Treatment with anti-factor XI / XIa antibodies

Abstract

To provide methods of preventing, treating, managing, or reducing the risk of stroke or thromboembolism.SOLUTION: This method comprises the step of administering, to a subject afflicted with end stage renal disease, an effective amount of a pharmaceutical composition comprising an antibody or antigen-binding fragment that binds within the catalytic domain of Factor XI ("FXI") and / or activated FXI ("FXIa").SELECTED DRAWING: None

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 438,654, filed Dec. 23, 2016, and U.S. Provisional Patent Application No. 62 / 589,851, filed Nov. 22, 2017, each of which is incorporated herein by reference in its entirety. 12月23日に出願された米国特許仮出願第62 / 438,654号明細書、および20 17年11月22日に出願された米国特許仮出願第62 / 589,851号明細書の利益 を主張する。

[0002] This application is electronically filed in ASCII format and contains a sequence listing that is incorporated herein by reference in its entirety. The ASCII copy, created on Nov. 30, 2017, is named PAT057550-WO-PCT_SL.txt and is 45,591 bytes in size. 本明細書に組み込まれる配列表を含有する。2017年11月30日に作成された前記A SCIIコピーは、PAT057550-WO-PCT_SL.txtと名付けられ、45,591バイトのサイ ズである。

Background Art

[0003] Thrombosis refers to the formation of a thrombus inside a blood vessel following a combination of a hereditary risk factor known as a thrombotic predisposition or a hypercoagulable state and an acquired risk factor. Damage to the blood vessel wall, congestion, increased platelet reactivity, and activation of blood coagulation factors are some of the root features of thrombosis. Thrombosis can occur in either the venous circulation or the arterial circulation and can result in the development of deep vein thrombosis (DVT), pulmonary embolism, and stroke. When a thrombus occurs in the arterial system, ischemia occurs downstream, which can lead to acute coronary syndrome (ACS), ischemic stroke, and acute lower limb ischemia. Thrombosis in the venous system typically results in deep vein thrombosis, pulmonary embolism, and chronic thromboembolic pulmonary hypertension. Coagulation can also form in the left atrium of patients with AF (AF), and the detached thrombus 板の反応性の増大、および凝血因子の活性化は、血栓症の根源的な特色のうちの一部であ る。血栓症は、静脈循環および動脈循環のいずれにおいても生じる可能性があり、深部静 脈血栓症(DVT)、肺塞栓症、および脳卒中の発症を結果としてもたらしうる。動脈系 ]T]内で血栓が生じると、下流で虚血症が生じることから、急性冠動脈症候群(ACS)、虚 血性脳卒中、および急性下肢虚血症がもたらされうる。静脈系内の血栓形成は、深部静脈 血栓症、肺塞栓症、および慢性血栓塞栓性肺高血圧症をもたらすことが典型的である。凝 血はまた、AF(AF)を伴う患者の左心耳内でも形成される可能性があり、脱離した血 ​The thrombus can lead to serious complications, namely thromboembolic stroke and systemic embolism. This can result from: low molecular weight heparin (LMWH), thrombin inhibitor, All currently available antithrombotic drugs, including factor Xa (FXa) inhibitors, are markedly effective. It is associated with a risk of bleeding (Weitz JI (2010) Thromb. Haemost. 103, 62). It casts a shadow on hemostasis. The development of antithrombotic agents that do not have adverse effects and therefore do not result in bleeding complications is crucial. It is desired.

[0004] Current anticoagulants are administered by injection or orally. Injectable anticoagulant LMWH It is widely used and has a superior therapeutic profile compared to unfractionated heparin, which was previously used. This has brought about improvements. Over the past several decades, the most commonly used oral anticoagulants have been: It was warfarin. Warfarin has a narrow therapeutic window, and therefore, the clotting state... It requires frequent monitoring and exhibits various drug interactions. More recently, Orally available direct FXa and thrombin inhibitors enter the anticoagulant market. Its application is increasing.

[0005] LMWH, FXa inhibitor, and thrombin inhibitor are all used in postoperative veins. Prevention of thromboembolic diseases, management of spontaneous DVT and pulmonary embolism, and in atrial fibrillation These anticoagulants are effective in preventing strokes. However, these anticoagulants are also a step down from older drugs. Bleeding complications generally equivalent to those observed with rufarin and unfractionated heparin. It is also associated with the disease. In the ADVANCE-2 clinical trial, the FXa inhibitor apixaban ( Eliquis) is used in patients after total knee arthroplasty, and enoxapari is a LMWH (Leading Membrane Heat Stretch). It was compared to . Acute apixaban therapy is used to prevent venous thromboembolic disease, and enoki Although more effective than saparin, all drugs were associated with a significant risk of bleeding. The most problematic bleeding occurs in 4% of patients treated with apixaban, and enoxapari. It occurred in 5% of patients treated with [the drug] (Lassen, MR, et al. (2009) N. Eng (I. J. Med. 361, 594).

[0006] In the RE-LY trial, the direct thrombin inhibitor dabigatran (Prada) xa) was compared to warfarin in patients at risk of AF and stroke. Connolly, SJ, et al. (2009) N. Engl. J. Med. 361, 1139). Chronic dabigatran therapy. This was associated with a marked reduction in the risk of stroke or systemic embolism. However, in cases of massive bleeding... Comorbidities occurred in 3.1% of patients receiving 150 mg of dabigatran daily, and warf This occurred in 3.4% of patients receiving falin (p=0.31).

[0007] Atrial fibrillation (AF) remains the most common cardiac arrhythmia in clinical practice. It accounts for about one-third of hospitalizations due to tuning problems. Currently, AF accounts for 60 in Europe. It is estimated to affect over 10,000 patients, and approximately 2.3 million in the United States. Due to the increasing proportion of the aging population, this number continues to grow rapidly. (People over 65 years old) It is estimated that approximately 5% of the population and 10% of people over 80 years old will develop atrial fibrillation (AF). However, the prevalence of AF is increasing beyond what can be explained by age alone. Hypertension, congestive heart failure, left ventricular hypertrophy, coronary artery disease, and diabetes, as well as obstructive sleep disorders. Risk factors for AF, such as sleep apnea, are also increasing. In fact, among Westerners, this is expected to increase two to three times over the next 30 years (Kannel). and Benjamin (2008) Med Clin North Am. 2008; 92:17-40; Bunch, et al. (2012) JI nnovations of Card Rhythm Manag 2012; 3: 855-63).

[0008] The primary risk factor for AF is a 4-5 times increased risk of embolic stroke. This is attributed to its association with AF. The risk of stroke increases sharply with age, rising to 23.5% for those aged 80-89. It is significant. AF is associated with a doubling of mortality in both sexes (Kannel and Benjamin). (min 2008). AF is also independently associated with cognitive decline and all forms of dementia. (Marzona, et al. (2012) CMAJ 2012; 184: 329-36; Geita et al 2013; Bunch et al. (al 2012).

[0009] Most patients with AF need to take precautions throughout their lives to prevent cardioembolic stroke and systemic embolism. The patient requires continuous anticoagulation therapy. The CHA2DS2-VASc risk score has been validated. Therefore, to predict the risk of thromboembolism in AF patients and identify patients who would benefit from anticoagulation therapy, It is a widely used stratification tool for determining (LIP 2011; Camm, et al. (2012) Eu (Heart J 2012; 33: 2719-2747), the accumulation of evidence shows that CHA2DS2-VASc is associated with stroke. And to identify patients who will develop thromboembolism, scores such as CHADS2 and at least It is equally accurate, or perhaps even better, in patients with AF. It is definitively superior in identifying patients who are "truly at low risk." It is estimated that 85–90% of AF patients will require anticoagulation therapy.

[0010] In recent years, new oral anticoagulants (NOA), also known as direct oral anticoagulants (DOACs), have emerged. C) has been approved and introduced into clinical practice. These drugs reduce the risk of thromboembolic disease. In reducing the dosage, it is at least as effective as warfarin, or even better. (Connolly, et al. (2009) N Engl J Med; 361:1139-51; Connolly, et al. (2011) N Engl J Med; 364:806-17; Patel, et al. (2011) N Engl J Med 2011; 365:883-91). NOACs also have a lower risk of the most serious complications of warfarin, namely hemorrhagic stroke and cerebral infarction. It was also associated with a significant reduction in internal bleeding. Massive bleeding events were associated with well-administered warfarin therapy and They were equivalent or slightly less. In addition, NOACs were smaller than warfarin. In relation to the possibility of drug-drug interactions, use without routine monitoring is... This is expected to facilitate their use in routine medical practice.

[0011] Despite recent improvements, the risk of bleeding associated with anticoagulant use remains high. It goes up to this point. For example, the annual incidence rates of massive bleeding and clinically significant non-massive bleeding are 14 0.9%, and in the ROCKET study, among patients treated with rivaroxaban, The annual incidence rate of massive bleeding events was 3.6% (Patel et al 2011). The risk of bleeding In patients with a high HAS Bled risk score of ≥3, massive bleeding The annual incidence rate was >5% (Gallego, et al. (2012) Carc Arrhythm Electrophysiology) l.; 5:312-318). Massive bleeding is a particularly problematic clinical outcome, for example, ROCKET In the study, the all-cause mortality rate was 20% lower in the rivaroxaban group when massive bleeding occurred. The rates were 4% in the 4% group and 26.1% in the warfarin group. If a massive bleeding event occurs, 4.7% and 5.4% of patients in the varoxaban group and warfarin group, respectively. % of patients experienced stroke and systemic embolism (Piccini, et al. (2014) Eur Heart J; 35:1 873-80). Hospitalization, intravenous administration of blood products, and the use of blood supply sources are also necessary to prevent massive bleeding. It had a significant impact. The risk of bleeding is also high in eligible patients who do not receive anticoagulants. This is also a necessary reason. 182 hospitals in 35 countries and 5,333 outpatients with AF and inpatients The Euro Heart Survey on AF, which includes data from hospital AF patients, Of the eligible patients, 67% were only given oral anticoagulants upon discharge. wlaat, et al (2005) Eur Heart J;26, 2422-2434). Therefore, equivalent to existing treatments. While effective, it reduced the risk of bleeding, stroke, systemic embolism, cognitive decline, and Safer treatments that can reduce thromboembolic complications of AF, such as mortality, are needed to satisfy the need for safer treatments. There is a significant medical need that has not yet been addressed.

[0012] In end-stage renal disease (ESRD), the incidence and risk of thrombotic events increase, particularly, In ESRD patients undergoing hemodialysis, the use of anticoagulants is common. However, bleeding occurs The high birth rate is also a problem that occurs frequently, leading to further challenges in the management of anticoagulation therapy. To come. [Overview of the project]

[0013] Furthermore, AF is also a common comorbidity with a high prevalence in patients with ESRD (Zimmer). man et al., Nephrol Dial Transplant (2012) 27: 3816-3822). For example, AF, ES In patients with RD, this is associated with an increased risk of stroke and mortality (Zimmerman et al.). al., Nephrol Dial Transplant (2012) 27: 3816-3822). Therefore, accompanied by ESRD In patients, especially those undergoing dialysis and those with AF and ESRD, renal clearance is not achieved. There is a great, unmet medical need for safe anticoagulants.

[0014] This disclosure relates to the treatment of subjects with end-stage renal disease (ESRD) and to thrombosis or This relates to methods for preventing, treating, managing, or reducing the risk of thromboembolism. The target is human coagulation factor XI and XIa (activated factor XI) (hereinafter, depending on the case) This refers to the monoclona that combines with the "FXI", "FXIa", and similar terms. The procedure includes administering an antibody or its antigen-binding fragment. This is related to the treatment of end-stage renal disease. , thrombosis or thromboembolic disease / disorder (e.g., thrombotic stroke, AF, brain in AF) Stroke prevention (SPAF), deep vein thrombosis, venous thromboembolism, pulmonary embolism, ischemic stroke, In the prevention and treatment of acute lower limb ischemia, chronic thromboembolic pulmonary hypertension, and systemic embolism. Effective, but carries no risk of bleeding, or carries a minimal risk of bleeding. Developing antithrombotic drugs that are merely a means to an end would satisfy a great unmet medical need. It is likely.

[0015] In some embodiments, the subject is undergoing dialysis. For example, the subject has end-stage renal disease and The patient has AF (for example, non-valvular AF) and is undergoing dialysis.

[0016] In certain aspects, this disclosure relates to end-stage renal disease (ESRD) and AF (e.g., non-valvular heart disease). To prevent and treat the risk of thrombosis or thromboembolism in patients undergoing dialysis with AF (Atrial Fibre). A method of placing, controlling, or reducing an anti-FXI / FXIa antibody (e.g.) on a target. For example, a method including the step of administering an anti-FXI / FXIa antibody as listed in Table 1. Regarding.

[0017] In some embodiments, the target is obesity.

[0018] In a specific embodiment, the target is the catalytic domain (CD) of human FXIa and FXI, It binds with similar high affinity, and within FXIa, the inactive protease domain confer An antibody or fragment presented herein (e.g., human monoclonal) that induces a reaction. Monoclonal antibody or fragment, chimeric monoclonal antibody or fragment, humanized monoclonal antibody Administer the whole or fragment.

[0019] In some embodiments, an antibody or so for use in the methods described herein. The antigen-binding fragment is located within the catalytic domain of FXI and / or FXIa, specifically, activated It binds to the surface of the sexual site region.

[0020] The methods described herein are combined with FXI and / or FXIa as shown in Table 1. Antibodies or antigens that compete for binding with the antibody that is already bound (e.g., NOV1401) The procedure may include a step of administering a binding fragment, such as an antibody and / or as described herein. The "competition" between the antigen-binding fragments means that both antibodies (or their binding fragments) are the same. Or binding to overlapping FXI epitopes and / or FXIa epitopes ( For example, determined in a competitive binding assay by any method well known to those skilled in the art. The antibody or its antigen-binding fragment used herein means the competitive antibody. The body or its antigen-binding fragment is the same FXI epithelium as the antibody or antigen-binding fragment of this disclosure. FXIa epitope and / or overlapping FXI epitopes and Unless it binds to a f / or FXIa epitope, the FXI antibody and / or the FXI antibody of this disclosure / or FXIa antibody or antigen-binding fragment (e.g., NOV1401 or NOV1 090) does not "compete". The competing antibodies or their antigen-binding fragments used herein are (i) sterically blocking the binding of the antibody or antigen-binding fragment of this disclosure to its target Determination (for example, the competing antibody detects nearby, non-overlapping FXI epitopes and / or F The antibody or antigen-binding fragment of this disclosure binds to the XIa epitope and its target. (ii) if it is physically prevented from happening; and / or (ii) different, non-overlapping FXI episodes It binds to the tope and / or FXIa epitope, and to the FXI protein and / or F The XIa protein is bound to the FXI antibody and / or FXIa antibody or antigen of the present disclosure. The sex fragments can no longer be bound in a way that occurs in the absence of conformational changes. a competitive antibody or antigen that induces the conformational change in the protein. It does not contain binding fragments.

[0021] In one embodiment, the method involves binding to the active FXI(FXIa) and the active FXI(FXI a) When it binds to the catalytic domain, FXIa changes its conformation to an inactive conformation. The procedure includes administering an antibody or an antigen-binding fragment thereof that is converted into a morphation. In another embodiment, the antibody or its antigen-binding fragment is the N-terminus of the inactive conformation. The four residues at the end, loops 145, 188, and 220, are compared to the active conformation. In comparison, this induces further changes that are shifted and / or irregular.

[0022] In one embodiment, the method binds to FXI (e.g., human FXI) and binds to FXI. The FXI catalytic domain is located in loops 145, 188, and 220, which are part of the FXIa catalytic domain. This prevents the active conformation from being regular, as is the case within the structure of the element. The procedure includes the step of administering an antibody or an antigen-binding fragment thereof.

[0023] One embodiment, a method, involves binding to FXI, and when bound to FXI, the FXI catalytic domain However, the four N-terminal residues, loops 145, 188, and 220, form the FXIa catalytic domain. This prevents the active conformation from being regular, as is the case within the structure. The procedure includes the step of administering an antibody or an antigen-binding fragment thereof.

[0024] In one embodiment, the method involves coupling to FXI, and upon coupling to FXI, within the Zymogen structure It induces conformational changes and inhibits FXIa when it binds to FXIa. This further brings about inhibitory FXI conformations that are closely related to the conformation. Therefore, the antibody prevents the FXI catalytic domain from adopting an active conformation. The procedure includes the step of administering the antigen-binding fragment.

[0025] In one embodiment, the method involves coupling to FXI and changing the conformation within the zymogen structure. This induces a change in the FXI conformation observed when binding to FXIa. By resulting in an inhibitory FXI conformation that is closely related to the catalyst, The antibody or antigen-binding cleavage prevents the domain from adopting an active conformation. The procedure includes the step of administering a piece.

[0026] The methods described herein use the antibodies listed in Table 1 (e.g., NOV1401). The step includes administering an antibody or antigen-binding fragment that binds to the same epitope. ru.

[0027] Anti-FXI antibodies and / or FXIa antibodies or antigens used in the methods described. The binding fragments are factor IX (also known as FIX), factor X (FX), and Direct or indirect activation of thrombin, less than 100 nM, 50 nM The following ICs have a minimum impedance of 35nM, 25nM, 10nM, or 5.2nM.50 hindered It can be harmful. More specifically, an antibody or its antigen-binding fragment can cause harm to factor IX ( Also known as FIX), factor X (FX), and / or thrombin, Direct or indirect activation, below 100 nM, below 50 nM, below 35 nM, 25 n ICs with a minimum impedance of M, 10nM or less, or 5.2nM or less. 50 This can be inhibited. More specifically, The antibody or its antigen-binding fragment is factor IX (also known as FIX), Direct or indirect activation of factor X (FX) and / or thrombin, 100 nM or less, 50nM or less, 35nM or less, 25nM or less, 20nM or less, or 18nM The following ICs 50 It can be inhibited by the IX Factor (also known as FIX), factor X (FX), and / or thrombi Direct or indirect activation of n, below 100 nM, below 50 nM, below 35 nM, ICs with a impedance of 25nM or less, 10nM or less, or 5nM or less 50 This can be hindered. Specific implementation details In this state, the anti-FXI / FXIa antibody or its antigen-binding fragment is its natural substrate F The activation of IX, mediated by FXIa, is performed by ICs of 2nM or less, for example, 1.8nM. 50 hindered To harm.

[0028] In some embodiments, the method is performed, for example, by the aPTT assay described in the Examples section. As determined, the clotting time of human plasma (for example, until a blood clot begins to form) is concentration-dependent. The procedure includes the step of administering an antibody or an antigen-binding fragment to extend the duration of the reaction. In one embodiment, the clotting time (aPTT) is determined by an aPTT assay, A total anti-FXI antibody in the range of 0nM to 20nM, for example, about 14nM or 15nM (e.g., In certain embodiments, the concentration (NOV1401) doubles compared to baseline. The body or its antigen-binding fragments can be analyzed, for example, by the aPTT assay described in the Examples section. As determined, the IC50 range is 5nM to 20nM, for example, at approximately 13nM, and is concentration-dependent. Specifically, it prolongs the clotting time of human plasma.

[0029] In some embodiments, the method is performed, for example, by the aPTT assay described in the Examples section. As determined, for example, in a concentration-dependent manner, at least 1.1 times, 1.2 times, 1.3 times, 1 0.4x, 1.5x, 1.6x, 1.7x, 1.8x, 1.9x, or 2x, human plasma Antibodies or their antigens prolong the clotting time (for example, the time it takes for a blood clot to begin forming). The procedure includes the step of administering a compatible fragment. In specific embodiments, the antibody or its antigen-binding properties The fragments are determined, for example, by the aPTT assay described in the Examples section, and are less than Both are 1.4 times, 1.5 times, 1.6 times, or 1.7 times, human plasma clotting time (for example, blood Extend the time it takes for the mochi to begin forming.

[0030] In some embodiments, the method involves F in the presence of a very low concentration of tissue factor (TF). To measure the effect of XIa inhibition on the thrombin → FXIa feedforward loop. In the human plasma thrombin generation assay (TGA), the amount of thrombin is determined by the concentration. The procedure includes administering an antibody or an antigen-binding fragment to substantially reduce the antibody. Morphologically, antibodies or their antigen-binding fragments are used in thrombinogenesis assays (T) in human plasma. In general, for ICs in the range of 10nM to 30nM, for example, approximately 20nM or 24nM. 50 The value and residual thrombin concentration of approximately 159 nM reduce the amount of thrombin.

[0031] In some embodiments, the method involves the catalytic domain of human FXI and / or FXIa. It specifically binds and the terminal phase elimination half-life (t) of all antibodies in cynomolgus monkeys. 1 / 2 ) to approximately 14 The treatment period is approximately 15 days, and the antibody (e.g., NOV1401, or HCDR1 of NOV1401) is used. Antibodies including ~3 and LCDR1~3, etc. (antibodies in Table 1), or their antigen-binding properties The procedure includes the step of administering a fragment. In specific embodiments, an antibody or its antigen-binding fragment is used. It exhibits an absolute subcutaneous (sc) bioavailability of approximately 61-66%.

[0032] In one embodiment, the method specifically binds to human FXI and / or FXIa, and Features below: (i) For example, apparent K at approximately 1-2 pM and 4-5 pM respectively D So, human F Specific binding to the catalytic domain (CD) of XI and FXIa; (ii) Condensation assessed by activated partial thromboplastin time (aPTT) assay Prolonging the blood flow time; (iii) F by activated factor XII (FXIIa) and thrombin, respectively Inhibiting thrombin production in human plasma by inhibiting XI activation; (iv) In FXI- / - mice reconstituted with human FXI, antithrombotic activity and anti To exhibit coagulation activity; (v) For example, in cynomolgus monkeys, free FXI (FXIf )Reduce the level or or extend the reduction; (vi) For example, the terminal phase elimination half-life of the whole antibody in cynomolgus monkeys is about 14 to 15 days between; (vii) Specifically bind to human and monkey FXI and / or FXIa, but not specifically bind to mouse or rat FXI and / or FXIa; and also (viii) One or more (for example, 2, 3 410, Arg413, Leu415, Cys416, His431, Cys432, T yr434, Gly435, Glu437, Tyr472~Glu476, Tyr521 ~Lys527, Arg548, His552, Ser575, Ser594~Glu5 97, and one or more (for example, 2, 3 4, 5, 6, or 7, or more than this), or part, or all of Arg602~Arg604 contact; [[ID=二十九]]One or more (for example, 2, or 3, or 4, or 5, or 6, or 7), or all of the antibodies or antigen-binding fragments thereof (for example, N OV1401, etc., antibodies described in Table 1) presenting the step of administration. s

[0033] The antibodies or antigen-binding fragments thereof used in the methods described herein are monoclonal antibodies, human or humanized antibodies, chimeric antibodies, single-chain antibodies, Fab fragments, Fv fragments , F(ab’)2 fragments, or scFv fragments, and / or IgG isotypes ([[]] s For example, IgG1 such as human IgG1). In a specific embodiment, the antibody is a combination ​It may be a substitute human antibody. In a specific embodiment, the antibody is human IgG1 / lambda (λ) It is an antibody. In a specific embodiment, the antibody has an effector function (for example, ADCC and Fc domains manipulated to reduce the possibility of (and / or CDC), e.g., D26 Human IgG1 / Lactic Acid containing human Fc domains including 5A substitution and / or P329A substitution It is a useless (λ) antibody.

[0034] For use in the methods described herein, the antibody or its antigen-binding fragment is Furthermore, the amino acids are, respectively, those of the human VH germline sequence or the human VL germline sequence. This may also include frameworks that have been replaced with antibody frameworks derived from [the original source].

[0035] The methods described herein use the heavy chain and light chain sequences of the antibodies listed in Table 1. The procedure may include the step of administering an antibody or an antigen-binding fragment thereof. More specifically, The antibody or its antigen-binding fragment is a heavy chain sequence of NOV1090 or NOV1401. It may have a light chain sequence.

[0036] The method described herein involves the heavy chain variable domain sequence of the Fabs listed in Table 1. and Steps to administer an antibody or its antigen-binding fragment having a light chain variable domain sequence It may contain p. More specifically, the isolated antibody or its antigen-binding fragment may contain NOV1090 It may also have the heavy chain and light chain variable domain sequences of NOV1401.

[0037] The methods described herein include Kabat CDR, IMGT CDR, and Chothi a. Heavy chain variable of antibodies listed in Table 1, such as CDRs or combined CDRs. Domain CDR (i.e., HCDR1, HCDR2, and HCDR3) sequences and light chain Variable domain CDR (i.e., LCDR1, LCDR2, and LCDR3) sequences and The procedure may include the step of administering an antibody or an antigen-binding fragment thereof. More specifically, The release antibody or its antigen-binding fragment is Kabat CDR, IMGT CDR, Chot hia CDR, or combined CDR, for example, NOV1090 as shown in Table 1. and NOV1401, HCDR1 sequence, HCDR2 sequence, HCDR3 sequence, LCDR It may have sequence 1, LCDR2, and LCDR3.

[0038] In specific embodiments, the methods described herein are as defined by Chothia. Variable heavy chains HCDR1, HCDR2, and HCDR3 of sequence numbers 9 and 29, and Antibodies containing variable light chains LCDR1, LCDR2, and LCDR3 of SEQ ID NOs. 19 and 39. or the step of administering the antigen-binding fragment thereof may include Alternatively, the antigen-binding fragment may be the heavy chain of sequence numbers 9 and 29 as defined by Kabat. The variant domain sequences HCDR1, HCDR2, and HCDR3, as well as sequence number 19 It has LCDR1, LCDR2, and LCDR3 of the light chain variable domain sequences 39. ru.

[0039] In specific embodiments, the methods described herein are sequence numbers as defined by IMGT. HCDR1, HCDR2, and HCDR3 of variable heavy chains No. 9 and 29, and their sequences Antibodies containing variable light chains LCDR1, LCDR2, and LCDR3 with numbers 19 and 39. or the step of administering the antigen-binding fragment thereof may include Alternatively, the antigen-binding fragment is defined by Combined, as specified by Sequence IDs 9 and 29. The heavy chain variable domain sequences HCDR1, HCDR2, and HCDR3, as well as the sequence numbers. LCDR1, LCDR2, and LCDR3 of 19 and 39 light chain variable domain sequences It is possible.

[0040] In specific embodiments, the methods described herein include the group consisting of Sequence IDs 9 and 29. The antibody or its antigen-binding fragment containing a selected heavy chain variable domain sequence is administered. Includes a . The isolated antibody or antigen-binding fragment further contains a light chain variable domain sequence. This is possible, and in this case, the heavy chain variable domain and the light chain variable domain combine, It forms an antigen-binding site for FXIa. In particular, the light chain variable domain sequence is the sequence number. 19 and 39 can be selected, in which case the isolated antibody or its antigen-binding properties The fragments are joined to FXI and / or FXIa.

[0041] In specific embodiments, the methods described herein are the group consisting of Sequence IDs 19 and 39. Includes a light chain variable domain sequence selected from human FXI and / or human FXIa The procedure includes administering an antibody or antigen-binding fragment that binds to the isolated antibody or anti- The primordial-binding fragment may further contain a heavy chain variable domain sequence, in which case the light chain The variable domain and the heavy chain variable domain, when combined, form FXI and / or FXI. It forms an antigen-binding site for a.

[0042] In specific embodiments, the methods described herein apply to FXI and / or FXIa. The heavy chains are joined and contain sequences 9 and 19; or 19 and 39, respectively. The step includes administering an antibody or an antigen-binding fragment that may have a light chain variable domain. .

[0043] In specific embodiments, the methods described herein include the group consisting of Sequence IDs 9 and 29. The selected arrays have a success rate of at least 80%, 85%, 90%, 95%, 97%, and 98%, and also This refers to an antibody or its antigen-binding fragment containing a heavy chain variable domain with 99% sequence identity. The procedure includes the step of administration. In this case, the antibody is linked to FXI and / or FXIa. Combine. In one embodiment, the isolated antibody or its antigen-binding fragment is also used in SEQ ID NOs. 19 and 3 Sequences selected from a group of 9, with at least 80%, 85%, 90%, 95%, and 97% This also includes light chain variable domains having 98% or 99% sequence identity. Further disclosures In this embodiment, the isolated antibody or antigen-binding fragment is defined by Kabat and is listed in Table 1. These include HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and L It has CDR3. In specific embodiments, the isolated antibody or antigen-binding fragment is Chot HCDR1, as defined by hia, IMGT, or a combination thereof, as listed in Table 1. It includes HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3.

[0044] In specific embodiments, the methods described herein are the group consisting of Sequence IDs 19 and 39. The array selected from and at least 80%, 85%, 90%, 95%, 97%, 98%, Or an antibody having a light chain variable domain with 99% sequence identity or its antigen-binding decryption The procedure includes the step of administering a sample. In this case, the antibody is FXI and / or FXIa. Combine.

[0045] In specific embodiments, the methods described herein apply to FXI and / or FXIa. An antibody or antigen binding that may have a heavy chain containing the sequence of SEQ ID NO: 11 or 31. The procedure includes a step of administering a sex fragment. The isolated antibody is also combined with the heavy chain to produce human FXI and / or may also include light chains capable of forming antigen-binding sites for human FXIa. The light chain may have a sequence containing sequence number 21 or 41. In particular, FXI and / or The isolated antibody or antigen-binding fragment that binds to FXIa is SEQ ID NOs. 11 and 21 ; or it may have heavy and light chains containing sequences 31 and 41, respectively.

[0046] In specific embodiments, the methods described herein are the group consisting of Sequence ID No. 11 or 31. An antibody or a heavy chain having at least 90% sequence identity with a sequence selected from the above. The procedure includes the step of administering an antigen-binding fragment. In this case, the antibody is FXI and / or It binds to FXIa. In one embodiment, the isolated antibody or its antigen-binding fragment is also sequence Sequences selected from the group consisting of numbers 21 or 41 and at least 80%, 85%, or 90% This also includes light chains having 95%, 97%, 98%, or 99% sequence identity.

[0047] In specific embodiments, the methods described herein are the group consisting of Sequence ID No. 21 or 41. The array selected from and at least 80%, 85%, 90%, 95%, 97%, 98%, Alternatively, administer an antibody or its antigen-binding fragment containing a light chain with 99% sequence identity. It includes a TEPS. In this case, the antibody binds to FXI and / or FXIa.

[0048] In specific embodiments, the methods described herein include, for example, the antibody NOV1090 and a pharmaceutical composition containing the antibodies or antigen-binding fragments listed in Table 1, such as NOV1401, is administered. The method includes the step of providing the isolated antimicrobial agent of Table 1. In a specific embodiment, the method described herein includes the isolation antimicrobial agent of Table 1. Administer a pharmaceutical composition containing two or more combinations of the body or its antigen-binding fragments. Includes steps.

[0049] This disclosure also relates to methods for treating, improving, or preventing thromboembolic diseases in subjects. And, bound to the target, an effective amount of FXI and / or FXIa as described herein. The method also includes the step of administering a composition containing an antibody or an antigen-binding fragment thereof. In one aspect, thromboembolic diseases are thrombotic disorders (e.g., thrombosis, thrombotic stroke, A F, prevention of stroke in AF (SPAF), deep vein thrombosis, venous thromboembolism, and This refers to pulmonary embolism. The target population is also intended to be humans.

[0050] Any of the isolated antibodies or their antigen-binding fragments mentioned above are monoclonal antibodies. It may be an antigen-binding fragment thereof.

[0051] Non-limiting embodiments of this disclosure are described in the following ways:

[0052] 1. In a manner that prevents, treats, manages, or reduces the risk of stroke or thromboembolism. In patients suffering from end-stage renal disease, catalytic domedin of FXI and / or FXIa is administered. A steroid administers an effective amount of a pharmaceutical composition containing an antibody or antigen-binding fragment that binds to the steroid. A method that includes a top. 2. The method according to embodiment 1, wherein the subject is undergoing dialysis or extracorporeal membrane oxygenation. 3. The method according to aspect 1 or 2, wherein the subject is suffering from atrial fibrillation. 4. The method according to aspect 3, wherein the subject suffers from non-valvular atrial fibrillation. 5. Methods for preventing or reducing the risk of stroke or thromboembolism, including atrial fibrillation and For those suffering from end-stage renal disease and undergoing dialysis or extracorporeal membrane oxygenation, FX Includes an antibody or antigen-binding fragment that binds to the catalytic domain of I and / or FXIa. a method comprising the step of administering an effective amount of a pharmaceutical composition. 6. The method according to aspect 5, wherein the subject suffers from non-valvular atrial fibrillation. 7. The subject is a supported method of embodiment 3, 4, 5, or 6 that carries a high risk of bleeding. . 8. The antibody or a fragment thereof is one or more epithelial cells of FXI and / or FXIa. The epitopes are Pro410, Arg413, Leu415, and Cys416. , His431, Cys432, Tyr434, Gly435, Glu437, Tyr4 72, Lys473, Met474, Ala475, Glu476, Tyr521, Ar g522, Lys523, Leu524, Arg525, Asp526, Lys527, Arg548, His552, Ser575, Ser594, Trp595, Gly59 6. Two or more of the following: Glu597, Arg602, Glu603, and Arg604 A method comprising the amino acid residues of any one of embodiments 1 to 7. 9. The antibody or fragment thereof is one or more epithelial cells of anti-FXI and / or FXIa. The epitopes are Pro410, Arg413, Leu415, and Cys41 6, His431, Cys432, Tyr434, Gly435, Glu437, Tyr 472, Lys473, Met474, Ala475, Glu476, Tyr521, A rg522, Lys523, Leu524, Arg525, Asp526, Lys527 , Arg548, His552, Ser575, Ser594, Trp595, Gly5 96, Glu597, Arg602, Glu603, and Arg604 (choose four or less) The method according to embodiment 8, comprising the above amino acid residue. 10. The antibody or fragment thereof is one or more epidermal of anti-FXI and / or FXIa. The epitopes are Pro410, Arg413, Leu415, and Cys4. 16, His431, Cys432, Tyr434, Gly435, Glu437, Ty r472, Lys473, Met474, Ala475, Glu476, Tyr521, Arg522, Lys523, Leu524, Arg525, Asp526, Lys52 7, Arg548, His552, Ser575, Ser594, Trp595, Gly Six of the following: 596, Glu597, Arg602, Glu603, and Arg604 The method according to embodiment 8, comprising the above amino acid residues. 11. The antibody or fragment thereof is one or more epidermal of anti-FXI and / or FXIa. The epitopes are Pro410, Arg413, Leu415, and Cys4. 16, His431, Cys432, Tyr434, Gly435, Glu437, Ty r472, Lys473, Met474, Ala475, Glu476, Tyr521, Arg522, Lys523, Leu524, Arg525, Asp526, Lys52 7, Arg548, His552, Ser575, Ser594, Trp595, Gly Eight of the following: 596, Glu597, Arg602, Glu603, and Arg604 The method according to embodiment 8, comprising the above amino acid residues. 12. The antibody or fragment thereof is one or more epidermal of anti-FXI and / or FXIa. The epitopes are Pro410, Arg413, Leu415, and Cys4. 16, His431, Cys432, Tyr434, Gly435, Glu437, Ty r472, Lys473, Met474, Ala475, Glu476, Tyr521, Arg522, Lys523, Leu524, Arg525, Asp526, Lys52 7, Arg548, His552, Ser575, Ser594, Trp595, Gly Contains residues 596, Glu597, Arg602, Glu603, and Arg604 , the method of embodiment 8. 13. The antibody or fragment thereof is one or more epidermal of anti-FXI and / or FXIa. The epitope binds to the amino acids Pro410, Arg413, and Lys527. The residues are Leu415, Cys416, His431, Cys432, Tyr434, and G ly435, Glu437, Tyr472, Lys473, Met474, Ala475 , Glu476, Tyr521, Arg522, Lys523, Leu524, Arg5 25, Asp526, Arg548, His552, Ser575, Ser594, Tr p595, Gly596, Glu597, Arg602, Glu603, and Arg6 The method according to embodiment 8, comprising one or more amino acid residues from among 04. 14. The antibody or fragment thereof is one or more epidermal of anti-FXI and / or FXIa. The epitope binds to the amino acids Pro410, Arg413, and Lys527. The residues are Leu415, Cys416, His431, Cys432, Tyr434, and G ly435, Glu437, Tyr472, Lys473, Met474, Ala475 , Glu476, Tyr521, Arg522, Lys523, Leu524, Arg5 25, Asp526, Arg548, His552, Ser575, Ser594, Tr p595, Gly596, Glu597, Arg602, Glu603, and Arg6 The method according to embodiment 8, comprising four or more amino acid residues among 04. 15. The antibody or fragment thereof is one or more epidermal of anti-FXI and / or FXIa. The epitope binds to the amino acids Pro410, Arg413, and Lys527. The residues are Leu415, Cys416, His431, Cys432, Tyr434, and G ly435, Glu437, Tyr472, Lys473, Met474, Ala475 , Glu476, Tyr521, Arg522, Lys523, Leu524, Arg5 25, Asp526, Arg548, His552, Ser575, Ser594, Tr p595, Gly596, Glu597, Arg602, Glu603, and Arg6 The method according to embodiment 8, comprising six or more amino acid residues from among 04. 16. The antibody or fragment is of FXI and / or FXIa, factor IX, factor XIIa. One of embodiments 1 to 15 blocks the binding of the child and thrombin to one or more of them. That's one way. 17. The antibody or fragment is of FXI and / or FXIa, factor IX, factor XIIa. It blocks the binding of thrombin, or to one or more of the other components of the coagulation pathway. A method of making a decision, according to aspect 16. 18. The antibody or fragment is one or more of FIX, FXI, and FXIa. A method, one of embodiments 1 to 15, for blocking binding to platelet receptors. 19. An embodiment in which an antibody or fragment prevents the activation of the intrinsic coagulation pathway or the common coagulation pathway. One of the following methods from 1 to 15. 20. The antibody or a fragment thereof is a human FXI protein and / or human FXIa protein The substance contains a concentration of 34 nM or less, as measured by the BIACORE® assay, or in a solution. K₀ ≤ 4 pM as measured by intermediate equilibrium titration assay (SET) D Combined by, aspect 1~ One of 19 methods. 21. The antibody or fragment is found to be less effective against at least one of the CDRs listed in Table 1. Embodiments 1-2 include at least one complementarity determination region having at least 90% identity. One of the following methods. 22. The antibody or fragment comprises CDR1, CDR2, and CDR3 of Table 1, as described in Embodiment 1. One of 20 methods. 23. The antibody or fragment is selected from the group consisting of SEQ ID NOs. 5 and 25. A method which includes any one of embodiments 1 to 20. 24. The antibody or fragment is VH selected from the group consisting of SEQ ID NOs. 9 and 29, or In contrast, amino acid sequences with 90% identity; as well as sequence numbers 19 and 39 A VL selected from the following group, or an amino acid sequence having 90% identity with it. One of the methods described in embodiments 1 to 23, including the above. 25. The antibody or fragment is a VH selected from the group consisting of SEQ ID NOs. 9 and 29, or In contrast, amino acid sequences with 95% identity; as well as sequence numbers 19 and 39 A VL selected from the following group, or an amino acid sequence having 95% identity thereto. The method according to embodiment 24, including the method according to embodiment 24. 26. The antibody or fragment is VH selected from the group consisting of SEQ ID NOs. 9 and 29, or In contrast, amino acid sequences with 97% identity; and sequence numbers 19 and 39 A VL selected from the following group, or an amino acid sequence having 97% identity thereto. The method according to embodiment 24, including the method according to embodiment 24. 27. The antibody or fragment is a variable heavy chain sequence selected from the group consisting of SEQ ID NOs: 9 and 29. The method according to embodiment 24, including the method according to embodiment 24. 28. A variable light chain combination in which the antibody or fragment is selected from the group consisting of SEQ ID NOs: 19 and 39. The method according to embodiment 24, including a column. 29. A variable heavy chain selected from the group consisting of SEQ ID NOs: 9 and 29, which is an antibody or fragment. Furthermore, the variable light chain sequence is selected from the group consisting of sequence numbers 19 and 39, aspect 24 The method. 30. The antibody or fragment contains (i) the variable heavy chain of SEQ ID NO: 9 and the variable light chain of SEQ ID NO: 19. (ii) an antibody or fragment containing a column; (ii) the variable heavy chain of SEQ ID NO: 29 and the variable chain of SEQ ID NO: 39 (iii) an antibody or fragment containing a light chain sequence; (iii) a heavy chain containing the amino acid sequence of SEQ ID NO: 29 , an antibody comprising a light chain containing the amino acid sequence of SEQ ID NO: 39; and (iv) SEQ ID NO: 9 An antibody comprising a heavy chain containing an amino acid sequence and a light chain containing the amino acid sequence of SEQ ID NO: 19. A method according to embodiment 24, selected from the group. 31. The antibody or fragment contains (i) the C of the heavy chain variable region, which includes the amino acid sequence of SEQ ID NO: 46. DR1; contains the amino acid sequence of SEQ ID NO: 4; CDR2; contains the amino acid sequence of SEQ ID NO: 5 DR3; and (ii) CDR1 of the light chain variable region, including the amino acid sequence of SEQ ID NO: 33. ;CDR2 containing the amino acid sequence of SEQ ID NO: 14; and containing the amino acid sequence of SEQ ID NO: 15 Any one of the methods described in embodiments 1 to 30, including CDR3. 32. The antibody or fragment is (i) a heavy chain selected from the group consisting of SEQ ID NOs: 3 and 23. CDR1 of the variable region; CDR2 selected from the group consisting of sequence numbers 4 and 24; and CDR3 selected from the group consisting of 25; and (ii) from Sequence IDs 13 and 33 From the group consisting of CDR1 of the light chain variable region selected from the group consisting of sequence numbers 14 and 34 Selected CDR2; and CDR selected from the group consisting of sequence numbers 15 and 35. One of the methods of embodiments 1 to 30, including 3. 33. The antibody or fragment is (i) a heavy chain selected from the group consisting of SEQ ID NOs: 6 and 26. CDR1 of the variable region; selected from the group consisting of sequence numbers 7 and 27; CDR2; 8 and CDR3 selected from a group of 28; and (ii) from Sequence IDs 16 and 36 From the group consisting of CDR1 of the light chain variable region selected from the group consisting of sequence numbers 17 and 37 Selected CDR2; and CDR selected from the group consisting of sequence numbers 18 and 38. One of the methods of embodiments 1 to 30, including 3. 34. The antibody or fragment is the heavy chain variable region CDR1 of SEQ ID NO: 3; heavy chain variable region of SEQ ID NO: 4 CDR2 of the region; CDR3 of the heavy chain variable region of sequence number 5; light chain variable region of sequence number 13 CDR1; Light chain variable region of SEQ ID NO: 14; CDR2; and Light chain variable region of SEQ ID NO: 15 Any one of embodiments 1 to 30, including CDR3. 35. The antibody or fragment is the heavy chain variable region CDR1 of SEQ ID NO: 23; the heavy chain of SEQ ID NO: 24 Variable region CDR2; Heavy chain variable region CDR3 of SEQ ID NO: 25; Light chain variable region of SEQ ID NO: 33 CDR1 of the region; CDR2 of the light chain variable region of sequence number 34; and light chain variable of sequence number 35. A method according to any one of embodiments 1 to 30, including a variable region CDR3. 36. The antibody or fragment is the heavy chain variable region CDR1 of SEQ ID NO: 6; heavy chain variable region of SEQ ID NO: 7 CDR2 of the region; CDR3 of the heavy chain variable region of sequence number 8; light chain variable region of sequence number 16 CDR1; Light chain variable region of SEQ ID NO: 17; CDR2; and Light chain variable region of SEQ ID NO: 18 Any one of embodiments 1 to 30, including CDR3. 37. The antibody or fragment is the heavy chain variable region CDR1 of SEQ ID NO: 26; the heavy chain of SEQ ID NO: 27 Variable region CDR2; Heavy chain variable region CDR3 of SEQ ID NO: 28; Light chain variable region of SEQ ID NO: 36 CDR1 of the region; CDR2 of the light chain variable region of sequence number 37; and light chain variable region of sequence number 38. A method according to any one of embodiments 1 to 30, including a variable region CDR3. 38. The antibody or fragment contains the variable heavy chain sequence of SEQ ID NO: 9 and the variable light chain sequence of SEQ ID NO: 19. An antibody containing the variable heavy chain sequence of SEQ ID NO: 29 and the variable light chain sequence of SEQ ID NO: 39 One of the methods described in embodiments 1 to 30, which involves binding to the same epitope. 39. The antibody or fragment is human FXI protein and / or human FXIa protein Regarding binding to the antibody, the antibody contains the variable heavy chain sequence of SEQ ID NO: 9 and the variable light chain sequence of SEQ ID NO: 19. or compete with antibodies containing the variable heavy chain sequence of SEQ ID NO: 29 and the variable light chain sequence of SEQ ID NO: 39. or any one of the methods described in embodiments 1 to 30. 40. The antibody or fragment is selected from the group consisting of NOV1090 and NOV1401. or any one of the methods described in embodiments 1 to 30. 41. Subjects suffering from end-stage renal disease and who are receiving catalytic doping for FXI and / or FXIa Treated with an anti-FXI / FXIa antibody or antigen-binding fragment that binds to the in-vitre, or This was a method of managing or reducing bleeding or the risk of bleeding in subjects to whom it was administered. And, anti-idioms that specifically bind to anti-FXI / FXIa antibodies target the target that needs them. Administer type antibody or fragment thereof, and use anti-FXI / FXIa antibody, FXI and / or The step includes blocking binding to FXIa, wherein an anti-idiotype antibody or a fragment thereof A method for reversing the anticoagulant activity of anti-FXI / FXIa antibodies. 42. Inject an anti-idiotype antibody or a fragment thereof into the target once or several times (e.g., 2 times). The anticoagulant effect of the anti-FXI / FXIa antibody is reversed by administering it once, three times, or four times. The method of causing, according to embodiment 41. 43. Subjects suffering from end-stage renal disease and who are receiving catalytic doping for FXI and / or FXIa Treated with an anti-FXI / FXIa antibody or antigen-binding fragment that binds to the in-vitre, or This was a method of managing or reducing bleeding or the risk of bleeding in subjects to whom it was administered. And, below: (i) colloids, crystalloids, human plasma, or plasma proteins such as albumin (ii) Replacement of body fluids using (i) blood; (ii) transfusion of packed red blood cells or whole blood; or (i ii) Fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), factor VIII Activated PCCs (APCCs) such as child inhibitors, and / or recombinant activated type V One of the factor II administrations provides an anticoagulant effect that lasts long enough to manage bleeding. A method that includes a temporary reversal of the result. 44. The subject is a person undergoing dialysis, such as hemodialysis, and is one of the individuals described in any of the descriptions in 41 to 43. Law. 45. The subject is suffering from atrial fibrillation, and one of the methods described in 41 to 43. 46. ​​The method of aspect 45, wherein the subject is suffering from non-valvular atrial fibrillation. 47. The method of aspect 45 or 46, wherein the subject has a substantiated high risk of bleeding. 48. An anti-FXI / FXIa antibody or antigen-binding fragment consisting of SEQ ID NOs. 9 and 29. A VH selected from the group, or an amino acid sequence having 90% identity to it; VL selected from the group consisting of SEQ ID NOs. 19 and 39, or 90% of them A method comprising an amino acid sequence having the same identity as described in any one of embodiments 41 to 47. 49. Anti-FXI / FXIa antibodies or antigen-binding fragments are found to be human FXI protein and / Alternatively, regarding binding to the human FXIa protein, the variable heavy chain of SEQ ID NO: 9 and SEQ ID NO: An antibody containing 19 variable light chain sequences, or the variable heavy chain of SEQ ID NO: 29 and the variable light chain of SEQ ID NO: 39. A method, one of embodiments 41 to 47, in which an antibody containing a modified light chain sequence competes in a concentration-dependent manner. . 50. The antibody is a recombinant human antibody or a humanized antibody, one of any one of embodiments 1 to 49. method. 51. Prevention of the risk of stroke or thromboembolism in subjects suffering from end-stage renal disease. For use in stopping, treating, controlling, or reducing, FXI and / or FX An antibody or its antigen-binding fragment that binds to the catalytic domain of Ia, or an antibody or A pharmaceutical composition comprising the antigen-binding fragment wherein the antibody has the amino acid sequence of SEQ ID NO: 31 An antibody or its antigenic chain containing a heavy chain and a light chain containing the amino acid sequence of SEQ ID NO: 41 A pharmaceutical composition comprising a composite fragment, or an antibody or its antigen-binding fragment. 52. The antibody or antigen-binding fragment thereof described in Embodiment 51, wherein the subject is undergoing dialysis. Or a pharmaceutical composition. 53. The subject is undergoing hemodialysis or other types of dialysis, such as peritoneal dialysis, as described in section 5. The antibody or its antigen-binding fragment or pharmaceutical composition as described in 1 or 52. 54. The subject is suffering from atrial fibrillation, such as non-valvular atrial fibrillation, as described in paragraphs 51-53. The antibody or its antigen-binding fragment or pharmaceutical composition described in any one of the following. 55. Individuals suffering from atrial fibrillation and end-stage renal disease who are receiving dialysis such as hemodialysis. For use in preventing or reducing the risk of stroke or thromboembolism in, Antibodies or antigens that bind to the catalytic domain of FXI and / or FXIa A pharmaceutical composition comprising a sex fragment, or an antibody or its antigen-binding fragment, wherein the antibody is distributed It contains a heavy chain containing the amino acid sequence of sequence number 31 and a light chain containing the amino acid sequence of sequence number 41. a drug containing an antibody or its antigen-binding fragment, or an antibody or its antigen-binding fragment A pharmaceutical composition. 56. The subject is suffering from non-valvular atrial fibrillation, as described in one of the descriptions in 51-55. The listed antibody or its antigen-binding fragment or pharmaceutical composition. 57. In subjects suffering from end-stage renal disease who have started catheter-based hemodialysis, Use in the prevention, treatment, management, or reduction of the risk of catheter-related thrombosis. For this purpose, an antibody or the thereof that binds to the catalytic domain of FXI and / or FXIa A pharmaceutical composition comprising an antigen-binding fragment, or an antibody or its antigen-binding fragment, wherein the antibody The body has a heavy chain containing the amino acid sequence of SEQ ID NO: 31 and a light chain containing the amino acid sequence of SEQ ID NO: 41. An antibody or its antigen-binding fragment, including a chain, or an antibody or its antigen-binding fragment A pharmaceutical composition containing the following: 58. The subject has a substantiated high risk of bleeding, one of the characteristics described in 51-58. The antibody or its antigen-binding fragment or pharmaceutical composition as described above. 59. Thromboembolism such as stroke or systemic embolism in patients with atrial fibrillation For use in preventing or reducing the risk of disease, FXI and / or FXIa An antibody or its antigen-binding fragment that binds to the catalytic domain, or an antibody or its A pharmaceutical composition containing an antigen-binding fragment, wherein the target is CHA2DS2VASc with a risk of ≥2. Characterized by the score, supported by evidence of a high risk of bleeding, antibodies, SEQ ID NO: A heavy chain containing the amino acid sequence of 31 and a light chain containing the amino acid sequence of SEQ ID NO: 41, A pharmaceutical composition containing a body or its antigen-binding fragment, or an antibody or its antigen-binding fragment. thing. 60. The antibody described in any one of the descriptions in 51-59, in which the subject is at least 55 years old. or its antigen-binding fragment or pharmaceutical composition. 61. The subjects are (i) CHA2DS2VASc hazard score of ≥ 2 and (ii) hazard score of ≥ 2. Sex factor: (a) being over 65 years of age; (b) A history of stroke or transient ischemic attack; (c) A history of major bleeding or clinically significant bleeding; (d) The patient has stage 3 or 4 of chronic kidney disease (CKD); (e) Treatment with monotherapy or dual antiplatelet therapy; and (f) History of falls or other symptoms associated with bruising due to hematoma Characterized by having one, two, or more of the following risk factors As described in any one of embodiments 51 to 60, which is supported by evidence and has a high risk of bleeding. An antibody, its antigen-binding fragment, or a pharmaceutical composition. 62. The antibody or its antigen-binding fragment is administered subcutaneously to the subject, as in the embodiments of 51-61. An antibody or its antigen-binding fragment or pharmaceutical composition as described in any one of the above. 63. The antibody or its antigen-binding fragment contains at least 90 mg, 120 mg, or 150 mg , administered in doses of 180 mg or 210 mg, according to one of the embodiments 37 to 48. The antibody or its antigen-binding fragment or pharmaceutical composition as described above. 64. The antibody or its antigen-binding fragment is present in 120 mg, 150 mg, or 180 mg doses. The antibody or antigen-binding thereof described in any one of embodiments 51 to 63, administered in a dose. Fragments or pharmaceutical compositions. 65. An antibody or its antigen-binding fragment is administered once a month, in any of embodiments 51 to 64. The antibody or its antigen-binding fragment or pharmaceutical composition as described in one of the above. 66. In individuals suffering from end-stage renal disease, the risk of stroke or thromboembolism can be reduced. For the manufacture of pharmaceuticals for stopping, treating, managing, or reducing, FXI and / or This involves the use of an antibody or its antigen-binding fragment that binds to the catalytic domain of FXIa, The antibody contains a heavy chain containing the amino acid sequence of SEQ ID NO: 31 and an amino acid sequence containing the amino acid sequence of SEQ ID NO: 41 Use, including light chains. 67. The use described in aspect 66, wherein the subject is undergoing dialysis. 68. The subject is undergoing hemodialysis or other types of dialysis, such as peritoneal dialysis, as described in section 6. Use as described in 6 or 67. 69. The subject is suffering from atrial fibrillation, such as non-valvular atrial fibrillation, as described in paragraphs 66-68. Use as described in one of the following. 70. Individuals suffering from atrial fibrillation and end-stage renal disease who are receiving dialysis such as hemodialysis. In the manufacture of pharmaceuticals for preventing or reducing the risk of stroke or thromboembolism For this purpose, an antibody or antigen that binds to the catalytic domain of FXI and / or FXIa. The use of a binding fragment, wherein the antibody has a heavy chain containing the amino acid sequence of SEQ ID NO: 31 and a sequence number Uses include a light chain containing the amino acid sequence of No. 41. 71. The subject is suffering from non-valvular atrial fibrillation, as described in one of the descriptions in 66-70. Use on a vehicle. 72. In subjects suffering from end-stage renal disease who have started catheter-based hemodialysis, Medical devices for preventing, treating, managing, or reducing the risk of catheter-related thrombosis. For the manufacture of antibodies or The use of the antigen-binding fragment, wherein the antibody has a heavy chain containing the amino acid sequence of SEQ ID NO: 31 Uses include a light chain containing the amino acid sequence of SEQ ID NO: 41. 73. The subject has a substantiated high risk of bleeding, as described in any one of the descriptions 66-72. Use as described above. 74. Thromboembolism such as stroke or systemic embolism in patients with atrial fibrillation FXI and / or F for the manufacture of pharmaceuticals to prevent or reduce the risk of disease The use of an antibody or its antigen-binding fragment that binds to the catalytic domain of XIa, and the target However, supported by a CHA2DS2VASc hazard score of ≥2, The blood has a high risk, and the antibody contains a heavy chain with the amino acid sequence of SEQ ID NO: 31 and SEQ ID NO: 41 Uses include a light chain containing the amino acid sequence. 75. Use as described in any one of the descriptions in 66 to 74, wherein the subject is at least 55 years old. 76. The subjects are (i) CHA2DS2VASc hazard scores of ≥ 2 and (ii) hazards of ≥ 2. Sex factor: (a) being over 65 years of age; (b) A history of stroke or transient ischemic attack; (c) A history of major bleeding or clinically significant bleeding; (d) The patient has stage 3 or 4 of chronic kidney disease (CKD); (e) Treatment with monotherapy or dual antiplatelet therapy; and (f) History of falls or other symptoms associated with bruising due to hematoma Characterized by having one, two, or more of the following risk factors As described in any one of embodiments 66 to 75, which is supported by evidence and has a high risk of bleeding. use. 77. The use of the pharmaceutical product as described in any one of embodiments 66 to 76, which is suitable for subcutaneous administration to the target. . 78. Pharmaceuticals that contain at least 90 mg, 120 mg, 150 mg, 180 mg of the target substance. Alternatively, the method described in any one of embodiments 66 to 77, which is suitable for administration at a dose of 210 mg. use. 79. A drug administered to a subject in doses of 120 mg, 150 mg, or 180 mg. Use as described in any one of embodiments 66 to 78, which is suitable for giving. 80. A pharmaceutical product is suitable for monthly administration to the target subject, as described in one of the embodiments 66 to 79. Use on a vehicle. 81. An embodiment further comprising the step of administering one or more therapeutically active agents to a subject. One of the methods from 1 to 40. 82.1 or more therapeutically active agents, thromboxane inhibitors (e.g., aspirin) Phosphorus), thienopyridine derivatives (e.g., clopidogrel and prasugrel) and non-thie Adenosine diphosphate receptors such as nopyridine derivatives (e.g., ticagrelor and cangrelor) Virus antagonists (or P2Y12 inhibitors) and protease activators Select from a group consisting of field 1 (PAR1) antagonists (e.g., Vorapaxar) The method of embodiment 81, as applicable. 83. The one or more therapeutic active agents are proton pump inhibitors (PPIs), and the subject has a GI disorder such as a history of prior GI bleeding or prodromal symptoms of peptic ulcer, or has this history, the method of embodiment 81. 84. For use in combination with one or more therapeutic active agents, the antibody or antigen-binding fragment thereof or pharmaceutical composition according to any one of embodiments 51 to 64. 85. The one or more therapeutic active agents are selected from the group consisting of thromboxane inhibitors (e.g., aspirin), thienopyridines (e.g., clopidogrel and prasugrel), and non-thienopyridines (e.g., ticagrelor and Cangrelor), such as adenosine diphosphate receptor antagonists (or P2Y12 inhibitors), and protease-activated receptor 1 (PAR1) antagonists (e.g., Vorapaxar), the antibody or antigen-binding fragment thereof or pharmaceutical composition according to embodiment 84. selected, the antibody or antigen-binding fragment thereof or pharmaceutical composition according to embodiment 84. 86. The subject has a GI disorder such as a history of prior GI bleeding or prodromal symptoms of peptic ulcer, or has this history, the antibody or antigen-binding fragment thereof or pharmaceutical composition according to embodiment 84. 87. A method for preventing, treating, or managing, or reducing the risk of thromboembolism such as stroke or systemic embolism, comprising administering an anti-factor XI ("FXI") antibody or antigen-binding fragment thereof of about 100 mg to about 250 mg that specifically binds within the catalytic domain of FXI, and the subject has the following characteristics: (i) male and female subjects aged ≧ 55 years and < 85 years; (ii) a body weight between 50 and 130 kg including the endpoints; ​​​​(iii) Atrial fibrillation (AF) or atrial flutter recorded by electrocardiogram; (iv) CHA2DS2-VASc risk score ≥ 2 for male and female subjects ; (v) A CHA2DS2VASc risk score of 1 for males and anticoagulation treatment is justified. A certain thing; and (vi) Not receiving anticoagulant treatment, or more than 8 weeks prior to treatment, The patient is receiving stable treatment with a novel oral anticoagulant (NOAC) in sufficient quantities. A method comprising one, two, more than, or all of the above. 88. The method of aspect 87, wherein the subject is suffering from non-valvular atrial fibrillation. 89. The anti-FXI antibody contains a heavy chain with the amino acid sequence of SEQ ID NO: 31 and the amino acid sequence of SEQ ID NO: 41. The method of embodiment 87 or 88, comprising a light chain containing an acid sequence. 90. Anti-FXI antibody or its antigen-binding fragment, in doses of 120 mg, 150 mg, or 18 The method according to any one of the above embodiments, wherein the dose is 0 mg and administered once a month.

[0053] term Unless otherwise defined, all technical and scientific terms used herein are defined in this text. The term has the same meaning as it is generally understood by those skilled in the art in the field relating to the disclosure.

[0054] The terms "FXI protein," "FXI antigen," and "FXI" are used interchangeably. It is used to refer to the factor XI protein in different species. Factor XI is a limited protein When protein breakdown leads to conversion to active serine proteases, they become part of the intrinsic pathway of blood coagulation. As zymogens that participate in this process, glycoproteins present in human plasma at concentrations of 25-30 nM It is a mammalian plasma XI coagulation factor.

[0055] 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 mediates thrombin via the contact phase of blood coagulation or on the platelet surface. Through activation, it is converted to its active form, Xla coagulation factor (FXIa). Upon this activation of factor XI, the internal peptide bond is cleaved into each of the two chains, disulfide. A serine is composed of two heavy chains and two light chains, held together by phytobonds. This serine protease results in activated Xla factor, which is a rotease. XFIa converts coagulation factor IX to IXa, and then IXa converts to coagulation factor X. Xa activates coagulation factors. Subsequently, Xa activates the second coagulation factor / thrombin. It can mediate. For example, human FXI has the sequence shown in Table 1 (Sequence ID 1), and precedent Reports and literature (Mandle RJ Jr, et al. (1979) Blood; 54(4):850; NCBI reference sequence) This is described in :AAA51985).

[0056] In the context of this disclosure, the terms “FXI” and “FXIa” (etc.) refer to natural FX Mutants and variants of protein I and protein FXIa, respectively The amino acid sequence of the natural primary structure (amino acid sequence) described in the above report and This includes mutants and variants that have substantially the same amino acid sequence.

[0057] The terms "catalytic domain," "serine protease catalytic domain," and the foregoing are used herein. A similar term used is the number of Glu1s counted from the N-terminus of a circulating mature protein. It refers to amino acids Ile370 to Val607. This can also be described as residues 388 to 625 at the C-terminus of FXI. As used herein, the term "active site" refers to a catalytic triad of amino acids including His413, Asp462, and Ser557 (Bane and Gailani (2014) Drug Disc. 19(9)).

[0058] The term "about" with respect to a numerical value x means, for example, x ± 10%.

[0059] As used herein, the term "antibody" refers to whole antibodies and any antigen-binding fragment (i.e., "antigen-binding portion") or single-chain forms thereof. A whole antibody is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain comprises a heavy-chain variable region (abbreviated herein as VH) and a heavy-chain constant region. The heavy-chain constant region comprises three domains, CH1, CH2, and CH3. Each light chain comprises a light-chain variable region (abbreviated herein as VL) and a light-chain constant region. The light-chain constant region comprises one domain, CL. The VH region and the VL region can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs) interspersed with more conserved regions called framework regions (FRs). Each VH and each VL consists of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with an antigen. The constant region of the body is the host tissue or diverse cells of the immune system (e.g., Eff). It mediates binding to factor cells and factors containing the first component of the classical complement system (Clq). In some specific embodiments, the antibody may be a monoclonal antibody, a human antibody, a humanized antibody, or a ra It can be a tubular antibody or a chimeric antibody. The antibody can be any isotype (e.g., Ig IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, I) With antibodies of IgG2, IgG3, IgG4, IgA1, and IgA2, or their subclasses. It's possible.

[0060] As used herein, the terms “antigen-binding portion” or “antigen-binding fragment” of an antibody are used in a manner that The word retains the ability to specifically bind to a given antigen (e.g., factor XIa (FXIa)). This refers to one or more fragments of an intact antibody. The antigen-binding function of an antibody is... This can be accomplished by a fragment of an antibody. The antigen-binding portion or antigen-binding fragment of the antibody Examples of binding fragments included within the term are Fab fragments, VL domains, VH domains, and C A monovalent fragment consisting of an L domain and a CH1 domain; disulfide in the hinge region F(ab)2 fragment is a divalent fragment containing two Fab fragments linked by crosslinking; VH Fd fragment consisting of the main and CH1 domains; VL domain of a single arm of the antibody Fv fragment consisting of VH domains; single domain consisting of VH domain or VL domain Antibody (dAb) fragments (Ward et al., 1989 Nature 341:544~546); and isolation and complementarity determination. Includes area (CDR).

[0061] Furthermore, the two domains of the Fv fragment, the VL domain and the VH domain, are separate Encoded by genes, but using recombination, they can be processed into a single protein chain. It can be attached by an artificial peptide linker that makes it possible to produce, in this case The VL and VH regions pair up to form a monovalent molecule (known as single-chain Fv(scFv)). For example, Bird et al., 1988 Science 242:423~426; and Huston et al., 1988 Proc. Natl. See Acad. Sci. 85:5879~5883. Such single-chain antibodies form antibodies It contains one or more antigen-binding moieties or antigen-binding fragments. These antibody fragments Obtained using conventional techniques known to the manufacturer, the fragments are also useful in the same form as intact antibodies. Screening will be conducted for this.

[0062] Antigen-binding fragments also include single-domain antibodies, maxi-bodies, mini-bodies, and intra-bodies. i, Diabody, Triabody, Tetrabody, v-NAR, and bis-scFv (For example, Hollinger and Hudson, 2005, Nature Biotechnology, 23, 9, 1126-1136) It can also be incorporated into (see reference). The antigen-binding portion of the antibody is type III fibrous. Polypeptides such as nectin (Fn3) (fibronectin polypeptide monobody) To scaffolding based on U.S. Patent No. 6,703,199 (see U.S. Patent No. 6,703,199 for further details) It can be grafted.

[0063] The antigen-binding fragment, together with a complementary light chain polypeptide, forms a pair of antigen-binding domains. It is incorporated into a single-chain molecule containing a pair of tandem Fv segments (VH-CH1-VH-CH1). It can be incorporated (Zapata et al., 1995 Protein Eng. 8(10):1057~1062; and US Patent No. 5,641,870).

[0064] As used herein, the term "affinity" refers to the resistance of a single antigenic site. This refers to the strength of the interaction between the body and the antigen. Within each antigenic site, the variable region of the antibody "arm" The region interacts with the antigen via weak non-covalent forces at numerous sites, and the interaction The larger the size, the stronger the affinity. Antibodies or their antigen-binding fragments (e.g., Fa With respect to fragment b), the term “high affinity” as used herein generally refers to 10 -9 K below M D (For example, 10 -10 K below M D , 10 -11 K below M D , 10 -12 K below M D , 10 -13 K below M D , 10 -14 K below M D Antibodies or antigen-binding fragments having (etc.) It refers to.

[0065] The term "amino acid" includes naturally occurring amino acids and synthetic amino acids, as well as naturally occurring amino acids. This also refers to amino acid analogs and amino acid mimes that function in a similar manner to amino acids. The amino acids in question include not only those encoded by the genetic code, but also those that have been modified later. No acids, for example, hydroxyproline, γ-carboxyglutamic acid, and O-phosphosate. It is also phosphorus. Amino acid analogs are compounds that have the same basic chemical structure as naturally occurring amino acids, in other words, Hydrogen, carboxyl group, amino group, and R group, for example, homoserine, norleucine , methionine sulfoxide, methionine methylsulfonium has an alpha carbon bonded to it This refers to compounds that have a modified R group (e.g., norleucine) or modified Although it has a peptide skeleton, it retains the same basic chemical structure as naturally occurring amino acids. Acid mimetic compounds are compounds that have a structure different from the typical chemical structure of amino acids, but are not naturally occurring amino acids. This refers to chemical compounds that function in a similar manner to acids.

[0066] As used herein, the term “binding specificity” refers to the reaction with only one antigenic determinant. This refers to the ability of individual antigen-binding sites.

[0067] Antibodies (e.g., FXI-binding antibodies and / or FXIa-binding antibodies) are "specifically" The phrase "to bind (or selectively)" refers to a heterogeneous group of proteins and other biomolecules. Cognitive antigens within (e.g., human FXI and / or FXIa or cynoquiza) This refers to the binding reaction that determines the presence of FXI and / or FXIa. The phrases "antibody that recognizes an antigen" and "antibody that is specific to an antigen" are equivalent to "antibody that is specific to an antigen." This term is used interchangeably with "antibody that binds to."

[0068] The term "mediating FXI and / or FXIa" means FXI and / or F XIa is the IXth factor (also known as FIX), the Xth factor (FX), and / or by directly or indirectly activating thrombin, and / also By binding to platelet receptors, it mediates the intrinsic coagulation pathway and / or common coagulation pathway. It refers to the fact of mediation.

[0069] The term "hemostasis" refers to the primary mechanism for stopping blood flow at the site of injury, and wound This represents each of the major mechanisms for restoring vascular patency during healing. Normal hemostasis and disease In physical thrombosis, there are three mechanisms: primary thrombosis, which involves the interaction of activated platelets with the blood vessel wall. The formation of blood, fibrin, and a process called fibrinolysis are activated simultaneously.

[0070] Terms such as "coagulation and coagulation cascade" and "coagulation cascade model" are used in relation to wounds. A protein-based system used to stabilize the blood clot that forms to seal the blood vessel. This refers to the coagulation pathway, which is a proteolytic cascade. Each enzyme in the pathway is present in the plasma. When activated, it undergoes proteolytic cleavage, releasing the activating factor from the precursor molecule. It exists as zymogen (in an inactive form). The coagulation cascade controls the activation process. It functions as a series of positive and negative feedback loops that control the process. The ultimate goal of the process is to Then, thrombin can convert soluble fibrinogen into fibrin, which forms blood clots. The purpose is to produce [something].

[0071] The process of thrombin production involves three phases: the intrinsic pathway, and the activation of the coagulation factor FXa (active The extrinsic pathway, an alternative pathway for generating sexualized factor X, and thrombin It can be divided into a final common path that results in the formation of (Hoffman MM a nd Monroe DM (2005) Curr Hematol Rep. 4:391 -396; Johne J, et al. (2006) Biol Chem. 387:173-178).

[0072] "Platelet aggregation" refers to the phenomenon that occurs when a blood vessel ruptures, where substances that normally do not come into direct contact with the blood flow... This refers to the process of exposure to these substances (mainly collagen and von Willebrand oxalool). The platelet allows the platelet to adhere to the fractured surface. Then, it releases chemicals that attract more platelets to the damaged area, but this is called platelet aggregation. These two processes are the initial response to stop bleeding.

[0073] As used herein, the term "thromboembolic disorder" or similar terms refers to intrinsic coagulation. The pathway and / or common coagulation pathway are abnormally activated or spontaneously inactivated. (For example, without treatment) refers to any number of conditions or diseases. These conditions are , thromboembolic stroke, and other types of ischemic stroke, atrial fibrillation, in atrial fibrillation This includes stroke prevention (SPAF), deep vein thrombosis, venous thromboembolism, and pulmonary embolism. However, these are not limited to these. These also include catheter-related thrombosis, where the catheter becomes thrombotic. Diseases (e.g., Hickman catheter in cancer patients), as well as tubing and oxygenation This may also include preventing and managing extracorporeal membrane oxygenation (ECMO), which can lead to the development of blood clots in the membrane.

[0074] As used herein, the term “thromboembolic” or similar terms also apply to the anti-inflammatory drugs of this disclosure. Prevention using FXI antibodies and / or anti-FXIa antibodies or their antigen-binding fragments The following can be stopped or treated: Paroxysmal atrial fibrillation or paroxysmal atrial flutter, persistent atrial fibrillation or persistent atrial flutter, Alternatively, if cardiac arrhythmias such as persistent atrial fibrillation or persistent atrial flutter are suspected or confirmed. Thromboembolism in the subject being treated; • Subjects with atrial fibrillation requiring stroke prevention (SPAF), and whose subgroups are The target group consists of AF patients undergoing percutaneous coronary intervention (PCI); • Management of acute venous thromboembolic events (VTE) in patients at high risk of bleeding. and prevention of long-term secondary VTE; • In secondary prevention following transient ischemic attack (TIA) or non-functional stroke For the prevention of thromboembolic events in cerebral and cardiovascular events, as well as in heart failure with sinus rhythm. Cerebral and cardiovascular events in this context; • Clot formation and thromboembolism in the left atrium in patients undergoing cardiac defibrillation for cardiac arrhythmias. Embolism; Thrombosis before, during, and after ablation procedures for cardiac arrhythmias; • Venous thrombosis, which is deep vein thrombosis or superficial vein thrombosis in the lower or upper extremities. Vessel thrombosis, thrombosis in the abdominal and thoracic veins, sinus thrombosis and jugular vein thrombosis This includes, but is not limited to, treatment and secondary prevention; Catheters, pacemaker leads, synthetic arterial grafts; mechanical heart valves or biological Thrombus on any artificial surface in a vein or artery, such as an artificial heart valve or left ventricular assist device. disease; • Pulmonary embolism in patients with or without venous thrombosis; Chronic thromboembolic pulmonary hypertension (CTEPH); • Arterial thrombosis on ruptured atherosclerotic plaque, on arterial prostheses or catheters These are thrombosis in the arteries and thrombosis in seemingly normal arteries, and these are acute coronary syndrome. Group, ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, unstable angina, stent thrombosis, arterial Thrombosis of any artificial surface within the system, and in subjects with or without pulmonary hypertension. This includes, but is not limited to, pulmonary thrombosis; • Thrombosis and thrombosis in patients undergoing percutaneous coronary intervention (PCI) Embolism; • Cardioembolic stroke and cryptogenic stroke; Thrombosis in patients with invasive and non-invasive cancerous malignancies; • Thrombosis involving indwelling catheters; • Thrombosis and thromboembolism in critically ill patients; • Cardiac thrombosis and thromboembolism, including cardiac thrombosis after myocardial infarction and cardiovascular thrombosis. Conditions such as aneurysms, cardiomyopathy, cardiac hypertrophy and cardiac dysfunction, myocarditis, and artificial surfaces within the heart This includes, but is not limited to, cardiothrombosis associated with the condition; Thromboembolism in patients with valvular heart disease, with or without atrial fibrillation; • Thromboembolism involving mechanical or biological prostheses for heart valves; • After cardiac repair for simple or complex cardiac malformations, natural or artificial cardiac pads Thromboembolism in patients with arterial or venous conduits; • Total knee replacement, total hip replacement, and orthopedic surgery, thoracic surgery, or abdominal surgery Venous thrombosis and thromboembolism following; • Following neurosurgical procedures including intracranial and spinal interventions Arterial thrombosis or venous thrombosis; • Factor V Leiden, prothrombin mutation, antithrombin III, prote Protein C deficiency and protein S deficiency, factor XIII mutations, familial fibrosis Linogenemia, congenital plasminogen deficiency, elevated factor XI levels, sickle cell disease, Antiphospholipid syndrome, autoimmune diseases, chronic bowel disease, nephrotic syndrome, hemolytic uremic disease, bone marrow Proliferative disorders, disseminated intravascular coagulation, paroxysmal nocturnal hemoglobinuria, and heparin-induced hematologic dysplasia Congenital or acquired thrombotic predisposition, including but not limited to thrombotic plaque; • Thrombosis and thromboembolism in chronic kidney disease; and • Thrombosis and Thromboembolism It may also refer to any number among them.

[0075] The term "chimeric antibody" refers to (a) the antigen-binding site (variable region), class, effervescence. The effector function, and / or the type, or class, the effector function, and / or a modified constant region of the species, or a completely different one that confers new properties to a chimeric antibody. To link to molecules such as enzymes, toxins, hormones, growth factors, drugs, etc. Antibody molecules in which the normal region or a part thereof has been modified, replaced, or exchanged; or (b) The variable region or a part thereof has different antigen specificity or altered antigen specificity. This refers to antibody molecules that have been modified, replaced, or exchanged using a specified variable region. For example, mouse antibodies use a constant region derived from human immunoglobulins. It can be modified by changing. Due to replacement by the human constant region, texture The antibody reduces antigenicity in humans compared to the original mouse antibody, while still recognizing the antigen. It can retain its unique characteristics in that context.

[0076] The term "conservatively modified variant" refers to a variant of either the amino acid sequence or the nucleic acid sequence. This also applies. With respect to a specific nucleic acid sequence, a conservatively modified variant is the same as an amino acid. Nucleic acids that encode an amino acid sequence or an essentially identical amino acid sequence, or nucleic acids that encode an amino acid sequence If a sequence does not code, it refers to essentially the same sequence. Due to the degenerate nature of genetic coding, A large number of functionally identical nucleic acids code for any given protein. For example, codons GCA, GCC, GCG, and GCU all contain the amino acid alanine. Therefore, alanine is coded at every position specified by the codon. Without modifying the polypeptide, the codon is changed to one of the corresponding codons listed. It can be modified. Such nucleic acid mutations are one type of conservatively modified mutation. It is a "silent mutation." Any nucleic acid encoding polypeptide as defined herein The column also describes all possible silent mutations in nucleic acids. Those skilled in the art will know that within nucleic acids... Each codon (AUG, which is usually the codon for methionine only, and AUG, which is usually the codon for tryptophan only) It has been recognized that modifying the codon (excluding TGG) can result in a functionally identical molecule. They will recognize. Therefore, within each sequence described, nucleic acids encoding polypeptides Each of these silent mutations is implied.

[0077] In polypeptide sequences, "conservatively modified variants" are chemically similar to amino acids. Individual substitutions and deletions in polypeptide sequences, resulting in amino acid substitutions. , or addition. In the art, this includes conservative substitutions that present functionally similar amino acids. Tables are well known. Such conservedly modified mutants are polymorphic mutants and interspecific phases of the disclosed information. This adds to the same organism and alleles, and does not exclude them. The eight groups are: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamate 1) Asparagine (E); 2) Asparagine (N), Glutamine (Q); 3) Arginine (R), Li Syn(K); 5) Isoleucine(I), Leucine(L), Methionine(M), Valine(V) );6) Phenylalanine (F), tyrosine (Y), tryptophan (W);7) Serine (S), threonine (T); and (8) cysteine ​​(C), methionine (M) are related to each other. In contrast, it contains amino acids that are conservative substitutions (for example, Creighton, Proteins (1984) (See reference). In some embodiments, the term “conservative sequence modification” refers to an amino acid It does not significantly affect or alter the binding characteristics of antibodies containing the sequence. It is used to refer to amino acid modifications.

[0078] The term "epitope" refers to a protein determinant that is capable of specific binding to an antibody. Epitopes are typically composed of chemically active surface molecules, such as amino acids or sugar side chains. In addition to their distinctive three-dimensional structural features, they typically also possess distinctive charge characteristics. The difference between conformal epitopes and non-conformal epitopes is that the former binds to a denaturing solvent. It is distinguished in that it is lost in the presence of the latter, but the bond to the latter is not lost. In a test, one antibody is converted to a second antibody by any method well known to those skilled in the art. When two antibodies are shown to bind to the same epitope, they are said to "compete" with each other.

[0079] As used herein, the term "human antibody" refers to the framework region and the CDR region. Each region is intended to contain antibodies that have variable regions derived from human sequences. Furthermore, if the antibody contains a constant region, the constant region also contains such human sequences, for example If so, by human germline sequences or mutated versions of human germline sequences The human antibodies of this disclosure contain amino acid residues not encoded by the human sequence (e.g., i Induced by random mutagenesis or site-directed mutagenesis in the in vitro. A mutation introduced by a somatic mutation in vivo. (May include mutations.)

[0080] The term "human monoclonal antibody" refers to an antibody that exhibits a single binding specificity. Both the framework region and the CDR region contain variable regions derived from human sequences. This refers to an antibody that performs human immunoglobulin genetic testing. In one embodiment, a human monoclonal antibody is a human immunoglobulin gene. Prepare the child library using a phage display method for screening. ru.

[0081] "Humanized" antibodies are those that have low immunogenicity in humans but retain the reactivity of non-human antibodies. This is an antibody that, for example, retains the non-human CDR region and the rest of the antibody. In their human counterparts (i.e., the steady-state region and framework portion of the variable region), This can be achieved by doing so. For example, Morrison et al., Proc. Natl. Acad. Sci. U SA, 81:6851~6855, 1984; Morrison and Oi, Adv. Immunol., 44:65~92, 1988; Verho eyen et al., Science, 239:1534~1536, 1988; Padlan, Molec. Immun., 28:489~498, 1991 See also Padlan, Molec. Immun., 31:169-217, 1994. In addition to human manipulation techniques. Examples include the Xoma technology disclosed in US5,766,886, but these include Not limited.

[0082] "Identical" or "identical" in the context of two or more nucleic acid sequences or polypeptide sequences. The term "percent" refers to two or more sequences or subsequences being identical. Use one of the array comparison algorithms below, or manual alignment and The maximum correspondence is compared across a comparison range or designated area measured by visual inspection. If sequenced, the specified percentage of amino acid residues or nucleos of the two sequences. If the chid is the same (i.e., across the specified area, or if not specified) , 60% identity across the entire sequence, 65%, 70%, 75%, 80% at will, If the two sequences have 85%, 90%, 95%, or 99% identity, then they are "substantially" identical. They are "identical." By choice, identity is defined as having at least approximately 50 nucleotides (or 10 nucleotides). over a range of lengths of (no acid), or more preferably 100 to 500, or 1000 Over a region of length greater than a nucleotide (or 20, 50, or 200 amino acids or more) It exists.

[0083] In sequence comparison, one sequence acts as a reference sequence against which the test sequences are compared. This is typical. When using a sequence comparison algorithm, the sample sequence and the reference sequence are Input into the computer, specify sub-array coordinates if necessary, and then input the array algorithm program. Specify the Gram parameters. You can also use the default program parameters. Alternatively, you can also specify alternative parameters. Then, using the array comparison algorithm, Based on the program parameters, the sequence identity parity of the test sequence is compared with the reference sequence. Calculate the value.

[0084] As used herein, the "comparison region" is the region after the two sequences have been optimally sequenced. A reference sequence that can be compared with the same number of consecutive positions, ranging from 20 to 600, typically about 50 to 20. 0, more typically, a number bag with consecutive positions selected from a group consisting of approximately 100 to 150 numbers. Includes a reference to the segment by any one of the following. In this technical field, for comparison Sequence alignment methods are well known. The optimal sequence alignment for comparison is, for example, Sm The local homology algorithm by ith and Waterman (1970) Adv. Appl. Math. 2:482c This can also be done by homology according to Needleman and Wunsch, J. Mol. Biol. 48:443, 1970. This can also be done using a sex alignment algorithm, as demonstrated by Pearson and Lipman, and Proc. Nat'l. This can also be done using the similarity search method according to Acad. Sci. USA 85:2444, 1988, and these algorithms Computerized implementation of Gorhythm (Wisconsin Genetics Software) tware Package, Genetics Computer Group, 57 5 Science Dr., Madison, WI, GAP, BESTFIT, This can also be done by FASTA and TFASTA, and manual alignment and Visual inspection (e.g., Brent et al., Current Protocols in Molecular Biology, John Wiley & Sons) This can also be done by (see Ringbou, Inc., ed., 2003).

[0085] Algorithms suitable for determining sequence identity percentage and sequence similarity percentage The two examples are, respectively, Altschul et al., (1977) Nuc. Acids Res. 25:3389~3402; and BLA, as described by Altschul et al. (1990) J. Mol. Biol. 215:403~410 The ST algorithm and the BLAST 2.0 algorithm are used. BLAST analysis is performed. The software for this purpose is from the National Center for Biotech This algorithm is published by Nology Information. When determining the sequence using words of the same length within a database array, a positive threshold score T is used. To identify short word lengths W in the query array that match or satisfy this condition This involves first identifying high-scoring sequence pairs (HSPs). T is the adjacent word score threshold. These are called values ​​(Altschul et al., previously cited). These initial adjacent word hits contain them It acts as a seed to initiate a search for HSPs with longer durations. Cumulative alignments As long as the core can be increased, word hits can be extended in any direction along each sequence. The cumulative score is calculated using the parameter M (matching residue pairs) in nucleotide sequences. Reward score (always > 0) and N (penalty for mismatched residues) The core (always < 0) is used for calculation. For amino acid sequences, the scoring matrix is ​​used. Use this to calculate the cumulative score. The cumulative alignment score is the maximum value achieved. If the amount X decreases; due to the accumulation of alignment of one or more negative score residues , if the cumulative score falls to zero or below; or if it reaches any end of the sequence This stops the expansion of word hits in each direction. (BLAST algorithm parameter) The W, T, and X values ​​determine the sensitivity and speed of the alignment. BLASTN In the program (for nucleotide sequences), the word length (W) is 11, and the expected value (E) is 10. ), using M=5 and N=-4 as defaults, compare both chains. Amino acid sequence The BLASTP program for this has a word length of 3 and an expected value (E) of 10, and 50 BLOSUM62 scoring matrices (Henikoff and Henikoff, Proc. See Natl. Acad. Sci. USA 89:10915, 1989) Alignment (B), 10 periods We will use the default values ​​(E), M=5, and N=-4 to compare both chains.

[0086] The BLAST algorithm also performs statistical analysis of the similarity between two sequences (e.g.) For example, see Karlin and Altschul, Proc. Natl. Acad. Sci. USA 90:5873~5787, 1993. (to be done) will also be implemented. One measure of similarity provided by the BLAST algorithm is The probability that a match occurs by chance between two nucleotide sequences or amino acid sequences. This is the minimum summation probability (P(N)) that yields the target. For example, comparing the test nucleic acid to a reference nucleic acid... The minimum sum probability when compared is less than approximately 0.2, and more preferably less than approximately 0.01. Yes, and most preferably, if the nucleic acid is less than about 0.001, it is considered similar to the reference sequence. It can be done.

[0087] The percentage of identity between two amino acid sequences is also expressed in the PAM120 weighted residue table, 1 ALIGN uses a gap length penalty of 2 and a gap penalty of 4. E. Meyers and W. Miller (Computer) were incorporated into the program (version 2.0). It can also be determined using the algorithm described in Appl. Biosci., 4:11~17, 1988. In addition, the percentage of identity between the two amino acid sequences is Blossom 62 matrix. Rix or PAM250 matrix, and 16, 14, 12, 10, 8, 6, Alternatively, use a gap weighting of 4 and a length weighting of 1, 2, 3, 4, 5, or 6. The GCG software package (available on the internet at gcg.com) Needleman and Wunsch (J. Mol, Biol. 48:44) were incorporated into the internal GAP program. The decision can also be made using the algorithm described in 4-453 (1970).

[0088] In addition to the sequence identity percentage mentioned above, two nucleic acid sequences or polypeptides are essentially Another indicator of identity is encoded by the first nucleic acid, as described below. The polypeptide is immunologically opposed to the polypeptide encoded by the second nucleic acid. It is cross-reactivity. Therefore, for example, if two peptides are only conserved substitutions Therefore, if they are different, the polypeptide is typically substantially identical to the second polypeptide. Another indicator that two nucleic acid sequences are substantially identical is described below. Two molecules or their complements hybridize with each other under strict conditions. Another indicator that the two nucleic acid sequences are substantially identical is that they use the same primer. The ability to amplify the sequence using this method.

[0089] The term "isolated antibody" refers to an antibody that substantially does not contain other antibodies with different antigen specificities. Refers to the body (for example, an isolated antibody that specifically binds to FXI and / or FXIa is F (Substantially contains antibodies that specifically bind to antigens other than XI and / or FXIa.) However, isolated antibodies that specifically bind to FXI and / or FXIa may not bind to other antigens. It may exhibit cross-reactivity with other intracellular substances and / or chemicals. Furthermore, isolated antibodies may react with other intracellular substances and / or chemicals. In some cases, the substance may be virtually nonexistent.

[0090] The term "isotype" refers to the antibody class resulting from heavy chain constant region genes. For example, it refers to IgM, IgE, IgG1, or IgG4 (IgG). Isotype It also includes a qualified version of one of these classes, whose qualification is the Fc function. Modify it, for example, by enhancing or reducing its effector function or binding to Fc receptors. It is applied to the sea urchin.

[0091] The term "K" used in this specification assoc " or "K a The term "a specific antibody-antigen interphase" While "K" is intended to refer to the association rate of interactions, as used herein, dis "Also is "K d The term "dissociation rate" is intended to refer to the dissociation rate of a particular antibody-antigen interaction. The term "K" used in this specification refers to... D The term "K" is d K a The ratio to (i.e., K d / K a This refers to the dissociation constant obtained from ) and is expressed as molar concentration (M). K of the antibody D value This can be determined using methods well established in the art. The K of the antibody D of The method for making the decision is a biosensor system such as the BIACORE™ system. Surface plasmon resonance can be measured using solution equilibrium titration (SET) or by solution equilibrium titration. This includes a step of measuring the affinity inside.

[0092] The terms "monoclonal antibody" or "monoclonal antibody composition" used herein and The term refers to a preparation of antibody molecules with a single molecular composition. Monoclonal antibody composition This demonstrates a single binding specificity and affinity for a particular epitope.

[0093] In this specification, the term "nucleic acid" is used interchangeably with the term "polynucleotide." Used to form deoxyribonucleotides or ribonucleotides and their single-stranded forms. This refers to polymers in a double-stranded form. The term "nucleic acid" refers to known nucleotides. Nucleic acids containing analogues or modified skeletal residues or modified links, which are synthetic nucleic acids, spontaneously occurring These are raw nucleic acids and non-naturally occurring nucleic acids, which have similar binding properties to the reference nucleic acid, and the reference nucleic acid It includes nucleic acids that are metabolized in a similar manner to rheotides. Examples of such analogues are, without limitation, To elaborate, phosphorothioates, phosphoramidates, methylphosphonates, chiral methyl It contains phosphonates, 2-O-methylribonucleotides, and peptide nucleic acids (PNA).

[0094] Unless otherwise indicated, a particular nucleic acid sequence is also a conservatively modified version of that sequence. It implicitly includes variants (e.g., degenerate codon substitutions) and complementary sequences, as well as explicitly including them. It also includes the indicated sequence. In particular, as detailed below, degenerate codon substitution is 1 The third position of one or more selected (or all) codons is a mixed base and / or Alternatively, this can be achieved by creating sequences substituted with deoxyinosine residues. (Batzer et al., Nucleic Acid Res. 19:5081, 1991; Ohtsuka et al., J. Biol. Chem. 260:2605 ~2608, 1985; and Rossolini et al., Mol. Cell. Probes 8:91~98, 1994).

[0095] The term "operably linked" refers to two or more polynucleotides (e.g., DN A) Refers to the functional relationship between segments. The term “operatably linked” is a transcription. Typically, this refers to the functional relationship between a regulatory sequence and the sequence being transcribed. For example, p The romor sequence or enhancer sequence is expressed in an appropriate host cell or other expression system. When stimulating or modulating the transcription of the code sequence within, it is operably linked to the code sequence. Generally, a promoter transcriptional regulatory sequence is operably linked to the sequence to be transcribed. It is physically adjacent to the sequence being transcribed, i.e., it is cis-acting. However, enhance Some transcriptional regulatory sequences, such as sensors, physically transfer their transcription to the coding sequences that enhance them. They don't need to be adjacent or placed in close proximity.

[0096] As used herein, the term "optimized" refers to a nucleotide sequence that has been optimized for production cells. Or producing organisms, generally eukaryotic cells, for example, Pichia cells, Chinese herbs In Muster ovary cells (CHO) or human cells, amino acids are produced using preferred codons. This means that it has been modified to encode an acid sequence. Optimized nucleotide sequence This is the amino that is originally encoded by the starting nucleotide sequence, which is also known as the "parent" sequence. The acid sequence is manipulated to be preserved completely or as much as possible. Optimization as described herein The sequence has been manipulated to have preferred codons in mammalian cells. Furthermore, this specification also describes the optimization of these sequences in other eukaryotic or prokaryotic cells. Expression is also planned. The amino acid sequence encoded by the optimized nucleotide sequence is also They also claim it is optimized.

[0097] In this specification, the terms “polypeptide” and “protein” refer to amino acid residues. The terms "polymer" and "protein" are used interchangeably. The term refers to the artificial chemical composition of one or more amino acid residues that correspond to naturally occurring amino acids. In addition to amino acid polymers that are natural mimics, there are also naturally occurring amino acid polymers and non-naturally occurring ones. This also applies to amino acid polymers. Unless otherwise indicated, certain polymers The ptydo sequence also implicitly includes its conservatively modified variants.

[0098] As used herein, the term “recombinant human antibody” refers to a human immunoglobulin gene. Regarding animals that are transgenic or transchromosomal (e.g., mice) Alternatively, the antibodies isolated from the hybridoma prepared in this way, or human antibodies, are expressed. A host cell transformed in such a way, for example, an antibody isolated from a transfectoma, Antibodies isolated from alternative combinatorial human antibody libraries, and human immunoglobulins. Splicing of all or part of the brin gene sequence into other DNA sequences Antibodies prepared, expressed, created, or isolated by any means or prepared, expressed, created, or isolated by recombinant means, Includes all human antibodies. Such recombinant human antibodies include framework regions and CDRs. The region has a variable region derived from the immunoglobulin sequence of human germline cells. However, In certain embodiments, such recombinant human antibodies induce in vitro mutagenesis. (Alternatively, if you use an animal that is transgenic for the human Ig sequence, in It can be subjected to vivo somatic mutagenesis, and therefore recombinant antibody VH The amino acid sequences of the region and VL region are derived from the VH and VL sequences of the human germline. These are related to the germline repertoire of in vivo human antibodies. This is a sequence that may not exist in nature.

[0099] The term "recombinant host cell" (or simply "host cell") refers to recombinant expression vectors. This refers to cells into which a ter has been introduced. Such terminology is intended to refer only to specific target cells. It is important to understand that this does not refer to the cells themselves, but rather to the descendant cells of such cells. In subsequent generations, certain modifications may occur due to mutations or environmental influences. Therefore, these offspring cells may not actually be identical to the parent cells. This falls within the scope of the term "host cell" as used in this specification.

[0100] The term "subject" includes humans and non-human animals. Non-human animals are non-human primates. (For example, crab-eating macaques), sheep, rabbits, dogs, cows, chickens, amphibians, and reptiles. This includes all vertebrates, such as reptiles (e.g., mammals and non-mammals). Except where otherwise specified, the terms “patient” and “subject” are used interchangeably in this specification. The terms "cynomolgus" or "cyno-molgus" used in the specification and The term refers to the crab-eating macaque (Cynomolgus monkey) (Macaca fascicularis). This refers to a person. In specific cases, the patient or subject is a human being.

[0101] In one embodiment, any disease or disorder (e.g., thromboembolic) used herein is described herein. Disorder) "To treat ~" or these terms "treatment" refer to improving a disease or disorder. To improve (i.e., to slow the onset of at least one of the disease or its clinical symptoms) It refers to (to do, stop, or mitigate). In another embodiment, it means "to treat ~ "Doing" or "treatment" includes parameters that may not be identifiable by the patient. This refers to mitigating or improving at least one physical parameter. In this context, "to treat ~" or "treatment" means to physically modulate a disease or disorder. It either rates (for example, stabilization of identifiable symptoms) or modulates physiologically (for example) (For example, stabilizing physical parameters) or modulating them physically and physiologically. In yet another embodiment, "~to treat" or "treatment" means a disease or This refers to preventing or delaying the occurrence, onset, or progression of a disorder.

[0102] For example, "prevention" in the context of the indications described herein, including thromboembolic disorders, means For example, in patients at risk of the aforementioned worsening, the following thromboembolic disease symptoms This refers to any effect that prevents or slows the worsening of lameth.

[0103] The term "vector" refers to a vector that transports another polynucleotide that it has linked together. This is intended to refer to possible polynucleotide molecules. One type of vector is... "P" refers to a circular double-stranded DNA loop that can ligate various DNA segments. This is "Rasmid." Another type of vector uses a further DNA segment, the viral geno. Adeno-associated virus vectors (AAV or AAV2) that can ligate to the virus Which viral vector is it? A certain type of vector (for example, a bacterial origin of replication). Vectors (and mammalian episomal vectors) are introduced into the host cells into which they are... It is capable of self-replication. Other vectors (e.g., non-mammalian episomal vectors) When introduced into a host cell, it can be incorporated into the host cell's genome, thereby allowing the host They replicate together with the main genome. Furthermore, certain types of vectors are genes that are operationally linked to each other. It is possible to direct the expression of genes. In this specification, such vectors are referred to as "combinations." This is called a recombinant expression vector (or simply, an expression vector). Generally, recombinant DN In method A, useful expression vectors are often in the form of plasmids. Plasmids Since it is the most commonly used form of vector, in this specification we will refer to it as "plasmid" and " It can be used interchangeably with "Vector". However, this disclosure provides equivalent functionality. Viral vectors (e.g., replication-deficient retroviruses, adenoviruses, and adenoviruses) This is intended to include other forms of expression vectors, such as associated viruses. [Brief explanation of the drawing]

[0104] [Figure 1-1] Figures 1A-1C show the effect of NOV1401 on FeCl3-induced thrombosis in FXI- / - mice reconstituted with human FXI protein. NOV1401 inhibited thrombosis in a dose-dependent manner. The antibody prolonged aPTT to the same extent as in untreated FXI- / - mice. [Figure 1-2] This is the same as in Figure 1-1. [Figure 2] Figures 2A-2B show the relationship between the effect of multiple intravenous (iv) (A; N=2) or subcutaneous (sc) (B; N=2) administrations of NOV1401 at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg on aPTT (diamond) and total plasma NOV1401 levels (square) in cynomolgus monkeys. A single dose of 3 mg / kg resulted in approximately a twofold increase in aPTT, which was maintained for 5-6 weeks. All test doses prolonged aPTT to a similar degree, and higher test doses did not appear to increase the magnitude of the aPTT prolongation observed at the 3 mg / kg dose. [Figure 3] Figures 3A-3B show the relationship between the effects of multiple IV (A; N=2) or sc (B; N=2) administrations of NOV1401 at doses of 3 mg / kg, 10 mg / kg, and 30 mg / kg on plasma free FXI (square) and aPTT (diamond) in cynomolgus monkeys. A single dose of 3 mg / kg reduced free FXI by approximately 90% over 5-6 weeks. All test doses reduced free FXI to a similar degree, and higher test doses did not appear to increase the magnitude of the reduction in free FXI observed at the 3 mg / kg dose. [Figure 4-1]Figures 4A-4C show composite response curves for anti-FXI / FXIa antibodies. Figure 4A shows inhibition of factor XIa activity by NOV1401. This is a representative composite response curve for NOV1401, an antibody that inhibits the enzyme activity of full-length human FXIa. The assay measures the cleavage of a fluorescently labeled peptide, as described in Example 2. A nonlinear curve fitting using the logistic fitting model [y=A2+(A1-A2) / (1+(x / IC50)p)[wherein y is the inhibition percentage when the inhibitor concentration is x, A1 is the minimum inhibition value, A2 is the maximum inhibition value, and the exponent p is the Hill coefficient] is obtained for this representative dataset, yielding an IC50 value of 160 pM. Figure 4B shows a composite response curve for aPTT. This is a representative composite response curve for prolongation of coagulation time by the antibody NOV1401 in an aPTT assay using pooled human plasma. The assay measures coagulation time after initiating the intrinsic coagulation cascade in the presence of different concentrations of NOV1401, as described in Example 3. The black line represents the fit using a logistic nonlinear fitting model. The dotted line represents the baseline coagulation time of pooled human plasma in the absence of NOV1401. The baseline coagulation time is 32.3 seconds, indicated by the gray dashed line in the graph. The gray dotted line indicates the antibody concentration at which the coagulation time doubled compared to baseline, i.e., reached a value of 2 × aPTT, which is 14 nM. Figure 4C shows the TGA response curve. It shows a representative composite response curve for inhibition of thrombin generation by the antibody NOV1401 in TGA with pooled human plasma. The assay, as described in Example 3, measures the effect of different concentrations of NOV1401 on thrombin generation that can be induced by very low concentrations of tissue factor (TF) via a so-called thrombin-to-FXIa feedforward loop. The black line represents the fit using a four-parameter dose-response curve model. The dotted line represents the residual thrombin concentration resulting from thrombin generation induced by small amounts of TF. The IC50 value of 24 nM and the residual thrombin concentration of 159 nM (dotted line) were calculated for this composite response curve. [Figure 4-2] This is the same as in Figure 4-1. [Figure 5-1] Figures 5A-5B show the effects of NOV1401 on aPTT and FXI activity (FXI:C) with sc administration at 10 mg / kg (N=3) and 100 mg / kg (N=5) weekly for 13 weeks (14 doses), or IV administration at 50 mg / kg (N=3) weekly for 4 weeks (5 doses). Figure 5A shows the effect on aPTT as measured on days 2, 23, and 79 of the study. aPTT increased 2.1 to 3 times in all animals treated with NOV1401 and remained high throughout the administration period of the study. No dose-dependency was observed, and no sex-related differences were found. Figure 5B shows the effect on FXI:C as measured on days 2, 23, and 79 of the study, depicted as a percentage of plasma FXI activity. FXI:C levels decreased to 5–12% in all animals treated with NOV1401 and remained at these levels throughout the study's administration period. No dose-dependent differences were observed, nor were there any sex-related differences. [Figure 5-2] This is the same as in Figure 5-1. [Modes for carrying out the invention]

[0105] This disclosure relates to antibody molecules that specifically bind to FXIa and inhibit its biological activity (e.g., (NOV1090 or NOV1401) and undergoing hemodialysis, accompanied by ESRD The risk of thrombosis or thromboembolism, such as stroke, in subjects with ESRD. This specification is partly based on the discovery of antibody molecules for use in the prevention or reduction of [unspecified]. In certain cases, this includes patients undergoing hemodialysis, those with ESRD, and other patients with AF and ESRD. To prevent the risk of thrombosis or thromboembolism, such as stroke or systemic embolism, in the target population. Or methods for reducing bleeding are presented. In a specific embodiment, such subjects are subject to bleeding There is a high risk.

[0106] This disclosure relates to full-length IgG format antibodies (e.g., human antibodies), as well as Fab fragments ( For example, antibodies NOV1090 and NOV1401, and both of their antigen-binding fragments Regarding usage.

[0107] Factor XI FXI occurs in both the intrinsic and extrinsic coagulation pathways, as well as in plasma. It plays an important role in bridging the initial and amplification phases of hemostasis. Factor XIIa and Both thrombins, as a result of activating FXI, lead to sustained thrombin production. It can lead to inhibition of fibrinolysis. FXI is used in a high-tissue-factor environment "after vascular injury". Although it plays a small role in normal hemostasis, it is thought to play a key role in thrombosis. Severe factor XI deficiency is associated with a reduced incidence of ischemic stroke and venous thromboembolic events. Related to (Salomon et al 2008; Salomon, et al. (2011) Thromb Haemost.; 105:269- 73). Bleeding symptoms in subjects with severe factor XI deficiency are infrequent and mild. It is often damage-inducing, and increases fibrinolytic activity in the oral mucosa, nasal mucosa, and urinary tract. It is preferable that the tissue is affected (Salomon et al 2011). Bleeding in life-threatening organs is It is either extremely rare or not recognized.

[0108] Plasma coagulation is a sequential process in which coagulation factors in the blood interact and become activated, and the final In essence, this results in the production of fibrin and the formation of a blood clot. In the genotype model, the process of fibrin formation involves two distinctly different pathways, namely the intrinsic pathway. It can be initiated by both the pathway and the extrinsic pathway (Mackman, 2008).

[0109] In the extrinsic pathway, vascular injury leads to the production of extravascular tissue factor (TF) and factor VII (FVII). It interacts with and activates it, thereby activating factor X and prothrombin. It brings about a sequential transformation. Active thrombin ultimately converts soluble fibrinogen into fibrin. It then converts to n. The extrinsic pathway is central to hemostasis, and the influence of coagulation factors within this pathway Wataru carries the risk of bleeding as a result.

[0110] In the intrinsic pathway, factor XII is sometimes activated through a process called contact activation. It is possible. The production of activated factor XIIa is due to the sequential activation of factor XI and factor IX. It brings about a change. Factor IXa activates Factor X, thus affecting both the extrinsic and intrinsic pathways. The pathways merge at this stage (common pathway). Thrombin activity is when thrombin is factor XI. The child is activated independently of factor XII via a feedforward loop. This is boosted by amplifying its own generation. This feedforward loop is It contributes to sustained thrombus growth, but coagulation requires strong activation by extravascular tissue factor. Since this is sufficient, its involvement in hemostasis is limited to a minimum. Therefore, the intrinsic pathway is... It is not substantially involved in blood (Gailani and Renne (2007) Arterioscler Thromb Vasc Biol 2007, 27(12):2507-13, Muller, Gailiani, and Renne 2011).

[0111] Preclinical studies using various methods to inhibit FXI or FXIa across various species However, this has contributed to the validation of this target. FXI- / - mice were experimentally shown to have venous thrombosis (Wa ng, et al. (2006) J Thromb Haemost; 4:1982-8) and arterial thrombosis (Wang, et al. (20 05) It is resistant to J Thromb Haemost; 3:695-702). Treatment of mice with an antibody that blocks activation (Ab; 14E11) resulted in experimentally observed thrombosis. This results in inhibition (Cheng, et al. (2010) Blood, 116:3981-9), and ischemic stroke. Reduced stroke size in a mouse model of [the substance] (Leung, et al. (2012) Transl Stroke Res 2012; 3:381-9). Anti-FXI blocking FXIa binding and activation. In baboons administered Ab, on collagen-coated vascular grafts, A reduction in the proliferation of platelet-rich thrombi was observed (Tucker, et al. (2009) Blood 2009; 113:93). 6-44) Similar results were also found in this model by 14E11 (Cheng (2010). No excessive bleeding was observed in any of these studies.

[0112] Mice (Zhang, et al. (2010) Blood 2010; 116:4684-92), cynomolgus monkeys (Younis, et al. (2012) Blood 2012; 119:2401-8), and baboons (Crosby, et al. (2013) Arteri In oscler Thromb Vasc Biol 2013; 33:1670-8), antisense oligonucleotides Blocking the synthesis of FXI by this method provides antithrombotic and anti-inflammatory effects without excessive bleeding. This resulted in a coagulation effect. Furthermore, in rats (Schumacher, et al. (2007) Eur J Pharmacol 2007; 570:167-74) and rabbits (Wong, et al. (2011) J Thromb Thromboly In the venous thrombosis model and arterial thrombosis model described in sis 2011; 32:129-37), low molecular weight Blocking FXIa with inhibitors has yielded similar results.

[0113] Patients with severe FXI deficiency rarely experience spontaneous bleeding and have high fibrinolytic activity. Except for severe tissue bleeding, it is limited to mild trauma-induced bleeding. Severe FXI deficiency is rare. The study aims to clarify the thrombotic profiles of these patients compared to the general population. This makes the use of research inevitable. In particular, such research shows that in these patients, ischemic stroke (Salomon 2008) and deep vein thrombosis (DVT) (Salomon, et al. (2011) Blood 200 8; 111: 4113-17) The incidence of severe FXI is reported to be reduced. The number of ischemic strokes observed in 115 patients with deficiency (N=1) is, The number of cases was lower than the predicted number in El's general population (N=8.6) (p<0.003). The number of DVT cases in patients with severe FXI deficiency (N=0) was lower than in the control population. The number of cases was lower than the predicted number (N=4.7) (p<0.019). Conversely, FXI Individuals whose Bell number is above the 90th percentile had twice the risk of developing DVT (Meijer). (2000) N Engl J Med. 2000; 342:696-701).

[0114] In recent years, patients undergoing total knee arthroplasty, a procedure that predisposes them to DVT, have been referred to as FXI AN. Antisense therapy or standard treatment (enoxaparin) was used. Antisense group (300m g) Compared to standard treatment, the incidence of venous thrombosis was reduced by one-seventh, and bleeding events decreased. (Not statistically significant) was shown (Buller et al, (2014) N Engl J Med. 372(3):232-40. i: 10.1056 / NEJMoa1405760. Epub 2014 Dec 7).

[0115] In summary, the above studies strongly support FXI as a valid target for antithrombotic therapy.

[0116] FXIa antibody and antigen-binding fragments This disclosure relates to the treatment, prevention, or reduction of the risk of thrombosis or thromboembolism, such as stroke. We present antibodies that specifically bind to FXI and / or FXIa for use in [the specified context]. In some embodiments, this disclosure relates to the FXI and of humans, rabbits, and cynomolgus monkeys. / or present an antibody that specifically binds to FXIa. The antibody of this disclosure is described in the examples. This includes, but is not limited to, human monoclonal antibodies and Fab isolated as described above. stomach.

[0117] This disclosure relates to the FXI protein and / or FXIa protein (e.g., human, u). Antibodies that specifically bind to FXI and / or FXIa) in herons and cynomolgus monkeys. The present invention provides an antibody containing a VH domain having the amino acid sequences of SEQ ID NOs. 9 and 29. This disclosure also specifically binds to FXI protein and / or FXIa protein. The antibody that matches one of the VH CDRs listed in Table 1 below. We also provide antibodies containing VH CDRs having no acid sequences. In particular, this disclosure concerns the FXI protein F(x) and / or F(x)a proteins (e.g., F(x)a proteins of humans, rabbits, and cynomolgus monkeys) Antibodies that specifically bind to XI and / or FXIa) and are listed in Table 1 below. One, two, three, or any of the amino acid sequences of VH CDRs Present an antibody containing (or, alternatively, consisting of) VH CDRs exceeding (2 Filed on June 24, 2016, as brochure international publication no. 2016 / 207858 The PCT International Patent Publications, which were published and are incorporated herein in their entirety by reference, (See Application No. PCT / IB2016 / 053790).

[0118] This disclosure relates to an antibody that specifically binds to the FXIa protein, as described herein. Methods (for example, in subjects with ESRD and / or AF, stroke and / or For use in methods to reduce the risk of systemic embolism, SEQ ID NO: 19 or 3 This disclosure presents an antibody containing a VL domain having a 9-amino acid sequence. This disclosure also presents an FXI Proteins and / or FXIa proteins (e.g., human, rabbit, and cynomolgus proteins) An antibody that specifically binds to FXI and / or FXIa) of the substance described herein. Methods used (for example, in subjects with ESRD and / or AF, stroke and / For use in methods to reduce the risk of systemic embolism, see Table 1 below. An antibody containing a VL CDR having one of the amino acid sequences of the VL CDRs. This disclosure also presents the FXIa protein (e.g., human, rabbit, and crab). Antibodies that specifically bind to quis monkey FXI and / or FXIa), as shown in the table below. 1, 2, 3 have one of the amino acid sequences among the VL CDRs listed in 1. The present invention provides an antibody containing (or, alternatively, consisting of) one or more very long cell dendritic compounds (VL CDRs).

[0119] Methods described herein (for example, in subjects with ESRD and / or AF) Other uses in methods to reduce the risk of stroke and / or systemic embolism. The antibody is mutated, but within the CDR region, it is depicted within the sequence listed in Table 1. At least 60, 70, 80, 85, 90, or 95 percent of the CDR area. It contains an amino acid having the identity of the present invention. In some embodiments, other antibodies of the present invention are CD Within the R region, compared to the CDR region depicted in the sequences listed in Table 1, there are one and two The amino acid composition of a mutant is one in which three, four, or five or fewer amino acids have been mutated. Includes columns.

[0120] [Table 1-1]

[0121] [Table 1-2]

[0122] [Table 1-3]

[0123] [Table 1-4]

[0124] [Table 1-5]

[0125] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0126] Methods described herein (for example, in subjects with ESRD and / or AF) Other uses in methods to reduce the risk of stroke and / or systemic embolism. The antibodies have mutations in the amino acids or nucleic acids encoding amino acids, as shown in Table 1. For the listed sequences, at least 60, 65, 70, 75, 80, 85, 90, or It contains antibodies with 95 percent identity. In some embodiments, within the variable region, While maintaining qualitatively the same antigen-binding activity, the variable activity is depicted within the sequences listed in Table 1. When compared to a region, it involves mutations of one, two, three, four, or five or fewer amino acids. It contains the amino acid sequence of the mutant.

[0127] Each of these antibodies can bind to FXI and / or FXIa, so the VH sequence , VL sequence, full-length light chain sequence, and full-length heavy chain sequence (amino acid sequence and amino acid sequence are coded The nucleotide sequence to be used is "mixed and matched" with other FXI-binding antibodies of the present disclosure. It is possible to create antibodies that bind to the body and / or FXIa. Such "mixed, Matched FXI-binding antibodies and / or FXIa-binding antibodies are used in this technology. Known binding assays (e.g., ELISA and other assays described in the Examples section) It can be used to investigate. When mixing and matching these strands, a specific VH / V The VH sequence derived from L pairing will be replaced with a structurally similar VH sequence. In addition, a full-length heavy chain sequence derived from a specific full-length heavy chain / full-length light chain pair is structurally similar to a full-length heavy chain. The chain sequence will be replaced. Similarly, the VL sequence derived from a specific VH / VL pairing will be replaced. The VL sequence will be replaced with a structurally similar one. Similarly, specific full-length heavy chains / full-length light chains will be replaced. The full-length light chain sequence derived from pairing will be replaced with a structurally similar full-length light chain sequence. .

[0128] Therefore, the methods described herein (e.g., those involving ESRD and / or AF) Methods for reducing the risk of stroke and / or systemic embolism in the subject In one aspect for use, the present disclosure relates to an ami selected from the group consisting of Sequence IDs 9 and 29. Selected from the group consisting of a heavy chain variable domain containing an acid sequence and SEQ ID NOs: 19 and 39. An isolated antibody or its antigen-binding region having a light chain variable domain containing an amino acid sequence In this case, the antibodies are FXI and / or FXIa (e.g., human, rabbit, etc.) It specifically binds to FXIa) in cynomolgus monkeys.

[0129] More specifically, in certain aspects, this disclosure relates to Sequence IDs 9 and 29; or 19 and Heavy chain variable domains and light chain variable domains containing amino acid sequences selected from each of the 39. This provides an isolated antibody or its antigen-binding region having a main component.

[0130] Methods described herein (for example, in subjects with ESRD and / or AF) For use in methods to reduce the risk of stroke and / or systemic embolism, In a specific embodiment, the present specification specifically binds to human FXI and / or FXIa. The antibody or antigen-binding fragment presented in the document is a heavy chain containing the amino acid sequence of SEQ ID NO: 9. It includes a variable region and a light chain variable region containing the amino acid sequence of SEQ ID NO: 19.

[0131] Methods described herein (for example, in subjects with ESRD and / or AF) For use in methods to reduce the risk of stroke and / or systemic embolism, In a specific embodiment, the present specification specifically binds to human FXI and / or FXIa. The antibody or antigen-binding fragment presented in this document contains the amino acid sequence of SEQ ID NO: 29. It includes a chain variable region and a light chain variable region containing the amino acid sequence of SEQ ID NO: 39.

[0132] In other aspects for use in the methods described herein, this disclosure (i) An amino acid sequence optimized for expression in mammalian cells, and sequence number 11 and This refers to a full-length heavy chain containing an amino acid sequence selected from a group of 31, and also to mammalian cells. An amino acid sequence optimized for expression, starting from sequence number 21 or 41. (ii) an isolated antibody having a full-length light chain containing an amino acid sequence selected from the group, or (ii) the It provides a functional protein containing an antigen-binding moiety. More specifically, in certain embodiments, This disclosure relates to sequence numbers 11 and 31; or selected from 19 and 39, respectively. This provides an isolated antibody having a heavy chain and a light chain containing a mino acid sequence, or its antigen-binding region. .

[0133] In specific embodiments for use in the methods described herein, human FX Antibodies or their anti-Is that specifically bind to I and / or FXIa as presented herein. The primordial fragment consists of a heavy chain containing the amino acid sequence of SEQ ID NO: 11 and the amino acid sequence of SEQ ID NO: 21. Includes a light chain containing a column.

[0134] In specific embodiments for use in the methods described herein, human FX Antibodies or their anti-Is that specifically bind to I and / or FXIa as presented herein. The primordial-binding fragment consists of a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 31 and the amino acid sequence of SEQ ID NO: 41. It includes a light chain variable region containing a mino acid sequence.

[0135] As used herein, the terms “complementarity-determining region” and “CDR” refer to antigen specificity. This refers to the sequence of amino acids within the antibody variable region that confer antigen-binding affinity. Generally, within each heavy chain variable region (HCDR1, HCDR2, HCDR3), there are three CDRs. There are three CDRs within each light chain variable region (LCDR1, LCDR2, LCDR3). be.

[0136] 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, National In Institutes of Health, Bethesda, MD ("Kabat" numbering scheme), Al-Lazikani et al., (1997) JMB 273, 927-948 ("Chothia" numbering scheme), Lefranc e According to t al., (2003) Dev. Comp. Immunol., 27, 55-77 ("IMGT" numbering scheme) The schemes described, or the "combination" systems, and many other well-known schemes. You can easily make a decision using one of these options.

[0137] For example, according to Kabat, NOV109 is an antibody located within the heavy chain variable domain (VH). The CDR amino acid residues of 0 are 31-35 (HCDR1), 50-66 (HCDR2), They are numbered 99-111 (HCDR3) and are located within the light chain variable domain (VL). The CDR amino acid residues are 22-35 (LCDR1), 51-57 (LCDR2), and They are numbered 90-100 (LCDR3). According to Chothia, within VH CDR amino acids are 26-32 (HCDR1), 52-57 (HCDR2), and 99 It is numbered ~111 (HCDR3), and the amino acid residues in VL are 25~33 ( Numbered as LCDR1), 51-53 (LCDR2), and 92-99 (LCDR3). This involves combining CDR definitions from both Kabat and Chothia. Furthermore, CDRs are amino acid residues 26-35 (HCDR1) and 50-66 (H) in human VH. CDR2), and 99-111 (HCDR3), as well as two amino acid residues in human VL. 2-35 (LCDR1), 51-57 (LCDR2), and 90-100 (LCDR3) ) consists of combining CDR definitions from both Kabat and Chothia. Furthermore, the "combination" CDR is the amino acid residues 26-35 (HCDR1) and 50 in human VH. ~66 (HCDR2), and 99~108 (HCDR3), as well as mycelium in human VL. 24-38 (LCDR1), 54-60 (LCDR2), and 93-101 ( It consists of LCDR3). Another example, according to IMGT, is within the heavy chain variable domain (VH). The CDR amino acid residues are 26-33 (HCDR1), 51-58 (HCDR2), and They are numbered 97-108 (HCDR3), and are C within the light chain variable domain (VL). The DR amino acid residues are 27-36 (LCDR1), 54-56 (LCDR2), and 9 They are numbered 3-101 (LCDR3). Table 1 shows examples of anti-FXI / FXIa antibodies. For example, regarding NOV1090 and NOV1401, Kabat, Chothia, and Examples of HCDR1, HCDR2, HCDR3, and LCDR by IMGT. 1. LCDR2 and LCDR3 are presented. In another embodiment, this disclosure is as described in Table 1. The heavy and light chains CDR1, CDR2, and CDR3, or combinations thereof. This provides an FXIa-binding antibody containing [a specific component]. The amino acid sequence of the antibody's VH CDR1 is [a specific component]. Shown in numbers 3 and 23. The amino acid sequences of the antibody's VH CDR2 are shown in SEQ ID NOs: 4 and 2 As shown in 4. The amino acid sequence of the antibody VH CDR3 is 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 the antibody VL CDR2 are shown in SEQ ID NOs. 14 and 34. The amino acid sequences of the antibody's VL CDR3 are shown in SEQ ID NOs. 15 and 35. These CDR areas are represented using the Kabat system.

[0138] Alternatively, the Chothia system (Al-Lazikani et al., (1997), JMB 273 927~948) As specified using, the amino acid sequence of the antibody VH CDR1 is as follows: SEQ ID NO: 6 and The amino acid sequence of the antibody VH CDR2 is shown in 26. The amino acid sequences of the antibody's VH CDR3 are shown in SEQ ID NOs. 8 and 28. The amino acid sequences of the antibody VL CDR1 are shown in SEQ ID NOs. 16 and 36. The amino acid sequences of the antibody's VL CDR2 are shown in SEQ ID NOs: 17 and 37. The amino acid sequences of the antibody's VL CDR3 are shown in SEQ ID NOs. 18 and 38.

[0139] Alternatively, the amino acid of the antibody VH CDR1 as defined using a combination system. The acid sequence is shown in SEQ ID NO: 46. The amino acid sequence of the antibody VH CDR2 is: It is shown in number 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 is shown in SEQ ID NO: 33. The amino acid sequence of L CDR2 is shown in SEQ ID NO: 14. The amino acid sequence is shown in SEQ ID NO: 15.

[0140] Alternatively, the VH CDR of the antibody as defined using the IMGT numbering scheme. The amino acid sequence of 1 is shown in SEQ ID NO: 43. The amino acid sequence of the antibody VH CDR2 The sequence is shown in SEQ ID NO: 44. The amino acid sequence of the antibody VH CDR3 is SEQ ID NO: It is shown in 45. The amino acid sequence of the antibody VL CDR1 is shown in SEQ ID NO: 47. The amino acid sequence of the antibody VL CDR2 is shown in SEQ ID NO: 37. The amino acid sequence of L CDR3 is shown in SEQ ID NO: 15.

[0141] Each of these antibodies is capable of binding to FXI and / or FXIa. Antigen binding specificity is mainly determined by the CDR1, CDR2, and CDR3 regions. Given that each antibody is a fxi-binding molecule and / or other fxi-binding molecules of the Disclosure, each antibody is a fxi-binding molecule and / or To create FXIa-binding molecules, VH CDR1, VH CDR2, and VH C This contains DR3, as well as VL CDR1, VL CDR2, and VL CDR3. This is preferable, but VH CDR1 sequence, VH CDR2 sequence, and VH CDR3 sequence , as well as the VL CDR1 sequence, VL CDR2 sequence, and VL CDR3 sequence, It is possible to "mix and match" (i.e., mix CDRs derived from different antibodies). (and can be matched). Such "mixed and matched" FXI binding components The child and / or FXIa-binding antibody can be used in binding assays and procedures known in the art. The binding assays described in the example (e.g., ELISA, SET, BIACORE®) This can be investigated using (Say). When mixing and matching VH CDR sequences. This is a CDR1 sequence, CDR2 sequence, and / or CDR3 sequence derived from a specific VH sequence. The columns will be replaced with structurally similar CDR sequences. Similarly, the VL CDR sequences When mixing and matching, the CDR1 and CDR2 sequences derived from a specific VL sequence , and / or the CDR3 sequence shall be replaced with a structurally similar CDR sequence. Those skilled in the art can use novel VH and VL sequences to represent one or more VH CDR regions. The column and / or VL CDR region sequence for the monoclonal antibody of this disclosure, Created by substituting a structurally similar sequence derived from the CDR sequence shown in the detailed document. It will be readily apparent that this is possible. In addition to the foregoing, in one embodiment, as described herein The antigen-binding fragments of the antibodies are VH CDR1, VH CDR2, and VH CDR 3, or possibly including VL CDR1, VL CDR2, and VL CDR3 Yes, in this case the fragment is a single variable domain in FXI and / or FXIa. They combine.

[0142] In certain embodiments of this disclosure, the antibody or its antigen-binding fragment is as described in Table 1. It may have the heavy and light chain sequences of the Fab. More specifically, an antibody or its antigen. The binding fragment may have the heavy and light chain sequences of NOV1090 and NOV1401.

[0143] In other embodiments of this disclosure, antibodies that specifically bind to FXI and / or FXIa are used. Alternatively, the antigen-binding fragment is defined by Kabat and listed in Table 1, and is heavy-chain variable. CDR1 region, CDR2 heavy chain variable region, CDR3 heavy chain variable region, C light chain variable region This includes DR1, the light chain variable region CDR2, and the light chain variable region CDR3. Further disclosures of this disclosure In other embodiments, an antibody or antigen that specifically binds to FXI and / or FXIa. The binding fragments are defined by Chothia and are described in Table 1 as heavy chain variable regions. CDR1 in the heavy chain variable region, CDR2 in the heavy chain variable region, CDR3 in the light chain variable region, CD Includes R1, CDR2 of the light chain variable region, and CDR3 of the light chain variable region. The antibody or antigen-binding fragment that specifically binds to FXI and / or FXIa is a combination of the two. The CDR1 and heavy chain variable regions are defined by the matching system and are listed in Table 1. CDR2 of the chain variable region, CDR3 of the heavy chain variable region, CDR1 of the light chain variable region, light chain variable region This includes the CDR2 region and the CDR3 region of the light chain variable region. In yet another embodiment of this disclosure, Antibodies or antigen-binding fragments that specifically bind to FXI and / or FXIa are IM The heavy chain variable region CDR1, defined by GT and described in Table 1, and the heavy chain variable region CDR2 in the region, CDR3 in the heavy chain variable region, CDR1 in the light chain variable region, CD in the light chain variable region Includes R2 and the light chain variable region CDR3.

[0144] In specific embodiments for use in the methods described herein, this disclosure is F An antibody that specifically binds to XI and / or FXIa, wherein the heavy chain variable region of SEQ ID NO: 3 CDR1 of the region; CDR2 of the heavy chain variable region of sequence number 4; CD of the heavy chain variable region of sequence number 5 R3; CDR1 of the light chain variable region of SEQ ID NO: 13; CDR2 of the light chain variable region of SEQ ID NO: 14 ; and an antibody containing the CDR3 of the light chain variable region of SEQ ID NO: 15.

[0145] In specific embodiments, this disclosure specifically binds to FXI and / or FXIa. The antibody is such that the heavy chain variable region CDR1 of SEQ ID NO: 23 and the heavy chain variable region of SEQ ID NO: 24 CDR2 of the heavy chain variable region of sequence number 25, CDR3 of the light chain variable region of sequence number 33 DR1, CDR2 of the light chain variable region of sequence number 34, and the light chain variable region of sequence number 35 Contains antibodies including CDR3.

[0146] In specific embodiments, this disclosure specifically binds to FXI and / or FXIa. The antibody is such that CDR1 is in the heavy chain variable region of SEQ ID NO: 6, and C is in the heavy chain variable region of SEQ ID NO: 7. DR2, CDR3 of the heavy chain variable region of SEQ ID NO: 8, and CDR1 of the light chain variable region of SEQ ID NO: 16 , CDR2 of the light chain variable region of SEQ ID NO: 17, and CDR of the light chain variable region of SEQ ID NO: 18 Contains antibodies that include 3.

[0147] In specific embodiments, this disclosure specifically binds to FXI and / or FXIa. The antibody is such that the heavy chain variable region CDR1 of SEQ ID NO: 26 and the heavy chain variable region of SEQ ID NO: 27 CDR2 of the heavy chain variable region of sequence number 28, CDR3 of the light chain variable region of sequence number 36 DR1, CDR2 of the light chain variable region of sequence number 37, and the light chain variable region of sequence number 38 Contains antibodies including CDR3.

[0148] In specific embodiments of this specification, binding specifically occurs to FXI and / or FXIa. An antibody, wherein the heavy chain variable region CDR1 of SEQ ID NO: 43; the heavy chain variable region of SEQ ID NO: 44 CDR2; Heavy chain variable region of SEQ ID NO: 45; CDR3; Light chain variable region of SEQ ID NO: 47 R1; CDR2 of the light chain variable region of SEQ ID NO: 37; and C of the light chain variable region of SEQ ID NO: 15 Antibodies containing DR3 are presented.

[0149] In specific embodiments of this specification, binding specifically occurs to FXI and / or FXIa. The antibody is characterized by CDR1 in the heavy chain variable region of SEQ ID NO: 46; and C in the heavy chain variable region of SEQ ID NO: 4. DR2; CDR3 of the heavy chain variable region of SEQ ID NO: 5; CDR1 of the light chain variable region of SEQ ID NO: 33 ;CDR2 of the light chain variable region of SEQ ID NO: 14; and CDR of the light chain variable region of SEQ ID NO: 15 Antibodies containing 3 are presented.

[0150] In certain embodiments, this disclosure relates to the FXI and / or FX listed in Table 1. The method described herein includes an antibody or antigen-binding fragment that specifically binds to Ia. In a specific embodiment for use in this context, coupling with FXI and / or FXIa is possible. The antibody or antigen-binding fragments are NOV1090 and NOV1401.

[0151] The variable region or full-length chain of the antibody uses human germline immunoglobulin genes. When obtained from a system, the human antibodies used herein are produced from a specific germline sequence. If it is "a thing" or "derived from" it, heavy chain or light chain variable region or full-length heavy chain It contains a light chain. Such a system is a transgenic organism that possesses human immunoglobulin genes. The mice are immunized with the target antigen, or the antigen is presented on a phage containing the target antigen. This includes screening a library of human immunoglobulin genes. Human antibodies that are "products" of or "derived from" a cell lineage immunoglobulin sequence are The amino acid sequence of human antibodies was compared with the amino acid sequence of human germline immunoglobulins. , human germline antibody whose sequence most closely resembles the sequence of a human antibody (i.e., has the highest identity %) By selecting the immunoglobulin sequence of the cell lineage, it can be identified as such. ru.

[0152] It is a "product" of or derived from an immunoglobulin sequence of a specific human germ cell lineage. Human antibodies that "do" are, for example, intentionally produced by spontaneous somatic mutations or site-directed mutations. Due to the introduction of this gene, it may contain differences in amino acids compared to the germline sequence. In the VH framework region or VL framework region, the selected human antibody is The amino acid sequence is encoded by the immunoglobulin genes of the human germline. The sequence is at least 90% identical to that of human antibodies, and the germline immunoglobulins of other species When compared to an amino acid sequence (e.g., a mouse germline sequence), it can be identified as human. Typically, they contain amino acid residues. In some cases, human antibodies contain amino acids. The amino acid sequence is the amino acid sequence encoded by the germline immunoglobulin gene, At least 60%, 70%, 80%, 90%, or at least 95%, or less At the very least, they can be 96%, 97%, 98%, or even 99% identical.

[0153] Recombinant human antibodies are human antibodies within the VH framework region or VL framework region. 10 amino acids with the amino acid sequence encoded by germline immunoglobulin genes Typically, it presents differences below the acid level. In certain cases, human antibodies are germ cells. The amino acid sequence encoded by the immunoglobulin gene series is 5 amino acids or less. It may present differences of 4, 3, 2, or 1 amino acid or less. Human germline Examples of immunoglobulin genes include the germline variable domain fragments described below, as well as This includes, but is not limited to, DP47 and DPK9.

[0154] homologous antibody Methods described herein (for example, in subjects with ESRD and / or AF) (Methods to reduce or prevent the risk of stroke and / or systemic embolism) In yet another embodiment for use, the present disclosure relates to the arrangements listed in Table 1 (for example, An antibody or its anti- The antibody presents a primordial binding fragment, and the antibody detects FXI and / or FXIa proteins (e.g., hi Combined with FXIa) of rabbits and cynomolgus macaques, NOV1090 and NOV1 The antibodies listed in Table 1, such as 401, retain the desired functional properties. Specific embodiments So, these homologous antibodies have the CDR amino acid sequence listed in Table 1 (for example, Ka (bat CDR, Chothia CDR, IMGT CDR, or combined CDR) To hold.

[0155] For example, this disclosure relates to an isolated antibody or so comprising a heavy chain variable domain and a light chain variable domain. It provides a functional antigen-binding fragment, in which case the heavy chain variable domain is SEQ ID NO: 9 and An amino acid sequence selected from a group of 29, and at least 80%, at least 90%, or containing at least 95% identical amino acid sequences; the light chain variable domain is SEQ ID NO: 19 and an amino acid sequence selected from the group consisting of 39, and at least 80%, at least 9 Containing 0% or at least 95% identical amino acid sequences; the antibody is FXI and / or This applies to FXIa (e.g., human FXIa, rabbit FXIa, and cynomolgus macaque FXIa). It binds specifically. In one embodiment, the isolated antibody or its functional antigen-binding fragment is heavy It includes a chain variable domain and a light chain variable domain, in which case the heavy chain variable domain is sequence number The amino acid sequence of No. 9, and at least 80%, at least 90%, or at least 95% It contains the same amino acid sequence; the light chain variable domain has the same amino acid sequence as SEQ ID NO: 19 and a small amount Containing at least 80%, at least 90%, or at least 95% identical amino acid sequences; Antibodies include FXI and / or FXIa (e.g., human FXIa, rabbit FXIa, and It specifically binds to cynomolgus monkeys (FXIa). In one embodiment, the isolated antibody or its mechanism The active antigen-binding fragment includes a heavy chain variable domain and a light chain variable domain, in this case, The heavy chain variable domain has the amino acid sequence of SEQ ID NO: 29 and at least 80% and at least 9 Containing 0% or at least 95% identical amino acid sequences; the light chain variable domain is sequence number The amino acid sequence of No. 39 and at least 80%, at least 90%, or at least 95% % Contains identical amino acid sequences; the antibody is FXI and / or FXIa (e.g., human F It specifically binds to XIa, rabbit FXIa, and cynomolgus monkey FXIa. In certain embodiments, the heavy and light chain sequences are defined by Kabat, HCDR1 sequence Column, HCDR2 sequence, HCDR3 sequence, LCDR1 sequence, LCDR2 sequence, and LCD The R3 sequence further includes, for example, sequence numbers 3, 4, 5, 13, 14, and 15, respectively. In certain other aspects of this disclosure, the heavy chain sequence and light chain sequence are provided by Chothia. The specified sequences are HCDR1, HCDR2, HCDR3, LCDR1, and LC. DR2 sequences and LCDR3 sequences, for example, sequence numbers 6, 7, 8, 16, and 1, respectively. The following further include 7 and 18. In certain other embodiments, the heavy chain sequence and the light chain sequence are combined. The HCDR1 sequence, HCDR2 sequence, HCDR3 sequence, LC are defined by the system. DR1 sequence, LCDR2 sequence, and LCDR3 sequence, for example, sequence number 46, respectively. , further including 4, 5, 33, 14, and 15. In some other embodiments, the heavy chain sequence and The light chain sequence is defined by IMGT, consisting of the HCDR1 sequence, HCDR2 sequence, and HCDR 3 sequences, LCDR1 sequence, LCDR2 sequence, and LCDR3 sequence, for example, respectively, This further includes sequence numbers 43, 44, 45, 47, 37, and 15.

[0156] In other embodiments for use in the methods described herein, the VH amino acid sequence and / or VL amino acid sequences are the sequences shown in Table 1, and 50%, 60%, 70%, They can be 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical. In the embodiment, the VH amino acid sequence and / or VL amino acid sequence are 1, 2, 3, 4, Alternatively, they may be identical except for amino acid substitutions at five or fewer amino acid positions. See Table 1. Significant (i.e., 80% or more) identity between the VH and VL regions of the listed antibody. Antibodies having VH and VL regions are sequence numbers 10 or 30, and sequence numbers Mutagenesis of nucleic acid molecules encoding numbers 20 and 40, respectively (e.g., site-specific mutagenesis) After mutagenesis (or PCR-mediated mutagenesis), the functional assemblies described herein Using (i), the encoded modified antibody is obtained by examining its function retention. It is possible.

[0157] Other embodiments for use in the methods described herein include full-length heavy-chain amino acids. The sequence and / or full-length light chain amino acid sequence is the sequence shown in Table 1 (for example, sequence number). 11 and / or 21, or 31 and / or 41), 50%, 60%, 70 They can be 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical. The full-length heavy chain of either SEQ ID NO: 11 or 31, and SEQ ID NO: 21 or 41 A full-length heavy chain having significant (i.e., 80% or more) identity with any of our full-length light chains. And antibodies with full-length light chains are mutations of nucleic acid molecules encoding such polypeptides. After meta-induction (e.g., site-directed mutagenesis or PCR-mediated mutagenesis), this specification Using the functional assay described in the book, the encoded modified antibody is tested for retention of its function. It can be obtained by investigating.

[0158] In one aspect of this specification, an isolated antibody comprising a heavy chain and a light chain or its functional antigen-binding properties A fragment is presented, and in this case, the heavy chain is selected from the group consisting of SEQ ID NOs: 11 and 31. The amino acid sequence and the a that is at least 80%, at least 90%, or at least 95% identical It contains a amino acid sequence; the light chain is an amino acid selected from the group consisting of SEQ ID NOs: 21 and 41. The sequence and amino acids that are at least 80%, at least 90%, or at least 95% identical. The sequence is included; the antibody is FXI and / or FXIa (e.g., human FXIa, rabbit F). It specifically binds to XIa and cynomolgus monkey FXIa). In one embodiment, isolated antibody Alternatively, the functional antigen-binding fragment comprises a heavy chain and a light chain, in which case the heavy chain is sequence The amino acid sequence of number 11, and at least 80%, at least 90%, or at least 9 It contains 5% identical amino acid sequences; the light chain has the amino acid sequence of SEQ ID NO: 21 and at least 8 The antibody contains 0%, at least 90%, or at least 95% identical amino acid sequences; FXI and / or FXIa (e.g., human FXIa, rabbit FXIa, and crab FXIa) It specifically binds to isal fXIa). In one embodiment, the isolated antibody or its functional antibody The primordial fragment includes a heavy chain and a light chain, in which case the heavy chain is the amino acid sequence of SEQ ID NO: 31. The row and the amino acid composition which is at least 80%, at least 90%, or at least 95% identical. The light chain contains the amino acid sequence of SEQ ID NO: 41, and at least 80%, at least 90% Containing %, or at least 95%, identical amino acid sequences; the antibody is FXI and / or FXIa (e.g., human FXIa, rabbit FXIa, and cynomolgus monkey FXIa) They bind heteromorphically. In certain aspects of this disclosure, the heavy chain sequence and the light chain sequence are linked to Kabat. The following are defined: HCDR1 sequence, HCDR2 sequence, HCDR3 sequence, LCDR1 sequence, LCDR2 sequence and LCDR3 sequence, for example, sequence numbers 3, 4, 5, and 13, respectively. , 14, and 15 further include. In certain other aspects of the present disclosure, heavy chain sequences and light chains The sequences are defined by Chothia: HCDR1 sequence, HCDR2 sequence, HCDR 3 sequences, LCDR1 sequence, LCDR2 sequence, and LCDR3 sequence, for example, respectively, The sequence numbers 6, 7, 8, 16, 17, and 18 are further included. In certain other embodiments, The chain sequence and light chain sequence are defined by a combination system, HCDR1 sequence, HCDR 2 sequences, HCDR3 sequence, LCDR1 sequence, LCDR2 sequence, and LCDR3 sequence, example For example, each further includes sequence numbers 46, 4, 5, 33, 14, and 15. In other embodiments, the heavy chain sequence and light chain sequence are defined by IMGT, HCDR1 sequence Column, HCDR2 sequence, HCDR3 sequence, LCDR1 sequence, LCDR2 sequence, and LCD R3 sequences, for example, sequence numbers 43, 44, 45, 47, 37, and 15 respectively It also includes.

[0159] In other embodiments for use in the methods described herein, full-length heavy chain and / Alternatively, the nucleotide sequence of the full-length light chain is the sequence shown in Table 1 (for example, sequence number 12 and (and / or 22, or 32 and / or 42) and 60%, 70%, 80%, 90% They can be 95%, 96%, 97%, 98%, or 99% identical.

[0160] In other embodiments for use in the methods described herein, the heavy chain variable region and The nucleotide sequence of the light chain variable region is the sequence shown in Table 1 (e.g., Sequence ID). 10 and / or 20, or 30 and / or 40) and 60%, 70%, 80 They can be 90%, 95%, 96%, 97%, 98%, or 99% identical.

[0161] As used herein, the percentage of 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. A function of the number of identical positions shared by the array (i.e., identity %= identical positions) (Number / Total number of positions × 100). Comparison of arrays and identity percentage between two arrays. The decision can be achieved using a mathematical algorithm, as described in the non-restrictive example below. It is possible.

[0162] In addition, or alternatively, the protein sequences of this disclosure are compared with published databases. To perform a search, for example, as a "query sequence" to identify related sequences, It can also be used for this purpose. For example, such a search was conducted by Altschul et al., 1990 J. Mol. Biol. This should be done using the BLAST program (version 2.0) as specified in 215:403~10. It is possible.

[0163] Antibodies with Conservative Modifications In certain embodiments, the methods described herein (e.g., ESRD and / or This reduces or prevents the risk of stroke and / or systemic embolism in individuals with AF. For use in methods to stop the CDR1 sequence, the antibody of this disclosure comprises the CDR1 sequence, CDR2 sequence The heavy chain variable region includes the column and the CDR3 sequence, and the CDR1 sequence, CDR2 sequence, and C It has a light chain variable region containing a DR3 sequence, and in this case, one of these CDR sequences or multiple thereof are based on the antibodies described herein or their conservative modifications, specified Having an amino acid sequence, in this case the antibody is the FXIa-binding antibody of this disclosure, with the desired functional properties. It retains its characteristics.

[0164] Therefore, for use in the methods described herein, this disclosure is distributed in CDR1. Heavy chain variable region including column, CDR2 sequence, and CDR3 sequence, as well as CDR1 sequence, C An isolated antibody or its antigenic chain consisting of a light chain variable region containing the DR2 sequence and the CDR3 sequence. A composite fragment in which the CDR1 amino acid sequence of the heavy chain variable region is the same as sequence numbers 3 and 23. Furthermore, selected from the group consisting of these conserved modifications, the CDR2 amino acid configuration of the heavy chain variable region The columns are selected from the group consisting of sequence numbers 4 and 24, and their conservative modifications, and The CDR3 amino acid sequences of the chain variable region are those of SEQ ID NOs. 5 and 25, as well as their conserved sequences. Selected from a group consisting of modifications, the CDR1 amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 13 Selected from the group consisting of and 33, and their conservative modifications, the CDR of the light chain variable region. The two amino acid sequences are a group consisting of SEQ ID NOs. 14 and 34, and their conserved modifications. The CDR3 amino acid sequences of the light chain variable region were selected from sequence numbers 15 and 35, and An antibody is selected from the group consisting of those conserved modifications and which specifically binds to FXIa. It provides the antigen-binding fragment.

[0165] In one aspect of this specification, a heavy chain comprising the CDR1 sequence, the CDR2 sequence, and the CDR3 sequence is used. Variable region, and light chain variable region including CDR1 sequence, CDR2 sequence, and CDR3 sequence. An isolated antibody or its antigen-binding fragment comprising a region, wherein the heavy chain variable region is CDR1 amino The acid sequence is selected from the group consisting of amino acid sequences and their conserved modifications listed in Table 1. Furthermore, the CDR2 amino acid sequence of the heavy chain variable region is the same as the amino acid sequence listed in Table 1. Selected from a group consisting of conserved modifications; the CDR3 amino acid sequence of the heavy chain variable region is shown. Selected from the group consisting of amino acid sequences and their conserved modifications described in 1; light chain possible The CDR1 amino acid sequence of the variant region is the amino acid sequence and its conservation sequence listed in Table 1. Selected from the group consisting of modifications; the CDR2 amino acid sequence of the light chain variable region is listed in Table 1. Selected from the group consisting of amino acid sequences and their conserved modifications; CD of the light chain variable region The R3 amino acid sequence consists of the amino acid sequences and their conserved modifications listed in Table 1. Selected from a group; the antibody or its antigen-binding fragment specifically binds to FXIa.

[0166] In other embodiments for use in the methods described herein, the antibodies of this disclosure are: Optimized for expression in mammalian cells, including full-length heavy chain sequence and full-length light chain sequence. It has, and one or more of these sequences is an antibody or so described herein. The antibody has the specified amino acid sequence based on the conservation modifications of the present disclosure, and the antibody is FXIa-conjugated. The desired functional properties of the sex antibody are preserved. Therefore, this disclosure relates to the full-length heavy chain and full-length light chain. An isolated antibody optimized for expression in mammalian cells, comprising a full-length heavy chain However, amino acids selected from the group of SEQ ID NOs: 11 or 31, and their conserved modifications. The sequence is such that the full-length light chain is sequence number 21 or 41, and the group of their conservative modifications. Having an amino acid sequence selected from among FXI and / or FXIa (e.g., human, u This invention provides antibodies that specifically bind to herons and cynomolgus monkeys (FXIa).

[0167] The same epitope-binding antibody This disclosure covers the methods described herein (e.g., the methods involving ESRD and / or AF). For reducing or preventing the risk of stroke and / or systemic embolism in elephants. FXI and / or FXIa bindings listed in Table 1 for use in the Act It presents an antibody that binds to the same epitope as the antibody. Therefore, FXI and / or F XIa binding assay (FXI and / or FXIa binding assay as described in the Examples section) In such cases, the binding of the antibody to the antibody(s) competes with other antibodies in the Disclosure (for example, the binding of other antibodies in the Disclosure By binding to the same or overlapping epitopes, competitive binding occurs in a statistically significant manner. Based on their ability to inhibit, further antibodies can be identified. The test antibody inhibits the binding of the FXI protein and / or FXIa protein. Depending on the capability, the test antibody will have a better understanding of how it binds to FXI and / or FXIa. It is possible for such antibodies to compete with the FXI protein, according to a non-limiting theory. on the protein and / or FXIa protein, whether it is the same as the competing antibody or It binds to related (for example, structurally similar or spatially close) epitopes. This is supported. In certain embodiments, the same FXI and / or antibodies as the antibodies of this disclosure The antibody that binds to the epitope on FXIa is a human monoclonal antibody. Human monoclonal antibodies can be prepared and isolated as described herein. can.

[0168] As used herein, in the presence of equimolar concentrations of competing antibodies, the competing antibodies are as disclosed herein. The same FX as the antibody or antigen-binding fragment (e.g., NOV1401 or NOV1090) Binds to the I epitope and / or FXIa epitope, and binds to the antibody or antigen of the present disclosure. The binding of the sex fragment to FXI and / or FXIa exceeds 50% (e.g., 80%) If the antibody inhibits 85%, 90%, 95%, 98%, or 99%, then the antibody will bind to the target substance. "To be in competition" means, for example, by any of the methods well known to those skilled in the art, This can be determined in a combined assay.

[0169] The antibodies or antigen-binding fragments used herein are the competing antibodies or their antigens. The binding fragment is the same FXI epitope as the antibody or antigen-binding fragment of this disclosure and / or ku is an FXIa epitope, or an overlapping FXI epitope and / or FX Unless it binds to the Ia epitope, the FXI antibody and / or FXI of this disclosure a antibody or antigen-binding fragment (e.g., NOV1401 or NOV1090) and "competition" "Do not." The competitive antibodies or antigen-binding fragments used herein are (i) of the Disclosure Steric blocking the binding of an antibody or antigen-binding fragment to its target (for example, before The competitive antibody is located near non-overlapping FXI epitopes and / or FXIa epitopes. Binding and physically preventing the antibody or antigen-binding fragment of this disclosure from binding to its target. (ii) different, non-overlapping FXI epitopes and / or It binds to the FXIa epitope, and the FXI antibody of this disclosure and / or the protein This occurs when an FXIa antibody or antigen-binding fragment is formed in the absence of the conformational change. To prevent binding in that form, conformational changes are made to the FXI protein and / or It does not contain competitive antibodies or their antigen-binding fragments that induce the FXIa protein.

[0170] Modified antibodies and manipulated antibodies For use in the methods described herein, the antibodies of this disclosure may also be used as starting antibodies. As a starting material for manipulating modified antibodies whose properties have been altered, the VH sequence shown herein It can also be prepared using an antibody having one or more of the following sequences: The antibody can be detected within one or both of the variable regions (i.e., VH and / or VL), for example. For example, within one or more CDR areas, and / or one or more frame widths This can be manipulated by modifying one or more residues within the hyphen region. Alternatively, the antibody may modify residues within its constant region to create, for example, an effector of the antibody. It can also be operated by modifying its functions.

[0171] One type of variable region manipulation that can be performed is CDR grafting. The antibody is , primarily through amino acid residues located within the six heavy and light chain complementarity-determining regions (CDRs) It then interacts with the target antigen. For this reason, the amino acid sequence within the CDR is between individual antibodies. The diversity of the CDR sequence is greater than that of the sequence outside the CDR. The CDR sequence is the most antibody-antigen interaction Because this is one of the factors, the framework sequences are derived from different antibodies with different properties. By constructing an expression vector containing a CDR sequence derived from a rafted specific spontaneously occurring antibody, This makes it possible to express recombinant antibodies that mimic the characteristics of specific naturally occurring antibodies. (For example, Riechmann, L. et al., 1998 Nature 332:323~327; Jones, P. et al., 1986 Nature) 321:522~525; Queen, C. et al., 1989 Proc. Natl. Acad. USA 86:10029~10033; Win U.S. Patent No. 5,225,539 by ter, and U.S. Patent No. 5,225,539 by Queen et al. Patent No. 5,530,101; Patent No. 5,585,089; Patent No. 5,693 See also Specification No. 762 and Specification Nos. 6,180,370.

[0172] Therefore, another embodiment of the present disclosure is selected from the group consisting of Sequence IDs 3 and 23. Selected from the group consisting of CDR1 sequences, SEQ ID NOs: 4 and 24, which have the amino acid sequence. A selection from the group consisting of CDR2 sequences having amino acid sequences, SEQ ID NOs. 5 and 25. A heavy chain variable region containing each of the CDR3 sequences having a mino acid sequence, and Sequence ID No. 13 and CDR1 sequence having an amino acid sequence selected from a group of 33, SEQ ID NO: 14 and A CDR2 sequence having an amino acid sequence selected from a group of 34, and Sequence ID No. 1 Each of the CDR3 sequences consisting of amino acid sequences selected from the groups of 5 and 35 is This relates to an isolated antibody or its antigen-binding fragment containing a light chain variable region. Therefore, Such antibodies contain the VH CDR sequence and VL CDR sequence of the monoclonal antibody. They possess, but may contain different framework sequences derived from these antibodies.

[0173] Such framework sequences include published D sequences, which include germline antibody gene sequences. This can be obtained from the NA database or published references. For example, human heavy chain The germline DNA sequences of the light chain variable region genes are from the human germline sequence database. The "VBase" (available on the internet at mrc-cpe.cam.ac.uk / vbase) In addition to the above, the contents of each of them are expressly incorporated herein by reference, Kaba t, EA et al., 1991. Sequences of Proteins of Immunological Interest, 5th edition, US Department. rtment of Health and Human Services, NIH Publication No. 91-3242; Tomlinson, I. M. . et al., 1992 J. Mol. Biol. 227:776~798; and Cox, JPL et al., 1994 Eur. J Immunol It can also be found in 24:827-836.

[0174] Examples of framework sequences for use in antibodies of this disclosure are selected antibodies of this disclosure. Framework sequences used by the body, for example, used by the monoclonal antibody of this disclosure The consensus sequence and / or framework sequence used are structurally similar to the framework These are the VH CDR1 sequence, VH CDR2 sequence, and VH CDR3 sequence. The sequences, as well as the VL CDR1 sequence, VL CDR2 sequence, and VL CDR3 sequence are The framework sequence is found within germline immunoglobulin genes from which it originates. It is also possible to graft the column into a framework region that has the same sequence, and the CDR sequence is Compared to germline sequences, framework regions containing one or more mutations It is also possible to graft into a domain. For example, in certain cases, within a framework domain It is considered beneficial to mutate residues to maintain or enhance the antigen-binding ability of antibodies. (For example, U.S. Patent No. 5,530,101 by Queen et al.; same) Specification No. 5,585,089; Specification No. 5,693,762; and Specification No. 6,18 See Specification No. 0,370. Antibodies and antigen-binding fragments described herein. Frameworks that can be used as scaffolding to build upon it include VH1A, VH1B, and V This includes, but is not limited to, H3, Vk1, Vl2, and Vk2. In the art, Further frameworks are known, for example, the internet's vbase.mrc-cpe.cam. It can be found in the vBase database at ac.uk / index.php?&MMN_position=1:1 can.

[0175] Therefore, for use in the methods described herein, embodiments of this disclosure are An amino acid sequence selected from the group consisting of SEQ ID NOs: 9 and 29, or such a sequence One, two, three, four, or five amino acid substitutions or deletions within the framework region. or containing a heavy chain variable region including an amino acid sequence having amino acid addition, SEQ ID NO: 19 or an amino acid sequence selected from the group consisting of 39, or a frame of such a sequence Within the - region, there are 1, 2, 3, 4, or 5 amino acid substitutions, amino acid deletions, or The isolated FXIa string further contains a light chain variable region having an amino acid sequence with amino acid addition. This relates to composite antibodies or their antigen-binding fragments.

[0176] Another type of variable region modification is known as "affinity maturation" in the VH CDR1 region. Within the region, within the VH CDR2 region, and / or within the VH CDR3 region, and / or This is within the VL CDR1 region, the VL CDR2 region, and / or the VL CDR3 region. By mutating the amino acid residues within the molecule, the binding properties of one or more of the target antibody are altered. The goal is to improve sex (e.g., affinity). Site-directed mutagenesis or P Mutations can be introduced by performing CR-mediated mutagenesis, as described herein. As presented in the Examples section, in vitro assays or in vivo assays In this way, the effect on antibody binding or other functional properties of the target can be assessed. Conservative modifications (discussed above) can be introduced. Mutation occurs at the site of amino acid substitution. There may be additions, deletions, and moreover, typically within the CDR region. Modify one, two, three, four, or five or fewer residues.

[0177] Therefore, in another embodiment for use in the method described herein, The disclosure is an amino acid sequence selected from the group consisting of SEQ ID NOs. 3 and 23, or SEQ ID NOs. Compared to 3 and 23, there are 1, 2, 3, 4, or 5 amino acid substitutions or amino acid deficiencies. VH CDR1 region having an amino acid sequence that is missing or has an added amino acid, SEQ ID NO: An amino acid sequence selected from the group consisting of 4 and 24, or a ratio of SEQ ID NOs: 4 and 24 In comparison, 1, 2, 3, 4, or 5 amino acid substitutions, amino acid deletions, or ami VH CDR2 region having an amino acid sequence with no acid addition, from SEQ ID NOs: 5 and 25 The amino acid sequence selected from the group, or compared with SEQ ID NOs. 5 and 25, 1, 2, It has 3, 4, or 5 amino acid substitutions, deletions, or additions. Selected from the group consisting of VH CDR3 regions having amino acid sequences, and SEQ ID NOs: 13 and 33. The amino acid sequence, or compared to SEQ ID NOs. 13 and 33, 1, 2, 3, 4, if ku is an amino acid sequence having five amino acid substitutions, amino acid deletions, or amino acid additions. An amino acid selected from the group consisting of a VL CDR1 region having a region, and SEQ ID NOs: 14 and 34. Compared to the acid sequence, or SEQ ID NOs. 14 and 34, 1, 2, 3, 4, or 5 locations VL having an amino acid sequence with amino acid substitution, amino acid deletion, or amino acid addition CDR2 region and amino acid mixture selected from the group consisting of SEQ ID NOs: 15 and 35 Compared to the row, or sequence numbers 15 and 35, there are 1, 2, 3, 4, or 5 meshes. VL C having an amino acid sequence with an acid substitution, amino acid deletion, or amino acid addition. Isolated FXIa-binding antibodies or their antigenic bonds consisting of heavy chain variable regions having a DR3 region. Provides compatible fragments.

[0178] Therefore, in another embodiment for use in the method described herein, The disclosure is an amino acid sequence selected from the group consisting of SEQ ID NOs. 6 and 26, or SEQ ID NOs. Compared to 6 and 26, there are 1, 2, 3, 4, or 5 amino acid substitutions or amino acid deficiencies. VH CDR1 region having an amino acid sequence that is missing or has an added amino acid, SEQ ID NO: An amino acid sequence selected from the group consisting of 7 and 27, or a ratio of SEQ ID NOs. 7 and 27. In comparison, 1, 2, 3, 4, or 5 amino acid substitutions, amino acid deletions, or ami The VH CDR2 region having an amino acid sequence with an acid no addition, and SEQ ID NO: 8 and An amino acid sequence selected from a group of 28, or compared with SEQ ID NOs: 8 and 28, 1, 2, 3, 4, or 5 amino acid substitutions, amino acid deletions, or amino acid additions A heavy chain variable region having a VH CDR3 region having an amino acid sequence having, and Sequence ID No. 1 An amino acid sequence selected from the group consisting of 6 and 36, or sequence numbers 16 and 36. In comparison, 1, 2, 3, 4, or 5 amino acid substitutions, amino acid deletions, or VL CDR1 region having an amino acid sequence with a mino acid addition, SEQ ID NOs: 17 and 37 An amino acid sequence selected from the group consisting of, or compared with SEQ ID NOs: 17 and 37, , 2, 3, 4, or 5 amino acid substitutions, amino acid deletions, or amino acid additions The VL CDR2 region having the amino acid sequence, and from SEQ ID NOs. 18 and 38 The amino acid sequence selected from the group, or compared with SEQ ID NOs: 18 and 38, 1, 2 , having 3, 4, or 5 amino acid substitutions, amino acid deletions, or amino acid additions Isolation FXI consists of a light chain variable region having a VL CDR3 region having an amino acid sequence. This invention provides an α-binding antibody or an antigen-binding fragment thereof.

[0179] Antibodies with extended half-life This disclosure provides for use in the methods described herein, in vivo This invention provides an antibody with an extended half-life that specifically binds to the FXIa protein.

[0180] Many factors can affect the half-life of a protein in vivo. For example... For example, filtration in the kidneys, metabolism in the liver, and protein-degrading enzymes (proteases) Degradation and immunogenic response (e.g., neutralization of proteins by antibodies and macrophages) (Uptake by dendritic and dendritic cells). Various strategies are used to extend the half-life of the antibodies of this disclosure. It is possible. For example, polyethylene glycol (PEG), reCODE PEG Antibody scaffold, polysialic acid (PSA), hydroxyethyl starch (HES), albumin Through chemical linkage with a ligand that binds to IgG, and a carbohydrate shield, albumin, IgG , FcRn, and proteins that bind to serum proteins such as transferrin Through gene fusion, nanobodies, Fab, DARPin, avimers, aphibodies, and It couples with other binding sites that bind to serum proteins, such as antikalin (genes). By means of (either physically or chemically), rPEG, albumin, albumin domain, album By gene fusion with mine-binding proteins and Fc, or by nanocarriers, sustained-release formulations, Alternatively, the half-life of the antibody of the present invention can be extended by incorporating it into a medical device. .

[0181] To prolong the circulation of antibodies in serum in vivo, high molecular weight PEG, etc. Site-specific conjugation of the active polymer molecule to the N-terminus or C-terminus of PEG or the antibody. Via gating, or via the epsilon-amino group present on lysine residues, To antibodies or fragments thereof, with or without functional linkers. It can be attached to. To PEGylate an antibody, the antibody or a fragment of it is attached to polyethylene. PEG, such as a reactive ester or aldehyde derivative of PEG, and one Alternatively, the reaction is typically carried out under conditions in which multiple PEG groups are attached to the antibody or antibody fragment. PEGylation involves the interaction of reactive PEG molecules (or similar reactive water-soluble polymers) with each other. This can be carried out by acylation or alkylation reactions. The term "polyethylene glycol" refers to mono(C1-C10) alkoxy-polyethylene Polyethylene glycol or aryloxy polyethylene glycol or polyethylene glycol PEG, which is used to derivatize other proteins such as recall-maleimide It is intended to encompass any of the forms. In certain embodiments, P Antibodies that undergo EG conversion are deglycosylating antibodies. Linear polymers or branched polymers. Derivatization is used which derivatization results in minimal loss of biological activity. It is likely that the degree of conjugation will be closely determined by SDS-PAGE and mass spectrometry. By monitoring this, we can confirm the proper conjugation of the PEG molecule to the antibody. Yes, it is possible. Unreacted PEG can be removed by size exclusion chromatography or ion exchange chromatography. PEG can be separated from antibody-PEG conjugates by matrixing. Derivatized antibodies are prepared using methods well known to those skilled in the art, for example, as described herein. The assay can be used to investigate binding activity and in vivo efficacy. Yes, it is possible. In this field, methods for PEGylating proteins are known, and the antibody disclosed herein It can be applied to EP0154316 by Nishimura et al. See also EP0401384 by Ishikawa et al.

[0182] Other modified PEGylation techniques include tRNA synthetase and tRNA-containing reconstitution systems. Through this process, chemically identified side chains are incorporated into biosynthetic proteins, a reconstitution chemical direct method. reconstituting chemically orthogonal directed engineering ( Includes ReCODE PEG). This technology involves over 30 new amino acids in E. coli. Incorporation into biosynthetic proteins within E. coli cells, yeast cells, and mammalian cells. It is possible. tRNA can move non-natural amino acids to any position where an amber codon is located. It incorporates the stop amber codon and the incorporation signal of a chemically identified amino acid. It is converted into a codon for transmission.

[0183] Recombinant PEGylation technology (rPEG) can also be used to extend the serum half-life. This technology uses an unstructured protein tail of 300-600 amino acids to create an existing pharmaceutical-grade protein tail. This involves gene fusion with protein. Since the molecular weight is about 15 times its actual molecular weight, the serum half-life of a protein is significantly different. It increases. In contrast to conventional PEGylation, which requires chemical conjugation and repurification. As a result, the manufacturing process is greatly simplified, and the product is homogeneous.

[0184] Polysialylation uses polysialic acid (PSA), a natural polymer, to activate longevity Another technology that extends life and improves the stability of therapeutic peptides and therapeutic proteins. PSA is a polymer of sialic acid (sugar). It is used in proteins and therapeutic peptides. When used for drug delivery, polysialic acid provides a protective microenvironment during conjugation. This results in extending the active lifespan of therapeutic proteins in circulation, which in turn affects the immune system. To prevent recognition. PSA polymers are found naturally in the human body. SA has evolved over millions of years to coat those walls with PSA. It was adopted by the species of bacteria. Subsequently, these naturally polysiallylated bacteria were molecular Through imitation, it became possible to disable the body's internal defense systems. Nature's ultimate stealth technology. PSA can be easily obtained in large quantities from such bacteria, and with specific physical characteristics. It can be produced in this way. Bacterial PSA is chemically identical to PSA in the human body. Furthermore, even when coupled to a protein, it remains completely non-immunogenic.

[0185] Another technique involves the use of hydroxyethyl starch ("HES") derivatives linked to antibodies. It contains HES, a modified natural polymer derived from waxy corn starch. It is present and can be metabolized by enzymes in the body. HES solution is typically used to replenish blood volume and improve blood circulation. It is administered to improve the ology properties. HES conversion of the antibody increases the stability of the molecule. In addition to this, reducing renal clearance also makes it possible to extend the circulating half-life. This results in increased biological activity. Different parameters such as the molecular weight of HES are used. By modifying them, a wide range of HES antibody conjugates can be customized. can.

[0186] Antibodies with an extended half-life in vivo also exhibit one or more amino acid modifications. (i.e., substitution, insertion, or deletion) of the IgG constant domain or its FcRn binding Even when introduced into a sexual fragment (preferably an Fc domain fragment or a hinged Fc domain fragment), It can be extracted. For example, in the International Patent Publication No. 98 / 23289 pamphlet, International Patent Pamphlet No. 97 / 34631; and U.S. Patent No. 6,277,375 Please refer to the book.

[0187] Furthermore, to make antibodies or antibody fragments more stable in vivo, To extend the half-life in vivo, antibodies are used in albumin (e.g., human blood It can also be conjugated to clear albumin (HSA). In this technology, the technique This is well known, for example, in the pamphlet of International Patent Publication No. 93 / 15199, and the same No. 93 / 1 Brochure No. 5200, and Brochure No. 01 / 77137; and European Patent Please refer to Specification No. 413,622. In addition, the context of the bispecific antibodies described above. So, the specificity of an antibody is that one binding domain of the antibody binds to FXIa, The second binding domain of the antibody is configured to bind to serum albumin, preferably HSA. You can also design it.

[0188] Strategies for extending the half-life are desired when the half-life is extended in vivo. Nanobodies, fibronectin-based binders, and other antibodies or protein odors It is particularly useful.

[0189] Antibody conjugate This disclosure describes how to create a fusion protein using heterologous proteins or heterologous polypeptides. to (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, at least 80 (to polypeptides of at least 90, or at least 100 amino acids), by recombinant To fuse or chemically conjugate (covalent conjugation) (Including both covalent and non-covalent conjugations), specifically binds to the FXIa protein. To provide antibodies or fragments thereof for use in the methods described herein. Provides. In particular, this disclosure provides antigen-binding fragments of antibodies described herein (e.g., Fab Fragments, Fd fragments, Fv fragments, F(ab)2 fragments, VH domains, VH CDRs, VL domains (or VL CDR) and heterologous proteins, heterologous polypeptides, or heterologous peptides This provides a fusion protein containing a protein, polypeptide, and Alternatively, methods are known for fusing or conjugating peptides with antibodies or antibody fragments. Yes, for example, U.S. Patent No. 5,336,603 and U.S. Patent No. 5,622,929. Specification No. 5,359,046, Specification No. 5,349,053, No. 5,44 Specifications No. 7,851 and No. 5,112,946; European Patent Nos. 307,43 Specification No. 4 and Specifications EP367 and EP366; International Patent Publication No. 96 / 04388 Pamphlet and Pamphlet No. 91 / 06570; Ashkenazi et al., 1991, Proc. N atl. Acad. Sci. USA 88:10535~10539; Zheng et al., 1995, J. Immunol. 154:5590~5600; See also Vil et al., 1992, Proc. Natl. Acad. Sci. USA 89:11337~11341.

[0190] Further fusion proteins are involved in gene shuffling, motif shuffling, and exonescence. Shuffling, and / or codon shuffling (collectively, "DNA shuffling") It can be produced through the technique (named) of DNA shuffling, as disclosed in this disclosure. Modify the activity of antibodies or fragments thereof (e.g., high affinity, rapid dissociation) This can be an antibody with a low degree of efficacy or a fragment thereof. Generally, U.S. 5,605,7 Specification No. 93, Specification No. 5,811,238, Specification No. 5,830,721, Specification No. 5,830,721, Patent No. 5,834,252 and Patent No. 5,837,458; Patent et al., 19 97, 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 Bla SCO, 1998, Biotechniques 24(2):308~313 (Each of these patents and publications is referenced by...) See (which are incorporated into this specification in their entirety) for reference. Antibodies or Those fragments, or the antibodies that encode them, or those fragments, were subjected to errors before recombination. Random mutagenesis by prone PCR, random nucleotide insertion, or other methods It can be modified by applying the law. Anti-binding agent that specifically binds to the FXIa protein. A polynucleotide that codes for a body or a fragment thereof is one or more heterologous molecules. Alternatively, it can be rearranged using multiple components, motifs, segments, parts, domains, or fragments. .

[0191] Furthermore, antibodies or fragments thereof can be linked to marker sequences such as peptides to facilitate purification. They can also be fused with them. In a preferred embodiment, the amino acid sequence of the marker is one of them. Among the many commercially available options, pQE vectors (QIAGEN, Inc.) are particularly noteworthy. (9259 Eton Avenue, Chatsworth, CA 91311) The tag provided is a hexahistidine peptide (SEQ ID NO: 48). As described in z et al., 1989, Proc. Natl. Acad. Sci. USA 86:821~824, for example, For example, hexahistidine (SEQ ID NO: 48) allows for the simple purification of fusion proteins. Other peptide tags useful for purification are derived from influenza hemagglutinin protein. Hemagglutinin ("HA") corresponding to the epitope (Wilson et al., 1984, Cell 37:767) This includes, but is not limited to, the tags "g" and "flag".

[0192] In other embodiments, antibodies or fragments thereof are used in diagnostic agents or detectable agents. To conjugate with such antibodies, the onset, development, progression, and The severity and / or condition may be part of a clinical testing procedure, such as determining the effectiveness of a particular treatment. This can be useful for monitoring or prognosis diagnosis. Such diagnosis and detection are Antibodies were used to test for horseradish peroxidase, alkaline phosphatase, and beta-galactosidase. These include, but are not limited to, a variety of enzymes such as acetylcholinesterase. ;Streptavidin / biotin and avidin / biotin, etc., but not limited to these. Non-existent prosthetic group; umbelliferone, fluorescein, fluorescein isothiocyanate Rhodamine, dichlorotriazinylamine fluorescein, dansilchloride, and Examples of fluorescent materials include phycoerythrin, but are not limited to these; luminol, for example. Luminescent materials, but not limited to these; luciferase, luciferin, and aequorin. Bioluminescent materials, but not limited to these; iodine (131I, 125I, 123I) , and 121I), carbon (14C), sulfur (35S), tritium (3H), indiu M (115In, 113In, 112In, and 111In), Technetium (99T c) Thallium (20¹Tl), Gallium (68Ga, 67Ga), Palladium (10³ Pd), molybdenum (99Mo), xenon (133Xe), fluorine (18F), 153 Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 9 0Y, 47Sc, 186Re, 188Re, 142Pr, 105Rh, 97Ru, 68G e, 57Co, 65Zn, 85Sr, 32P, 153Gd, 169Yb, 51Cr, 54 Examples of emission molecules include Mn, 75Se, 113Sn, and 117Tin, but are not limited to these. Electromagnetic materials; as well as positron-emitting metals and non-radioactive materials using various positron emission tomography techniques. It couples to detectable substances containing, but not limited to, paramagnetic metal ions. This can be achieved by doing so.

[0193] This disclosure also includes the use of antibodies or fragments thereof conjugated into therapeutic portions. It includes antibodies or fragments thereof, cytotoxins, for example, cell proliferation inhibitors or cytotoxic agents. , the therapeutic agent or radioactive metal ions, for example, alpha emitters, to the therapeutic part of the condyloma. It can be used to negate any drug that is harmful to cells. Cytotoxins or cytotoxic agents can negate any drug that is harmful to cells. include.

[0194] Furthermore, antibodies or fragments of antibodies are therapeutic parts or drugs that modify a given biological response. It can also be conjugated into parts. The therapeutic or drug part is classically chemical It shall not be considered limited to therapeutic agents. For example, the drug portion may be a desired biological agent. It may be a protein, peptide, or polypeptide that possesses specific activity. Proteins include, for example, abrin, lysine A, Pseudomonas exotoxins, cholera toxin, and These include toxins such as diphtheria toxin; tumor necrosis factor, α-interferon, β-interferon Ron, nerve growth factor, platelet-derived growth factor, tissue plasminogen activator, apotosis Protein-modifying agents such as lymphokines, anti-angiogenic agents; or, for example, other bio-response modifiers. It may include quality.

[0195] Furthermore, antibodies contain radioactive metal ions such as alpha emitters like 213Bi, and 131I Radiation including, but not limited to, n, 131LU, 131Y, 131Ho, and 131Sm. Macrocyclic chelating agents useful for conjugating metal ions into polypeptides. It can be conjugated to any therapeutic part. In certain embodiments, a large ring The chelating agent can be attached to the antibody via a linker molecule, specifically 1,4,7,10-teto It is laazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA). In this technical field, such linker molecules are generally known, and each of them is referred to as such. It is incorporated throughout the whole, Denardo et al., 1998, Clin Cancer Res. 4(10):2483~90; Peterson et al., 1999, Bioconjug. Chem. 10(4):553~7; and Zimmerman et al., 1999, Nucl This is described in Med. Biol. 26(8):943~50.

[0196] Techniques for conjugating the therapeutic portion into an antibody are well known, for example, Arno n et al., “Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy”, M Onoclonal Antibodies and Cancer Therapy, Reisfeld et al. (eds.), pp. 243-256 (Alan R. Li ss, Inc. 1985); Hellstrom et al., “Antibodies For Drug Delivery,” Controlled Drug Delivery (2nd edition), Robinson et al. (eds.), pp. 623-623 (Marcel Dekker, Inc. 1987); Thorpe , “Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review”, Monoclo nal Antibodies 84: Biological And Clinical Applications, Pinchera et al. (eds.), 475~ 506 pages (1985); “Analysis, Results, And Future Prospective Of The Therapeutic Us e Of Radiolabeled Antibodies In Cancer Therapy”, Monoclonal Antibodies For Cancer Detection and Therapy, Baldwin et al. (eds.), pp. 303-316 (Academic Press 1985); See Thorpe et al., 1982, Immunol. Rev. 62:119-58.

[0197] Antibodies can also adhere to solid supports, which is particularly useful for immunoassays or the purification of target antigens. It can also be done that way. Such solid supports include glass, cellulose, and polyacrylamine. This includes nylon, polystyrene, polyvinyl chloride, or polypropylene, but these are not included. Not limited.

[0198] Methods for producing antibodies nucleic acids that encode antibodies This disclosure includes segments or domains of the FXIa-binding antibody chain described above. In addition to substantially purified nucleic acid molecules encoding lipeptides, there are also materials for producing antibodies. The researchers and host cells are also presented. Some of the nucleic acids in this disclosure are sequence numbers 10 or 30. The nucleotide sequence encoding the heavy chain variable region shown in and / or Sequence ID No. 20 or includes a nucleotide sequence encoding the light chain variable region shown in 40. Specific implementation In this context, nucleic acid molecules are those identified in Table 1. Nucleic acid molecules are substantially (for example,) the nucleotide sequences of the nucleic acid molecules identified in Table 1. Contains at least 65%, 80%, 95%, or 99% identical nucleotide sequences. Appropriate When expressed from an expression vector, the polynucleotides encoded by these polynucleotides The peptide may exhibit FXI and / or FXIa antigen-binding ability. In a physical sense, due to the degenerate nature of the code, various nucleic acid sequences are immunoglobulin amino acids. This will code each element of the array.

[0199] Nucleic acid molecules can encode both the variable and constant regions of antibodies. Nucleic acid sequences of this disclosure Some of these are substantially (for example,) the heavy chain sequence shown in SEQ ID NO: 11 or 31. Nucleotides that encode identical heavy chain sequences (at least 80%, 90%, or 99%) Includes. Several other nucleic acid sequences are substantially the same as the light chain sequence shown in SEQ ID NO: 21 or 41. Nu encoding a light chain sequence that is identical to (for example, at least 80%, 90%, or 99%) Contains creotide.

[0200] Polynucleotide sequences are used in de novo solid-phase DNA synthesis, or by FXIa-binding antibodies or For existing sequences encoding the binding fragment (for example, the sequences described in the examples below) It can be produced by mutation induction by PCR. Direct chemical synthesis of nucleic acids is Narang et al., 1979, Phosphotryester method by Meth. Enzymol. 68:90; Brown et al., Meth. Phosphodiester method according to Enzymol. 68:109, 1979; Beaucage et al., Tetra. Lett., 22:185 9. Diethyl phosphoramidite method according to 1981; and U.S. Patent No. 4,458,066 This can be achieved by methods known in the art, such as the solid support method described in the specification. The introduction of mutations into polynucleotide sequences by PCR is, for example, PCR Technology. In: Principles and Applications for DNA Amplification, HA Erlich (ed.), Freeman. Press, NY, NY, 1992; PCR Protocols: A Guide to Methods and Applications, Innis et al. (eds.), Academic Press, San Diego, CA, 1990; Mattila et al., Nucleic Acids Res. 19:96 7, 1991; and described in Eckert et al., PCR Methods and Applications 1:17, 1991. It can be implemented as described.

[0201] By utilizing diverse expression vectors, we encode FXIa-binding antibody chains or binding fragments. It is possible to express polynucleotides using virus-based expression vectors and non Regardless of which viral expression vector is used, the goal is to produce antibodies within mammalian host cells. This is possible. Nonviral vectors and nonviral systems are plasmids, typically proteins. Episome vectors with expression cassettes for expressing quality or RNA, and human This includes artificial chromosomes (see, for example, Harrington et al., Nat Genet 15:345, 1997). For example, FXIa-binding polynucleotides and LO in mammalian (e.g., human) cells. A non-viral vector useful for expressing X-1 binding polypeptides is pThioHis A , pThioHis B, and pThioHis C, pcDNA3.1 / His, p EBVHis A, pEBVHis B, and pEBVHis C (Invitrog (en, San Diego, CA), expresses MPSV vectors and other proteins. This includes numerous other vectors known in the art for the purpose of [details omitted]. Useful viral vectors This is based on retroviruses, adenoviruses, adeno-associated viruses, and herpesviruses. Vector, SV40-based vector, papillomavirus, HBP Epstein-Barr Includes viruses, vaccinia virus vectors, and Semryki Forest Fever Virus (SFV). Brent et al., cited above; Smith, Annu. Rev. Microbiol. 49:807, 1995; and Rosenfeld et al., C See ell 68:143, 1992.

[0202] The expression vector also encodes the polypeptide by the inserted FXIa-binding antibody sequence. The location of the secretory signaling sequence can also be determined to form a fusion protein with cytoplasm. The imported FXI-binding antibody sequence and / or FXIa-binding antibody sequence are contained within the vector. Often, the signal sequence is ligated before incorporation. FXI-binding antibodies and / or or sequences encoding the light chain variable domain and heavy chain variable domain of the FXIa-binding antibody The vectors used to receive may also be the constant region or part of them. It also encodes the variable region as a fusion protein with the constant region. This enables expression, which in turn leads to the creation of intact antibodies or fragments thereof. Such steady-state regions are typically human steady-state regions.

[0203] Possessing and / or expressing FXI-binding antibody chains and / or FXIa-binding antibody chains. The host cell for this can be a prokaryotic cell or a eukaryotic cell. (E. coli) ) is a prokaryotic molecule useful for cloning and expressing the polynucleotides of this disclosure. It is a physical host. Other suitable microbial hosts include rod-shaped bacteria such as Bacillus subtilis. Bacteria, and species of the genera Salmonella, Serratia, and various species of bacteria This includes other Enterobacteriaceae species, such as the genus Pseudomonas. These are the prokaryotic hosts. Within it, it also typically contains expression regulatory sequences (e.g., origins of replication) that are compatible with the host cell. Expression vectors can also be created using lactose promoter systems and tryptose. Fan (trp) promoter system, beta-lactamase promoter system, or far There are also various well-known promoters, including those derived from dilambda. The promoter typically controls expression by an operator sequence through optional selection. However, this includes ribosome-binding site sequences for initiating and terminating transcription and translation. It also has other microorganisms such as yeast to express the FXIa-binding polypeptide of this disclosure. Materials can also be used. In addition, insect cells can be combined with baculovirus vectors. Cells can also be used.

[0204] In specific embodiments, the FXI-binding polypeptide and / or FXIa binding of the disclosed herein. Mammalian host cells are used to express and produce sex polypeptides. The cells are any normal non-immortalized animal cells or normal immortalized animal cells or non-immortalized animal cells. This includes cellular or human cells. For example, CHO cell lines, various Cos cell lines, and HeLa cells. Cells, myeloma cell lines, and transformed B cells, which secrete intact immunoglobulins. Numerous suitable host cell systems have been developed that can express polypeptides. For the use of mammalian tissue cell cultures, see, for example, Winnacker, FROM GENES TO C This is generally discussed in LONES, VCH Publishers, NY, NY, 1987. Mammalian habitat Expression vectors for chief cells include origins of replication, promoters, and enhancers. If the current control sequence is (see, for example, Queen et al., Immunol. Rev. 89:49~68, 1986), then In addition, ribosome-binding sites, RNA splice sites, polyadenylation sites, and transcription sites It may include necessary processing information regions, such as the minifier sequence.

[0205] The method for introducing an expression vector containing the target polynucleotide sequence depends on the cell host species. It varies depending on the type. For example, calcium chloride transfection is generally performed on prokaryotic cells. While this method is used, calcium phosphate treatment or electroporation is used for other cell hosts. It is possible (see Sambrook et al., previously mentioned). Other methods include, for example, electricity. Perforation, calcium phosphate treatment, liposome-mediated transformation, injection and microinjection Cation, gene gun law, wirosom, immunoliposome, polycation: nucleic acid conjugate Gate, naked DNA, artificial virion, herpesvirus structural protein (VP) Fusion with 22 (Elliot and O'Hare, Cell 88:223, 1997), drug-enhancing uptake of DNA This includes transduction in vivo and the long-term high performance of recombinant proteins. For yield production, stable expression is often desired. For example, FXIa-binding antibodies. Cell lines that stably express chains or binding fragments are considered to be the origins of viral replication or endogenous expression. Using the expression vector of the present invention, which contains elements and a selectable marker gene, It can be prepared. After introducing the vector, the cells are kept in a fortified medium for 1-2 days. The cells can be grown and then switched to a selective medium. The purpose of the selection marker is to facilitate selection. It confers resistance to the introduced agent, and its presence enables cell growth, thereby allowing the introduced agent to... The goal is to successfully express the row in a selective medium. Stable transfection with resistance is achieved. The selected cells can be propagated using a tissue culture method appropriate for the cell type.

[0206] Preventive and therapeutic use Antibodies that bind to FXI and / or FXIa as described herein (e.g., NO Table 1 shows examples of anti-FXI / FXIa antibodies, including V1401 VL CDR and VH CDR. The antibodies listed are for patients undergoing dialysis, with ESRD and / or AF. Thromboembolic diseases, such as reducing the risk of stroke and / or systemic embolism. Alternatively, it can be used at therapeutically useful concentrations for the treatment of thromboembolic disorders. The disclosure involves administering an effective amount of the antibody of this disclosure to a subject who requires it, via blood. This disclosure presents a method for treating thromboembolic disorders. This disclosure provides an effective amount to those who need it. By administering the anti-FXI / FXIa antibody of this disclosure, thromboembolic disorders (e.g., Prevention of thrombotic stroke (cardioembolic, thrombotic) or systemic embolism, AF, and stroke in AF. Thromboembolism (SPAF), deep vein thrombosis, venous thromboembolism, pulmonary embolism, acute coronary syndrome (AC) S) Patients treating acute lower limb ischemia, chronic thromboembolic pulmonary hypertension, or systemic embolism. The law is presented. Combination therapies are also presented in this specification.

[0207] The antibodies described herein (e.g., NOV1401 or NOV1090, or Anti-FX VL CDRs and VH CDRs including NOV1401 or NOV1090 Antibodies listed in Table 1, such as I / FXIa antibodies, are discussed in more detail in this specification. As stated, thromboembolic conditions or thrombosis, including but not limited to thrombotic disorders. It can be used to treat, prevent, and improve embolic injuries.

[0208] The antibodies presented herein (e.g., VL C of NOV1401 or NOV1090) Antibodies listed in Table 1, including anti-FXI / FXIa antibodies such as DR and VH CDR ) may also be used in combination with other drugs to prevent, treat, or improve thromboembolic disorders. It can also be used for thrombotic disorders and / or thromboembolism. For example, statin therapy is used for thrombotic disorders and / or thromboembolism. To treat patients with sexual dysfunction, the FXIa antibody and antigen-binding fragment of this disclosure are combined They can be used together.

[0209] In specific embodiments of this specification, the treatment or prevention of stroke in patients with AF is described. A method for which an effective amount of the anti-FXI / FXIa antibody described herein, for example, N Anti-FXI containing OV1401, or NOV1401 VL CDR and VH CDR. Anti-FXI / FXIa antibodies, such as / FXIa antibodies, as listed in Table 1, as needed. A method is presented that includes the step of administering the drug to the patient.

[0210] In specific embodiments of this specification, cardioembolic stroke and systemic stroke in patients with AF are described. Methods for managing or preventing risks or conditions associated with atrial fibrillation (AF), such as atrial embolism. and an effective amount of the anti-FXI / FXIa antibody described herein, for example, NOV1 Anti-FXI / FX, including VL and VH CDRs of 401 or NOV1401. Anti-FXI / FXIa antibodies, such as Ia antibodies, as listed in Table 1, should be administered to patients who require them. A method is presented that includes the step of administering to [the substance].

[0211] In specific embodiments of this specification, cardioembolic stroke and systemic stroke in patients with AF are described. Methods for treating, managing, or preventing conditions associated with atrial fibrillation (AF), such as atrial embolism. That is, an effective amount of the anti-FXI / FXIa antibody described herein, for example, NOV140 1, or anti-FXI / FXIa, including VL CDR and VH CDR of NOV1401. Antibodies, such as the anti-FXI / FXIa antibodies listed in Table 1, should be administered to patients who require them. A method is presented that includes the step of administration. In certain embodiments, AF patients are at risk of bleeding. The risk is high. In certain cases, AF patients have a CHA2DS2VASc risk score of ≥2. It is determined that there is a high risk of bleeding. Specifically, AF patients have a non-valvular heart condition. High risk of bleeding is determined by AF and a CHA2DS2VASc risk score of ≥2. In a specific example, the AF patient is 55 years of age or older and has non-valvular heart disease. High risk of bleeding, determined by sexual AF and a CHA2DS2VASc risk score of ≥2. It has the following characteristics.

[0212] In specific embodiments of this specification, the subject (for example, those with deep vein thrombosis or...) In individuals at risk of developing this condition, treatment for deep vein thrombosis or related conditions is administered. Methods for placing, controlling, or preventing an effective amount of anti-FXI / F as described herein. XIa antibodies, e.g., NOV1401, or VL CDR and VH of NOV1401 Anti-FXI / FXIa antibodies, including CDRs, as listed in Table 1. A method is presented that includes the step of administering an antibody to a target that needs it.

[0213] In specific embodiments of this specification, the subject (for example, with or with venous thromboembolism) is referred to as Venous thromboembolism (VTE) or related conditions in individuals at risk of developing this condition. A method for treating, controlling or preventing a condition, comprising an effective amount of the antimicrobial agent described herein. FXI / FXIa antibody, e.g., NOV1401, or VL CDR of NOV1401 And anti-FXI / FXIa antibodies including VH CDR, as listed in Table 1. A method is presented that includes the step of administering the / FXIa antibody to a target that requires it. In certain embodiments, subjects treated with the anti-FXI / FXIa antibodies presented herein This includes cancer patients, 1) those with a low risk of bleeding, first-time induced or idiopathic VTE, 2) Recurrence of idiopathic VTE, or 3) VTE associated with thrombotic diathesis. In a specific manner The subjects treated for VTE are between 0 and 18 years of age. In certain aspects, VTE The subjects treated for this condition are between 1 and 18 years of age. In certain cases, treatment for VTE is performed. The subjects are between 2 and 18 years of age. In certain cases, the subjects treated for VTE The elephant is between 0 and 12 years old. In certain cases, the subjects treated for VTE are between 1 and 12 years old. The age range is 12 years. In certain cases, the subjects treated for VTE are between 2 and 12 years old. In certain cases, the subjects treated for VTE are between 12 and 18 years of age. In certain embodiments, the subjects treated for VTE are at least 2 years of age and 18 The child is under one year of age. In certain aspects, the subject treated for VTE is at least one The child is 2 years old and under 18 years of age.

[0214] In specific embodiments of this specification, secondary prevention of venous thromboembolism (e.g., 28 days to 1 A method for secondary prevention over a period of up to eight years, and for those who need it. And an effective amount of the anti-FXI / FXIa antibody described herein, for example, NOV1401 , or anti-FXI / FXIa anti-VL CDR and VH CDR of NOV1401 A method including the step of administering anti-FXI / FXIa antibodies listed in Table 1 to the body, etc. The following are presented herein: Secondary prevention of venous thromboembolism (e.g., 28 days to 1 In certain aspects of methods for secondary prevention over a period of up to eight years, the subject is , between 0 and 18 years of age. Secondary prevention of venous thromboembolism presented herein (e.g., Specific aspects of methods for secondary prevention over a period ranging from 28 days to 18 years Therefore, the target group is between 0 and 12 years of age. The secondary prevention of venous thromboembolism presented herein In certain embodiments of the methods for stopping, the subjects are between 12 and 18 years of age. In certain aspects of the methods for the secondary prevention of venous thromboembolism presented, the target The child is at least 2 years old and under 18 years of age. The static present herein In certain aspects of methods for the secondary prevention of vascular thromboembolism, the subjects include at least 1 The child is 2 years old and under 18 years of age.

[0215] In specific embodiments of this specification, the subject (for example, a patient with or developing pulmonary embolism) is considered. In individuals at risk of developing the disease, treatment, management, and treatment of pulmonary embolism or related conditions. or a method of prevention, comprising an effective amount of the anti-FXI / FXIa antibody described herein. For example, including NOV1401, or VL and VH CDRs of NOV1401. Anti-FXI / FXIa antibodies, such as those listed in Table 1, A method is presented that includes the step of administering the substance to a target that requires it.

[0216] In specific embodiments of this specification, acute coronary syndrome (ACS) or the subject is described. A method for treating, managing, or preventing a condition related thereto, in an effective amount, as specified herein. The anti-FXI / FXIa antibody listed, for example, NOV1401, or NOV1401's V Table 1 lists anti-FXI / FXIa antibodies, including L CDR and VH CDR. A method comprising the step of administering an anti-FXI / FXIa antibody to a subject in need thereof. It will be presented.

[0217] In specific embodiments of this specification, the subject (for example, those with or suffering from ischemic stroke) is referred to. Methods for treating, managing, or preventing ischemic stroke in individuals at risk of developing ischemic stroke. and an effective amount of the anti-FXI / FXIa antibody described herein, for example, NOV1 Anti-FXI / FX, including VL and VH CDRs of 401 or NOV1401. Anti-FXI / FXIa antibodies, such as Ia antibodies, as listed in Table 1, should be used for the target population that requires them. A method is presented that includes the step of administering to [the substance].

[0218] In specific embodiments of this specification, acute lower limb ischemia in a subject is treated, managed, or A method of prevention, comprising an effective amount of the anti-FXI / FXIa antibody described herein, for example If, then, anti- FXI / FXIa antibodies, etc., as listed in Table 1, must be used. A method is presented that includes the step of administering the drug to the target subject.

[0219] In specific embodiments of this specification, chronic thromboembolic pulmonary hypertension in a subject is treated and managed A method for treating or preventing the use of an effective amount of anti-FXI / FXIa as described herein. Antibodies, e.g., NOV1401, or VL CDR and VH CD of NOV1401 Anti-FXI / FXIa antibodies, including those containing R, as listed in Table 1. A method is presented that includes the step of administering it to a person who needs it.

[0220] In specific embodiments of this specification, the subject (for example, with or with systemic embolism) is a subject (e.g., with systemic embolism or similar). Methods for treating, managing, or preventing systemic embolism in individuals at risk of developing the condition. and an effective amount of the anti-FXI / FXIa antibody described herein, for example, NOV1 Anti-FXI / FX, including VL and VH CDRs of 401 or NOV1401. Anti-FXI / FXIa antibodies, such as Ia antibodies, as listed in Table 1, should be used for the target population that requires them. A method is presented that includes the step of administering to [the substance].

[0221] In certain embodiments of this specification, a catheter becomes thrombosed (for example, In cancer patients, this is a Hickman catheter-related condition, or the tubing is clotting. Treating, managing, or preventing thromboembolic states caused by extracorporeal membrane oxygenation (ECMO). A method for stopping the process, comprising an effective amount of the anti-FXI / FXIa antibody described herein, for example. Anti-F containing NOV1401, or VL CDR and VH CDR of NOV1401 Anti-FXI / FXIa antibodies, such as XI / FXIa antibodies, as listed in Table 1, as needed. A method is presented that includes the step of administering the drug to the target subject.

[0222] In specific embodiments of this specification, the risk of catheter-related thrombosis is to be prevented, treated, or mediated by a catheter. A method of treating or reducing ESRD, which involves catheterization (e.g., insertion) Hemodialysis using a tunnel-shaped catheter was initiated, and this was then delivered to the patient who needed it. Anti-FXI / FXIa antibodies as described in the specification, e.g., NOV1401 or NOV1 401 VL CDRs and VH CDRs (for example, VH CDR with sequence number 31, and Anti-FXI / FXIa antibodies, including VL CDR (SEQ ID NO: 41), as listed in Table 1. A method comprising the step of administering an effective amount of a pharmaceutical composition containing an anti-FXI / FXIa antibody. This is presented. In certain aspects of the methods presented herein, the subject is supported, It carries a high risk to blood. In certain embodiments of the methods presented herein, patients suffering from ESRD The subjects were those with AF such as non-valvular AF and those with a CHA2DS2VASc risk score of ≥2. It is determined to have a high risk of bleeding. In specific embodiments, the method presented herein In certain aspects of the law, subjects suffering from ESRD are those with AF such as non-valvular AF and ≥2 The individual is at high risk of bleeding, as determined by the CHA2DS2VASc risk score, and is 55 years of age. Or they are older than that.

[0223] In specific embodiments of this specification, thrombosis in patients undergoing hemodialysis for ESRD Reduce the incidence of the disease and maintain vascular access (e.g., tunnel catheters, arteriovenous catheters). It improves phlegm and arteriovenous aplasia, and can be used alone or with unfractionated heparin or low molecular weight heparin. When used in combination with other anticoagulants, etc., methods for preventing extracorporeal thrombosis and Use is to deliver an effective amount of NOV1401 (e.g., SEQ ID NOs. 31 and 41) to the patient. The step of administering an anti-FXI / FXIa antibody as described herein, such as an antibody containing [specific antibody]. The accompanying methods or uses are presented.

[0224] In other embodiments, this specification describes acute VTE treatment, primary prevention of VTE, and long-term secondary VTE. Prevention of major thromboembolism in dialysis patients (with or without AF) Prevention of adverse events, patients with CAD undergoing PCI and receiving monotherapy or dual antihistamines. In patients undergoing plate therapy, and in patients after acute coronary syndrome (ACS), major cardiovascular and Prevention of cerebrovascular events (MACCE), heparin-induced thrombocytopenia (HIT), and in patients with heart failure. A method for preventing thromboembolic events and secondary strokes, which An effective amount of the anti-FXI / FXIa antibody described herein, for example, is directed to the target where it is needed. Anti-F containing NOV1401, or VL CDR and VH CDR of NOV1401 Administer anti-FXI / FXIa antibodies, such as XI / FXIa antibodies, as listed in Table 1. A method including a top is presented.

[0225] In certain embodiments, an anti-FXI / FXIa antibody as described herein, for example, NOV 1401 (For example, a heavy chain containing the amino acid sequence of SEQ ID NO: 31 and the amino acid sequence of SEQ ID NO: 41) (Antibodies containing light chains containing sequences), or VL CDR and VH CD of NOV1401 Anti-FXI / FXIa antibodies, including those containing R, as listed in Table 1. Those who require treatment by: • Indications for chronic anticoagulation therapy (e.g., AF, left ventricular thrombosis, history of cardioembolic stroke) Target; • Patients at moderate to high risk of massive bleeding; • To prevent stent thrombosis, monotherapy or dual antiplatelet therapy (e.g., Aspirin) Stents that may require the application of phosphorus and / or P2Y12 receptor antagonists. Undergoing elective percutaneous coronary intervention (PCI) or direct PCI with IV line placement target It may include.

[0226] In a particular embodiment, the following state: Paroxysmal atrial fibrillation or paroxysmal atrial flutter, persistent atrial fibrillation or persistent atrial flutter, Alternatively, if cardiac arrhythmias such as persistent atrial fibrillation or persistent atrial flutter are suspected or confirmed. Thromboembolism in the subject being treated; • Subjects with atrial fibrillation requiring stroke prevention (SPAF), and whose subgroups are The target group consists of AF patients undergoing percutaneous coronary intervention (PCI); • Management of acute venous thromboembolic events (VTE) in patients at high risk of bleeding. and prevention of long-term secondary VTE; • In secondary prevention following transient ischemic attack (TIA) or non-functional stroke In the prevention of cerebral and cardiovascular events, as well as thromboembolic events in heart failure with sinus rhythm. Cerebral and cardiovascular events; • Clot formation and thromboembolism in the left atrium in patients undergoing cardiac defibrillation for cardiac arrhythmias. Embolism; Thrombosis before, during, and after ablation procedures for cardiac arrhythmias; • Venous thrombosis, which is deep vein thrombosis or superficial vein thrombosis in the lower or upper extremities. Vessel thrombosis, thrombosis in the abdominal and thoracic veins, sinus thrombosis and jugular vein thrombosis This includes, but is not limited to, treatment and secondary prevention; Thrombosis on any artificial surface within a vein, such as a catheter or pacemaker lead; • Pulmonary embolism in patients with or without venous thrombosis; Chronic thromboembolic pulmonary hypertension (CTEPH); • Arterial thrombosis on ruptured atherosclerotic plaque, on arterial prostheses or catheters These are thrombosis in the arteries and thrombosis in seemingly normal arteries, and these are acute coronary syndrome. Group, ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, unstable angina, stent thrombosis, arterial Thrombosis of any artificial surface within the system, and in subjects with or without pulmonary hypertension. This includes, but is not limited to, pulmonary thrombosis; • Thrombosis and thrombosis in patients undergoing percutaneous coronary intervention (PCI) Embolism; • Cardioembolic stroke and cryptogenic stroke; Thrombosis in patients with invasive and non-invasive cancerous malignancies; • Thrombosis involving indwelling catheters; • Thrombosis and thromboembolism in critically ill patients; • Cardiac thrombosis and thromboembolism, including cardiac thrombosis after myocardial infarction and cardiovascular thrombosis. Conditions such as aneurysms, cardiomyopathy, cardiac hypertrophy and cardiac dysfunction, myocarditis, and artificial surfaces within the heart This includes, but is not limited to, cardiothrombosis associated with the condition; Thromboembolism in patients with valvular heart disease, with or without atrial fibrillation; • Thromboembolism involving mechanical or biological prostheses for heart valves; • After cardiac repair for simple or complex cardiac malformations, natural or artificial cardiac pads Injuries or trauma in patients with arterial or venous conduits; • Total knee replacement, total hip replacement, and orthopedic surgery, thoracic surgery, or abdominal surgery Venous thrombosis and thromboembolism following; • Following neurosurgical procedures including intracranial and spinal interventions Arterial thrombosis or venous thrombosis; • Factor V Leiden, prothrombin mutation, antithrombin III, prote Protein C deficiency and protein S deficiency, factor XIII mutations, familial fibrosis Linogenemia, congenital plasminogen deficiency, elevated factor XI levels, sickle cell disease, Antiphospholipid syndrome, autoimmune diseases, chronic bowel disease, nephrotic syndrome, hemolytic uremic disease, bone marrow Proliferative disorders, disseminated intravascular coagulation, paroxysmal nocturnal hemoglobinuria, and heparin-induced hematologic dysplasia Congenital or acquired thrombotic predisposition, including but not limited to thrombotic plaque; Thrombosis and thromboembolism in chronic kidney disease (e.g., stage 3 or 4); • Thrombosis and thromboembolism in end-stage renal disease (ESRD); • Thrombosis or blood clots in patients with chronic kidney disease or ESRD undergoing hemodialysis. Obstruction of vascular access (e.g., catheter thrombosis, arteriovenous graft thrombosis, or arteriovenous thrombosis) Arterial and venous thrombosis and thromboembolism, including phlegm; • Major cardiac and cerebrovascular events in patients undergoing hemodialysis with ESRD (e.g.) For example, prevention of cardiovascular death, myocardial infarction, stroke, and emergency vascular reconstruction; • Prevention of major lower limb adverse events (MALEs) (e.g., vascular reconstruction in severe lower limb ischemia) Therapy involving amputation or any major vascular reintervention in the index lower limb. Thrombolysis (thrombectomy, thrombolysis, or major surgical procedure [new bypass graft, ja Vascular reconstructive therapy, including graft modification by interposition / interposition. One of these is an anti-FXI / FXIa antibody as described herein, for example, NOV140 1, or anti-FXI / FXIa, including VL CDR and VH CDR of NOV1401. Treatment or management can be performed with anti-FXI / FXIa antibodies, such as those listed in Table 1. Cut.

[0227] The incidence and prevalence of atrial fibrillation (AF) in patients with end-stage renal disease (ESRD) are in the population Overall, the risk is high and is associated with an increased risk of stroke and mortality (Zimmerman et al., Nephrol Dial Transplant (2012) 27: 3816-3822). ESRD or end-stage renal failure is chronic. This is typically associated with the end stage of kidney disease (e.g., stage 4) and a decline in renal function. For example, in patients with ESRD, the glomerular filtration rate (GFR) indicates renal function of less than 15%. Typical symptoms of ESRD include anemia, easy bleeding, easy bruising, and headaches. Fatigue and drowsiness, physical weakness, mental symptoms (decreased mental agility, decreased concentration, confusion, etc.) Symptoms include: nausea, vomiting, generally decreased appetite, muscle spasms, muscle contractions, nocturnal enuresis (urinating at night), Numbness in the extremities, diarrhea, itchy skin, itchy eyes, changes in skin color (in some cases) Symptoms include a yellowish-brown, grayish complexion, swelling and edema, and difficulty breathing (in the lungs). This may include, but is not limited to, fluid retention (due to anemia), hypertension, and indigestion. ESR Treatment option D is dialysis (e.g., hemodialysis or peritoneal dialysis).

[0228] Therefore, in this specification, in particular, stroke or thromboembolism (e.g., systemic embolism) Methods for preventing, treating, managing, or reducing the risk of end-stage renal disease (E) For subjects suffering from SRD, the anti-FXI / FXIa antibodies described herein, for example If, then, anti- Effective anti-FXI / FXIa antibodies, including FXI / FXIa antibodies, as listed in Table 1. A method is presented which includes the step of administering a certain amount of a pharmaceutical composition. In a specific embodiment, the subject is They are undergoing dialysis or extracorporeal membrane oxygenation. In certain aspects, the subjects are patients with stage 4 chronic disease. They have been diagnosed with chronic kidney disease. In certain aspects, the subjects are patients with stage 3 or 4 chronic kidney disease. It has been diagnosed as being associated with a disease. In certain cases, the subject is consuming approximately 15-60 mL / min of creatine. It was determined that it has a tinine clearance rate (CrCl: 15-60 mL / min). Yes, they are.

[0229] Therefore, in this specification, in particular, stroke or thromboembolism (e.g., systemic embolism) Methods for preventing, treating, managing, or reducing the risk of end-stage renal disease (E) SEQ ID NOs. 29 and 3 are respectively given to individuals suffering from SRD who require it. A heavy chain containing VH and VL containing 9, or containing the amino acid sequence of SEQ ID NO: 31, and An effective amount of an anti-FXI / FXIa antibody containing a light chain containing the amino acid sequence of column number 41. A method is presented which includes the step of administering a pharmaceutical composition. In a specific embodiment, the subject is blood They are undergoing dialysis, such as fluid dialysis, or extracorporeal membrane oxygenation. In certain cases, the subject is They have been diagnosed with chronic kidney disease of stage 4. In certain cases, the subjects are those with stage 3 or The patient has been diagnosed with chronic kidney disease. In certain cases, the patient's volume is approximately 15-60 mL. It must have a creatinine clearance rate of 15-60 mL / min (CrCl: 15-60 mL / min). This has been decided. Specifically, the target is also atrial fibrillation such as non-valvular AF (A It also has F).

[0230] In specific embodiments of this specification, in particular, hemodialysis for ESRD and related stroke Or to prevent, treat, or manage the risk of thromboembolism (e.g., systemic embolism), or A method of reduction for those suffering from end-stage renal disease (ESRD) and those who require it. To each of these, VH and VL containing sequence numbers 29 and 39, or sequence numbers Antibody comprising a heavy chain containing the amino acid sequence of sequence number 31 and a light chain containing the amino acid sequence of sequence number 41. A method is presented that includes the step of administering an effective amount of a pharmaceutical composition containing an FXI / FXIa antibody. In specific cases, the subjects are those undergoing dialysis such as hemodialysis or extracorporeal membrane oxygenation. In certain cases, the subjects are diagnosed with stage 4 chronic kidney disease. In certain cases, the subjects are diagnosed with chronic kidney disease of stage 3 or 4. In this embodiment, the target is a creatinine clearance rate (Cr C) of approximately 15-60 mL / min. It has been determined that it has a flow rate of 15-60 mL / min. In specific cases, the subject is In addition, they also have atrial fibrillation (AF), such as non-valvular AF.

[0231] In other specific aspects of this specification, the risk of stroke or thromboembolism is prevented or reduced. This method is for patients suffering from atrial fibrillation (AF) and ESRD, and who undergo hemodialysis or other similar procedures. For subjects undergoing electrocautery or extracorporeal membrane oxygenation, the anti-FXI / FX described herein is used. Ia antibodies, e.g., NOV1401, or VL CDR and VH of NOV1401 Anti-FXI / FXIa antibodies, including CDR, as listed in Table 1. A method is presented which includes the step of administering an effective amount of a pharmaceutical composition, including a body. Specific embodiments Therefore, the subjects are those suffering from non-valvular AF. More specifically, the subjects are supported by He has been diagnosed with non-valvular atrial fibrillation (AF) with a high risk of bleeding. In certain cases, The target group is those with a high bleeding risk, characterized by a CHA2DS2VASc risk score of ≥2. It has.

[0232] In other specific aspects of this specification, the risk of stroke or thromboembolism is prevented or reduced. This method is for patients suffering from atrial fibrillation (AF) and ESRD, and who undergo hemodialysis or other similar procedures. The target being analyzed is subjected to an anti-FXI / FXIa antibody as described herein, for example, sequence VH containing amino acid sequence number 29, VL containing amino acid sequence number 39, and It contains a heavy chain containing the amino acid sequence of SEQ ID NO: 31, or the amino acid sequence of SEQ ID NO: 41. The patient administers an effective amount of a pharmaceutical composition containing an anti-FXI / FXIa antibody containing a light chain containing columns. A method including a step is presented. In certain embodiments, the subject is suffering from non-valvular AF. More specifically, the subjects are those with confirmed, high-risk non-valvular heart disease. The subject suffers from sexual AF. In certain cases, the subject is at risk of CHA2DS2VASc ≥ 2. They have a high risk of bleeding, characterized by a sex score.

[0233] In specific embodiments of this specification, the risk of thromboembolism, such as stroke or systemic embolism, is A method of prevention, treatment, control, or reduction, which is directed to the target that requires it. Approximately 100 mg to 250 mg of anti-FXI / F specifically binds to the catalytic domain of XI. XIa antibodies (for example, VH containing the amino acid sequence of SEQ ID NO: 29 and amino acid sequence of SEQ ID NO: 39) It comprises a VL containing an acid sequence, or a heavy chain containing the amino acid sequence of SEQ ID NO: 31, or Anti-FXI / FXIa antibodies containing a light chain with the amino acid sequence of SEQ ID NO: 41 or those The procedure includes administering an antigen-binding fragment, wherein the subject has the following characteristics: (i) Targeting men or women who are ≥ 55 years old and < 85 years old; (ii) Body weight between 50 and 130 kg including the endpoint; (iii) Atrial fibrillation (AF) or atrial flutter recorded by electrocardiogram; (iv) CHA2DS2-VASc risk score ≥ 2 for male and female subjects ; (v) The CHA2DS2-VASc risk score for males is 1, and anticoagulation therapy is justified. Being; and (vi) Not receiving anticoagulant treatment, or more than 8 weeks prior to treatment, The patient is receiving stable treatment with a novel oral anticoagulant (NOAC) in sufficient quantities. A method is presented that includes one, two, more than, or all of the following: ru.

[0234] In certain cases, the risk of stroke and systemic embolism is moderate to high. Elephants have a CHA2DS2VASc hazard score of ≥2. In further specific embodiments, H Subjects with an AS BLED risk score of ≥3 are considered to have a high risk of bleeding. Marked (Gallego, et al., (2012) Carc Arrhythm Electrophysiol.; 5:312-318, See and Friberg et al., (2012) Circulation.; 125:2298-2307).

[0235] Stroke, systemic embolism, coronary thrombosis or peripheral artery thrombosis, venous thrombosis, and pulmonary embolism. The risks of thromboembolic events, including embolism, include a tendency to form thrombi, damage to the blood vessel wall, and congestion. The risk increases with the presence of predisposing factors, including medical history, familial precedents, and related factors. Assessment of comorbidities helps stratify patients according to their thromboembolic risk. In patients with AF, several rating systems are used, such as CHADS2 and C. HA2DS2-VASc is being developed to assess the risk of stroke. TEM is a randomized controlled trial, as well as clinical and etiological cohort studies, and a simplified version. And, easy-to-use and easy-to-remember devices, algorithms, calculators, or online tools. Data on stroke risk factors converted and weighted using multivariate formulas Developed based on the following: The CHADS2 risk score is a measure of thromboembolic risk in AF patients. It was used as a stratification tool to predict (LIP 2011; Camm et al 2012), but the accumulated data The evidence suggests that CHA2DS2-VASc is useful in identifying patients who develop stroke and thromboembolism. In this regard, the score is at least as good as, or even better than, the score of CHADS2, etc. In addition, this is better, and in the identification of patients with AF who are "truly low risk," it is definitively better. It indicates good results. The CHA2DS2-VASc score is currently used in the guidelines. This guides decisions regarding patients who should benefit from anticoagulation therapy, and also determines whether anticoagulation therapy is justified. It is also recommended for identifying low-risk patients (Camm et al. Eur Heart J (2020) 12) 33, 2719-2747; January et al, AHA / ACC / HRS Atrial Fibrillation Guideline; JA m Coll Cardiol 2014;64:2246-80).

[0236] A bleeding risk assessment tool specific to AF patients, e.g., HAS-BLED, ATRI A, HEMORR2HAGES, ORBIT, and ABC hazard scores are associated with AF. It was developed to predict the risk of bleeding in patients. Unfortunately, the risk of bleeding is related to stroke. Because it is closely correlated with the risk of internal effects, vitamin K esters such as warfarin or NOACS are used. The value of these risk scores, which guide therapeutic decisions to use tagonists, is limited. However, the bleeding risk score was used to reduce the risk of bleeding, and in some cases... For example, patients who benefit from anti-FXI / FXIa antibodies (e.g., the antibody NOV1401) This can be extremely useful in identifying individuals.

[0237] In certain aspects, subjects with confirmed high risk of bleeding are subject to bleeding, for example, during surgery. Bleeding or postoperative bleeding, or treated with anticoagulants (e.g., warfarin) In addition, a high risk of bleeding is underlying. The subjects of this study are known in vitro / ex vivo assays in the art, e.g. For example, it can be identified by an aPTT assay using the target plasma. Bleeding risk factors Other non-limiting examples include a history of stroke / TIA, a history of major bleeding, or clinically significant symptoms. The bleeding in question, stage 3 or 4 CKD (CrCl: 15-60 mL / min), for example, Treatment with dual antiplatelet therapy after ACS / PCI, and its association with hematoma-induced bruising. This includes a history of falls or other symptoms.

[0238] In specific embodiments, the object treated by the method presented herein is at least 18 He is 18 years old. In another embodiment, the subject treated by the method presented herein is at least He is also 50 years old. In another embodiment, the subject treated by the method presented herein is At least 55 years old. In another embodiment, the subject treated by the method presented herein he is at least 60 years old. In another embodiment, he is treated by the method presented herein. The target group is at least 65 years old.

[0239] In specific embodiments, the object treated by the method presented herein is 18 kg / m³ 2 The above body mass index (BMI) is present. In another embodiment, the method presented herein The target group for treatment is 30 kg / m 2 The BMI is as described above. In another embodiment, this specification The subjects treated by the method presented are 35 kg / m 2 The person has the above BMI. In some embodiments, the object treated by the method presented herein is 40 kg / m 2 The above B It has MI. In specific embodiments, the object treated by the method presented herein is H It is the target.

[0240] In specific embodiments, the methods presented herein have therapeutic benefits: (i) anticoagulation; (ii) (iii) Shortening of hospital stay; (iv) Prolongation of clotting time, for example, as determined by aPTT; (iv) (v) Reduction of the incidence or frequency of thrombosis; and (v) thromboembolic disorders (e.g., brain Stroke, systemic embolism, myocardial infarction, deep vein thrombosis, pulmonary embolism, cardiovascular death, emergency vascular reconstruction Relief of one or more symptoms related to the need for (or related to) thromboembolic disorders, or As a result, one or more of the following symptoms may be reduced in severity: To drip. In certain embodiments, the methods presented herein are determined, for example, by aPTT. The prolongation of clotting time is 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1 This results in an extension of 0.7x, 1.8x, 1.9x, or 2x.

[0241] In specific embodiments, this disclosure provides a combination of another therapeutic agent to subjects that require it. Combined with an effective amount of the anti-FXI / FXIa antibody described herein (e.g., NOV14) 01) By administering this drug, the risk of thromboembolic disorders can be treated, prevented, or managed. This presents methods to reduce the risk. Such combination therapies are effective for ischemic stroke (cardioembolic, thrombotic) ) or systemic embolism, AF, prevention of stroke in AF (SPAF), deep vein thrombosis , venous thromboembolism, pulmonary embolism, acute coronary syndrome (ACS), acute lower limb ischemia, chronic thrombosis It may be useful in treating thromboembolic disorders such as embolic pulmonary hypertension and systemic embolism. .

[0242] In certain embodiments, the anti-FXI / FXIa antibody described herein (e.g., NOV14) A non-limiting example of a therapeutic active agent suitable for use in combination with 01) is thromboxane. Inhibitors (e.g., aspirin), thienopyridine derivatives (e.g., clopidogrel and p Rasgrel) and non-thienopyridine derivatives (e.g., ticagrelor and cangrelor) Which adenosine diphosphate receptor antagonist (or P2Y12 inhibitor), pro Thease-activated receptor 1 (PAR1) antagonist (e.g., volapaxar and ) Topaxar, and proton pump inhibitors (PPIs) (e.g., omeprazoline) Lu, diazepam, phenytoin, lansoprazole, dexlansoprazole, rabeprazole Includes zole, pantoprazole, esomeprazole, and naproxen. Combination therapy The use of PPIs in treatment is appropriate for patients with a history of GI bleeding or prodromal symptoms of peptic ulcers. This may be suitable for patients with or with a history of GI disorder.

[0243] In specific embodiments of this specification, anti-FXI / FXIa antibodies presented herein (e.g., , anti-FXI / FXIa antibodies including VL CDR and VH CDR of NOV1401, etc. Bleeding in patients treated with or administered with antibodies (listed in Table 1) For example, a method for managing bleeding associated with trauma, surgery, menstruation, or postpartum, and anticoagulant Methods including reversal of solidification effects are presented. FXI deficiency is associated with spontaneous bleeding symptoms. It is rare, and in specific cases, bleeding is associated with trauma, surgery, menstruation, or postpartum. This is the most typical example. Prolonged bleeding occurs after major trauma, or in the oral mucosa, nasal mucosa, It can occur after surgery involving organs with areas of high fibrinolysis, such as the genital mucosa or urinary tract mucosa. Tooth extraction, tonsillectomy, and uterine or prostate ablation carry a high risk of bleeding. This is an example of surgery involving sexuality. Also, people with disabilities tend to develop nosebleeds and ecchymosis. The symptoms are severe, and although rare, they can also cause bleeding in the urine or intestines. FXI deficiency In patients with this condition, the frequency of spontaneous muscle or joint bleeding and intracranial hemorrhage is not increased. Pulse puncture is not typically associated with prolonged bleeding. Other gene mutations associated with FXI deficiency. This may contribute to heterogeneous and unexpected bleeding tendencies in patients with severe FXI deficiency. The combined use of platelet agents, other anticoagulants, and fibrinolytic agents may increase the risk of bleeding.

[0244] In certain embodiments of this specification, the anti-FXI / FXIa antibodies presented herein (for example) For example, an anti-FXI / FXIa antibody containing VL CDR and VH CDR of NOV1401 Patients treated with antibodies (listed in Table 1) (e.g., ESRD and / or A A method for managing bleeding in patients with F, wherein there is sufficient time to manage the bleeding. A method is presented that includes the reversal of the primary anticoagulant effect. In a specific embodiment, anti The step of reversing the coagulation effect is (i) colloid, crystalloid, human plasma, or albumin (ii) Replacement of body fluids using plasma proteins such as (ii) packed red blood cells or whole This includes blood transfusion. In certain embodiments, for example, in severe emergency cases, anticoagulation Therapeutic agents for reversing the effects of drugs include fresh frozen plasma (FFP) and prothrombin complex concentrate. The substance (PCC), and activated PCC (APCC); for example, factor VIII inhibitor - Bypass activity (FEIBA) and recombinant activated factor VII (rFVIIa) This includes, but is not limited to, blood components that promote hemostasis. In one embodiment, 30 μg Following administration of rFVIIa at a dose of / kg, every 6 hours for 5-7 days, In addition to g of tranexamic acid, take a dose of 15-30 μg / kg every 2-4 hours for 24 hours. A regimen including rFVIIa administration over 48 hours is used in patients undergoing major surgery as described herein. The presented anti-FXI / FXIa antibody (e.g., NOV1401 or NOV1401's V) Subjects treated with antibodies (including L CDR and VH CDR), and inaccessible bleeding. It may have the potential to restore hemostasis and stop bleeding in patients with ongoing bleeding in the affected area. For example, Riddelle et al. have shown that surgery is necessary for severe FXI deficiency without inhibitors. We reported on our experience with four patients who underwent this treatment (Riddell et al., 2011, Thromb. Ha emost.; 106: 521-527), the patient received 30 μg / kg of rFVIIa and 1 g of tranexamic acid. Samic acid was administered intravenously during anesthesia induction. Subsequently, 15-30 μg / kg of rFVI was administered. Bolus administration of Ia is performed using rotational thrombecometry. The medication was administered at 2-4 hour intervals, as indicated by the guidelines based on the (ROTEM) results. The patient was The above-mentioned dose of rFVIIa was administered over a period of 24-48 hours. 1 g was administered every 6 hours. Tranexamic acid was administered continuously for 5 days. In this small dose series, tranexamic acid The low dose of rFVIIa, 15-30 μg / kg, combined with this, was used in the severity of this study. It was safe and effective in correcting hemostatic abnormalities in FXI deficiency. Inhibitor (Typically acquired after transfusion or administration of blood products to patients with severe FXI deficiency) Four patients who underwent five surgeries and had severe FXI deficiency accompanied by autologous FXI neutralizing antibodies. In another study, the authors (Livnat et al., 2009, Thromb. Haemost.; 102: 487-492) The following protocol was applied: 1 g of oral tranexamic acid 2 hours before surgery. Next, immediately before the intervention, the patient was given another 1g of IV tranexamic acid. Recombinant FVIIa, administered at a dose in the range of 15-30 μg / kg, was injected upon completion of the surgery. He took it. After that, he took 1 g of oral tranexamic acid every 6 hours for at least 7 days. The procedure was performed. Fibrin adhesive was sprayed onto the excised gallbladder bed in one patient. Rotocol is used in patients with severe FXI deficiency accompanied by inhibitors to achieve normal hemostasis. We secured it.

[0245] In one embodiment, fibrin adhesive is used in dental treatment for patients with FXI deficiency. It can restore local hemostasis during surgery (Bolton-Maggs (2000) Haemophilia; 6 (S1): 100-9). With the anti-FXI / FXIa antibody presented herein (e.g., NOV1401) In certain embodiments of methods for managing bleeding in a patient being treated, fibrillation In association with the use of adhesives, tranexamic acid 1g every 6 hours for 5-7 days is used. The regimen includes patients undergoing minor surgery and those experiencing bleeding events in the oral and nasal cavities. It is used to establish local hemostasis in subjects where the bleeding site is accessible. ru.

[0246] In certain aspects of this specification, the anti-FXI antibody described herein (e.g., NOV14) Table 1 lists anti-FXI antibodies including HCDR and LCDR of 01 or NOV1401. Patients treated with or administered with the listed antibodies (e.g., ESRD) A method for managing bleeding or bleeding risk in patients with and / or AF. To patients who need it, anti-FXI antibodies, anti-idiotype antibodies or their antigenicity The procedure includes the step of administering a compatible fragment (e.g., Fab), and an anti-idiotype antibody or The antigen-binding fragment (e.g., Fab) specifically binds to the anti-FXI antibody, and the anti-FXI antibody A method is presented to block the binding of to FXI. In a specific embodiment, anti-idio Type antibodies or their antigen-binding fragments (e.g., Fab) are used, for example, during emergency major surgery. Or, in the event of trauma, the effect of the anti-FXI antibody described herein is reversed, reducing the risk of bleeding. To alleviate sexuality.

[0247] In specific embodiments, anti-idiotype antibodies or their antigen-binding fragments (e.g., Fab ) reverses or inhibits the anticoagulant effect of anti-FXI antibodies. In certain embodiments This involves using an anti-idiotype antibody or its antigen-binding fragment (e.g., Fab), which requires it. To administer to patients, the anti-FXI antibody described herein (e.g., NOV1401) is administered. Alternatively, anti-FXI antibodies containing HCDR and LCDR of NOV1401, as listed in Table 1. It temporarily reverses the anticoagulant effect of the antibody (which is currently present).

[0248] In certain aspects of this specification, such as NOV1401 (e.g., SEQ ID NOs. 31 and 41), In patients treated with or administered with anti-FXI antibodies, bleeding or hemorrhage A method for managing risks, and for patients who need it, NOV1401 (for example, Anti-FXI antibodies such as SEQ ID NOs. 31 and 41), anti-idiotype antibodies or their antigens The procedure includes the step of administering a binding fragment (e.g., Fab), and an anti-idiotype antibody or The antigen-binding fragment (e.g., Fab) is NOV1401 (e.g., SEQ ID NO. 31) It specifically binds to the antigen-binding region of anti-FXI antibodies such as (41), and the anti-FXI antibody, FX A method is presented for blocking coupling to I and / or FXIa. In a specific embodiment, This is an anti-FXI antibody such as NOV1401 (e.g., SEQ ID NOs. 31 and 41) Otyped antibodies or their antigen-binding fragments (e.g., Fab) are used with anti-FXI antibodies (e.g., It reverses or inhibits one or more of the anticoagulant effects of NOV1401. It harms. In certain embodiments, the anticoagulant effect of an anti-FXI antibody (e.g., NOV1401) One or more of the effects are temporarily reversed or inhibited. Specific Embodiments So, after transient reversal or inhibition of an anti-FXI antibody (e.g., NOV1401), The patient is given antibody I (e.g., NOV1401) again.

[0249] Anti-idiotype antibodies can be produced by a variety of methods already described. (See, for example, Pan et al., 1995, FASEB J. 9:43-49). Anti-idiotype anti The body is triggered by an antibody molecule (e.g., NOV1401), and within the antibody's binding site, It is directed towards the nearby antigenic determinant (idiotype). Anti-idiotype Antibodies recognize antigenic determinants that overlap with a portion of the binding site that contacts the original antigen, and induce anti- It can be imitated from the original.

[0250] Pharmaceutical composition This disclosure relates to the methods described herein (for example, stroke and / or systemic embolism) Formulated with a pharmaceutically acceptable carrier for use in methods that reduce risk. FXIa-binding antibodies (whole antibody or binding fragment), for example, those listed in Table 1. We present a pharmaceutical composition containing an anti-FXI / FXIa antibody. In addition, the composition may also be used for, for example, thromboembolism. One or more other therapeutic agents suitable for the treatment or prevention of thrombotic disorders (e.g., thrombotic disorders) It may also contain. Pharmaceutically acceptable carriers enhance or stabilize the composition. Alternatively, it can be used to facilitate the preparation of the composition. pharmaceutically acceptable The body is a physiologically compatible solvent, dispersion medium, coating, antimicrobial and antifungal agent, isotonic agent. and includes absorption retarders, etc.

[0251] The pharmaceutical compositions for use in this disclosure are administered by various methods known in the art. This is possible. The route and / or method of administration will vary depending on the desired outcome. Administration can be done intravenously (IV), intramuscularly (IM), or intraperitoneally (IP). It is preferable to administer the drug subcutaneously (sc) or in close proximity to the target site. Pharmacologically acceptable carriers include intravenous, intramuscular, subcutaneous, parenteral, and spinal administration. It shall be suitable for administration via the skin (e.g., by injection or infusion), depending on the route of administration. Therefore, active compounds, namely antibodies which are dispecific and polyspecific molecules, are activated by the compound. , coated with a material that protects the compound from the action of acids and other natural elements that can inactivate it. It is possible.

[0252] In certain embodiments, the anti-FXI / FXIa antibody described herein (e.g., NOV14) Antibodies containing LCDR and HCDR of 01, or NOV1401, as listed in Table 1. The antibody (containing) is placed in a fluid vial for subcutaneous injection, with approximately 75 mg per 1 mL to 1 mL equivalent. Formulated at a concentration of approximately 200 mg. In certain embodiments, the pharmaceutical composition is carried by a pharmaceutical carrier. or pharmaceutical excipients, for example, sucrose and polysorbate 20. Specific embodiments The pharmaceutical composition contains L-histidine and / or histidine HCl monohydrate. In certain embodiments, the pharmaceutical composition has a pH of about 4-7 or 5-6.

[0253] In certain embodiments, the anti-FXI / FXIa antibody described herein (e.g., NOV14) Antibodies containing LCDR and HCDR of 01, or NOV1401, as listed in Table 1. The antibody (which is present in the body) is prepared in a fluid vial for subcutaneous injection at a concentration of 150 mg per 1 mL. Formulation is performed. In one embodiment, a 150 mg / mL fluid formulation is prepared with a pH of 5.5 ± 0.5. The medication contains 150 mg of anti-FXI / FXIa antibody, L-histidine, and histidine HCl monohydrate. It contains sucrose and polysorbate 20. The composition is sterile and fluid. Assume it is a body. Appropriate fluidity can be achieved by using a coating such as lecithin. This allows for maintenance, and in the case of a dispersion, it maintains the required particle size and the boundary This can be maintained by using surfactants. In many cases, isotonic agents are included in the composition. For example, sugars, polyhydric alcohols such as mannitol or sorbitol, and sodium chloride It is preferable to include um. Long-term absorption of the injectable composition is possible if the composition contains substances that delay absorption. By incorporating a drug such as aluminum monostearate or gelatin It can bring about.

[0254] The pharmaceutical compositions for use in this disclosure are well known in the art and are routinely used. It can be prepared according to the established method. For example, Remington: The Science and Practice Ice of Pharmacy, Mack Publishing Co., 20th edition, 2000; and Sustained and Controlled Release Drug Delivery Systems, edited by J.R. Robinson, Marcel Dekker, Inc., New York; See 1978. Pharmaceutical compositions are preferably manufactured under GMP conditions. In the pharmaceutical composition, a therapeutically effective dose or therapeutically effective use of the FXIa-binding antibody Quantitatively, this involves utilizing the quantity. FXIa-binding antibodies are produced by conventional methods known to those skilled in the art. The drug is formulated into a more pharmaceutically acceptable dosage form. The administration regimen is designed to achieve the desired optimal response. For example, adjust to produce a therapeutic response. For example, administer a single bolus. It is also possible to administer multiple divided doses over a period of time, depending on the treatment situation. Depending on the circumstances, the dosage may be proportionally reduced or increased. It is possible. For ease of administration and uniformity of dosage, parenteral compositions are available in dosage unit form. Formulation is particularly advantageous. The dosage unit forms used herein refer to treatments. This refers to a physically individual unit that is suitable as a unit dose for the target being treated. Each unit is required A predetermined amount of active ingredients, calculated to produce the desired therapeutic effect in relation to the required drug carrier. It contains a sexual compound.

[0255] The actual dosage levels of the active ingredients in the pharmaceutical compositions disclosed herein are not toxic to patients. A certain amount of [unclear] effective to achieve the desired therapeutic response in a given patient, composition, and method of administration. It can be modified to obtain the active ingredient. The selected dosage level is determined by the book used. The specific compositions disclosed, their activity, route of administration, timing of administration, and the elimination of specific compounds used. Discharge rate, duration of treatment, other drugs used in combination with the specific composition being utilized, Compounds and / or materials, age, sex, weight, condition, and overall health of the patient being treated. It also depends on various pharmacokinetic factors, including factors such as medical history.

[0256] A physician administers the antibodies of this disclosure, used in a pharmaceutical composition, to achieve the desired therapeutic effect. Start at a level below the required level and gradually increase the dosage until the desired effect is achieved. It can be increased. Generally, thrombotic and / or thromboembolic as described herein The dosage of the composition of this disclosure that is effective in treating the disorder depends on the means of administration, the target site, and the patient's physiological response. This includes the medical condition, other medications being administered, and whether the treatment is preventive or therapeutic. The treatment dosage varies depending on many different factors. The treatment dosage is optimized for safety and efficacy. It is necessary to titrate in this manner. For systemic administration of antibodies, the dose is per kg of host body weight. The dosage ranges from approximately 0.01 to 15 mg. In antibody administration (e.g., subcutaneous administration), the dosage... This can range from 0.1 mg to 5 mg or from 1 mg to 600 mg. For example, in this specification The anti-FXI / FXIa antibodies described are 0.1 mg / kg, 0.2 mg / kg, and 0.3 mg / kg. mg / kg, 0.4mg / kg, 0.5mg / kg, 0.6mg / kg, 0.7mg / k g, 0.8mg / kg, 0.9mg / kg, 1.0mg / kg, 1.1mg / kg, 1. 2mg / kg, 1.3mg / kg, 1.4mg / kg, 1.5mg / kg, 1.6mg / kg, 1.7mg / kg, 1.8mg / kg, 1.9mg / kg, 2.0mg / kg, 2 .1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3.0mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4m g / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg , 3.9mg / kg, 4.0mg / kg, 4.1mg / kg, 4.2mg / kg, 4.3 mg / kg, 4.4mg / kg, 4.5mg / kg, 4.6mg / kg, 4.7mg / k Administer in doses of g, 4.8 mg / kg, 4.9 mg / kg, or 5.0 mg / kg. This can be done. An example treatment regimen is once every two weeks, or once a month, or 3-6 times. This involves systemic administration once every month. An exemplary treatment regimen is once a week, then once every two weeks. , once every three weeks, once a month, or once every three to six months, or as needed ( This involves systemic administration of PRN.

[0257] In certain embodiments, anti-FXI / FXIa antibodies described herein (e.g., NO Antibodies containing VL CDR and VH CDR of V1401, or NOV1401, The antibodies listed in Table 1 are administered, for example, via IV or SC, at a dose of 3 mg / kg. Administer in the specified dose. Specifically, such anti-FXI / FXIa antibodies are administered once a week. It is administered every other week, every three weeks, or every four weeks (or once a month).

[0258] In certain embodiments, anti-FXI / FXIa antibodies described herein (e.g., NO Antibodies containing VL CDR and VH CDR of V1401, or NOV1401, The antibodies listed in Table 1 are administered, for example, via IV or SC, at a dose of 10 mg / kJ. Administer in a dose of g. Specifically, such anti-FXI / FXIa antibodies are administered weekly. Administer once every two weeks, once every three weeks, or once every four weeks (or once a month). .

[0259] In certain embodiments, anti-FXI / FXIa antibodies described herein (e.g., NO Antibodies containing VL CDR and VH CDR of V1401, or NOV1401, The antibodies listed in Table 1 are administered, for example, via IV or SC, at a dose of 30 mg / kJ. Administer in a dose of g. Specifically, such anti-FXI / FXIa antibodies are administered weekly. Administer once every two weeks, once every three weeks, or once every four weeks (or once a month). .

[0260] In certain embodiments, anti-FXI / FXIa antibodies described herein (e.g., NO Antibodies containing VL CDR and VH CDR of V1401, or NOV1401, The antibodies listed in Table 1 are administered, for example, via IV or SC, at a dose of 50 mg / kJ. Administer in a dose of g. Specifically, such anti-FXI / FXIa antibodies are administered weekly. Administer once every two weeks, once every three weeks, or once every four weeks (or once a month). .

[0261] In certain embodiments, anti-FXI / FXIa antibodies described herein (e.g., NO Antibodies containing VL CDR and VH CDR of V1401, or NOV1401, The antibodies listed in Table 1 are administered, for example, via IV or SC, at a dose of 100 mg / Administer in a dose of kg. Specifically, such anti-FXI / FXIa antibodies are administered weekly. Administer once, every other week, every three weeks, or every four weeks (or once a month). ru.

[0262] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDR are administered via, for example, the IV or SC pathway, at a dose of 5 mg. Administer in doses in the range of 600 mg. In certain embodiments, the method presented herein. (For example, preventing, treating, or managing the risk of thromboembolism such as stroke or systemic embolism) For use in methods for treating or reducing the anti-FXI described herein / FXIa antibody (e.g., NOV1401, or other antibodies listed in Table 1, or NO Antibodies containing V1401 VL CDR and VH CDR, for example, via the IV pathway Alternatively, via the SC route, a dose in the range of 100 mg to 200 mg, for example, once a week. Administer every other week, every three weeks, or every four weeks (or once a month).

[0263] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are administered via, for example, the IV pathway or the SC pathway. Approximately 5 mg, 10mg, 15mg, 20mg, 30mg, 40mg, 50mg, 60mg, 90 mg, 100mg, 120mg, 150mg, 180mg, 200mg, 210mg, 2 40mg, 250mg, 270mg, 300mg, 330mg, 350mg, 360mg , 390mg, 400mg, 420mg, 450mg, 480mg, 500mg, 510 Administer in doses of mg, 540 mg, 550 mg, 570 mg, or 600 mg. In a typical scenario, such anti-FXI / FXIa antibodies are administered once a week, once every two weeks, or every three weeks. It is administered once, or once every four weeks (or once a month). In certain embodiments, Una anti-FXI / FXIa antibody, once every two weeks, once every three weeks, or once every four weeks (Or once a month) Administer.

[0264] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are used in patients who require them (e.g., those with atrial fibrillation and / or other conditions). For patients with ESRD, for example, administer a dose of 5 mg via the sc pathway. In specific cases, such anti-FXI / FXIa antibodies are administered once a week, once every two weeks, or for three weeks. It is administered once every two weeks, or once every four weeks (or once a month). In certain embodiments, These anti-FXI / FXIa antibodies are administered every other week, every three weeks, or every four weeks. It is administered once a day (or once a month).

[0265] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are used in patients who require them (e.g., those with atrial fibrillation and / or other conditions). For patients with ESRD, for example, administer a dose of 15 mg via the sc pathway. In specific cases, such anti-FXI / FXIa antibodies are administered once a week, once every two weeks, and 3 times. It is administered once a week, or once every four weeks (or once a month). In certain forms Such anti-FXI / FXIa antibodies are administered every other week, every three weeks, or every four weeks. It is administered once every two weeks (or once a month).

[0266] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are used in patients who require them (e.g., those with atrial fibrillation and / or other conditions). For patients with ESRD, for example, administer a dose of 50 mg via the sc pathway. In specific cases, such anti-FXI / FXIa antibodies are administered once a week, once every two weeks, and 3 times. It is administered once a week, or once every four weeks (or once a month). In certain forms Such anti-FXI / FXIa antibodies are administered every other week, every three weeks, or every four weeks. It is administered once every two weeks (or once a month).

[0267] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are used in patients who require them (e.g., those with atrial fibrillation and / or other conditions). For example, administer a dose of 120 mg via the sc pathway to patients (or those with ESRD). In specific cases, such anti-FXI / FXIa antibodies are administered once a week, once every two weeks, Administer once every three weeks, or once every four weeks (or once a month) in a specific manner. This involves administering such anti-FXI / FXIa antibodies every other week, every three weeks, or for four weeks. Administer once per session (or once per month).

[0268] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are used in patients who require them (e.g., those with atrial fibrillation and / or other conditions). For example, administer a dose of 150 mg via the sc pathway to patients (or those with ESRD). In specific cases, such anti-FXI / FXIa antibodies are administered once a week, once every two weeks, Administer once every three weeks, or once every four weeks (or once a month) in a specific manner. This involves administering such anti-FXI / FXIa antibodies every other week, every three weeks, or for four weeks. Administer once per session (or once per month).

[0269] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are used in patients who require them (e.g., those with atrial fibrillation and / or other conditions). For example, administer a dose of 180 mg via the sc pathway to patients (or those with ESRD). In specific cases, such anti-FXI / FXIa antibodies are administered once a week, once every two weeks, Administer once every three weeks, or once every four weeks (or once a month) in a specific manner. This involves administering such anti-FXI / FXIa antibodies every other week, every three weeks, or for four weeks. Administer once per session (or once per month).

[0270] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are used in patients who require them (e.g., those with atrial fibrillation and / or other conditions). For example, administer a dose of 210 mg via the sc pathway to patients (or those with ESRD). In specific cases, such anti-FXI / FXIa antibodies are administered once a week, once every two weeks, Administer once every three weeks, or once every four weeks (or once a month) in a specific manner. This involves administering such anti-FXI / FXIa antibodies every other week, every three weeks, or for four weeks. Administer once per session (or once per month).

[0271] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are used in patients who require them (e.g., those with atrial fibrillation and / or other conditions). For example, administer a dose of 300 mg via the sc pathway to patients (or those with ESRD). In specific cases, such anti-FXI / FXIa antibodies are administered once a week, once every two weeks, Administer once every three weeks, or once every four weeks (or once a month) in a specific manner. This involves administering such anti-FXI / FXIa antibodies every other week, every three weeks, or for four weeks. Administer once per session (or once per month).

[0272] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are used in patients who require them (e.g., those with atrial fibrillation and / or other conditions). For example, administer a dose of 600 mg via the sc pathway to patients (or those with ESRD). In specific cases, such anti-FXI / FXIa antibodies are administered once a week, once every two weeks, Administer once every three weeks, or once every four weeks (or once a month) in a specific manner. This involves administering such anti-FXI / FXIa antibodies every other week, every three weeks, or for four weeks. Administer once per session (or once per month).

[0273] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are used in patients who require them (e.g., those with atrial fibrillation and / or other conditions). (or to subjects with ESRD), for example, via the sc pathway, 5 mg or more Administer in the appropriate dose. Specifically, such anti-FXI / FXIa antibodies are administered once a week. It is administered every other week, every three weeks, or every four weeks (or once a month). In certain embodiments, such anti-FXI / FXIa antibodies are administered every other week, or once every three weeks. Alternatively, administer once every four weeks (or once a month).

[0274] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are used in patients who require them (e.g., those with atrial fibrillation and / or other conditions). (or patients with ESRD), for example, via the sc pathway, 15 mg or more Administer in a dose that is appropriate. Specifically, such anti-FXI / FXIa antibodies are administered weekly. Administer once every two weeks, once every three weeks, or once every four weeks (or once a month). In certain embodiments, such anti-FXI / FXIa antibodies are administered every other week, or once every three weeks. , or once every four weeks (or once a month).

[0275] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are used in patients who require them (e.g., those with atrial fibrillation and / or other conditions). For example, via the sc pathway, 50 mg or more (or to subjects with ESRD) Administer in a dose that is appropriate. Specifically, such anti-FXI / FXIa antibodies are administered weekly. Administer once every two weeks, once every three weeks, or once every four weeks (or once a month). In certain embodiments, such anti-FXI / FXIa antibodies are administered every other week, or once every three weeks. , or once every four weeks (or once a month).

[0276] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are used in patients who require them (e.g., those with atrial fibrillation and / or other conditions). For example, to subjects with ESRD, via the sc pathway, 120 mg or this Administer in doses exceeding the recommended dose. Specifically, such anti-FXI / FXIa antibodies are administered weekly. Administer once, every other week, every three weeks, or every four weeks (or once a month). In certain embodiments, such anti-FXI / FXIa antibodies are administered every other week, every three weeks. Administer once, or once every four weeks (or once a month).

[0277] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are used in patients who require them (e.g., those with atrial fibrillation and / or other conditions). For example, to subjects with ESRD, via the sc pathway, 150 mg or this Administer in doses exceeding the recommended dose. Specifically, such anti-FXI / FXIa antibodies are administered weekly. Administer once, every other week, every three weeks, or every four weeks (or once a month). In certain embodiments, such anti-FXI / FXIa antibodies are administered every other week, every three weeks. Administer once, or once every four weeks (or once a month).

[0278] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are used in patients who require them (e.g., those with atrial fibrillation and / or other conditions). For example, to subjects with ESRD, via the sc pathway, 180 mg or this Administer in doses exceeding the recommended dose. Specifically, such anti-FXI / FXIa antibodies are administered weekly. Administer once, every other week, every three weeks, or every four weeks (or once a month). In certain embodiments, such anti-FXI / FXIa antibodies are administered every other week, every three weeks. Administer once, or once every four weeks (or once a month).

[0279] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are used in patients who require them (e.g., those with atrial fibrillation and / or other conditions). For example, to subjects with ESRD, via the sc pathway, 210 mg or this Administer in doses exceeding the recommended dose. Specifically, such anti-FXI / FXIa antibodies are administered weekly. Administer once, every other week, every three weeks, or every four weeks (or once a month). In certain embodiments, such anti-FXI / FXIa antibodies are administered every other week, every three weeks. Administer once, or once every four weeks (or once a month).

[0280] In certain embodiments, the methods presented herein (e.g., stroke or systemic embolism) (Methods to prevent, treat, manage, or reduce the risk of thromboembolism, such as in certain diseases.) For use in the specified context, an anti-FXI / FXIa antibody (e.g., NOV1) described herein is appropriate. Antibodies listed in Table 1, such as 401, or VL CDR and V Antibodies containing H CDRs are used in patients who require them (e.g., those with atrial fibrillation and / or other conditions). For example, to subjects with ESRD, 300 mg or this via the sc pathway. Administer in doses exceeding the recommended dose. Specifically, such anti-FXI / FXIa antibodies are administered weekly. Administer once, every other week, every three weeks, or every four weeks (or once a month). In certain embodiments, such anti-FXI / FXIa antibodies are administered every other week, every three weeks. Administer once, or once every four weeks (or once a month).

[0281] In certain embodiments, anti-FXI / FXIa antibodies described herein (e.g., NO Antibodies containing VL CDR and VH CDR of V1401, or NOV1401, The antibodies listed in Table 1 can be administered via, for example, the IV pathway or the SC pathway to aP The average duration of TT was extended by more than double, to 30 days, 35 days, 36 days, and 37 days. 38 days, 39 days, 40 days, 41 days, 42 days, 43 days, 44 days, 45 days, Alternatively, administer a dose sufficient to achieve the desired result over a period not exceeding 50 days.

[0282] In certain embodiments, anti-FXI / FXIa antibodies described herein (e.g., NO Antibodies containing VL CDR and VH CDR of V1401, or NOV1401, The antibodies listed in Table 1 can be administered via, for example, the IV pathway or the SC pathway to aP Achieved an extension of more than double the average duration of TT, over a period not exceeding 42 days. Administer a dose sufficient to achieve this.

[0283] In certain embodiments, the antibody NOV1401 (for example, the amino acid of SEQ ID NO. 31) is used. An antibody comprising a heavy chain containing the sequence and a light chain containing the amino acid sequence of SEQ ID NO 41, or NO A pharmaceutical composition comprising V1401 and a pharmaceutically acceptable carrier is used for ESRD, such as in hemodialysis. Prevention of the risk of thromboembolism, such as stroke or systemic embolism, associated with treatment for this purpose. For use in treatment, management, or reduction, in which case the antibody is It is administered subcutaneously in doses ranging from 100 mg to 300 mg.

[0284] In a specific embodiment, the antibody NOV1401 (for example, the amino acid sequence of SEQ ID NO. 31) An antibody comprising a heavy chain containing and a light chain containing the amino acid sequence of SEQ ID NO: 41, or NOV1 A pharmaceutical composition comprising 401 and a pharmaceutically acceptable carrier is used in the subject of hemodialysis, etc. , the risk of thromboembolism, such as stroke or systemic embolism, associated with treatment for ESRD. For use in the prevention, treatment, or management or reduction of sexuality, in this case The antibodies are available in doses of approximately 100 mg, 120 mg, 150 mg, 180 mg, 210 mg, or 2 mg. The drug is administered subcutaneously once a month at a dose of 40 mg. Specifically, the target population includes AF and I have ESRD.

[0285] In certain embodiments, the antibody NOV1401 (for example, the amino acid of SEQ ID NO. 31) is used. An antibody comprising a heavy chain containing the sequence and a light chain containing the amino acid sequence of SEQ ID NO 41, or NO A pharmaceutical composition comprising V1401 or its antigen-binding fragments and a pharmaceutically acceptable carrier. The substance is used in subjects suffering from atrial fibrillation, such as non-valvular atrial fibrillation, to treat stroke or systemic embolism. For use in the prevention, treatment, management, or reduction of any risk of thromboembolism In this case, the antibody is administered once a month in a dose ranging from 100 mg to 300 mg, applied to the skin. It is administered as follows. In specific cases, the target is, for example, CHA2DS2VASc risk ≥ 2. The patient has non-valvular AF with a high risk of bleeding, as determined by the score. In this case, the subjects are 55 years of age or older.

[0286] In a specific embodiment, the antibody NOV1401 (for example, the amino acid sequence of SEQ ID NO. 31) An antibody comprising a heavy chain containing and a light chain containing the amino acid sequence of SEQ ID NO: 41, or NOV1 A pharmaceutical composition comprising 401 or its antigen-binding fragment and a pharmaceutically acceptable carrier is non In patients suffering from AF, such as valvular AF, thrombosis such as stroke or systemic embolism For use in the prevention, treatment, management, or reduction of the risk of embolism. In this case, the antibody doses are approximately 100mg, 120mg, 150mg, 180mg, and 210mg. It is administered subcutaneously once a month in doses of g, 240 mg, or 300 mg. Specific details So, the target is determined, for example, by a CHA2DS2VASc risk score of ≥2. The patient has non-valvular AF with a high risk of bleeding, and in this case, the patient is 55 years old. Or older. In specific cases, such anti-FXI / FXIa antibodies, Weekly, bi-weekly, every three weeks, or every four weeks (or monthly) In certain embodiments, such anti-FXI / FXIa antibodies are administered every other week, every three weeks. It is administered once, or once every four weeks (or once a month). In specific cases, this Anti-FXI / FXIa antibodies such as 100mg, 110mg, 120mg, 130mg , or 140 mg, administered once a week or once every two weeks. In specific cases, Anti-FXI / FXIa antibodies like the following are available in doses of approximately 140 mg, 150 mg, 160 mg, and 170 mg. g, or 180 mg dose, once every 3 weeks or once every 4 weeks (or monthly). Administer once. In certain embodiments, such anti-FXI / FXIa antibodies are administered in doses of 150 mg. Alternatively, a dose of 180 mg is administered once every 3 weeks or once every 4 weeks (or once a month). Administer.

[0287] In a specific embodiment, the antibody NOV1401 (for example, the amino acid sequence of SEQ ID NO. 31) An antibody comprising a heavy chain containing and a light chain containing the amino acid sequence of SEQ ID NO: 41, or NOV1 A pharmaceutical composition comprising 401 or its antigen-binding fragment and a pharmaceutically acceptable carrier is non In patients suffering from AF, such as valvular AF, thrombosis such as stroke or systemic embolism For use in the prevention, treatment, management, or reduction of the risk of embolism. In this case, the antibody is administered once a month in doses of 120 mg, 150 mg, or 180 mg. It is administered subcutaneously. In specific cases, the target is, for example, CHA2DS2VASc with a dose of ≥2. Non-valvular AF with a high risk of bleeding, as determined by the risk score. Yes, and in this case, the subject is 55 years of age or older.

[0288] Antibodies are typically administered multiple times. The interval between single doses can be weekly, bi-weekly, monthly, or daily. It can be years. The interval also depends on the patient's FXI-binding antibodies and / or FXIa binding. As indicated by measuring the blood levels of compatible antibodies, this can also be irregular. In addition, a doctor may determine an alternative dosing interval, such as monthly or as needed for effective administration. Administer at intervals of 1 to 1. In some methods of systemic administration, the dose is equal to the plasma concentration of the antibody. Adjust to achieve 000 μg / mL or 1-1200 μg / mL, and for several people The method involves adjusting the concentration to achieve 25-500 μg / mL. Alternatively, the antibody is sustained-release. It can also be administered as a compound, in which case low-frequency administration is required. Dosage and The frequency varies depending on the half-life of the antibody and its target in the patient. Generally, in humans Humanized antibodies have a half-life in humans that is longer than that of chimeric antibodies and non-human antibodies. The dosage and frequency of administration vary depending on whether the treatment is preventive or therapeutic. Yes, it is possible. For prophylactic use, relatively low doses are administered over a long period at relatively infrequent intervals. In some cases, the treatment will continue for the rest of the lives of some patients. This means that relatively high doses are required at relatively short intervals until the progression of the disease is reduced or terminated. It is requested, preferably, until the patient shows partial or complete improvement in the symptoms of the disease. Subsequently, the patient can be administered a prophylactic regimen. [Examples]

[0289] The following embodiments are provided to further illustrate the present disclosure and do not limit its scope. This is not presented for the purpose of determination. Other variations of this disclosure will be readily apparent to those skilled in the art. This would likely be the case, and is also covered by the attached claims.

[0290] [Example 1] Combined data Surface plasmon resonance (SPR) analysis of FXI catalytic domains SPR measurement is performed using BIACORE, a surface plasmon resonance-based optical biosensor. (Trademark) T200 (BIACORE (Trademark), GE Healthcare, Uppsa The procedure was carried out on la). Series S sensor chip (CM5), immobilization kit, and The regeneration buffer was purchased from GE Healthcare (Uppsala). IgG Alternatively, depending on the ligand format of Fab, two different assay setups can be implemented. The procedure was performed. First, N-hydroxysuccinimide (NHS) and N-(3-dimethylami The surface is activated by (nopropyl)-N-ethylcarbodiimide hydrochloride (EDC). It was converted using the standard amine coupling method (GE Healthcare, Uppsal). a) By using the activated dextran matrix on the CM5 chip, NOV1401-Fab It was covalently attached to the custard. A capture assay was performed on NOV1401-IgG. Then, the goat anti-human IgG-Fc antibody (JIR) was immobilized on the chip at 14,000 RU. The remaining active surface groups were inactivated with ethanolamine (EA). The ligand was immobilized. Prepare reference cells that have not been treated, and set the system in 1x concentration HBS-EP+ buffer (10mM). HEPES, 150 mM NaCl, 3 mM EDTA, 0.05% P2O, pH 7 .4; Equilibrium was achieved using Teknova H8022.

[0291] All binding experiments were performed using HBS-EP+ buffer at 25°C and a flow rate of 50 μL / min. The assay was performed. For the capture assay, NOV1401-IgG was subjected to a RU level of 80. Captured until the end. For reaction rate studies, in the range of 0-200 nM in HBS-EP+ buffer. A dilution series of the FXI catalytic domain was used at the following concentrations. The association time was 120 seconds. The dissociation time was 180 seconds. The surface was treated with a single injection of 10 mM glycine, pH 1.5. The data was regenerated by (a contact time of 60 seconds and a stabilization time of 120 seconds). Processing and k on , k off , and K D The decision is based on T200 BiaEvaluation. Achieved with software version 1.0. Dual criteria (reference injection and blank injection) The bulk effects and other systematic artifacts were corrected by applying the deduction of 1. :1-coupled model (R max By applying the settings (which are set globally), the sensor graph I applied the character "mu".

[0292] Equilibrium titration (SET) in solution for FXI and FXIa 22 1.6x antigen dilution series (serial 1.6 n dilution) were prepared using sample buffer (0.5% Prepared in PBS (pH 7.4) containing BSA and 0.02% Tween 20. Furthermore, for NOV1401-Fab(huFXI) at a certain concentration, it is set to 200 pM, and hu For FXIa, it was set to 500 pM) or NOV1401 antibody (huFXI and For huFXIa, 10 pM was added to each antigen concentration. Antigen Dilution Series The starting concentrations are 100 nM for huFXIa and 20 nM (Fab assay) or 1nM (Ig...

Claims

1. A pharmaceutical composition for preventing, treating, managing, or reducing the risk of thromboembolic disease in a subject suffering from end-stage renal disease (ESRD), The aforementioned pharmaceutical composition (a) Heavy chain variable region CDR1 of sequence number 23; heavy chain variable region CDR2 of sequence number 24; heavy chain variable region CDR3 of sequence number 25; light chain variable region CDR1 of sequence number 33; light chain variable region CDR2 of sequence number 34; and light chain variable region CDR3 of sequence number 35; (b) Heavy chain variable region CDR1 of sequence number 26; heavy chain variable region CDR2 of sequence number 27; heavy chain variable region CDR3 of sequence number 28; light chain variable region CDR1 of sequence number 36; light chain variable region CDR2 of sequence number 37; and light chain variable region CDR3 of sequence number 38; (c) 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; light chain variable region CDR2 of sequence number 37; and light chain variable region CDR3 of sequence number 15; or (d) Heavy chain variable region CDR1 of sequence number 46; heavy chain variable region CDR2 of sequence number 4; heavy chain variable region CDR3 of sequence number 5; light chain variable region CDR1 of sequence number 33; light chain variable region CDR2 of sequence number 14; and light chain variable region CDR3 of sequence number 15 A compound comprising an anti-factor XI (FXI) and / or activated factor XI (FXIa) antibody or its antigen-binding fragment, The antibody or its antigen-binding fragment is administered to the subject. The aforementioned pharmaceutical composition.

2. The anti-FXI and / or FXIa antibody or its antigen-binding fragment (a) the heavy chain variable region (VH) of the sequence of Sequence ID No. 29, or an amino acid sequence having at least 90% identity thereto; and the light chain variable region (VL) of Sequence ID No. 39, or an amino acid sequence having at least 90% identity thereto; or (b) The heavy chain variable region (VH) of the sequence of Sequence ID No. 9, or an amino acid sequence having at least 90% identity thereto; and the light chain variable region (VL) of Sequence ID No. 19, or an amino acid sequence having at least 90% identity thereto A pharmaceutical composition according to claim 1, comprising:

3. The anti-FXI and / or FXIa antibody or its antigen-binding fragment (a) VH of the sequence of sequence number 29 and VL of the sequence of sequence number 39; or (b) VH of the sequence of sequence number 9 and VL of the sequence of sequence number 19 A pharmaceutical composition according to claim 1, comprising:

4. The pharmaceutical composition according to claim 1, wherein the anti-FXI and / or FXIa antibody or its antigen-binding fragment comprises the heavy chain of the sequence of SEQ ID NO: 31, or an amino acid sequence having at least 90% identity thereto, and the light chain of the sequence of SEQ ID NO: 41, or an amino acid sequence having at least 90% identity thereto.

5. The pharmaceutical composition according to claim 1, wherein the anti-FXI and / or FXIa antibody or its antigen-binding fragment comprises a heavy chain of the sequence of SEQ ID NO: 31 and a light chain of the sequence of SEQ ID NO:

41.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the subject is undergoing dialysis.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the subject is undergoing hemodialysis or other types of dialysis.

8. The pharmaceutical composition according to claim 7, wherein the other type of dialysis includes peritoneal dialysis.

9. The pharmaceutical composition according to any one of claims 1 to 5, wherein the thromboembolic disease includes thromboembolic stroke.

10. The pharmaceutical composition according to any one of claims 1 to 5, wherein the thromboembolic disease includes atrial fibrillation.

11. The pharmaceutical composition according to claim 10, wherein the atrial fibrillation includes non-valvular atrial fibrillation.

12. The pharmaceutical composition according to any one of claims 1 to 5, wherein the thromboembolic disease includes catheter-related thrombosis, and the subject is a subject who has started hemodialysis after insertion of a tunnel-type catheter.

13. The pharmaceutical composition according to any one of claims 1 to 5, wherein the thromboembolic disease includes systemic embolism.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the subject has a substantiated high risk of bleeding.

15. The pharmaceutical composition according to any one of claims 1 to 5, wherein the thromboembolic disease includes atrial fibrillation, and the subject has a supported high risk of bleeding, characterized by a CHA2DS2VASc risk score of ≥2.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the subject is at least 55 years old.

17. The subject has a CHA2DS2VASc risk score of ≥2, and / or the following risk factors: (a) Being over 65 years of age; (b) A history of stroke or transient ischemic attack; (c) A history of major bleeding or clinically significant bleeding; (d) The patient has stage 3 or 4 of chronic kidney disease (CKD); (e) Treatment with monotherapy or dual antiplatelet therapy; and (f) History of falls or other symptoms associated with bruising due to hematoma The pharmaceutical composition according to claim 16, characterized by one, two or more of the following risk factors, which is supported by a high risk of bleeding.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the antibody or its antigen-binding fragment is administered subcutaneously to the subject.

19. The pharmaceutical composition according to any one of claims 1 to 17, wherein the antibody or its antigen-binding fragment is administered intravenously to the subject.

20. The pharmaceutical composition according to any one of claims 1 to 19, wherein the antibody or its antigen-binding fragment is administered to the subject in a dose of at least 90 mg, 120 mg, 150 mg, 180 mg, or 210 mg.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein the antibody or its antigen-binding fragment is administered to the subject once a month.

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