Pharmaceutical compositions containing anti-FXI / FXIa antibodies and uses thereof

Abstract

A pharmaceutical composition comprising an anti-FXI / FXIa antibody and uses thereof. A specifically relevant pharmaceutical composition comprises an anti-FXI / FXIa antibody or an antigen-binding fragment thereof and a buffer.

Description

[Technical field]

[0001] This disclosure claims priority to the following patent application(s) having a filing date of January 5, 2022, application number 202210006206.X, and a Chinese patent application having a filing date of January 18, 2022, application number 202210053441.2, and entitled "Pharmaceutical Composition Containing Anti-FXI / FXIa Antibody and Use Thereof," the entire contents of which are incorporated herein by reference.

[0002] The present disclosure is in the field of drug formulations, and specifically relates to pharmaceutical compositions comprising anti-FXI / FXIa antibodies and antigen-binding fragments thereof, and their use as medicines. [Background technology]

[0003] The FXI gene is located on human chromosome 4 and encodes a secreted protein consisting of 607 amino acids; the FXI protein molecule contains four apple domains and one catalytic domain; it exists in the form of a homodimer in human blood; the protein FXI forms a non-covalent complex with HK and circulates in human plasma at a FXI concentration of approximately 30 nM (15-45 nM); the human FXI molecule has 88%, 67%, and 58% homology with monkey and mouse FXI molecules, respectively (two species, three homology data).

[0004] At present, there are already many literature and clinical trials showing that inhibiting the activity of FXI and its transformed form FXIa can effectively reduce the formation of thrombus without causing the bleeding risk seen. According to the currently disclosed clinical results, compared with conventional oral anticoagulants (NOACs), anti-FXI / FXIa antibodies have similar or better antithrombotic effects, and with a lower bleeding risk, patients can receive a safer treatment.

[0005] Due to their characteristics, therapeutic proteins such as human monoclonal antibodies are generally administered as liquid drug formulations by injection. However, antibody drugs have a large molecular weight and a complex structure, and are prone to become unstable due to decomposition, polymerization, undesirable chemical modification, etc. Research into stabilized formulations of antibody drugs is particularly important so that antibodies are suitable for administration, maintain stability during storage and subsequent use, and can achieve better effects. The present disclosure aims to provide a pharmaceutical composition (formulation) containing an anti-FXI / FXIa antibody that is sufficiently stable and more suitable for administration. Summary of the Invention

[0006] The present disclosure provides pharmaceutical compositions comprising the proteins (e.g., anti-FXI / FXIa antibodies or antigen-binding fragments thereof), as well as methods for preparing the pharmaceutical compositions and methods for treating or preventing diseases or related pharmaceutical uses thereof.

[0007] In some embodiments, the protein (e.g., an anti-FXI / FXIa antibody or antigen-binding fragment thereof) in the pharmaceutical composition of the present disclosure has a PI value of about 5.0 to about 6.6, for example, about 5.2 to about 6.4, about 5.3 to about 6.3, about 5.4 to about 6.2, about 5.5 to about 6.1, about 5.6 to about 6.0, about 5.7 to about 5.9 (e.g., about 5.8), or any range between these values. In some embodiments, the PI value is obtained by detection using a capillary electrophoresis apparatus (ProteinSimple, Maurice), and the detection conditions are as follows: Experiment temperature: 15℃, Focus time: 1500V 1min, 3000V 6min Method: Control and test articles (if desalted, select the desalted test article) were prepared and mixed uniformly, and centrifuged at 13000 rpm for 5 minutes. 80 μL was taken and transferred to Maurice 96-well plate or Maurice iCIEF injection flask, and centrifuged at 13000 rpm for 5 minutes (injection into injection flask) or 4000 rpm for 5 minutes (injection into 96-well plate).

[0008] In some embodiments, a pharmaceutical composition containing a protein of the present disclosure (e.g., an anti-FXI / FXIa antibody or an antigen-binding fragment thereof) has a conductivity of about 100 to about 300 mS / cm, for example, about 120 to about 260 mS / cm, about 130 to about 250 mS / cm, about 140 to about 240 mS / cm, about 150 to about 220 mS / cm, about 170 to about 200 mS / cm, about 180 to about 190 mS / cm (e.g., about 183.7 mS / cm), or any range between these values. In some embodiments, the conductivity is measured using a conductivity meter (Mettler, FE38-Standard).

[0009] In some embodiments, a pharmaceutical composition containing a protein of the present disclosure (e.g., an anti-FXI / FXIa antibody or an antigen-binding fragment thereof) has an osmolality of about 250 to about 450 mOsmol / kg, for example, about 270 to about 430 mOsmol / kg, about 290 to about 410 mOsmol / kg, about 300 to about 400 mOsmol / kg, about 310 to about 390 mOsmol / kg, about 320 to about 380 mOsmol / kg, about 330 to about 370 mOsmol / kg, about 340 to about 360 mOsmol / kg (e.g., about 350 mOsmol / kg), or any range between these values. In some embodiments, the osmolality is measured using an osmometer (Luther, OM819.C), and the detection method is freezing point depression method.

[0010] In some embodiments, a protein (e.g., an anti-FXI / FXIa antibody or antigen-binding fragment thereof) in a pharmaceutical composition according to the present disclosure has a PI value of about 5.7 to about 5.9. In some embodiments, a pharmaceutical composition containing a protein (e.g., an anti-FXI / FXIa antibody or antigen-binding fragment thereof) of the present disclosure has a conductivity of about 180 to about 190 mS / cm (e.g., about 183.7 mS / cm) and / or an osmolality of about 320 to about 380 mOsmol / kg.

[0011] self-buffering system The present disclosure provides a pharmaceutical composition comprising any one of the above described proteins (e.g., an anti-FXI / FXIa antibody or an antigen-binding fragment thereof). The pharmaceutical composition is self-buffering. The composition has therapeutic or prophylactic activity. Moreover, the composition may also have the advantage of good stability.

[0012] In some embodiments, the pharmaceutical composition comprises a basic amino acid, such as histidine, arginine, lysine, or any combination thereof. In some embodiments, the basic amino acid (e.g., histidine) and the protein (e.g., an anti-FXI / FXIa antibody or antigen-binding fragment thereof) form a self-buffering system.

[0013] In some embodiments, the histidine concentration in any one of the above pharmaceutical compositions is about 1 mM to about 100 mM, for example, about 2 mM to about 80 mM, about 5 mM to about 70 mM, about 10 mM to about 60 mM, about 20 mM to about 50 mM, about 25 mM to about 45 mM, about 30 mM to about 40 mM, about 30 mM to about 100 mM, about 60 mM to about 100 mM, about 30 mM to about 90 mM, or any range between these values. In some embodiments, the histidine concentration is about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 31 mM, about 32 mM, about 33 mM, about 34 mM, about 35 mM, about 36 mM, about 37 mM, about 38 mM, about 39 mM, about 40 mM, about 41 mM, about 42 mM, about 43 mM, about 44 mM, about 45 mM, about 46 mM, about 47 mM, about 48 mM, about 49 mM, about 50 mM, e.g., about 35 mM.

[0014] In some embodiments, the pharmaceutical composition according to any one of the above further comprises a surfactant. In some embodiments, the surfactant is a non-ionic surfactant. In some embodiments, the surfactant is a poloxamer (e.g., poloxamer 188), polysorbate (e.g., polysorbate 20 (i.e., PS20), polysorbate 80 (i.e., PS80)), poloxamer, Triton, sodium dodecyl sulfonate, sodium lauryl sulfonate, sodium octyl glucoside, lauryl-sulfobetaine, myristyl-sulfobetaine, linoleic-sulfobetaine, stearic-sulfobetaine, lauryl-sarcosine, myristyl-sarcosine, linoleic-sarcosine, stearic-sarcosine, linoleic-betaine, myristyl -betaine, cetyl-betaine, lauramidopropyl-betaine, cocamidopropyl-betaine, linoleamidopropyl-betaine, myristamidopropyl-betaine, palmitamidopropyl-betaine, isostearamidopropyl-betaine, myristamidopropyl-dimethylamine, palmitamidopropyl-dimethylamine, isostearamidopropyl-dimethylamine, sodium methyl cocoyl, sodium methyl oleyl taurate, polyethylene glycol, polypropylene glycol, copolymers of ethylene and propylene glycol, and the like, or any combination thereof. In some embodiments, the surfactant is a polysorbate or a poloxamer. In some embodiments, the surfactant is polysorbate 80, polysorbate 20, or poloxamer 188. In some embodiments, the surfactant is poloxamer 188.

[0015] In some embodiments, the concentration of the surfactant is about 0.1 mg / mL to about 10 mg / mL, for example, about 0.2 mg / mL to about 8 mg / mL, about 0.5 mg / mL to about 6 mg / mL, about 0.8 mg / mL to about 5 mg / mL, about 1.0 mg / mL to about 4 mg / mL, about 1.2 mg / mL to about 3.8 mg / mL, about 1.3 mg / mL to about 3.6 mg / mL, about 1.4 mg / mL to about 3.4 mg / mL, or about 1.5 mg / mL. L to about 3.3 mg / mL, about 1.6 mg / mL to about 3.2 mg / mL, about 1.7 mg / mL to about 3 mg / mL, about 1.8 mg / mL to about 2.8 mg / mL, about 1.9 mg / mL to about 2.5 mg / mL, about 1.8 mg / mL to about 2.4 mg / mL, about 1.9 mg / mL to about 2.2 mg / mL, about 1.8 mg / mL to about 2.2 mg / mL, about 1.9 mg / mL to about 2.1 mg / mL, or any range between those point values. For example, about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1.0 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2.0 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, about 3.0 mg / mL, about 3.1 mg / mL, about 3.2 mg / mL, about 3.3 mg / mL, about 3.4 mg / mL, about 3.5 mg / mL, about 3.6 mg / mL, about 3.7 mg / mL, about 3.8 mg / mL, about 3.9 mg / mL, about 4.0 mg / mL, about 4.5 mg / mL, about 5.0 mg / mL, about 5.5 mg / mL, about 6.0 mg / mL, about 6.5 mg / mL, about 7.0 mg / mL, about 7.5 mg / mL, about 8.0 mg / mL, about 8.5 mg / mL, about 9.0 mg / mL, about 9.5 mg / mL, about 10.0 mg / mL, for example, about 2 mg / mL.

[0016] In some embodiments, the pharmaceutical composition according to any one of the above further comprises an osmolality modifier. In some embodiments, the osmolality modifier is a sugar (including monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, etc.), an amino acid (including arginine, glycine, cysteine, histidine, etc.), or a salt (sodium chloride, potassium chloride, calcium chloride, etc.). In some embodiments, the osmolality modifier is a sugar, and the sugar is selected from glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerin, erythritol, glycerol, arabitol, xylitol, sorbitol (also called sorbitol), mannitol, melibiose, melezitose, raffinose, manninotriose, stachyose, maltose, lactulose, maltulose, maltitol, lactitol, and iso-maltulose. In some embodiments, the osmotic modifier is one or more selected from the group consisting of sucrose, trehalose, sorbitol, arginine, proline, glycine, and sodium chloride. In some embodiments, the osmotic modifier is a non-reducing disaccharide, in some embodiments, the osmotic modifier is trehalose or sucrose, and in some embodiments, the osmotic modifier is sucrose.

[0017] In some embodiments, the concentration of the osmotic pressure adjusting agent in any one of the pharmaceutical compositions described above is about 1 mg / mL to about 300 mg / mL, about 1 mg / mL to about 400 mg / mL, for example, about 10 mg / mL to about 400 mg / mL, about 5 mg / mL to about 200 mg / mL, about 10 mg / mL to about 150 mg / mL, about 20 mg / mL to about 140 mg / mL, about 30 mg / mL to about 130 mg / mL, about 40 mg / mL to about 120 mg / mL, 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 110 mg / mL, about 60 mg / mL to about 100 mg / mL, about 70 mg / mL to about 90 mg / mL (e.g., about 80 mg / mL), or any range between these values. In some embodiments, the concentration of the osmotic agent is about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, or about 200 mg / mL.

[0018] In some embodiments, the pH value of the pharmaceutical composition described above is about 4.0 to about 8.5, for example, about 5.0 to about 8.0, about 6.0 to about 7.5, about 6.5 to about 7.5, about 6.6 to about 7.4, about 6.7 to about 7.3, about 6.8 to about 7.2, about 6.9 to about 7.1 (e.g., about 7.0), or any range between these values. Some non-limiting examples of pH values ​​include about 4.0, about 4.5, about 5.0, about 6.0, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, and about 8.5.

[0019] Generally, the pH of the pharmaceutical composition obtained by replacing the buffer is approximately the same as the pH of the buffer.At the same time, as known to those skilled in the art, in the process of drug formulation, there may be pH drift, but the pH drift of drug formulation is generally small (within the range of ±0.3).In some embodiments, the pH drift of drug formulation is within the range of ±0.1.

[0020] In some embodiments, the concentration of the protein (e.g., anti-FXI / FXIa antibody or antigen-binding fragment thereof) in any one of the above pharmaceutical compositions is about 0.1 mg / mL to about 1000 mg / mL, for example, about 1 mg / mL to about 500 mg / mL, about 1 mg / mL to about 300 mg / mL, about 10 mg / mL to about 400 mg / mL, about 20 mg / mL to about 350 mg / mL, about 30 mg / mL to about 300 mg / mL, about 30 mg / mL to about 20 0 mg / mL, about 130 mg / mL to about 200 mg / mL, about 40 mg / mL to about 250 mg / mL, about 50 mg / mL to about 200 mg / mL, about 60 mg / mL to about 180 mg / mL, about 50 mg / mL to about 150 mg / mL, about 60 mg / mL to about 150 mg / mL, about 70 mg / mL to about 130 mg / mL, about 80 mg / mL to about 120 mg / mL, about 90 mg / mL to about 110 mg / mL, or any range between those point values.For example, about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 61 mg / mL, about 62 mg / mL, about 63 mg / mL, about 64 mg / mL, about 65 mg / mL, about 66 mg / mL, about 67 mg / mL, about 68 mg / mL, about 69 mg / mL, about 70 mg / mL, about 71 mg / mL, about 72 mg / mL, about 73 mg / mL, about 74 mg / mL, about 75 mg / mL, about 76 mg / mL, about 77 mg / mL, about 78 mg / mL, about 79 mg / mL, about 80 mg / mL, about 81 mg / mL, about 82 mg / mL, about 83 mg / mL, about 84 mg / mL, about 85 mg / mL, about 86 mg / mL, about 87 mg / mL, about 88 mg / mL, about 89 mg / mL, about 90 mg / mL, about 91 mg / mL, about 92 mg / mL, about 93 mg / mL, about 94 mg / mL, about 95 mg / mL, about 96 mg / mL, about 97 mg / mL, about 98 mg / mL, about 99 mg / mL, about 100 mg / mL, about 101 mg / mL, about 102 mg / mL, about 103 mg / mL, about 104 mg / mL, about 105 mg / mL, about 106 mg / mL, about 107 mg / mL, about 108 mg / mL, about 109 mg / mL, about 11 g / mL, approximately 75 mg / mL, approximately 76 mg / mL, approximately 77 mg / mL, approximately 78 mg / mL, approximately 79 mg / mL, approximately 80 mg / mL, approximately 81 mg / mL, approximately 82 mg / mL, approximately 83 mg / mL, approximately 84 mg / mL, approximately 85 mg / mL, approximately 86 mg / mL, approximately 87 mg / m L, about 88 mg / mL, about 89 mg / mL, about 90 mg / mL, about 91 mg / mL, about 92 mg / mL, about 93 mg / mL, about 94 mg / mL, about 95 mg / mL, about 96 mg / mL, about 97 mg / mL, about 98 mg / mL, about 99 mg / mL, about 100 mg / mL, about 101mg / mL, about 102mg / mL, about 103mg / mL, about 104mg / mL, about 105mg / mL, about 106mg / mL, about 107mg / mL, about 108mg / mL, about 109mg / mL, about 110mg / mL, about 111mg / mL, about 112mg / mL, about 113mg / mL, about 114mg / mL, about 115mg / mL, about 116mg / mL, about 117mg / mL, about 118mg / mL, about 119mg / mL, about 120mg / mL, about 121mg / mL, about 122mg / mL, about 123mg / mL, about 124mg / mL, about 1 25 mg / mL, about 126 mg / mL, about 127 mg / mL, about 128 mg / mL, about 129 mg / mL, about 130 mg / mL, about 131 mg / mL, about 132 mg / mL, about 133 mg / mL, about 134 mg / mL, about 135 mg / mL, about 140 mg / mL, about 145 mg / mL, about 150 mg / mL, about 155 mg / mL, about 160 mg / mL, about 165 mg / mL, about 170 mg / mL, about 175 mg / mL, about 180 mg / mL, about 185 mg / mL, about 190 mg / mL, about 195 mg / mL, about 200 mg / mL.

[0021] In some embodiments, the pharmaceutical composition described above comprises any one of a) to g): a) about 1 mg / mL to about 500 mg / mL of a protein (e.g., an anti-FXI / FXIa antibody or an antigen-binding fragment thereof), and about 1 mM to about 100 mM histidine, the pH of the pharmaceutical composition being about 4.0 to about 8.5, and optionally, the pharmaceutical composition may further contain about 1 mg / mL to about 500 mg / mL of sucrose or trehalose, and / or about 0.1 mg / mL to about 10 mg / mL of poloxamer 188 or polysorbate.

[0022] b) about 10 mg / mL to about 300 mg / mL of protein (e.g., an anti-FXI / FXIa antibody or an antigen-binding fragment thereof), about 5 mM to about 80 mM histidine, the pH of the pharmaceutical composition is about 6.0 to about 8.0, and optionally, the pharmaceutical composition may further contain about 10 mg / mL to about 400 mg / mL of sucrose or trehalose, and / or about 0.5 mg / mL to about 8.0 mg / mL of poloxamer 188 or polysorbate.

[0023] c) about 30 mg / mL to about 200 mg / mL of a protein (e.g., an anti-FXI / FXIa antibody or an antigen-binding fragment thereof) and about 10 mM to about 60 mM, about 20 mM to about 50 mM, or about 30 mM to about 40 mM (e.g., about 35 mM) of histidine; d) about 50 mg / mL to about 150 mg / mL of a protein (e.g., an anti-FXI / FXIa antibody or an antigen-binding fragment thereof) and about 10 mM to about 60 mM, about 20 mM to about 50 mM, or about 30 mM to about 40 mM (e.g., about 35 mM) of histidine; e) about 70 mg / mL to about 130 mg / mL of a protein (e.g., an anti-FXI / FXIa antibody or an antigen-binding fragment thereof) and about 10 mM to about 60 mM, about 20 mM to about 50 mM, or about 30 mM to about 40 mM (e.g., about 35 mM) histidine; h) about 130 mg / mL to about 200 mg / mL of a protein (e.g., an anti-FXI / FXIa antibody or an antigen-binding fragment thereof), and about 30 mM to about 100 mM, about 60 mM to about 100 mM, or about 60 mM to about 90 mM histidine; I) about 30 mg / mL to about 200 mg / mL of a protein (e.g., an anti-FXI / FXIa antibody or an antigen-binding fragment thereof), and about 30 mM to about 100 mM, about 60 mM to about 100 mM, or about 60 mM to about 90 mM histidine; Among them, the pH of the pharmaceutical compositions in c) to e) and h) to I) is about 6.5 to about 7.5 (e.g., about 6.7 to about 7.3, e.g., about 7.0); Optionally, the pharmaceutical compositions in c) to e), h) to I) further comprise sucrose or trehalose, and poloxamer 188 or a polysorbate (e.g., polysorbate 80 or polysorbate 20); In some embodiments, the pharmaceutical compositions in c) to e) and h) to I) contain sucrose and have a concentration of about 40 mg / mL to about 300 mg / mL, about 50 mg / mL to about 200 mg / mL, about 60 mg / mL to about 150 mg / mL, about 70 mg / mL to about 120 mg / mL (e.g., about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL), In some embodiments, the pharmaceutical compositions in c)-e), h)-I) contain poloxamer 188 at a concentration of about 1.5 mg / mL to about 6 mg / mL, about 1.5 mg / mL to about 5.0 mg / mL, about 1.8 mg / mL to about 3.5 mg / mL, about 1.8 mg / mL to about 2.8 mg / mL (e.g., about 1.8 mg / mL, about 1.9 mg / mL, about 2.0 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL).

[0024] f) about 70 mg / mL to about 130 mg / mL of a protein (e.g., an anti-FXI / FXIa antibody), about 30 mM to about 40 mM (e.g., about 35 mM) of histidine, about 60 mg / mL to about 200 mg / mL of sucrose, and about 1.8 mg / mL to about 2.8 mg / mL of poloxamer 188; g) About 70 mg / mL to about 130 mg / mL of a protein (e.g., an anti-FXI / FXIa antibody), about 30 mM to about 40 mM (e.g., about 35 mM) of histidine, about 80 mg / mL of sucrose, and about 2.0 mg / mL of poloxamer 188.

[0025] In some embodiments, the pharmaceutical composition comprises any one of the following: (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 35 mM histidine; (c) about 80 mg / mL sucrose; (d) poloxamer 188 at about 2 mg / mL; the pH of the pharmaceutical composition is about 7.0; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 35 mM histidine; (c) about 80 mg / mL sucrose; (d) poloxamer 188 at about 2 mg / mL; the pH of the pharmaceutical composition is about 6.7; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 35 mM histidine; (c) about 80 mg / mL sucrose; (d) poloxamer 188 at about 2 mg / mL; the pH of the pharmaceutical composition is about 7.3; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 30 mM histidine; (c) about 80 mg / mL sucrose; (d) poloxamer 188 at about 1.8 mg / mL; the pH of the pharmaceutical composition is about 7.0; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 30 mM histidine; (c) about 80 mg / mL sucrose; (d) poloxamer 188 at about 2.8 mg / mL; the pH of the pharmaceutical composition is about 7.0; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 40 mM histidine; (c) about 80 mg / mL sucrose; (d) poloxamer 188 at about 1.8 mg / mL; the pH of the pharmaceutical composition is about 7.0; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 40 mM histidine; (c) about 80 mg / mL sucrose; (d) poloxamer 188 at about 2.3 mg / mL; the pH of the pharmaceutical composition is about 7.0; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 40 mM histidine; (c) about 80 mg / mL sucrose; (d) poloxamer 188 at about 2.8 mg / mL; the pH of the pharmaceutical composition is about 7.0; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 35 mM histidine; (c) about 80 mg / mL sucrose; (d) poloxamer 188 at about 2.3 mg / mL; the pH of the pharmaceutical composition is about 7.0; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 35 mM histidine; (c) about 80 mg / mL sucrose; (d) poloxamer 188 at about 1.8 mg / mL; The pH of the pharmaceutical composition is about 7.0.

[0026] Other buffer systems The present disclosure provides a pharmaceutical composition comprising an anti-FXI / FXIa antibody and a buffer. In some embodiments, the buffer is selected from acetate buffer, histidine buffer, Tris-hydrochloride buffer, Tris-citrate buffer, and phosphate buffer. The composition has therapeutic or prophylactic activity. Moreover, the composition may also have the advantage of good stability.

[0027] In some embodiments, the pH value of the pharmaceutical composition is about 4.0 to about 8.5, e.g., about 5.0 to about 8.0, about 6.0 to about 7.5, about 6.5 to about 7.5, about 6.6 to about 7.4, about 6.7 to about 7.3, about 6.8 to about 7.2, about 6.9 to about 7.1 (e.g., about 7.0), or any range between these values. Some non-limiting examples of pH values ​​include about 4.0, about 4.5, about 5.0, about 6.0, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8.0, about 8.1, about 8.2, about 8.3, about 8.4, and about 8.5.

[0028] Generally, the pH of the pharmaceutical composition obtained by replacing the buffer is approximately the same as the pH of the buffer.At the same time, as known to those skilled in the art, in the process of drug formulation, there may be pH drift, but the pH drift of drug formulation is generally small (within the range of ±0.3).In some embodiments, the pH drift of drug formulation is within the range of ±0.1.

[0029] In some embodiments, in the pharmaceutical composition according to any one of the above, the concentration of the anti-FXI / FXIa antibody or antigen-binding fragment thereof is about 0.1 mg / mL to about 1000 mg / mL, for example, about 1 mg / mL to about 500 mg / mL, about 1 mg / mL to about 300 mg / mL, about 10 mg / mL to about 400 mg / mL, about 20 mg / mL to about 350 mg / mL, about 30 mg / mL to about 300 mg / mL, about 40 mg / mL to about 200 mg / mL, or about 50 mg / mL to about 200 mg / mL. 50 mg / mL, about 50 mg / mL to about 200 mg / mL, about 60 mg / mL to about 180 mg / mL, about 50 mg / mL to about 150 mg / mL, about 60 mg / mL to about 150 mg / mL, about 70 mg / mL to about 130 mg / mL, about 80 mg / mL to about 120 mg / mL, about 90 mg / mL to about 110 mg / mL, about 1 mg / mL to about 300 mg / mL, about 1 mg / mL to about 200 mg / mL, or any range between these values. In some embodiments, the concentration of the anti-FXI / FXIa antibody is 1 mg / mL to 100 mg / mL. In some embodiments, the concentration of the anti-FXI / FXIa antibody is 40 mg / mL to 100 mg / mL. In some non-limiting embodiments, the concentration of the anti-FXI / FXIa antibody is about 1 mg / mL, about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL or about 200 mg / mL.

[0030] In some embodiments, the pharmaceutical composition according to any one of the above, wherein the pharmaceutical composition comprises a surfactant. In some embodiments, the surfactant is a non-ionic surfactant. In some embodiments, the surfactant is a poloxamer (e.g., poloxamer 188), polysorbate (e.g., polysorbate 20, polysorbate 80), poloxamer, Triton, sodium dodecyl sulfonate, sodium lauryl sulfonate, sodium octyl glucoside, lauryl-sulfobetaine, myristyl-sulfobetaine, linoleic-sulfobetaine, stearic-sulfobetaine, lauryl-sarcosine, myristyl-sarcosine, linoleic-sarcosine, stearic-sarcosine, linoleic-betaine, myristyl-betaine. The surfactant may be selected from the group consisting of methyl methacrylate, ethyl ...

[0031] In some embodiments, in the pharmaceutical composition according to any one of the above, the concentration of the surfactant is 0.05 mg / mL to 10 mg / mL, for example, 0.1 mg / mL to 10 mg / mL, 0.05 mg / mL to 1.0 mg / mL, 0.1 mg / mL to 1.0 mg / mL, or 0.2 mg / mL to 0.8 mg / mL. In some embodiments, the concentration of the surfactant is 0.2 mg / mL to 0.6 mg / mL. In some embodiments, the concentration of the surfactant is 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, or 1.0 mg / mL, or any range between these point values. In some embodiments, the concentration of the surfactant is 0.4 mg / mL. In some embodiments, the surfactant is 0.4 mg / mL poloxamer 188. In some embodiments, the surfactant is 0.4 mg / mL polysorbate 80.

[0032] In some embodiments, the pharmaceutical composition according to any one of the above further comprises an osmolality modifier. In some embodiments, the osmolality modifier is a sugar (including monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, etc.), an amino acid (including arginine, glycine, cysteine, histidine, etc.), or a salt (sodium chloride, potassium chloride, calcium chloride, etc.). In some embodiments, the osmolality modifier is a sugar, and the sugar is selected from glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerin, erythritol, glycerol, arabitol, xylitol, sorbitol (also called sorbitol), mannitol, melibiose, melezitose, raffinose, manninotriose, stachyose, maltose, lactulose, maltulose, maltitol, lactitol, and iso-maltulose. In some embodiments, the osmotic modifier is one or more selected from the group consisting of sucrose, trehalose, sorbitol, arginine, proline, glycine, and sodium chloride. In some embodiments, the osmotic modifier is a non-reducing disaccharide, in some embodiments, the osmotic modifier is trehalose or sucrose, in some embodiments, the osmotic modifier is sucrose. In some embodiments, the osmotic modifier is selected from sucrose, proline and sucrose, or glycine and sucrose.

[0033] In some embodiments, in the pharmaceutical composition according to any one of the above, the concentration of the osmotic pressure adjusting agent is 1 mg / mL to 300 mg / mL, for example, about 5 mg / mL to about 200 mg / mL, about 10 mg / mL to about 150 mg / mL, about 20 mg / mL to about 140 mg / mL, about 30 mg / mL to about 130 mg / mL, about 40 mg / mL to about 120 mg / mL, about 50 mg / mL to about 110 mg / mL, about 60 mg / mL to about 100 mg / mL, about 75 mg / mL to about 100 mg / mL, about 70 mg / mL to about 90 mg / mL, about 75 mg / mL to about 85 mg / mL, about 75 mg / mL to about 80 mg / mL, about 1 mg / mL to about 100 mg / mL, about 1 mg / mL to about 80 mg / mL, about 1 mg / mL to about 40 mg / mL, or any range between these values. In some embodiments, non-limiting examples of the concentration of the osmotic modifier include about 7.5 mg / mL, about 11.5 mg / mL, about 40 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL. In some embodiments, the pharmaceutical composition is an isotonic formulation. In some embodiments, the osmotic modifier is 80 mg / mL sucrose. In some embodiments, the osmotic modifier is 40 mg / mL sucrose. In some embodiments, the osmotic modifier is about 10 mM to about 300 mM proline and about 1 mg / mL to about 200 mg / mL sucrose. In some embodiments, the osmotic pressure adjusting agent is about 10 mM to about 200 mM proline and about 10 mg / mL to about 100 mg / mL sucrose. In some embodiments, the osmotic pressure adjusting agent is about 50 mM to about 150 mM proline and about 10 mg / mL to about 80 mg / mL sucrose. In some embodiments, the osmotic pressure adjusting agent is about 80 mM to about 120 mM proline and about 40 mg / mL to about 80 mg / mL sucrose. In some embodiments, the osmotic pressure adjusting agent is about 100 mM proline and about 40 mg / mL sucrose. In some embodiments, the osmotic pressure adjusting agent is about 10 mM to about 300 mM glycine and about 1 mg / mL to about 200 mg / mL sucrose.In some embodiments, the osmotic pressure adjusting agent is about 10 mM to about 200 mM glycine and about 10 mg / mL to about 100 mg / mL sucrose. In some embodiments, the osmotic pressure adjusting agent is about 50 mM to about 150 mM glycine and about 10 mg / mL to about 80 mg / mL sucrose. In some embodiments, the osmotic pressure adjusting agent is about 80 mM to about 120 mM glycine and about 40 mg / mL to about 80 mg / mL sucrose. In some embodiments, the osmotic pressure adjusting agent is about 100 mM glycine and about 40 mg / mL sucrose.

[0034] In some embodiments, in the pharmaceutical composition according to any one of the above, the buffering agent has a concentration of about 5 mM to about 100 mM. In some embodiments, the buffering agent has a concentration of about 10 mM to about 30 mM. In some embodiments, the buffering agent has a concentration of about 5 mM to about 15 mM. In some embodiments, the buffering agent has a concentration of about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 40 mM, about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, or about 100 mM, and any range between these values. In some embodiments, the buffering agent is about 10 mM histidine-hydrochloride. In some embodiments, the buffering agent is about 10 mM sodium dihydrogen phosphate-disodium hydrogen phosphate. In some embodiments, the buffering agent is about 10 mM Tris-hydrochloride.

[0035] In some embodiments, the pharmaceutical composition described above comprises any one of a) to i): a) about 1 mg / mL to about 300 mg / mL of a protein (e.g., an anti-FXI / FXIa antibody) and about 5 mM to about 100 mM, about 10 mM to about 30 mM, or about 5 mM to about 15 mM (e.g., about 10 mM) of histidine hydrochloride, sodium dihydrogen phosphate-disodium hydrogen phosphate, or Tris-hydrochloride; b) about 50 mg / mL to about 150 mg / mL of a protein (e.g., an anti-FXI / FXIa antibody) and about 5 mM to about 100 mM, about 10 mM to about 30 mM, or about 5 mM to about 15 mM (e.g., about 10 mM) of histidine-hydrochloride, sodium dihydrogen phosphate-disodium hydrogen phosphate, or Tris-hydrochloride; c) about 70 mg / mL to about 130 mg / mL of a protein (e.g., an anti-FXI / FXIa antibody) and about 5 mM to about 100 mM, about 10 mM to about 30 mM, or about 5 mM to about 15 mM (e.g., about 10 mM) of histidine-hydrochloride or sodium dihydrogen phosphate-disodium hydrogen phosphate or Tris-hydrochloride; Among them, the pH of the pharmaceutical compositions in a) to c) is about 4.0 to about 8.5 (e.g., about 6.5 to about 7.5, e.g., about 7.0); Optionally, the pharmaceutical compositions in a) to c) further comprise sucrose, or trehalose, or glycine and sucrose, or proline and sucrose, and poloxamer 188 or a polysorbate (e.g., polysorbate 80 or polysorbate 20); In some embodiments, the pharmaceutical compositions in a) to c) further contain sucrose or trehalose, for example, at a concentration of about 1 mg / mL to about 300 mg / mL, about 10 mg / mL to about 150 mg / mL, about 75 mg / mL to about 100 mg / mL (e.g., about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL), In some embodiments, the pharmaceutical compositions in a) to c) further contain glycine and sucrose, for example, at concentrations of about 10 mM to about 300 mM glycine and about 1 mg / mL to about 200 mg / mL sucrose, about 10 mM to about 200 mM glycine and about 10 mg / mL to about 100 mg / mL sucrose, about 80 mM to about 120 mM glycine and about 40 mg / mL to about 80 mg / mL sucrose (e.g., about 100 mM glycine and about 40 mg / mL sucrose, about 90 mM glycine and about 50 mg / mL sucrose, about 110 mM glycine and about 30 mg / mL sucrose), In some embodiments, the pharmaceutical compositions in a) to c) further contain proline and sucrose, for example, at concentrations of about 10 mM to about 300 mM proline and about 1 mg / mL to about 200 mg / mL sucrose, about 10 mM to about 200 mM proline and about 10 mg / mL to about 100 mg / mL sucrose, about 80 mM to about 120 mM proline and about 40 mg / mL to about 80 mg / mL sucrose (e.g., about 100 mM proline and about 40 mg / mL sucrose, about 90 mM proline and about 50 mg / mL sucrose, about 110 mM proline and about 30 mg / mL sucrose), In some embodiments, the pharmaceutical compositions in a) to c) further comprise poloxamer 188 or polysorbate (e.g., polysorbate 80 or polysorbate 20) at a concentration of about 0.1 mg / mL to about 10 mg / mL, about 1.5 mg / mL to about 4.0 mg / mL, about 1.8 mg / mL to about 3.5 mg / mL, about 1.8 mg / mL to about 2.8 mg / mL (e.g., about 1.8 mg / mL, about 1.9 mg / mL, about 2.0 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL).

[0036] d) about 1 mg / mL to about 300 mg / mL of a protein (e.g., an anti-FXI / FXIa antibody or an antigen-binding fragment thereof), about 10 mM histidine-hydrochloride or sodium dihydrogen phosphate-disodium hydrogen phosphate or Tris-hydrochloride, the pH of the pharmaceutical composition being about 6.5 to about 7.5, and optionally the pharmaceutical composition may further contain about 80 mg / mL of sucrose, and about 0.1 mg / mL to about 10 mg / mL of poloxamer 188 or polysorbate.

[0037] e) About 1 mg / mL to about 300 mg / mL of a protein (e.g., an anti-FXI / FXIa antibody or an antigen-binding fragment thereof), about 10 mM histidine-hydrochloride or sodium dihydrogen phosphate-disodium hydrogen phosphate or Tris-hydrochloride, the pH of the pharmaceutical composition being about 6.5 to about 7.5, and optionally, the pharmaceutical composition may further contain about 100 mM glycine or proline, about 40 mg / mL sucrose, and about 0.1 mg / mL to about 10 mg / mL of poloxamer 188 or polysorbate.

[0038] f) about 50 mg / mL to about 150 mg / mL of a protein (e.g., an anti-FXI / FXIa antibody or an antigen-binding fragment thereof), about 5 mM to about 100 mM of histidine hydrochloride or sodium dihydrogen phosphate-disodium hydrogen phosphate or Tris-hydrochloride, the pH of the pharmaceutical composition being about 4.0 to about 8.5, and optionally, the pharmaceutical composition may further contain about 10 mg / mL to about 150 mg / mL of sucrose, and about 0.1 mg / mL to about 10 mg / mL of poloxamer 188 or polysorbate.

[0039] g) about 50 mg / mL to about 150 mg / mL of a protein (e.g., an anti-FXI / FXIa antibody or an antigen-binding fragment thereof), about 5 mM to about 100 mM of histidine hydrochloride or sodium dihydrogen phosphate-disodium hydrogen phosphate or Tris-hydrochloride, the pH of the pharmaceutical composition being about 4.0 to about 8.5, and optionally, the pharmaceutical composition may further contain about 10 mM to about 200 mM of glycine or proline, about 10 mg / mL to about 100 mg / mL of sucrose, and about 0.1 mg / mL to about 10 mg / mL of poloxamer 188 or polysorbate.

[0040] h) about 70 mg / mL to about 130 mg / mL of a protein (e.g., an anti-FXI / FXIa antibody or an antigen-binding fragment thereof), about 5 mM to about 15 mM of histidine-hydrochloride or sodium dihydrogen phosphate-disodium hydrogen phosphate or Tris-hydrochloride, the pH of the pharmaceutical composition being about 6.5 to about 7.5, and optionally, the pharmaceutical composition may further contain about 80 mg / mL of sucrose, and about 1.5 mg / mL to about 4 mg / mL of poloxamer 188 or polysorbate.

[0041] i) about 70 mg / mL to about 130 mg / mL of protein (e.g., an anti-FXI / FXIa antibody or an antigen-binding fragment thereof), about 5 mM to about 15 mM of histidine-hydrochloride or sodium dihydrogen phosphate-disodium hydrogen phosphate or Tris-hydrochloride, the pH of the pharmaceutical composition being about 6.5 to about 7.5, and optionally, the pharmaceutical composition may further contain about 100 mM glycine or proline, about 40 mg / mL of sucrose, and about 1.5 mg / mL to about 4 mg / mL of poloxamer 188 or polysorbate.

[0042] The pharmaceutical composition of the present disclosure further comprises a solvent, which is selected from non-toxic physiologically acceptable liquid vectors, such as, but not limited to, saline, water for injection, glucose solution (e.g., 5% glucose injection, glucose sodium chloride injection), etc.

[0043] The present disclosure further provides a pharmaceutical composition comprising an anti-FXI / FXIa antibody or antigen-binding fragment thereof, histidine, sucrose, and poloxamer 188, the concentration of which is available as an intravenous injection, obtained by diluting the pharmaceutical composition with 0.9% saline or 5% glucose solution, or after diluting the pharmaceutical composition with 0.9% saline or 5% glucose solution. In some embodiments, the concentration of the anti-FXI / FXIa antibody or antigen-binding fragment thereof in the pharmaceutical composition is about 0.01 mg / mL to about 50 mg / mL. In some embodiments, the concentration of the anti-FXI / FXIa antibody or antigen-binding fragment thereof in the pharmaceutical composition is about 0.1 mg / mL to about 30 mg / mL. In some embodiments, the concentration of the anti-FXI / FXIa antibody or antigen-binding fragment thereof in the pharmaceutical composition is about 0.20 mg / mL to about 13.30 mg / mL.

[0044] In some embodiments, the protein in the pharmaceutical composition of the present disclosure is an antibody, an antibody fragment, or an Fc fusion protein. In some embodiments, the antigen targeted by the antibody, antibody fragment, or Fc fusion protein is factor VIIIC, factor IX, factor XI / factor XIa (FXI / FXIa), tissue factor, vascular endothelial growth factor (VEGF), renin, growth hormone, growth hormone releasing factor, parathyroid hormone, thyroid stimulating hormone, lipoprotein, alpha-1-antitrypsin, bone-derived neurotrophic factor (BDNF), neurotrophin-3, -4, -5, or -6 (NT-3, NT-4, NT-5, or NT-6), epidermal growth factor (EGF), transforming growth factor (TGF), interferon, M-CSF, GM-CSF, G-CSF, IL-1 to IL-10, HER2, HER3 or HER4 receptor, CTLA-4, PD-1, PD-L1, PD-L2, TIM3, 41BB, 41BBL, OX40, OX40L, GITRL, GITR, CD25, CD27, CD70, CD80, TNFRSF25, CD40L, CD40, B7 H3, B7 H4, VISTA, TMIGD2, HHLA2-TMIGD2, butyrophilin (including BTNL2), Siglec family, TIGIT and PVR family members, KIRs, ILTs and LIRs, CD79, GARP, GITR, PSMA, Neuropilin, CD160, CD30 and CD155, and fragments of any of the above polypeptides. In some embodiments, the protein in the pharmaceutical composition is an anti-FXI / FXIa antibody or an antigen-binding fragment thereof.

[0045] In some embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof described in the pharmaceutical composition comprises a heavy chain variable region and a light chain variable region, wherein: The heavy chain variable region comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NOs: 7, 8, and 9, respectively, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NOs: 10, 11, and 12, respectively.

[0046] In some embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof described in the pharmaceutical composition may be selected from a murine antibody, a chimeric antibody, or a humanized antibody, for example a humanized antibody.

[0047] In an alternative embodiment, the sequences of the light and heavy chain FRs in the light and heavy chain variable regions of the humanized anti-FXI / FXIa antibody described in the pharmaceutical composition are derived from human germline light and heavy chain FRs, respectively, or mutated sequences thereof.

[0048] In some embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof described in the pharmaceutical composition comprises an antibody heavy chain variable region and a light chain variable region, wherein: the sequence of the heavy chain variable region is SEQ ID NO:5 or a sequence having at least 80%, at least 85%, at least 90% identity thereto, and the sequence of the light chain variable region is SEQ ID NO:6 or a sequence having at least 80%, at least 85%, at least 90% identity thereto; the sequence of the heavy chain variable region is SEQ ID NO: 13 or a sequence having at least 80%, at least 85%, at least 90% identity thereto, and the sequence of the light chain variable region is SEQ ID NO: 14 or a sequence having at least 80%, at least 85%, at least 90% identity thereto; the sequence of the heavy chain variable region is SEQ ID NO: 15 or a sequence having at least 80%, at least 85%, at least 90% identity thereto, and the sequence of the light chain variable region is SEQ ID NO: 16 or a sequence having at least 80%, at least 85%, at least 90% identity thereto; the sequence of the heavy chain variable region is SEQ ID NO: 17 or a sequence having at least 80%, at least 85%, at least 90% identity thereto, and the sequence of the light chain variable region is SEQ ID NO: 16 or a sequence having at least 80%, at least 85%, at least 90% identity thereto; In some specific embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof described in the pharmaceutical composition comprises an antibody heavy chain variable region and a light chain variable region, wherein the sequence of the heavy chain variable region is set forth in SEQ ID NO: 17 and the sequence of the light chain variable region is set forth in SEQ ID NO: 16.

[0049] In some embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof further comprises a heavy chain constant region and a light chain constant region. In alternative embodiments, the heavy chain constant region is selected from human IgG1, IgG2, IgG3, IgG4, IgG4P (i.e., S241P mutant of IgG4) constant regions, and the light chain constant region is selected from human κ and λ chain constant regions. The sequence of the IgG4P Fc (i.e., IgG4 Fc containing S241P) is, for example, set forth in SEQ ID NO: 19. In some embodiments, the sequence of the heavy chain CH1 is set forth in SEQ ID NO: 18 or a sequence having at least 80%, at least 85%, at least 90% identity thereto, and / or the sequence of the light chain constant region is set forth in SEQ ID NO: 20 or a sequence having at least 80%, at least 85%, at least 90% identity thereto.

[0050] In some embodiments, the anti-FXI / FXIa antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein the heavy chain is the sequence set forth in SEQ ID NO: 21 or a sequence having at least 80%, at least 85%, or at least 90% identity thereto, and the light chain is the sequence set forth in SEQ ID NO: 22 or a sequence having at least 80%, at least 85%, or at least 90% identity thereto.

[0051] In the present disclosure, the above-mentioned "at least 90% identity" covers at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity.

[0052] In the present disclosure, the above "at least 90% identity" covers at least 80%, at least 85%, at least 87%, at least 88%, at least 89%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identity.

[0053] In some specific embodiments, the anti-FXI / FXIa antibody described in the pharmaceutical composition comprises an antibody heavy chain and a light chain, of which the sequence of the heavy chain is shown in SEQ ID NO: 21 and the sequence of the light chain is shown in SEQ ID NO: 22.

[0054] In some embodiments, the antigen-binding fragment of the anti-FXI / FXIa antibody is a Fab, Fv, sFv, Fab', F(ab')2, linear antibody, single chain antibody, scFv, sdAb, sdFv, nanobody, peptide antibody, domain antibody and multispecific antibody (bispecific antibody, diabody, triabody and tetrabody, tandem di-scFv, tandem tri-scFv), e.g., specifically a scFv, Fv, Fab or Fab' fragment.

[0055] In some embodiments, the heavy and / or light chain variable region of the anti-FXI / FXIa antibody contains 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid changes. The amino acid changes may be conservative substitutions of amino acid residues in the variable regions.

[0056] In some embodiments, the anti-FXI / FXIa antibody is Preventing activation of the intrinsic or common blood coagulation pathway; blocking the binding of FXI and / or FXIa to one or more of blood clotting factors IX, XIIa or thrombin and other components of the blood clotting pathway; Blocking one or more of FIX, FXI and FXIa from binding to platelet receptors; <= 10 -9 Binding to human FXI and / or FXIa protein at a KD; When bound to FXI / FXIa, it prevents the catalytic domain of FXI / FXIa from adopting an active conformation; It is applicable to subcutaneous or intravenous administration; The present invention may have any one or more of the following characteristics.

[0057] The above affinity measurement method is, for example, BIACORE TM It is.

[0058] In some embodiments, any one of the pharmaceutical compositions may be administered as an intravenous injection, a subcutaneous injection, an intraperitoneal injection, or an intramuscular injection.

[0059] In some embodiments, the disclosure provides a method of preparing any one of the above pharmaceutical compositions, the method comprising replacing a stock solution of an anti-FXI / FXIa antibody or antigen-binding fragment thereof with a buffer.

[0060] The present disclosure further provides a liquid formulation comprising any one of the above described pharmaceutical compositions.

[0061] The pharmaceutical composition according to the present disclosure has sufficient drug stability and can be left stably for a long period of time.

[0062] The present disclosure further provides a method for preparing a lyophilized formulation of a pharmaceutical composition comprising an anti-FXI / FXIa antibody, said method comprising the step of lyophilizing said pharmaceutical composition.

[0063] The present disclosure further provides a lyophilized formulation of a pharmaceutical composition comprising an anti-FXI / FXIa antibody, the lyophilized formulation being obtainable by lyophilizing any one of the pharmaceutical compositions described above.

[0064] In some embodiments, the lyophilized formulation is stable for at least 1 month, at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, or at least 30 months when stored in the dark at 2-8° C.

[0065] In some embodiments, the lyophilized formulation is stable at 25° C. for at least 1 month, at least 3 months, at least 6 months, or at least 12 months.

[0066] In some embodiments, the lyophilized formulation is stable at 40° C. for at least 7 days, at least 14 days, or at least 30 days.

[0067] The present disclosure further provides a reconstituted solution comprising an anti-FXI / FXIa antibody pharmaceutical composition, the reconstituted solution being prepared by reconstituting any one of the above lyophilized formulations.

[0068] The present disclosure further provides an article of manufacture comprising a container containing any one of the pharmaceutical compositions, liquid formulations, lyophilized formulations, or reconstituted solutions described above. In some embodiments, the container may be, but is not limited to, a neutral borosilicate glass injection vial.

[0069] The present disclosure further provides the use of any one of the above pharmaceutical compositions, any one of the above liquid formulations, any one of the above lyophilized formulations, any one of the above reconstituted solutions, or any one of the above products in the preparation of a medicament for treating a disease.

[0070] The present disclosure further provides a method for treating or preventing a disease, comprising administering to a subject in need thereof an effective amount of any one of the above pharmaceutical compositions, any one of the above liquid formulations, any one of the above lyophilized formulations, any one of the above reconstituted solutions, or any one of the above products.

[0071] The present disclosure further provides any one of the above pharmaceutical compositions, any one of the above liquid formulations, any one of the above lyophilized formulations, any one of the above reconstituted solutions, or any one of the above products for use in treating a disease.

[0072] In some embodiments, the disease described in any one of the above is a thrombogenic or thromboembolic disease and / or a thrombogenic or thromboembolic complication, or arrhythmia, cardiogenic thromboembolism, diffuse intravascular coagulation.

[0073] In some embodiments, in any one of the above diseases, the thrombogenic or thromboembolic disease is selected from, but is not limited to, cardiac coronary artery disease, such as acute coronary syndrome (ACS), ST elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (non-STEMI), stable angina, unstable angina, reocclusion and restenosis after coronary intervention, and peripheral arterial occlusive disease, pulmonary embolism, venous thromboembolism, venous thrombosis, transient ischemic attack, and thrombotic or thromboembolic disease in other vessels causing thrombotic stroke and thromboembolic stroke, pulmonary disease with chronic thromboembolism (CTEPH) and pulmonary arterial hypertension, or a combination thereof.

[0074] The present disclosure provides a method for treating or preventing a disease, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of any one of the pharmaceutical compositions described above, any one of the liquid formulations described above, any one of the lyophilized formulations described above, any one of the reconstituted solutions described above, or any one of the products described above, wherein the disease is a thrombogenic or thromboembolic disease and / or a thrombogenic or thromboembolic complication, or arrhythmia, cardiogenic thromboembolism, diffuse intravascular blood coagulation. In some embodiments, the thrombogenic or thromboembolic disease or its complications are selected from, but are not limited to, coronary heart disease, such as acute coronary syndrome (ACS), ST elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (non-STEMI), stable angina, unstable angina, reocclusion and restenosis after coronary intervention, and peripheral arterial occlusive disease, pulmonary embolism, venous thromboembolism, venous thrombosis, transient ischemic attack, and thrombotic and thromboembolic stroke in other blood vessels, chronic thromboembolic (CTEPH) pulmonary disease and pulmonary arterial hypertension, or combinations thereof. In some embodiments, the mode of administration is subcutaneous or intravenous injection. [Brief description of the drawings]

[0075] [Figure 1] In vitro FXIIa-mediated FXI-activating enzyme activity inhibition test of anti-FXI / FXIa antibodies. [Diagram 2] Detection of aPTT / PT anticoagulant activity in human blood, of which Figures 2A and 2B are the aPTT and PT test results of anti-FXI / FXIa antibodies in human blood, respectively. 1209 is another anti-FXI / FXIa antibody obtained by screening in the present application. [Diagram 3] 3A and 3B show the aPTT and PT test results of anti-FXI / FXIa antibodies in monkey blood, respectively. [Figure 4] Figure 4A shows the change curves of aPTT, plasma drug concentration, FXI:C% and free FXI in cynomolgus monkeys for antibody 3882, Figure 4B shows the inhibitory effect of antibody 3882 on thrombus formation in cynomolgus monkeys, and Figures 4C and 4D show the safety test of antibody 3882 in cynomolgus monkeys, showing the results of bleeding time measurement and PT detection, respectively. [Diagram 5] The results of in vivo pharmacodynamics (PD) test of anti-FXI / FXIa antibody in cynomolgus monkeys are shown in Figure 5A, where Figure 5B shows the APTT(s) detection results and Figure 5B shows the FXI:C(%) detection results. 3882 (1 mg / kg) was administered intravenously and subcutaneously, and the control BAY1213790 (1 mg / kg) was administered intravenously. [Figure 6] Screening of the pH value of the buffer system of anti-FXI / FXIa antibody formulation, in which Figures 6A, 6B, and 6C respectively show the change trends of SEC, NRCE, and iCIEF under different pH / buffer conditions at 40°C. [Figure 7]This is fine screening of pH, additives and surfactant concentrations in anti-FXI / FXIa antibody formulations, of which Figures 7A, 7B and 7C show the change trends of SEC, NRCE and CEX under different pH / buffer conditions at 40°C. [Figure 8] Screening of buffer systems and types of surfactants for anti-FXI / FXIa antibody formulations, in which Figures 8A and 8B show the change trends of SEC and CEX for different surfactants at 40°C. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0076] term In order that the present disclosure may be more readily understood, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art.

[0077] "Buffer" refers to a buffer that resists changes in pH by the action of its acid-base conjugate components. Examples of buffers that control pH in the appropriate range include acetate, succinate, gluconate, histidine, oxalate, lactate, phosphate, citrate, tartrate, fumarate, glycylglycine and other organic acid buffers.

[0078] A "histidine buffer" is a buffer containing histidine ions. Examples of histidine buffers include histidine-hydrochloride, histidine-acetate, histidine-phosphate, histidine-sulfate, and the like, and preferably histidine-hydrochloride buffers. Histidine-hydrochloride buffers are prepared with histidine and hydrochloric acid or histidine and histidine hydrochloride.

[0079] "Self-buffering" refers to the sufficient ability of a substance such as a drug protein (e.g., an antibody or antigen-binding fragment thereof, in some embodiments an anti-FXI / FXIa antibody, e.g., the 3882 antibody of the present disclosure) to withstand pH changes of certain uses in the absence of other buffering agents.

[0080] "Tris-citrate buffer" is a buffer containing citrate ions. Examples of Tris-citrate buffers include Tris-hydrochloride, Tris-acetate, Tris-phosphate, Tris-sulfate, Tris-citrate, and the like buffers, and preferably Tris-citrate.

[0081] A "Tris-hydrochloride buffer" is a buffer that contains hydrochloride ions. Examples of Tris-hydrochloride buffers include Tris-hydrochloride, Tris-acetate, Tris-phosphate, Tris-sulfate, Tris-citrate, and the like buffers. A preferred citrate buffer is Tris-hydrochloride buffer.

[0082] A "phosphate buffer" is a buffer that contains phosphate ions. Examples of phosphate buffers include disodium hydrogen phosphate-sodium dihydrogen phosphate, disodium hydrogen phosphate-potassium dihydrogen phosphate, etc. A preferred phosphate buffer is disodium hydrogen phosphate-sodium dihydrogen phosphate buffer.

[0083] An "acetate buffer" is a buffer that contains acetate ions. Examples of acetate buffers include acetic acid-sodium acetate, acetic acid-histidine salt, acetic acid-potassium acetate, acetic acid-calcium acetate, acetic acid-magnesium acetate, etc. A preferred acetate buffer is acetic acid-sodium acetate buffer.

[0084] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein or their physiologically / pharmaceutical acceptable salts or prodrugs, and other chemical components such as physiologically / pharmaceutical acceptable vectors and excipients. The pharmaceutical composition is intended to facilitate administration to a living body and contribute to the absorption of the active ingredient to further exert biological activity. In this specification, the terms "pharmaceutical composition" and "formulation" are not mutually exclusive.

[0085] In the solution forms of the pharmaceutical compositions described in this disclosure, unless otherwise specified, the solvent therein is water.

[0086] The term "about" as used herein means that the numerical value is within an acceptable error range of the specific value as determined by one of ordinary skill in the art, the numerical portion being determined by how it is measured or determined (i.e., the limitations of the measurement system). For example, in the practice of the art, "about" may mean within or more than one standard difference. Alternatively, "about" or "essentially including" may mean a range of at most 20%. Moreover, particularly for biological systems or processes, the term may mean at most an order of magnitude or at most 5 times the numerical value. Unless otherwise stated, when a specific value appears in the present application and claims, the meaning of "about" or "essentially including" should be assumed to be within an acceptable error range of the specific value.

[0087] The pharmaceutical compositions described in the present disclosure can achieve a stable effect, i.e., the antibody therein essentially retains its physical and / or chemical stability and / or biological activity after storage, and preferably, the pharmaceutical composition essentially retains its physical and chemical stability and its biological activity after storage. The storage period is generally selected based on the desired shelf life of the pharmaceutical composition. Currently, there are several analytical techniques for measuring protein stability, which can measure stability after storage at a given temperature for a given period of time.

[0088] A stable drug antibody formulation is one that does not show significant changes when stored at refrigerated temperatures (2-8°C) for at least 3 months, preferably 6 months, more preferably 1 year, and even more preferably up to 2 years. Stable liquid formulations also include liquid formulations that exhibit the desired characteristics after storage at temperatures including 25°C for periods including 1 month, 3 months, 6 months, or 40°C for periods including 1 month. A typical acceptable criterion for stability is that typically no more than about 10%, preferably no more than about 5%, of the antibody monomer is degraded as measured by SEC-HPLC. By visual analysis, the drug antibody formulation is colorless or yellow, clear to slightly opalescent. The concentration, pH, and osmolality of the formulation have a variation of no more than ±10%. Typically no more than about 10%, preferably no more than about 5%, cleavage is observed, and typically no more than about 10%, preferably no more than about 5% of aggregates are formed.

[0089] An antibody "retains its physical stability" in a drug formulation if it does not exhibit significant increased aggregation, precipitation, and / or denaturation as determined by visual inspection of color and / or clarity or by UV light scattering, size exclusion chromatography (SEC), and dynamic light scattering (DLS). Changes in protein conformation can be assessed by fluorescence spectroscopy (which determines the tertiary structure of proteins) and by FTIR spectroscopy (which determines the secondary structure of proteins).

[0090] If the antibody does not show significant chemical changes, the antibody "retains its chemical stability" in the drug formulation. Chemical stability can be assessed by detecting and quantifying chemically altered proteins. Degradation processes that constantly change the chemical structure of proteins include hydrolysis or cleavage (assessed by methods such as size exclusion chromatography and SDS-PAGE), oxidation (assessed by methods such as peptide mapping combined with mass spectrometry or MALDI / TOF / MS), deamidation (assessed by methods such as ion exchange chromatography, capillary isoelectric focusing, peptide mapping, measurement of isoaspartic acid, etc.) and isomerization (assessed by measurement of isoaspartic acid content, peptide mapping, etc.).

[0091] An antibody "retains its biological activity" in a drug formulation if the biological activity of the antibody over a given time period is within a given range of the biological activity exhibited when the drug formulation was prepared. Antibody biological activity can be determined, for example, by antigen binding assays.

[0092] "Factor XI", also referred to herein as "blood clotting factor XI", "FXI" or "fXI", is a two-chain glycoprotein with a molecular weight of about 160 kilodaltons (kD). The two chains may be a polypeptide with a molecular weight of about 80,000 daltons linked via identical disulfide bonds. FXI contains four "apple domains" (A1-A4 from the N-terminus, heavy chain) and a C-terminal catalytic domain (light chain). Without wishing to be limited to a particular theory, the four apple domains are believed to contain FXI binding sites to other proteins, e.g., A1 to thrombin, A2 to HK, A3 to factor IX (FIX), GPIb to heparin, and A4 to FXIIa. FXI can be transformed into its active form, blood clotting factor XIa (FXIa), by factor XIIa (FXIIa). The serine protease FXIa transforms blood clotting factor IX to blood clotting factor IXa, which then activates blood clotting factor X (Xa), which can then mediate the activation of blood clotting factor II / thrombin.

[0093] The three-letter and one-letter codes for amino acids used in this disclosure are as described in J. Biol. Chem, 243, p3558 (1968).

[0094] The term "antibody" or "immunoglobulin" is used in the broadest sense and covers a variety of antibody structures, including, but not limited to, conventional antibodies (tetrapeptide chain structure antibodies consisting of two identical heavy chains and two identical light chains linked by interchain disulfide bonds), as well as Fab, Fv, sFv, F(ab')2, linear antibodies, single-chain antibodies, scFv, sdAb, sdFv, nanobodies, peptide antibodies, peptibodies, domain antibodies (heavy chain (VH) antibodies, light chain (VL) antibodies), and multispecific antibodies (diabodies, triabodies and tetrabodies, tandem di-scFv, tandem tri-scFv) having antigen-binding activity. The term "antibody" as used in this disclosure includes full-length antibodies, single chains thereof, and any portion thereof (i.e., antigen-binding fragments), domains or fragments thereof that have antigen-binding activity, as well as multispecific antibodies (including, but not limited to, antigen-binding domains or fragments, e.g., VHH domains or VH / VL domains, respectively) that comprise a single chain thereof and any portion, domain or fragment thereof that has antigen-binding activity. Conventional antibodies or immunoglobulins are usually tetrapeptide chain structures consisting of two identical heavy chains and two identical light chains linked by interchain disulfide bonds. Depending on the amino acid composition and sequence order of the heavy chain constant region, immunoglobulins can be divided into five types or may be referred to as immunoglobulin isotypes, IgM, IgD, IgG, IgA and IgE, with the corresponding heavy chains being μ, δ, γ, α and ε chains, respectively. Ig of the same type can be further divided into different subclasses depending on the difference in the amino acid composition of the hinge region and the number and position of the heavy chain disulfide bonds; for example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4. Light chains are divided into κ chains and λ chains depending on the difference in the constant region. Each of the five types of Ig may have a κ (kappa) chain or a λ (lambda) chain. In some embodiments, the antibody of the present disclosure specifically or essentially specifically binds to human FXI / FXIa.

[0095] In the heavy and light chains of an antibody, the sequence of about 110 amino acids near the N-terminus is highly variable and forms the variable region (Fv region), while the remaining amino acid sequence near the C-terminus is relatively stable and forms the constant region. The variable region includes three hypervariable regions (HVR) and four framework regions (FR) whose sequences are relatively conservative. The three hypervariable regions determine the specificity of the antibody and are also called complementarity determining regions (CDRs). Each light chain variable region (LCVR) and heavy chain variable region (HCVR) consists of three CDR regions and four FR regions, which are arranged in the following order from the amino terminus to the carboxy 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. The CDR amino acid residues of the LCVR and HCVR regions of the antibodies or antigen-binding fragments described in this disclosure conform in number and position to the known Kabat numbering convention (LCDR1-3, HCDR2-3) or conform to the Kabat and Chothia numbering convention (HCDR1).

[0096] The antibodies of the present disclosure include murine antibodies, chimeric antibodies, and humanized antibodies, preferably humanized antibodies.

[0097] The term "chimeric antibody" refers to an antibody in which the variable region of a mouse antibody is fused with the constant region of a human antibody, and can reduce the immune response reaction induced by the mouse antibody. To generate a chimeric antibody, first, a hybridoma secreting a mouse-specific monoclonal antibody is generated, and then the variable region gene is cloned from the mouse hybridoma cell, and if necessary, the constant region gene of a human antibody is cloned, and the mouse variable region gene and the human constant region gene are linked to form a chimeric gene, which is then inserted into a human vector, and finally the chimeric antibody molecule is expressed in a eukaryotic or prokaryotic cell system. In one preferred embodiment of the present disclosure, the antibody light chain of the FXI chimeric antibody further comprises a light chain constant region of a human κ, λ chain or a mutant thereof. The antibody heavy chain of the FXI chimeric antibody further comprises a heavy chain constant region of a human IgG1, IgG2, IgG3, IgG4 or a mutant thereof.

[0098] The term "humanized antibody", also called CDR-grafted antibody, refers to an antibody generated by grafting mouse CDR sequences onto a human antibody variable region framework, i.e., a different type of human germline antibody framework sequence. This overcomes the strong antibody response induced by chimeric antibodies having a large amount of mouse protein components. Such framework sequences can be obtained from a common DNA database containing germline antibody gene sequences or from the disclosed references. For example, germline DNA sequences of human heavy and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet at www.mrccpe.com.ac.uk / vbase) and Kabat, EA et al., 1991 Sequences of Proteins of Immunological Interest, 5th edition. To avoid a decrease in activity associated with a decrease in immunogenicity, the activity can be maintained by performing the least possible back mutations or reverse mutations on the human antibody variable region framework sequences. The humanized antibodies of the present disclosure further include phage-displayed humanized antibodies that have been affinity-matured against the CDRs.

[0099] The "mutation" in the mutant sequence described in this disclosure includes, but is not limited to, "back mutation," "conservative modification," or "conservative substitution or replacement." The "conservative modification" or "conservative substitution or replacement" described in this disclosure means that the substitution of an amino acid in a protein with another amino acid having similar characteristics (e.g., charge, side chain size, hydrophobicity / hydrophilicity, main chain conformation or rigidity, etc.) can be frequently changed without changing the biological activity of the protein. As is known to those skilled in the art, a single amino acid substitution in a non-essential region of a polypeptide generally does not fundamentally change the biological activity (see, for example, Watson et al. (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub.Co., p. 224, (4th edition)). In addition, substitution of an amino acid with a similar structure or function is unlikely to destroy the biological activity.

[0100] The "mutated sequence" described in this disclosure refers to a nucleotide sequence and / or amino acid sequence having a different percentage of sequence identity from the nucleotide sequence and / or amino acid sequence of the present disclosure obtained by performing a mutation modification such as appropriate substitution, insertion, or deletion on the nucleotide sequence and / or amino acid sequence of the present disclosure. The sequence identity described in this disclosure may be at least 85%, 90% or 95%, for example, at least 95%. Non-limiting examples include 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and 100%. Sequence comparison and percentage identity measurement between two sequences can be performed using the default settings of the BLASTN / BLASTP algorithm available from the homepage of the National Center For Biotechnology Institute.

[0101] The term "binds to FXI / FXIa" in the present disclosure refers to being capable of interacting with FXI / FXIa or an epitope thereof, which may be of human origin. The term "antigen-binding site" in the present disclosure refers to a three-dimensional spatial site that is not contiguous in an antigen and is recognized by an antibody or antigen-binding fragment of the present disclosure.

[0102] The term "specific binding" refers to binding as measured by techniques available in the art, such as competitive ELISA, BIACORE® assay, or KINEXA® assay. The term also applies, for example, when the antigen-binding domain of an antibody according to the present disclosure is specific for a particular epitope carried by many antigens, in which case the antibody carrying the antigen-binding domain can specifically bind to multiple antigens carrying the epitope.

[0103] "Conservative modification" or "conservative substitution or replacement" refers to the substitution of amino acids in a protein with other amino acids having similar characteristics (e.g., charge, side chain size, hydrophobicity / hydrophilicity, main chain conformation or rigidity, etc.), which can be frequently changed without changing the biological activity of the protein. As is known to those skilled in the art, single amino acid substitutions in non-essential regions of a polypeptide generally do not fundamentally change the biological activity (see, for example, Watson et al. (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub.Co., p. 224, (4th edition)). In addition, substitution of amino acids with similar structures or functions is unlikely to destroy biological activity.

[0104] "Identity" of amino acid sequences refers to the similarity of sequences between two proteins or polypeptides. If both positions in two compared sequences are occupied by the same amino acid residue, e.g., if a position in two polypeptides is occupied by the same amino acid residue, then the molecules are homologous at that position. Examples of algorithms suitable for determining percentage sequence identity and percentage sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1990) J. Mol. Biol. 215:403-410 and Altschul et al. (1977) Nucleic Acids Res. 25:3389-3402, respectively. Software for performing BLAST analyses is publicly available from the National Center for Biotechnology Information (http: / / www.ncbi.nlm.nih.gov / ).

[0105] Methods for producing and purifying antibodies and antigen-binding fragments well known in the art are described, for example, in chapters 5-8 and 15 of the Cold Spring Harbor Antibody Laboratory Techniques Manual. The antibodies or antigen-binding fragments described in the invention have one or more human FR regions added to the non-human CDR regions by genetic engineering methods. Human FR germline sequences can be obtained from the ImMunoGeneTics (IMGT) homepage http: / / imgt.cines.fr by aligning the IMGT human antibody variable region germline gene database with MOE software, or from the Immunoglobulin journal 2001 ISBN 012441351.

[0106] The engineered antibodies or antigen-binding fragments according to the present disclosure can be prepared and purified by conventional methods. For example, cDNA sequences encoding the heavy and light chains can be cloned and recombined into a GS expression vector. The recombinant immunoglobulin expression vector can be stably transfected into CHO cells. In one of the more preferred conventional techniques, the mammalian expression system leads to glycosylation of the antibody, especially at the highly conserved N-terminal site of the Fc region. Stable clones are obtained by expressing an antibody that specifically binds to human FXI. Positive clones are expanded in serum-free medium in a bioreactor to produce the antibody. The culture medium from which the antibody is secreted can be purified by conventional techniques. For example, purification is performed on an A or G Sepharose FF column with a regulated buffer. Non-specifically bound components are washed away. Furthermore, the bound antibody is eluted by a pH gradient method, and the antibody fragment is detected and collected by SDS-PAGE. The antibody can be filtered and concentrated by conventional methods. Soluble mixtures and polymers may be removed by conventional methods such as molecular sieving, ion exchange, etc. The resulting product must be immediately frozen, such as at -70°C, or lyophilized.

[0107] "Administration" and "treatment", when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refers to contact of an exogenous agent, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid. "Administration" and "treatment" may 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. "Administration" and "treatment" also refer to treating, for example, cells ex vivo and in vitro, with a reagent, diagnostic, binding composition, or through another cell. "Treatment", when used in human, veterinary, or research subjects, refers to therapeutic treatment, preventative or prophylactic measures, research, and diagnostic uses.

[0108] "Treatment" refers to providing a patient with an oral or topical therapeutic agent, for example, comprising a composition of any one of the binding compounds of the present disclosure, where the patient has one or more disease symptoms, and the known therapeutic agent has a therapeutic effect on these symptoms. Typically, the patient or population being treated is provided with a therapeutic agent in an amount that effectively relieves one or more disease symptoms, thereby inducing the resolution of these symptoms, or inhibiting these symptoms from progressing to any clinically measurable extent. The amount of therapeutic agent that effectively relieves any particular disease symptom (also referred to as a "therapeutically effective amount") can vary depending on a variety of factors, including the disease state, age and weight of the patient, and the ability of the drug to produce the required therapeutic effect in the patient. Reduction of disease symptoms can be assessed by any clinical detection method commonly used by physicians or other professional health care providers to assess the severity or progression of the condition. An embodiment of the present disclosure (e.g., a method of treatment or product) may be ineffective in alleviating the respective target disease symptom, but may reduce the target disease symptom in a statistically significant number of patients, as determined by 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.

[0109] An "effective amount" includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical disease. Effective amount also refers to an amount sufficient to permit or facilitate diagnosis. The effective amount used in a particular patient or veterinary subject can vary depending on factors such as, for example, the condition being treated, the overall health of the patient, the route and dose of administration, and the severity of side effects. An effective amount may be the maximum dose or dosing regimen in which significant side effects or toxic effects are avoided.

[0110] "Tm value" refers to the thermal denaturation temperature of a protein, i.e., the temperature at which half of the protein is unfolded; in this case, the spatial structure of the protein is destroyed, so the higher the Tm value, the higher the thermal stability of the protein.

[0111] Working Example The present disclosure will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present disclosure. Experimental methods for which specific conditions are not specified in the examples of the present disclosure generally follow standard conditions, such as those in the Cold Spring Harbor Antibody Technology Laboratory Manual, the Molecular Cloning Manual, etc., or conditions suggested by raw material or product manufacturers. Reagents for which a specific source is not specified are standard commercially available reagents.

[0112] Example 1. Screening and preparation of anti-FXI / FXIa hybridoma monoclonal antibodies 1. Preparation of human FXI / FXIa antigen and detection protein Human FXI / FXIa protein (Uniprot Acc No. P03951) was purchased from Enzyme research laboratories (FXI: Cat. HFXI1111, FXIa: HFXIa 1111a) as the antigen and detection protein of the present disclosure. Unless otherwise specified, the following FXI / FXIa antigens all refer to human FXI / FXIa.

[0113] >Amino acid sequence of human FXI / FXIa: [ka] At the same time, the following KLH-conjugated FXIa-specific polypeptides were artificially synthesized and used for immunization of mice.

[0114] [ka] [ka] [ka]

[0115] 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: For purification of mouse hybridoma supernatant, affinity chromatography is preferably performed using Protein G packing material (KANEKA: Cat. KanCapTMG), the cultured hybridoma is centrifuged to collect the supernatant, and a gravity column containing Protein G packing material is used for purification. The column is first regenerated with 6M guanidine hydrochloride (Simga: Cat. G3272-1KG) for 3-5 column volumes, then washed with pure water for 3-5 column volumes, and then washed with 1x PBS (pH 7.4) (Sangon). The chromatography column was equilibrated with 3-5 column volumes of Sigma Biotech (Shanghai) co., Ltd. (Cat. E607016-0500) buffer system as equilibration buffer, the cell supernatant was loaded onto the column at a low flow rate to bind, and the flow rate was controlled so that the retention time was about 1 min or more. The chromatography column was washed with 1×PBS (pH 7.4) at 3-5 column volumes until the UV absorption fell back to the baseline, and 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, and 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 eluted product can be displaced by methods well known to those skilled in the art, such as, for example, ultrafiltration concentration using ultrafiltration tubes, displacement of the solution into a desired buffer system, or molecular exclusion chromatography, e.g., G-25 desalting, displacement into a desired buffer system.

[0116] (2) Extraction of human Fc-tagged fusion proteins or antibodies by Protein A affinity chromatography: First, the cell culture supernatant expressing the Fc fusion protein or antibody was centrifuged at high speed, and the supernatant was collected. A Protein A (GE, Cat: 17-5474-99) affinity column was regenerated with 0.1 M NaOH (Sigma: Cat: 71687-500g) for 5 column volumes, and then washed with 1× PBS (pH 7.4) (Sangon Biotech (Shanghai) co., Ltd.: Cat. E607016-0500) for 5 column volumes to equilibrate. The cell supernatant was applied to the column at a low flow rate to bind, and the flow rate was controlled so that the retention time was about 1 min or more. After the binding was completed, the chromatography column was washed with 1× PBS (pH 7.4) for 5 column volumes until the UV absorption fell to the baseline. The sample was eluted with 0.1M Glycine (pH 3.0) (Sigma: Cat. 410225-250G) buffer, the elution peak was collected by UV detection, and the elution product was quickly adjusted to pH 7-8 with 1M Tris-HCl (pH 8.0) (Vetec, Cat. V900483) and stored for a while. The elution product can be replaced by a method 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 molecular exclusion chromatography, such as replacement with a desired buffer system using G-25 desalting.

[0117] (3) Purification of antibodies by anion chromatography: First, the sample was diluted with equilibration buffer 20 mM Tris pH 8.0 (Vetec, Cat. V900483) until the conductivity was less than 3 ms / cm, and then equilibrated with a Q HP (GE, Cat: 17-1014-01) anion chromatography column by regenerating with 0.5 M NaOH (Sigma: Cat: 71687-500g) for 5 column volumes, and then washing with 20 mM Tris pH 8.0 (Vetec, Cat. V900483) for 15 column volumes. The sample was loaded onto the column at a low flow rate and bound, the flow rate was controlled to achieve a retention time of about 2 min or more, and 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 absorption fell back to baseline. The elution was performed with a gradient of 0-100% with elution buffer 20 mM Tris pH 8.0 (Vetec, Cat. V900483) 0.5 M NaCl (Vetec, Cat. V900058), and the elution peak was detected and collected by SEC-UPLC (Column: Waters ACQUITY UPLC® Protein BEH SEC column 200 Å, 1.7 μm, Cat. 186005225) purity. The elution product can be replaced by methods well known to those skilled in the art, such as ultrafiltration concentration with an ultrafiltration tube, replacement of the solution with a desired buffer system, or molecular exclusion chromatography, e.g., replacement with a desired buffer system by G-25 desalting.

[0118] 3. Antibody screening Five SJL white mice and five Balb / c white mice were immunized with 25μg of FXIa antigen and three KLH-complexed polypeptides mixed with adjuvant. The time points were 0, 14, and 35 days. On day 0, the emulsified antigen was intraperitoneally (IP) injected at 25μg / mouse. On days 14 and 35, it was injected at 12.5μg / mouse. Blood was collected on days 21 and 42, and the antibody titers in the mouse serum were determined by ELISA. After the 4th to 5th immunization, mice with high and stable antibody titers in the serum were selected and splenocyte fusion was performed.

[0119] Through the optimized PEG-mediated fusion step, splenic lymphocytes were fused with myeloma cells Sp2 / 0-Ag14 cells to obtain hybridoma cells. According to the growth density of hybridoma cells, purification, cell binding experiment and cell blocking experiment were performed on the hybridoma culture supernatant by binding ELISA method, and the positive well cells were amplified, frozen, stockpiled and sequenced in a timely manner. After further screening of hybridoma cells by ELISA method, hybridoma clones were obtained, and then antibodies were prepared and purified.

[0120] A positive clone 3807 was obtained, and the amino acid sequence of the variable region of the corresponding antibody is as follows: >3807-VH: [ka] >3807-VL: [ka]

[0121] [Table 1]

[0122] Example 2. Humanization and immunogenicity modification of anti-FXI / FXIa hybridoma antibodies 1. Humanization Three-dimensional homology modeling was performed on the antibody molecule 3807, and the results were aligned with the V-base human germline sequence database and the IMGT human antibody heavy chain variable region germline gene database. The heavy chain variable region germline gene with high homology to the screened antibody was selected as a template, and the CDR of the mouse-derived monoclonal antibody was grafted to the corresponding human module. The grafted antibody was again subjected to three-dimensional structure simulation and analysis, and specific sites in the FR region that affect the structural form of the CDR region were back-mutated. The amino acid residues were determined and annotated according to the Kabat numbering system.

[0123] The humanized architecture of hybridoma clone 3807 is as follows: light chain template IGKV3-11*01, heavy chain template IGHV1-69-2*01, and the humanized variable region sequences are as follows (CDRs are underlined): >3807VH-CDR graft [ka] >3807VL-CDR graft [ka] The backmutation sites and mutation scheme of the hybridoma clone 3807 were designed as shown in Table 2.

[0124] [Table 2]

[0125] Among them, the specific sequences of 3807-VH1 and 3807-VL3 are as follows: >3807-VH1: [ka] >3807-VL3: [ka] Antibody 3871 has a VH of 3807-VH1 and a VL of 3807-VL3.

[0126] 2. Modification of immunogenicity Genetic modifications were made to 3871 to make the antibody more stable and less immunogenic. Only the heavy chain variable region FR region was modified, and the light chain variable region was left unchanged.

[0127] The genetically engineered heavy chain variable region sequence of humanized antibody 3871 is as follows (the light chain is unchanged): >3807-VH1(GTFS) [ka]

[0128] Antibody 3882 has a VH of 3807-VH1(GTFS) and a VL of 3807-VL3.

[0129] Each of the heavy chain variable regions described above was fused to the corresponding human antibody heavy chain CH1 (sequence number 18) and human antibody IgG4 Fc (containing S241P mutation) (sequence number 19), and the light chain variable region was fused to human kappa (sequence number 20) to construct a recombinant chimeric antibody for subsequent detection.

[0130] >Human antibody heavy chain CH1: [ka] > Human antibody IgG4PFc (i.e., containing the S241P mutation): [ka] >Human antibody light chain Cκ: [ka] 3882 shows an example of a full-length antibody sequence. >3882-HC: [ka] >3882-LC: [ka] The antibody expression vector was prepared by conventional methods, and the CHO cells were transfected, isolated, purified and detected to obtain the target antibody.

[0131] Example 3. Verification of the function of anti-FXI / FXIa antibodies 1. Affinity Measurement The Biacore method was used. After affinity capturing a certain amount of antibody to be measured with a Protein A biosensor chip (Cat.#29127556, GE), human FXI / FXIa was passed over the chip surface in a series of concentration gradients, and the reaction signal was detected in real time by a Biacore instrument (Biacore T200, GE) to obtain binding-dissociation curves. After each cycle of dissociation was completed, the biochip was regenerated by washing with the regeneration solution provided in the human antibody capture reagent kit or a glycine-HCl regeneration solution at pH 1.5 (Cat.#BR-1003-54, GE). The buffer used in the experiment was HBS-EP+10× buffer solution (Cat.#BR-1006-69, GE) diluted to 1× (pH 7.4) with DIWater.

[0132] The experimental data were fitted with the (1:1) Langmuir model by BIAevaluation version 4.1, GE software to obtain affinity values, and the test results are shown in Table 3.

[0133] [Table 3]

[0134] 2. In vitro FXIIa-mediated inhibition of FXI-activating enzyme activity The ability of anti-FXI / FXIa antibodies to bind trypsinogen FXI and block the enzymatic cleavage of FXIIa to FXI was detected.

[0135] A SpectraMax M5 plate reader was set to 37°C in advance, and a 384-well plate was pre-cooled on ice. 10 μL of FXI (12 μg / mL), 10 μL of FXIIa (7.8 μg / mL), 10 μL of FXI / FXIa antibody to be measured (300 μg / mL), and 10 μL of Dextran (100 μg / mL) were added, each diluted with buffer (20 mM HEPES, pH 7.4, 150 mM NaCl, and 0.1% BSA), and incubated at 37°C for 60 min, then placed on ice for 5 min, and 10 μL of S-2366 (8 mM) (Chromogenix, S821090) was added, followed by detection by the plate reader. The results are shown in Figure 1, in which human IgG isotype was used as a negative control (NC).

[0136] 3. Detection of aPTT / 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 plasma was removed.

[0137] 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 reagent was added to initiate blood clotting, and the time when blood clotting occurred was measured. The concentration (EC50) of the candidate antibodies that prolonged the aPTT by 50% was measured, and the test results of some antibodies are shown in Figure 2A, Figure 3A and Table 4. Among them, 1209 is another anti-FXI / FXIa antibody obtained by screening in this application.

[0138] The Sysmex reagent kit measured the prothrombin time (PT) in the presence of different concentrations of candidate antibodies (diluted in PBS), the candidate antibodies to be tested were incubated with plasma at 37°C for 3 minutes, blood clotting was then initiated by adding thromboplastin, and the time for blood clotting to occur was measured. The test results of some antibodies are shown in Figures 2B and 3B.

[0139] [Table 4]

[0140] 4. In vivo pharmacokinetic (PK) / pharmacodynamic (PD) study in cynomolgus monkeys Normal adult male cynomolgus monkeys (body weight range 4.0 kg to 4.7 kg) were assigned to groups based on body weight (the first, fourth, and fifth weight-heavy monkeys were assigned to one group, and the second, third, and sixth weight-heavy monkeys were assigned to the other group), with three monkeys per group, and observed for 14 days.

[0141] The day before administration, blood samples were collected using sodium citrate blood collection tubes, and aPTT, PT, plasma drug concentration, plasma activated factor XI (FXI) percentage (FXI:C%, i.e., percentage of FXI with blood coagulation activity), and plasma free FXI concentration were measured as pre-administration samples, and the bleeding time of each animal was measured at the same time. Of the two groups of animals, one group was left unadministered as a blank, and the other group was administered 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.

[0142] In the blank control group, the bleeding time was observed 15 minutes (min) and 3 hours (h) after administration, and plasma was collected according to the above method at 15 min, 3 h, 6 h, and 1 day (d) after administration to observe aPTT and PT. In the administration group, the bleeding time was observed 15 min, 3 h, 2 d, 4 d, 1 week (w), 2 w, and 3 w after administration, and plasma was collected according to the above method at 15 min, 3 h, 6 h, 1 d, 2 d, 4 d, 1 w, 2 w, 3 w, 4 w, 5 w, and 6 w after administration to observe aPTT, PT, plasma drug concentration, plasma FXI:C% and plasma free FXI concentration. In both groups of animals, thrombi were created by AV-shunt 1 d after administration, and the thrombi creation time was 10 min. After the thrombi were created, the net weight of the thrombi was weighed.

[0143] Among them, aPTT, PT and plasma FXI:C% were measured by blood coagulation device and corresponding reagent kit, plasma free FXI concentration and plasma drug concentration were measured by ELISA method. The weight of thrombus was compared between the treatment group and the control group, and statistical analysis was performed by t-test.

[0144] The antibody test results are shown in Figures 4A to 4D, of which the negative control (NC) was not administered. As a result, at 5mpk, the antibody effectively inhibited the formation of thrombus and extended the intrinsic blood coagulation time, but had no significant effect on the animal bleeding time and the extrinsic blood coagulation time. The PK results showed that the half-life was about 20 days.

[0145] 5. In vivo pharmacodynamics (PD) study in cynomolgus monkeys Six normal adult male cynomolgus monkeys (weight range 7kg-9kg) were randomly divided into three groups: BAY1213790 intravenously at 1 mg / kg, BAY3882 intravenously at 1 mg / kg, and BAY3882 subcutaneously at 1 mg / kg. Blood samples were collected in sodium citrate blood collection tubes from animals in the intravenous group before and 5min, 1h, 1d, 2d, 3d, 5d, 1w, 2w, 3w, and 4w after administration, and from animals in the subcutaneous group before and 1h, 1d, 2d, 3d, 5d, 1w, 2w, 3w, and 4w after administration, and aPTT and plasma FXI:C% were measured using a blood coagulation apparatus and corresponding reagent kits.

[0146] The test results are shown in Figures 5A and 5B. As a result, both subcutaneous and intravenous administration of 3882 can significantly prolong the intrinsic blood clotting time and inhibit the activity of FXI. Compared with BAY1213790 at the same dose, 3882 maintained the prolongation of the intrinsic blood clotting time for a longer period and had a stronger inhibitory effect on FXI.

[0147] >BAY1213790 heavy chain: [ka] >BAY1213790 light chain: [ka]

[0148] The anti-FXI / FXIa antibody in Examples 4 to 9 is 3882, whose heavy chain sequence is shown in SEQ ID NO:21 and whose light chain sequence is shown in SEQ ID NO:22.

[0149] Example 4. Screening of pH value of buffer system for anti-FXI / FXIa antibody formulation The buffers in Table 5 were prepared, and an antibody formulation with an anti-FXI / FXIa antibody concentration of 120 mg / mL was prepared. Samples were then taken and examined for high temperature (40°C), shaking, and freeze-thaw stability.

[0150] [Table 5-1] [Table 5-2]

[0151] Note: C=colorless, CL=clear, WO=slightly opalescent, SO=strongly opalescent, P+ (few particles), P++ (many particles), P+++ (large amount of particles) According to the appearance results, after 5D shaking, no particles were produced in any of the formulations, and after 5 cycles of freezing and thawing, particles were produced in all of the formulations, of which the 10 mM acetic acid-sodium acetate pH 4.5 and pH 5.0 systems, the 10 mM histidine-histidine hydrochloride pH 6.5 system, and the 10 mM sodium dihydrogen phosphate-disodium hydrogen phosphate pH 7.0 system produced relatively few particles. After 15D at 40°C, particles were produced in the appearance of all of the formulations, and the 10 mM histidine-histidine hydrochloride pH 6.5 and 10 mM sodium dihydrogen phosphate-disodium hydrogen phosphate pH 7.0 systems produced fewer particles than the other two systems.

[0152] According to the results of SEC (Figure 6A), in the case of 40°C-15D, the aggregates of all the formulations were increased. In the case of 40°C-15D, within the pH range of 4.5-6.5, the SEC aggregates were obviously reduced with increasing pH. In the case of 40°C-15D, when the pH was increased from 8.0 to 8.5, the SEC aggregates were obviously increased. In the case of 40°C-15D, when the pH was between 6.0-8.0, the SEC aggregates were increased by <2.5% compared to T0, which was within the acceptable range.

[0153] According to the results of NRCE (Figure 6B), in the case of 40°C-15D, the NRCE purity decreased, and in the 10 mM Tris-HCl system, the NRCE purity clearly decreased with increasing pH (pH 7.5 to 8.5), while there was no clear difference in NRCE purity in other buffer systems in the pH range of 4.5 to 7.5.

[0154] According to the results of iCIEF (FIG. 6C), in the same buffer system, the acidic peak was clearly enhanced with increasing pH.

[0155] Combining the results of appearance, SEC, NRCE and iCIEF, buffer systems of pH 6.5 to 7.5 (histidine-histidine hydrochloride, sodium dihydrogen phosphate-disodium hydrogen phosphate and Tris-hydrochloric acid systems) are relatively suitable.

[0156] Example 5. Screening of pH, additives and surfactant concentrations in anti-FXI / FXIa antibody formulations In the range of pH 6.5-7.5, 10 mM histidine-histidine hydrochloride, 10 mM sodium dihydrogen phosphate-disodium hydrogen phosphate, 10 mM Tris-citric acid and 10 mM Tris-hydrochloric acid buffer systems were selected to prepare preparations containing 120 mg / mL anti-FXI / FXIa antibody, different kinds of additives and different kinds of surfactants. The samples were placed in a 40±2°C, 75±5% RH incubator to examine the stability. The results showed that the 3882 antibody was relatively sensitive to ionic strength, and at high ionic strength, the antibody stability was relatively low and particles were easily generated.

[0157] Buffer systems of 10 mM histidine-histidine hydrochloride pH 6.5, 7.0 and 10 mM Tris-hydrochloride pH 7.0, 7.5 were selected, and formulations containing 60 mg / mL anti-FXI / FXIa antibody, 0.4 mg / mL to 0.8 mg / mL polysorbate 80, and additives of 80 mg / mL sucrose, 100 mM glycine + 40 mg / mL sucrose, or 100 mM proline + 40 mg / mL sucrose were prepared, and their high temperature (40°C), shaking, and freeze-thaw stability were examined: F2) 10 mM histidine-histidine hydrochloride pH 6.5, 0.4 mg / mL polysorbate 80, 80 mg / mL sucrose; F3) 10 mM histidine-histidine hydrochloride pH 6.5, 0.6 mg / mL polysorbate 80, 80 mg / mL sucrose; F4) 10 mM histidine-histidine hydrochloride pH 6.5, 0.8 mg / mL polysorbate 80, 80 mg / mL sucrose, F5) 10 mM histidine-histidine hydrochloride pH 6.5, 0.4 mg / mL polysorbate 80, 100 mM glycine + 40 mg / mL sucrose; F6) 10 mM histidine-histidine hydrochloride pH 6.5, 0.4 mg / mL polysorbate 80, 100 mM proline + 40 mg / mL sucrose; F7) 10 mM histidine-histidine hydrochloride pH 7.0, 0.4 mg / mL polysorbate 80, 80 mg / mL sucrose, F8) 10 mM histidine-histidine hydrochloride pH 7.0, 0.4 mg / mL polysorbate 80, 100 mM proline + 40 mg / mL sucrose; F10) 10 mM Tris-HCl pH 7.0, 0.4 mg / mL polysorbate 80, 80 mg / mL sucrose, F11) 10 mM Tris-HCl pH 7.5, 0.4 mg / mL polysorbate 80, 80 mg / mL sucrose,

[0158] [Table 6-1] [Table 6-2]

[0159] Note: C=colorless, CL=clear, WO=slightly opalescent, SO=strongly opalescent, P(few particles), P+(few particles), P++(many particles), P+++(large amount of particles), According to the appearance results, after 5 cycles of freezing and thawing, all of the 10 mM histidine-histidine hydrochloride pH 6.5 systems produced a large amount of particles, among which the F4 and F6 formulations produced a large amount of particles even after 3D shaking, while F2, F3 and F5 produced no particles after shaking, and none of the 10 mM histidine-histidine hydrochloride pH 7.0 systems (F7 and F8) produced any particles after 3D shaking. After 5 cycles of freezing and thawing, only F7 produced a small amount of particles. At 40°C 2W, only F7 and F8 produced no particles, and all of the remaining formulations produced particles, among which F3 (8% sucrose + 0.06% polysorbate 80), F4 (8% sucrose + 0.08% polysorbate 80), F5 (100 mM Gly + 4% sucrose + 0.04% polysorbate 80), F6 (100 mM Gly + 4% sucrose + 0.04% polysorbate 80), F7 (100 mM Gly + 4% sucrose + 0.04% polysorbate 80), F8 (100 mM Gly + 4% sucrose + 0.04% polysorbate 80), F9 (100 mM Gly + 4% sucrose + 0.04% polysorbate 80), F10 (100 mM Gly + 4% sucrose + 0.04% polysorbate 80), F11 (100 mM Gly + 4% sucrose + 0.04% polysorbate 80), F12 (100 mM Gly + 4% sucrose + 0.04% polysorbate 80), F13 (100 mM Gly + 4% sucrose + 0.04% polysorbate 8 At 40°C and 1M, all of the formulations produced particles, while F7 and F8 formulations were still well expressed, with F7 formulation producing a small amount of particles and F8 producing a few particles. The 10mM histidine-histidine hydrochloride pH 7.0 system was obviously superior to the 10mM histidine-histidine hydrochloride pH 6.5 and 10mM Tris-HCl systems. At 40°C and 1M, all of the formulations F2 to F6 produced a large amount of particles, indicating that the addition of glycine, proline and the increase in the concentration of polysorbate 80 did not have any obvious improvement on the appearance.

[0160] According to the results of SEC (Figure 7A), under the conditions of freezing, thawing and shaking, the SEC had no obvious difference compared to T0. After high temperature, the SEC of different formulations all decreased compared to T0. There was no obvious difference between the formulations F2 to F8 (10 mM histidine-histidine hydrochloride system), and the SEC purity of the formulations F10 and F11 (10 mM Tris-hydrochloride system) was slightly higher than that of the 10 mM histidine-histidine hydrochloride system.

[0161] According to the results of NRCE (Figure 7B), under the conditions of freezing, thawing and shaking, the NRCE had no obvious difference compared to T0. After high temperature, the NRCE of the different formulations all decreased compared to T0, with no obvious difference between the formulations.

[0162] According to the results of CEX (Figure 7C), under the conditions of freezing, thawing and shaking, the acidic peak had no significant difference compared to T0. After high temperature, the acidic peaks of the different formulations all increased compared to T0. In the same buffer system, the acidic peaks increased obviously with increasing pH.

[0163] The results of appearance, SEC, NRCE and CEX combined show slight changes in purity detection items, but all are within the acceptable range. From the viewpoint of appearance, 10 mM histidine-histidine hydrochloride pH 7.0 system is superior to 10 mM histidine-histidine hydrochloride pH 6.5 and 10 mM Tris-hydrochloric acid systems. According to the results of pH / Buffer screening and additive and surfactant screening, the antibody has relatively good stability in the pH range of 6.5-7.5, the histidine-histidine hydrochloride system is superior to systems such as sodium dihydrogen phosphate-disodium hydrogen phosphate, Tris-hydrochloric acid, acetic acid-sodium acetate and Tris-citric acid, and the 3882 antibody is relatively sensitive to ionic strength. The inventors further optimized the formulation using a histidine-antibody self-buffering system.

[0164] Example 6. Screening of buffer systems and surfactant types for anti-FXI / FXIa antibody formulations A histidine-antibody self-buffering system at pH 7.0 was selected to prepare anti-FXI / FXIa antibody formulations containing 60 mg / mL protein, 80 mg / mL sucrose as an additive, and poloxamer 188 or polysorbate 80 as a surfactant. The samples were placed in a 40±2°C, 75±5% RH incubator to examine the stability: F1) 35 mM histidine pH 7.0, 1 mg / mL polysorbate 80, 80 mg / mL sucrose, F2) 35 mM histidine pH 7.0, 1 mg / mL poloxamer 188, 80 mg / mL sucrose; F3) 35 mM histidine pH 7.0, 2 mg / mL poloxamer 188, 80 mg / mL sucrose;

[0165] [Table 7]

[0166] Note: C=colorless, Y=pale yellow, Y+=yellow, CL=transparent According to the appearance results, no particles were generated in any of the formulations at 40°C 2W and 40°C 4W.

[0167] According to the results of SEC (Figure 8A), after high temperature, the SEC of different formulations all decreased compared to T0, among which, formulation F1 (35 mM His + 8% sucrose + 0.1% polysorbate 80) had the largest decrease, which was obviously lower than F2 (35 mM His + 8% sucrose + 0.1% poloxamer 188) and F3 (35 mM His + 8% sucrose + 0.2% poloxamer 188).

[0168] According to the NRCE results, after high temperature, the NRCE of the different formulations all decreased compared to T0, and there was no obvious difference between the formulations.

[0169] According to the results of CEX (FIG. 8B), after high temperature, the acidic peaks of the different formulations were all increased compared to T0, among which, the F1 formulation had the largest increase, which was obviously higher than those of F2 and F3.

[0170] Combining the results of appearance, SEC, NRCE and CEX, when using the histidine-antibody self-buffering system, the pH can be maintained at about 7.0, no particles are generated in any of the formulations at 40°C, and the formulation using the surfactant polysorbate 80 has a significant difference from T0 in the purity detection items. Therefore, the pH / buffer is determined to be pH 7.0 for the histidine-antibody self-buffering system, and the surfactant is preferably poloxamer 188.

[0171] Example 7. Confirmation of buffer system for anti-FXI / FXIa antibody formulation and screening of surfactant concentration Considering the final dose of the drug, the concentration of anti-FXI / FXIa antibody was increased, a histidine-antibody self-buffering system pH 7.0 was selected, and a formulation containing 80 mg / mL protein, 80 mg / mL sucrose as an additive, and 1 mg / mL to 2 mg / mL poloxamer 188 as a surfactant was prepared. The sample was left at -35°C / room temperature for 5 cycles of freezing and thawing, and then shaken (25°C, 300 rpm) at 40°C-2W and 40°C-4W for 3 days to examine its stability: F1) 35 mM histidine pH 7.0, 1 mg / mL poloxamer 188, 80 mg / mL sucrose; F2) 35 mM histidine pH 7.0, 1.5 mg / mL poloxamer 188, 80 mg / mL sucrose; F3) 35 mM histidine pH 7.0, 2 mg / mL poloxamer 188, 80 mg / mL sucrose;

[0172] [Table 8-1] [Table 8-2]

[0173] Note: Y = pale yellow, WO = slightly opalescent, SO = strongly opalescent, P+ (small amount of particles) According to the appearance results, after 3D shaking, no particles were produced in any of the formulations, after 5 cycles of freezing and thawing, small amounts of particles were produced in F1 (35 mM His, 0.1% poloxamer 188) and F2 (35 mM His, 0.15% poloxamer 188), after 40°C 2W, no particles were produced in any of the formulations, and after 40°C 4W, small amounts of particles were produced in F1 and F2.

[0174] According to the SEC results, under the conditions of freezing, thawing and shaking, the SEC had no obvious difference compared to T0. After high temperature, the SEC of the different formulations all decreased compared to T0, and there was no obvious difference between the formulations.

[0175] According to the NRCE results, under the conditions of freezing, thawing and shaking, the NRCE had no obvious difference compared to T0, and after high temperature, the NRCE of the different formulations all decreased compared to T0, with no obvious difference between the formulations.

[0176] According to the CEX results, under the conditions of freezing, thawing and shaking, the acidic peak had no obvious difference compared to T0, and after high temperature, the acidic peak of different formulations was increased compared to T0, with no obvious difference between the formulations.

[0177] Combining the results of appearance, SEC, NRCE and CEX, the pH / buffer was determined to be a histidine-antibody self-buffering system pH 7.0, and the surfactant was 0.2% poloxamer 188.

[0178] Example 8. Screening of antibody concentration in anti-FXI / FXIa antibody preparations A histidine-antibody self-buffering system at pH 7.0 was selected to prepare a formulation containing 60 mg / mL to 100 mg / mL of anti-FXI / FXIa antibody, 2 mg / mL of poloxamer 188, and 80 mg / mL of sucrose as an additive. The sample was left at -35°C / room temperature for 5 cycles of freeze-thawing, and then shaken (25°C, 300 rpm) at 40°C-2W and 40°C-4W for 3 days to examine its stability: F1) 35 mM histidine pH 7.0, 2 mg / mL poloxamer 188, 80 mg / mL sucrose, 60 mg / mL protein, F2) 35 mM histidine pH 7.0, 2 mg / mL poloxamer 188, 80 mg / mL sucrose, 80 mg / mL protein; F3) 35 mM histidine pH 7.0, 2 mg / mL poloxamer 188, 80 mg / mL sucrose, 100 mg / mL protein,

[0179] [Table 9]

[0180] Note: Y = pale yellow, WO = slightly opalescent According to the appearance results, no particles were generated in any of the formulations after 3D shaking, 5 cycles of freezing and thawing, and 40℃ 2W and 40℃ 4W. According to the SEC results, under the conditions of freezing, thawing and shaking, the SEC had no obvious difference compared to T0. After high temperature, the SEC of the different formulations all decreased compared to T0, and there was no obvious difference between the formulations.

[0181] According to the NRCE results, under the conditions of freezing, thawing and shaking, the NRCE had no obvious difference compared to T0, and after high temperature, the NRCE of the different formulations all decreased compared to T0, with no obvious difference between the formulations.

[0182] According to the CEX results, under the conditions of freezing, thawing and shaking, the acidic peak had no obvious difference compared to T0, and after high temperature, the acidic peak of different formulations was increased compared to T0, with no obvious difference between the formulations.

[0183] Combining the visual, SEC, NRCE and CEX results, the formulation was initially determined to be 35 mM histidine, 80 mg / mL sucrose, 2 mg / mL poloxamer 188, pH 7.0, with an anti-FXI / FXIa antibody concentration of 80 mg / mL.

[0184] Example 9. Consideration of the robustness of anti-FXI / FXIa antibody formulations Considering the manipulability of production, DoE design was carried out with histidine-protein self-buffer system, histidine concentration, protein concentration and poloxamer 188 concentration as variables, and the factor levels were histidine concentration 30mM-40mM, protein concentration 70mg / mL-130mg / mL, and poloxamer 188 concentration 1.8g / L-2.8g / L. DoE experiments were carried out using Minitab software to obtain a series of formulations. The samples were left at -35℃ / room temperature, freeze-thawed for 5 cycles, and then shaken (25℃, 300rpm) at 40℃-2W, 40℃-26D, and 3 days to investigate the stability: F1) 30 mM histidine pH 7.0, 1.8 mg / mL poloxamer 188, 80 mg / mL sucrose, 70 mg / mL protein, F2) 30 mM histidine pH 7.0, 1.8 mg / mL poloxamer 188, 80 mg / mL sucrose, 130 mg / mL protein; F3) 30 mM histidine pH 7.0, 2.8 mg / mL poloxamer 188, 80 mg / mL sucrose, 70 mg / mL protein; F4) 30 mM histidine pH 7.0, 2.8 mg / mL poloxamer 188, 80 mg / mL sucrose, 130 mg / mL protein, F5) 40 mM histidine pH 7.0, 1.8 mg / mL poloxamer 188, 80 mg / mL sucrose, 70 mg / mL protein, F6) 40 mM histidine pH 7.0, 1.8 mg / mL poloxamer 188, 80 mg / mL sucrose, 130 mg / mL protein, F7) 40 mM histidine pH 7.0, 2.8 mg / mL poloxamer 188, 80 mg / mL sucrose, 70 mg / mL protein, F8) 40 mM histidine pH 7.0, 2.8 mg / mL poloxamer 188, 80 mg / mL sucrose, 130 mg / mL protein, F9) 35 mM histidine pH 7.0, 2.3 mg / mL poloxamer 188, 80 mg / mL sucrose, 100 mg / mL protein, F10) 35 mM histidine pH 7.0, 2.3 mg / mL poloxamer 188, 80 mg / mL sucrose, 100 mg / mL protein, F11) 35 mM histidine pH 7.0, 2.3 mg / mL poloxamer 188, 80 mg / mL sucrose, 100 mg / mL protein, F12) 35 mM histidine pH 7.0, 2 mg / mL poloxamer 188, 80 mg / mL sucrose, 120 mg / mL protein,

[0185] [Table 10-1] [Table 10-2] [Table 10-3]

[0186] Note: C=colorless, Y=pale yellow, CL=transparent According to the appearance results, no particles were generated in any of the formulations after 3D shaking, 5 cycles of freezing and thawing, 2W at 40°C, and 26D at 40°C.

[0187] According to the SEC results, under the conditions of freezing, thawing and shaking, the SEC had no obvious difference compared to T0. After high temperature, the SEC of the different formulations all decreased compared to T0, and there was no obvious difference between the formulations.

[0188] According to the NRCE results, under the conditions of freezing, thawing and shaking, the NRCE had no obvious difference compared to T0, and after high temperature, the NRCE of the different formulations all decreased compared to T0, with no obvious difference between the formulations.

[0189] According to the CEX results, under the conditions of freezing, thawing and shaking, the acidic peak had no obvious difference compared to T0, and after high temperature, the acidic peak of different formulations was increased compared to T0, with no obvious difference between the formulations.

[0190] Combining the results of appearance, SEC, NRCE and CEX, i.e., when the anti-FXI / FXIa antibody is in the range of 70 mg / mL to 130 mg / mL, the histidine concentration is in the range of 30 mM to 40 mM, and the poloxamer 188 concentration is in the range of 1.8 g / L to 2.8 g / L, there is no significant difference in the purity items and the formulation stability is relatively good in all cases.

[0191] Example 10. Stability of anti-FXI antibody formulations during use The finished anti-FXI antibody preparation was taken and diluted to 0.20mg / mL and 13.30mg / mL in an infusion bag using 0.9% saline injection (infusion bag material: polypropylene) and 5% glucose injection (infusion bag material: polypropylene), respectively. At the same time, the stability of the diluted drug solution was examined in a disposable infusion line (line material: polypropylene, filtration membrane material: polyethersulfone) at 2℃~8℃ for 24h + room temperature for 6h under light irradiation. The experimental results are shown in Table 12.

[0192] After diluting the anti-FXI antibody preparation with 5% glucose and 0.9% saline (0.20mg / mL~13.30mg / mL), it was exposed to light at 2℃~8℃ for 24h + room temperature for 6h, and all the detected items were within the acceptable standard range. Therefore, the diluted drug solution has good compatibility with the infusion system, and after dilution in the infusion system, it can be used within 2℃~8℃ for 24h + room temperature for 6h.

[0193] [Table 11]

Claims

1. A pharmaceutical composition comprising an anti-FXI / FXIa antibody or an antigen-binding fragment thereof, and a buffering agent, wherein the buffering agent is one or more selected from an acetate buffer, a histidine buffer, a Tris-hydrochloride buffer, a Tris-citrate buffer, and a phosphate buffer; Preferably, the buffer is a histidine salt buffer, a Tris-hydrochloride buffer or a phosphate buffer. Pharmaceutical compositions.

2. the pH value of the buffer or the pharmaceutical composition is about 4.0 to about 8.5, preferably about 6.5 to about 7.5, more preferably about 7.0; The pharmaceutical composition of claim 1.

3. The concentration of the buffering agent is about 5 mM to about 100 mM, preferably about 10 mM to about 30 mM, more preferably about 5 mM to about 15 mM. The pharmaceutical composition of claim 1.

4. the concentration of the anti-FXI / FXIa antibody or antigen-binding fragment thereof is about 1 mg / mL to about 300 mg / mL, preferably about 50 mg / mL to about 150 mg / mL; The pharmaceutical composition of claim 1.

5. further comprising a surfactant, Preferably, the surfactant is poloxamer 188, polysorbate 80 or polysorbate 20. The pharmaceutical composition of claim 1.

6. the concentration of the surfactant is about 0.1 mg / mL to about 10 mg / mL, preferably about 1.5 mg / mL to about 4 mg / mL, preferably about 0.4 mg / mL to about 0.8 mg / mL; The pharmaceutical composition according to claim 5.

7. further comprising an osmolality adjuster; Preferably, the osmolality adjusting agent is one or more selected from the group consisting of sucrose, trehalose, sorbitol, arginine, proline, glycine and sodium chloride; More preferably, the osmolality modifier is selected from sucrose, proline and sucrose, or glycine and sucrose. The pharmaceutical composition of claim 1.

8. The osmotic pressure adjusting agent is about 10 mg / mL to about 150 mg / mL sucrose; about 10 mM to 200 mM glycine and about 10 mg / mL to about 100 mg / mL sucrose, or selected from about 10 mM to 200 mM proline and about 10 mg / mL to about 100 mg / mL sucrose; Preferably, the osmolality adjusting agent is about 80 mg / mL sucrose, about 100 mM glycine and about 40 mg / mL sucrose, or about 100 mM proline and about 40 mg / mL sucrose; The pharmaceutical composition of claim 7.

9. A pharmaceutical composition comprising an anti-FXI / FXIa antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition is a self-buffering system, and preferably, the pharmaceutical composition comprises a basic amino acid, and more preferably, the basic amino acid is histidine. Pharmaceutical compositions.

10. the concentration of the anti-FXI / FXIa antibody or antigen-binding fragment thereof is about 1 mg / mL to about 300 mg / mL, preferably about 30 mg / mL to about 200 mg / mL, more preferably about 70 mg / mL to about 130 mg / mL; The pharmaceutical composition of claim 9.

11. the concentration of the basic amino acid is about 1 mM to about 100 mM, preferably 10 mM to about 60 mM, more preferably about 30 mM to about 40 mM, and most preferably about 35 mM; The pharmaceutical composition of claim 9.

12. The pH value is about 4.0 to about 8.5, preferably about 6.5 to about 7.5, more preferably about 6.7 to about 7.3, and most preferably about 7.0; The pharmaceutical composition of claim 9.

13. further comprising an osmolality adjuster; Preferably, the osmolality adjusting agent is one or more selected from sucrose, trehalose, sorbitol, arginine, proline, glycine and sodium chloride; More preferably, the osmolality adjusting agent is sucrose. The pharmaceutical composition of claim 9.

14. the concentration of the osmotic agent is about 10 mg / mL to about 400 mg / mL, preferably about 50 mg / mL to about 200 mg / mL, more preferably about 80 mg / mL; The pharmaceutical composition of claim 13.

15. further comprising a surfactant, Preferably, the surfactant is poloxamer 188, polysorbate 80 or polysorbate 20. The pharmaceutical composition of claim 9.

16. The concentration of the surfactant is about 0.1 mg / mL to about 10 mg / mL, preferably about 1.8 mg / mL to about 2.8 mg / mL, and more preferably about 2 mg / mL; 16. The pharmaceutical composition of claim 15.

17. A pharmaceutical composition comprising (a) and (b), and optionally further comprising (c) and / or (d), wherein: (a) about 1 mg / mL to about 500 mg / mL of an anti-FXI / FXIa antibody; (b) about 1 mM to about 100 mM histidine; (c) about 10 mg / mL to about 400 mg / mL of sucrose or trehalose, and (d) about 0.5 mg / mL to about 80 mg / mL of poloxamer, polysorbate 80, or polysorbate 20; the pH of the pharmaceutical composition is from about 4.0 to about 8.5; Or, (a) about 30 mg / mL to about 200 mg / mL anti-FXI / FXIa antibody, (b) about 10 mM to about 60 mM histidine; (c) about 50 mg / mL to about 200 mg / mL of sucrose, and (d) about 1.5 mg / mL to about 5.0 mg / mL of poloxamer 188; the pH of the pharmaceutical composition is about 6.5 to about 7.5; Or, (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody; (b) about 30 mM to about 40 mM histidine; (c) about 60 mg / mL to about 150 mg / mL of sucrose, and (d) about 1.8 mg / mL to about 2.8 mg / mL of poloxamer 188; the pH of the pharmaceutical composition is about 6.7 to about 7.3; Or, (a) about 70 mg / mL to about 200 mg / mL of an anti-FXI / FXIa antibody; (b) about 30 mM to about 100 mM histidine; (c) about 60 mg / mL to about 150 mg / mL of sucrose, and (d) about 1.8 mg / mL to about 2.8 mg / mL of poloxamer 188; The pH of the pharmaceutical composition is about 6.7 to about 7.

3. Pharmaceutical compositions.

18. The pharmaceutical composition comprises: (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 35 mM histidine; (c) about 80 mg / mL sucrose, and (d) about 2 mg / mL of poloxamer 188; the pH of the pharmaceutical composition is about 7.0; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 35 mM histidine; (c) about 80 mg / mL sucrose, and (d) about 2 mg / mL of poloxamer 188; the pH of the pharmaceutical composition is about 6.7; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 35 mM histidine; (c) about 80 mg / mL sucrose, and (d) about 2 mg / mL of poloxamer 188; the pH of the pharmaceutical composition is about 7.3; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 30 mM histidine; (c) about 80 mg / mL sucrose, and (d) about 1.8 mg / mL poloxamer 188; the pH of the pharmaceutical composition is about 7.0; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 30 mM histidine; (c) about 80 mg / mL sucrose, and (d) about 2.8 mg / mL of poloxamer 188; the pH of the pharmaceutical composition is about 7.0; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 40 mM histidine; (c) about 80 mg / mL sucrose, and (d) about 1.8 mg / mL poloxamer 188; the pH of the pharmaceutical composition is about 7.0; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 40 mM histidine; (c) about 80 mg / mL sucrose, and (d) about 2.3 mg / mL of poloxamer 188; the pH of the pharmaceutical composition is about 7.0; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 40 mM histidine; (c) about 80 mg / mL sucrose, and (d) about 2.8 mg / mL of poloxamer 188; the pH of the pharmaceutical composition is about 7.0; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 35 mM histidine; (c) about 80 mg / mL sucrose, and (d) about 2.3 mg / mL of poloxamer 188; the pH of the pharmaceutical composition is about 7.0; or (a) about 70 mg / mL to about 130 mg / mL of an anti-FXI / FXIa antibody or antigen-binding fragment thereof; (b) about 35 mM histidine; (c) about 80 mg / mL sucrose, and (d) about 1.8 mg / mL poloxamer 188; The pH of the pharmaceutical composition is about 7.

0.

18. The pharmaceutical composition of claim 17.

19. A pharmaceutical composition obtained by diluting the pharmaceutical composition of claim 17 with 0.9% saline or 5% glucose solution, Preferably, the concentration of the anti-FXI / FXIa antibody or antigen-binding fragment thereof is about 0.01 mg / mL to about 50 mg / mL; More preferably, the concentration of the anti-FXI / FXIa antibody or antigen-binding fragment thereof is about 0.1 mg / mL to about 30 mg / mL; Most preferably, the concentration of the anti-FXI / FXIa antibody or antigen-binding fragment thereof is from about 0.20 mg / mL to about 13.30 mg / mL. Pharmaceutical compositions.

20. The anti-FXI / FXIa antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3 shown in SEQ ID NOs: 7, 8, and 9, respectively, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3 shown in SEQ ID NOs: 10, 11, and 12, respectively; The pharmaceutical composition according to any one of claims 1 to 19.

21. The anti-FXI / FXIa antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region and the light chain variable region are selected from: the sequence of the heavy chain variable region is SEQ ID NO: 5 or a sequence having at least 90% identity thereto, and the sequence of the light chain variable region is SEQ ID NO: 6 or a sequence having at least 90% identity thereto; the sequence of the heavy chain variable region is SEQ ID NO: 13 or a sequence having at least 90% identity thereto, and the sequence of the light chain variable region is SEQ ID NO: 14 or a sequence having at least 90% identity thereto; the sequence of the heavy chain variable region is SEQ ID NO: 15 or a sequence having at least 90% identity thereto, and the sequence of the light chain variable region is SEQ ID NO: 16 or a sequence having at least 90% identity thereto; or the sequence of the heavy chain variable region is SEQ ID NO: 17 or a sequence having at least 90% identity thereto, and the sequence of the light chain variable region is SEQ ID NO: 16 or a sequence having at least 90% identity thereto; 21. The pharmaceutical composition of claim 20.

22. The anti-FXI / FXIa antibody or antigen-binding fragment thereof further comprises a human IgG1 Fc or a human IgG4 Fc, and preferably the human IgG4 Fc comprises a S241P mutation.

21. The pharmaceutical composition of claim 20.

23. The anti-FXI / FXIa antibody or antigen-binding fragment thereof comprises a heavy chain and a light chain, wherein the sequence of the heavy chain comprises SEQ ID NO: 21 or a sequence having at least 90% identity thereto, and the sequence of the light chain comprises SEQ ID NO: 22 or a sequence having at least 90% identity thereto.

21. The pharmaceutical composition of claim 20.

24. 20. A lyophilized formulation obtainable by lyophilizing the pharmaceutical composition of any one of claims 1 to 19, or which, when reconstituted, can form the pharmaceutical composition of any one of claims 1 to 19.

25. A reconstituted solution prepared by reconstituting the freeze-dried formulation according to claim 24.

26. an intravenous injection, a subcutaneous injection, an intraperitoneal injection, or an intramuscular injection, preferably an intravenous or subcutaneous injection; The pharmaceutical composition according to any one of claims 1 to 19.

27. A product comprising a container containing the pharmaceutical composition of any one of claims 1 to 19.

28. A method for treating or preventing a disease, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of the pharmaceutical composition of any one of claims 1 to 19, wherein: the disease is a thrombogenic or thromboembolic disease and / or a thrombogenic or thromboembolic complication, or arrhythmia, cardiogenic thromboembolism, diffuse intravascular coagulation, Preferably, the thrombogenic or thromboembolic disease or its complications is selected from coronary heart disease, such as acute coronary syndrome (ACS), ST elevation myocardial infarction (STEMI) and non-ST elevation myocardial infarction (non-STEMI), stable angina, unstable angina, re-occlusion and restenosis after coronary intervention, and peripheral arterial occlusive disease, pulmonary embolism, venous thromboembolism, venous thrombosis, transient ischemic attack, and thrombotic and thromboembolic stroke in other blood vessels, chronic thromboembolic pulmonary disease (CTEPH) and pulmonary arterial hypertension, or a combination thereof; Preferably, the mode of administration is subcutaneous or intravenous injection. method.

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