Anti-FXI / FXIa antibodies, their antigen-binding fragments, and pharmaceutical uses

Abstract

The present invention provides anti-FXI / FXIa antibodies, antigen-binding fragments thereof and pharmaceutical uses, pharmaceutical compositions containing anti-FXI / FXIa antibodies or antigen-binding fragments thereof, and methods for treating and preventing diseases, particularly methods for treating thrombus formation or thromboembolism-related diseases or conditions.

Description

[Technical Field]

[0001] This application claims priority from Chinese Patent Application No. 202010633951.8, filed on July 2, 2020.

[0002] The present application relates to anti-FXI / FXIa antibodies, antigen-binding fragments thereof, pharmaceutical compositions containing the anti-FXI / FXIa antibodies and antigen-binding fragments thereof, and their medical uses for treating or preventing thrombosis-related diseases. [Background technology]

[0003] In recent years, with the global aging population and changing lifestyles, thromboembolic diseases have become one of the diseases with the highest mortality and disability rates worldwide. Unwanted bleeding events caused by conventional antithrombotic / anticoagulant drugs remain a major problem (Katherine et al., 2015, West J Emerg Med;16(1): 11-17).

[0004] Previous animal studies and clinical data have demonstrated that inhibiting the intrinsic pathway, particularly the blood clotting factor FXI, can reduce thrombus formation and prevent significant bleeding events (Felicitas Mueller et al, Curr Opin Hematol. 2011 Sep;18(5): 349-355).

[0005] FXI is a key blood coagulation factor in the intrinsic pathway. FXIa, the activated form of FXI, can be activated by the intrinsic blood coagulation factor FXIIa to form FXIa in the blood coagulation cascade. It can also be activated by thrombin II to amplify the blood coagulation cascade, forming more thrombin and fibrin. This process can lead to the formation of excessive thrombin and fibrin, potentially causing thrombotic disorders. The mild bleeding phenotype of human patients with FXI deficiency (hemophilia C) suggests that FXI inhibition reduces the risk of bleeding. Further studies have shown that patients with FXI deficiency have significantly lower rates of ischemic stroke and deep vein thrombosis, suggesting that FXI inhibition is beneficial in reducing the risk of ischemic stroke and deep vein thrombosis.

[0006] The FXI gene, located on human chromosome 4, encodes a secreted protein of 607 amino acids. The FXI protein molecule contains four apple domains and one catalytic domain. FXI exists in a homodimeric form in human blood, and the concentration of FXI circulating in human plasma in a noncovalent complex with HK is approximately 30 nM (15-45 nM). Human FXI molecules share 88%, 67%, and 58% homology with monkey and mouse FXI molecules, respectively (two species, three homology data).

[0007] There is already a large body of literature and clinical evidence demonstrating that inhibiting the activity of FXI and its transformed form, FXIa, can effectively reduce thrombus formation without causing the observed bleeding risk. Currently disclosed clinical results show that, compared with conventional oral anticoagulants (NOACs), anti-FXI / FXIa antibodies have similar or better antithrombotic effects, with a lower bleeding risk, allowing patients to receive safer treatment.

[0008] There remains a need in the pharmaceutical field to provide anti-FXI / FXIa antibody drugs that are less immunogenic and effectively inhibit thrombus formation without increasing the risk of bleeding, so that antithrombotic treatments can be made safer. Summary of the Invention

[0009] The present disclosure provides anti-FXI / FXIa antibodies or antigen-binding fragments thereof, their encoding nucleic acids, vectors, host cells, pharmaceutical compositions, methods of using them to treat or delay thrombus formation or thromboembolic-related diseases or conditions or complications thereof, and detection uses thereof.

[0010] In one embodiment, the anti-FXI / FXIa antibody or antigen-binding fragment thereof is a heavy chain HCDR1 comprising the sequence represented by X1X2X3MH (SEQ ID NO: 63), wherein X1 is selected from E, S, G, or D, X2 is selected from L, I, V, or D, and X3 is selected from S, F, L, or Y; and / or X4X5DPX6X7GX8TX9YAX 10 X4 is selected from G or W, X5 is selected from F or I, X6 is selected from E or Q, X7 is selected from D or N, X8 is selected from E or D, X9 is selected from I, R, V or E, and X 10 a heavy chain HCDR2 selected from Q or S, and / or a heavy chain HCDR3 comprising the sequence set forth in DPHRTWWRYFDWLYPRGMDV (SEQ ID NO: 9) or GNFYYFDY (SEQ ID NO: 39), and / or a light chain LCDR1 comprising the sequence RASQTVGKNYLA (SEQ ID NO: 10) or SASSSINYMH (SEQ ID NO: 40), and / or X 11 X 12 SX 13 X 14 AX 15 (SEQ ID NO: 65), wherein X 11 is selected from G, E or D, and X 12 is selected from A or T, and X 13 is selected from N, V ​​or K, and X14 is selected from R or L, and X 15 a light chain LCDR2 selected from T, L or S, and / or X 17 QX 18 X 19 X 20 X 21 PX 22 T (SEQ ID NO: 66), 17 is selected from Q or H, and X 18 is selected from F or R, and X 19 is selected from R or S, and X 20 is selected from S or F, and X 21 is selected from Y or S, and X 22 a light chain LCDR3 selected from Y or L; Includes.

[0011] In some embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof is A heavy chain HCDR1 comprising a sequence set forth in one of SEQ ID NOs: 7, 22, 24, 26, 28, and 37; a heavy chain HCDR2 comprising a sequence set forth in one of SEQ ID NOs: 8, 23, 25, 27, and 38; A heavy chain HCDR3 comprising a sequence set forth in one of SEQ ID NOs: 9 and 39; A light chain LCDR1 comprising a sequence shown in one of SEQ ID NOs: 10 and 40; a light chain LCDR2 comprising a sequence set forth in one of SEQ ID NOs: 11, 29, and 41; A light chain LCDR3 comprising a sequence shown in one of SEQ ID NOs: 12 and 42; Includes.

[0012] In some embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof is (a) heavy chain HCDR1, HCDR2, and HCDR3 comprising the sequences shown in SEQ ID NOs: 7, 8, and 9, respectively, and light chain LCDR1, LCDR2, and LCDR3 comprising the sequences shown in SEQ ID NOs: 10, 11, and 12, respectively; (b) heavy chain HCDR1, HCDR2, and HCDR3 comprising the sequences shown in SEQ ID NOs: 22, 23, and 9, respectively, and light chain LCDR1, LCDR2, and LCDR3 comprising the sequences shown in SEQ ID NOs: 10, 29, and 12, respectively; (c) heavy chain HCDR1, HCDR2, and HCDR3 comprising the sequences shown in SEQ ID NOs: 24, 25, and 9, respectively, and light chain LCDR1, LCDR2, and LCDR3 comprising the sequences shown in SEQ ID NOs: 10, 29, and 12, respectively; (d) heavy chain HCDR1, HCDR2, and HCDR3 comprising the sequences shown in SEQ ID NOs: 26, 27, and 9, respectively, and light chain LCDR1, LCDR2, and LCDR3 comprising the sequences shown in SEQ ID NOs: 10, 29, and 12, respectively; (e) heavy chain HCDR1, HCDR2, and HCDR3 comprising the sequences shown in SEQ ID NOs: 28, 25, and 9, respectively, and light chain LCDR1, LCDR2, and LCDR3 comprising the sequences shown in SEQ ID NOs: 10, 29, and 12, respectively; (f) heavy chain HCDR1, HCDR2, HCDR3 comprising the sequences shown in SEQ ID NOs: 37, 38, 39, respectively, and light chain LCDR1, LCDR2, LCDR3 comprising the sequences shown in SEQ ID NOs: 40, 41, 42, respectively; (g) a heavy chain HCDR having 0 to 10 amino acid mutations compared to the heavy chain HCDR of any one of (a) to (f), and a light chain CDR having 0 to 10 amino acid mutations compared to the light chain LCDR of any one of (a) to (f); Includes.

[0013] In some embodiments, an anti-FXI / FXIa antibody or antigen-binding fragment thereof selectively binds to FXIa without binding to FXI when it comprises CDR sequences of form (a), (b), (c), (d), (e) or related (g).

[0014] In some other embodiments, an anti-FXI / FXIa antibody or antigen-binding fragment thereof, when comprising a CDR sequence of form (f) or the related (g), binds to FXI as well as FXIa, and in some specific embodiments, binds to FXIa but does not affect the activity of FXIa.

[0015] In some embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof is a murine antibody, chimeric antibody, humanized antibody, human antibody, or fragment thereof, and in some specific embodiments, a humanized antibody, human antibody, or fragment thereof. It may be a full-length antibody or a fragment thereof.

[0016] In some embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof is a humanized antibody or fragment thereof, and the light chain template for humanization may be IGKV3-11*01 and the heavy chain template may be IGHV1-69-2*01.

[0017] In some embodiments, the humanization process further includes backmutation of VH and VL. In some specific embodiments, for example, VH has any one or any combination of the following backmutations: Y27F, T28N, F29I, T30K, A93L, R94Y, E73T, R66K, V67A, T75A, and T76N. In some specific embodiments, VL has any one or any combination of the following backmutations: R45K, L46R, L47W, I58V, and F71Y.

[0018] In some specific embodiments, the heavy chain HCDR1, HCDR2, and HCDR3 of the humanized antibody or fragment thereof comprise the sequences set forth in SEQ ID NOs: 37, 38, and 39, respectively, and the light chain LCDR1, LCDR2, and LCDR3 comprise the sequences set forth in SEQ ID NOs: 40, 41, and 42, respectively.

[0019] In some embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof is VH represented by one of SEQ ID NOs: 5, 17 to 20, 30 to 33, 35, 43, 45 to 49, 53 to 58, or having at least 80% identity thereto, and / or VL represented by one of SEQ ID NOs: 6, 21, 34, 36, 44, 50 to 52 or having at least 80% identity thereto; Includes.

[0020] In some specific embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof is (h) a VH as set forth in SEQ ID NO: 5 or having at least 80% identity thereto, and a VL as set forth in SEQ ID NO: 6 or having at least 80% identity thereto; (i) a VH as set forth in SEQ ID NO: 17 or having at least 80% identity thereto, and a VL as set forth in SEQ ID NO: 21 or having at least 80% identity thereto; (j) a VH as set forth in SEQ ID NO: 18 or having at least 80% identity thereto, and a VL as set forth in SEQ ID NO: 21 or having at least 80% identity thereto; (k) a VH as set forth in SEQ ID NO: 19 or having at least 80% identity thereto, and a VL as set forth in SEQ ID NO: 21 or having at least 80% identity thereto; (l) a VH as set forth in SEQ ID NO: 20 or having at least 80% identity thereto, and a VL as set forth in SEQ ID NO: 21 or having at least 80% identity thereto; (m) a VH as set forth in SEQ ID NO: 30 or having at least 80% identity thereto, and a VL as set forth in SEQ ID NO: 34 or having at least 80% identity thereto; (n) a VH as set forth in SEQ ID NO: 31 or having at least 80% identity thereto, and a VL as set forth in SEQ ID NO: 34 or having at least 80% identity thereto; (o) a VH as set forth in SEQ ID NO: 32 or having at least 80% identity thereto, and a VL as set forth in SEQ ID NO: 34 or having at least 80% identity thereto; (p) a VH as set forth in SEQ ID NO: 35 or having at least 80% identity thereto, and a VL as set forth in SEQ ID NO: 36 or having at least 80% identity thereto; (q) a VH as set forth in SEQ ID NO: 43 or having at least 80% identity thereto, and a VL as set forth in SEQ ID NO: 44 or having at least 80% identity thereto; (r) a VH as set forth in SEQ ID NO: 45 or having at least 80% identity thereto, and a VL as set forth in SEQ ID NO: 51 or having at least 80% identity thereto; (s) a VH as set forth in SEQ ID NO: 49 or having at least 80% identity thereto, and a VL as set forth in SEQ ID NO: 51 or having at least 80% identity thereto; (t) a VH as set forth in SEQ ID NO: 58 or having at least 80% identity thereto, and a VL as set forth in SEQ ID NO: 51 or having at least 80% identity thereto; Includes.

[0021] In some embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof has a VH linked to a human or mouse CH1 and a VL linked to a human or mouse CL or Cκ, where the human CH is set forth in SEQ ID NO: 13 or 59, and the Cκ is set forth in, for example, SEQ ID NO: 14.

[0022] In some embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof is a mouse antibody or fragment thereof. The light chain variable region comprises the light chain FR region and / or light chain constant region of a mouse κ or λ chain or a variant thereof. In some specific embodiments, the mouse anti-FXI / FXIa antibody or antigen-binding fragment thereof comprises the heavy chain FR region and / or heavy chain constant region of a mouse IgG1, IgG2, IgG3, IgG4 or a variant thereof.

[0023] In some embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof is a chimeric antibody or fragment thereof, which comprises the light chain FR region and / or light chain constant region of a human kappa or lambda chain or variant thereof, and / or the heavy chain FR region and / or heavy chain constant region of a human IgG1, IgG2, IgG3, or IgG4 or variant thereof.

[0024] In some embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof comprises an Fc constant region, for example, the Fc of IgG1, IgG2, IgG3, IgG4, or IgG4P (i.e., the S241P mutant of IgG4). The IgG1 Fc sequence is shown, for example, in SEQ ID NO: 67, and the IgG4P Fc (i.e., the IgG4 Fc containing S241P) sequence is shown, for example, in SEQ ID NO: 60.

[0025] In some embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof has a heavy chain set forth in SEQ ID NO: 15 or having at least 80% identity thereto and a light chain set forth in SEQ ID NO: 16 or having at least 80% identity thereto; or The heavy chain is set forth in SEQ ID NO: 61 or has at least 80% identity thereto, and the light chain is set forth in SEQ ID NO: 62 or has at least 80% identity thereto.

[0026] In some embodiments, the antigen-binding fragment of an anti-FXI / FXIa antibody is a Fab, Fv, sFv, Fab', F(ab')2, linear antibody, single-chain antibody, scFv, sdAb, sdFv, nanobody, peptibody, domain antibody and multispecific antibody (bispecific antibody, diabody, triabody and tetrabody, tandem di-scFv, tandem tri-scFv), for example, specifically a scFv, Fv, Fab or Fab' fragment.

[0027] In some embodiments, an anti-FXI / FXIa antibody or antigen-binding fragment thereof that binds to the same epitope as the anti-FXI / FXIa antibody or antigen-binding fragment thereof is provided.

[0028] In some other embodiments, there is provided an anti-FXI / FXIa antibody or an antigen-binding fragment thereof that cross-blocks the binding of the above-mentioned anti-FXI / FXIa antibody or antigen-binding fragment thereof to human FXI / FXIa.

[0029] In some other embodiments, there is provided an anti-FXI / FXIa antibody or antigen-binding fragment thereof whose binding to human FXI / FXIa is cross-blocked by the above-mentioned anti-FXI / FXIa antibody or antigen-binding fragment thereof.

[0030] In some embodiments, the present invention provides an anti-FXI / FXIa antibody or antigen-binding fragment thereof that has at least 80% identity with the heavy chain and / or light chain of the anti-FXI / FXIa antibody or antigen-binding fragment thereof.

[0031] In the context of the present disclosure, "at least 80%" includes 80% or more, e.g., at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%.

[0032] In some embodiments, an anti-FXI / FXIa antibody or antigen-binding fragment thereof variant is provided, which comprises 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid changes in the heavy chain variable region and / or light chain variable region of the anti-FXI / FXIa antibody or antigen-binding fragment thereof, which may be conservative substitutions of amino acid residues in the variable region.

[0033] In some embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof is Preventing activation of the intrinsic or common blood coagulation pathway; blocking the binding of FXI and / or FXIa to members in the blood coagulation pathway (preferably, said members are one or more selected from blood coagulation factor IX, blood coagulation factor XIIa, and thrombin); blocking the binding of FIX, FXI, and FXIa to one or more platelet receptors; ≦10 -9 binding to human FXI and / or FXIa proteins at a KD; When bound to FXI / FXIa, it prevents the catalytic domain of FXI / FXIa from assuming an active conformation; It can be administered subcutaneously or intravenously; It may have any one or more of the following characteristics.

[0034] The affinity measurement method is, for example, BIACORE TM is.

[0035] In another aspect, the present disclosure provides a polynucleotide encoding any one of the above anti-FXI / FXIa antibodies or antigen-binding fragments thereof, or an anti-FXI / FXIa antibody or antigen-binding fragment thereof, wherein the polynucleotide may be DNA or RNA.

[0036] In a further aspect, the present disclosure provides an expression vector comprising the above-described polynucleotide, wherein the expression vector is selected from a eukaryotic expression vector, a prokaryotic expression vector, and a viral vector.

[0037] In a further aspect, the present disclosure provides a host cell transformed with the above-described expression vector, which may be a eukaryotic or prokaryotic cell.

[0038] In some embodiments, the host cell is selected from bacteria, yeast, and mammalian cells. In some specific embodiments, the host cell is selected from Escherichia coli, Pichia yeast, Chinese hamster ovary (CHO) cells, or human embryonic kidney (HEK) 293 cells.

[0039] In a further aspect, the present disclosure provides a method for preparing an anti-FXI / FXIa antibody or antigen-binding fragment thereof, the method comprising expressing the antibody or antigen-binding fragment thereof in the above-described host cell and isolating the antibody or antigen-binding fragment thereof from the host cell.

[0040] In a further aspect, the present disclosure provides compositions, such as pharmaceutical compositions, comprising a pharmaceutically acceptable excipient, diluent, or vector and a therapeutically or prophylactically effective amount of the anti-FXI / FXIa antibody or antigen-binding fragment thereof. In some specific embodiments, a unit dose of the pharmaceutical composition may contain 0.01 to 99 wt% of the anti-FXI / FXIa antibody or antigen-binding fragment thereof, or the content of the anti-FXI / FXIa antibody or antigen-binding fragment thereof in a unit dose of the pharmaceutical composition is 0.1 to 2000 mg, and in some specific embodiments, 1 to 1000 mg.

[0041] In some specific embodiments, the pharmaceutical composition is in a subcutaneous dosage form or an intravenous dosage form.

[0042] In some embodiments, a subcutaneous pharmaceutical composition is provided which comprises a therapeutically or prophylactically effective amount of the anti-FXI / FXIa antibody or antigen-binding fragment thereof of the present disclosure, for example, the heavy chain variable region of the antibody comprises the sequence set forth in SEQ ID NO: 58 and the light chain variable region comprises the sequence set forth in SEQ ID NO: 51, for example, the full-length heavy chain of the antibody comprises the sequence set forth in SEQ ID NO: 61 and the full-length light chain comprises the sequence set forth in SEQ ID NO: 62.

[0043] In a further aspect, the present disclosure provides the use of any one of an anti-FXI / FXIa antibody or antigen-binding fragment thereof according to the present disclosure, a pharmaceutical composition according to the present disclosure, or a combination thereof in the preparation of a medicament.

[0044] In some embodiments, the agent is used in the treatment or prevention of a thrombus- or thromboembolic-related disease or condition, such as ischemic stroke associated with atrial fibrillation and / or deep vein thrombosis.

[0045] The present disclosure provides a method for treating or preventing a thrombus formation or thromboembolism-related disease or condition (or a complication thereof) or delaying the progression of a thrombus formation or thromboembolism-related disease or condition (or a complication thereof), comprising administering to a subject an anti-FXI / FXIa antibody or antigen-binding fragment thereof according to the present disclosure, or a pharmaceutical composition according to the present disclosure, in an amount effective to treat or delay the disease.

[0046] The anti-FXI / FXIa antibodies or antigen-binding fragments thereof, and pharmaceutical compositions of the present disclosure are applicable to clot formation, thrombus formation, or thromboembolism-related diseases or conditions.

[0047] Such thrombus- or thromboembolic-related diseases or conditions include, but are not limited to, coronary artery disease (e.g., acute coronary syndrome (ACS)), ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction (non-STEMI), stable angina, unstable angina, re-occlusion and restenosis after coronary intervention (e.g., angioplasty, stent grafting, or aortocoronary bypass grafting), peripheral arterial occlusive disease, pulmonary embolism, venous thromboembolism, venous thrombosis (particularly in the deep veins of the lower extremities and renal veins), transient ischemic attack and thrombotic and thromboembolic stroke, chronic thromboembolic pulmonary disease (CTEPH) or pulmonary arterial hypertension.

[0048] Stimulation of the blood coagulation system can occur due to various triggers or related pathologies. In cases such as surgical intervention, immobility, being bedridden, infection, inflammation, or cancer or cancer treatment, the blood coagulation system can be highly activated, and thrombogenic complications, particularly venous thrombosis, may occur. Therefore, the anti-FXI / FXIa antibody or antigen-binding fragment thereof, and pharmaceutical composition of the present disclosure can be used to prevent thrombosis in cases of surgical intervention, particularly in patients with cancer or patients who have undergone orthopedic surgery (e.g., hip or knee replacement). Therefore, the anti-FXI / FXIa antibody or antigen-binding fragment thereof, and pharmaceutical composition of the present disclosure can also be used to prevent thrombosis in patients with an activated blood coagulation system, for example, when stimulated as described above.

[0049] The anti-FXI / FXIa antibodies or antigen-binding fragments thereof and pharmaceutical compositions of the present disclosure are used for the treatment and / or prevention of acute, intermittent, or sustained arrhythmias (e.g., atrial fibrillation), or cardiogenic thromboembolism (e.g., cerebral arterial ischemia, stroke, and systemic and local thromboembolism) in patients who have undergone defibrillation, or who suffer from valvular heart disease, or who have prosthetic heart valves.

[0050] The anti-FXI / FXIa antibodies or antigen-binding fragments thereof, and pharmaceutical compositions of the present disclosure are used to treat and / or prevent diffuse intravascular coagulation (DIC), which may occur in particular with sepsis, but may also result from surgical intervention, oncological disease, burns, or other injuries, and which may result in severe organ damage due to microthrombi.

[0051] The anti-FXI / FXIa antibodies or antigen-binding fragments thereof, and pharmaceutical compositions of the present disclosure are used to treat and / or prevent thromboembolic complications, such as those that can occur in microangiopathic hemolytic anemia and are caused by contact of blood with external surfaces when circulating extracorporeally (e.g., methods such as hemodialysis, ECMO ("extracorporeal membrane oxygenation"), and LVAD ("left ventricular assist device").

[0052] The anti-FXI / FXIa antibodies or antigen-binding fragments thereof, and pharmaceutical compositions of the present disclosure are used for the treatment and / or prevention of diseases associated with microclot formation or fibrin deposition in cerebral blood vessels, which may lead to dementia such as vascular dementia and Alzheimer's disease.

[0053] The anti-FXI / FXIa antibodies or antigen-binding fragments thereof and pharmaceutical compositions of the present disclosure are used to prevent and / or treat thrombotic and / or thromboembolic complications, e.g., venous thromboembolism, in cancer patients, particularly those who have undergone major surgical intervention or chemotherapy or radiation therapy.

[0054] The anti-FXI / FXIa antibodies or antigen-binding fragments thereof and pharmaceutical compositions of the present disclosure are used to treat and / or prevent diffuse intravascular coagulation in the context of the following diseases, including, but not limited to, infectious diseases and / or systemic inflammatory response syndrome (SIRS), septic organ dysfunction, septic organ failure and multiple organ failure, acute respiratory distress syndrome (ARDS), acute lung injury (ALI), septic stroke and / or septic organ failure. In the event of infection, there may be general activation of the blood coagulation system (disseminated intravascular coagulation, also known as "DIC"), accompanied by microthrombus formation and secondary hemorrhagic complications in multiple organs. Endothelial damage may occur, accompanied by increased vascular permeability and diffusion of fluids and proteins, e.g., extravasation into the air spaces. As the infection progresses, organ failure (e.g., renal failure, liver failure, respiratory failure, central nervous system dysfunction and cardiovascular failure) or multiple organ failure may occur. In DIC, there is massive activation of the blood coagulation system on compromised endothelial cell surfaces, foreign body surfaces, or cross-linked extravascular tissue surfaces. Therefore, blood clots are present in small blood vessels in multiple organs suffering from ischemia and subsequent organ dysfunction. A secondary effect is the consumption of blood coagulation factors (e.g., factor X, prothrombin, and fibrinogen) and platelets, which reduces the blood's coagulability and can lead to severe bleeding.

[0055] The anti-FXI / FXIa antibodies or antigen-binding fragments thereof and pharmaceutical compositions of the present disclosure are used for the treatment and / or prevention of thrombogenic or thromboembolic diseases and / or inflammatory diseases and / or diseases of increased vascular permeability in patients with the following: i.e., the patients have genetic mutations that cause increased enzyme activity or elevated zymogen levels, which are determined by experiments / measurements of enzyme activity or zymogen concentration.

[0056] The present disclosure provides the use of the anti-FXI / FXIa antibody or antigen-binding fragment thereof, or pharmaceutical composition of the present disclosure for preparing a medicament for treating and / or preventing a disease, particularly the above-mentioned disease, for example, a medicament for treating and / or preventing a thrombogenic or thromboembolic disease.

[0057] The present disclosure provides methods for treating and / or preventing the above-mentioned diseases using the anti-FXI / FXIa antibodies or antigen-binding fragments thereof, and pharmaceutical compositions of the present disclosure.

[0058] In a further aspect, the present disclosure provides a composition for detecting FXI / FXIa, comprising an anti-FXI / FXIa antibody or an antigen-binding fragment thereof. The present disclosure further provides a method, system, or device for detecting FXI / FXIa in vivo or in vitro, comprising treating an anti-FXI / FXIa antibody.

[0059] In some embodiments, the in vitro detection method, system, or device may include, for example: (1) contacting the sample to be measured with a FXI / FXIa-binding antibody or antigen-binding fragment thereof; (2) detecting a complex formed between the FXI / FXIa-binding antibody or antigen-binding fragment thereof and the sample to be measured; and / or (3) contacting a reference sample (e.g., a control sample) with the antibody; and (4) determining the extent of complex formation between the antibody and the sample to be measured by comparison with a reference sample; may include:

[0060] For example, a change (eg, a statistically significant change) in complex formation in the sample or subject being measured relative to that in a control sample or subject indicates the presence of FXI / FXIa in the sample being measured.

[0061] In some further embodiments, the in-vivo detection method, system, or device comprises: (1) administering to a subject a FXI / FXIa binding antibody or antigen-binding fragment thereof; (2) detecting the formation of a complex between the FXI / FXIa-binding antibody or antigen-binding fragment thereof and the subject to be measured; may include:

[0062] Detection may include determining the location or time of complex formation. The FXI / FXIa-binding antibody may be directly or indirectly labeled with a detectable substance to facilitate detection of bound or unbound antibody. Suitable detectable substances include various enzymes, prosthetic groups, fluorescent substances, luminescent substances, and radioactive substances. Formation of a complex between the FXI / FXIa-binding antibody or antigen-binding fragment thereof and FXI / FXIa can be detected by measuring or visualizing the FXI / FXIa-bound or unbound antibody. Conventional detection assays, such as enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), or tissue immunohistochemistry, can be used.

[0063] In some embodiments, the presence of FXI / FXIa in a sample is analyzed by a competitive immunoassay, which uses a standard labeled with a detectable substance and an unlabeled FXI / FXIa-binding antibody.

[0064] In some embodiments, for detection purposes, antibodies or fragments thereof of the present disclosure can be labeled with fluorophores and chromophores.

[0065] In some embodiments, a reagent kit is further provided, comprising an anti-FXI / FXIa antibody or antigen-binding fragment thereof, and optionally including a diagnostic manual. The reagent kit may further comprise at least one additional reagent, such as a marker or an additional diagnostic agent. For in vivo use, the antibody can be formulated as a pharmaceutical composition. [Brief explanation of the drawings]

[0066] [Figure 1] [Figures 1A and 1B] SPR detection of binding of FXI / FXIa antibodies to human FXI / FXIa proteins. Figure 1A shows the SPR analysis of binding of 3,882 molecules to FXI, and Figure 1B shows the SPR analysis of binding of 1,209 molecules to FXIa. [Figure 2][Figures 2A-2B] In vitro FXIa enzyme activity inhibition test of FXI / FXIa antibodies. Figure 2A shows the results of an in vitro FXIa enzyme activity inhibition test of anti-FXI / FXIa antibodies, and Figure 2B shows the results of an in vitro FXIIa-mediated FXI activation enzyme activity inhibition test of anti-FXI / FXIa antibodies. [Figure 3] [Figures 3A and 3B] Detection of aPTT and PT anticoagulant activity in human blood. Figures 3A and 3B show the aPTT and PT test results, respectively, for anti-FXI / FXIa antibodies in human blood. [Figure 4] [Figures 4A and 4B] Detection of aPTT and PT anticoagulant activity in monkey blood. Figures 4A and 4B show the aPTT and PT test results, respectively, for anti-FXI / FXIa antibodies in monkey blood. [Figure 5] [Figures 5A-5D] Animal testing of FXI / FXIa antibodies in cynomolgus monkeys. Figure 5A shows the change curves of aPTT, blood drug concentration, FXI:C%, and free FXI for antibody 3882 in cynomolgus monkeys. Figure 5B shows the thrombus formation inhibitory effect of 3882 in cynomolgus monkeys. Figures 5C and 5D show the results of bleeding time and PT detection, respectively, from safety testing of 3882 in cynomolgus monkeys. [Figure 6] [Figures 6A-6B] Pharmacodynamic (PD) results of an in vivo study of FXI / FXIa antibodies in cynomolgus monkeys. Figure 6A shows the APTT(s) measurement results, and Figure 6B shows the FXI:C (%) measurement results. 3882 (1 mg / kg) was administered intravenously and subcutaneously, and the control BAY1213790 (1 mg / kg) was administered intravenously. DETAILED DESCRIPTION OF THE INVENTION

[0067] term In order that the present disclosure may be more readily understood, certain technical and scientific terms are specifically defined below. Unless otherwise specifically defined elsewhere herein, all other technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art. The three-letter and one-letter codes for amino acids used in this disclosure are as described in J. Biol. Chem, 243, p. 3558 (1968).

[0068] "Factor XI," also referred to herein as "blood clotting factor XI," "FXI," or "fXI," is a two-chain glycoprotein with a molecular weight of approximately 160 kilodaltons (kD). The two chains may be polypeptides, each with a molecular weight of approximately 80,000 daltons, and are linked by a disulfide bond. FXI contains four "apple domains" (A1-A4, derived from the N-terminus, heavy chain) and a C-terminal catalytic domain (light chain). Without wishing to be bound by a particular theory, the four apple domains are thought to contain binding sites for other proteins, e.g., A1 to thrombin, A2 to HK, A3 to factor IX (FIX), GPIb to heparin, and A4 to FXIIa. FXI is transformed into its active form, blood clotting factor XIa (FXIa), by factor XIIa (FXIIa). The serine protease FXIa transforms blood clotting factor IX to IXa, which then activates blood clotting factor X (Xa), which can then mediate the activation of blood clotting factor II / thrombin.

[0069] Within the scope of this disclosure, FXI and FXIa should be understood in the broadest sense. The terms encompass native forms of FXI and FXIa, naturally occurring variants, and artificially expressed forms. Unless the context dictates otherwise, when referring to antigen-antibody interactions, FXI (or FXIa) encompasses the entire protein and its range of epitopes.

[0070] The term "antibody" is used in the broadest sense to refer to any antibody that exhibits the desired antigen-binding activity, and covers a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, and antibody fragments (or antigen-binding fragments or antigen-binding portions). Antibodies may also refer to immunoglobulins, which have a tetrapeptide chain structure consisting of two heavy chains and two light chains linked by interchain disulfide bonds. Immunoglobulins differ in the amino acid composition and sequence of the heavy chain constant regions, resulting in different antigenicities. Therefore, immunoglobulins can be divided into five types, or immunoglobulin isotypes: IgM, IgD, IgG, IgA, and IgE, and the corresponding heavy chains are μ, δ, γ, α, and ε chains, respectively. Ig of the same type can be further divided into different subclasses based on differences in the amino acid composition of the hinge region and the number and location of heavy chain disulfide bonds. For example, IgG may be divided into IgG1, IgG2, IgG3, and IgG4. Light chains are divided into κ chains and λ chains depending on the constant region. Each of the five types of Ig may have either κ chains or λ chains. In antibody heavy and light chains, the sequence of approximately 110 amino acids near the N-terminus is highly variable and forms the variable region (V region), while the remaining amino acid sequence near the C-terminus is relatively stable and forms the constant region (C region). The variable region contains three hypervariable regions (CDRs) and four framework regions (FRs) with relatively conserved sequences. The three hypervariable regions determine the specificity of the antibody and are also called complementarity-determining regions (CDRs). Each light chain variable region (VL) and heavy chain variable region (VH) consists of three CDR regions and four FR regions, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CDR regions of the light chain are referred to as LCDR1, LCDR2, and LCDR3, and the three CDR regions of the heavy chain are referred to as HCDR1, HCDR2, and HCDR3.

[0071] The determination or definition of CDRs can be achieved by solving the structure of the antibody and / or the structure of the antibody-ligand complex, thereby accurately delineating the CDRs and identifying the residues that comprise the antibody's binding site. This can be accomplished by any one of a variety of techniques known to those of skill in the art, such as X-ray crystallography. Various analytical methods can be used to identify CDRs, including, but not limited to, the Kabat numbering system, the Chothia numbering system, the AbM numbering system, the IMGT numbering system, contact definitions, and conformational definitions.

[0072] The Kabat numbering system is a standard for numbering residues in antibodies and is commonly used to identify CDR regions (see, eg, Johnson & Wu, 2000, Nucleic Acids Res., 28:214-8).

[0073] The Chothia numbering system is similar to the Kabat numbering system, but takes into account the location of some structural loop regions (see, e.g., Chothia et al., 1986, J. Mol. Biol., 196:901-17; Chothia et al., 1989, Nature, 342:877-83).

[0074] The AbM numbering system uses an integrated suite of computer programs from the Oxford Molecular Group that model antibody structure (see, e.g., Martin et al., 1989, ProcNatl Acad Sci(USA), 86:9268-9272; "AbMTM, A Computer Program for Modeling Variable Regions of Antibodies", Oxford, UK; Oxford Molecular, Ltd.). The AbM numbering system uses a combination of knowledge databases and de novo methods to model the tertiary structure of antibodies from the base sequence (see, e.g., "Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach" in Samudrala et al., 1999, PROTEINS, Structure, Function and Genetics Suppl., 3:194-198).

[0075] Contact definitions are based on analysis of available complex crystal structures (see, e.g., MacCallum et al., 1996, J. Mol. Biol., 5:732-45). In defining the conformation, CDR positions can be identified as residues that make enthalpic contributions to antigen binding (see, e.g., Makabe et al., 2008, Journal of Biological Chemistry, 283:1156-1166).

[0076] It should be noted that other CDR boundary definitions may not strictly follow one of the above methods, but still overlap with at least a portion of the Kabat CDRs. Predictions or experimental results of particular residues or groups of residues that do not significantly affect antigen binding may result in shortening or lengthening. As used herein, a CDR may refer to a CDR defined by any method (including a combination of methods) known in the art.

[0077] The CDR amino acid residues of the VL and VH regions of the antibodies or antigen-binding fragments of the present disclosure conform to the known Kabat numbering system in terms of number and position. If the Kabat numbering system is not used, those skilled in the art can determine corresponding equivalent positions under different numbering rules by comparing the amino acid positions in the CDRs of the present disclosure. For example, those skilled in the art can also determine such equivalent positions by aligning and analyzing amino acid sequences.

[0078] "CL," "CL region," and "CL domain" may be used interchangeably herein to refer to the light chain constant region.

[0079] The terms "CH", "CH region" and "CH domain" may be used interchangeably herein to refer to a heavy chain constant region, and include "CH1", "CH2", and "CH3" regions or domains.

[0080] "Human antibody" or "recombinant human antibody" includes human antibodies prepared, expressed, produced or isolated by recombinant methods, including techniques and methods well known in the art, such as: (1) Antibodies isolated from transgenic or transchromosomal animals (e.g., mice) containing human immunoglobulin genes, or from hybridomas prepared thereby; (2) antibody isolated from a host cell transformed to express the antibody, e.g., a transfectoma; (3) antibodies isolated from a recombinant combinatorial human antibody library, and (4) Antibodies prepared, expressed, created, or isolated by methods such as splicing human immunoglobulin gene sequences into other DNA sequences.

[0081] Such recombinant human antibodies contain variable and constant regions that utilize specific human germline immunoglobulin sequences encoded by germline genes, but also contain subsequent rearrangements and mutations that occur, for example, during antibody maturation.

[0082] The term "mouse antibody" as used herein refers to a monoclonal antibody against human FXI / FXIa or an epitope thereof prepared using knowledge and techniques in this field. During preparation, FXI / FXIa antigen is injected into a test subject, and hybridomas expressing antibodies with desired sequence or functional characteristics are isolated. In one specific embodiment of the present disclosure, the mouse anti-human FXI / FXIa antibody or antigen-binding fragment thereof may further comprise a light chain constant region of a mouse κ or λ chain or a variant thereof, or may further comprise a heavy chain constant region of a mouse IgG1, IgG2, IgG3, or IgG4 chain or a variant thereof.

[0083] The term "human antibody" includes antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies of the present disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody" does not include humanized antibodies.

[0084] The term "humanized antibody," also known as a CDR-grafted antibody, refers to an antibody produced by grafting the CDR sequence of a non-human species onto a human antibody variable region framework. This can overcome the strong immune response induced by chimeric antibodies containing a large amount of heterologous protein components. To avoid a decrease in activity due to reduced immunogenicity, minimal back mutations can be made to the human antibody variable region so that activity is maintained.

[0085] The term "chimeric antibody" refers to an antibody in which the variable region of an antibody of one species is fused with the constant region of a second species, and can reduce the immune response elicited by the antibody of the first species. For example, to prepare a chimeric antibody, first prepare a hybridoma secreting a mouse-specific monoclonal antibody, then clone the variable region genes from the mouse hybridoma cells, and optionally clone the constant region genes of a human antibody. The mouse variable region genes and the human constant region genes are ligated to form a chimeric gene, which is then inserted into a human vector. Finally, the chimeric antibody molecule is expressed in a eukaryotic or prokaryotic cell system. The constant region of the human antibody may be selected from the heavy chain constant regions of human IgG1, IgG2, IgG3, or IgG4 or variants thereof. Preferably, it contains a human IgG2 or IgG4 heavy chain constant region. Alternatively, an IgG1 that lacks ADCC (antibody-dependent cell-mediated cytotoxicity) toxicity after amino acid mutation is used.

[0086] "Antigen-binding fragment" includes single-chain antibodies (i.e., heavy or light chains), Fab, modified Fab, Fab', modified Fab', F(ab')2, Fv, Fab-Fv, Fab-dsFv, single-domain antibodies (e.g., VH or VL or VHH), scFv, bivalent, trivalent or tetravalent antibodies, Bis-scFv, two-chain antibodies (diabodies), three-chain antibodies (triabodies), four-chain antibodies (tetrabodies), and epitope-binding fragments of any of the above (see, e.g., Holliger and Hudson, 2005, Nature Biotech. 23(9):1126-1136; Adair and Lawson, 2005, Drug Design Reviews-Online 2(3), 209-217). Methods for producing and preparing these antibody fragments are known in the art (see, e.g., Verma et al., 1998, Journal of Immunological Methods, 216, 165-181). The Fab-Fv form was first disclosed in WO 2009 / 040562, and its disulfide-stabilized form, Fab-dsFv, was first disclosed in WO 2010 / 035012. Antigen-binding fragments according to the present disclosure further include the Fab and Fab' fragments described in WO 2005 / 003169, WO 2005 / 003170, and WO 2005 / 003171. Multivalent antibodies may include those with multiple specificities, e.g., bispecific or monospecific (see, e.g., WO 92 / 22583 and WO 05 / 113605).

[0087] A "variant" refers to a polypeptide containing at least one amino acid modification (e.g., substitution, deletion, or insertion) compared to the "parent" amino acid sequence, provided that the variant is still capable of binding to FXI / FXIa, particularly human FXI / FXIa as set forth in SEQ ID NO: 1. Preferably, the variant exhibits similar or even improved properties compared to antibodies 0012, 1209, 1267, 3807, 3871, and 3882 in the examples of the present disclosure. Variants of binding molecules (e.g., antibodies or antigen-binding fragments thereof) of the present disclosure are generally prepared by introducing appropriate nucleotide changes into nucleic acids encoding the antibodies or antibody fragments, or by peptide synthesis. Typically, such amino acid modifications can be introduced into the variable or constant regions, and can be introduced, for example, to adjust antibody properties that affect pharmaceutical development, such as thermodynamic stability, solubility, or viscosity ("sequence optimization"), compared to the anti-FXI / FXIa antibodies in the examples of the present disclosure.

[0088] Amino acid modifications include, for example, deletions and / or insertions and / or substitutions of residues in the amino acid sequence of the binding molecule (preferably, an antibody or antigen-binding fragment). Any combination of deletions, insertions, and substitutions can be introduced into the "parent" amino acid sequence to obtain the final variant. Amino acid modifications also include post-translational processes that can alter the binding molecule, such as changing the number or location of glycosylation sites. For example, depending on the length of the CDRs and FRs themselves, 1, 2, 3, 4, 5, or 6 amino acids can be inserted into or deleted from each CDR, and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 25 amino acids can be inserted into or deleted from each FR. Insertional variants of the binding molecules (especially antibodies or antibody fragments) of the present disclosure include fusion products of an antibody or antibody fragment with an enzyme or other functional polypeptide (e.g., which increases the serum half-life of the binding molecule (e.g., antibody or antibody fragment)). Amino acid substitutions can also be introduced into the CDR, VH, or FR regions of the heavy and / or light chains. Conservative substitutions are preferred, and can be made, for example, because of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and / or the amphipathic nature of such residues.

[0089] "Conservative substitution" refers to a substitution of an amino acid residue with another amino acid residue having similar properties to the original amino acid residue. For example, lysine, arginine, and histidine have similar properties in that they have basic side chains, and aspartic acid and glutamic acid have similar properties in that they have acidic side chains. Furthermore, glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, and tryptophan have similar properties in that they have uncharged polar side chains, and alanine, valine, leucine, threonine, isoleucine, proline, phenylalanine, and methionine have similar properties in that they have nonpolar side chains. Furthermore, tyrosine, phenylalanine, tryptophan, and histidine have similar properties in that they have aromatic side chains. Therefore, it is clear to those skilled in the art that substitution of amino acid residues in the above-mentioned group showing similar properties does not result in a specific change in properties.

[0090] In addition to the CDRs and FRs, modifications may be introduced into the Fc portion of a binding molecule (preferably, an antibody or antigen-binding fragment thereof). Such modifications can be used to modulate the functional properties of the antibody, for example, its interaction with complement proteins (e.g., C1q and / or Fc receptors) on other immune cells, or to modulate serum half-life or antigen-dependent cellular cytotoxicity (ADCC). Mutations that alter effector function can be introduced into the Fc domain by routine methods known in the art. Exemplary modifications include Asn297→Ala297 and Asn297→Gln297, or Lys322→Ala322 and optionally Leu234→Ala234 and Leu235→Ala234, which result in IgG1 glycosylation, and have been reported to reduce or eliminate antibody-mediated cell-mediated cytotoxicity (ADCC) and / or complement-mediated cytotoxicity (CDC).

[0091] Examples of methods for extending serum half-life include the addition of peptides or protein domains that bind to other proteins in the human body (e.g., serum albumin, immunoglobulin Fc regions, or neonatal Fc receptor (FcRn)). Other conceivable methods for extending serum half-life include amino-terminal extension with polypeptide chains of different lengths (e.g., XTEN technology or PASylation). (R) ), conjugation with non-protein polymers or sugars, where the non-protein polymers include various polyols such as polyethylene glycol (PEGylated), polypropylene glycol, polyoxyalkylenes or copolymers of polyethylene glycol and polypropylene glycol, or hydroxyethyl starch (e.g., HESylation (R) ) or polysialic acid (e.g., PolyXen (R) Additionally, as is known in the art, amino acid substitutions at multiple positions in the binding molecule can facilitate the addition of the polymer.

[0092] The term "bind to FXI / FXIa" in the present disclosure refers to being able to interact with FXI / FXIa or an epitope thereof, and the FXI / FXIa or epitope thereof may be of human origin.

[0093] The term "antigen-binding site" of the present disclosure refers to the non-contiguous three-dimensional spatial region on an antigen that is recognized by an antibody or antigen-binding fragment of the present disclosure.

[0094] The term "epitope" refers to the site on an antigen that binds to an immunoglobulin or antibody. Epitopes may be formed from contiguous amino acids or non-contiguous amino acids (where non-contiguous amino acids are spatially close together due to tertiary folding of a protein). Epitopes formed from contiguous amino acids are typically retained after exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost after treatment with denaturing solvents. Epitopes typically exist in a particular spatial conformation and contain at least 3-15 amino acids. Methods for determining epitopes are well known in the art and include immunoblotting and immunoprecipitation detection assays. Methods for determining the spatial conformation of epitopes include techniques known in the art and described herein, such as X-ray crystallography and two-dimensional nuclear magnetic resonance.

[0095] The terms "specific binding" and "selective binding" refer to the binding of an antibody to an epitope in a predetermined antigen. Typically, when human FXI / FXIa or an epitope thereof is used as an analyte and an antibody is used as a ligand, and measurement is performed by surface plasmon resonance (SPR) technology in an instrument, the antibody binds to an epitope in an amount of about 10 -7 The equilibrium dissociation constant (K D ) and the binding affinity for the predetermined antigen or its epitope is at least twice its binding affinity for the predetermined antigen or its epitope (or a non-specific antigen other than a closely related antigen, such as BSA).

[0096] "Affinity" refers to the overall strength of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding ligand (e.g., an antigen). Unless otherwise specified, as used herein, "binding affinity" refers to internal binding affinity, indicating that members of a binding pair (e.g., an antibody and an antigen) interact at a 1:1 ratio. The affinity of a molecule X for its ligand Y can typically be expressed as an equilibrium dissociation constant (KD). Affinity is measured by conventional methods known in the art (as described herein). The terms "kassoc" or "ka" refer to the association rate of a particular antibody-antigen interaction, while the terms "kdis" or "kd" as used herein refer to the dissociation rate of a particular antibody-antigen interaction. As used herein, the term "KD" refers to the equilibrium dissociation constant, which is obtained from the ratio of kd to ka (i.e., kd / ka) and is expressed as a molar concentration (M). The KD value of an antibody can be measured by methods known in the art. For example, methods for measuring antibody KD include measuring surface plasmon resonance using a biosensor system, such as a system, or measuring affinity in solution using solution equilibrium titration (SET). "Cross-reactivity" refers to the ability of an antibody of the present disclosure (or a fragment thereof) to bind to FXI / FXIa from a different species. For example, an antibody of the present disclosure that binds to human FXI / FXIa may also bind to FXI / FXIa from another species. Cross-reactivity is measured by detecting specific reactivity with purified antigen in binding assays (e.g., SPR and ELISA) or binding or functional interaction with cells that physiologically express FXI / FXIa. Methods for determining cross-reactivity include standard binding assays such as those described herein, such as surface plasmon resonance analysis and flow cytometry.

[0097] "Inhibition" and "blocking" may be used interchangeably and cover partial and complete inhibition or blocking. Preferably, inhibition / blocking of FXI / FXIa reduces or alters the normal level or type of activity that occurs when FXI / FXIa binding occurs in the absence of inhibition or blocking. Inhibition and blocking are also intended to include any measurable reduction in FXI / FXIa binding affinity when contacted with an anti-FXI / FXIa antibody compared to FXI / FXIa not contacted with an anti-FXI / FXIa antibody.

[0098] "Inhibition of growth" (eg, of a cell) is intended to include any measurable decrease in cell growth.

[0099] Methods for producing and purifying antibodies and antigen-binding fragments are well known in the art and can be found, for example, in Reizei Port's Antibody Laboratory Techniques Manual (Chapters 5-8 and 15). For example, mice can be immunized with human FXI / FXIA or a fragment thereof, and the resulting antibodies can be renatured, purified, and amino acid sequenced using conventional methods. Antigen-binding fragments can also be prepared using conventional methods. The antibodies or antigen-binding fragments described in the invention have one or more human FR regions added to non-human CDR regions by genetic engineering methods. Human FR germline sequences can be obtained from ImMunoGeneTics (IMGT) or from the Immunoglobulin Journal, 2001, ISBN 012441351.

[0100] The engineered antibodies or antigen-binding fragments of the present disclosure can be prepared and purified using conventional methods. For example, cDNA sequences encoding the heavy and light chains can be cloned and recombined into expression vectors. The recombinant expression vectors can be stably transfected into CHO cells. Mammalian expression systems result in glycosylation of antibodies, particularly at the highly conserved N-terminus of the Fc region. Stable clones are obtained by expressing antibodies that specifically bind to human antigens. Positive clones are expanded in serum-free medium in a bioreactor to produce antibodies. The culture medium from which the antibodies are secreted can be purified and collected using conventional techniques. The antibodies can be filtered and concentrated using conventional methods. Soluble admixtures and multimers may be removed using conventional methods, such as molecular sieving or ion exchange. The resulting product should be immediately frozen, for example, at -70°C, or lyophilized.

[0101] The antibody of the present disclosure refers to a monoclonal antibody (mAb), which refers to an antibody obtained from a single clonal cell line, including but not limited to eukaryotic, prokaryotic, or phage clonal cell lines. Monoclonal antibodies or antigen-binding fragments can be obtained recombinantly, for example, by hybridoma technology, recombinant technology, phage display technology, synthetic technology (e.g., CDR-grafting), or other conventional techniques.

[0102] Antibodies can be competitively screened for binding to the same epitope using conventional techniques known to those skilled in the art. For example, antibodies that compete with or cross-compete with each other to bind to an antigen can be obtained by performing competition and cross-competition studies. A high-throughput method for obtaining antibodies that bind to the same epitope through such cross-competition is described in International Patent Publication WO 03 / 48731. Therefore, antibodies and antigen-binding fragments thereof that compete with the antibody molecules of the present disclosure to bind to the same epitope on FXI / FXIa can be obtained using conventional techniques known to those skilled in the art.

[0103] "Giving," "administration," and "treatment," when applied to an animal, human, or experimental subject, cell, tissue, organ, or biological fluid, refer to contact of an exogenous agent, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid. "Giving," "administration," and "treatment" can refer, for example, to therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Treatment of cells includes contact of a reagent with a cell and contact of a reagent with a fluid, where the fluid contacts the cell. "Giving," "administration," and "treatment" also refer to ex vivo and in vitro treatment, e.g., of a cell, with a reagent, diagnostic, binding composition, or through another cell. "Treatment," when applied to a human, veterinary, or research subject, refers to therapeutic treatment, preventative or prophylactic measures, and research and diagnostic applications.

[0104] "Treatment" refers to the administration of an internal or external therapeutic agent, e.g., a composition comprising any one of the antibodies or antigen-binding fragments thereof disclosed herein, to a subject suffering from, at risk of, or prone to one or more diseases or symptoms thereof, where the therapeutic agent is known to have a therapeutic effect on those symptoms. Typically, the therapeutic agent is administered to the subject or population being treated in an amount that effectively alleviates one or more disease symptoms, whether by inducing regression of such symptoms or by inhibiting such symptoms so that they do not progress to any clinically measurable extent. The amount of therapeutic agent that effectively alleviates any particular disease symptom (also called a "therapeutically effective amount") can vary depending on several factors, including the disease state, age, and weight of the subject, and the ability of the drug to produce the desired therapeutic effect in the subject. Reduction of disease symptoms can be assessed by any clinical detection method commonly used by physicians and other professional health care providers to assess the severity and progression of the condition. An embodiment of the present disclosure (e.g., a method of treatment or product) may be ineffective in alleviating a target disease symptom in a subject, but it may be determined to be able to alleviate a target disease symptom in a statistically significant number of subjects using any statistical testing method known in the art, such as Student's t-test, chi-square test, Mann and Whitney U test, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test.

[0105] An "effective amount" includes an amount sufficient to ameliorate or prevent the symptoms of a medical condition. An effective amount also refers to an amount sufficient to permit or facilitate diagnosis. The effective amount used in a particular subject or veterinary subject can vary depending on factors such as the condition being treated, the subject's overall health, the method, route and dose of administration, and the severity of side effects. An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

[0106] "Homology" or "identity" refers to the sequence similarity between two polynucleotide sequences or two polypeptides. When a position in two compared sequences is occupied by the same base or amino acid monomer subunit, for example, if each position in two DNA molecules is occupied by adenine, the molecules are homologous at that position. The percentage of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences, divided by the number of positions compared, multiplied by 100%. For example, if 6 of 10 positions in two sequences are matched or homologous when the sequences are optimally aligned, the two sequences are 60% homologous. Generally, two sequences are compared when aligned to obtain the maximum percentage of homology.

[0107] The terms "cell," "cell line," and "cell culture" may be used interchangeably and all such designations include progeny thereof. It is understood that all progeny may not be precisely identical in DNA content, due to intentional or inadvertent mutations. Mutant progeny that have the same function or biological activity as screened for from the originally transformed cell are included.

[0108] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes both cases where the event or circumstance occurs and cases where it does not. For example, "optionally comprising 1 to 3 antibody heavy chain variable regions" means that antibody heavy chain variable regions of a particular sequence may or may not be present.

[0109] A "pharmaceutical composition" is intended to include a mixture of one or more antibodies or antigen-binding fragments described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, and other components such as physiologically / pharmaceutically acceptable vectors and excipients, to facilitate administration to the body and contribute to the absorption of the active ingredients, thereby further exerting biological activity.

[0110] Example The present disclosure will be further explained below in conjunction with examples, but these examples do not limit the scope of the present disclosure.

[0111] Experimental methods for which specific conditions are not specified in the Examples or Test Examples generally follow conventional conditions or conditions recommended by the raw material or product manufacturers. See Sambrook et al., Molecular Cloning, A Laboratory Manual, Reisenko Laboratory, and Modern Molecular Biology Methods, Ausubel et al., Greene Publishing Company, Wiley Interscience, NY. Reagents for which specific sources are not specified are conventional commercially available reagents.

[0112] Example 1. Preparation of human FXI / FXIa antigen and detection protein 1. Human FXI / FXIa Protein Human FXI / FXIa protein (Uniprot Acc No. P03951) was purchased from Enzyme Research Laboratories (FXI: Cat. HFXI 1111; FXIa: HFXIa 1111a) as an antigen and detection protein for the present disclosure. Unless otherwise specified, all FXI / FXIa antigens below refer to human FXI / FXIa. >Amino acid sequence of human FXI / FXIa: [ka] The following KLH-conjugated FXIa-specific polypeptides were artificially synthesized and used for immunization of mice. KLH- CFYGVESPKILRVYSGIL (SEQ ID NO: 2) KLH- CGYRKLRDKIQNTLQKAKIPL (SEQ ID NO: 3) KLH- CGVQEIIIHDQYKMAESGYDI (SEQ ID NO: 4).

[0113] 2. Purification of FXI / FXIa-related recombinant proteins, and purification of hybridoma and recombinant antibodies (1) Isolation and purification of mouse hybridoma supernatant / Protein G affinity chromatography: The mouse hybridoma supernatant was preferably purified by affinity chromatography using Protein G packing material (KANEKA: Cat. KanCap™G). The cultured hybridoma was centrifuged to collect the supernatant, which was then used for purification in a gravity column containing Protein G packing material. First, the column was regenerated with 3 to 5 column volumes of 6 M guanidine hydrochloride (Sigma: Cat. G3272-1KG), and then washed with 3 to 5 column volumes of pure water. The chromatography column was equilibrated with 3 to 5 column volumes of 1x PBS (pH 7.4) (Sangon Biotech (Shanghai) Co., Ltd.: Cat. E607016-0500) buffer system as the equilibration buffer. The supernatant was applied to the column at a low flow rate for binding, and the flow rate was controlled so that the retention time was approximately 1 min or longer. The chromatography column was washed with 3 to 5 column volumes of 1x PBS (pH 7.4) until the UV absorption returned to the baseline. The sample was eluted with 0.1 M glycine (pH 3.0) (Sigma: Cat. 410225-250G) buffer, and the elution peak was collected by UV detection. The eluted product was then purified by elution with 1 M Tris-HCl (pH 8.0) (Vetec, Cat. The eluate was quickly adjusted to pH 7-8 using a centrifuge (V900483) and stored for a while. The eluate can be replaced by methods well known to those skilled in the art, such as ultrafiltration concentration using an ultrafiltration tube, replacing the solution with a desired buffer system, or replacing the solution with a desired buffer system by molecular exclusion chromatography (e.g., G-25 desalting). (2) Extraction of human Fc-tagged fusion proteins or antibodies by Protein A affinity chromatography: First, cell culture supernatants expressing Fc fusion proteins or antibodies were centrifuged at high speed and the supernatants were collected. A Protein A (GE, Cat. 17-5474-99) affinity column was regenerated with 5 column volumes of 0.1 M NaOH (Sigma, Cat. 71687-500g) and then washed and equilibrated with 5 column volumes of 1x PBS (pH 7.4) (Sangon Biotech (Shanghai) Co., Ltd., Cat. E607016-0500). For binding, the supernatant was applied to the column at a slow flow rate, controlled so that the retention time was approximately 1 min or longer. After binding was complete, the chromatography column was washed with 5 column volumes of 1x PBS (pH 7.4) until the UV absorbance returned to baseline. The sample was eluted with 0.1 M glycine (pH 3.0) buffer (Sigma: Cat. 410225-250G), and the elution peak was collected by UV detection. The elution product was quickly adjusted to pH 7-8 with 1 M Tris-HCl (pH 8.0) (Vetec, Cat. V900483) and stored for a while. The elution product can be subjected to solution replacement by methods well known to those skilled in the art, such as ultrafiltration concentration using an ultrafiltration tube, replacement of the solution with a desired buffer system, or exchange with a desired buffer system by molecular exclusion chromatography (e.g., G-25 desalting). (3) Purification of antibodies by anion chromatography: The sample was first diluted with 20 mM Tris pH 8.0 (Vetec, Cat. V900483) equilibration buffer to a conductivity of less than 3 mS / cm. A Q HP (GE, Cat. 17-1014-01) anion chromatography column was regenerated with 5 column volumes of 0.5 M NaOH (Sigma, Cat. 71687-500g) and equilibrated by washing with 15 column volumes of 20 mM Tris pH 8.0 (Vetec, Cat. V900483). The supernatant was applied to the column at a slow flow rate for binding, with the flow rate controlled to achieve a retention time of approximately 2 min or longer. After binding was complete, the chromatography column was washed with 10 column volumes of 20 mM Tris pH 8.0 (Vetec, Cat. V900483) until the UV absorbance returned to baseline. The elution buffer was 20 mM Tris pH 8.0 (Vetec, Cat. V900483) with 0.5 M NaCl (Vetec, Cat. V900058) using a gradient of 0-100%. The eluate was analyzed by SEC-UPLC (Column: Waters ACQUITY UPLC (R) Elution peaks were detected and collected by filtration using a Protein BEH SEC column (200 Å, 1.7 μm, Cat. 186005225). The eluted product can be purified by methods well known to those skilled in the art, such as ultrafiltration concentration using an ultrafiltration tube, replacing the solution with a desired buffer system, or replacing the solution with a desired buffer system using molecular exclusion chromatography (e.g., G-25 desalting).

[0114] Example 2. Selection of antibodies that specifically bind to FXI / FXIa Antibodies with high affinity for FXIa were obtained by screening a fully human single-chain antibody phage library. 2 μg of randomly biotinylated FXIa protein was bound to 100 μg of Dynabeads MyOne Streptavidin T1 and incubated at room temperature for 1 hour. After washing three times with PBST (0.05% Tween-20), nonfat milk dissolved in 1x PBS at a final concentration of 2% was added as a blocking agent and blocked for 1 hour at room temperature. A fully human single-chain antibody phage display library, blocked with 2% milk for 1 hour at room temperature, was then added and incubated for 1 hour at room temperature. Unbound phages were removed by washing 11 times with PBST (0.05% Tween-20), pH 7.4, inverting 20 times each time. The remaining phages that specifically bound to FXIa were eluted with 0.5 mL of 1 mg / mL trypsin and used to infect logarithmic-phase E. coli TG1. The phages were purified and used for the next round of selection. The same selection process was repeated two to three rounds, gradually reducing the amount of FXIa used to 0.5 μg (for the second round of selection) and 0.1 μg (for the third round of selection). After the third round of selection, many positive clones were collected.

[0115] From the selected clones, monoclonal colonies were selected and packaged into single-chain antibody phages, which were then used in phage ELISA tests. ELISA plates were coated with 1 μg / mL FXIa protein and incubated overnight at 4°C. After washing three times with PBST (0.05% Tween-20), the plates were blocked with 2% nonfat milk at room temperature for 1 hour. Phage supernatant diluted with the blocking solution was added and incubated at room temperature for 1 hour. The plates were then washed six times with PBST (0.05% Tween-20). Anti-M13 HRP (Sino Biological Inc., 11973-MM05T-H) was added and incubated at room temperature for 1 hour. The plates were then washed three times with PBST (0.05% Tween-20). 100 μL of TMB chromogenic substrate was added, and the reaction was stopped with 100 μL of 1 M sulfuric acid. Absorbance readings were performed at 450 nm using a SpectraMax M5 microplate reader. Clones with OD450 values ​​greater than three times the background value in the ELISA binding assay were sequenced to obtain high-affinity single-chain antibodies.

[0116] Example 3. Construction of a complete anti-FXI / FXIa monoclonal antibody Fully recombinant antibodies were constructed using the specific sequences with high affinity selected in Example 2. Subsequently, ELISA binding experiments, ForteBio protein interaction experiments, and FXIa enzyme activity inhibition experiments confirmed that two of the antibodies had strong binding affinity and could effectively inhibit FXIa enzyme activity. The complete variable region sequences are as follows: >0012-VH: [ka] >0012-VL: [ka] (Note: antibody numbering convention is Kabat). The antibody heavy and light chain variable region sequences are arranged in the order FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, with the underlined CDR1, CDR2, and CDR3 sequences, respectively. The CDR sequences for each heavy and light chain are summarized in Table 1.

[0117] [Table 1]

[0118] Example 4. Affinity maturation of anti-FXI / FXIa monoclonal antibodies The 3D structure of antibody molecule 0012 was simulated, and its binding with a known antigen structure (PDB ID: 6AOD Chain: C) was simulated. Referring to the mutation hotspots of human germline genes, the 3D structure, and the binding simulation results, some amino acid residues were selected, and several random mutation phage libraries were created. Functional antibodies with improved affinity were selected using phage library display technology. New amino acid residues obtained from different libraries were combined and verified to obtain functional antibodies with improved affinity and function. The variable region heavy and light chain sequences of the obtained antibody molecules are as follows: >F-VH: [ka] >H-VH: [ka] >J-VH: [ka] >K-VH: [ka] >3-VL: [ka] The numbering rules for the above sequences are Kabat, the order is FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, and the underlines in the sequences are CDR1, CDR2, and CDR3 sequences, respectively. The heavy and light chain variable regions of 0012-F3 are F-VH and 3-VL, respectively; the heavy and light chain variable regions of 0012-H3 are H-VH and 3-VL, respectively; the heavy and light chain variable regions of 0012-J3 are J-VH and 3-VL, respectively; and the heavy and light chain variable regions of 0012-K3 (i.e., 1209) are K-VH and 3-VL, respectively.

[0119] [Table 2-1] [Table 2-2]

[0120] Example 5. Modifications to reduce the immunogenicity of anti-FXI / FXIa fully human monoclonal antibodies The selected fully human specific antibody molecules were subjected to three-dimensional structural homology modeling, and alignments were performed with the V-base human germline sequence database and the IMGT human antibody heavy chain variable region germline gene database. The heavy and light chain variable region germline genes with high homology to the selected antibody were then selected as templates. The original monoclonal antibody FR and CDR regions were then modified to retain function while aligning the sequence more closely to the human germline genes. The 3D structure of the grafted antibody was then simulated and analyzed, and specific sites in the FR region that affect the structural conformation of the CDR region were backmutated. Amino acid residues were annotated using the Kabat numbering system. The modified antibody exhibited higher stability and reduced immunogenicity.

[0121] Selection of affinity matured antibody germline gene architectures Analysis showed that antibody 0012 used the human germline gene VH1-24 in the Vbase database as the heavy chain template and the human germline gene VKIIIA27 in the Vbase database as the light chain template.

[0122] After gene modification, antibodies Fg3g (i.e., 1268), Hg3g, Jg3g, and Kg3g (i.e., 1267) were obtained, and their heavy and light chain variable region sequences are as follows: > Fg3g VH: [ka] > Hg3g VH: [ka] > Jg3g's VH: [ka] >Kg3g VH: [ka] > VL of Fg3g or Hg3g or Jg3g or Kg3g: [ka] The CDR numbering system for the above antibody is Kabat, and the order is FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, with the underlined sequences representing CDR1, CDR2, and CDR3, respectively. Each of the heavy chain variable regions was fused to the CH1 (sequence number 13) of the corresponding human antibody, and then fused to IgG1 Fc (sequence number 67). The light chain variable region was fused to human kappa (sequence number 14), and recombinant antibodies were constructed for subsequent detection.

[0123] >CH1 of human antibody: [ka] > Human antibody IgG1Fc: [ka] >Human antibody light chain Cκ: [ka] The full-length heavy and light chain sequences of the 1209 antibody are exemplified below: >1209-HC: [ka] >1209-LC: [ka]

[0124] Example 6. Selection and preparation of anti-FXI / FXIa hybridoma monoclonal antibodies 1. Immunization of Mice Shanghai Ruizhi Chemical was commissioned to perform immunization and splenocyte fusion experiments. Five SJL white mice and five Balb / c white mice were immunized with 25 μg of FXIa antigen and three KLH-conjugated polypeptides mixed with adjuvant. The immunization times were days 0, 14, and 35. On day 0, mice were injected intraperitoneally (IP) with 25 μg of emulsified antigen per mouse. On days 14 and 35, mice were injected with 12.5 μg per mouse. Blood samples were collected on days 21 and 42, and serum antibody titers were determined using ELISA. After the fourth or fifth immunization, mice with high and stable serum antibody titers were selected for splenocyte fusion. Three days before splenocyte fusion, a booster immunization was performed, followed by an intraperitoneal (IP) injection of 50 μg of antigen solution prepared in saline.

[0125] 2. Splenocyte Fusion Splenic lymphocytes were fused with myeloma Sp2 / 0-Ag14 cells using an optimized PEG-mediated fusion process to obtain hybridoma cells. The fused hybridoma cells were seeded into 96-well plates at 1x10^4-1x10^5 cells per well and incubated at 37°C, 5% CO2, supplemented with 100 μL of HAT complete medium per well. ELISA detection was performed after 10-14 days.

[0126] 3. Hybridoma cell selection Hybridoma culture supernatants were detected using a binding ELISA method according to the growth density of hybridoma cells. Cell supernatants from wells that showed positive results in the binding ELISA were purified and subjected to cell binding and cell blocking experiments. Cells from wells that showed positive results in both the binding and blocking experiments were amplified, cryopreserved, and sequenced.

[0127] 4. Further selection of hybridoma cells Depending on the growth density of hybridoma cells, hybridoma culture supernatants were detected using a binding ELISA method. Furthermore, enzyme activity inhibition experiments were performed on the cell supernatants from wells that were positive for binding ELISA. Wells that showed positive results for both binding and function experiments were diluted once or twice for subcloning until single-cell clones were obtained. Each subcloning cell required FXI / FXIa binding ELISA and FXIa enzyme activity inhibition experiments. Hybridoma clones were selected using the above experiments, expanded, and further antibody preparations were made. The antibodies were purified according to the purification example and prepared for use in the detection example.

[0128] 5. Determination of hybridoma-positive clone sequences Hybridoma cells in the logarithmic growth phase were harvested, and RNA was extracted using the RNeasy Micro Reagent Kit (Qiagen, Cat. No. 74004) according to the instructions in the kit's manual. TMThe cDNA was reverse transcribed using a Reverse Transcriptase Reagent Kit (Takara, Cat. No. 2680A). PCR amplification of the reverse-transcribed cDNA was performed using a Mouse Ig Primer Set (Novagen, TB326 Rev.B 0503) and then sequenced. A positive clone, 3807, was obtained, and the corresponding antibody variable region amino acid sequence is as follows: >3807-VH: [ka] >3807-VL: [ka]

[0129] [Table 3]

[0130] Example 7. Humanization of anti-FXI / FXIa hybridoma antibodies Three-dimensional homology modeling was performed on antibody molecule 3807, and alignments were performed with the V-base human germline sequence database and the IMGT human antibody heavy chain variable region germline gene database. A heavy chain variable region germline gene with high homology to the selected antibody was selected as a template, and the CDRs of a mouse monoclonal antibody were grafted onto the corresponding human module. The grafted antibody was then subjected to further three-dimensional structural simulation and analysis, and specific sites in the FR region that affect the structural conformation of the CDR region were backmutated. Amino acid residues were annotated using the Kabat numbering system.

[0131] 1. Selection of humanized architecture of hybridoma clone 3807 The humanized light chain template for murine antibody 3807 is IGKV3-11*01, the heavy chain template is IGHV1-69-2*01, and the humanized variable region sequences are as follows (CDRs are underlined): >3807VH-CDR transplant [ka] >3807VL-CDR ported [ka]

[0132] 2. Reversion of hybridoma clone 3807 The site and mutation scheme are shown in Table 4. [Table 4] The specific sequence is as follows: >3807-VH1: [ka] >3807-VH2: [ka] >3807-VH3: [ka] >3807-VH4: [ka] >3807-VH5: [ka] >3807-VL1: [ka] >3807-VL2: [ka] >3807-VL3: [ka] >3807-VL4: [ka] Antibody 3871 has a VH of 3807-VH1 and a VL of 3807-VL3, and antibody 3875 has a VH of 3807-VH5 and a VL of 3807-VL3.

[0133] Example 8. Modifications to reduce the immunogenicity of anti-FXI / FXIa humanized monoclonal antibodies To make the antibodies more stable and less immunogenic, 3871 and 3875 were genetically modified according to the method of Example 5. Only the heavy chain FR region was modified, and the light chain variable region was not changed.

[0134] 1. The genetically engineered heavy chain variable region sequence of humanized antibody 3875 is as follows (light chain unchanged): >3807-VH5(ESAN) [ka] >3807-VH5(TSTN) [ka] >3807-VH5(ESTN) [ka]

[0135] 2. The genetically engineered heavy chain variable region sequence of humanized antibody 3871 is as follows (the light chain is unchanged): >3807-VH1(AR) [ka] >3807-VH1(YTFT) [ka] >3807-VH1(GTFS) [ka] Antibody 3882 has a VH of 3807-VH1(GTFS) and a VL of 3807-VL3. Each of the heavy chain variable regions was fused to the corresponding human antibody heavy chain CH1 (SEQ ID NO: 59) and human antibody IgG4 Fc (containing the S241P mutation) (SEQ ID NO: 60), and the light chain variable region was fused to the human kappa constant region CL1 (SEQ ID NO: 14) to construct a recombinant chimeric antibody for subsequent detection.

[0136] >Human antibody heavy chain CH1: [ka] >Human antibody IgG4PFc (i.e., containing the S241P mutation) [ka] 3882 shows an example of a full-length antibody sequence. >3882-HC: [ka] >3882-LC: [ka] [Table 5]

[0137] Example 9. Preparation of anti-FXI / FXIa antibodies and detection of their binding ability to human FXI / FXIa The heavy chain variable region of the anti-FXI / FXIa mouse or humanized antibody of the present disclosure was cloned into a mammalian cell expression vector containing the human antibody heavy chain IgG1, and the light chain variable region was cloned into a mammalian cell expression vector containing the human antibody kappa light chain constant region Cκ1. ExpiCHO cells were transfected with the expression vector. Transfection was performed using the ExpiCHO Expression System (Cat. no. A29133) at a transfection ratio of 1 μg of DNA / mL of transfected cells, according to the manufacturer's instructions. The cells were cultured at 37°C in a shaker (8% CO2) using standard methods. On day 8, the cell culture medium was collected, centrifuged at 4000 rpm, and the supernatant was filtered through a 0.45 μM filter. The target antibody was obtained by detection.

[0138] Biacore measurement A fixed amount of antibody to be measured was affinity captured using a Protein A biosensor chip (Cat. # 29127556, GE), and a gradient series of human FXI / FXIa was flowed across the chip surface. The reaction signal was detected in real time using a Biacore instrument (Biacore T200, GE), and binding and dissociation curves were obtained. After each dissociation cycle was completed, the biochip was regenerated by washing with the regeneration solution provided in the human anti-capture reagent kit or a pH 1.5 glycine-HCl regeneration solution (Cat. # BR-1003-54, GE). The buffer used in the experiment was HBS-EP + 10x buffer solution (Cat. # BR-1006-69, GE) diluted to 1x (pH 7.4) with double-distilled water.

[0139] The experimental data was fitted with the (1:1) Langmuir model using BIAevaluation version 4.1, GE software, to obtain affinity values. The test results for some antibodies are shown in Figure 1A, Figure 1B and Table 6 below. [Table 6]

[0140] Example 10. In vitro FXIa enzyme activity inhibition test of anti-FXI / FXIa antibodies To test the function of anti-FXI / FXIa antibodies, we detected their ability to bind to trypsin FXIa and inhibit the FXIa enzyme cleavage-specific substrate, and to bind to trypsinogen FXI and block the enzymatic cleavage of FXIIa to FXI.

[0141] A SpectraMax M5 microplate reader was preset to 37°C, and a 384-well plate (Thermo, Cat. 94410153) was pre-cooled on ice. 20 μL of ready-to-measure antibody (10 μg / mL) and 10 μL of FXIa trypsin (5 μg / mL), each diluted with 1x PBS, were added. The plate was then incubated at 37°C for 5 min, and then placed on ice for another 5 min. 10 μL of S-2366 (2 mM) (Chromogenix, S821090) was added. The kinetic curve was then read at 405 nm at 37°C (one reading per minute, 60 min) using the SpectraMax M5 microplate reader.

[0142] The test results of some antibodies are shown in Figure 2A, among which human IgG isotype was used as a negative control (NC).

[0143] The ability of anti-FXI / FXIa antibodies to block the enzymatic cleavage of FXIIa to FXI was detected by pre-cooling a 384-well plate on ice. 10 μL of FXI (12 μg / mL), 10 μL of FXIIa (7.8 μg / mL), 10 μL of FXI / FXIa antibody (300 μg / mL), and 10 μL of Dextran (100 μg / mL) diluted in buffer (20 mM HEPES, pH 7.4, 150 mM NaCl, and 0.1% BSA) were added to the plate. The plate was incubated at 37°C for 60 min, then placed on ice for 5 min. After addition of 10 μL of S-2366 (8 mM) (Chromogenix, S821090), the plate was detected using a microplate reader.

[0144] The test results for some antibodies are shown in Figure 2B, among which the human IgG isotype was used as a negative control (NC).

[0145] Example 11. Detection of aPTT and PT anticoagulant activity in human blood / monkey blood Fresh human / monkey blood was collected in a sodium citrate tube and centrifuged at 3000 rpm for 15 minutes, and the upper layer of plasma was collected.

[0146] The activated partial thromboplastin time (aPTT) was measured in the presence of different concentrations of candidate antibodies (diluted in PBS) using a Sysmex reagent kit. The candidate antibodies to be tested were incubated with plasma at 37°C for 3 minutes, and then 25 mM calcium chloride was added to initiate blood clotting. The time it took for blood clotting to occur was measured. The concentration of the candidate antibody that prolonged the aPTT by 50% compared to PBS (i.e., aPTT1.5) was measured, and the test results for some antibodies are shown in Figures 3A and 4A and Table 7.

[0147] The prothrombin time (PT) was measured in the presence of different concentrations of candidate antibodies (diluted in PBS) using a Sysmex reagent kit. The candidate antibodies to be tested were incubated with plasma at 37°C for 3 minutes, and then thromboplastin was added to initiate blood clotting, and the time it took for blood clotting to occur was measured. The test results for some antibodies are shown in Figures 3B and 4B.

[0148] The results showed that 3807, 3871, 3875, and 3882 could achieve a 1.5-fold prolongation of aPTT at lower concentrations than Bay1213790, had stronger inhibitory effects on FXI, and could more effectively inhibit blood coagulation. Furthermore, none of the above antibodies had the effect of prolonging PT. [Table 7]

[0149] Example 12. Pharmacokinetic (PK) / pharmacodynamic (PD) study in cynomolgus monkeys Normal adult male cynomolgus monkeys (body weight range 4.0–4.7 kg) were assigned to groups based on body weight (the first, fourth, and fifth weights were assigned to one group, and the second, third, and sixth weights were assigned to the other group), with three monkeys per group, and observed for 14 days.

[0150] Blood samples were collected using sodium citrate blood collection tubes the day before administration. Pre-administration samples were used to measure aPTT, PT, blood drug concentration, plasma activated factor XI (FXI) percentage (FXI:C%, i.e., the percentage of FXI with blood coagulation activity), and plasma free FXI concentration, as well as the bleeding time of each animal. One group of animals was left untreated, while the other group received 3882 at 5 milligrams per kilogram body weight (mg / kg, mpk). The drug was dissolved in phosphate buffered saline (PBS) at a concentration of 5 milligrams per milliliter (mg / mL) and administered intravenously.

[0151] In the blank control group, bleeding times were observed 15 minutes (min) and 3 hours (h) after administration. Plasma samples were collected at 15 minutes, 3 hours, 6 hours, and 1 day (d) after administration, and aPTT and PT were measured according to the methods described above. In the treatment group, bleeding times were observed at 15 minutes, 3 hours, 2 days, 4 days, 1 week (w), 2 weeks, and 3 weeks after administration. Plasma samples were collected at 15 minutes, 3 hours, 6 hours, 1 day (w), 2 weeks, 3 weeks, 4 weeks, 5 weeks, and 6 weeks after administration, and aPTT, PT, blood drug concentrations, plasma FXI:C%, and plasma free FXI concentrations were measured according to the methods described above. In both groups, thrombi were formed via AV shunt 1 day after administration. The thrombus formation time was 10 minutes, and the net weight of the thrombi was weighed.

[0152] The aPTT, PT, and plasma FXI:C% were measured using a blood coagulation analyzer and corresponding reagent kit, while plasma free FXI and blood drug concentrations were measured using ELISA. The weight of thrombus was compared between the treatment and control groups, and statistical analysis was performed using t-tests.

[0153] The antibody test results are shown in Figures 5A-5D, where the negative control (NC) was unadministered. The results showed that 5 mpk effectively inhibited thrombus formation and prolonged the intrinsic blood clotting time, but had no significant effect on the animal bleeding time or the exogenous blood clotting time. PK results indicated a half-life of approximately 20 days. The "**" in Figure 5B indicates a significant difference (P<0.01).

[0154] Example 13. In vivo pharmacodynamics (PD) study in cynomolgus monkeys Six normal adult male cynomolgus monkeys (weight range 7-9 kg) were randomly divided into three groups as follows: BAY1213790 intravenous administration 1 milligram per kilogram body weight (mg / kg) group, 3882 Intravenous administration 1 milligram per kilogram body weight (mg / kg) group, 3882 subcutaneous administration 1 milligram per kilogram body weight (mg / kg) group. Blood samples were collected using sodium citrate blood collection tubes from animals in the intravenous administration group before administration and 5 min, 1 h, 1 d, 2 d, 3 d, 5 d, 1 w, 2 w, 3 w, and 4 w after administration, and from animals in the subcutaneous administration group before administration and 1 h, 1 d, 2 d, 3 d, 5 d, 1 w, 2 w, 3 w, and 4 w after administration, and aPTT and plasma FXI:C% were measured using a blood coagulation device and corresponding reagent kit.

[0155] The test results are shown in Figures 6A and 6B. The results show that both subcutaneous and intravenous administration of 3882 significantly prolonged the intrinsic blood clotting time and inhibited FXI activity. Compared with BAY1213790 at the same dose, 3882 maintained the prolonged intrinsic blood clotting time for a longer period and had a stronger inhibitory effect on FXI.

[0156] >BAY1213790 heavy chain: [ka] >BAY1213790 light chain: [ka] Embodiments of the present disclosure are further described in the following sections: [Section 1] A heavy chain HCDR1 comprising the sequence set forth in SEQ ID NO: 63; A heavy chain HCDR2 comprising the sequence set forth in SEQ ID NO: 64; a heavy chain HCDR3 comprising the sequence set forth in SEQ ID NO: 9 or SEQ ID NO: 39; a light chain LCDR1 comprising the sequence set forth in SEQ ID NO: 10 or SEQ ID NO: 40; a light chain LCDR2 comprising the sequence set forth in SEQ ID NO: 65; a light chain LCDR3 comprising the sequence set forth in SEQ ID NO: 66; Including, An anti-FXI / FXIa antibody or an antigen-binding fragment thereof. [Section 2] (a) heavy chain HCDR1, HCDR2, HCDR3 comprising the sequences shown in SEQ ID NOs: 37, 38, 39, respectively, and light chain LCDR1, LCDR2, LCDR3 comprising the sequences shown in SEQ ID NOs: 40, 41, 42, respectively; (b) heavy chain HCDR1, HCDR2, and HCDR3 comprising the sequences shown in SEQ ID NOs: 7, 8, and 9, respectively, and light chain LCDR1, LCDR2, and LCDR3 comprising the sequences shown in SEQ ID NOs: 10, 11, and 12, respectively; (c) heavy chain HCDR1, HCDR2, and HCDR3 comprising the sequences shown in SEQ ID NOs: 22, 23, and 9, respectively, and light chain LCDR1, LCDR2, and LCDR3 comprising the sequences shown in SEQ ID NOs: 10, 29, and 12, respectively; (d) heavy chain HCDR1, HCDR2, HCDR3 comprising the sequences shown in SEQ ID NOs: 24, 25, 9, respectively, and light chain LCDR1, LCDR2, LCDR3 comprising the sequences shown in SEQ ID NOs: 10, 29, 12, respectively; (e) heavy chain HCDR1, HCDR2, and HCDR3 comprising the sequences shown in SEQ ID NOs: 26, 27, and 9, respectively, and light chain LCDR1, LCDR2, and LCDR3 comprising the sequences shown in SEQ ID NOs: 10, 29, and 12, respectively; or (f) heavy chain HCDR1, HCDR2, HCDR3 comprising the sequences shown in SEQ ID NOs: 28, 25, and 9, respectively, and light chain LCDR1, LCDR2, LCDR3 comprising the sequences shown in SEQ ID NOs: 10, 29, and 12, respectively; Including, The anti-FXI / FXIa antibody or antigen-binding fragment thereof according to item 1 above. [Section 3] a murine antibody, a chimeric antibody, a humanized antibody, a human antibody, or a fragment thereof; Preferably, it is a humanized antibody or a fragment thereof, More preferably, the light chain template of the humanized antibody or fragment thereof is IGKV3-11*01 and the heavy chain template is IGHV1-69-2*01. The anti-FXI / FXIa antibody or antigen-binding fragment thereof according to any one of items 1 and 2 above. [Section 4] the VH has any one or any combination of back mutations: Y27F, T28N, F29I, T30K, A93L, R94Y, E73T, R66K, V67A, T75A, T76N, and / or the VL has any one or any combination of back mutations: R45K, L46R, L47W, I58V, F71Y; The anti-FXI / FXIa antibody or antigen-binding fragment thereof according to item 3 above. [Section 5] A VH represented by one of SEQ ID NOs: 5, 17 to 20, 30 to 33, 35, 43, 45 to 49, and 53 to 58, or having at least 90% identity thereto; A VL represented by one of SEQ ID NOs: 6, 21, 34, 36, 44, 50 to 52, or having at least 90% identity thereto; Including, 5. The anti-FXI / FXIa antibody or antigen-binding fragment thereof according to any one of items 1 to 4 above. [Section 6] A VH set forth in SEQ ID NO: 58 or having at least 90% identity thereto, and VL as set forth in SEQ ID NO: 51 or having at least 90% identity thereto; A VH as set forth in SEQ ID NO: 5 or having at least 90% identity thereto, and VL as set forth in SEQ ID NO: 6 or having at least 90% identity thereto; A VH as set forth in SEQ ID NO: 17 or having at least 90% identity thereto, and VL as set forth in SEQ ID NO: 21 or having at least 90% identity thereto; A VH as set forth in SEQ ID NO: 18 or having at least 90% identity thereto, and VL as set forth in SEQ ID NO: 21 or having at least 90% identity thereto; A VH as set forth in SEQ ID NO: 19 or having at least 90% identity thereto, and VL as set forth in SEQ ID NO: 21 or having at least 90% identity thereto; A VH as set forth in SEQ ID NO: 20 or having at least 90% identity thereto, and VL as set forth in SEQ ID NO: 21 or having at least 90% identity thereto; A VH set forth in SEQ ID NO: 30 or having at least 90% identity thereto, and VL as set forth in SEQ ID NO: 34 or having at least 90% identity thereto; A VH as set forth in SEQ ID NO: 31 or having at least 90% identity thereto, and VL as set forth in SEQ ID NO: 34 or having at least 90% identity thereto; A VH as set forth in SEQ ID NO: 32 or having at least 90% identity thereto, and VL as set forth in SEQ ID NO: 34 or having at least 90% identity thereto; A VH set forth in SEQ ID NO: 35 or having at least 90% identity thereto, and VL as set forth in SEQ ID NO: 36 or having at least 90% identity thereto; A VH set forth in SEQ ID NO: 43 or having at least 90% identity thereto, and VL as set forth in SEQ ID NO: 44 or having at least 90% identity thereto; A VH set forth in SEQ ID NO: 45 or having at least 90% identity thereto, and VL as set forth in SEQ ID NO: 51 or having at least 90% identity thereto; A VH set forth in SEQ ID NO: 49 or having at least 90% identity thereto, and VL as set forth in SEQ ID NO: 51 or having at least 90% identity thereto; Including, The anti-FXI / FXIa antibody or antigen-binding fragment thereof according to Item 5 above. [Section 7] VH is linked to human or mouse CH1, and VL is linked to human or mouse CL or Cκ; Preferably, the human CH1 is represented by SEQ ID NO: 13 or 59, and the sequence of the Cκ is represented by SEQ ID NO: 14. 7. The anti-FXI / FXIa antibody or antigen-binding fragment thereof according to any one of items 1 to 6 above. [Section 8] containing a constant region Fc, Preferably, the Fc is an IgG1 Fc, an IgG4 Fc, or an IgG4P Fc; More preferably, the IgG1 Fc sequence is set forth in SEQ ID NO: 67 and the IgG4P Fc sequence is set forth in SEQ ID NO: 60. 8. The anti-FXI / FXIa antibody or antigen-binding fragment thereof according to any one of items 1 to 7. [Section 9] the heavy chain is set forth in SEQ ID NO: 61 or has at least 80% identity thereto; the light chain is set forth in SEQ ID NO: 62 or has at least 80% identity thereto; or the heavy chain is set forth in SEQ ID NO: 15 or has at least 80% identity thereto; The light chain is set forth in SEQ ID NO: 16 or has at least 80% identity thereto; 9. The anti-FXI / FXIa antibody or antigen-binding fragment thereof according to any one of items 1 to 8. [Section 10] the antigen-binding fragment is selected from an scFv, Fv, Fab, or Fab' fragment; 10. The anti-FXI / FXIa antibody or antigen-binding fragment thereof according to any one of items 1 to 9 above. [Section 11] Preventing or inhibiting activation of blood coagulation pathways; blocking the binding of FXI / FXIa to one or more of FIX, FXIIa, and thrombin; blocking the binding of FIX, FXI, and FXIa to one or more platelet receptors; 10 -9 K D binds to human FXI and / or FXIa protein with an affinity of When bound to FXI / FXIa, it prevents its catalytic domain from assuming an active conformation; It can be administered subcutaneously or intravenously; having one or more of the following characteristics: 11. The anti-FXI / FXIa antibody or antigen-binding fragment thereof according to any one of items 1 to 10 above. [Section 12] 12. A polynucleotide encoding the anti-FXI / FXIa antibody or antigen-binding fragment thereof according to any one of items 1 to 11 above. [Section 13] A vector comprising the polynucleotide according to Item 12 above. [Section 14] A host cell comprising the vector according to item 13 above. [Section 15] 1. A method for preparing an anti-FXI / FXIa antibody or antigen-binding fragment thereof, comprising: expressing an anti-FXI / FXIa antibody or an antigen-binding fragment thereof in the host cell according to item 14; isolating the anti-FXI / FXIa antibody or antigen-binding fragment thereof from the host cell; Including, method. [Section 16] a pharmaceutically acceptable excipient, diluent or vector; - a pharmaceutical composition comprising any one selected from the anti-FXI / FXIa antibody or antigen-binding fragment thereof according to any one of items 1 to 11, the polynucleotide according to item 12, and the vector according to item 13, or any combination thereof, Preferably, the pharmaceutical composition is a subcutaneous or intravenous injection. Pharmaceutical compositions. [Section 17] A use of any one selected from the anti-FXI / FXIa antibody or antigen-binding fragment thereof according to any one of Items 1 to 11, the polynucleotide according to Item 12, and the vector according to Item 13, or any combination thereof, in the preparation of a medicament or pharmaceutical composition, comprising: The medicament or pharmaceutical composition is used for the treatment and / or prevention of any one selected from thrombogenic or thromboembolic diseases, thrombogenic or thromboembolic complications, arrhythmia, cardiogenic thromboembolism, and diffuse intravascular coagulation; Preferably, the thrombogenic or thromboembolic disease or complication thereof is selected from coronary artery disease, ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (non-STEMI), stable angina, unstable angina, re-occlusion and restenosis after coronary intervention, peripheral arterial occlusive disease, pulmonary embolism, venous thromboembolism, venous thrombosis, transient ischemic attack, thrombotic and thromboembolic stroke, chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary arterial hypertension due to CTEPH, or a combination thereof; Preferably, the coronary artery disease is acute coronary syndrome. Use. [Section 18] 1. A method for treating and / or preventing a disease, comprising: The disease is any one selected from thrombogenic or thromboembolic diseases, thrombogenic or thromboembolic complications, arrhythmias, cardiogenic thromboembolism, and diffuse intravascular coagulation; The method comprises: Administering to a subject an anti-FXI / FXIa antibody or antigen-binding fragment thereof according to any one of Items 1 to 11, a polynucleotide according to Item 12, a vector according to Item 13, or any combination thereof, in an amount effective for the treatment or prevention of a disease; Preferably, the thrombogenic or thromboembolic disease or complication thereof is selected from coronary artery disease, ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (non-STEMI), stable angina, unstable angina, re-occlusion and restenosis after coronary intervention, peripheral arterial occlusive disease, pulmonary embolism, venous thromboembolism, venous thrombosis, transient ischemic attack, thrombotic and thromboembolic stroke, chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary arterial hypertension due to CTEPH, or a combination thereof; Preferably, the coronary artery disease is an acute coronary syndrome; Preferably, the subject suffers from ischemic stroke and / or deep vein thrombosis associated with atrial fibrillation. method. While specific embodiments of the present disclosure have been described above, those skilled in the art should understand that these are merely illustrative examples and that various changes and modifications can be made to these embodiments without departing from the principles and spirit of the present invention. Accordingly, the scope of the present disclosure is limited by the appended claims.

Claims

1. heavy chain HCDR1, HCDR2, HCDR3 comprising the sequences shown in SEQ ID NOs: 37, 38, 39, respectively, and light chain LCDR1, LCDR2, LCDR3 comprising the sequences shown in SEQ ID NOs: 40, 41, 42, respectively; An anti-FXI / FXIa antibody or an antigen-binding fragment thereof.

2. a murine antibody, a chimeric antibody, a humanized antibody, or a fragment thereof; The light chain template of the humanized antibody or fragment thereof is IGKV3-11*01 and the heavy chain template is IGHV1-69-2*01; The anti-FXI / FXIa antibody or antigen-binding fragment thereof according to claim 1.

3. the VH has any one or any combination of back mutations: Y27F, T28N, F29I, T30K, A93L, R94Y, E73T, R66K, V67A, T75A, T76N; and / or the VL has any one or any combination of back mutations: R45K, L46R, L47W, I58V, F71Y; The anti-FXI / FXIa antibody or antigen-binding fragment thereof according to claim 2.

4. A VH represented by one of SEQ ID NOs: 35, 43, 45-49, 53-58, or having at least 90% identity thereto; A VL represented by one of SEQ ID NOs: 36, 44, 50-52 or having at least 90% identity thereto; Including, An anti-FXI / FXIa antibody or an antigen-binding fragment thereof according to any one of claims 1 to 3.

5. A VH set forth in SEQ ID NO: 58 or having at least 90% identity thereto; and VL as set forth in SEQ ID NO: 51 or having at least 90% identity thereto; A VH as set forth in SEQ ID NO: 35 or having at least 90% identity thereto; and VL as set forth in SEQ ID NO: 36 or having at least 90% identity thereto; A VH as set forth in SEQ ID NO: 43 or having at least 90% identity thereto; and VL as set forth in SEQ ID NO: 44 or having at least 90% identity thereto; A VH set forth in SEQ ID NO: 45 or having at least 90% identity thereto; and VL as set forth in SEQ ID NO: 51 or having at least 90% identity thereto; Or, A VH set forth in SEQ ID NO: 49 or having at least 90% identity thereto; and VL as set forth in SEQ ID NO: 51 or having at least 90% identity thereto; Including, The anti-FXI / FXIa antibody or antigen-binding fragment thereof according to claim 4.

6. VH is linked to human or mouse CH1 and VL is linked to human or mouse CL or CK; An anti-FXI / FXIa antibody or an antigen-binding fragment thereof according to any one of claims 1 to 5.

7. comprising a constant region Fc, The Fc is an IgG1 Fc, an IgG4 Fc, or an IgG4P Fc; An anti-FXI / FXIa antibody or an antigen-binding fragment thereof according to any one of claims 1 to 6.

8. the heavy chain is set forth in SEQ ID NO: 61 or has at least 90% identity thereto; The light chain is set forth in SEQ ID NO: 62 or has at least 90% identity thereto; An anti-FXI / FXIa antibody or an antigen-binding fragment thereof according to any one of claims 1 to 7.

9. the antigen-binding fragment is selected from an scFv, Fv, Fab, or Fab′ fragment; An anti-FXI / FXIa antibody or an antigen-binding fragment thereof according to any one of claims 1 to 6.

10. Preventing or inhibiting activation of blood coagulation pathways; Blocking the binding of FXI / FXIa to one or more of FIX, FXIIa, thrombin; blocking the binding of FIX, FXI, FXIa to one or more platelet receptors; 10 －９ K Ｄ binds to human FXI and / or FXIa protein with an affinity of Preventing its catalytic domain from assuming an active conformation when bound to FXI / FXIa; It can be administered subcutaneously or intravenously; having one or more of the following characteristics: An anti-FXI / FXIa antibody or an antigen-binding fragment thereof according to any one of claims 1 to 9.

11. A polynucleotide encoding the anti-FXI / FXIa antibody or antigen-binding fragment thereof according to any one of claims 1 to 10.

12. A vector comprising the polynucleotide of claim 11.

13. A host cell comprising the vector of claim 12.

14. 1. A method for preparing an anti-FXI / FXIa antibody or antigen-binding fragment thereof, comprising: Expressing an anti-FXI / FXIa antibody or antigen-binding fragment thereof in the host cell of claim 13; isolating the anti-FXI / FXIa antibody or antigen-binding fragment thereof from the host cell; Including, method.

15. a pharmaceutically acceptable excipient, diluent or vector, - a pharmaceutical composition comprising any one of the anti-FXI / FXIa antibody or antigen-binding fragment thereof according to any one of claims 1 to 10, the polynucleotide according to claim 11, the vector according to claim 12, or any combination thereof.

16. Use of any one selected from the anti-FXI / FXIa antibody or antigen-binding fragment thereof according to any one of claims 1 to 10, the polynucleotide according to claim 11, and the vector according to claim 12, or any combination thereof, in the preparation of a medicament or pharmaceutical composition, The medicament or pharmaceutical composition is used for the treatment and / or prevention of any one selected from thrombogenic or thromboembolic diseases, thrombogenic or thromboembolic complications, arrhythmia, cardiogenic thromboembolism, and diffuse intravascular coagulation. use.

17. The thrombogenic or thromboembolic disease or complication thereof is selected from coronary artery disease, ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (non-STEMI), stable angina, unstable angina, re-occlusion and restenosis after coronary intervention, peripheral arterial occlusive disease, pulmonary embolism, venous thromboembolism, venous thrombosis, transient ischemic attack, thrombotic stroke and thromboembolic stroke, chronic thromboembolic pulmonary disease (CTEPH), pulmonary arterial hypertension due to CTEPH, or a combination thereof; 17. The use according to claim 16.

18. The coronary artery disease is acute coronary syndrome.

18. The use according to claim 17.

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