIa antibody (e.g., heavy chain having the amino acid sequence of SEQ ID NO: 9 or 29) Variable light chain having a variable domain (VH) and the amino acid sequence of SEQ ID NO: 19 or 39. Antibodies with a domain (VL), 10-30 mM histidine buffer, 200-300 mM of sugar or sugar alcohol (e.g., sucrose), and 0.02% to 0.06% It contains polysorbate (e.g., polysorbate 20) and has a pH of 5.0-6.0. In certain embodiments, the pharmaceutical formulation contains 100-200 mg / mL of factor XI and / or or Factor XIa antibody (for example, a heavy chain variable having the amino acid sequence of SEQ ID NO: 9 or 29) Domain (VH) and light chain variable domain having the amino acid sequence of SEQ ID NO: 19 or 39 Antibody containing (VL), approximately 20 mM histidine buffer, approximately 220 mM sugar or Sugar alcohols (e.g., sucrose), as well as about 0.04% polysorbate (e.g., It contains polysorbate (20) and has a pH of 5.0 to 6.0. In a particular embodiment, The pharmaceutical formulation contains factor XI and / or factor XIa antibodies at a concentration of 100-200 mg / mL. Approximately 20 mM histidine buffer, approximately 220 mM sugar or sugar alcohol (e.g., sucrose It contains (a), as well as approximately 0.04% polysorbate (e.g., polysorbate 20). The pH is 5.2 to 5.8. In a particular embodiment, the pharmaceutical formulation is 100 to 200 ml g / mL factor XI and / or factor XIa antibody (e.g., SEQ ID NO: 9 or 29) A heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 19 or 39 Antibodies containing a light chain variable domain (VL) with a minoic acid sequence, and approximately 20 mM histidine. A buffer, approximately 220 mM sugar or sugar alcohol (e.g., sucrose), and approximately 0. Contains 0.4% polysorbate (e.g., polysorbate 20) and has a pH of 5.45-5.5 The answer is 5.

[0185] In a particular embodiment, the pharmaceutical formulation contains 1.00 to 2.00 mg / mL of factor XI. and / or Factor XIa antibody (for example, having the amino acid sequence of SEQ ID NO: 9 or 29) A light chain having a heavy chain variable domain (VH) and the amino acid sequence of SEQ ID NO: 19 or 39. Antibodies with variable domains (VL), 0.10-0.30 mM histidine buffer, 2 0.00-3.00 mM sugar or sugar alcohol (e.g., sucrose), and 0.00 Contains 0.2% to 0.0006% polysorbate (e.g., polysorbate 20), pH The range is 5.0 to 6.0. In a particular embodiment, the pharmaceutical formulation is 1.00 to 2.00 mg Factor XI and / or Factor XIa antibody (e.g., SEQ ID NO: 9 or 29) / mL A heavy chain variable domain (VH) having an amino acid sequence, and the amino acid sequence of SEQ ID NO: 19 or 39. Antibodies containing a light chain variable domain (VL) with an acid sequence, approximately 0.20 mM histidine A buffering agent, approximately 2.20 mM sugar or sugar alcohol (e.g., sucrose), and approximately Contains 0.0004% polysorbate (e.g., polysorbate 20) and has a pH of 5.0~ 6.0. In a particular embodiment, the pharmaceutical formulation is 1.00 to 2.00 mg / mL Factor XI and / or Factor XIa antibodies (e.g., amino acids of SEQ ID NO: 9 or 29) A heavy chain variable domain (VH) having a sequence, and the amino acid sequence of SEQ ID NO: 19 or 39. Antibodies containing a light chain variable domain (VL), approximately 0.20 mM histidine buffer. , approximately 2.20 mM sugar or sugar alcohol (e.g., sucrose), and approximately 0.00 Contains 0.4% polysorbate (e.g., polysorbate 20) and has a pH of 5.2-5.8. Yes. In a particular embodiment, the pharmaceutical formulation contains 1.00 to 2.00 mg / mL of factor XI. A child and / or factor XIa antibody (e.g., having the amino acid sequence of SEQ ID NO: 9 or 29) It has a heavy chain variable domain (VH) and the amino acid sequence of SEQ ID NO: 19 or 39. Antibodies containing a light chain variable domain (VL), approximately 0.20 mM histidine buffer, approximately 2. 20 mM sugar or sugar alcohol (e.g., sucrose), and about 0.0004% It contains polysorbate (e.g., polysorbate 20) and has a pH of 5.45 to 5.55. .

[0186] In a particular embodiment, the pharmaceutical formulation contains 100-200 mg / mL of factor XI and / or Factor XIa antibody (e.g., heavy chain having the amino acid sequence of SEQ ID NO: 9 or 29) Variable light chain having a variable domain (VH) and the amino acid sequence of SEQ ID NO: 19 or 39. Antibodies with a domain (VL), 10-30 mM histidine buffer, 200-300 It contains mM sucrose and 0.02% to 0.06% polysorbate 20, and has a pH of 5 The range is 0.0 to 6.0. In a particular embodiment, the pharmaceutical formulation is 100 to 200 mg / mL Factor XI and / or Factor XIa antibodies, approximately 20 mM histidine buffer, approximately 22 Contains 0 mM sucrose and approximately 0.04% polysorbate 20, pH 5.0-6 It is 0. In a particular embodiment, the pharmaceutical formulation is 100-200 mg / mL of the XI. Factor and / or Factor XIa antibody (e.g., amino acid sequence of SEQ ID NO: 9 or 29) It has a heavy chain variable domain (VH) and the amino acid sequence of SEQ ID NO: 19 or 39. Antibodies containing a light chain variable domain (VL), approximately 20 mM histidine buffer, approximately 220 It contains mM sucrose and approximately 0.04% polysorbate 20, with a pH of 5.3-5. 7. In a particular embodiment, the pharmaceutical formulation contains 100-200 mg / mL of factor XI. A child and / or factor XIa antibody (e.g., having the amino acid sequence of SEQ ID NO: 9 or 29) It has a heavy chain variable domain (VH) and the amino acid sequence of SEQ ID NO: 19 or 39. Antibodies containing light chain variable domains (VLs), approximately 20 mM histidine buffer, approximately 220 mM Contains M sucrose and approximately 0.04% polysorbate 20, with a pH of 5.45-5. It is 55.

[0187] In a particular embodiment, the pharmaceutical formulation contains 1.00 to 2.00 mg / mL of factor XI. and / or Factor XIa antibody (for example, having the amino acid sequence of SEQ ID NO: 9 or 29) A light chain having a heavy chain variable domain (VH) and the amino acid sequence of SEQ ID NO: 19 or 39. Antibodies with variable domains (VL), 0.10-0.30 mM histidine buffer, 2 0.00-3.00 mM sucrose and 0.0002-0.0006% polysol It contains β-20 and has a pH of 5.0 to 6.0. In a particular embodiment, the pharmaceutical formulation is Factor XI and / or Factor XIa antibody at 1.00-2.00 mg / mL (e.g., A heavy chain variable domain (VH) having the amino acid sequence of sequence number 9 or 29, and sequence number Antibodies having a light chain variable domain (VL) with amino acid sequence 19 or 39, approximately 0.20 mM histidine buffer, approximately 2.20 mM sucrose, and approximately 0.0004 It contains % polysorbate 20 and has a pH of 5.0 to 6.0. In a particular embodiment, The pharmaceutical formulation contains factor XI and / or factor XIa inhibitors at a concentration of 1.00 to 2.00 mg / mL. Body, 20 mM histidine buffer, approximately 2.20 mM sucrose, and approximately 0.0004 It contains % polysorbate 20 and has a pH of 5.3 to 5.7. In a particular embodiment, The pharmaceutical formulation contains factor XI and / or factor XIa inhibitors at a concentration of 1.00 to 2.00 mg / mL. Body (for example, a heavy chain variable domain (VH) having the amino acid sequence of SEQ ID NO: 9 or 29, and having a light chain variable domain (VL) having the amino acid sequence of SEQ ID NO: 19 or 39 (Antibody), approximately 0.20 mM histidine buffer, approximately 2.20 mM sucrose, and approximately It contains 0.0004% polysorbate 20 and has a pH of 5.45-5.55.

[0188] In some embodiments, the present disclosure relates to binding to FXI and / or FXIa proteins. A pharmaceutical preparation comprising an antibody or an antigen-binding fragment thereof, contained in a vial, In the vial, the formulation contains anti-FXI and / or anti-FXIa antibodies or their antigen-binding fragments. To provide a pharmaceutical formulation that includes an excess volume so that the therapeutically effective amount can be completely extracted. In certain embodiments, the vial contains FXI and / or FXIa proteins (e.g., For example, humans, rabbits, crab-eating macaques, and baboons (FXI and / or FXIa) are bound to this species. An antibody that 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 Contains approximately 150 mg of antibody; approximately 20 mM concentration of histidine buffer; approximately 220 mM concentration A pharmaceutical product containing sucrose and polysorbate 20 at a concentration of approximately 0.04% (v / v). This product contains a pharmaceutical preparation, the preparation having a pH of approximately 5.5.

[0189] In some embodiments, the present disclosure relates to FXI and / or FXIa proteins (e.g., Antibody binding to humans, rabbits, cynomolgus monkeys, and baboons (FXI and / or FXIa) A heavy chain having the amino acid sequence of SEQ ID NO: 9 or 29, which is a body or its antigen-binding fragment. Variable light chain having a variable domain (VH) and the amino acid sequence of SEQ ID NO: 19 or 39. Approximately 1.5 mg of antibody or its antigen-binding fragment containing a domain (VL); approximately 0.20 mg Histidine buffer at a concentration of M; sucrose at a concentration of approximately 2.20 mM; approximately 0.0004% Polysorbate 20 at a concentration of v / v, and a diluent (e.g., 5% glucose in water (D5) An intravenous delivery pharmaceutical formulation containing W), wherein the pH of the formulation is approximately pH 5.5, We provide delivered pharmaceutical formulations.

[0190] Stability of Factor XI and / or Factor Xia antibodies The pharmaceutical formulation of the present invention exhibits a high level of stability. The pharmaceutical formulation contains factor XI and and / or Factor XIa antibodies are physically acceptable after storage under defined conditions. Stable if it retains its properties, chemical structure, and / or biological function.

[0191] A standard for determining the stability of factor XI and / or factor XIa antibodies in pharmaceutical formulations. A typical method is described in Example 1 of this disclosure. Furthermore, the stability of the protein is The binding affinity or WO2 of factor XI and / or factor XIa antibodies to their respective targets. Some special features include the aPTT and FXI activity assays described in 016 / 207858. Factor XI and / or Factor XIa antibodies in a specific in vitro assay It can be evaluated by measuring biological activity.

[0192] Pharmaceutical formulations can be prepared and stored as liquid formulations. In certain embodiments, The pharmaceutical formulation is a liquid formulation intended for storage at 2-8°C (e.g., 4°C). In terms of form, the pharmaceutical formulation is a liquid formulation for storage at 4°C and protected from light.

[0193] Stability testing has shown that the 150 mg / mL concentrate of antibody 1 for injection solution has its excipients and It was found to be compatible with the primary packaging material. 150 mg / mL concentrate of antibody 1 for injection. This involves using a disposable syringe, without dilution or with a carrier buffer, such as 5% budol. Suitable for subcutaneous administration with dilution in sugar (D5W). Injection using a commercially available disposable syringe. The injectable concentrate has been demonstrated for a dose range from 0.5 mg / target to 600 mg / target. The materials found to be compatible with antibody 1 are polypropylene or polycarbonate. Includes an injection syringe made of nate and an injection needle made of stainless steel. The suitability of the concentrated body 1 for injection solutions is for antibody concentrations from 0.5 mg / mL to 150 mg / mL. The concentration of antibody 1 has been demonstrated using a 1 mL syringe. Injectable solution of antibody 1 concentrate. Compatibility is as follows: 3m³ filled to approximately 2mL for a 150mg / mL antibody concentration. This has been demonstrated using L syringes, and in total, 0.0 per 1 mL syringe per injection. Dosage range from 5 mg to a maximum of 150 mg, and 3 mL syringe (filled with approximately 2 mL). This includes a dose of approximately 300 mg for the product (that which has been used).

[0194] Dosage form Before use as a pharmaceutical product, the pharmaceutical preparation is diluted in an aqueous carrier if suitable for the route of administration. It is possible. For intravenous administration, sterile water for injection (SWFI) is used as an appropriate carrier. Bacteriostatic water for injection (BWFI), pH buffer (e.g., phosphate buffered saline), sterile physiological salt Examples include solutions, Ringer's solution, or glucose solution. For example, a pharmaceutical preparation for intravenous administration. When prepared, the pharmaceutical formulation contains a 5% glucose solution (D5W). In a specific embodiment... Therefore, a diluted pharmaceutical preparation is isotonic and suitable for administration by intravenous infusion, for example, It is D5W. In a particular embodiment, the formulation is divided into approximately 50 mL of D5W and 100 mL of D5 W, 150mL D5W, 200mL D5W, 250mL D5W, 300mL D5 W, 350mL D5W, 400mL D5W, 450mL D5W, 500mL D5 Dilute in W or 1L of D5W.

[0195] The pharmaceutical formulation contains factor XI and / or factor XIa antibodies in concentrations suitable for storage. In a particular embodiment, the pharmaceutical formulation contains factor XI and / or factor XIa antibodies. 00~200mg / mL, 100~190mg / mL, 100~180mg / mL, 10 0~170mg / mL, 100~160mg / mL, 110~150mg / mL, 120 ~150mg / mL, 130~150mg / mL, 140~150mg / mL, 140~ 160mg / mL, 140~170mg / mL, 140~180mg / mL, 140~1 90mg / mL, 150~190mg / mL, 150~180mg / mL, 150~17 It contains at a concentration of 0 mg / mL or 150-160 mg / mL. In certain embodiments, The pharmaceutical formulation contains factor XI and / or factor XIa antibodies at approximately 10 mg / mL, approximately 15 mg / mL, approx. 25 mg / mL, approx. 50 mg / mL, approx. 75 mg / mL, approx. 100 mg / mL mL, approx. 120mg / mL, approx. 125mg / mL, approx. 130mg / mL, approx. 135mg / mL, approx. 140mg / mL, approx. 145mg / mL, approx. 150mg / mL, approx. 155mg / mL, approx. 160 mg / mL, approx. 165 mg / mL, approx. 170 mg / mL, approx. 175 mg / mL, approx. 180mg / mL, approx. 185mg / mL, approx. 190mg / mL, approx. 195mg / It contains mL, or at a concentration of approximately 200 mg / mL.

[0196] The pharmaceutical formulation contains factor XI and / or factor XIa antibodies in concentrations suitable for storage. In a particular embodiment, the pharmaceutical formulation contains factor XI and / or factor XIa antibodies. .00~2.00mg / mL, 1.00~1.90mg / mL, 1.00~1.80mg / mL, 1.00~1.70 mg / mL, 1.00~1.60 mg / mL, 1.10~1 .50mg / mL, 1.20~1.50mg / mL, 1.30~1.50mg / mL, 1 .40~1.50mg / mL, 1.40~1.60mg / mL, 1.40~1.70mg / mL, 1.40-1.80 mg / mL, 1.40-1.90 mg / mL, 1.50-1 .90mg / mL, 1.50~1.80mg / mL, 1.50~1.70mg / mL, It is contained at a concentration of 1.50 to 1.60 mg / mL. In a particular embodiment, the pharmaceutical formulation is Factor XI and / or Factor XIa antibodies at approximately 0.10 mg / mL and approximately 0.15 mg / mL, approx. 0.25mg / mL, approx. 0.50mg / mL, approx. 0.75mg / mL, approx. 1. 00mg / mL, approx. 1.20mg / mL, approx. 1.25mg / mL, approx. 1.30mg / mL , about 1.35mg / mL, about 1.40mg / mL, about 1.45mg / mL, about 1.50m g / mL, approx. 1.55 mg / mL, approx. 1.60 mg / mL, approx. 1.65 mg / mL, approx. 1 .70mg / mL, approx. 1.75mg / mL, approx. 1.80mg / mL, approx. 1.85mg / m L, concentrations of approximately 1.90 mg / mL, approximately 1.95 mg / mL, or approximately 2.00 mg / mL It includes.

[0197] In certain embodiments, pharmaceutical formulations are stored in vials (e.g., vials, bags, pens, etc.) Fill a syringe with the contents. In certain embodiments, the vial contains the intended dose. Includes an excess filling to allow for removal. In a particular embodiment, by Al can be filled with 5-35%, 10-30%, 15-25%, or 10-20% excess filling. Includes. In certain embodiments, the vial contains approximately 20% excess filling.

[0198] In certain embodiments, the formulation may be a liquid formulation. In certain embodiments, a container The amount of factor XI and / or factor XIa antibodies in the solution is suitable for administration as a single dose. In a particular embodiment, the XI factor and / or XIa factor in the container The antibody quantity is suitable for administration in multiple doses. In certain embodiments, pharmaceutical-grade The drug contains factor XI and / or factor XIa antibodies in amounts of 0.1 to 200 mg. In a particular embodiment, the pharmaceutical formulation contains factor XI and / or factor XIa antibodies in a 1- 200mg, 10~200mg, 20~200mg, 50~200mg, 100~200 mg, 200~200mg, 500~2000mg, 1000~2000mg, 0.1~ 1000mg, 1~1000mg, 10~1000mg, 20~1000mg, 50~1 000mg, 100~1000mg, 200~1000mg, 500~1000mg, 0 .1~500mg, 1~500mg, 10~500mg, 20~500mg, 50~50 0mg, 100~500mg, 200~500mg, 0.1~200mg, 1~200m g, 10~200mg, 20~200mg, 50~200mg, 100~200mg, 0 .1~100mg, 1~100mg, 10~100mg, 20~100mg, 50~10 0mg, 0.1~50mg, 1~50mg, 10~50mg, 20~50mg, 0.1~ 20mg, 1-20mg, 10-20mg, 0.1-10mg, 1-10mg, or 0 It contains an amount of 0.1 to 1 mg. In certain embodiments, the pharmaceutical formulation contains factor XI and / or Alternatively, factor XIa antibody is administered in therapeutic effective doses of approximately 0.1 mg, 0.5 mg, 1 mg, and 1 mg. .5mg, about 2mg, about 2.5mg, about 5mg, about 10mg, about 20mg, about 30mg, About 40mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100 mg, about 150mg, about 200mg, about 250mg, about 300mg, about 400mg, about 4 50mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, It contains approximately 1000mg, 1500mg, or 2000mg.

[0199] Medication regimens and therapeutic use In another aspect, the present disclosure relates to a method for treating cancer, which is required for treatment of a subject in addition, factor XI and / or factor XIa antibodies (e.g., antibody 1) disclosed herein The present invention provides a method that includes administering the drug once a month.

[0200] In a particular embodiment, the method involves applying factor XI to the subject after the first treatment cycle. And / or factor XIa antibody in one or more monthly treatment cycles, for example, 3 Further including administering over a period of months, where factor XI and / or the Factor XIa antibodies are administered on days 1, 31, and 61. The target is Factor XI. and / or receiving factor XIa antibody once a month, the subsequent treatment cycle is for the target In this context, a certain level of factor XI and / or factor XIa antibodies is maintained. Designed to allow for at least one, two subsequent treatment cycles. In certain embodiments, the subject undergoes at least one, two subsequent treatment cycles. 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 cycles In some embodiments, the subject continues to receive treatment for life.

[0201] In some embodiments, the person is suffering from or at risk of developing a thromboembolic disorder. In patients undergoing surgical procedures, intravenous drug delivery preparations are administered on the same day as the surgical procedure. In one embodiment, the intravenous drug delivery formulation is administered 2 to 10 hours after surgery. In this embodiment, the intravenous drug delivery formulation is administered 4 to 8 hours after surgery. In terms of administration methods, intravenous drug delivery formulations are administered approximately 1 hour, 2 hours, 3 hours, and approximately 1 hour after surgery. 4 hours later, approximately 5 hours later, approximately 6 hours later, approximately 7 hours later, approximately 8 hours later, approximately 9 hours later, or approximately 1 Administer 0 hours later.

[0202] In a particular embodiment, once in the first treatment cycle and in subsequent treatment cycles Alternatively, multiple doses may contain factor XI and / or factor XIa antibodies at approximately 0.1 mg / kg. , about 0.2mg / kg, about 0.3mg / kg, about 0.4mg / kg, about 0.5mg / kg Approximately 0.6 mg / kg, approximately 0.7 mg / kg, approximately 0.8 mg / kg, approximately 0.9 mg / kg , about 1.0mg / kg, about 1.1mg / kg, about 1.2mg / kg, about 1.3mg / kg , about 1.4mg / kg, about 1.5mg / kg, about 1.6mg / kg, about 1.7mg / kg Approximately 1.8 mg / kg, approximately 1.9 mg / kg, approximately 2.0 mg / kg, approximately 2.1 mg / kg , about 2.2mg / kg, about 2.3mg / kg, about 2.4mg / kg, about 2.5mg / kg Approximately 2.6 mg / kg, approximately 2.7 mg / kg, approximately 2.8 mg / kg, approximately 2.9 mg / kg , about 3.0mg / kg, about 3.1mg / kg, about 3.2mg / kg, about 3.3mg / kg , about 3.4mg / kg, about 3.5mg / kg, about 3.6mg / kg, about 3.7mg / kg Approximately 3.8 mg / kg, approximately 3.9 mg / kg, approximately 4.0 mg / kg, approximately 4.1 mg / kg , about 4.2mg / kg, about 4.3mg / kg, about 4.4mg / kg, about 4.5mg / kg Approximately 4.6 mg / kg, approximately 4.7 mg / kg, approximately 4.8 mg / kg, approximately 4.9 mg / kg or administer subcutaneously at a dose of approximately 5.0 mg / kg.

[0203] In a particular embodiment, once in the first treatment cycle and in subsequent treatment cycles Alternatively, multiple doses may contain approximately Factor XI and / or Factor XIa antibodies (e.g., antibody 1). 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, Approx. 40mg, approx. 45mg, approx. 50mg, approx. 55mg, approx. 60mg, approx. 65mg, approx. 70m g, about 75mg, about 80mg, about 85mg, about 90mg, about 100mg, about 110mg, Approx. 120mg, approx. 130mg, approx. 140mg, approx. 150mg, approx. 160mg, approx. 170m g, approximately 180 mg, approximately 185 mg, approximately 190 mg, approximately 195 mg, or approximately 200 mg This includes subcutaneous administration in a specified dose. In some embodiments, factor XI and / or factor XI Factor α antibody is administered subcutaneously at a dose of approximately 90 mg. In some embodiments, Factor XI and / or administer factor XIa antibody subcutaneously at a dose of approximately 120 mg. In some embodiments, Administer factor XI and / or factor XIa antibodies subcutaneously at a dose of approximately 150 mg. In this embodiment, factor XI and / or factor XIa antibodies are administered in a dose of approximately 180 mg to the skin. Administer below. In any of the above embodiments, factor XI and / or factor XIa anticoagulant The body is administered subcutaneously once a month.

[0204] In some embodiments, factor XI and / or factor XIa antibodies (e.g., after subcutaneous administration) The effective therapeutic dose range for antibody 1) is approximately 75 mg to 165 mg, and approximately 80 mg to 160 mg. g is approximately 85 mg to 155 mg, or approximately 90 mg to 160 mg. In terms of administration method, factor XI and / or factor XIa antibodies (e.g., antibody 1) are administered subcutaneously. The effective therapeutic dose range is approximately 90 mg to 160 mg.

[0205] In a particular embodiment, once in the first treatment cycle and in subsequent treatment cycles Alternatively, multiple doses may contain approximately Factor XI and / or Factor XIa antibodies (e.g., antibody 1). 0.1mg / kg, approx. 0.2mg / kg, approx. 0.3mg / kg, approx. 0.4mg / kg, approx. 0.5mg / kg, approx. 0.6mg / kg, approx. 0.7mg / kg, approx. 0.8mg / kg, approx. 0.9 mg / kg, approximately 1.0 mg / kg, approximately 1.1 mg / kg, approximately 1.2 mg / kg, approximately 1.3mg / kg, approx. 1.4mg / kg, approx. 1.5mg / kg, approx. 1.6mg / kg, approx. 1.7 mg / kg, approximately 1.8 mg / kg, approximately 1.9 mg / kg, approximately 2.0 mg / kg, approximately 2.1mg / kg, approx. 2.2mg / kg, approx. 2.3mg / kg, approx. 2.4mg / kg, approx. 2.5mg / kg, approx. 2.6mg / kg, approx. 2.7mg / kg, approx. 2.8mg / kg, approx. 2.9 mg / kg, approximately 3.0 mg / kg, approximately 3.1 mg / kg, approximately 3.2 mg / kg, approximately 3.3mg / kg, approx. 3.4mg / kg, approx. 3.5mg / kg, approx. 3.6mg / kg, approx. 3.7 mg / kg, approximately 3.8 mg / kg, approximately 3.9 mg / kg, approximately 4.0 mg / kg, approximately 4.1mg / kg, approx. 4.2mg / kg, approx. 4.3mg / kg, approx. 4.4mg / kg, approx. 4.5mg / kg, approx. 4.6mg / kg, approx. 4.7mg / kg, approx. 4.8mg / kg, approx. This includes intravenous administration at a dose of 4.9 mg / kg or approximately 5.0 mg / kg.

[0206] In a particular embodiment, once in the first treatment cycle and in subsequent treatment cycles Alternatively, multiple doses may contain approximately Factor XI and / or Factor XIa antibodies (e.g., antibody 1). 5mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, Approx. 40mg, approx. 45mg, approx. 50mg, approx. 55mg, approx. 60mg, approx. 65mg, approx. 70m g, about 75mg, about 80mg, about 85mg, about 90mg, about 100mg, about 110mg, Approx. 120mg, approx. 130mg, approx. 140mg, approx. 150mg, approx. 160mg, approx. 170m g, approximately 180 mg, approximately 185 mg, approximately 190 mg, approximately 195 mg, or approximately 200 mg This includes administering the dose intravenously. In some embodiments, factor XI and / or factor X Factor Ia antibody is administered intravenously at a dose of approximately 30 mg. In some embodiments, factor XI is also administered. Administer factor XIa antibody intravenously at a dose of approximately 60 mg. In some embodiments, This involves intravenously administering factor XI and / or factor XIa antibodies at a dose of approximately 75 mg. In some embodiments, a dose of approximately 150 mg of factor XI and / or factor XIa antibody is administered. It is administered intravenously. In some embodiments, factor XI and / or factor XIa antibodies are used. Administer intravenously as a single dose (for example, to patients undergoing medical surgery, e.g., one entire knee). For example, patients undergoing total knee arthroplasty (TKA) on the same day as the surgical procedure.

[0207] A physician may use a dose of the antibody of this disclosure (e.g., antibody 1) used in a pharmaceutical composition to treat a desired condition. It starts at a lower level than necessary to achieve the desired effect, and the desired effect is achieved. The dosage can be gradually increased up to [a certain number]. Generally, thromboembolic disorders as described herein The effective dose of the composition of this disclosure for treating the condition depends on the means of administration, the target site, and the patient's physiological state. This includes other medications being administered, and whether the treatment is preventive or therapeutic. It varies depending on many different factors. The treatment dosage is optimized for safety and efficacy. The dosage can be set accordingly. For systemic administration of antibodies, the dosage is 1 / 1 of the host's body weight. The dosage ranges from approximately 0.01 mg to 15 mg per kg. Antibody administration (e.g., subcutaneous administration) For intravenous administration, the dosage is from 0.1 mg to 5 mg, or from 1 mg. May be up to 600 mg. For example, anti-FXI / FXIa antibodies as described herein (e.g. If antibody 1) is administered at approximately 0.1 mg / kg, approximately 0.2 mg / kg, approximately 0.3 mg / kg, and approximately 0.4 mg / kg mg / kg, approx. 0.5mg / kg, approx. 0.6mg / kg, approx. 0.7mg / kg, approx. 0.8 mg / kg, approximately 0.9 mg / kg, approximately 1.0 mg / kg, approximately 1.1 mg / kg, approximately 1.2 mg / kg, approx. 1.3 mg / kg, approx. 1.4 mg / kg, approx. 1.5 mg / kg, approx. 1.6 mg / kg, approximately 1.7 mg / kg, approximately 1.8 mg / kg, approximately 1.9 mg / kg, approximately 2.0 mg / kg, approx. 2.1 mg / kg, approx. 2.2 mg / kg, approx. 2.3 mg / kg, approx. 2.4 mg / kg, approx. 2.5 mg / kg, approx. 2.6 mg / kg, approx. 2.7 mg / kg, approx. 2.8 mg / kg, approximately 2.9 mg / kg, approximately 3.0 mg / kg, approximately 3.1 mg / kg, approximately 3.2 mg / kg, approx. 3.3 mg / kg, approx. 3.4 mg / kg, approx. 3.5 mg / kg, approx. 3.6 mg / kg, approximately 3.7 mg / kg, approximately 3.8 mg / kg, approximately 3.9 mg / kg, approximately 4.0 mg / kg, approx. 4.1 mg / kg, approx. 4.2 mg / kg, approx. 4.3 mg / kg, approx. 4.4 mg / kg, approx. 4.5 mg / kg, approx. 4.6 mg / kg, approx. 4.7 mg / kg, approx. 4.8 It can be administered in doses of mg / kg, approximately 4.9 mg / kg, or approximately 5.0 mg / kg. Cut.

[0208] In certain embodiments, factor XI and / or factor XIa antibodies are administered intravenously. For example, in a particular embodiment, factor XI and / or factor XIa antibodies are used. For example, using a pre-filled bag, pre-filled pen, or pre-filled syringe for intravenous injection. Therefore, it is administered. In certain embodiments, factor XI and / or factor XIa antibodies are used. Dilute it in the pharmaceutical formulations disclosed herein before administration. For example, in a certain implementation In this procedure, the pharmaceutical preparation is diluted with 5% glucose (D5W) in water and administered intravenously from a bag. Intravenous infusion may last for approximately one hour (e.g., 50–80 minutes). In certain embodiments, This connects the bag to the channel containing the tube and / or needle.

[0209] Factor XI and / or Factor XIa antibodies or pharmaceutical formulations disclosed herein The types of thromboembolic disorders that can be treated using this method are not limited to these, but include The terms “thromboembolic” or similar, when used herein, also include the following: Anti-FXI and / or FXIa antibodies or antigen-binding fragments prevent or treat Refer to any number of these that may be used: paroxysmal, persistent, or permanent atrial fibrillation Or, for individuals suspected of having cardiac arrhythmias such as atrial flutter, or for whom cardiac arrhythmias have been confirmed. Thromboembolism; prevention of stroke due to atrial fibrillation (SPAF), percutaneous coronary intervention Subgroup of AF patients undergoing PCI; acute in patients at high risk of bleeding Treatment of venous thromboembolic events (VTE) and prevention of long-term secondary VTE; transient ischemic attacks Cerebral and cardiovascular events or non-incapacitating stroke during secondary prevention after a transient ischemic attack (TIA) Prevention of thromboembolic events in heart failure with sinus rhythm; venous thromboembolism in children (pediatric VTE); blood clot formation in the left atrium and electrical cardioversion for cardiac arrhythmias Thromboembolism in the subject; before and during ablation procedures for cardiac arrhythmias and subsequent thrombosis; venous thrombosis, which includes, but is not exclusive, lower or upper members. Deep vein or superficial vein thrombosis in club members, thrombosis in abdominal veins and thoracic veins. This includes the treatment and secondary prevention of thrombosis, sinus thrombosis, and jugular vein thrombosis; catheters, penetrating -Maker wire, synthetic arterial graft, or any artificial surface within a vein or artery. Thrombosis in patients; mechanical or biological heart valves or left ventricular assist devices; venous thrombosis Pulmonary embolism in patients with or without venous thrombosis; chronic thromboembolic pulmonary hypertension CTEPH (Chronic Arterial Thrombosis of the Arterial Pathogen); arterial thrombosis in ruptured arteriosclerotic lesions, intra-arterial prostheses or catheters Thrombosis in arteries and thrombosis in seemingly normal arteries, this includes only While not limited to these, acute coronary syndrome, ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, anxiety Patients with angina, stent thrombosis, thrombosis of any artificial surface in the arterial system, and pulmonary hypertension. This includes pulmonary artery thrombosis in patients who are not subject to or do not have pulmonary hypertension; percutaneous coronary Thrombosis and thromboembolism in patients undergoing percutaneous coronary intervention (PCI); heart Stroke due to encephalogenic causes and cryptogenic stroke; non-central nervous system embolism (non-CNS systemic embolism); hemorrhage Sexual stroke; thrombosis in patients with invasive and non-invasive cancerous malignancies; indwelling catheters Thrombosis; thrombosis and thromboembolism in severely ill patients; cardiac thrombosis and thromboembolism, This is not exclusive, but applies to cardiac thrombosis after myocardial infarction, ventricular aneurysm, myocardial fibrosis, cardiomegaly and Cardiac thrombosis, including conditions such as heart failure, myocarditis, and artificial heart surface; atrial fibrillation Thromboembolism in patients with valvular heart disease, with or without movement; mechanical or biological Thromboembolism on artificial heart valves; after cardiac repair of simple or complex cardiac malformations, native Thromboembolism in patients who have developed an artificial heart patch, arterial or venous conduit. Embolism; knee replacement, total hip replacement, and orthopedic surgery, thoracic or abdominal surgery Post-operative venous thrombosis and thromboembolism; arterial complications following neurosurgical procedures, including intracranial and spinal cord interventions. Or venous thrombosis; not exclusive, but factor V Leiden, prothrombin mutation, and Thythrombin III, protein C and protein S deficiency, factor XIII mutation Differential, familial abnormal fibrinogenemia, congenital plasminogen deficiency, level of factor XI Elevated blood glucose levels, sickle cell disease, antiphospholipid syndrome, autoimmune diseases, chronic bowel disease, nephrotic syndrome Syndrome, hemolytic uremic disease, myeloproliferative disorder, disseminated intravascular coagulation, paroxysmal nocturnal hemoglobinuria and congenital or acquired thrombotic tendencies, including heparin-induced thrombocytopenia; chronic kidney Thrombosis and thromboembolism in diseases; as well as patients undergoing hemodialysis and extracorporeal hemodialysis. Thrombosis and thromboembolism in patients receiving membrane oxygenation. In certain embodiments, , Factor XI and / or Factor XIa antibodies or pharmaceutical formulations disclosed herein The subjects receiving the treatment used are those with obesity (e.g., severe obesity, e.g., Body Mass Index (BMI)) ≥35 kg / m 2 (This is the case.) In certain embodiments, the XI factor disclosed herein is Children and / or those receiving treatment with factor XIa antibodies or pharmaceutical preparations are obese. No. In a particular embodiment, obese subjects receive the same dose as non-obese subjects, dose X Lower exposure is associated with the administration of factor I and / or factor XIa antibodies (e.g., antibody 1). In a particular embodiment, with respect to obese subjects, the same dose as for non-obese subjects is used for the Xth After administration of factor I and / or factor XIa antibodies (e.g., antibody 1), exposure is approximately 10%. Approximately 20%, approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, approximately 80%, or approximately 9 0% lower. In certain embodiments, obese subjects receive the same dose as non-obese subjects. Shorter aPTT after administration of factor XI and / or factor XIa antibodies (e.g., antibody 1) The duration of the extension is involved. In certain embodiments, with respect to obese subjects, they are not obese. After administration of the same dose of factor XI and / or factor XIa antibody (e.g., antibody 1) as the subject. aPTT extension is approximately 10%, 20%, 30%, 40%, 50%, 60%, and 7%. 0%, approximately 80%, or approximately 90% shorter.

[0210] The CHA2DS2-VASc risk score predicts thromboembolic risk in patients with atrial fibrillation (AF). To do so, and to identify patients for whom anticoagulation therapy should be beneficial, validated It is a widely used stratification tool (LIP 2011; Camm, et al. (2012) Eur H Eart J 2012; 33: 2719-2747); Based on accumulated evidence, CHA2DS2-VA Sc is used to identify patients who develop stroke and thromboembolism. Compared to any other score, it is at least as accurate, or in some cases, better. It is definitively better in terms of identifying AF patients who are "truly at low risk". It is shown that the CHA2DS2-VASc risk score ranges from 0 to a maximum score of 9. It spans. In certain embodiments, the XI factor and / or the details disclosed herein CHA2DS2-VAS patients are those who will receive treatment with factor XIa antibodies or pharmaceutical preparations. The C-risk score is 0-1 for men and 1-2 for women. In a particular embodiment... Therefore, the factor XI and / or factor XIa antibodies or pharmaceutical products disclosed herein For patients receiving treatment with the drug, the CHA2DS2-VASc risk score is ≥2 in men. Yes, and for women it is ≥3. In certain embodiments, factor XI disclosed herein and / or those receiving treatment with factor XIa antibodies or pharmaceutical preparations are CHA 2DS2-VASc risk score ≥4 or ≥3, and antiplatelet drugs (e.g., Aspirin) Combination therapy plan (phosphorus and / or P2Y12 inhibitors) or Cockcroft-Gaul The t-equation gives at least one of the following conditions: CrCl ≤ 50 ml / min.

[0211] The factor XI and / or factor XIa antibodies disclosed herein (e.g., antibody 1) are It can be used as a monotherapy or in combination with one or more other treatments. It is also possible to do so. Such combination therapies are used for ischemic stroke (cardioembolic, thrombotic) or all-in-one stroke. Somatic embolism, AF, prevention of stroke due to AF (SPAF), deep vein thrombosis, venous thromboembolism Thromboembolic pulmonary hypertension, acute coronary syndrome (ACS), acute limb ischemia, chronic thromboembolic pulmonary hypertension It may be useful in the treatment of thromboembolic disorders such as systemic embolism. In form, factor XI and / or factor XIa antibodies are used in the drug registration disclosed herein. It is used as monotherapy according to the instructions. In other embodiments, factor XI and / or Factor XIa antibodies are used in combination with one or more therapies, where factor XI and 1 A medication known to be suitable for the treatment of specific subjects with specific disorders, or one or more treatments. Administer according to the regimen.

[0212] In some embodiments, to treat patients with thrombotic and / or thromboembolic disorders , statin therapy with the FXI / FXIa antibody and antigen-binding fragment described in this disclosure, or prior Combined with a formulation containing the FXI / FXIa antibody and an antigen-binding fragment (e.g., antibody 1). It can be used in certain embodiments. For example, non-limiting examples of therapeutic active agents suitable for use in combination with antibody 1) include: Lomboxane inhibitors (e.g., aspirin), adenosine diphosphate receptor antagonists (or P2Y12 inhibitors) For example, thienopyridine (e.g., clopidogrel and p (Rasgrel) and non-thienopyridines (e.g., ticagrelor and cangrelor), etc. , receptor-1 (PAR1) antagonists activated by proteases (for example, (e.g., Lapaxar and Atopaxar), as well as proton pump inhibitors (PPIs) Omeprazole, diazepam, phenytoin, lansoprazole, dexlansoprazole (Zol, rabeprazole, pantoprazole, esomeprazole, and naproxen) Examples include: The use of PPIs in combination therapy is appropriate if the subject has GI disorder or G Applicable in cases with a history of I disorder, such as previous GI bleeding or prodromal symptoms of peptic ulcers. It is possible. In one embodiment, the subject receives treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). The anti-FXI / FXIa antibody described herein (e.g., antibody 1) is used with a proton pump. Inhibitors (e.g., omeprazole, diazepam, phenytoin, lansoprazole, decyl monoxide) Slansoprazole, rabeprazole, pantoprazole, esomeprazole, and na It is administered in combination with Proxen. In certain embodiments, it is used in combination with FXI / FXIa antifungal agents. Body and antigen-binding fragment, or the FXI / FXIa antibody and antigen-binding fragment (e.g.) If a patient is to receive treatment using a preparation containing antibody 1), direct oral anticoagulants (DOACs) will be administered. It is administered after the duration of the administration (for example, on the same day as the end of the procedure). In certain embodiments, FXI / FXIa antibody and antigen-binding fragment, or the FXI / FXIa antibody and anti For patients receiving treatment with a preparation containing a protoconjugate fragment (e.g., antibody 1), vitamin K ammonium compounds are used. The agonist (VKA) should be administered after the duration of the procedure (for example, about 5 days before the end of the procedure, or after the end of the procedure). Administer approximately 3 days before the end of the treatment period.

[0213] In certain embodiments, the treatment method disclosed herein may affect the disease response or target Alternatively, it can lead to improved patient survival. For example, in certain embodiments, it can improve disease response. This includes complete response, partial response, or stable disease. In certain embodiments, it involves improved survival. This refers to an improvement in progression-free survival (PFS) or overall survival. An improvement (e.g., an improvement in PFS) is This can be determined by comparing it to the period before the commencement of the measures in this disclosure. BTC (for example, progress BTC (biotuberculosis), metastatic BTC, or disease response to treatment of biliary tract tumors (e.g., complete Determine response (response, partial response, or stable disease) and patient survival (e.g., PFS, overall survival). The method is common in the art and is intended in the present invention. In the embodiment, the disease response is measured from the affected area (e.g., the upper region of the thoracic inlet) of the treated patient. Contrast-enhanced computed tomography (CT) of the chest / abdomen and pelvis, extending to the pubic symphysis. ) or after being subjected to magnetic resonance imaging (MRI), evaluate according to RECIST 1.1. . [Examples]

[0214] Herein, the generally described disclosure can be further illustrated by referring to the following examples. It should be easy to understand. The following examples merely illustrate certain aspects and embodiments of the present disclosure. These are included for illustrative purposes only and do not in any way limit the scope of this disclosure.

[0215] (Example 1) Preparation, packaging, and storage of antibody 1 Test design This test included the following experimental parts: - Substage A: Conformity and Feasibility Testing - SE-HPLC assay for appropriate quantification of drugs diluted in 5% glucose Evaluate the limits of quantification (linearity, reproducibility, LoQ, and autosampler stability). - Substage B: Simulated dosing suitability test - Bag administration - Part 1: Three types after adding the drug (low dose, medium dose, and high dose) to the infusion bag Stability during short-term use in IV infusion bag administration systems. The drug was diluted with 5% glucose. The target concentration was obtained. Dilution can be performed directly in the infusion bag (high dose) or by pre-dilution. This is done (medium dose, low dose). - Part 2: Simulated intravenous (IV) administration test using commercially available administration materials for clinical use The experiment was conducted using injection bags made of three types of materials (PE, PVC, PP) and two types of materials (P E, PVC) injection line, plus two types of in-line filters and catheter This was tested using a bracket design with low, medium, and high concentration levels. Ta. - The stability and recovery rate of the drug from the infusion system were determined.

[0216] material and method Test materials A 150 mg / 1 mL concentrate of antibody 1, which is an active drug (DP) for injection, is available. The following preparation contained: 20 mM L-histidine / histidine hydrochloride (H) at pH 5.5. Stidine buffer, 220 mM sucrose, 0.04% (w / v) polysorbate 20 pH 5.5, nominal concentration 150 mg / ml. All calculations are based on a nominal DP concentration of 150 mg / ml. It was used for this purpose. The nominal filling volume was 1 mL in a 6R glass vial (Type I).

[0217] Analysis method All instruments used for the analysis method must be recorded in the test data file, including iLAB and La boratory Information and Management System Use em(LIMS) and a unique identification number or serial number as needed. The software version was identified and recorded. All equipment used was appropriately qualified. It was deemed to be calibrated. Unless otherwise specified, one sample was used at each point in the test. Analysis was performed, or one injection was administered per sample. The test methods used are summarized in Table 2. [Table 2]

[0218] Calculation of recovery rate (%) For low, medium, and high doses, the recovery rate is calculated by the peak area according to the formula in Table 3. It was calculated using the concentration. [Table 3]

[0219] Experimental setup SE-HPLC analytical evaluation Depending on the recommended dosage level and diluent, the drugs were tested using a variety of methods used in the suitability test. The solution was serially diluted within a specified concentration range in the diluent. Table 4 shows examples of dilution concentrations used in this test. [Table 4]

[0220] Concentration Bracketing The concentration bracketing range is defined based on the medication provided by the customer, 0.50 mg / mL was defined as the minimum concentration (low dose), and 3.0 mg / mL as the maximum concentration (high dose) (Table 5). The intermediate dose was evaluated at 1.5 mg / mL. The medication solutions were as shown in Tables 5 and 7. It was prepared. [Table 5]

[0221] Preparation of medication solutions Take a suitable number of DP vials out of refrigeration and let them cool to the touch until they are no longer cold. Equilibrium was reached by temperature (should not be longer than 1 hour). Pre-dilution for substage A. The substances and samples were prepared by pipetting according to Table 6.

[0222] For substage B, which is a simulated clinical administration suitability test, the IV infusion bag was placed in a suitable position. Using a disposable syringe, preparations were made according to Table 7. The pre-diluted product was placed in a PETG bottle. The final medication solution was prepared in a direct infusion bag. [Table 6]

[0223] For low doses, DP was diluted to 15 mg / mL in 5% glucose in an appropriate container. Remove 3.2 mL of the diluent from the bag, then add the previously diluted DP 3.2 mL to B. Using a Braun Omnifix® 5mL syringe and a 21G SS needle... Then I injected it. I mixed the bag containing the injection solution.

[0224] For medium doses, DP was diluted to 15 mg / mL in 5% glucose in an appropriate container. Take 10.0 mL of the diluent out of the bag, then add 10.0 mL of the pre-diluted DP, Use a 10 mL BD Plastipak syringe and inject with a 21 G SS needle. The bags containing the injection solution were mixed.

[0225] For high doses, take 2.1 mL of the diluent out of the bag, and then the undiluted... DP 2.1 mL, using a 3 mL BD Plastipak syringe, 21 G S The injection was administered using an S-needle. The bag containing the injection solution was mixed. [Table 7]

[0226] Substage A: SE-HPLC evaluation SE-HPLC evaluation Using the prepared samples (according to Table 6), linearity, repeatability, limits of quantification, and The stability of the autosampler was evaluated. Substage B: Simulated Dosage Suitability Test

[0227] Stability during use The prepared infusion bags (according to Table 7) were incubated: - Expose to ambient room light at room temperature for 3 hours. - 20 hours at 2~8℃ - Expose to ambient room light for 1 hour at room temperature.

[0228] Simulated administration test At the end of the storage period (cumulative 24 hours), the infusion bag was used for a simulated dosing test.

[0229] The extension set, including the infusion line, inline filter, and catheter, is placed in the infusion bag. The connection was established. The bags were prepared with the target concentration solutions listed in Table 5. The bag system was then used as the first The solution was primed at a flow rate of 100 mL per hour until dripping. Infusion system (bag, line, After priming (in-line filter and catheter), the remaining solution in the infusion bag Using the infusion pump, simulated administration was performed at the flow rates listed in Table 5, and the infusion bag The injection was continued until the bottle was empty. After administration, the inline filter was disconnected. This allowed for the collection of samples from a portion of the bag and from the bag immediately before the filter.

[0230] For the LD sample, use an injection pump and inject a total of 60 mL at the flow rates listed in Table 5. A partial infusion was performed over the course of the administration. After administration, the remaining solution in the bag was collected separately. Disconnect the line filter and remove any remaining line and the bag immediately before the filter. This made it possible to collect samples.

[0231] The total contact time between the medication solution and the infusion set was approximately 1 hour. At the end of the simulated administration, the infusion was performed. The cumulative contact time with the material was approximately 25 hours. The drug solution was left at room temperature and under ambient light conditions. The cumulative time was approximately 5 hours. The simulated dose was administered under ambient temperature and ambient light conditions. The procedure was carried out inside a Class II safety cabinet.

[0232] Simulated administration test For each combination and dose level, the following samples were collected in sterile PETG bottles according to Table 8. I tested it. • Sample 1 (T0): The first solution (4 mL of sample). • Sample 2 (T24): Incubated for 4 hours at ambient temperature and 20 hours at 2-8°C. A fixed amount (4 mL of sample) from the bag after use. • Sample 3 (after filtration): Infusion solution from total dose (after in-line filtration) (total dose) Sample (4 mL) from the product. • Sample 4 (before filtration): Injection solution before inline filtration (from line and bag) Sample (4 mL). [Table 8]

[0233] Results and Discussion Analysis and evaluation of the substage A-SE-HPLC method Based on the recommended dosage level, the drug is administered in glucose (D5W) and during the mobile phase. A PPN mixture containing (MP) and aprotinin (APN) (MP:APN=1:1 The sample was diluted to a concentration range of 0.20 to 0.90 mg / mL. The sample was an SE-HPLC sample. Since it is diluted to 0.75 mg / mL during preparation, concentrations exceeding 0.90 mg / mL should not be evaluated. No additional benefits were gained from the valuation.

[0234] linearity The dilution scheme shown in Table 4 can be applied using glucose (D5W) or an APN mixture. The APN mixture was designed to minimize nonspecific binding of the generated proteins to the contact surface. It served as a positive control. Linearity was evaluated. 0.20~0.90 mg Linearity was established for glucose in the range of / mL (glucose is shown in Figure 1A). (The APN is shown in Figure 1B). For subsequent tests, a single-point evaluation is performed, and each The recovery rate of the diluent relative to the standard substance was quantified.

[0235] Repeatability and autosampler stability The drug was diluted to 0.48 mg / mL and 0.75 mg / mL, and each concentration was measured six times separately. Each preparation was prepared and injected once. The RSD for evaluating repeatability is shown in Table 9 (Repeatability [ [RSD%]). The first preparation of each concentration for repeatability evaluation was stored in an HPLC vial at 5°C. After standing for 24 hours, the sample was reinjected and the autosampler stability was evaluated as shown in Table 9. (Absolute peak percentage difference [comparing T24 to T0]). [Table 9]

[0236] Based on this evaluation, further testing of the SE-HPLC method (CHVI-260130) will be conducted. It was deemed suitable for the experiment. The sample concentration (mg / mL) was calculated from the SE-HPLC data. For high doses, DP was used as a reference (final concentration was determined as needed for each test method). (Diluted with ). For medium and low doses, an intermediate dilution was used as a reference (test (Diluted to the final concentration as needed for each test method.)

[0237] LoQ Adaptability Assessment The drug was diluted to 0.00075 mg / mL (0.1% of the nominal target concentration). The sample is injected once into the HPLC system, and the Empower custom field "USP s / n" is used. The relative signal-to-noise ratio was calculated using [this method]. The resulting ratio was 21.085, which means... This method is shown to be suitable for determining a concentration value of 0.1% of the nominal concentration from the test method. .

[0238] Substage B - Simulated Dosage Suitability Test Tables 10 and 11 summarize the results of the simulated dose suitability test.

[0239] At the full dose level, the first, incubated, and administered bag dosing setup. In the solution, the relationship between visible particles, color, turbidity, and purity measured by SE-HPLC is No changes were observed. The pH value remained 4 throughout the entire test for all dose levels and materials. The pH range was 0.5 to 5.9. The pH shift can be explained by the dilution of the buffer.

[0240] Particles invisible to the naked eye were measured using a light shielding method. In the sample collected after filtration, An effective reduction in particle count, invisible to the naked eye, was demonstrated. After filtration of all tested combinations... Regarding the material, particles invisible to the naked eye using the light shielding method have a volume smaller than 100 mL. Alternatively, assuming it is equivalent to that, the cumulative count of particles ≥25μm that are invisible to the naked eye is per container. The count is less than or equal to 600, and the particles are ≥10 μm and invisible to the naked eye. The cumulative count was less than or equal to 6,000 counts per container, which was within the permissible limits of USP<787>.

[0241] The recovery rate is calculated for all samples (low doses) in all material combinations (PE, PVC, and PP). For medium and high doses, the rate was ≥93%. [Table 10-1] [Table 10-2] [Table 11-1] [Table 11-2]

[0242] Conclusion and Recommendation The compatibility of diluted drugs (DP) is determined by three infusion bags and two different infusion tubes. Tests were conducted using the contact surfaces of two different in-line filters to identify representative clinically administered materials. The ingredients were adjusted to be appropriate.

[0243] Ambient conditions and low-temperature storage conditions (in darkness, at 2-8°C for 20 hours, and with exposure to light) Three types of infusion bags (PE, PVC, and PVC) were exposed to both of the ambient conditions for 4 hours. The physicochemical stability of the DP injection solution in P) up to 24 hours is determined by the physicochemical analysis data. Therefore, this is supported. Bag injection, each injection set (injection bag, injection line, inline This procedure was performed over approximately 60 minutes using a filter, a two-way stopcock, and a catheter. .

[0244] Tested injection bag combinations (PE bag, PE line, PES positively charged filter; P VC bags, PVC lines, PES neutral filters; PP bags, PVC lines, PES Regarding the neutral filter, no major changes were observed in the physicochemical analysis test [appearance of the solution]. (Turbidity, color, pH, purity by SE-HPLC) This allows for compatibility with the selected material. Compatibility is demonstrated. At all tested doses, virtually no visible particles were present. It was rare. After simulated administration using an in-line filter, particles invisible to the naked eye were detected by the drug. It was within the requirements of the Japanese Pharmacopoeia. The in-line filter prevented particles invisible to the naked eye from being filtered. An effective reduction was demonstrated, and all samples were within the acceptable limits for injection. The injection volume was 1 Assuming it is equal to 00 mL, the number of particles invisible to the naked eye (≥25 μm) is 600 per container. The count of particles less than or equal to the count, and invisible to the naked eye ≥ 10 μm, is in the container. The number of counts per unit was less than or equal to 6000. In clinical situations, The use of a filter is highly recommended.

[0245] This study includes a target concentration range from 0.5 mg / mL to a maximum of 3.0 mg / mL. Recovery rate as the concentration of the sample before and after filtration compared to the theoretical initial concentration (≧9 3%) at all dosage levels: low dose, medium dose and high dose (0.5 mg / mL, 1.5 For mg / mL and 3.0 mg / mL, all combinations of materials tested (PE bag) PVC bags, PVC lines, PES positively charged filters; PVC bags, PVC lines, PES neutral filters We obtained information on filters (PP bags, PVC lines, PES neutral filters).

[0246] DP is present in each of the following combinations at concentrations of 0.5 mg / mL to 3.0 mg / mL in 5% glucose. The target concentration range in mL is considered to be clinically appropriate for the component: Combination 1: ○ Injection bag (PE contact material) ○ Injection line (PE contact material) ○ In-line filter (PES, positive charge) ○ Three-way stopcock (PA contact material) ○ Catheter (PUR contact material) Combination 2: ○ Injection bag (PVC contact material) ○ Injection line (PVC contact material) ○ In-line filter (PES, neutral) ○ Three-way stopcock (PA contact material) ○ Catheter (PUR contact material) Combination 3: ○ Injection bag (PP contact material) ○ Injection line (PVC contact material) ○ In-line filter (PES, neutral) ○ Three-way stopcock (PA contact material) ○ Catheter (PUR contact material)

[0247] (Example 2) Treatment of patients with atrial fibrillation using antibody 1 summary This study is for individuals with a low risk of atrial fibrillation (AF), thromboembolic stroke, or peripheral embolism. Safety, tolerability, pharmacokinetics (PK), and drug of antibody 1 in patients with atrial flutter. A multicenter, randomized, subject- and physician-blind study to evaluate the dynamic (PD) effect. This was a controlled, placebo-controlled, parallel-group, repeated-dose-escalation study. Up to three different doses of antibody 1 for factor XI (FXI) inhibition, coagulation indicators, and thrombosis. The effect on biomarker formation was evaluated compared to placebo. The response at the injection site was also assessed. The incidence of bleeding events, immunogenicity, and systemic arterial and venous thromboembolic events was also evaluated. The results obtained from this study indicate the need for antibody 1 for a Phase 3 trial in patients with AF. It helps in selecting the appropriate dosage.

[0248] Detailed explanation This study is for patients with atrial fibrillation (AF) or atrial flutter who are at low risk of stroke. It was a randomized, blinded, placebo-controlled, dose-finding study. Patients were enrolled in up to three cohorts, each consisting of approximately 16 patients. The study lasted up to four weeks. After the leaning period, patients were randomized in a 3:1 ratio (1 antibody:placebo) and given monthly doses. Three subcutaneous (sc) injections were administered, and pharmacokinetic and pharmacodynamic studies were conducted over a 90-day treatment period. Efficacy and safety events were tracked. Patients were discontinued / followed up. Follow-up was conducted up to day 170 of the period.

[0249] Inclusion Criteria The inclusion criteria for patients to be enrolled in the clinical trial described in this example are as follows. - Patients who provided written informed consent before any evaluation was performed; - Individuals aged 18 to under 85 years with paroxysmal heart disease detected by 12-lead electrocardiogram at screening. Male and female patients with atrial fibrillation (PAF) or atrial flutter; or screen Even if PAF is not present during the training (remote measurement method, 12-lead electrocardiogram test or This has been demonstrated by portable [e.g., Holter] monitoring and under reversible conditions (e.g. (If,) a person has a history of PAF or atrial flutter that is not caused by excessive alcohol consumption. (There is no time limit for this) Patient; - CHA2DS2-VASc risk score (stroke risk in patients with AF) A tool used as a predictor for estimating the risk, Lip et al. 2010, found that for men... The range is 0-1, and for women it is 1-2, and at the discretion of the physician in charge of the examination, for stroke prevention. Patients who do not require the use of anticoagulants; - Patients whose weight, including both ends, is between 50 kg and 130 kg.

[0250] Exclusion criteria The criteria for excluding patients from enrollment in the clinical trial described in this embodiment are as follows: - At the time of registration, or within 5 half-lives prior to registration, or the predicted PD effect is baseline. Until returning, whichever is longer; or longer if required by local regulations. Patients who used other investigational drugs within the specified period; - Patients with a history of stroke, transient ischemic attack, or systemic embolism; - Patients with a history of significant bleeding during treatment with anticoagulant or antiplatelet therapy (1 year) Patients who have previously experienced significant bleeding during anticoagulant or antiplatelet therapy should be aware that bleeding may be more severe in the following cases. , if caused by a reversible condition, such as a gastric or duodenal ulcer, and successfully treated. Registration is only possible in certain cases; - Patients with a history of traumatic or non-traumatic intracranial, intraspinal, or intraocular hemorrhage; - Patients with a known predisposition to bleeding or any known active bleeding event; - Myocardial infarction, unstable angina, or coronary artery bile duct injury within 12 months prior to the screening period. Patients who have undergone CABG (catheter arterial bone transfer) surgery; - Moderate or severe mitral stenosis (valve area <1.5 cm²) 2 ) including known clinical Patients with critically important heart valve disease; - Patients with artificial heart valves; - SBP / DBP ≥ 160 / 100 mmHg is defined at the time of the screening visit. Patients with uncontrolled hypertension - New York Heart Association Patients with (NYHA) Class III-IV heart failure; - Are you currently receiving treatment with anticoagulant medication or have you received anticoagulant medication within the past 12 months? Patients who have received anticoagulation treatment; for potential patients who have received anticoagulation treatment more than 12 months prior, treatment will be administered before enrollment. Discussion with the trial sponsor is necessary; - Receiving treatment with P2Y12 inhibitors or antiplatelet therapy such as aspirin. Patients (low doses of aspirin, defined as ≤100 mg / day, are acceptable); - During the screening visit, Modification of Diet in R The glomerular filtration rate estimated by the endovascular disease (MDRD) equation is ≤4 5mL / min / 1.73m 2 Patients with severe renal impairment as defined below. - During screening, human immunodeficiency virus (HIV), hepatitis B (hepatitis B surface antibody) Test positive for hepatitis B1 (HBsAg) or hepatitis C (anti-hepatitis C antibody (anti-HCV)). Patients; - If the patient has not resolved within four weeks prior to medication administration, or has a serious illness as determined by the investigating physician. Patients who do this; - Physiological pregnancy is possible unless a highly effective method of contraception is used during the trial period. Patients who are women of childbearing potential, defined as all women who are capable of pregnancy. Highly effective contraception. The methods include: ○Total abstinence (if this aligns with the subject's preferred normal lifestyle). Periodic abstinence (for example) , calendar, ovulation, symptomatic body temperature, post-ovulation method, and abortion by intercourse are unacceptable methods of contraception. ru; ○ A woman has undergone sterilization (including hysterectomy or sterilization) at least 6 weeks prior to taking the drug for investigation. Bilateral oophorectomy (without ovarian ligation), hysterectomy, or tubal ligation. Oophorectomy alone. In some cases, the reproductive status of women is confirmed by follow-up hormone level assessments. Only in certain cases; ○ Male sexual partner must be sterilized (at least 6 months prior to screening). For female participants in the trial, the only partner of the participant was a male partner who had undergone a vasectomy. It should be toner; ○ Oral (estrogen or progesterone), injectable, or implantable hormones Contraceptive methods using IV fluids, or intrauterine devices (IUDs) or intrauterine systems (IUSs) Placement, or other forms of hormonal contraception with equivalent effectiveness (failure rate <1%), for example If so, use of a hormonal vaginal ring or transdermal hormonal contraception. In the case of oral contraception, women, The same birth control pill should be used consistently for at least three months prior to taking the investigational drug. - Women should have an appropriate clinical profile (e.g., age-appropriate, vasomotor symptoms). If there has been spontaneous amenorrhea for 12 months accompanied by a history of (such as) At least 6 weeks prior, a bilateral surgical removal of the oophores (with or without hysterectomy), or a total hysterectomy. If you have undergone tubal removal or tubal ligation, you are considered postmenopausal and the possibility of pregnancy is eliminated. It is considered that in the case of oophorectomy alone, the woman's reproductive status is monitored with follow-up hormones. Confirmed by a 1-level evaluation, it is determined that there is no possibility of pregnancy based on follicle-stimulating hormone (FSH). Only if applicable. Male participants also consent to the use of highly effective contraceptives during the trial. He must not become a father or donate sperm during this period; - Patients who are pregnant or breastfeeding (nursing / lactating) women Here, pregnancy is considered after contraception and positive human chorionic gonadotropin (hCG) laboratory testing. Therefore, it is defined as the condition of a woman up to the end of her pregnancy; - The opinion of the physician in charge of the study suggests that there is a risk of violating compliance with the study protocol. Patients with a history of mental illness or substance abuse; or - Based on the opinion of the physician conducting the trial, if a patient participates in the trial, that patient is at high risk. Exposure to or preventing the patient from meeting the requirements of the trial or completing the trial. A patient with a high probability of having any surgical or medical condition.

[0251] Dosage and administration Each patient was randomly assigned a dose level upon participation in the trial. In a particular embodiment, The patient receives 120 mg of antibody once a month via subcutaneous injection on day 1, and then once a month thereafter. The patient received two injections of the antibody 1 18 once a month on day 1. In one particular embodiment, the patient received one injection of the antibody 1 18 once a month on day 1. 0 mg was administered by subcutaneous injection, followed by two monthly injections. A specific implementation method In this scenario, the patient receives a placebo via subcutaneous injection once a month on day 1, and then once a month thereafter. I received two injections.

[0252] Outcome evaluation criteria The primary outcome measure is the trough level at day 91 for each dose cohort of antibody 1. Inhibition of FXI by ≥50%, ≥80%, or ≥90% (when free FXI is <50%, <20%) For each dose cohort of antibody 1, it is determined that a percentage or <10% has been achieved. Trough level (defined as the lowest concentration of antibody 1 reached) after the third dose (day 91) This was an inhibition of FXI at that time. This was evaluated on day 91 of the trial.

[0253] Secondary outcome evaluation criteria include the initial dose for each dose cohort of antibody 1. trough (before administering the next dose) after the second dose (on days 31 and 61, respectively) This includes inhibition of FXI at the lowest concentration (defined as the minimum concentration at which antibody 1 is reached), and each dose of antibody 1 For the cohort, at trough times on days 31 and 61, the percentage was ≥50%, ≥80%, or ≥9%. 0% inhibition of FXI (free FXI <50%, <20%, or <10%) is achieved. This was determined to be the case. This was evaluated on days 31 and 61 of the trial.

[0254] Additional pre-specified outcome criteria include major cardiovascular, cerebrovascular, and systemic arterial events. The effect of antibody 1 on the incidence of venous thromboembolic events was evaluated compared to placebo. To address serious cardiovascular, cerebrovascular, systemic arterial, and venous thromboembolic events (VTEs) An analysis of occurrences was included. If such an event occurred during treatment, the initial dose of the study or Record the dosage of the study drug up to the last dose, and permanently discontinue the study drug before the third dose on day 91. If so, it was recorded for an additional 30 days. D-dimer and other exploratory thrombus-forming biomass The concentration of the marker was also evaluated, and the D-dose when using antibody 1 was compared to placebo during the treatment period. Changes from baseline in IMER and other thrombus formation biomarkers were determined. The biomarkers were measured at the time of screening, as well as on days 1, 11, 31, and 61. Evaluations were performed on the 71st, 91st, and 121st day.

[0255] Safety evaluation The entire body, skin, lymph nodes, head, eyes, ears, nose and throat (HEENT), neck, and rib cage. A physical examination including assessment of the lungs, cardiovascular system, abdomen, musculoskeletal system, and nervous system is performed at the time of screening. , as well as day 1, day 11, day 31, day 61, day 91, day 121, and day 17 The decision was made on day 0. Biometrics including seated diastolic and systolic blood pressure, pulse, temperature, and weight. Screening of pre-dose, post-dose, and baseline values ​​at the time of tartness measurement. During the training period, as well as on day 1, day 11, day 31, day 41, day 61, day 71, and day 91. The results were determined on the 101st, 121st, and 170th day.

[0256] Measure 12-lead electrocardiogram (ECG) parameters at each time point for each procedure (QTc-Fred Erica, QT, RR, heart rate, PR, and QRS), list and descriptive statistics (n, average). The data was summarized using the mean, standard deviation (SD), median, minimum, and maximum values. A list of individuals with abnormal ECG results was displayed and calculated. The baseline was the first instance of the investigational drug. These were the values ​​immediately before administration. These parameters were measured at the time of screening, as well as on day 1 and day 9. The decision was made on day 1 and day 170.

[0257] Safety testing analysis for hematological tests, clinical chemistry tests, and urine analysis is screened. At the time of the event, as well as on day 1, day 11, day 31, day 41, day 61, day 91, and day 121 It was performed on day 170 and on day 170.

[0258] By evaluating symptoms or signs consistent with a reaction or hypersensitivity reaction at the injection site, Hypersensitivity reactions and reactions at the injection site will be monitored on days 1, 11, and 31. This was done on the 41st, 61st, and 71st days.

[0259] Including the incidence, severity, association, duration, and determination of whether the event is a SAE. Adverse events (AEs), including serious adverse events (SAEs), were recorded from the time of screening. All AEs or SAEs that occurred by the end of the trial (day 170) were recorded.

[0260] During the treatment period, serious bleeding events were observed when using antibody 1 compared to placebo. We recorded the occurrence of non-critical (CRNM) bleeding events and total bleeding. If such a bleeding event occurs during the procedure, continue taking the test drug from the first dose to the last dose. Record the data, and if the subject permanently discontinues the study drug before the third dose on day 91, add 30. I recorded it for several days.

[0261] The screening and confirmation of antidrugs (anti-antibody 1) and antibodies (ADA) were evaluated to determine the presence of antibody 1. Immunogenicity was evaluated compared to placebo. Screening was performed on days 1, 31, and 61. The tests were performed on days 71, 91, 121, and 170.

[0262] Biomarker evaluation The results of this study demonstrated the high efficacy of antibody 1. As shown in Figure 2A, 1 At a dose of 20 mg, the peak level of antibody 1 in plasma showed a gradual decrease, and this indicates that The long half-life of the antibody is highlighted. Similarly, the free factor XI observed in serum A sustained decrease was observed with a dose of 120 mg (Figure 2B). Multiple doses of antibody 1 When administered at doses of 120 mg and 180 mg, plasma levels were compared to a single dose. A significantly longer-lasting decrease in free FXI was observed (Figure 2C). Points were observed in each figure. The data is represented, and the line represents a smoothed "loess" curve (showing the relationship between two variables). The numbers at the bottom represent the percentage of BLQ records in each time group.

[0263] (Example 3) Treatment using antibody 1 in patients undergoing elective unilateral total knee arthroplasty (TKA). Objectives and rationale The purpose of this study was to evaluate the postoperative remission rate of patients undergoing elective unilateral total knee arthroplasty (TKA). Antibody 1 against standard treatment (enoxaparin) to prevent vascular thromboembolism (VTE) The objective was to demonstrate its antithrombotic efficacy early on.

[0264] In two Phase 1 mono-escalation dose studies, antibody 1 was safe and well-tolerated, and related Continuous doses for 4 weeks or longer produce robust and sustained factor XI (FX) I) It is thought to result in inhibition and prolongation of activated partial thromboplastin time (aPTT). It was done.

[0265] Intravenous administration (iv) of antibody 1 was tested at three doses (30 mg, 75 mg, and y (150 mg). With these doses, free FXI was released in 90% of subjects on day 10. From baseline, the percentage decreased by ≥43%, ≥97%, and ≥99%, reaching 90% of the target group by day 30. A decrease of ≥7%, ≥18%, and ≥93% was predicted.

[0266] It was predicted that all doses would be effective in preventing VTE.

[0267] the purpose The primary objective of this study is to determine the incidence of total vascular thrombosis (VTE) in patients undergoing unilateral total knee arthroplasty (TKA). After randomization, up to day 10, at least one dose of antibody 1 is administered to enoxapa. The objective was to evaluate whether it was non-inferior to phosphorus 40 mg. Non-inferiority (NI) They were satisfied, and then tested for superiority.

[0268] The secondary objectives of this clinical trial were as follows: - After randomization, significant bleeding and Compared to enoxaparin in terms of the incidence of clinically significant non-critical (CRNM) bleeding. To evaluate the effect of antibody 1; and - During the 30th day after randomization and at the end of the trial (EoS) visit, undergoing unilateral total knee arthroplasty (TKA). Regarding the incidence of total VTE determined in patients, at least one dose of antibody 1 However, evaluate whether it is non-inferior to enoxaparin 40 mg. If this is the case, a test will be conducted for superiority. A test for non-inferiority will be conducted during the treatment period, up to day 30. confirmed asymptomatic DVT, confirmed symptomatic VTE, and fatal cases up to day 110. Composite deaths of PE and non-fatal PE, or deaths of unknown cause in which PE cannot be ruled out. This is done by evaluating the occurrence of point markers.

[0269] The exploratory objectives of this clinical trial were as follows: - Multiple confirmed major bleeding and CRNM bleeding up to day 10 and day 30 Critical outcomes are assessed by the occurrence of the combined endpoint, up to day 10 and up to day 30. Regarding the incidence of normal bleeding events and CRNM bleeding events, antibody 1 compared to enoxaparin To evaluate the effect. - Multiple confirmed major bleeding and CRNM bleeding up to day 10 and day 30 Critical events up to day 10 and day 30 are assessed by the occurrence of the combined endpoint. The incidence of bleeding events, CRNM bleeding events, and total bleeding events compared to enoxaparin. Evaluate the effect of beta antibody 1. - Composite endpoint of confirmed major bleeding and CRNM bleeding up to day 110 Major bleeding events, CRN, and CRN are evaluated based on their occurrence up to day 10 and up to day 30. Efficacy of antibody 1 compared to enoxaparin regarding the incidence of M hemorrhagic events and total hemorrhagic events. To evaluate. - The percentage of patients who required blood transfusions by day 30 and by the time of EoS's visit, and 3 Evaluated by the number of blood units transfused on day 0 and by day 110 / EoS visit. Major bleeding events up to day 10 and day 30, CRNM bleeding events, and total bleeding To evaluate the effect of antibody 1 compared to enoxaparin on the incidence of blood events.

[0270] Test design This study is a randomized, open-label, blinded endpoint determination study, and is a maximum A 30-day screening period, a 10±2-day treatment period, and follow-up up to day 110. - This involved an up period. Each randomized patient underwent TKA on day 1 of the trial. The patient underwent surgery. During the treatment period, on day 1, the patient received antibody 1 after surgery, or E I received subcutaneous injections of noxaparin once daily until my next visit on the 10th day (±2 days). On the 10th day (±2 days) of the trial, unilateral venography of the leg that underwent surgery was completed. The treatment period for this study has now ended. After the treatment period, the patient will undergo the follow-up period of this study. I stepped in.

[0271] antibody 1 Antibody 1 was supplied as a liquid (150 mg / mL) in a vial concentrate. Store at 2-8°C according to the information on the label and do not freeze. Antibody 1 is a drug Prepared for intravenous infusion by a qualified pharmacist or authorized pharmacist.

[0272] Enoxaparin Enoxaparin (enox) 40mg sc was used as a comparator drug, and the requirements of the local country and It was used in accordance with regulations. Storage conditions as described in the prescription information were followed.

[0273] group This study included 600 male and female patients aged 18 or older who required elective unilateral knee replacement surgery. It was included in that evaluation of venography was not possible for approximately 20% of the randomized patients. It was predicted that approximately 600 patients (150 patients per group) would be treated as 48 Randomize to ensure that the primary trial endpoint can be reliably evaluated for 0 patients. If the rate of patients who cannot be evaluated appears to differ from the predicted 20%, randomization will be performed. The number of patients was adjusted to ensure that the primary endpoint of the trial was evaluated for 480 patients. I made it possible.

[0274] Inclusion Criteria The patient inclusion criteria for the clinical trial described in this embodiment are as follows: - Male and female patients (18 years of age or older, but under 80 years of age) - Patients scheduled to undergo elective unilateral total knee arthroplasty (TKA); - Patients who understand informed consent and are willing to provide it in writing. ; - Patients willing to comply with the examination requirements, including venography on day 10 ± 2 days; - Patients weighing between 50 kg and 130 kg, including both ends; and - aPTT and PT / INR are within the upper limit of normal (ULN) at the time of screening. A patient who is [a certain type of patient].

[0275] Exclusion criteria The criteria for excluding patients from enrollment in the clinical trial described in this embodiment are as follows: - Other investigational drugs should be administered within 5 half-lives prior to registration, or the predicted pharmacodynamic effect should be based on baseline. Patients who used the product during the longer period before returning to the hospital; - Either the test drug (including enoxaparin) or its excipients, or a similar chemical compound A history of hypersensitivity to drugs, or drugs of the same biological origin, or Patients with any of the contraindications listed on the noxaparin label; - Full-dose anticoagulant or antihistamines administered at least 7 days prior to surgery and before visiting EoS. The need for dual platelet therapy has been demonstrated, or the potential impact on trial outcomes has been identified. Certain anticoagulants / antiplatelet drugs or any other drugs that affect clotting (low-dose aspirin) Patients who are expected to require concomitant use of steroids (excluding short-acting NSAIDs); - Patients with known or suspected active bleeding at the time of participation in the study; - Patients with persistently positive urine protein or blood tests using urine dipsticks; - History of increased bleeding tendency (e.g., history of bleeding predisposition within the past year, angiogenesis abnormalities) Alternatively, known active gastrointestinal lesions such as gastrointestinal ulcers verified by endoscopy, or gastrointestinal discharge. (Blood history) or any other condition that increases the risk of bleeding in the opinion of the test physician. Patients at high risk of bleeding due to the cause, or patients with a history of intracranial or intraocular hemorrhage; - You have undergone major surgery, including brain, spinal cord, or ophthalmic surgery, within the past six months. a patient; - History of traumatic spinal cord injury, epidural anesthesia, or excessive bleeding during or immediately after surgery. Patients who have; - Patients who have suffered a serious trauma within the past six months; - Patients with a history of VTE; - Patients who have experienced a malignant tumor within the past year, including those with successfully treated basal cell carcinoma of the skin. Excluding squamous cell carcinoma or in situ carcinoma in situ of the cervix; - You have had a myocardial infarction, stroke, or transient ischemic attack within the past six months. patient; - Patients with uncontrolled hypertension as determined by the investigating physician; - Estimated glomerular filtration rate (eGFR) is <60 mL / min / 1.73 m² 2 The patient person; - Patients who, at the discretion of the investigating physician, have clinically significant anemia during screening; - Platelet count <150,000m at screening 3 is or heparin Patients with a history of causative thrombocytopenia; - Known allergies to contrast agents, anticipated poor venous access, and renal function If impaired, or for any other reason identified and indicated by the examining physician Patients who are unable to undergo venography due to this condition; - Patients who are expected to require intermittent use of pneumatic compression devices after total knee arthroplasty (TKA); - Liver dysfunction (ALT / AST > 3 × ULN or total bilirubin > 2 × ULN), liver Patients with a diagnosis of cirrhosis, a history of hepatic encephalopathy, esophageal varices, or portosystemic shunt; - During screening, human immunodeficiency virus (HIV), hepatitis B (hepatitis B surface antibody) Test positive for proto-HBsAg or hepatitis C (anti-hepatitis C antibody [anti-HCV]) patient; - If the patient has a clinically significant abnormal ECG at the time of screening, as determined by the physician conducting the study. Patients who do this; - Patients with a recent or current history of alcohol dependence or drug addiction; - Female patients who are pregnant or lactating; - All women of physiological fertile capacity, unless using highly effective contraception. Female patients who are defined as having the potential to become pregnant; - Patients who have experienced a serious illness that has not resolved within two weeks prior to the start of the investigational drug; - The patient has experienced any illness or other medical condition that prevents them from meeting the examination requirements. patient; or - Patients who are expected to undergo elective surgery (e.g., contralateral total knee arthroplasty) during the trial period.

[0276] Dosage and administration Each patient was randomly assigned a dose level upon participation in the trial. In a particular embodiment, The patient received 130 mg of antibody intravenously (iv) once a month. In a specific implementation... In one specific embodiment, the patient received 1.75 mg of antibody intravenously once a month. In one particular embodiment, the patient received 150 mg of antibody once a month intravenously. The patient then received enoxaparin 40 mg subcutaneously once daily (sc). Antibody 1 It was administered approximately 4-8 hours after TKA surgery. Enoxaparin was administered approximately 1 Administration began 2 hours later, followed by enoxaparin 40 mg until the venography visit on day 10. He received a single 40mg sc enoxaparin injection daily before the TKA surgery. This was done at the discretion of the investigating physician, in accordance with local guidelines.

[0277] Efficacy and safety evaluation Efficacy evaluation: Efficacy was evaluated throughout the entire treatment period up to day 10 (the day of venography), including the surgery. Asymptomatic deep vein thrombosis (D) is diagnosed by unilateral ascending venography of the affected leg. VT), confirmed symptomatic DVT, fatal and non-fatal pulmonary embolism (PE), or PE This was assessed by the occurrence of a composite endpoint of unexplained death that could not be ruled out. The venography interpreter and the primary assessor of the composite endpoint will have an opinion regarding the assignment of procedures. It was then blinded.

[0278] The patient made follow-up visits on days 3, 6, and 10 during the treatment period. The duration of subsequent hospitalization was at the discretion of the investigating physician and followed local medical practices. If a patient is discharged before the 10th day, the patient will be required to undergo clinical evaluation and venography for 10 days. Patients should return to the trial site on ±2 days. If the patient is discharged on or before the 3rd day... In that case, evaluations were collected during the visits on the 3rd and 6th days, but were not repeated. The patient had already completed the evaluation on day 3, although this was before the trial visit on day 4 (6±1 days). If the patient was discharged later, the facility collected an evaluation on day 6 before discharge.

[0279] During hospitalization and at all follow-up visits after discharge, the patient should be checked for signs and symptoms of DVT (swelling, local pain). Pain, redness, heat, local warmth) and signs and symptoms of non-fatal PE (i.e., unexplained cause) The following symptoms may be assessed: shortness of breath, chest pain that worsens with deep breaths, cough or chest movement, or coughing up blood. It was worth it.

[0280] All suspected DVT episodes are diagnosed with compression ultrasound (CUS) or unilateral or bilateral radiofrequency ablation. This was confirmed by rapid objective verification using venography. Scheduled venography (10±2 days) If symptomatic proximal DVT is objectively confirmed by CUS before the eye examination, venography can be omitted. If suspected DVT is not confirmed by CUS, venography may be performed. This should be planned and carried out. If DVT is suspected on the day of venography, venography should be carried out as scheduled. It can be implemented when suspected symptomatic DVT is objectively confirmed by CUS. In this case only, venography can be omitted.

[0281] All suspected PE episodes are diagnosed with ventilated / perfused lung scintigraphy, spiral composite This was confirmed by fluoroscopic tomography or pulmonary angiography.

[0282] If the presence of DVT or PE is confirmed using the above techniques during the treatment period, 10 days Do not perform venography during eye visits. If DVT or PE is not confirmed using the above techniques... If this is the case, the patient must undergo venography.

[0283] Unless otherwise specified above, compulsory venography was performed on the 10th day visit. Collect contrast-enhanced images or images from diagnostic tests for suspected symptomatic DVT and PE, Ce ntral Independent Adjudication Committee The matter was communicated as quickly as possible for review by the CIAC. Members of the CIAC will review the procedure. The allocation process remained blind.

[0284] During the follow-up period, patients will have additional follow-up appointments on days 30, 50, and 110. We conducted a visit to gather additional laboratory parameters related to safety, pharmacokinetics (PK), and other information. Pharmacodynamics (PD) were evaluated. The end-of-study (EoS) visit took place on day 110.

[0285] During the trial, venography, all suspected VTEs, all suspected bleeding events, and unexplained symptoms occurred. Death was continuously determined by CIAC. Total VTE (asymptomatic DVT, symptomatic VTE) Blinding regarding deaths related to PE, total bleeding events, and treatment assignments. The collected data on other safety events were compared to the overall clinical and data for this study. The Steering and Safety Committee (SS), which has scientific responsibility. This data was regularly reviewed by C) the clinical trial team directly involved in conducting the trial. It was kept secret from M. The main purpose of the scrutiny was that the rate of VTE was unacceptable. In such cases, the low-dose or low-to-medium-dose treatment should be discontinued.

[0286] Efficacy is assessed in the trial protocol up to 30 days after randomization and up to the end-of-service (EoS) visit. The confirmed venography of the surgically treated leg on 10±2 days later is detected by unilateral venography. Asymptomatic DVT, confirmed symptomatic DVT, fatal PE and non-fatal PE, Or, the occurrence of a composite endpoint of unexplained death in which PE cannot be ruled out I evaluated it.

[0287] Important safety assessments: Major bleeding and CRN throughout the treatment period and up to day 30. The occurrence of the composite outcome, which was determined to be a M bleeding event, was monitored. Raw, physical examination, hypersensitivity reactions and injection site reactions (ISR), as well as blood and Laboratory markers in urine were monitored.

[0288] Other assessments: For pharmacokinetic (PK) determination, total antibody levels were measured on day 1 and day 3 (pre-surgery). Measurements were taken on day 6, day 10, day 30, day 50, and day 110 (when EoS visited). The following PK parameters were derived using the post-treatment concentration of antibody 1: C max , T max AUC last, C last and T last . If feasible, AUC in f , T 1 / 2 , V d / F , and C L / F . The presence of anti-drug antibodies was measured on Day 1 (before surgery), Day 30, Day 50, and Day 110 (at the EoS visit).

[0289] Coagulation biomarkers including aPTT and PT / INR were measured at screening, on Day 1 (before surgery), Day 3, Day 6, Day 10, Day 30, Day 50, and Day 110 (at the EoS visit); calibrated aPTT and FXI:C were measured on Day 1 (before surgery), Day 3, Day 30, and Day 50; and free FXI and total FXI were measured on Day 1 (before surgery), Day 3, Day 6, Day 10, Day 30, Day 50, and Day 110 (at the EoS visit). (before surgery), Day 3, Day 6, Day 10, Day 30, Day 50, and Day 110 (at the EoS visit).

[0290] Data analysis: Primary stratified Cochran-Mantel-Haenszel (CMH) test efficacy analysis was used to test the null hypothesis that the difference in the incidence of total VTE events determined between low-dose, medium-dose, and high-dose antibody 1 and enoxaparin is equal to or greater than the pre-specified NI margin (14%) versus the alternative hypothesis that at least one difference is less than the NI margin. The primary analysis was based on an overall significance level of 0.025 (one-sided test) for the final analysis conducted together for each comparison. For the non-inferiority test, a confidence interval (CI) approach was used and 95% CIs are shown for the comparison of low-dose, medium-dose, and high-dose antibody 1 with enoxaparin. The difference in incidence was based on an overall significance level of 0.025 (one-sided test) for the final analysis conducted together for each comparison. For the non-inferiority test, a confidence interval (CI) approach was used and 95% CIs are shown for the comparison of low-dose, medium-dose, and high-dose antibody 1 with enoxaparin. The difference in incidence is shown for the comparison of low-dose, medium-dose, and high-dose antibody 1 with enoxaparin. The difference in incidence Since the upper limit of the confidence interval is less than or equal to the NI margin, non-inferiority is achieved. Non-inferiority was demonstrated, so a superiority trial was conducted. Furthermore, the non-inferiority trial and the superiority trial The p-values ​​(based on one-sided tests) for both tests are shown.

[0291] An analysis regarding efficacy was performed on the mITT-set. This population was used for the study drug. The patient receives at least one dose and can evaluate the primary efficacy outcome (i.e., evaluate Valuable venography or confirmed symptomatic DVT, fatal or non-fatal PE or primary This consisted of all patients (with deaths of unknown cause). Multiple comparison procedures were used in the statistical analysis. This was not considered; however, statistical testing was hierarchical.

[0292] Risk and adverse event monitoring Risks based on previous clinical experience with antibody 1 Antibody 1 has been generally well-tolerated in two clinical trials completed to date. Adverse events (AEs) were infrequent and mild in severity, and there was an equilibrium between the treatment group and the placebo group. The results were obtained. No dose-dependent safety findings were observed. Fecal occult blood was detected in a small number of subjects. The reaction test was positive, but these test results remained positive in repeated tests. If present, then absent, or if there were any clinical or laboratory signals indicating active bleeding It was not accompanied by any other symptoms. Therefore, based on previous clinical experience with antibody 1, there is a certain risk. It could not be identified.

[0293] Risk based on preclinical toxicity studies of antibody 1 Although no specific safety pharmacology studies have been conducted, antibody 1 dose was used in a 13-week toxicity study. Qualitative and quantitative electrocardiogram changes resulting from this, and respiratory and central nervous system function None of the following effects were observed. No deaths occurred, and there were no clinical signs, weight, or food intake. ophthalmic and electrocardiogram parameters, hematological test values, clinical chemistry test values, urinalysis values, macroscopic No effect of the test material on laboratory values ​​or histological examinations was observed, and in feces... No occult blood was detected. No adverse findings were identified in this study. The above data Based on the data, no specific predicted risks were identified.

[0294] Biological risks of antibody 1 13 weeks of Good Laboratory Practice (related to drug safety) In toxicity tests conducted in accordance with the Good Laboratory Practice (GLP) standards for conducting non-clinical trials, antibody 1 was used. After treatment, up to a weekly dose of 100 mg / kg sc or 50 mg / kg iv. No overt bleeding, venous puncture, or injection site bleeding was observed.

[0295] Treatment with antibody 1 resulted in bleeding phenotypes similar to those seen in patients with severe FXI deficiency. A phenotypic effect is expected. Unlike hemophilia A and B, FXI deficiency is not spontaneous. It rarely manifests as hemorrhagic bleeding. Hemorrhagic bleeding is infrequent in patients with severe FXI deficiency. It is low, often mild, and can be induced by injury, affecting the oral mucosa, nasal mucosa, and urine. It preferentially affects tissues with increased fibrinolytic activity, such as tracts and other tissues. Joint hemorrhage or intracranial hemorrhage is rare in FXI deficiency (Bolton-Maggs 2000, Dug a and Salomon 2013).

[0296] In healthy subjects (Liu et al 2011) and patients undergoing elective unilateral total knee arthroplasty First-in-human (first-in) -In the human (FIH) trial, FXI-antisense oligonucleotide (AS We also evaluated O). A robust and sustained reduction of >80% of free FXI was observed at the highest dose of 6~ This was achieved over a duration of more than 8 weeks (reaching undetectable levels in a small number of subjects). In this FIH trial, among the 88 subjects who received either FXI-ASO or placebo... No bleeding occurred. Furthermore, in patients undergoing unilateral TKA, FXI-ASO was used: Administering at a dose that achieves an 80% reduction in C compared to low-dose enoxaparin A tendency toward a lower incidence of serious or CRNM bleeding events was observed. High-dose FXI -One major bleeding event occurred in the ASO group (1% of patients) (Buller et al 2015). To reduce the risk of bleeding after treatment with antibody 1, subjects at high risk of bleeding events will be treated with this Exclude from the exam.

[0297] Potential risks associated with hypersensitivity reactions Injection of therapeutic proteins may cause immediate or delayed hypersensitivity reactions. Immediate-type reactions appear in the first few hours after drug administration. Clinical symptoms can range from a wide range of symptoms, for example. Symptoms may include fever, chills, nausea, skin symptoms, bronchospasm, difficulty breathing, dizziness, headache, and muscle pain. This may include tachycardia and / or hypotension. Anaphylaxis, urticaria, and angioedema may also occur. Swelling was also reported. Delayed-type hypersensitivity reactions can appear between 1-2 hours and up to 14 days after administration. It is possible and often accompanied by serum sickness-like symptoms (Corominas et al. 2014). The incidence of hypersensitivity reactions associated with anthropogenic antibodies (mAbs) depends on the degree of humanization and the cells from which the antibody was obtained. It depends on the strain and excipients. Hypersensitivity was observed in both 13-week toxicity studies and FIH studies. No symptomatic reactions were observed.

[0298] Management of hypersensitivity reactions depends on clinical symptoms and severity. Discontinuation of treatment (if applicable). Fluids, vasopressors, corticosteroids, antihistamines, bronchodilators, epinephrine Oxygen can be used as needed.

[0299] Potential complications associated with complement-dependent cell injury (CDC) or antibody-dependent cell injury (ADCC) risk IgG1 mAb is a receptor for the Fc gamma receptor (FcγR) and the human complement 1q subcomponent (C1 It is coupled to q) and therefore has the potential for Fc-mediated effector functionality. In this case, the mAb directly interacts with cells that express FcγR. In the CDC, the mAb interacts with C1q It interacts with, thereby activating the complement system as well as anaphylatoxins and opsonians This leads to the release of n.

[0300] FXI is a soluble target, but it binds to the cell surface, particularly the surface of activated platelets. Therefore, it binds to the platelet glycoprotein Ib α receptor. Any potential changes in platelet function resulting from possible antibody clustering via I To mitigate the risk, two Fc receptor functional silencing mutations were used in Fc dormancy. These were introduced into antibody 1. These two mutations resulted in changes to IgG1's FcγR and C1 The binding to q is reduced, and ADCC and CDC in vitro are It has been shown to reduce it (Idusogie et al 2000; Shields et al 2001). Therefore, the risk of ADCC and CDC being triggered by antibody 1 is expected to be low. It will be done.

[0301] Potential risks associated with the test procedure During the test, blood samples are frequently taken either by venipuncture or IV cannula. The risks associated with blood collection include pain, swelling, and / or at the needle insertion site. Contusions are one example. Although rare, local blood clot formation, infection, and nerve damage may occur. It is possible. Drowsiness and / or fainting may occur during or immediately after blood collection. As part of the trial, each randomized patient received 2 over a period of approximately 3.5 months. Collect blood of 00 mL or less. The estimated value of this blood sample will be monitored for any safety findings. This does not include additional sample collection during irregular visits for ringing purposes. This was not considered a risk to this patient population.

[0302] Venography takes 30 to 90 minutes. Bleeding, bruising, or discomfort at the injection site may occur after venography. Localized complications such as staining may occur. Side effects of X-ray contrast agents include itching. It ranges from minor discomfort to life-threatening emergencies. Contrast-induced nephropathy is also This is a well-known adverse reaction associated with the use of intra-arterial contrast agents. Other forms of adverse reactions include delayed response. These include hypersensitivity reactions, anaphylactic reactions, and skin reactions.

[0303] To reduce the risks associated with contrast agent use, patients with a known history of contrast agent intolerance should be treated accordingly. Patients with moderate to severe renal impairment were excluded from the study. Adequate hydration was administered to patients during and after the procedure.

[0304] Patients may have postoperative renal impairment (eGFR < 45 mL / min or baseline at the 6-day visit). If a 25% decrease occurs (defined as a reduction from), to minimize the risk of contrast-induced nephropathy Venography was not performed on the 10th day.

[0305] Potential benefits associated with the use of antibody 1 Patients with severe FXI deficiency have a lower risk of venous thrombosis and stroke than the general population. Salomon et al 2008, Salomon et al 2011, Preis et al 2017). moreover, With an average of 80% reduction in FXI suppression using FXI ASO, patients undergoing unilateral TKA... It showed superior efficacy compared to enoxaparin in terms of total VTE (Buller et al.) al 2015). In some patients, FXI levels are undetectable, but FXI ASO suppression is present. There was no excessive bleeding during the TKA surgery (Buller et al 2015).

[0306] Antibody 1 is an experimental drug, and its clinical utility has not been established; however, early clinical data Therefore, it is suggested that inhibiting FXI may be beneficial as an antithrombotic agent. In the study, in healthy subjects, antibody 1 at doses of 150 mg and higher showed that > This resulted in an average aPTT prolongation of >2x and an average FXI inhibition of >95% over a 4-week period. Based on preclinical data and data from the FIH trial, the safety profile was deemed acceptable. This is shown to be the case. Due to the long duration of action of antibody 1, regarding VTE protection, ene Additional advantages compared to xaparin may be offered (Falck-Ytter et al 2012).

[0307] Treatment assignment and randomization After successful screening according to the study protocol, patients will be divided into the following four treatment groups. One of them was randomized in a ratio of 1:1:1:1. ·Antibody 1 30mg iv×1 ·Antibody 1 75mg iv×1 ·Antibody 1 150mg iv×1 • Enoxaparin 40mg daily until day 10 of sc venography

[0308] Eligible patients were assigned randomization numbers in ascending order. The randomization numbers were assigned by the research physician. The CRF was filled out. The randomization number was provided by Covanc, or Covanc. Under the responsibility of e, random assignment to treatment groups in a specified ratio of randomization numbers is automatically performed. It was generated using a verified system.

[0309] The randomization scheme for patients is Covance Randomization G Reviewed and approved by members of the group. Randomization numbers are used to assign patients to treatment groups. To associate them and to assign a unique drug application number to antibody 1 distributed to the patient. It was used. Randomization numbers were used to ensure that the assignment of treatments was unbiased. I did it.

[0310] This study is an open-label, blinded, endpoint-evaluation study. The patient also received information regarding the assignment of treatment for antibody 1 compared to enoxaparin. The primary safety and efficacy endpoints of this study were determined by CIAC. CIAC members were blinded regarding treatment assignments. Randomization information was then... This information was not disclosed to the clinical trial team before the database lock-up.

[0311] Patient treatment Antibody 1 was administered to the patient via IV infusion by a qualified healthcare professional (Antibody 1). .

[0312] Antibody 1 was supplied to each testing site as an open-label, disposable vial. The test drug for administration was prepared by the pharmacist or designated pharmacist according to the assigned procedure. Each antibody dose was administered as 5% glucose (D5W) in water over approximately one hour. .

[0313] Enoxaparin for SC administration was procured locally by each individual testing site, or Alternatively, through the test sponsor or an agent working on behalf of the test sponsor, the local guidelines It was supplied with an open label in accordance with the regulations.

[0314] Antibody 1 is prepared by a pharmacist or staff at a designated facility, approximately 4-4 days after TKA surgery. Eight hours later, it was administered intravenously as a single infusion over approximately one hour.

[0315] Enoxaparin 40 mg is administered via sc administration approximately 12 hours after TKA surgery. Subsequently, enoxaparin 40 mg was administered daily via SC injection until the venography visit on the 10th day. The single sc dose of 40 mg of enoxaparin before TKA surgery is at the discretion of the investigator. The procedure was carried out in accordance with local guidelines. Enoxaparin treatment beyond venography on day 10. The extension of the period was carried out at the discretion of the investigating physician, in accordance with local medical practices. See Table 12. The administration of antibody 1 and enoxaparin should be described. [Table 12]

[0316] To manage adverse patient reactions or care, adjust the infusion rate (antibody 1) or interrupt the medication (antibody 1). If adjustments are needed for either body 1 or enoxaparin, the infusion rate / injection rate will need to be changed. Details were recorded in the CRF. The trial sponsor should be notified if any of the following occurs: ru: • Interruption of antibody 1 injection time for <30 minutes, ≥2 hours, or ≥60 minutes. • The total amount of drugs administered for either enoxaparin or antibody 1 is assigned. <90% or ≥110% of the dose

[0317] Regarding patients in the enoxaparin treatment group, if the patient is able to tolerate enoxaparin treatment If this is not possible, transient or permanent discontinuation of enoxaparin may be permitted at the discretion of the investigating physician. The quantity should be considered and recorded in an appropriate CRF.

[0318] Test completion and termination The patient completed the trial when the last scheduled visit in the trial protocol was completed. It was considered to be the case.

[0319] If the investigational drug is stopped before the duration of action planned in the study protocol, the patient will be subject to the following: The trial treatment was discontinued. The discontinuation of the study drug was initiated by either the patient or the research physician. It began.

[0320] For the given patient, after consideration, continuing the treatment would have a negative impact on the risks / benefits of participating in the study. If it was suspected that the treatment would cause adverse effects, the trial physician discontinued the trial procedure.

[0321] The trial procedure was discontinued under the following circumstances: patient request, pregnancy, use of prohibited treatment, or participation in the trial. Any situation in which a greater safety risk to the patient may arise, or the entire patient Taking into consideration the patient's condition, the trial physician's actions may prevent the patient from continuing to participate in the trial. Abnormal test values ​​determined by judgment.

[0322] Patients treated with antibody 1 received only one dose of the drug during the study; Therefore, it was not possible to discontinue the treatment. Considering the half-life of antibody 1, the PTT level was determined to discontinue the treatment. The patient was closely monitored by the study physician throughout the trial period and follow-up period.

[0323] If a bleeding event occurs in a patient who has received treatment with enoxaparin, the research team A physician may, based on the clinical situation, delay, temporarily discontinue, or permanently discontinue the drug. The question was whether it could be discontinued after a long time. The patient received treatment with enoxaparin. The management of bleeding events in patients is at the discretion of the investigating physician and in accordance with local clinical practice. It was done.

[0324] Platelets are closely monitored using local testing equipment in accordance with standard medical practices. The platelet count was 100,000 / mm³. 3 It decreased to less than 50% or more than 50% If the symptoms are mild, discontinue enoxaparin treatment and evaluate for heparin-induced thrombocytopenia. The evaluation was conducted. The continuation of VTE prevention measures is at the discretion of the investigating physician and local clinical practice. We should follow Xi Jinping's lead.

[0325] Symptomatic VTE events were observed in patients treated with enoxaparin. If so, administer a therapeutic dose of enoxaparin, followed by a therapeutic dose for an appropriate duration. Oral anticoagulants (DOACs) or warfarin may be prescribed by the investigator based on local clinical practice. It was considered accordingly.

[0326] Procedure and evaluation The evaluation schedule shown in Table 13 indicates the timing and type of evaluation during the test. This is explained in detail.

[0327] Screening period (-30 days to -1 day) Written informed consent regarding this examination will be provided in accordance with all examination-related procedures. I got it before.

[0328] After identifying potential patients, before conducting any screening evaluations related to any trial, The patient signed the Formed Consent Form (ICF). AE and SAE reporting period. It began when the ICF was signed.

[0329] It takes up to four weeks to complete the screening evaluation and determine the patient's eligibility for the trial. A period was provided during the screening period. During the screening period, the patient's medical history and vital signs were taken. I underwent a physical examination including a 12-lead ECG. Clinical laboratory tests and other screenings were also performed. Blood and urine samples were obtained for evaluation.

[0330] If a patient's test results are borderline abnormal, and / or if the surgical procedure is scheduled, In this case, re-screening of the patient was permitted. Only once during the patient re-screening trial was permitted. It was accepted. [Table 13-1] [Table 13-2] [Table 13-3]

[0331] Re-screening evaluations were collected right up until the TKA surgery on day 1. In this situation, turn To expedite the turnaround time, we sent the re-screening samples to the local laboratory. For patients enrolled in the trial, all results were available before the TKA surgery.

[0332] Treatment period (Day 1 to Day 10 ± 2) Patients randomized to antibody 1 received a single dose of the study drug approximately 4–8 hours after surgical wound closure. .v. Injection was received. For patients assigned to enoxaparin, post-TKA surgery Approximately 12 hours later, a 40 mg subcutaneous (sc) administration was started, followed by on day 10 ± 2. The drug was administered daily until the venography was completed.

[0333] The patient confirmed all visits within the designated date or time frame. (Surgery) The duration of hospitalization after surgery is at the discretion of the investigating physician and follows local medical practices. Yes, it was. The patient was on day 4 (before the trial visit on day 6±1), but the evaluation on day 3 had already been completed. If the patient was discharged (after the procedure), the facility collected the evaluation on day 6 before discharge. Day 10 (±2 All patients who were discharged before [date] will be required to return on the 10th day for clinical examinations and venography evaluation. Then I returned to the testing facility.

[0334] At every visit, the trial physician will provide a clinical assessment of AEs, including DVT / PE, bleeding events, and ISR. Observe and record any signs, symptoms, and changes in concomitant medications.

[0335] Follow-up period (10 days ± 2 to 110 days) After venography, the patient visited the testing center as an outpatient, as indicated in the evaluation schedule. —Returned to the clinic. Tracked the patient until their visit to the testing center on day 110 (when they visited EoS). Ta.

[0336] At every visit, the trial physician checked and recorded the following: DVT / PE, bleeding events. Clinical signs and symptoms of adverse events (AEs), as well as changes in concomitant medications.

[0337] Effectiveness The primary efficacy outcome was the rate of surgery throughout the treatment period up to day 10 (the day of venography). Asymptomatic DVT detected by unilateral ascending venography of the affected leg, confirmed symptomatic DVT T, lethal PE and non-lethal PE, or death of an unknown cause in which PE cannot be ruled out. It was a combination of "death" and "completion".

[0338] Secondary efficacy outcomes were measured up to day 30 and up to day 110 (EoS) of the trial. The implementation plan requires unilateral venography of the operated leg on day 10±2. Asymptomatic DVT detected, confirmed symptomatic DVT, fatal and non-fatal PE, Alternatively, it was a composite of deaths of unknown cause in which PE could not be ruled out.

[0339] Venography Unilateral ascending venography of the leg that underwent surgery was performed on the visit 10±2 days later (Rabinov and Paulin, 1972). Details regarding venography procedures and image acquisition are provided separately to each testing facility. This information was provided in the venography manual and event report.

[0340] The results of the detailed examination were as follows: • No blood clot • Distal blood clot • Proximal blood clot • Distal and proximal blood clots • Distal blood clots could not be evaluated, but there were no proximal blood clots. • Impossible to evaluate

[0341] Clinical tests for DVT / PE Patients should be diagnosed with signs and symptoms of DVT (e.g., swelling, local pain, redness, heat, local warmth). ) and signs and symptoms of PE (e.g., shortness of breath of unknown cause, chest pain that worsens with deep breaths) Regarding cough or hemoptysis, all patients during hospitalization after surgery and after discharge will be treated accordingly. The evaluation was performed during low-up contact.

[0342] All suspected DVT episodes were confirmed by CUS or venography. If T is suspected, it is acceptable to first perform CUS. The outcome of CUS is Venography was only necessary when proximal leg DVT was observed.

[0343] All suspicious PE episodes are treated with ventilation / perfusion scintigraphy, spiral compilation. This was demonstrated by transcatheter tomography (CT) or pulmonary angiography using the above techniques. If the presence of PE was confirmed, the above technique did not require venography on day 10. If PE was not confirmed after use, the patient underwent venography.

[0344] bleeding The primary safety outcome is observed during the treatment period (from the first administration of the study drug to venography on day 10). (and) when the End of Service (EoS) exam visits on day 30 and day 110 (or when the exam is terminated / end early) The combination of major bleeding and CRNM bleeding events up to that point was significant.

[0345] All suspected bleeding events were confirmed and reported by the research physician. If deemed necessary, additional tests were performed (for example, hemoglobin, as recorded). Robin (Hb), hematocrit (Hct), aPTT, PT, INR, and platelet count. A blood sample for testing, or an endoscopy depending on the type of bleeding, and, if applicable, packed red blood Number of blood transfusions and the amount of blood transfused per unit.

[0346] During the trial, other bleeding-related parameters were recorded: • Changes in Hb levels, Hct, and red blood cell count during the treatment period • Blood loss quantified using standard methods at each hospital (before and after surgery) • Number and amount of packed red blood transfusions up to 30 days after surgery (also related transfusions and autologous transfusions) (These need to be distinguished.)

[0347] Decreased hemoglobin, observed blood loss, or more blood transfusions than expected after total knee arthroplasty (TKA). Several suspected bleeding events were recorded.

[0348] Pharmacokinetics PK samples were collected at a given time. Ce regarding sample collection, numbering, processing, and transport. I followed the instructions summarized in the Central Laboratory Manual.

[0349] To better define the PK profile, the timing of PK sample collection will be changed to a new method. Changes were made based on the data. The number of sample / blood extractions and the total amount of blood collected were changed based on the test results. It did not exceed what was stipulated in the implementation plan. The timing of the PK evaluation was changed. In that case, the implementing facility was notified via a dosage adjustment record.

[0350] With the exception of patients assigned to the enoxaparin group, all patients at all dose levels are affected. PK samples were obtained and evaluated.

[0351] Total antibody 1 in plasma (i.e., antibody 1 bound to FXI or antibody 1 not bound to FXI) The concentration of antibody 1) was determined by a validated LC-MS / MS method. Total antibody 1 concentration A detailed explanation of the methods used to quantify the raw data of the bioanalysis and Bioana Included in the critical data report. Concentrations below LLOQ or missing data. All data was displayed in this way in the concentration data list.

[0352] If the data allows, the actual recorded sample collection time and Phoenix WinNonl Non-compartmental processing using in (Version 6.2 or higher) Using the t-method (one or more), the following PK parameters are determined based on plasma concentration data. Determined: C0 (final injection concentration), AUC last AUC inf , C0 / D, oyo AUC / D. The linear trapezoidal rule is used to calculate AUC. Terminal phase half-life (T) of antibody 1. 1 / 2) Distribution volume (Vss) and clearance (CL) are also calculated based on the data, if feasible. The following estimations were made. Additional PK parameters were calculated as needed.

[0353] Plasma total antibody concentration data is listed by dose, patient, and visit / sample collection time. Descriptive summarized statistics are presented for each dose and visit / sample collection time, where L The frequency (n, %) of concentrations below the LOQ was reported as zero.

[0354] The summarized statistics include the mean (arithmetic and geometric), standard deviation (SD), and coefficient of variation (CV) (arithmetic and geometric). The values ​​included the geometric, median, minimum, and maximum. max These are the median, minimum, and maximum. Only the largest values ​​are shown. Concentrations below LLOQ were excluded from the summarized statistics. The geometric mean was not reported if the value included zero. The PK parameter was calculated as described above. The data was then compiled into a list by dosage and patient.

[0355] Dose-proportional exposure was evaluated by measuring C0 and AUC after single-dose administration of antibody 1. last , and AUC inf The analysis was performed using the following method: the parameters were logarithmically transformed, and the analysis was performed using a power model. The formula is: ln(PK) = μ + β × ln(dose). The point estimation of the slope (β) is 90%. This was obtained from the model along with the confidence interval (CI).

[0356] Pharmacodynamic evaluation PD samples were collected at the time specified in the evaluation schedule. Regarding the processing of biological samples... The instructions concern sample collection, numbering, processing, and transportation at the Central Laboratories. It was included in the Ory Manual.

[0357] To better define the PD profile, the timing of sample collection will be updated with new data. The following changes were made based on the test results: the number of sample / blood extractions and the total amount of blood collected were measured by the test implementer. It did not exceed what was specified in the drawing book. PD trials were conducted for all patients at all dose levels. I obtained the fee and evaluated it.

[0358] While not limited to these, the following biomarkers were tested: • Free FXI - Free FXI measured in plasma (FXI not bound to antibody 1) • Total FXI - FXI, either bound to antibody 1 or free, as measured in plasma. • Calibrated aPTT for FXI deficiency • FXI coagulation activity (FXI:C) measured in plasma

[0359] The logarithmically transformed ratio of baseline free to FXI is used in the mixed model's repeated measures (Mix Using the Model Repeated Measure (MMRM) method, Placement, visit, treatment * Visit interaction, log (baseline) and log (baseline) *Including visitor interactions as an effect, the analysis was performed using an unstructured variance-covariance matrix. Other models can be considered. Dose-response can be explored using appropriate comparisons. This can be done. The ratio to baseline for each treatment and the baseline for each antibody dose can be calculated. Placebo-adjusted ratios relative to the line, along with their associated confidence intervals, after inverse transformation. Derive the result. Furthermore, compare the ratio to baseline among the dose groups that received antibody 1. aPTT and other PD and biomarker parameters were analyzed using the same method. The relationship between free FXI, FXI:C, and aPTT levels is examined using diagrammatic and regression methods. Explore using [this method].

[0360] immunogenicity Anti-antibody 1 anti-drug antibody (ADA) was detected using a ligand-binding assay.

[0361] Exploratory biomarkers (blood) Blood samples were collected at the time specified in the evaluation schedule. It was deemed appropriate. If so, these samples were deposited in a bank for potential future analysis. This includes, but is not limited to, the exploration of D-dimer and other thrombus-forming and coagulation activities. The target marker can be tested.

[0362] Effectiveness As listed in Table 12 above, receive antibody 1 after total knee arthroplasty (TKA) surgery. Based on the evaluation of venous thromboembolic (VTE) events in patients compared to enoxaparin. Antibody 1 was shown to be effective in preventing TKA-associated VTE. 30 mg ("Group B"), 75 mg ("Group C"), or 150 mg ("Group D") The results for patients who received a dose of enoxaparin 40 mg are shown in Figure 3A. The greatest efficacy was observed in patients who received 175 mg. The results of this study are similar to those of the previous study. In the patient population (those who undergo TKA surgery), Buller et al. NEJM (2015) found that Factor XI antisense oligonucleotide (FXI-ASO) (Figure 3B) and Weitz et al. JAMA (2020) used osocimab (FOXTROT) (Figure 3C) to treat VT Compare with publicly available clinical trials where E-events were evaluated. By comparison, antibody 1 is compared to TK Regarding the prevention of surgery-related VTE, which dose was tested in the FOXTROT trial? It was found to be more effective than osocimab, and also the highest dose of FXI-AS Similar effectiveness to O was demonstrated.

[0363] Biomarker analysis The preliminary results of this study demonstrated the high efficacy of antibody 1. (See Figure 4A) As shown, based on the peak level of antibody 1 in plasma, the TKA trial is performed on healthy subjects. A clear concentration in plasma compared to the PK / PD test performed (referred to as "PK" in the diagram) Differences and patterns were demonstrated. In contrast, the free factor XI observed in plasma was related to Therefore, as observed in the tests using antibody 1, approximately 5% of the treated subjects showed a decrease in antibody 1. A significant decrease was observed up to 7 days (Figure 4B). In each figure, the dots represent the observed data. The line represents a smoothed "loess" curve (showing the relationship between two variables), and the numbers at the bottom... This represents the percentage of BLQ records in each time group.

[0364] safety Serious adverse events (SAEs), including major bleeding events, and clinically significant but not serious events. Based on the analysis of (CRNM) bleeding, is antibody 1 safe in patients who have undergone TKA surgery after surgery? The tolerability was good. Patients who received antibody 1 compared to patients who received enoxaparin. The risk of SAE or bleeding events was slightly increased, but still low. These risks are observed in patients treated with FXI-ASO or FOXTROT. Compared to the above, the levels were slightly reduced. Antibody 1, FXI-ASO, or FOXTROT Table 14 shows the quantification of SAE from studies comparing it with anticoagulant compounds. [Table 14]

[0365] From stratification of safety data by dosage received in patients who received antibody 1, the majority SAEs and bleeding events occurred in Group D patients who received the highest dose (150 mg). This was shown. Two SAEs were observed in group D, and in one patient, surgical intervention was performed. Approximately four days later, the possibility of ileus arose, and in another patient, artificial insemination occurred approximately 12 days after surgery. A joint infection occurred around the joint. In patients who developed a joint infection around the prosthetic joint, there was significant bleeding. CRNM bleeding also occurred. The only other SAE observed was in patients in group C (75 mg). The infection was a joint infection around the artificial joint. CRNM bleeding was observed in two patients in group B (30 mg). Table 15 shows safety data for patients who received antibody 1 treatment compared to enoxaparin. This will be explained in detail. [Table 15]

[0366] In summary, these results suggest that antibody 1 is associated with VTE events in patients after TKA surgery. It has been shown to be a safe and effective treatment for prevention. Antibody 1 after TKA surgery In patients receiving a 5mg dose, optimal safety and efficacy results were observed.

[0367] (Example 4) Treatment with antibody 1 compared to rivaroxaban for patients with atrial fibrillation. Objectives and rationale The purpose of this study is to evaluate the safety and tolerability of antibody 1 in patients with atrial fibrillation (AF). The objective is to evaluate it in comparison to rivaroxaban.

[0368] In previous studies conducted on healthy volunteers, antibody 1 was found to be safe and well-tolerated. Yes, robust and sustained inhibition of factor XI was observed at doses of ≥150 mg for ≥4 weeks. This resulted in an extension of the associated activated partial thromboplastin time (aPTT). Robust Furthermore, sustained inhibition of FXI and associated aPTT prolongation are the propositions proposed in this study. This is expected to occur with the drug regimen.

[0369] This study investigated antibody levels after multiple doses in patients with moderate to high risk of stroke due to atrial fibrillation. Evaluate the safety and tolerability of antibody 1, as well as the PK and PD biomarkers of antibody 1. This study assists in dose selection of antibody 1 for Phase 3 in patients with atrial fibrillation. ru.

[0370] Purpose and endpoints The primary objective of this study was to address major or clinically significant non-major (CRNM) bleeding events. The objective is to evaluate the effect of antibody 1 on the rate compared to rivaroxaban, and the endpoint The International Society on Thrombosis and d Significant bleeding or CRNM as defined by Haemostasis (ISTH) This was the time to the first event in the composite of blood events.

[0371] The secondary objectives of this examination are as follows: - The effect of antibody 1 on the total number of serious or CRNM bleeding events compared to rivaroxaban. Evaluate everything. The endpoint is the first event (International Soc iety on Thrombosis and Haemostasis(ISTH) This is the time to a major bleeding event as defined by; and - The effect of antibody 1 on the rate of serious or minor bleeding events compared to rivaroxaban. To evaluate. The endpoint is the first event (critical or minor as defined by ISTH). This is the time until a minor bleeding event occurs.

[0372] The exploratory objectives of this study are as follows: - The effect of antibody 1 on the total number of serious or CRNM bleeding events compared to rivaroxaban. Evaluate all endpoints. Endpoints are critical or CRNM endpoints as defined by ISTH. This is the total number of blood events (i.e., initial and recurrent events); - To evaluate the effect of antibody 1 on the total number of gastrointestinal bleeding events compared to rivaroxaban. The endpoint is defined as a critical gastrointestinal or CRNM by the determined ISTH. This is the total number of bleeding events; - The effectiveness of antibody 1 against the rate of stroke or systemic embolism compared to rivaroxaban. To be evaluated, the endpoint is the time to the first ischemic stroke or systemic embolic event. be; - Evaluate the final clinical outcomes using antibody 1 compared to rivaroxaban. The endpoints were ischemic stroke, systemic embolism, major or CRNM bleeding events, and total This is the time to the first event in the composite mortality rate; - Treatment adherence with antibody 1 compared to rivaroxaban in patients with AF To evaluate: The endpoint is the rate of antibody 1 administration compared to the rate of rivaroxaban administration dropout. This is the percentage of drug deficiency; - To evaluate the pharmacokinetic (PK) of antibody 1 in patients with AF. The endpoint is indicated. This is the trough antibody 1 plasma concentration at the time of the observation; - To evaluate the progression of antibody 1 in patients with AF. The endpoint is indicated. These are aPTT, free FXI, and total FXI at the time of measurement; - The effect of antibody 1 on health-related quality of life (HRQOL) compared to rivaroxaban To explore. The endpoints are the EQ-5D-5L questionnaire and the anticoagulation treatment scale (Ant This is the i-Clot Treatment Scale (ACTS); - To evaluate the incidence of immunogenicity in patients treated with antibody 1. The dot point is the percentage of patients who developed anti-drug antibodies (ADA) after receiving treatment. Yes. And, the impact of ADA generation on safety, efficacy, PK and PD reactions is evaluated. to do; - The effect of antibody 1 on additional biomarkers for thrombus formation and coagulation using rivaroxa Evaluate it in comparison to the van. Endpoints are not limited to these, but D-Dyma - Thrombin-activated fibrinolysis inhibitors (TAFIs) and blood clot lysis time Exploratory coagulation parameters that may include; and - Individual genes related to drug target pathways or other related genetic pathways Exploratory DNA to investigate whether the specific mutation confers a differential response to antibody 1. Conduct the evaluation. The endpoints are genetic polymorphisms and safety, efficacy, PK, and P This is an exploratory evaluation of the associations between D reactions.

[0373] Test design This study is a randomized, double-blind, active-controlled, dose-range-finding study. After a week-long screening period, patients were divided into three treatment groups (low-dose or high-dose antibody 1 or 3). Randomize to one of the baloxabans in a 1:1:1 ratio, and administer at least Participants will be followed for 12 months and until the end of the trial. Randomization will be conducted on a country-by-country and patient basis. Patients are stratified during cleaning based on whether they are anticoagulant-naive (yes / no). This means that NOACs (novel oral anticoagulants) may be administered at the discretion of the physician in charge of the trial at the end of the trial (EoS). Transition to treatment using and / or other standard therapies.

[0374] group Approximately 90 male and female patients aged 55 or older with a history of atrial fibrillation or atrial flutter. 0 to 1200 participants will be randomized in this study.

[0375] Inclusion Criteria The patient inclusion criteria for the clinical trial described in this embodiment are as follows: - Male and female patients aged 18 years or older with non-valvular atrial fibrillation; - Patients with atrial fibrillation or atrial flutter as demonstrated by electrocardiogram; - Having a CHA2DS2-VASc risk score of ≥4 or ≥3, and for the duration of the trial The concomitant use of antiplatelet drugs (e.g., aspirin and / or P2Y12 inhibitors) is less common. At least one occurrence is planned, or by the Cockcroft-Gault equation Patients with CrCl ≤ 50 ml / min; - If the cause is a previous ischemic stroke, transient ischemic attack (TIA), or cardioembolic origin You have a history of non-central nervous system (CNS) systemic embolism that is suspected to be present, or you are at risk of the following: Patients who have two or more of the factors: ○ Heart failure and / or left ventricular ejection fraction ≤ 35% ○ Hypertension (use of antihypertensive drugs within the last 6 months, SBP ≥ 140 mmHg or DBP ≥ (Defined as 90 mmHg) ○ 75 years of age or older ○ Diabetes (history of type 1 or type 2 diabetes, or use of antidiabetic drugs within the past 6 months); - Anticoagulant naive or novel oral anticoagulant (NOAC) at recommended doses Patients who have received stable treatment for more than 8 weeks prior to screening; and - In the case of women, whether they have been sterilized or abstinent after menopause (more than 2 years), If you are sexually active, effective conception before and throughout the test is possible. Patients undergoing adjustment therapy; and women who may be pregnant, screening. Sometimes, patients who test negative for serum b-hCG pregnancy.

[0376] Exclusion criteria The criteria for excluding patients from enrollment in the clinical trial described in this embodiment are as follows: - Within 5 half-lives prior to registration or until the pharmacodynamic effect returns to baseline, whichever is correct. Patients who used other investigational drugs within the longer period; - Patients with active internal bleeding; - A history of conditions that increase the risk of bleeding, including but not limited to the following: Patients who have or are in that condition: ○ Major surgical procedure or trauma within the past 30 days ○ Clinically significant GI bleeding within 6 months ○ History of intracranial, intraocular, spinal cord, or non-traumatic intra-articular hemorrhage ○ Chronic bleeding disorder ○ Known intracranial neoplasms, arteriovenous malformations, or aneurysms - You have scheduled invasive procedures with the potential for uncontrolled bleeding, including major surgical procedure...

Claims

1. (a) A therapeutically effective dose of isolated anti-factor XI (FXI) and / or anti-activated factor XI Factor (FXIa) antibody or its antigen-binding fragment; (b) Histidine buffer; (c) sugars or sugar alcohols; and (d) Polysorbate A vial containing a drug delivery formulation with a pH of 5.0 to 6.0, The therapeutically effective amount of the anti-FXI and / or anti-FXIa antibody or its antigen-binding fragment A vial containing an excess amount to allow for complete extraction.

2. Prior to the isolated anti-FXI and / or anti-FXIa antibody or its antigen-binding fragment Claim 1, wherein the effective therapeutic dose is a concentration between 120 mg / ml and 180 mg / ml. The vial as described.

3. Prior to the isolated anti-FXI and / or anti-FXIa antibody or its antigen-binding fragment The vial according to claim 1 or 2, wherein the effective therapeutic dose is a concentration of approximately 150 mg / ml. 。

4. Claims 1 to 3, wherein the histidine buffer comprises histidine and a histidine salt. A vial as described in any one of the items.

5. The vial according to claim 4, wherein the histidine is L-histidine.

6. The histidine salt is histidine HCl monohydrate, according to claim 4 or 5. Iaru.

7. Claims 4 to 6, wherein the concentration of the histidine buffer is between 10 mM and 30 mM. A vial as described in any one of the items.

8. The vial according to claim 7, wherein the concentration of the histidine buffer is approximately 20 mM.

9. The sugar or sugar alcohol is a disaccharide, as described in any one of claims 1 to 8. vial.

10. The vial according to claim 9, wherein the disaccharide is sucrose.

11. The sucrose concentration is between 170 mM and 270 mM, according to claim 10. vial.

12. The vial according to claim 11, wherein the concentration of the sucrose is approximately 220 mM.

13. The polysorbate is polysorbate 20, in any one of claims 1 to 12. The vial described in item 1.

14. The concentration of the polysorbate 20 is from 0.02% (v / v) to 0.06% (v / v) The vial according to claim 13, which is in between.

15. The concentration of the polysorbate 20 is approximately 0.04% (v / v), as described in claim 14. vial.

16. The pH is 5.3 to 5.7, according to any one of claims 1 to 15. Iaru.

17. The vial according to any one of claims 1 to 16, wherein the pH is approximately 5.5 。

18. The aforementioned excess filling is between 10% (v / v) and 30% (v / v) of the drug delivery formulation. The vial is configured to contain 1.1 mL to 1.3 mL of the drug delivery formulation, if necessary. The vial according to any one of claims 1 to 17.

19. The aforementioned excess filling constitutes approximately 20% (v / v) of the drug delivery formulation, and as needed, The vial according to claim 18, wherein the vial contains about 1.2 mL of the drug delivery formulation.

20. The antibody or its antigen-binding fragment is the complementarity-determining region in SEQ ID NO: 9 or 29. Heavy chain variable region (VH) including HCDR1, HCDR2, and HCDR3; and sequence Includes complementarity determination regions LCDR1, LCDR2, and LCDR3 in number 19 or 39. A vial according to any one of claims 1 to 19, comprising a light chain variable region (VL).

21. The antibody or its antigen-binding fragment i. Heavy chain variable region CDR1 of SEQ ID NO: 23; heavy chain variable region CDR2 of SEQ ID NO: 24; distribution Heavy chain variable region CDR3 of column number 25; light chain variable region CDR1 of sequence number 33; sequence number 3 Light chain variable region CDR2 of sequence number 4; and light chain variable region CDR3 of sequence number 35; ii. Heavy chain variable region CDR1 of SEQ ID NO: 26; Heavy chain variable region CDR2 of SEQ ID NO: 27; Heavy chain variable region CDR3 of SEQ ID NO: 28; Light chain variable region CDR1 of SEQ ID NO: 36; SEQ ID NO: Light chain variable region CDR2 of sequence 37; and light chain variable region CDR3 of sequence number 38; iii. Heavy chain variable region CDR1 of sequence number 43; heavy chain variable region CDR2 of sequence number 44 ; Heavy chain variable region CDR3 of sequence number 45; Light chain variable region CDR1 of sequence number 47; Sequence number Light chain variable region CDR2 of sequence 37; and light chain variable region CDR3 of sequence number 15; or iv. Heavy chain variable region CDR1 of SEQ ID NO: 46; Heavy chain variable region CDR2 of SEQ ID NO: 4; Distribution Heavy chain variable region CDR3 of sequence number 5; light chain variable region CDR1 of sequence number 33; sequence number 14 Light chain variable region CDR2 of sequence number 15; and light chain variable region CDR3 of sequence number 15 A vial according to any one of claims 1 to 20, including the following:

22. The antibody or its antigen-binding fragment is selected from the group consisting of SEQ ID NOs: 9 and 29. A variable chain region (VH), and a VH having 90% identity therewith; and the sequence A light chain variable region (VL) selected from the group consisting of numbers 19 and 39, and 9 A via according to any one of claims 1 to 21, comprising a VL having 0% identity Ru.

23. The antibody or its antigen-binding fragment is selected from the group consisting of SEQ ID NOs: 9 and 29. A heavy chain variable region (VH); and a light selected from the group consisting of Sequence IDs 19 and 39. A vial according to any one of claims 1 to 22, comprising a chain variable region (VL).

24. The antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 31 and 31. and heavy chains having 90% identity thereto; and from Sequence IDs 41, 21 A light chain containing an amino acid sequence selected from the group, and having 90% identity thereto. A vial according to any one of claims 1 to 23, comprising a light chain.

25. The antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 31 and an amino acid sequence of SEQ ID NO:

41. A vial according to any one of claims 1 to 24, comprising a light chain including a column.

26. The antibody is a human monoclonal antibody, according to any one of claims 1 to 25. The vial as described.

27. The vial according to claim 26, wherein the antibody is a human IgG1 isotype.

28. The antibody contains D265A substitution and P329A substitution within the Fc domain, as needed. Therefore, 120 mg to 180 mg of the aforementioned anti-factor XI (FXI) is administered to the target. Therapeutic treatment of anti-activated factor XI (FXIa) antibody or its antigen-binding fragment A vial according to claim 26 or 27, which is an effective amount.

29. (a) A therapeutically effective dose of isolated anti-factor XI (FXI) at a concentration of approximately 150 mg and / or an anti-activated factor XI (FXIa) antibody or its antigen-binding fragment; (b) Histidine buffer at a concentration of approximately 20 mM; (c) Sucrose at a concentration of approximately 220 mM; and (d) Polysorbate 20 at a concentration of approximately 0.04% (v / v) A vial containing a drug delivery formulation with a pH of 5.5, The therapeutically effective amount of the anti-FXI and / or anti-FXIa antibody or its antigen-binding fragment A vial containing an excess amount to allow for complete extraction.

30. (a) A therapeutically effective amount of isolated anti-FXI and / or anti-FXIa antibody or its antigen Binding fragment; (b) Histidine buffer; (c) Sugars or sugar alcohols; (d) Polysorbate, and (e) Diluent An intravenous drug delivery preparation containing a pH of 5.0 to 6.0, The diluent is a solution containing a second sugar and water. Intravenous drug delivery formulation.

31. Prior to the isolated anti-FXI and / or anti-FXIa antibody or its antigen-binding fragment Claim that the effective therapeutic dose is between 1.20 mg / ml and 1.80 mg / ml. The intravenous drug delivery preparation described in 30.

32. Prior to the isolated anti-FXI and / or anti-FXIa antibody or its antigen-binding fragment The therapeutically effective dose concentration is approximately 1.50 mg / ml, according to claim 30 or 31. Intravascular drug delivery preparation.

33. Claims 30 to 32, wherein the histidine buffer comprises histidine and a histidine salt. An intravenous drug delivery preparation as described in any one of the items up to the above.

34. The intravenous drug delivery formulation according to claim 33, wherein the histidine is L-histidine.

35. The claim 33 or 34, wherein the histidine salt is histidine HCl monohydrate. An intravenous drug delivery preparation.

36. Claim 3, wherein the concentration of the histidine buffer is between 0.10 mM and 0.30 mM. An intravenous drug delivery preparation as described in any one of items 0 to 35.

37. The concentration of the histidine buffer is approximately 0.20 mM, according to claims 30 to 36. Any of the intravenous drug delivery preparations described in item 1.

38. The sugar or sugar alcohol is a disaccharide, according to any one of claims 30 to 37. The intravenous drug delivery formulation described.

39. The intravenous drug delivery preparation according to claim 38, wherein the disaccharide is sucrose.

40. The sucrose concentration is between 1.70 mM and 2.70 mM, as described in claim 39. Intravenous drug delivery preparations.

41. The intravenous drug delivery according to claim 40, wherein the concentration of sucrose is approximately 2.20 mM. formulation.

42. The polysorbate is polysorbate 20, as per any of claims 30 to 41. An intravenous drug delivery preparation as described in item 1.

43. Claim 42, wherein the concentration of the polysorbate 20 is less than 0.001% (v / v) The intravenous drug delivery formulation described.

44. Claim 43, wherein the concentration of the polysorbate 20 is approximately 0.0004% (v / v). The intravenous drug delivery formulation described.

45. The static gas according to any one of claims 30 to 44, wherein the pH is 5.3 to 5.

7. Intravascular drug delivery preparation.

46. The intravenous drug according to any one of claims 30 to 45, wherein the pH is approximately 5.5 Physical delivery formulation.

47. Any one of claims 30 to 46, wherein the second sugar in the diluent is a monosaccharide. Intravenous drug delivery formulation as described above.

48. The intravenous drug delivery preparation according to claim 47, wherein the monosaccharide is glucose.

49. The claim states that the concentration of the glucose is between 2.5% (v / v) and 7.5% (v / v). An intravenous drug delivery preparation as described in item 48.

50. The vein according to claim 48 or 49, wherein the glucose concentration is approximately 5% (v / v). Internal drug delivery preparation.

51. The antibody or its antigen-binding fragment is the complementarity-determining region in SEQ ID NO: 9 or 29. Heavy chain variable region (VH) including HCDR1, HCDR2, and HCDR3; and sequence Includes complementarity determination regions LCDR1, LCDR2, and LCDR3 in number 19 or 39. An intravenous drug according to any one of claims 30 to 50, comprising a light chain variable region (VL) Physical delivery formulation.

52. The antibody or its antigen-binding fragment i. Heavy chain variable region CDR1 of SEQ ID NO: 23; heavy chain variable region CDR2 of SEQ ID NO: 24; distribution Heavy chain variable region CDR3 of column number 25; light chain variable region CDR1 of sequence number 33; sequence number 3 Light chain variable region CDR2 of sequence number 4; and light chain variable region CDR3 of sequence number 35; ii. Heavy chain variable region CDR1 of SEQ ID NO: 26; Heavy chain variable region CDR2 of SEQ ID NO: 27; Heavy chain variable region CDR3 of SEQ ID NO: 28; Light chain variable region CDR1 of SEQ ID NO: 36; SEQ ID NO: Light chain variable region CDR2 of sequence 37; and light chain variable region CDR3 of sequence number 38; iii. Heavy chain variable region CDR1 of sequence number 43; heavy chain variable region CDR2 of sequence number 44 ; Heavy chain variable region CDR3 of sequence number 45; Light chain variable region CDR1 of sequence number 47; Sequence number Light chain variable region CDR2 of sequence 37; and light chain variable region CDR3 of sequence number 15; or iv. Heavy chain variable region CDR1 of SEQ ID NO: 46; Heavy chain variable region CDR2 of SEQ ID NO: 4; Distribution Heavy chain variable region CDR3 of sequence number 5; light chain variable region CDR1 of sequence number 33; sequence number 14 Light chain variable region CDR2 of sequence number 15; and light chain variable region CDR3 of sequence number 15 An intravenous drug delivery preparation according to any one of claims 30 to 51, including the following:

53. The antibody or its antigen-binding fragment is selected from the group consisting of SEQ ID NOs: 9 and 29. A variable chain region (VH), and a VH having 90% identity therewith; and the sequence A light chain variable region (VL) selected from the group consisting of numbers 19 and 39, and 9 A vein according to any one of claims 30 to 25, comprising a VL having 0% identity. Internal drug delivery preparation.

54. The antibody or its antigen-binding fragment is selected from the group consisting of SEQ ID NOs: 9 and 29. A heavy chain variable region (VH); and a light selected from the group consisting of Sequence IDs 19 and 39. An intravenous drug according to any one of claims 30 to 53, comprising a chain variable region (VL) Delivery formulation.

55. The antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 31 and 31. and heavy chains having 90% identity thereto; and from Sequence IDs 41, 21 A light chain containing an amino acid sequence selected from the group, and having 90% identity thereto. An intravenous drug delivery preparation according to any one of claims 30 to 54, comprising a light chain.

56. The antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 31 and an amino acid sequence of SEQ ID NO:

41. An intravenous drug delivery method according to any one of claims 30 to 55, comprising a light chain including a column Agent.

57. The antibody is a human monoclonal antibody, any one of claims 30 to 56. Intravenous drug delivery formulation as described above.

58. The intravenous drug delivery method according to claim 57, wherein the antibody is a human IgG1 isotype. Agent.

59. The antibody contains D265A substitution and P329A substitution within the Fc domain, as needed. Therefore, 120 mg to 180 mg of the aforementioned anti-factor XI (FXI) is administered to the target. Therapeutic treatment of anti-activated factor XI (FXIa) antibody or its antigen-binding fragment An effective amount of an intravenous drug delivery formulation according to claim 57 or 58.

60. (a) A therapeutically effective dose of isolated anti-FXI and / or anti-FX at a concentration of approximately 1.5 mg Ia antibody or its antigen-binding fragment; (b) Histidine buffer at a concentration of approximately 0.20 mM; (c) Sucrose at a concentration of approximately 2.20 mM; (d) Polysorbate 20 at a concentration of approximately 0.0004% (v / v), and (e) Diluent An intravenous drug delivery formulation with a pH of 5.5 containing, An intravenous drug delivery formulation wherein the diluent is 5% glucose in water (D5W).

61. Treat patients who have thromboembolic disorders or are at risk of developing them. A method relating to the presence of the vial described in any one of claims 1 to 28. Drug delivery formulation or intravenous drug delivery formulation according to any one of claims 30 to 59 A method comprising the step of administering a therapeutically effective dose to a subject in need of it.

62. The aforementioned thromboembolic disorder includes atrial fibrillation or atrial flutter, transient ischemic attack, ischemic stroke, Thromboembolic stroke, hemorrhagic stroke, venous thromboembolism (VTE), pediatric VTE, systemic embolism Non-central nervous system embolism, myocardial infarction, deep vein thrombosis, severe protein S deficiency, cerebrovascular disease The method according to claim 61, selected from the group consisting of seizures and cancer.

63. The drug delivery preparation or intravenous drug delivery preparation contained in the vial is administered once a month. The method according to claim 61 or 62.

64. The drug delivery preparation or intravenous drug delivery preparation present in the vial is divided into approximately 30 From mg, approximately 60 mg, approximately 90 mg, approximately 120 mg, approximately 150 mg, and approximately 180 mg The dose is administered according to any one of claims 61 to 63, selected from the group. method.

65. The claim is to administer the drug delivery formulation present in the vial in a dose of approximately 120 mg. The method described in any one of items 61 to 64.

66. The claim is to administer the drug delivery formulation present in the vial in a dose of approximately 150 mg. The method described in any one of items 61 to 64.

67. The drug delivery formulation present in the vial is administered subcutaneously, according to claims 61 to 66. The method described in any one of the items.

68. The thromboembolic disorder is atrial fibrillation or atrial flutter, according to claims 61 to 67. The method described in either of the above terms.

69. The atrial fibrillation or atrial flutter is paroxysmal atrial fibrillation (PAF), as described in claim 68. The method.

70. The drug delivery formulation present in the vial is delivered once a month for a period of three months. The method according to any one of claims 61 to 69, wherein the method is administered by [method].

71. The subject is in a state where the risk of stroke is low, according to any one of claims 61 to 70. The method described in section [section number].

72. The aforementioned target CHA ２ DS ２ Claim 71, wherein the VASc risk score is 0 to 1 The method.

73. The subject is in a state of moderate stroke risk, according to any of claims 61 to 70. The method described in item 1.

74. The subject is in a state of high risk of stroke, according to any one of claims 61 to 70. The method described in section [section number].

75. The aforementioned target CHA ２ DS ２ The VASc risk score is ≥2 for male subjects. The method according to claim 74, wherein for female subjects, the value is ≥ 3.

76. The effectiveness of the drug delivery formulation present in the vial is determined by the third administration of the drug delivery formulation. Further steps include evaluating the inhibition of factor XI at the trough level after dose. The method according to any one of claims 61 to 75, including the method according to any one of claims 61 to 75.

77. The efficacy of the drug delivery formulation present in the vial is determined by the free factor XI and total factor XI. Factors, factor XI coagulation activity, activated partial thromboplastin time, and D-dimer Evaluation is performed by evaluating one or more biomarkers selected from a list. The method according to any one of claims 61 to 76, further comprising the step of doing the following.

78. Adverse events of the drug delivery formulation present in the vial are classified as hemorrhagic events or anti-drug antibodies. Claims 61 to 77 further include the step of evaluating by measuring the presence of The method described in any one of the items.

79. In patients experiencing adverse events such as bleeding, the following should be administered: (i) colloids, crystalloids, and human plasma. Alternatively, fluid replacement using plasma proteins such as albumin; (ii) packed red blood cells or (iii) transfusion using whole blood; or (iii) fresh frozen plasma (FFP), concentrated prothrombin complex PCCs (physical PCCs), activated PCCs (APCCs), for example, factor VIII inhibitors, and Steps that involve administering one or more of the following: / or recombinant activated factor VII. The method according to claim 78, further comprising P.

80. If you have a thromboembolic disorder or are at risk of developing one, and are undergoing a surgical procedure... A method for treating an object, the vein according to any one of claims 30 to 59. The step includes administering an internal drug delivery formulation to a subject in need thereof, and to the subject, the intra A method of administering an intravascular drug delivery preparation on the same day as the surgical procedure.

81. The aforementioned surgical procedures include knee replacement, total hip replacement, orthopedic surgery, and pacemaker implantation. The procedure is selected from the group consisting of implantation, catheter placement, thoracic surgery, and abdominal surgery. The method described in claim 80.

82. The method according to claim 80 or 81, wherein the intravenous drug delivery preparation is administered once a month.

83. The aforementioned intravenous drug delivery formulation is administered in doses of approximately 30 mg, approximately 60 mg, approximately 90 mg, approximately 120 mg, and approximately Claim 80: Administered in a dose selected from the group consisting of 150 mg and approximately 180 mg. The method described in any one of paragraphs 82 to 82.

84. The intravenous drug delivery preparation is administered in a dose of approximately 30 mg, according to claims 80 to 83. The method described in any one of the items.

85. The intravenous drug delivery preparation is administered in a dose of approximately 60 mg, according to claims 80 to 83. The method described in any one of the items.

86. Claims 80 to 83, wherein the intravenous drug delivery preparation is administered in a dose of approximately 150 mg. The method described in any one of the items.

87. The intravenous drug delivery preparation is administered in a dose of approximately 75 mg, according to claims 80 to 82. The method described in any one of the items.

88. Claim 80, wherein the intravenous drug delivery preparation is administered approximately 4 to 8 hours after the surgical procedure. The method described in any one of the items up to item 87.

89. If you have a thromboembolic disorder or are at risk of developing one, and you are using nonsteroidal anti-steroidal therapy (NSAIDs) A method for treating a subject receiving a sexually transmitted anti-inflammatory drug (NSAID), as described in claims 1 to 28. The drug delivery formulation present in the vial described in any one of the items up to claim 30 A proton pump delivers an intravenous drug delivery preparation described in any one of items up to 59, in a therapeutically effective dose. A method comprising the step of administering an inhibitor in combination with a target that requires it.

90. The drug delivery preparation or intravenous drug delivery preparation present in the vial is administered once a month. The method according to claim 89, wherein the person administers the substance.

91. The drug delivery preparation or intravenous drug delivery preparation present in the vial is divided into approximately 30 From mg, approximately 60 mg, approximately 90 mg, approximately 120 mg, approximately 150 mg, and approximately 180 mg The method according to claim 89 or 90, wherein the dose is administered in a dose selected from the group.

92. The drug delivery preparation or intravenous drug delivery preparation present in the vial is divided into approximately 75 The method according to claim 88 or 89, wherein the dose is administered in mg.

93. Claims 89 to 91, wherein the drug delivery formulation present in the vial is administered subcutaneously. The method described in any one of the items in the paragraph.

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