Anti-coagulation factor xi / xia antibody formulation

Abstract

The present invention relates to the field of therapeutic antibodies. Specifically, the present invention relates to an anti-coagulation factor Ⅺ / Ⅺa antibody formulation, which comprises an anti-coagulation factor Ⅺ / Ⅺa antibody, a buffer, glutamic acid, and arginine. The anti-coagulation factor Ⅺ / Ⅺa antibody formulation of the present invention can maintain antibody stability after long-term storage while achieving sufficiently low viscosity at high concentrations. In addition, the present invention further relates to use of the anti-coagulation factor Ⅺ / Ⅺa antibody formulation in the preparation of a medicament for preventing and / or treating diseases or disorders related to blood coagulation or thromboembolism.

Description

An anti-coagulation factor XI / XIa antibody preparation

[0001] This application is based on the application with CN application number 202311792399.7 and application date December 22, 2023, and claims its priority. The disclosed content of the CN application is hereby introduced as a whole into this application. Technical Field

[0002] The present invention relates to the field of therapeutic antibodies, and more specifically, to a preparation of an anti-coagulation factor XI / XIa antibody or an antigen-binding fragment thereof and its medical use. Background Art

[0003] Thrombosis or embolism affects all organs in the body, primarily the heart, brain, and peripheral vascular diseases. It is characterized by high incidence, high disability, and high mortality, and is the leading cause of death from cardiovascular disease. Currently, the main medications for the prevention and treatment of thrombotic diseases include anticoagulants, antiplatelets, and thrombolytics. Anticoagulants are primarily used clinically to prevent and treat venous thromboembolism from various causes. They can also be used to prevent stroke in patients with atrial fibrillation and provide anticoagulant therapy for patients with acute coronary syndromes.

[0004] Coagulation factor XI (FXI) participates in the intrinsic coagulation cascade, with its active form being factor XIa (FXIa). The FXI protein is a dimer composed of two homologous monomers with a molecular weight of approximately 80 kDa, bonded by disulfide bonds. The FXI monomer consists of four apple domains and a catalytic domain. The formation of FXIa by factor XIIa (FXIIa) exposes the binding site for FIX. Binding to FIX promotes the conversion of FIX to active FIXa, activating the downstream coagulation cascade. Factor XI is present in mammalian plasma at concentrations of approximately 25-30 nM. It is a glycoprotein present as a zymogen. Almost all FXI forms a complex with a high molecular weight kininogen (HK) and circulates in the blood. The effect of HK on FXI function remains unclear. HK may facilitate the binding of FXI to platelets or endothelial cells, but studies have also observed that HK inhibits FXI activation. The activation process of FXI is that each monomer is cleaved between Arg369 and Ile370 under the action of different proteases, producing a protein composed of a heavy chain of approximately 50kDa containing the apple domain and a light chain of approximately 30kDa containing the catalytic domain. The heavy and light chains are connected by a disulfide bond formed by Cys362-Cys482. Activated FXI, FXIa, usually refers to the dimer FXI in which each monomer is cleaved at Arg369, but there are also cases where only one monomer is activated. 2+The enzyme FIX is cleaved by the enzyme FIXa, which converts it into activated FIX (FIXa), which then converts coagulation factor X into its active form, Xa. Xa can then mediate the activation of coagulation factor II / thrombin. Thrombin, as the terminal protease in the coagulation cascade, can further promote the production of FXIa by directly activating FXI in a feedback mechanism. Both coagulation factor XIIa and FXIa (autoactivation) in the coagulation cascade can convert FXI into FXIa.

[0005] Furthermore, activated FIX (FIXa) can directly bind to platelets, promoting the formation of platelet aggregates in the blood and leading to distal microvascular occlusion. Therefore, FIX / FIXa promotes thrombosis through multiple pathways. Furthermore, animal experiments and clinical observations have shown that the absence of FIX / FIXa only carries a minimal risk of bleeding. Therefore, FIX / FIXa is an ideal target for the prevention and treatment of diseases / conditions associated with coagulation or thromboembolism. (Zilberman-Rudenko J. et al. Coagulation factor XI promotes distal platelet activation and single platelet connumption in the bloodstream under shear flow. Arterioscler Thromb Vasc Biol. 2016 March; 36(3): 510-517.).

[0006] WO2020 / 211674 discloses novel anti-factor XI / XIa antibodies that effectively block the activity of FXI and / or FXIa in thrombosis, demonstrating promising therapeutic effects for coagulation or thromboembolism-related diseases. However, the clinical application of anti-factor XI / XIa antibodies requires addressing issues such as their physicochemical properties suitable for administration and their stability during storage.

[0007] Therefore, it is very necessary to develop a suitable formulation for anti-coagulation factor XI / XIa antibodies to obtain antibody preparations that meet the physiological compatibility and stability requirements. Summary of the Invention

[0008] After a large number of experiments and repeated explorations, the inventors of the present application unexpectedly discovered that a liquid preparation composed of an anti-coagulation factor XI / XIa antibody and a specific prescription has excellent stability and can obtain a high-concentration preparation with sufficiently low viscosity, thereby significantly reducing the difficulty of production and administration of high-concentration preparations, thereby improving patient compliance.

[0009] Therefore, in one aspect, the present application provides a liquid formulation comprising:

[0010] (1) an antibody or antigen-binding fragment thereof that specifically binds to FXI and / or FXIa;

[0011] (2) Arginine;

[0012] (3) glutamate; and

[0013] (4) Buffer solution.

[0014] In certain embodiments, the concentration of the antibody or antigen-binding fragment thereof that specifically binds FXI and / or FXIa is 20-250 mg / ml (e.g., 20-200 mg / ml, 20-180 mg / ml, 20-160 mg / ml, 20-150 mg / ml, 50-250 mg / ml, 50-200 mg / ml, 50-180 mg / ml, 50-150 mg / ml, 100-250 mg / ml, 100-200 mg / ml, 100-180 mg / ml, 100-150 mg / ml, 120-250 mg / ml, 120-200 mg / ml, 120-180 mg / ml, 120-150 mg / ml).

[0015] In certain embodiments, the concentration of the antibody or antigen-binding fragment thereof that specifically binds FXI and / or FXIa is 100-200 mg / ml (e.g., 100-180 mg / ml, 100-150 mg / ml, 120-200 mg / ml, 120-180 mg / ml, 120-150 mg / ml, 120 mg / ml, 150 mg / ml).

[0016] In certain embodiments, the arginine is at a concentration of 50-200 mM (e.g., 50-180 mM, 50-150 mM, 50-120 mM, 60-200 mM, 60-180 mM, 60-150 mM, 60-120 mM, 80-200 mM, 80-180 mM, 80-150 mM, 80-120 mM, 100-200 mM, 100-180 mM, 100-150 mM, 100-120 mM).

[0017] In certain embodiments, the arginine is at a concentration of 60-150 mM (e.g., 60-120 mM, 80-150 mM, 80-120 mM, 100-150 mM, 100-120 mM, 80 mM, 100 mM, 120 mM, 150 mM).

[0018] In certain embodiments, the concentration of glutamate is 50-200 mM (e.g., 50-180 mM, 50-150 mM, 50-120 mM, 60-200 mM, 60-180 mM, 60-150 mM, 60-120 mM, 80-200 mM, 80-180 mM, 80-150 mM, 80-120 mM, 100-200 mM, 100-180 mM, 100-150 mM, 100-120 mM).

[0019] In certain embodiments, the concentration of glutamate is 60-150 mM (e.g., 60-120 mM, 80-150 mM, 80-120 mM, 100-150 mM, 100-120 mM, 80 mM, 100 mM, 120 mM, 150 mM).

[0020] In certain embodiments, the total molar concentration of the arginine and the glutamate (i.e., the sum of the molar concentrations of the arginine and the glutamate) is 100-400 mM (e.g., 100-240 mM, 100-300 mM, 100-350 mM, 200-240 mM, 200-300 mM, 200-350 mM, 200-400 mM).

[0021] In certain embodiments, the molar concentration ratio of the arginine:the glutamate is in the range of 0.4:1 to 2.5:1 (e.g., 0.4:1 to 1:1, 0.4:1 to 1.5:1, 0.4:1 to 2:1, 0.7:1 to 1:1, 0.7:1 to 1.5:1, 0.7:1 to 2:1, 0.7:1 to 2.5:1, 1:1 to 1.5:1, 1:1 to 2:1, 1:1 to 2.5:1).

[0022] In certain embodiments, the molar concentration ratio of the arginine: glutamate is in the range of 0.5:1 to 2:1 (e.g., 0.7:1 to 1:1, 0.7:1 to 1.5:1, 0.7:1 to 2:1, 1:1 to 1.5:1, 1:1 to 2:1). In certain embodiments, the molar concentration ratio of the arginine: glutamate is 1:1.

[0023] In certain embodiments, the buffer has a concentration of 5-50 mM (e.g., 5-20 mM, 5-25 mM, 5-30 mM, 5-40 mM, 8-20 mM, 8-25 mM, 8-30 mM, 8-40 mM, 10-20 mM, 10-25 mM, 10-30 mM, 10-40 mM).

[0024] In certain embodiments, the concentration of the buffer is 10-40 mM (e.g., 10-20 mM, 10-25 mM, 10-30 mM, 10-40 mM, 10 mM, 20 mM).

[0025] In certain embodiments, the buffer is selected from the group consisting of histidine buffer, citric acid-citrate buffer, acetic acid-acetate buffer, and Tris buffer.

[0026] In certain embodiments, the buffer is a histidine buffer. In certain embodiments, the histidine in the histidine buffer exists alone or in the form of histidine-hydrochloride.

[0027] In certain embodiments, the liquid formulation further comprises a surfactant.

[0028] In certain embodiments, the surfactant is a nonionic surfactant.

[0029] In certain embodiments, the surfactant is polysorbate 80 or polysorbate 20. In certain embodiments, the surfactant is polysorbate 20.

[0030] In certain embodiments, the concentration of the surfactant is 0.001%-0.08% w / v (e.g., 0.001%-0.04% w / v, 0.001%-0.06% w / v, 0.003%-0.04% w / v, 0.003%-0.06% w / v, 0.003%-0.08% w / v, 0.005%-0.04% w / v, 0.005%-0.06% w / v, 0.005%-0.08% w / v).

[0031] In certain embodiments, the concentration of the surfactant is 0.005%-0.04% w / v (eg, 0.011% w / v, 0.02% w / v).

[0032] In certain embodiments, the surfactant is polysorbate 20 at a concentration of 0.005%-0.04% w / v.

[0033] In certain embodiments, the pH of the liquid formulation is 5.5-7.5 (e.g., 5.5-6.6, 5.5-7.0, 5.5-7.2, 5.8-6.6, 5.8-7.0, 5.8-7.2, 5.8-7.5, 6.0-6.6, 6.0-7.0, 6.0-7.2, 6.0-7.5).

[0034] In certain embodiments, the pH of the liquid formulation is 6.0-6.6.

[0035] In certain embodiments, the liquid formulation optionally comprises sodium chloride.

[0036] In certain embodiments, the concentration of sodium chloride is 0-130 mM (e.g., 0-120 mM, 0-60 mM, 0-40 mM, 0-20 mM, 10-130 mM, 10-120 mM, 10-60 mM, 10-40 mM, 10-20 mM, 20-130 mM, 20-120 mM, 20-60 mM, 20-40 mM).

[0037] In certain embodiments, the concentration of sodium chloride is 0-60 mM (e.g., 0-40 mM, 0-20 mM, 10-60 mM, 10-40 mM, 10-20 mM, 20-60 mM, 20-40 mM).

[0038] In certain embodiments, the liquid formulation does not contain sodium chloride.

[0039] In certain embodiments, the liquid formulation does not contain sucrose.

[0040] In certain embodiments, the antibody is selected from the antibodies that specifically bind to FXI and / or FXIa disclosed in patent application WO 2020 / 211674 A1.

[0041] In certain embodiments, the antibody or antigen-binding fragment thereof comprises:

[0042] (a) comprising CDR-H1, CDR-H2 and CDR-H3 contained in VH as shown in any one of SEQ ID NOs: 1, 16, 17, and 15; and / or, comprising CDR-L1, CDR-L2 and CDR-L3 contained in VL as shown in any one of SEQ ID NOs: 2, 19, 20, and 18; or,

[0043] (b) comprises CDR-H1, CDR-H2 and CDR-H3 contained in VH as shown in SEQ ID NO: 25 or 23; and / or comprises CDR-L1, CDR-L2 and CDR-L3 contained in VL as shown in SEQ ID NO: 26 or 24.

[0044] In certain embodiments, the CDRs are defined by the IMGT, AbM, Kabat, or Chothia numbering systems.

[0045] In certain embodiments, the antibody or antigen-binding fragment thereof comprises:

[0046] (1) CDR-H1 of SEQ ID NO: 3, CDR-H2 of SEQ ID NO: 4, CDR-H3 of SEQ ID NO: 5; and, CDR-L1 of SEQ ID NO: 6, CDR-L2 of SEQ ID NO: 7, CDR-L3 of SEQ ID NO: 8; in certain embodiments, the CDRs are defined by the IMGT numbering system;

[0047] (2) a CDR-H1 having a sequence of SEQ ID NO: 27, a CDR-H2 having a sequence of SEQ ID NO: 28, and a CDR-H3 having a sequence of SEQ ID NO: 29; and a CDR-L1 having a sequence of SEQ ID NO: 30, a CDR-L2 having a sequence of SEQ ID NO: 31, and a CDR-L3 having a sequence of SEQ ID NO: 32; in certain embodiments, the CDRs are defined by the IMGT numbering system;

[0048] (3) a CDR-H1 of SEQ ID NO: 9, a CDR-H2 of SEQ ID NO: 39, 40, or 10, and a CDR-H3 of SEQ ID NO: 11; and a CDR-L1 of SEQ ID NO: 12, a CDR-L2 of SEQ ID NO: 13, and a CDR-L3 of SEQ ID NO: 14; in certain embodiments, the CDRs are defined by the AbM numbering system;

[0049] or,

[0050] (4) CDR-H1 of SEQ ID NO: 33, CDR-H2 of SEQ ID NO: 34 or 41, CDR-H3 of SEQ ID NO: 35; and, CDR-L1 of SEQ ID NO: 36, CDR-L2 of SEQ ID NO: 37, CDR-L3 of SEQ ID NO: 38; in certain embodiments, the CDRs are defined by the AbM numbering system.

[0051] In certain embodiments, the antibody or antigen-binding fragment thereof comprises:

[0052] (1) CDR-H1 of SEQ ID NO: 3, CDR-H2 of SEQ ID NO: 4, CDR-H3 of SEQ ID NO: 5; and, CDR-L1 of SEQ ID NO: 6, CDR-L2 of SEQ ID NO: 7, CDR-L3 of SEQ ID NO: 8; in certain embodiments, the CDRs are defined by the IMGT numbering system;

[0053] or,

[0054] (2) CDR-H1 of SEQ ID NO: 9, CDR-H2 of SEQ ID NO: 39, CDR-H3 of SEQ ID NO: 11; and, CDR-L1 of SEQ ID NO: 12, CDR-L2 of SEQ ID NO: 13, CDR-L3 of SEQ ID NO: 14; in certain embodiments, the CDRs are defined by the AbM numbering system.

[0055] In certain embodiments, the antibody or antigen-binding fragment thereof comprises the following heavy chain variable region (VH) and light chain variable region (VL):

[0056] (a) a heavy chain variable region (VH) comprising the following three CDRs: CDR-H1 of SEQ ID NO: 3, CDR-H2 of SEQ ID NO: 4, and CDR-H3 of SEQ ID NO: 5; and a light chain variable region (VL) comprising the following three CDRs: CDR-L1 of SEQ ID NO: 6, CDR-L2 of SEQ ID NO: 7, and CDR-L3 of SEQ ID NO: 8; or

[0057] (b) a heavy chain variable region (VH) comprising the following three CDRs: CDR-H1 of SEQ ID NO: 27, CDR-H2 of SEQ ID NO: 28, and CDR-H3 of SEQ ID NO: 29; and a light chain variable region (VL) comprising the following three CDRs: CDR-L1 of SEQ ID NO: 30, CDR-L2 of SEQ ID NO: 31, and CDR-L3 of SEQ ID NO: 32.

[0058] In certain embodiments, the CDRs are defined by the IMGT numbering system.

[0059] In certain embodiments, the antibody or antigen-binding fragment thereof comprises the following heavy chain variable region (VH) and light chain variable region (VL):

[0060] (a) a heavy chain variable region (VH) comprising the following three CDRs: CDR-H1 of SEQ ID NO: 9, CDR-H2 of SEQ ID NO: 39, 40 or 10, and CDR-H3 of SEQ ID NO: 11; and a light chain variable region (VL) comprising the following three CDRs: CDR-L1 of SEQ ID NO: 12, CDR-L2 of SEQ ID NO: 13, and CDR-L3 of SEQ ID NO: 14; or

[0061] (b) a heavy chain variable region (VH) comprising the following three CDRs: CDR-H1 of SEQ ID NO: 33, CDR-H2 of SEQ ID NO: 34 or 41, and CDR-H3 of SEQ ID NO: 35; and a light chain variable region (VL) comprising the following three CDRs: CDR-L1 of SEQ ID NO: 36, CDR-L2 of SEQ ID NO: 37, and CDR-L3 of SEQ ID NO: 38.

[0062] In certain embodiments, the CDRs are defined by the AbM numbering system.

[0063] In certain embodiments, the antibody or antigen-binding fragment thereof comprises the following heavy chain variable region (VH) and light chain variable region (VL):

[0064] (a) a heavy chain variable region (VH) comprising the following three CDRs: CDR-H1 of SEQ ID NO: 3, CDR-H2 of SEQ ID NO: 4, and CDR-H3 of SEQ ID NO: 5; and a light chain variable region (VL) comprising the following three CDRs: CDR-L1 of SEQ ID NO: 6, CDR-L2 of SEQ ID NO: 7, and CDR-L3 of SEQ ID NO: 8; wherein the CDRs are defined by the IMGT numbering system;

[0065] or,

[0066] (b) a heavy chain variable region (VH) comprising the following three CDRs: CDR-H1 of SEQ ID NO: 9, CDR-H2 of SEQ ID NO: 39, and CDR-H3 of SEQ ID NO: 11; and a light chain variable region (VL) comprising the following three CDRs: CDR-L1 of SEQ ID NO: 12, CDR-L2 of SEQ ID NO: 13, and CDR-L3 of SEQ ID NO: 14; wherein the CDRs are defined by the AbM numbering system.

[0067] In certain embodiments, the VH of the antibody or antigen-binding fragment thereof comprises: (a) a sequence as shown in any one of SEQ ID NOs: 15, 1, 16, 17, or (b) a sequence having at least 70%, at least 80%, at least 85%, 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%, or at least 99% sequence identity compared to the sequence shown in any one of SEQ ID NOs: 15, 1, 16, 17; and / or the VL of the antibody or antigen-binding fragment thereof comprises: (a) a sequence as shown in any one of SEQ ID NOs: 18, 2, 19, 20, or (b) a sequence having at least 70%, at least 80%, at least 85%, 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%, or at least 99% sequence identity compared to the sequence shown in any one of SEQ ID NOs: 18, 2, 19, 20, or NO:18, 2, 19, 20 compared to the sequence shown in any one of the sequence having at least 70%, at least 80%, at least 85%, 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% or at least 99% sequence identity.

[0068] In certain embodiments, the VH of the antibody or antigen-binding fragment thereof comprises: (a) a sequence as set forth in SEQ ID NO: 23 or 25, or (b) a sequence having at least 70%, at least 80%, at least 85%, 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%, or at least 99% sequence identity compared to the sequence set forth in SEQ ID NO: 23 or 25; and / or the VL of the antibody or antigen-binding fragment thereof comprises: (a) a sequence as set forth in SEQ ID NO: 24 or 26, or (b) a sequence having at least 70%, at least 80%, at least 85%, 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%, or at least 99% sequence identity compared to the sequence set forth in SEQ ID NO: 24 or 26.

[0069] In certain embodiments, the VH of the antibody or antigen-binding fragment thereof comprises: (a) the sequence as set forth in SEQ ID NO: 15, or (b) a sequence having at least 70%, at least 80%, at least 85%, 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%, or at least 99% sequence identity compared to the sequence as set forth in SEQ ID NO: 15; and / or the VL of the antibody or antigen-binding fragment thereof comprises: (a) the sequence as set forth in SEQ ID NO: 18, or (b) a sequence having at least 70%, at least 80%, at least 85%, 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%, or at least 99% sequence identity compared to the sequence as set forth in SEQ ID NO: 18.

[0070] In certain embodiments, the antibody or antigen-binding fragment thereof comprises a VH as shown in any one of SEQ ID NOs: 15, 1, 16, and 17, and a VL as shown in any one of SEQ ID NOs: 18, 2, 19, and 20.

[0071] In certain embodiments, the antibody or antigen-binding fragment thereof comprises a VH as shown in SEQ ID NOs: 23 or 25, and a VL as shown in SEQ ID NOs: 24 or 26.

[0072] In certain embodiments, the antibody or antigen-binding fragment thereof comprises:

[0073] (a) VH of SEQ ID NO: 15 and VL of SEQ ID NO: 18;

[0074] (b) VH of the sequence shown in SEQ ID NO: 1 and VL of the sequence shown in SEQ ID NO: 2;

[0075] (c) VH of SEQ ID NO: 15 and VL of SEQ ID NO: 20;

[0076] (d) VH of SEQ ID NO: 16 and VL of SEQ ID NO: 18;

[0077] (e) VH of SEQ ID NO: 17 and VL of SEQ ID NO: 19;

[0078] (f) VH of SEQ ID NO: 17 and VL of SEQ ID NO: 18;

[0079] (g) the VH sequence of SEQ ID NO: 23 and the VL sequence of SEQ ID NO: 24; or

[0080] (h) VH of the sequence shown in SEQ ID NO: 25 and VL of the sequence shown in SEQ ID NO: 26.

[0081] In certain embodiments, the antibody or antigen-binding fragment thereof further comprises:

[0082] (a) a heavy chain constant region (CH) of a human immunoglobulin; and / or

[0083] (b) Light chain constant region (CL) of a human immunoglobulin.

[0084] In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region selected from:

[0085] (1) human IgG1 heavy chain constant region; or

[0086] (2) Human IgG4 heavy chain constant region.

[0087] In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region (CH) as shown in SEQ ID NO: 21 or a variant thereof having up to 20 conservative amino acid substitutions compared to SEQ ID NO: 21.

[0088] In certain embodiments, the antibody or antigen-binding fragment thereof comprises a light chain constant region (CL) as set forth in SEQ ID NO: 22 or a variant thereof having up to 20 conservative amino acid substitutions compared to SEQ ID NO: 22.

[0089] In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region (CH) as set forth in SEQ ID NO: 21 and a light chain constant region (CL) as set forth in SEQ ID NO: 22.

[0090] In certain embodiments, the antibody or antigen-binding fragment thereof comprises:

[0091] A heavy chain comprising an amino acid sequence selected from the group consisting of:

[0092] (i) a sequence comprising the VH region of SEQ ID NO: 15 and the heavy chain constant region (CH) of SEQ ID NO: 21; or

[0093] (ii) a sequence having one or more amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (i) (e.g., 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions or any combination thereof); and

[0094] A light chain comprising an amino acid sequence selected from the group consisting of:

[0095] (iii) a sequence comprising the VL region of SEQ ID NO: 18 and the light chain constant region (CL) of SEQ ID NO: 22; or

[0096] (iv) a sequence having one or more amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (iii) (e.g., 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions or any combination thereof).

[0097] In certain embodiments, the antibody or antigen-binding fragment thereof comprises:

[0098] A heavy chain comprising an amino acid sequence selected from the group consisting of:

[0099] (i) a sequence comprising the VH region of SEQ ID NO: 25 and the heavy chain constant region (CH) of SEQ ID NO: 21; or

[0100] (ii) a sequence having one or more amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (i) (e.g., 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions or any combination thereof); and

[0101] A light chain comprising an amino acid sequence selected from the group consisting of:

[0102] (iii) a sequence comprising the VL region of SEQ ID NO: 26 and the light chain constant region (CL) of SEQ ID NO: 22; or

[0103] (iv) a sequence having one or more amino acid substitutions, deletions or additions or any combination thereof compared to the sequence shown in (iii) (e.g., 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions or any combination thereof).

[0104] In certain embodiments, the antibody or antibody fragment thereof is selected from any one of the following groups:

[0105] (a) a heavy chain comprising the VH region of SEQ ID NO: 15 and the heavy chain constant region (CH) of SEQ ID NO: 21, and a light chain comprising the VL region of SEQ ID NO: 18 and the light chain constant region (CL) of SEQ ID NO: 22;

[0106] (b) a heavy chain comprising the VH represented by SEQ ID NO: 15 and the heavy chain constant region (CH) represented by SEQ ID NO: 21, and a light chain comprising the VL represented by SEQ ID NO: 20 and the light chain constant region (CL) represented by SEQ ID NO: 22;

[0107] (c) a heavy chain comprising the VH represented by SEQ ID NO: 16 and the heavy chain constant region (CH) represented by SEQ ID NO: 21, and a light chain comprising the VL represented by SEQ ID NO: 18 and the light chain constant region (CL) represented by SEQ ID NO: 22;

[0108] (d) a heavy chain comprising the VH region of SEQ ID NO: 17 and the heavy chain constant region (CH) of SEQ ID NO: 21, and a light chain comprising the VL region of SEQ ID NO: 19 and the light chain constant region (CL) of SEQ ID NO: 22;

[0109] (e) a heavy chain comprising the VH represented by SEQ ID NO: 17 and the heavy chain constant region (CH) represented by SEQ ID NO: 21, and a light chain comprising the VL represented by SEQ ID NO: 18 and the light chain constant region (CL) represented by SEQ ID NO: 22;

[0110] (f) A heavy chain comprising the VH represented by SEQ ID NO: 25 and the heavy chain constant region (CH) represented by SEQ ID NO: 21, and a light chain comprising the VL represented by SEQ ID NO: 26 and the light chain constant region (CL) represented by SEQ ID NO: 22.

[0111] In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain (HC) and a light chain (LC); wherein the HC comprises: (a) the sequence as set forth in SEQ ID NO: 42, or (b) a sequence having at least 70%, at least 80%, at least 85%, 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% or at least 99% sequence identity compared to the sequence as set forth in SEQ ID NO: 42; and / or the LC comprises: (a) the sequence as set forth in SEQ ID NO: 43, or (b) a sequence having at least 70%, at least 80%, at least 85%, 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% or at least 99% sequence identity compared to the sequence as set forth in SEQ ID NO: 43.

[0112] In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain (HC) as shown in SEQ ID NO:42 and a light chain (LC) as shown in SEQ ID NO:43.

[0113] In certain embodiments, the ingredients of the liquid formulation are selected from the group consisting of:

[0114] (a) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 120 mM arginine, 120 mM glutamic acid, 0.005%-0.04% (w / v) polysorbate 20 (e.g., 0.005% (w / v), 0.01% (w / v), 0.02% (w / v), or 0.04% (w / v) polysorbate 20), pH 6.0-6.6;

[0115] (b) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 120 mM arginine, 120 mM glutamic acid, 0.01% (w / v) or 0.02% (w / v) polysorbate 80, pH 6.0-6.6;

[0116] (c) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 80 mM arginine, 80 mM glutamic acid, 40 mM sodium chloride, 0.02% (w / v) polysorbate 80, pH 6.0-6.6;

[0117] (d) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 60 mM arginine, 100 mM glutamic acid, 40 mM sodium chloride, 0.02% (w / v) polysorbate 80, pH 6.0-6.6;

[0118] (e) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 80 mM arginine, 100 mM glutamic acid, 40 mM sodium chloride, 0.02% (w / v) polysorbate 80, pH 6.0-6.6;

[0119] (f) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 60 mM arginine, 60 mM glutamic acid, 60 mM sodium chloride, 0.02% (w / v) polysorbate 80, pH 6.0-6.6;

[0120] (g) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 100 mM arginine, 100 mM glutamic acid, 40 mM sodium chloride, 0.02% (w / v) polysorbate 80, pH 6.0-6.6;

[0121] (h) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 100 mM arginine, 100 mM glutamic acid, 0.02% (w / v) polysorbate 80, pH 6.0-6.6;

[0122] (i) 120 mg / ml of the antibody or antigen-binding fragment thereof, 10 mM histidine-histidine hydrochloride, 150 mM arginine, 150 mM glutamic acid, pH 6.0-6.6;

[0123] (j) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 100 mM arginine, 100 mM glutamic acid, 20 mM sodium chloride, 0.02% (w / v) polysorbate 80, pH 6.0-6.6.

[0124] In certain embodiments, the liquid formulations of the present invention can be stable at 5 ° C ± 3 ° C and can be stored for at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 1 year, at least about 2 years, at least about 3 years, at least about 4 years or at least about 5 years. In certain embodiments, the liquid formulations of the present invention are stable at 25 ° C ± 2 ° C and can be stored for at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months or at least about 1 year. In certain embodiments, the liquid formulations of the present invention are stable at about 40 ° C (e.g., 40 ° C ± 2 ° C) and can be stored for at least about 7 days, at least about 14 days, at least about 21 days, or at least about 28 days.

[0125] The liquid preparation of the present invention can be prepared by combining various components at predetermined concentrations using methods known in the art. For example, an antibody or antigen-binding fragment thereof that specifically binds to FXI and / or FXIa can be dialyzed into a solution containing the other components of the liquid preparation and adjusted to the desired concentration. The preparation is sterilized by filtration using a filter with a pore size of 0.22 μm. The prepared preparation is packaged for ease of use. The packaging material can be a glass bottle (e.g., a vial), a metal alloy container, a prefilled syringe, or a pen injector.

[0126] The liquid preparation of the present invention may be included in any container suitable for storing medicine and other pharmaceutical compositions. For example, the liquid preparation of the present invention may be included in a sealed and sterilized plastic container, metal alloy container or glass container with a certain volume, such as an ampoule, a vial or a syringe. Therefore, in certain preferred embodiments, the liquid preparation of the present invention is included in a glass bottle (such as an ampoule or a vial), a syringe or a microinfusion device. In certain exemplary embodiments, the liquid preparation of the present invention is included in a glass bottle (such as an ampoule or a vial).

[0127] In another aspect, the present application provides an article of manufacture comprising a container containing the liquid formulation as described above.

[0128] In certain embodiments, the container is a glass vial, a metal alloy container, or a prefilled syringe.

[0129] In certain embodiments, the article of manufacture may further comprise a package insert with instructions for use.

[0130] In certain embodiments, the article of manufacture comprises a therapeutically effective amount of the antibody or antigen-binding fragment thereof that specifically binds FXI and / or FXIa.

[0131] In certain embodiments, the preparation comprises 100-800 mg (e.g., 100-200 mg, 100-300 mg, 100-400 mg, 100-500 mg, 200-300 mg, 200-400 mg, 200-500 mg, 200-800 mg) of the antibody or antigen-binding fragment thereof that specifically binds FXI and / or FXIa.

[0132] In certain embodiments, the strength of the preparation is 100 mg (2 ml) / bottle to 500 mg (2 ml) / bottle.

[0133] In certain embodiments, the strength of the preparation is 100 mg (3 ml) / bottle to 800 mg (3 ml) / bottle.

[0134] In certain embodiments, the specifications of the liquid preparation are selected from the following group: 100 mg (2 ml) / bottle, 150 mg (2 ml) / bottle, 200 mg (2 ml) / bottle, 240 mg (2 ml) / bottle, 300 mg (2 ml) / bottle, 360 mg (2 ml) / bottle, 400 mg (2 ml) / bottle, 500 mg (2 ml) / bottle, 100 mg (3 ml) / bottle, 200 mg (3 ml) / bottle, 300 mg (3 ml) / bottle, 400 mg (3 ml) / bottle, 500 mg (3 ml) / bottle, 600 mg (3 ml) / bottle, 700 mg (3 ml) / bottle, 800 mg (3 ml) / bottle.

[0135] Liquid preparation of the present invention can be applied to experimenter by parenteral route, such as injection (for example, subcutaneous, intravenous, intramuscular, intraperitoneal etc.) or percutaneous, mucosal, nasal, respiratory tract and / or oral administration.In certain preferred embodiments, described liquid preparation is applied to experimenter (for example people) by intravenous injection or subcutaneous injection.

[0136] In another aspect, the present application provides the use of the liquid preparation or product as described above in the preparation of a medicament for:

[0137] (a) binding to the catalytic domain of FXI and / or FXIa, and / or inducing conformational changes thereof;

[0138] (b) inhibiting or blocking the binding of FXI and / or FXIa to a substrate;

[0139] (c) inhibiting or blocking the binding of FXI and / or FXIa to platelet receptors;

[0140] (d) inhibiting or blocking the binding of FXI to coagulation factor XIIa (FXIIa), thereby inhibiting the conversion of FXI to active FXIa;

[0141] (e) inhibiting or blocking the binding of FXIa and coagulation factor FIX, thereby inhibiting the conversion of FIX to active FIXa;

[0142] (f) inhibiting or blocking the activation of the intrinsic coagulation pathway mediated by FXI and / or FXIa;

[0143] (g) inhibiting or blocking the activity of FXI and / or FXIa in thrombosis;

[0144] (h) prolonging FXI and / or FXIa-mediated coagulation time;

[0145] (i) inhibiting thrombosis;

[0146] (j) preventing and / or treating diseases or conditions related to coagulation or thromboembolism mediated by FXI and / or FXIa; or

[0147] (k) Any combination of (a)-(j).

[0148] In certain embodiments, the disease or condition associated with coagulation or thromboembolism is selected from the group consisting of thrombosis, thrombotic stroke, atrial fibrillation, atrial fibrillation associated stroke prevention (SPAF), deep vein thrombosis, venous thromboembolism, acute coronary syndrome (ACS), ischemic stroke, acute limb ischemia, chronic thromboembolic pulmonary hypertension, systemic embolism, myocardial infarction (MI), acute myocardial infarction (AMI), stable angina, unstable angina, reocclusion and restenosis after coronary intervention, peripheral arterial occlusive disease (PAOD), renal vein thrombosis, transient ischemic attack (TIA), pulmonary thromboembolism, migraine, Disseminated intravascular coagulation, medical device (e.g., catheter)-induced thromboembolic disorders, severe systemic inflammatory response syndrome, metastatic cancer, infectious diseases, organ failure (e.g., renal failure), toxicity caused by in vivo administration of therapeutic proteins, multiple trauma, ischemia-reperfusion injury, localized fibrin deposition, pulmonary alveolar proteinosis in adults, thromboembolic events (VTE) before and after total knee arthroplasty (TKA) surgery, coronary artery disease, thromboembolism after myocardial infarction, stroke in patients with non-valvular atrial fibrillation, thrombosis and thromboembolism in chronic kidney disease, thrombosis and thromboembolism in patients undergoing hemodialysis and those who have undergone adventitial membrane oxygenation, deep vein thrombosis (DVT), or pulmonary embolism (PE).

[0149] On the other hand, the present application provides a method for preventing and / or treating a disease or condition related to coagulation or thromboembolism in a subject, and / or delaying the occurrence of a disease or condition related to coagulation or thromboembolism, and / or reducing or inhibiting the recurrence of a disease or condition related to coagulation or thromboembolism, the method comprising administering an effective amount of the liquid preparation or product as described above to a subject in need thereof.

[0150] In certain embodiments, the subject is a mammal; in certain embodiments, the subject is a human.

[0151] In certain embodiments, the disease or condition associated with coagulation or thromboembolism is selected from the group consisting of thrombosis, thrombotic stroke, atrial fibrillation, atrial fibrillation associated stroke prevention (SPAF), deep vein thrombosis, venous thromboembolism, acute coronary syndrome (ACS), ischemic stroke, acute limb ischemia, chronic thromboembolic pulmonary hypertension, systemic embolism, myocardial infarction (MI), acute myocardial infarction (AMI), stable angina, unstable angina, reocclusion and restenosis after coronary intervention, peripheral arterial occlusive disease (PAOD), renal vein thrombosis, transient ischemic attack (TIA), pulmonary thromboembolism, migraine, Disseminated intravascular coagulation, medical device (e.g., catheter)-induced thromboembolic disorders, severe systemic inflammatory response syndrome, metastatic cancer, infectious diseases, organ failure (e.g., renal failure), toxicity caused by in vivo administration of therapeutic proteins, multiple trauma, ischemia-reperfusion injury, localized fibrin deposition, pulmonary alveolar proteinosis in adults, thromboembolic events (VTE) before and after total knee arthroplasty (TKA) surgery, coronary artery disease, thromboembolism after myocardial infarction, stroke in patients with non-valvular atrial fibrillation, thrombosis and thromboembolism in chronic kidney disease, thrombosis and thromboembolism in patients undergoing hemodialysis and those who have undergone adventitial membrane oxygenation, deep vein thrombosis (DVT), or pulmonary embolism (PE).

[0152] Definition of terms

[0153] Unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the virology, biochemistry, and immunology laboratory procedures used herein are conventional procedures widely used in the respective fields. To facilitate a better understanding of the present invention, definitions and explanations of relevant terms are provided below.

[0154] When the terms "for example," "such as," "including," "including," "comprising," or variations thereof are used herein, these terms will not be considered as limiting terms, but will be interpreted to mean "but not limited to" or "not limited to."

[0155] The terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0156] As used herein, the terms "FXI" and "factor XI" are used interchangeably and refer to factor XI proteins from various species. The terms "FXIa" and "factor XIa" are used interchangeably and refer to activated factor XI proteins from various species. The terms "FXI" and "FXIa" (and similar terms) include mutants and variants of native FXI and FXIa proteins, respectively, having an amino acid sequence substantially identical to the native primary structure (amino acid sequence) described herein.

[0157] As used herein, the term "antibody" refers to an immunoglobulin molecule typically composed of two pairs of polypeptide chains, each pair having one light chain (LC) and one heavy chain (HC). Antibody light chains can be classified as kappa (κ) and lambda (λ) light chains. Heavy chains can be classified as μ, δ, γ, α, or ε, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. Within the light and heavy chains, the variable and constant regions are connected by a "J" region of approximately 12 or more amino acids, and the heavy chain also contains a "D" region of approximately 3 or more amino acids. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region consists of three domains (CH1, CH2, and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The light chain constant region consists of one domain, CL. The constant domains are not directly involved in antibody-antigen binding but exhibit various effector functions, such as mediating the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The VH and VL regions can be further subdivided into regions of high variability, termed complementarity-determining regions (CDRs), interspersed with more conserved regions, termed framework regions (FRs). Each VH and VL region consists of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions (VH and VL) of each heavy / light chain pair form the antigen-binding site. The allocation of amino acids within each region or domain can be defined according to numbering systems such as IMGT, Kabat, Chothia, or AbM.

[0158] Herein, unless the context clearly indicates otherwise, when referring to the term "antibody", it includes not only intact antibodies, but also antigen-binding fragments of antibodies.

[0159] As used herein, the term "complementarity determining region" or "CDR" refers to the amino acid residues in the antibody variable region that are responsible for antigen binding. The precise boundaries of these amino acid residues can be defined according to various numbering systems known in the art, for example, as defined in the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), the Chothia numbering system (Chothia & Lesk (1987) J. Mol. Biol. 196:901-917; Chothia et al. (1989) Nature 342:878-883), the IMGT numbering system (Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003), or the AbM numbering system (Martin ACR, Cheetham JC, Rees AR, Proc Natl Acad Sci USA 86:9268-9272, 1989). For a given antibody, those skilled in the art can easily identify the CDRs defined by each numbering system. Moreover, the correspondence between different numbering systems is well known to those skilled in the art (eg, see Lefranc et al., Dev. Comparat. Immunol. 27: 55-77, 2003).

[0160] As used herein, the term "antigen-binding fragment" of an antibody refers to a polypeptide of a full-length or partial fragment of an antibody, such as a polypeptide of a fragment of a full-length antibody, which retains the ability to specifically bind to the same antigen bound by the full-length antibody and / or competes with the full-length antibody for specific binding to the antigen, which is also referred to as an "antigen-binding portion". See generally, Fundamental Immunology, Ch. 7 (Paul, W., ed., 2nd ed., Raven Press, NY (1989), which is incorporated herein by reference in its entirety for all purposes. Antigen-binding fragments of antibodies can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Non-limiting examples of antigen-binding fragments include Fab, Fab', F(ab')2, Fd, Fv, dAb and complementarity determining region (CDR) fragments, single-chain antibodies (e.g., scFv), chimeric antibodies, diabodies, linear antibodies, nanobodies (technology from Domantis), domain antibodies (technology from Ablynx), and polypeptides that are small enough to have the specific antigen-binding ability of a full-length antibody. Engineered antibody variants are reviewed in Holliger et al., 2005; Nat Biotechnol, 23: 1126-1136.

[0161] As used herein, the term "buffer" refers to a buffered solution that resists changes in pH through the action of its acid-base conjugate components. Examples of such buffers include acetate, succinate, gluconate, histidine, citrate, glycylglycine, and other organic acid buffers. In certain preferred embodiments, the buffer suitable for use in the liquid formulations disclosed herein is selected from citric acid-citrate buffer, histidine buffer, and acetic acid-acetate buffer.

[0162] As used herein, the term "buffer concentration" has the meaning commonly understood by those skilled in the art, and generally refers to the content of the buffer substance in the buffer solution. For example, when the buffer is a histidine buffer, the buffer concentration refers to the total concentration of histidine and its salts in the buffer solution.

[0163] The term "histidine buffer" refers to a buffer comprising histidine, and the histidine in the buffer can exist alone or in the following form: for example, histidine hydrochloride, histidine acetate, histidine phosphate or histidine sulfate. When histidine is not present alone, an histidine buffer (such as a histidine hydrochloride buffer) can be prepared by titrating L-histidine (free alkali, solid) with a corresponding acid (such as hydrochloric acid). When histidine exists in a separate form, a pH adjusting agent can be added to the subsequent preparation step to obtain a liquid preparation of a suitable pH range according to actual conditions. In certain preferred embodiments, the histidine in the histidine buffer suitable for the liquid preparation disclosed herein exists alone or in the form of histidine hydrochloride or histidine acetate.

[0164] The term "citric acid-citrate buffer" refers to a mixture comprising citric acid and citrate. In certain preferred embodiments, the citric acid-citrate buffer is a citric acid-sodium citrate buffer, i.e., a mixture comprising citric acid and sodium citrate. A citric acid-citrate buffer (e.g., a citric acid-sodium citrate buffer) can be prepared by adding a base (e.g., sodium hydroxide) to citric acid to form a salt.

[0165] The term "acetic acid-acetate buffer" refers to a mixture of acetic acid and acetate. In certain preferred embodiments, the acetic acid-acetate buffer is an acetic acid-sodium acetate buffer, i.e., a mixture of acetic acid and sodium acetate. An acetic acid-acetate buffer (e.g., an acetic acid-sodium acetate buffer) can be prepared by adding a base (e.g., sodium hydroxide) to acetic acid to form a salt.

[0166] As used herein, the term "mass to volume ratio" or "w / v" refers to the percentage weight (in grams) of a single component relative to the total volume (in milliliters) of the mixture containing the component. For example, 20 mg of a component in a total volume of 100 ml is 0.02% w / v.

[0167] As used herein, the term "effective amount" refers to an amount sufficient to achieve, or at least partially achieve, a desired effect. For example, a prophylactic effective amount is an amount sufficient to prevent, arrest, or delay the onset of a disease; a therapeutic effective amount is an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. Determining such an effective amount is well within the capabilities of those skilled in the art. For example, an effective amount for therapeutic use will depend on the severity of the disease being treated, the overall state of the patient's own immune system, the patient's general condition such as age, weight, and sex, the mode of administration of the drug, and any other concurrently administered treatments.

[0168] Advantageous Effects of the Invention

[0169] The liquid preparation provided in the present application, which comprises an anti-factor XI / XIa antibody and a specific prescription, has excellent stability and can obtain a high-concentration preparation with sufficiently low viscosity, thereby significantly reducing the difficulty of production and administration of the high-concentration preparation, thereby improving patient compliance, and has significant clinical value.

[0170] The embodiments of the present invention will be described in detail below with reference to the accompanying drawings and examples, but it will be understood by those skilled in the art that the following drawings and examples are intended only to illustrate the present invention and are not intended to limit the scope of the invention. Various objects and advantages of the present invention will become apparent to those skilled in the art based on the following detailed description of the accompanying drawings and preferred embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0171] Figure 1: Viscosity-protein concentration trend.

[0172] Sequence information

[0173] A description of the sequences of the anti-Factor XI / XIa antibodies contemplated by this application is provided in the table below.

[0174] Table 1: Sequence information DETAILED DESCRIPTION

[0175] The invention will now be described with reference to the following examples which are intended to illustrate the invention but not to limit it.

[0176] The anti-coagulation factor XI / XIa antibody injection (hereinafter referred to as "protein") of the present application is a sterile, transparent, preservative-free injection obtained by aseptic filtration and filling of the anti-coagulation factor XI / XIa antibody stock solution. According to the device used for clinical administration, the injection thrust is 6.41N (75mm / min) and 12.68N (150mm / min). The monoclonal antibody against anti-coagulation factor XI / XIa is the humanized antibody 36G9.10hz73 in patent application WO 2020 / 211674 A1, which has a heavy chain as shown in SEQ ID NO:42 and a light chain as shown in SEQ ID NO:43.

[0177] Example 1

[0178] A series of protein solutions were prepared without adding any excipients, and their viscosities were measured. The viscosity-protein concentration trend is shown in Figure 1.

[0179] As the protein concentration increases, the viscosity of the preparation increases exponentially. High-concentration protein preparations have excessive viscosity, making production and injection very difficult.

[0180] Example 2

[0181] The antibody preparation was prepared according to the table below, the pH was adjusted to 6.0, and the viscosity was tested.

[0182] The viscosity of antibody preparation F1 was 8.7 cp, and the viscosities of antibody preparations F2 to F4 were 2.7 cp, 10.6 cp, and 3.3 cp, respectively. Thus, the combination of sodium chloride, arginine, and glutamic acid can reduce the viscosity of the preparation, while sucrose can increase the viscosity of the preparation.

[0183] Example 3

[0184] The antibody preparation was prepared according to the table below, the pH was adjusted to 6.1, the viscosity and appearance were tested, and the aggregate content was tested by SEC-HPLC.

[0185] The viscosity of antibody preparation F1 is 30.8 cp, and the viscosities of antibody preparations F2 to F4 are 10.1 cp, 10.1 cp, and 6.3 cp, respectively, indicating that sodium chloride can effectively reduce the viscosity of the preparation, PS80 (polysorbate 80) has little effect on the viscosity, and arginine can effectively reduce the viscosity of the preparation.

[0186] The antibody preparations F2 to F4 prepared above had a clear appearance and no visible protein particles. After shaking at 1000 rpm for 4 hours, trace protein flocs were visible in antibody preparation F2, while preparations F3 and F4 remained clear and free of visible protein particles, indicating that the addition of PS80 to the preparations improved the appearance of the preparations after shaking.

[0187] The aggregate contents of the antibody formulations F2-F4 prepared above were 1.6%, 1.7%, and 1.6%, respectively. After shaking at 1000 rpm for 4 hours, the aggregate contents of formulations F2-F4 remained unchanged. After 14 days at 40°C, the aggregate contents of formulations F2-F4 increased to 3.4%, 4.0%, and 4.5%, respectively, indicating that the aggregate content of the formulations containing PS80 increased more rapidly under high temperature conditions.

[0188] Example 4

[0189] The antibody preparation was prepared according to the table below, the pH was adjusted to 6.1, the viscosity and appearance were tested, and the aggregate content was tested by SEC-HPLC.

[0190] The viscosity of antibody preparations F1 and F2 was in the range of 6.0 to 8.0 cp, and their appearance met the requirements after being stored at 40°C for 14 days.

[0191] The aggregate contents of the antibody preparations F1 and F2 prepared above were 1.6% and 1.6%, respectively. After 14 days at 40°C, the aggregate contents of preparations F1 and F2 were 4.5% and 2.5%, respectively, indicating that the addition of glutamate and the reduction of arginine significantly reduced the growth rate of aggregates in the preparations under high temperature conditions.

[0192] Example 5

[0193] The antibody preparation was prepared according to the table below, the pH was adjusted to 6.1, the viscosity and appearance were tested, and the aggregate content was tested by SEC-HPLC.

[0194] The viscosity of antibody preparations F1 to F4 was in the range of 8.0 to 11.0 cp, and their appearance met the requirements after being stored at 40°C for 14 days.

[0195] The aggregate contents of the antibody formulations F1 to F4 prepared above were 1.5%, 1.4%, 1.4%, and 1.4%, respectively. After 14 days at 40°C, the aggregate contents of formulations F1 to F4 were 4.2%, 3.9%, 3.6%, and 2.6%, respectively, indicating that reducing the sodium chloride concentration in the formulation and increasing the arginine-glutamate concentration reduced aggregate formation.

[0196] Example 6

[0197] The antibody preparation was prepared according to the table below, the pH was adjusted to 6.1, the viscosity and appearance were tested, and the aggregate content was tested by SEC-HPLC.

[0198] The test results after 14 days at 40°C showed that the viscosity of antibody preparations F1 to F3 was in the range of 9.0 to 12.0 cp, the appearance met the requirements, and the aggregate content was less than 4.0%.

[0199] Example 7

[0200] The antibody preparation was prepared according to the table below, and the pH was adjusted to 6.0. Protein particles were detected by Flowcam.

[0201] The Flowcam test results after storage at 40°C are shown in the table below. The protein particles all meet the requirements, and the effect of surfactant on protein particle formation is that PS20 is better than PS80.

[0202] Example 8

[0203] The antibody preparation was prepared according to the table below, and the viscosity and appearance were tested. The aggregate content was tested by SEC-HPLC, and the protein particles were detected by Flowcam.

[0204] The viscosity of antibody preparations F1 and F2 was in the range of 8.0 to 10.0 cp, and the appearance, aggregate content, and protein particles all met the quality requirements.

[0205] The test results after storage at 40°C for 28 days showed that the appearance of preparations F1 and F2 met the requirements, the polymer content of preparation F1 was 3.2%, and the polymer content of preparation F2 was 2.3%.

[0206] After storage at 5°C for 3 years, the viscosity, appearance, aggregate content, and protein particle test results of formulations F1 and F2 did not change significantly compared to those before storage.

[0207] Although the specific embodiments of the present invention have been described in detail, those skilled in the art will understand that various modifications and changes can be made to the details based on all the teachings published, and these changes are all within the scope of protection of the present invention. The entire invention is given by the appended claims and any equivalents thereof.

Claims

1. A liquid preparation comprising: (1) an antibody or an antigen-binding fragment thereof that specifically binds to FXI and / or FXIa; (2) Arginine; (3) glutamate; and (4) Buffer solution.

2. The liquid preparation of claim 1, wherein The concentration of the antibody or antigen-binding fragment thereof that specifically binds to FXI and / or FXIa is 20-250 mg / ml (e.g., 20-200 mg / ml, 20-180 mg / ml, 20-160 mg / ml, 20-150 mg / ml, 50-250 mg / ml, 50-200 mg / ml, 50-180 mg / ml, 50-150 mg / ml, 100-250 mg / ml, 100-200 mg / ml, 100-180 mg / ml, 100-150 mg / ml, 120-250 mg / ml, 120-200 mg / ml, 120-180 mg / ml, 120-150 mg / ml); Preferably, the concentration of the antibody or antigen-binding fragment thereof that specifically binds to FXI and / or FXIa is 100-200 mg / ml (e.g., 100-180 mg / ml, 100-150 mg / ml, 120-200 mg / ml, 120-180 mg / ml, 120-150 mg / ml, 120 mg / ml, 150 mg / ml).

3. The liquid preparation according to claim 1 or 2, wherein The concentration of the arginine is 50-200mM (e.g., 50-180mM, 50-150mM, 50-120mM, 60-200mM, 60-180mM, 60-150mM, 60-120mM, 80-200mM, 80-180mM, 80-150mM, 80-120mM, 100-200mM, 100-180mM, 100-150mM, 100-120mM); Preferably, the concentration of arginine is 60-150 mM (e.g., 60-120 mM, 80-150 mM, 80-120 mM, 100-150 mM, 100-120 mM, 80 mM, 100 mM, 120 mM, 150 mM).

4. The liquid preparation according to any one of claims 1 to 3, wherein The concentration of glutamate is 50-200mM (e.g., 50-180mM, 50-150mM, 50-120mM, 60-200mM, 60-180mM, 60-150mM, 60-120mM, 80-200mM, 80-180mM, 80-150mM, 80-120mM, 100-200mM, 100-180mM, 100-150mM, 100-120mM); Preferably, the concentration of glutamate is 60-150 mM (e.g., 60-120 mM, 80-150 mM, 80-120 mM, 100-150 mM, 100-120 mM, 80 mM, 100 mM, 120 mM, 150 mM).

5. The liquid preparation according to any one of claims 1 to 4, wherein The concentration of the buffer is 5-50 mM (e.g., 5-20 mM, 5-25 mM, 5-30 mM, 5-40 mM, 8-20 mM, 8-25 mM, 8-30 mM, 8-40 mM, 10-20 mM, 10-25 mM, 10-30 mM, 10-40 mM); Preferably, the concentration of the buffer is 10-40 mM (e.g., 10-20 mM, 10-25 mM, 10-30 mM, 10-40 mM, 10 mM, 20 mM).

6. The liquid preparation according to any one of claims 1 to 5, wherein The buffer is selected from the group consisting of histidine buffer, citric acid-citrate buffer, acetic acid-acetate buffer, and Tris buffer; Preferably, the buffer is a histidine buffer; preferably, the histidine in the histidine buffer exists alone or in the form of histidine-hydrochloride.

7. The liquid preparation according to any one of claims 1 to 6, further comprising a surfactant; Preferably, the surfactant is a nonionic surfactant; Preferably, the surfactant is polysorbate 80 or polysorbate 20; Preferably, the surfactant is polysorbate 20.

8. The liquid preparation of claim 7, wherein The concentration of the surfactant is 0.001%-0.08% w / v (e.g., 0.001%-0.04% w / v, 0.001%-0.06% w / v, 0.003%-0.04% w / v, 0.003%-0.06% w / v, 0.003%-0.08% w / v, 0.005%-0.04% w / v, 0.005%-0.06% w / v, 0.005%-0.08% w / v); Preferably, the concentration of the surfactant is 0.005%-0.04% w / v (e.g., 0.011% w / v, 0.02% w / v); Preferably, the surfactant is polysorbate 20 at a concentration of 0.005%-0.04% w / v.

9. The liquid preparation according to any one of claims 1 to 8, wherein The pH of the liquid formulation is 5.5-7.5 (e.g., 5.5-6.6, 5.5-7.0, 5.5-7.2, 5.8-6.6, 5.8-7.0, 5.8-7.2, 5.8-7.5, 6.0-6.6, 6.0-7.0, 6.0-7.2, 6.0-7.5); Preferably, the pH of the liquid preparation is 6.0-6.

6.

10. The liquid formulation of any one of claims 1 to 9, optionally comprising sodium chloride; Preferably, the concentration of sodium chloride is 0-130mM (e.g., 0-120mM, 0-60mM, 0-40mM, 0-20mM, 10-130mM, 10-120mM, 10-60mM, 10-40mM, 10-20mM, 20-130mM, 20-120mM, 20-60mM, 20-40mM); Preferably, the concentration of sodium chloride is 0-60 mM (e.g., 0-40 mM, 0-20 mM, 10-60 mM, 10-40 mM, 10-20 mM, 20-60 mM, 20-40 mM).

11. The liquid preparation according to any one of claims 1 to 9, which does not contain sodium chloride.

12. The liquid preparation according to any one of claims 1 to 11, which does not contain sucrose.

13. The liquid preparation according to any one of claims 1 to 12, wherein The antibody or antigen-binding fragment thereof comprises: (a) comprising CDR-H1, CDR-H2 and CDR-H3 contained in VH as shown in any one of SEQ ID NOs: 1, 16, 17, 15; and / or, comprising CDR-L1, CDR-L2 and CDR-L3 contained in VL as shown in any one of SEQ ID NOs: 2, 19, 20, 18; or, (b) comprising CDR-H1, CDR-H2 and CDR-H3 contained in VH as shown in SEQ ID NO: 25 or 23; and / or, comprising CDR-L1, CDR-L2 and CDR-L3 contained in VL as shown in SEQ ID NO: 26 or 24.

14. The liquid preparation according to any one of claims 1 to 13, wherein The antibody or antigen-binding fragment thereof comprises: (1) CDR-H1 of SEQ ID NO: 3, CDR-H2 of SEQ ID NO: 4, CDR-H3 of SEQ ID NO: 5; and, CDR-L1 of SEQ ID NO: 6, CDR-L2 of SEQ ID NO: 7, CDR-L3 of SEQ ID NO: 8; (2) CDR-H1 of SEQ ID NO: 27, CDR-H2 of SEQ ID NO: 28, CDR-H3 of SEQ ID NO: 29; and, CDR-L1 of SEQ ID NO: 30, CDR-L2 of SEQ ID NO: 31, CDR-L3 of SEQ ID NO: 32; (3) a CDR-H1 of SEQ ID NO: 9, a CDR-H2 of SEQ ID NO: 39, 40 or 10, and a CDR-H3 of SEQ ID NO: 11; and a CDR-L1 of SEQ ID NO: 12, a CDR-L2 of SEQ ID NO: 13, and a CDR-L3 of SEQ ID NO: 14; or, (4) CDR-H1 of SEQ ID NO: 33, CDR-H2 of SEQ ID NO: 34 or 41, and CDR-H3 of SEQ ID NO: 35; and, CDR-L1 of SEQ ID NO: 36, CDR-L2 of SEQ ID NO: 37, and CDR-L3 of SEQ ID NO:

38.

15. The liquid preparation according to any one of claims 1 to 14, wherein the ingredients of the liquid preparation are selected from the group consisting of: (a) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 120 mM arginine, 120 mM glutamic acid, 0.005%-0.04 (w / v) polysorbate 20 (e.g., 0.005% (w / v), 0.01% (w / v), 0.02% (w / v) or 0.04% (w / v) polysorbate 20), pH 6.0-6.6; (b) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 120 mM arginine, 120 mM glutamic acid, 0.01% (w / v) or 0.02% (w / v) polysorbate 80, pH 6.0-6.6; (c) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 80 mM arginine, 80 mM glutamic acid, 40 mM sodium chloride, 0.02% (w / v) polysorbate 80, pH 6.0-6.6; (d) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 60 mM arginine, 100 mM glutamic acid, 40 mM sodium chloride, 0.02% (w / v) polysorbate 80, pH 6.0-6.6; (e) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 80 mM arginine, 100 mM glutamic acid, 40 mM sodium chloride, 0.02% (w / v) polysorbate 80, pH 6.0-6.6; (f) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 60 mM arginine, 60 mM glutamic acid, 60 mM sodium chloride, 0.02% (w / v) polysorbate 80, pH 6.0-6.6; (g) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 100 mM arginine, 100 mM glutamic acid, 40 mM sodium chloride, 0.02% (w / v) polysorbate 80, pH 6.0-6.6; (h) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 100 mM arginine, 100 mM glutamic acid, 0.02% (w / v) polysorbate 80, pH 6.0-6.6; (i) 120 mg / ml of the antibody or antigen-binding fragment thereof, 10 mM histidine-histidine hydrochloride, 150 mM arginine, 150 mM glutamic acid, pH 6.0-6.6; (j) 150 mg / ml of the antibody or antigen-binding fragment thereof, 20 mM histidine-histidine hydrochloride, 100 mM arginine, 100 mM glutamic acid, 20 mM sodium chloride, 0.02% (w / v) polysorbate 80, pH 6.0-6.

6.

16. An article of manufacture comprising a container containing the liquid formulation of any one of claims 1 to 15.

17. The article according to claim 16, characterized in that The container is a glass bottle, a metal alloy container or a prefilled syringe.

18. Use of the liquid preparation according to any one of claims 1 to 15 or the product according to claim 16 or 17 in the preparation of a medicament for: (a) binding to the catalytic domain of FXI and / or FXIa, and / or inducing conformational changes thereof; (b) inhibiting or blocking the binding of FXI and / or FXIa to a substrate; (c) inhibiting or blocking the binding of FXI and / or FXIa to platelet receptors; (d) inhibiting or blocking the binding of FXI to coagulation factor XIIa (FXIIa), thereby inhibiting the conversion of FXI to active FXIa; (e) inhibiting or blocking the binding of FXIa and coagulation factor FIX, thereby inhibiting the conversion of FIX into active FIXa; (f) inhibiting or blocking the activation of the intrinsic coagulation pathway mediated by FXI and / or FXIa; (g) inhibiting or blocking the activity of FXI and / or FXIa in thrombosis; (h) prolonging the coagulation time mediated by FXI and / or FXIa; (i) inhibiting thrombosis; (j) preventing and / or treating diseases or conditions related to coagulation or thromboembolism mediated by FXI and / or FXIa; or (k) Any combination of (a)-(j).

19. The use according to claim 18, wherein The disease or condition associated with coagulation or thromboembolism is selected from the group consisting of thrombosis, thrombotic stroke, atrial fibrillation, atrial fibrillation associated stroke prevention (SPAF), deep vein thrombosis, venous thromboembolism, acute coronary syndrome (ACS), ischemic stroke, acute limb ischemia, chronic thromboembolic pulmonary hypertension, systemic embolism, myocardial infarction (MI), acute myocardial infarction (AMI), stable angina, unstable angina, reocclusion and restenosis after coronary artery intervention, peripheral arterial occlusive disease (PAOD), renal vein thrombosis, transient ischemic attack (TIA), pulmonary thromboembolism, diffuse intravascular coronary syndrome (IVCS ... chronic thromboembolic pulmonary hypertension, systemic embolism, acute myocardial infarction (AMI), acute myocardial infarction (AMI), stable angina, unstable angina, reocclusion and restenosis after coronary artery intervention, peripheral arterial occlusive disease (PAOD), renal vein thrombosis, transient ischemic attack (TIA), pulmonary thromboembolism, diffuse intravascular coronary syndrome (IVS), acute myocardial infarction (AMI), chronic thromboembolism, acute intravascular coronary syndrome (ACS), acute intravascular coronary syndrome (ACS), acute intravascular coronary syndrome (ACS), acute intravascular coronary syndrome (ACS), acute intravascular coronary syndrome (ACS), acute intravascular coronary syndrome Coagulation, thromboembolic disorders induced by medical devices (e.g., catheters), severe systemic inflammatory response syndrome, metastatic cancer, infectious diseases, organ failure (e.g., renal failure), toxicity caused by in vivo administration of therapeutic proteins, multiple trauma, ischemia-reperfusion injury, localized fibrin deposition, pulmonary alveolar proteinosis in adults, thromboembolic events (VTE) before and after total knee arthroplasty (TKA) surgery, coronary artery disease, thromboembolism after myocardial infarction, stroke in patients with non-valvular atrial fibrillation, thrombosis and thromboembolism in chronic kidney disease, thrombosis and thromboembolism in patients undergoing hemodialysis and in patients subjected to adventitial membrane oxygenation, deep vein thrombosis (DVT), or pulmonary embolism (PE).

20. A method for preventing and / or treating a disease or condition associated with coagulation or thromboembolism in a subject, and / or delaying the occurrence of a disease or condition associated with coagulation or thromboembolism, and / or reducing or inhibiting the recurrence of a disease or condition associated with coagulation or thromboembolism, the method comprising administering an effective amount of the liquid preparation of any one of claims 1 to 15, or the preparation of claim 16 or 17 to a subject in need thereof; Preferably, the subject is a mammal; preferably, the subject is a human.

21. The method of claim 20, wherein The disease or condition associated with coagulation or thromboembolism is selected from the group consisting of thrombosis, thrombotic stroke, atrial fibrillation, atrial fibrillation associated stroke prevention (SPAF), deep vein thrombosis, venous thromboembolism, acute coronary syndrome (ACS), ischemic stroke, acute limb ischemia, chronic thromboembolic pulmonary hypertension, systemic embolism, myocardial infarction (MI), acute myocardial infarction (AMI), stable angina, unstable angina, reocclusion and restenosis after coronary artery intervention, peripheral arterial occlusive disease (PAOD), renal vein thrombosis, transient ischemic attack (TIA), pulmonary thromboembolism, diffuse intravascular coronary syndrome (IVCS ... chronic thromboembolic pulmonary hypertension, systemic embolism, acute myocardial infarction (AMI), acute myocardial infarction (AMI), stable angina, unstable angina, reocclusion and restenosis after coronary artery intervention, peripheral arterial occlusive disease (PAOD), renal vein thrombosis, transient ischemic attack (TIA), pulmonary thromboembolism, diffuse intravascular coronary syndrome (IVS), acute myocardial infarction (AMI), chronic thromboembolism, acute intravascular coronary syndrome (ACS), acute intravascular coronary syndrome (ACS), acute intravascular coronary syndrome (ACS), acute intravascular coronary syndrome (ACS), acute intravascular coronary syndrome (ACS), acute intravascular coronary syndrome Coagulation, thromboembolic disorders induced by medical devices (e.g., catheters), severe systemic inflammatory response syndrome, metastatic cancer, infectious diseases, organ failure (e.g., renal failure), toxicity caused by in vivo administration of therapeutic proteins, multiple trauma, ischemia-reperfusion injury, localized fibrin deposition, pulmonary alveolar proteinosis in adults, thromboembolic events (VTE) before and after total knee arthroplasty (TKA) surgery, coronary artery disease, thromboembolism after myocardial infarction, stroke in patients with non-valvular atrial fibrillation, thrombosis and thromboembolism in chronic kidney disease, thrombosis and thromboembolism in patients undergoing hemodialysis and in patients subjected to adventitial membrane oxygenation, deep vein thrombosis (DVT), or pulmonary embolism (PE).

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