Pharmaceutical composition containing Anti-LAG-3 antibody and use of pharmaceutical composition

Abstract

The present application relates to the technical field of antibody formulations, and specifically provides a pharmaceutical composition containing an anti-LAG-3 antibody and a use of the pharmaceutical composition. The pharmaceutical composition has good stability.

Description

Pharmaceutical compositions containing anti-LAG-3 antibodies and uses thereof

[0001] Priority information

[0002] This disclosure claims priority to Chinese invention patent application 202311446616.7 filed on November 2, 2023, which is incorporated by reference in its entirety into this disclosure. Technical Field

[0003] The present disclosure relates to the field of antibody preparations, and in particular to a pharmaceutical composition containing an anti-LAG-3 antibody or an antigen-binding fragment thereof and uses thereof. Background Art

[0004] LAG-3, also known as CD223, is the full name of Lymphocyte Activation Gene 3. It is not expressed on naive T cells (initial T cells), but can be expressed on CD4 T cells under antigen stimulation. + and CD8 + LAG-3 is an immunosuppressive receptor that negatively regulates T cell function and plays an important role in maintaining the homeostasis of the body's immune system. However, due to the continuous antigen stimulation in the tumor microenvironment, the induction of CD4 + and CD8 + The expression of LAG-3 and other immunosuppressive receptors (including PD-1, TIM-3, and TIGIT) on T cells is upregulated, leading to T cell dysfunction. + LAG-3 is constitutively expressed on regulatory T cells (Tregs). Tregs that overexpress LAG-3 produce large amounts of the immunomodulatory cytokines IL-10 and TGF-β, thereby suppressing tumor-specific T cells. In addition, LAG-3 is also expressed on γδ T cells, natural killer T cells, plasmacytoid dendritic cells (pDCs), and activated B cells. Using therapeutic antibodies to inhibit LAG-3 can reduce LAG-3-induced T cell suppression and enhance the body's immune response to tumors.

[0005] Antibodies, with their large molecular weight and complex structure, are susceptible to degradation, aggregation, or undesirable chemical modifications, leading to instability. Any instability can potentially impact the safety and efficacy of therapeutic antibodies. Therefore, therapeutic antibodies must be formulated in appropriate formulations to prevent denaturation, oxidation, aggregation, and other effects during storage, transportation, and administration that could disrupt their structure and activity.

[0006] Summary of the Invention

[0007] The present disclosure provides a pharmaceutical composition, wherein the pharmaceutical composition comprises: (a) an anti-LAG-3 antibody or an antigen-binding fragment thereof, (b) a buffer, (c) a stabilizer, and (d) a surfactant.

[0008] In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof can specifically bind to LAG-3 (e.g., human LAG-3) and / or block LAG-3 signaling, including but not limited to polyclonal antibodies, monoclonal antibodies, multispecific antibodies, monospecific antibodies, monovalent antibodies, and single-chain antibodies.

[0009] The present disclosure also provides a method for preparing the pharmaceutical composition of the present disclosure, comprising the steps of mixing the anti-LAG-3 antibody or antigen-binding fragment thereof, a buffer, a stabilizer, and a surfactant to prepare the pharmaceutical composition. In some embodiments, the method further comprises sterilizing the resulting mixture.

[0010] The present disclosure also provides a lyophilized preparation, which is obtained by freeze-drying the pharmaceutical composition of the present disclosure.

[0011] The present disclosure also provides a lyophilized formulation, which can form the pharmaceutical composition of the present disclosure after reconstitution (ie, reconstitution).

[0012] The present disclosure also provides an article of manufacture comprising the pharmaceutical composition of the present disclosure.

[0013] The present disclosure also provides a method for treating a disease in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition, lyophilized formulation, or product of the present disclosure. The present disclosure also provides use of the pharmaceutical composition, lyophilized formulation, or product of the present disclosure in the preparation of a medicament for treating a disease in a subject.

[0014] The present disclosure also provides a method for enhancing an immune response in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition, lyophilized formulation, or product of the present disclosure. The present disclosure also provides use of the pharmaceutical composition, lyophilized formulation, or product of the present disclosure in the preparation of a medicament for enhancing an immune response in a subject.

[0015] The present disclosure also provides a method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition, lyophilized formulation, or product of the present disclosure. The present disclosure also provides use of the pharmaceutical composition, lyophilized formulation, or product of the present disclosure in the preparation of a medicament for treating cancer in a subject.

[0016] The present disclosure also provides a method for treating an infectious disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition, lyophilized formulation, or product of the present disclosure. The present disclosure also provides use of the pharmaceutical composition, lyophilized formulation, or product of the present disclosure in the preparation of a medicament for treating an infectious disease in a subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] In order to more clearly illustrate the technical solutions in the embodiments of the present disclosure and to more completely understand the present disclosure and its beneficial effects, the following briefly introduces the drawings required for describing the embodiments.

[0018] FIG1 is a graph showing the main peak content change curves of pharmaceutical compositions F1a-b3-c1 and F1a-b7-c1 at 2-8° C. (SEC-HPLC);

[0019] FIG2 is a graph showing the change in monomer content of pharmaceutical compositions F1a-b3-c1 and F1a-b7-c1 at 2-8° C. (non-reducing CGE);

[0020] FIG3 is a graph showing the change in monomer content of pharmaceutical compositions F1a-b3-c1 and F1a-b7-c1 at 2-8° C. (CIEX);

[0021] FIG4 is a graph showing the main peak content change curves of pharmaceutical compositions F1a-b3-c1 and F1a-b7-c1 at 25° C. (SEC-HPLC);

[0022] FIG5 is a graph showing changes in monomer content of pharmaceutical compositions F1a-b3-c1 and F1a-b7-c1 at 25° C. (non-reducing CGE);

[0023] FIG6 is a graph showing the change in monomer content of pharmaceutical compositions F1a-b3-c1 and F1a-b7-c1 at 25° C. (CIEX);

[0024] FIG7 is a graph showing the main peak content change curves of pharmaceutical compositions F1a-b3-c1 and F1a-b7-c1 under light conditions (SEC-HPLC);

[0025] FIG8 is a graph showing changes in monomer content of pharmaceutical compositions F1a-b3-c1 and F1a-b7-c1 under light irradiation conditions (non-reducing CGE). DETAILED DESCRIPTION

[0026] The present disclosure will be further described in detail below in conjunction with the accompanying drawings, embodiments and examples. It should be understood that these embodiments and examples are only used to illustrate the present disclosure and are not used to limit the scope of the present disclosure. The purpose of providing these embodiments and examples is to make the content of the present disclosure more thoroughly understood and comprehensive. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of the present disclosure. The terms used in the specification of the present disclosure are only for the purpose of describing the embodiments and examples and are not used to limit the present disclosure.

[0027] the term

[0028] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0029] The terms "and / or", "or / and", and "and / or" used in this disclosure include any one of two or more related listed items, and also include any and all combinations of the related listed items, wherein the arbitrary and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that in this disclosure, the technical solution undoubtedly includes technical solutions that are all connected by "logical and", and also undoubtedly includes technical solutions that are all connected by "logical or". For example, "A and / or B" includes three parallel solutions of A, B and A+B. For example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, the technical solution of all being connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, the combination of any two or any three of A, B, C, and D, and also includes the four-item combination of A, B, C, and D (that is, the technical solution of all being connected by "logical AND").

[0030] In the present disclosure, “plurality”, “multiple”, “multiple times”, “multiples”, etc., unless otherwise specified, refer to a quantity greater than or equal to 2. For example, “one or more” means one or more than or equal to two.

[0031] The terms "combination thereof", "any combination thereof", "any combination thereof" and the like used in this disclosure include all suitable combinations of any two or more of the listed items.

[0032] In the present disclosure, “further”, “further”, “particularly”, etc. are used for descriptive purposes to indicate differences in content, but should not be understood as limiting the scope of protection of the present disclosure.

[0033] In this disclosure, the terms "optionally," "optional," and "optional" mean optional or dispensable, i.e., they refer to either option being selected from two parallel options: "with" or "without." If a technical solution contains multiple "optional" clauses, each "optional" clause is considered independent unless otherwise specified and there are no conflicts or constraints.

[0034] Throughout this disclosure, terms such as "one," "another," and "yet another" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or quantity, nor as implicitly indicating the importance or quantity of the technical features being referenced. Furthermore, terms such as "one," "another," and "yet another" are used for descriptive purposes only and should not be construed as constituting a closed limitation on quantity.

[0035] In the present disclosure, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0036] In the present disclosure, when referring to a numerical interval (i.e., a numerical range), unless otherwise specified, the optional numerical distribution is considered continuous within the above numerical interval and includes the two numerical endpoints of the numerical range (i.e., the minimum value and the maximum value), as well as each numerical value between the two numerical endpoints. Unless otherwise specified, when a numerical interval refers only to integers within the numerical interval, it includes the two endpoint integers of the numerical range, as well as each integer between the two endpoints. In this document, it is equivalent to directly listing each integer, such as t is an integer selected from 1 to 10, indicating that t is any integer selected from the group of integers consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be merged. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all subranges included therein.

[0037] Unless otherwise specified, the temperature parameters in this disclosure may be either constant temperature or fluctuating within a certain temperature range. It should be understood that the constant temperature treatment allows for temperature fluctuations within the precision range of instrument control. Fluctuations within ranges such as ±5°C, ±4°C, ±3°C, ±2°C, and ±1°C are permitted.

[0038] In the present disclosure, % (w / w) and wt% both refer to weight percentage, % (v / v) refers to volume percentage, and % (w / v) refers to mass volume percentage.

[0039] Throughout this disclosure, "about" means within the acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., on the limitations of the measurement system. For example, "about" may mean within one or more standard deviations, as practiced in the art. Alternatively, "about" may mean a range of up to ±5%, for example, within ±2%, ±1%, or ±0.5% of the range of a given specific value. Whenever specific values ​​or parameters are given herein or in the claims, they are assumed to be modified by "about" unless otherwise indicated.

[0040] All documents mentioned in this disclosure are cited as references in this disclosure, just as each document is cited as a reference individually. Unless they conflict with the invention purpose and / or technical solution of this disclosure, the cited documents involved in this disclosure are cited in their entirety and for all purposes. When citing documents are involved in this disclosure, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When citing documents are involved in this disclosure, the examples and preferred embodiments of the cited relevant technical features may also be incorporated into this disclosure as references, but are limited to the ability to implement this disclosure. It should be understood that when the content of the citation conflicts with the description in this disclosure, the present disclosure shall prevail or be modified adaptively according to the description in this disclosure.

[0041] The term "buffer" refers to a pharmaceutically acceptable buffer, which refers to a substance that helps maintain the pH of a pharmaceutical composition within a desired pH range. Suitable buffers for use in the present disclosure include phosphate buffers, acetate buffers, citrate buffers, Tris buffers, or histidine buffers. In addition, mixtures of two or more buffers may also be used.

[0042] The term "phosphate buffer" refers to a buffer containing phosphate ions. Examples of phosphate buffers include sodium phosphate buffers. Sodium phosphate buffers can be prepared using disodium hydrogen phosphate or a hydrate thereof (e.g., disodium hydrogen phosphate dodecahydrate) and sodium dihydrogen phosphate or a hydrate thereof (e.g., sodium dihydrogen phosphate dihydrate).

[0043] The term "acetate buffer" refers to a buffer containing acetate ions. Examples of acetate buffers include sodium acetate buffers. Sodium acetate buffers can be prepared using acetic acid and sodium acetate or a hydrate thereof (e.g., anhydrous sodium acetate or sodium acetate trihydrate). The sodium acetate buffers described in the Examples can be prepared from sodium acetate trihydrate and acetic acid (e.g., 20 mmol / L acetic acid-sodium acetate buffer (pH 5.5) can be prepared from approximately 2.34 g / L sodium acetate trihydrate and approximately 0.47 g / L acetic acid (36%)), or from anhydrous sodium acetate and acetic acid (e.g., 20 mmol / L acetic acid-sodium acetate buffer (pH 5.5) can be prepared from approximately 1.41 g / L anhydrous sodium acetate and approximately 0.17 g / L acetic acid).

[0044] The term "citrate buffer" refers to a buffer containing citrate ions. Examples of citrate buffers include sodium citrate buffers. Sodium citrate buffers can be prepared using citric acid and sodium citrate or a hydrate thereof (e.g., trisodium citrate dihydrate).

[0045] The term "histidine buffer" refers to a buffer containing histidine ions. Examples of histidine buffers include histidine-histidine hydrochloride buffers. Histidine-histidine hydrochloride buffers can be prepared using histidine (e.g., L-histidine) and histidine hydrochloride or a hydrate thereof (e.g., histidine hydrochloride monohydrate).

[0046] The term "stabilizer" refers to a substance that helps maintain the structural integrity of the active ingredient (e.g., antibody) in a pharmaceutical composition, particularly during freezing, lyophilization, storage, and / or transportation (especially when exposed to stress). In this context, a stabilizer may also function as a viscosity reducer, antioxidant, and / or isotonicity agent.

[0047] The term "antioxidant" refers to a substance that can prevent or reduce oxidation of an active ingredient (eg, an antibody) in a pharmaceutical composition.

[0048] The term "isotonic agent" refers to a substance that helps maintain the osmotic pressure of a pharmaceutical composition at or near physiological osmotic pressure.

[0049] The term "antibody" refers to an antigen-binding protein having at least one antigen-binding domain. The antibody or fragment thereof disclosed herein may be a whole antibody or any fragment thereof, including a monoclonal antibody or fragment thereof and an antibody variant or fragment thereof. Examples of antibodies or antigen-binding fragments disclosed herein include monospecific antibodies, bispecific antibodies, multispecific antibodies, single-domain antibodies, Fab fragments, Fab' fragments, F(ab)'2 fragments, Fv fragments, isolated CDR regions, single-chain Fv molecules (scFv) and other antibody fragments known in the art. Unless otherwise indicated, "antibodies or antigen-binding fragments thereof" disclosed herein include whole antibodies and any antigen-binding fragments thereof or single chains. Conventional "whole antibodies" are glycoproteins comprising two heavy (H) chains and two light (L) chains, which are connected by disulfide bonds. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region consists of three domains, namely CH1, CH2 and CH3. Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The light chain constant region is composed of a domain, CL. The VH and VL regions can also be divided into hypervariable regions, i.e., complementary determining regions (CDRs), and framework regions (FRs) whose sequences are relatively conserved. Each VH and VL is composed of three CDRs and four FRs, respectively, from amino terminus to carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable region of an antibody comprises a binding domain that interacts with an antigen. The constant region of an antibody can mediate the binding of an immunoglobulin to a host tissue or factor, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. At the same time, as will be appreciated by those skilled in the art, a special "whole antibody," such as a nanobody, has only a heavy (H) chain and no light (L) chain.

[0050] An "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding to an antigen. It has been demonstrated that the antigen-binding function of an antibody can be implemented by fragments of the entire antibody. Examples encompassed within the term "antigen-binding fragment" of an antibody include: (i) a Fab fragment: a monovalent fragment consisting of a VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments connected by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of a VH and CH1 domain; (iv) an Fv fragment consisting of the VL and VH domains of a single antibody arm; (v) a dAb fragment consisting of a VH domain (see Ward et al., Nature. 341: 544-546 (1989)); (vi) an isolated complementary determining region (CDR); and (vii) a nanobody, a heavy chain variable region comprising a single variable domain and two constant domains. In addition, although the two domains VL and VH of the Fv fragment are encoded by different genes, VH and VL can be connected into a single protein chain by a recombinant method through a synthetic linker, wherein VL and VH pair to form a monovalent molecule (called single-chain Fv (scFv); see, for example, Bird et al., Science. 242: 423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85: 5879-5883 (1988)). These single-chain antibodies are also encompassed by the term antigen-binding fragment. In addition, recombinant polypeptides, fusion proteins, small modular immunopharmaceuticals (SMIPs) and immunoconjugates comprising the antigen-binding fragment are also encompassed by the term antigen-binding fragment.

[0051] The term "identity" is also known as consistency. The "percentage (%) identity" of an amino acid sequence refers to the percentage of amino acid residues in the sequence to be aligned that are identical to the amino acid residues in the specific amino acid sequence shown in this article, after comparing the sequence to be aligned and, if necessary, introducing gaps to achieve maximum sequence identity, and not considering any conservative substitutions as part of sequence identity. The alignment of amino acid sequences for identity can be performed in a variety of ways within the scope of the art, such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithm needed to obtain maximum alignment over the full length of the comparison sequence.

[0052] The term "pharmaceutical composition" refers to a preparation that is in a form that allows the biological activity of the active ingredient (e.g., antibody) therein to be effectively exerted, and does not contain other components that are unacceptably toxic for the subject to whom the pharmaceutical composition is to be administered. Such pharmaceutical compositions are typically sterile. Pharmaceutical compositions of the present disclosure can be prepared into liquid preparations in aqueous form, such as, for example, filled in pre-filled syringes or vials, or prepared into lyophilized preparations, and reconstituted by dissolving and / or being suspended in a physiologically acceptable solution before use. In some embodiments, pharmaceutical compositions of the present disclosure are liquid preparations. In the present disclosure, "pharmaceutical composition" and "preparation" can be used interchangeably.

[0053] The term "stable" pharmaceutical composition refers to a pharmaceutical composition that substantially retains the physical stability and / or chemical stability and / or biological activity of the active ingredient (eg, antibody) when stored therein.

[0054] The term "high molecular weight impurities" or "aggregates" refers to a general term for impurities with a molecular weight greater than that of the target active ingredient (eg, antibody).

[0055] The term "treatment" generally refers to an operation to obtain a desired pharmacological and / or physiological effect. The effect can be preventive, in terms of completely or partially preventing a disease or its symptoms; and / or therapeutic, in terms of partially or completely stabilizing or curing a disease and / or side effects produced by the disease. As used herein, "treatment" encompasses any treatment of a patient's disease, including but not limited to preventing the occurrence or recurrence of the disease, alleviating the symptoms of the disease, reducing any direct or indirect pathological consequences of the disease, preventing the metastasis of the disease, slowing the progression of the disease, improving or alleviating the state of the disease, prolonging the frequency and duration of symptom-free periods, and resolving or improving the prognosis of the disease.

[0056] The term "therapeutically effective amount" or "therapeutically effective dose" refers to any amount of a therapeutic agent that protects a patient from the onset of disease or promotes disease regression, as evidenced by a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or the prevention of impairment or disability resulting from disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to skilled practitioners, such as in human patients during clinical trials, in animal model systems predictive of efficacy in humans, or by measuring the activity of the agent in in vitro assays.

[0057] The terms "administering" or "administering" refer to the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0058] The terms "subject" or "patient" are used interchangeably. "Subject" or "patient" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents (e.g., mice, rats, and guinea pigs). In some embodiments, the subject or patient is a mammal. In some embodiments, the subject or patient is a mouse. In some embodiments, the subject or patient is a human.

[0059] Pharmaceutical composition

[0060] The present disclosure provides a pharmaceutical composition, wherein the pharmaceutical composition comprises: (a) an anti-LAG-3 antibody or an antigen-binding fragment thereof, (b) a buffer, (c) a stabilizer, and (d) a surfactant.

[0061] In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is at a concentration of 1-50 mg / mL, 2-50 mg / mL, 5-40 mg / mL, 10-40 mg / mL, or 10-30 mg / mL. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is present at a concentration including, but not limited to, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 11 mg / mL, 12 mg / mL, 13 mg / mL, 14 mg / mL, 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 40 mg / mL, or 50 mg / mL. In some embodiments, the concentration of the anti-LAG-3 antibody or antigen-binding fragment thereof is 10-25 mg / mL, 15-23 mg / mL, or 18.5-21.5 mg / mL. In some embodiments, the concentration of the anti-LAG-3 antibody or antigen-binding fragment thereof is 20 mg / mL.

[0062] In some embodiments, the buffer comprises a histidine buffer, an acetate buffer, a Tris buffer, a phosphate buffer, or a citrate buffer. In some embodiments, the buffer comprises an acetate buffer or a citrate buffer. In some embodiments, the buffer comprises an acetate buffer. In some embodiments, the acetate buffer is a sodium acetate buffer.

[0063] In some embodiments, the concentration of the buffer is 1-150 mmol / L, 1-120 mmol / L, 2-100 mmol / L, 5-80 mmol / L, 10-60 mmol / L, or 10-40 mmol / L. In some embodiments, the concentration of the buffer includes but is not limited to 2mmol / L, 3mmol / L, 4mmol / L, 5mmol / L, 6mmol / L, 7mmol / L, 8mmol / L, 9mmol / L, 10mmol / L, 11mmol / L, 12mmol / L, 13mmol / L, 14mmol / L, 15mmol / L, 16mmol / L, 17mmol / L, 18mmol / L, 19mmol / L, 20mmol / L, 21mmol / L, 22mmol / L, 23mmol / L, 24mmol / L, 25mmol / L, 26mmol / L, 27mmol / L, 28mmol / L, 29mmol / L, 30mmol / L, 40mmol / L, 50mmol / L, 60mmol / L, 70mmol / L or 80mmol / L. In some embodiments, the concentration of the buffer is 10-30 mmol / L, 10-25 mmol / L, 15-23 mmol / L, or 18.5-21.5 mmol / L. In some embodiments, the concentration of the buffer is 20 mmol / L.

[0064] In some embodiments, the buffer is 1-150 mmol / L, 1-120 mmol / L, 2-100 mmol / L, 5-80 mmol / L, 10-60 mmol / L, or 10-40 mmol / L acetate buffer. In some embodiments, the buffer is 10-30 mmol / L, 10-25 mmol / L, 15-23 mmol / L, or 18.5-21.5 mmol / L acetate buffer. In some embodiments, the buffer is 20 mmol / L acetate buffer. In some embodiments, the acetate buffer is sodium acetate buffer.

[0065] In some embodiments, the pH of the buffer is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.8. In some embodiments, the pH of the buffer includes, but is not limited to, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7. In some embodiments, the pH of the buffer is 5. In some embodiments, the pH of the buffer is 5.2. In some embodiments, the pH of the buffer is 5.5. In some embodiments, the pH of the buffer is 5.8. In some embodiments, the pH of the buffer is 6.

[0066] In some embodiments, the stabilizer comprises a sugar alcohol (e.g., mannitol, sorbitol), a disaccharide (e.g., trehalose, sucrose, maltose, lactose), a monosaccharide (e.g., dextrose (D-glucose)), an amino acid (e.g., lysine, glycine, proline, arginine, or a pharmaceutically acceptable salt thereof), or a salt (e.g., sodium chloride). In some embodiments, the stabilizer comprises trehalose or proline.

[0067] In some embodiments, the concentration of the stabilizer is 1-200 mg / mL, 5-100 mg / mL, 10-80 mg / mL, 15-60 mg / mL, 10-60 mg / mL, or 15-55 mg / mL. In some embodiments, the concentration of the stabilizer includes but is not limited to: 5 mg / mL, 5.8 mg / mL, 6 mg / mL, 10 mg / mL, 11.5 mg / mL, 12 mg / mL, 15 mg / mL, 17 mg / mL, 17.3 mg / mL, 20 mg / mL, 23 mg / mL, 25 mg / mL, 28.8 mg / mL, 29 mg / mL, 30 mg / mL, 34.5 mg / mL, 35 mg / mL, 40 mg / mL, 40.3 mg / mL, 4 In some embodiments, the concentration of the stabilizer is 20-55 mg / mL, 30-55 mg / mL, or 45-55 mg / mL. In some embodiments, the concentration of the stabilizer is 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL or 55 mg / mL. In some embodiments, the concentration of the stabilizer is 20 mg / mL. In some embodiments, the concentration of the stabilizer is 50 mg / mL. In some embodiments, the concentration of the stabilizer is 15-50 mg / mL, 15-40 mg / mL, or 30-40 mg / mL. In some embodiments, the concentration of the stabilizer is 17 mg / mL, 17.3 mg / mL, 20 mg / mL, 23 mg / mL, 28.8 mg / mL, 29 mg / mL, 30 mg / mL, 34.5 mg / mL, or 35 mg / mL. In some embodiments, the concentration of the stabilizer is 17.3 mg / mL. In some embodiments, the concentration of the stabilizer is 34.5 mg / mL.

[0068] In some embodiments, the concentration of the stabilizer is 1-800mmol / L, 10-600mmol / L, 15-500mmol / L, 20-400mmol / L, 50-400mmol / L, or 50-350mmol / L. In some embodiments, the concentration of the stabilizer includes but is not limited to: 10mmol / L, 14.6mmol / L, 15mmol / L, 29mmol / L, 29.2mmol / L, 43.8mmol / L, 44mmol / L, 50mmol / L, 58mmol / L, 58.4mmol / L, 73mmol / L, 87.6mmol / L, 88mmol / L, 100mmol / L, 102mmol / L, 102.3mmol / L, 116.9mmol / L, 117mmol / L, 131.5mmol / L, 13 In some embodiments, the concentration of the stabilizer is 50-200 mmol / L, 50-150 mmol / L, or 140-150 mmol / L. In some embodiments, the concentration of the stabilizer is 50 mmol / L, 58 mmol / L, 58.4 mmol / L, 73 mmol / L, 87.6 mmol / L, 88 mmol / L, 102 mmol / L, 102.3 mmol / L, 116.9 mmol / L, 117 mmol / L, 131.5 mmol / L, 132 mmol / L, 146 mmol / L, or 146.1 mmol / L. In some embodiments, the concentration of the stabilizer is 58 mmol / L or 58.4 mmol / L. In some embodiments, the concentration of the stabilizer is 146 mmol / L or 146.1 mmol / L. In some embodiments, the concentration of the stabilizer is 100-350 mmol / L, 150-350 mmol / L, or 250-350 mmol / L. In some embodiments, the concentration of the stabilizer is 150 mmol / L, 200 mmol / L, 250 mmol / L, 300 mmol / L, or 350 mmol / L.In some embodiments, the concentration of the stabilizer is 150 mmol / L. In some embodiments, the concentration of the stabilizer is 300 mmol / L.

[0069] In some embodiments, the stabilizer is 1-200 mg / mL, 5-100 mg / mL, 10-80 mg / mL, 15-60 mg / mL, 10-60 mg / mL, or 15-55 mg / mL of trehalose or proline. In some embodiments, the stabilizer is 15-55 mg / mL (e.g., 15 mg / mL, 16 mg / mL, 17 mg / mL, 18 mg / mL, 19 mg / mL, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 26 mg / mL, 27 mg / mL, 28 mg / mL, 29 mg / mL, 30 mg / mL, 31 mg / mL, 32 mg / mL, 33 mg / mL, In some embodiments, the stabilizer is 20-55 mg / mL, 30-55 mg / mL or 45-55 mg / mL of trehalose. In some embodiments, the stabilizer is 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL or 55 mg / mL of trehalose. In some embodiments, the stabilizer is 20 mg / mL of trehalose. In some embodiments, the stabilizer is 50 mg / mL of trehalose. In some embodiments, the stabilizer is 15-50 mg / mL, 15-40 mg / mL, or 30-40 mg / mL of proline. In some embodiments, the stabilizer is 17 mg / mL, 17.3 mg / mL, 20 mg / mL, 23 mg / mL, 28.8 mg / mL, 29 mg / mL, 30 mg / mL, 34.5 mg / mL, or 35 mg / mL of proline. In some embodiments, the stabilizer is 17.3 mg / mL of proline. In some embodiments, the stabilizer is 34.5 mg / mL of proline.

[0070] In some embodiments, the stabilizer is 1-800mmol / L, 10-600mmol / L, 15-500mmol / L, 20-400mmol / L, 50-400mmol / L, or 50-350mmol / L of trehalose or proline. In some embodiments, the stabilizer is 50-200mmol / L, 50-150mmol / L, or 140-150mmol / L of trehalose. In some embodiments, the stabilizer is 50mmol / L, 58mmol / L, 58.4mmol / L, 73mmol / L, 87.6mmol / L, 88mmol / L, 102mmol / L, 102.3mmol / L, 116.9mmol / L, 117mmol / L, 131.5mmol / L, 132mmol / L, 146mmol / L, or 146.1mmol / L of trehalose. In some embodiments, the stabilizer is 58 mmol / L or 58.4 mmol / L trehalose. In some embodiments, the stabilizer is 146 mmol / L or 146.1 mmol / L trehalose. In some embodiments, the stabilizer is 50-350 mmol / L (e.g., 50 mmol / L, 60 mmol / L, 70 mmol / L, 80 mmol / L, 90 mmol / L, 100 mmol / L, 110 mmol / L, 120 mmol / L, 130 mmol / L, 140 mmol / L, 150 mmol / L, 160 mmol / L, 170 mmol / L, 180 mmol / L, 190 mmol / L, 200 mmol / L, 210 mmol / L, 220 mmol / L, 230 mmol / L, 240 mmol / L, 250 mmol / L, 260 mmol / L, 270 mmol / L, 280 mmol / L, 290 mmol / L, 300 mmol / L, 310 mmol / L, 320 mmol / L, 330 mmol / L, 340 mmol / L, 350 mmol / L) of proline. In some embodiments, the stabilizer is 100-350 mmol / L, 150-350 mmol / L, or 250-350 mmol / L proline. In some embodiments, the stabilizer is 150 mmol / L, 200 mmol / L, 250 mmol / L, 300 mmol / L, or 350 mmol / L proline. In some embodiments, the stabilizer is 150 mmol / L proline. In some embodiments, the stabilizer is 300 mmol / L proline.

[0071] In some embodiments, the surfactant is a nonionic surfactant. In some embodiments, the surfactant comprises polysorbate (e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85). In some embodiments, the surfactant comprises polysorbate 80 or polysorbate 20. In some embodiments, the surfactant comprises polysorbate 20.

[0072] In some embodiments, the concentration of the surfactant is 0.02-2 mg / mL, 0.04-1.5 mg / mL, 0.06-1 mg / mL, 0.08-0.8 mg / mL, 0.1-0.5 mg / mL, or 0.1-0.3 mg / mL. In some embodiments, the concentration of the surfactant includes but is not limited to: 0.06 mg / mL, 0.08 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 mg / mL. In some embodiments, the concentration of the surfactant is 0.2 mg / mL.

[0073] In some embodiments, the surfactant is 0.02-2 mg / mL, 0.04-1.5 mg / mL, 0.06-1 mg / mL, 0.08-0.8 mg / mL, 0.1-0.5 mg / mL, or 0.1-0.3 mg / mL of polysorbate 20. In some embodiments, the surfactant is 0.2 mg / mL polysorbate 20.

[0074] In some embodiments, the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.8. In some embodiments, the pH of the pharmaceutical composition includes, but is not limited to, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7. In some embodiments, the pH of the pharmaceutical composition is 5. In some embodiments, the pH of the pharmaceutical composition is 5.2. In some embodiments, the pH of the pharmaceutical composition is 5.5. In some embodiments, the pH of the pharmaceutical composition is 5.8. In some embodiments, the pH of the pharmaceutical composition is 6.

[0075] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 1-50 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 1-150 mmol / L buffer (e.g., acetate buffer or citrate buffer), (c) a stabilizer (e.g., trehalose or proline), and (d) 0.02-2 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20), and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.8.

[0076] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 2-50 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 1-120 mmol / L buffer (e.g., acetate buffer or citrate buffer), (c) a stabilizer (e.g., trehalose or proline), and (d) 0.04-1.5 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20), and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.8.

[0077] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5-40 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 2-100 mmol / L buffer (e.g., acetate buffer or citrate buffer), (c) a stabilizer (e.g., trehalose or proline), and (d) 0.06-1 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20), and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.8.

[0078] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 10-40 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 5-80 mmol / L buffer (e.g., acetate buffer or citrate buffer), (c) a stabilizer (e.g., trehalose or proline), and (d) 0.08-0.8 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20), and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.8.

[0079] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 10-40 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 10-60 mmol / L buffer (e.g., acetate buffer or citrate buffer), (c) a stabilizer (e.g., trehalose or proline), and (d) 0.1-0.5 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20), and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.8.

[0080] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 10-30 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 10-40 mmol / L buffer (e.g., acetate buffer or citrate buffer), (c) a stabilizer (e.g., trehalose or proline), and (d) 0.1-0.3 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20), and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.8.

[0081] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 1-50 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 1-150 mmol / L buffer (e.g., acetate buffer, preferably sodium acetate buffer), (c) a stabilizer (e.g., 1-200 mg / mL trehalose or 1-800 mmol / L proline), and (d) 0.02-2 mg / mL surfactant (e.g., polysorbate 20), and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.8.

[0082] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 2-50 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 1-120 mmol / L buffer (e.g., acetate buffer, preferably sodium acetate buffer), (c) a stabilizer (e.g., 5-100 mg / mL trehalose or 10-600 mmol / L proline), and (d) 0.04-1.5 mg / mL surfactant (e.g., polysorbate 20), and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.8.

[0083] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5-40 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 2-100 mmol / L buffer (e.g., acetate buffer, preferably sodium acetate buffer), (c) a stabilizer (e.g., 10-80 mg / mL trehalose or 15-500 mmol / L proline), and (d) 0.06-1 mg / mL surfactant (e.g., polysorbate 20), and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.8.

[0084] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 10-40 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 5-80 mmol / L buffer (e.g., acetate buffer, preferably sodium acetate buffer), (c) a stabilizer (e.g., 15-60 mg / mL trehalose or 20-400 mmol / L proline), and (d) 0.08-0.8 mg / mL surfactant (e.g., polysorbate 20), and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.8.

[0085] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 10-40 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 10-60 mmol / L buffer (e.g., acetate buffer, preferably sodium acetate buffer), (c) a stabilizer (e.g., 10-60 mg / mL trehalose or 50-400 mmol / L proline), and (d) 0.1-0.5 mg / mL surfactant (e.g., polysorbate 20), and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.8.

[0086] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 10-30 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 10-40 mmol / L buffer (e.g., acetate buffer, preferably sodium acetate buffer), (c) a stabilizer (e.g., 15-55 mg / mL trehalose or 50-350 mmol / L proline), and (d) 0.1-0.3 mg / mL surfactant (e.g., polysorbate 20), and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.8.

[0087] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 10-25 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 10-25 mmol / L buffer (e.g., acetate buffer, preferably sodium acetate buffer), (c) a stabilizer (e.g., 20-55 mg / mL trehalose or 150-350 mmol / L proline), and (d) 0.1-0.3 mg / mL surfactant (e.g., polysorbate 20), and the pH of the pharmaceutical composition is 5-6, 5.2-5.8, or 5.5-5.8.

[0088] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 15-23 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 15-23 mmol / L buffer (e.g., sodium acetate buffer), (c) a stabilizer (e.g., 45-55 mg / mL trehalose or 250-350 mmol / L proline), and (d) 0.1-0.3 mg / mL surfactant (e.g., polysorbate 20), and the pH of the pharmaceutical composition is 5-6, 5.2-5.8, or 5.5-5.8.

[0089] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 20 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 20 mmol / L buffer (e.g., sodium acetate buffer), (c) a stabilizer (e.g., 50 mg / mL trehalose or 300 mmol / L proline), and (d) 0.2 mg / mL surfactant (e.g., polysorbate 20), and the pH of the pharmaceutical composition is 5-6, 5.2-5.8, or 5.5-5.8.

[0090] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 20 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 20 mmol / L sodium acetate buffer, (c) 50 mg / mL trehalose, and (d) 0.2 mg / mL polysorbate 20, and the pH of the pharmaceutical composition is 5.5-5.8 (e.g., 5.5).

[0091] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 20 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 20 mmol / L sodium acetate buffer, (c) 300 mmol / L proline, and (d) 0.2 mg / mL polysorbate 20, and the pH of the pharmaceutical composition is 5.5-5.8 (e.g., 5.5).

[0092] Anti-LAG-3 antibodies or antigen-binding fragments thereof

[0093] In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, and HCDR3 in the heavy chain variable region of SEQ ID NO: 7 or 17, and LCDR1, LCDR2, and LCDR3 in the light chain variable region of SEQ ID NO: 8 or 18. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, and HCDR3 in the heavy chain variable region of SEQ ID NO: 7, and LCDR1, LCDR2, and LCDR3 in the light chain variable region of SEQ ID NO: 8. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, and HCDR3 in the heavy chain variable region of SEQ ID NO: 17, and LCDR1, LCDR2, and LCDR3 in the light chain variable region of SEQ ID NO: 18.

[0094] In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a HCDR1 set forth in SEQ ID NO: 1 or 11, a HCDR2 set forth in SEQ ID NO: 2 or 12, a HCDR3 set forth in SEQ ID NO: 3 or 13, a LCDR1 set forth in SEQ ID NO: 4 or 14, a LCDR2 set forth in SEQ ID NO: 5 or 15, and a LCDR3 set forth in SEQ ID NO: 6 or 16. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a HCDR1 set forth in SEQ ID NO: 1, a HCDR2 set forth in SEQ ID NO: 2, a HCDR3 set forth in SEQ ID NO: 3, a LCDR1 set forth in SEQ ID NO: 4, a LCDR2 set forth in SEQ ID NO: 5, and a LCDR3 set forth in SEQ ID NO: 6. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises HCDR1 set forth in SEQ ID NO: 11, HCDR2 set forth in SEQ ID NO: 12, HCDR3 set forth in SEQ ID NO: 13, LCDR1 set forth in SEQ ID NO: 14, LCDR2 set forth in SEQ ID NO: 15, and LCDR3 set forth in SEQ ID NO: 16. The CDR sequences of the anti-LAG-3 antibodies or antigen-binding fragments thereof are shown in Table A.

[0095] Table A. CDR sequences of anti-LAG-3 antibodies or antigen-binding fragments thereof

[0096] It will be understood by those skilled in the art that, unless otherwise specified, the term "CDR" or "complementarity determining region" of a given antibody or region thereof (e.g., variable region) should be understood to encompass complementarity determining regions defined by any known scheme. Although CDR regions are shown in Table A, when referring to antibodies defined by specific CDR sequences, the scope of the antibodies encompasses antibodies defined by CDR sequences defined by any numbering system (e.g., a combination of one or more of the AbM, Kabat, CCG, Chothia, IMGT, or Contact definitions known in the art).

[0097] In some embodiments, the heavy chain variable region of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the sequence set forth in SEQ ID NO: 7 or 17, or a sequence that is at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.99%, or 100%) identical to SEQ ID NO: 7 or 17. In some embodiments, the sequence of the heavy chain variable region of the anti-LAG-3 antibody or antigen-binding fragment thereof differs from SEQ ID NO: 7 or 17 in no more than 10 residues, optionally no more than 5, 4, or 3 residues, optionally wherein the different residues are conservative amino acid substitutions. In some embodiments, the heavy chain variable region of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the sequence set forth in SEQ ID NO:7, or a sequence at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.99%, or 100%) identical to SEQ ID NO:7. In some embodiments, the heavy chain variable region of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the sequence of SEQ ID NO: 17, or a sequence at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.99%, or 100%) identical to SEQ ID NO: 17.

[0098] In some embodiments, the light chain variable region of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the sequence set forth in SEQ ID NO: 8 or 18, or a sequence that is at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.99%, or 100%) identical to SEQ ID NO: 8 or 18. In some embodiments, the sequence of the light chain variable region of the anti-LAG-3 antibody or antigen-binding fragment thereof differs from SEQ ID NO: 8 or 18 in no more than 10, optionally no more than 5, 4, or 3 residues, optionally wherein the different residues are conservative amino acid substitutions. In some embodiments, the light chain variable region of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the sequence set forth in SEQ ID NO:8, or a sequence at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.99%, or 100%) identical to SEQ ID NO:8. In some embodiments, the light chain variable region of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the sequence of SEQ ID NO: 18, or a sequence at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.99%, or 100%) identical to SEQ ID NO: 18.

[0099] In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region set forth in SEQ ID NO: 7 or 17 and a light chain variable region set forth in SEQ ID NO: 8 or 18. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region set forth in SEQ ID NO: 7 and a light chain variable region set forth in SEQ ID NO: 8. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region set forth in SEQ ID NO: 17 and a light chain variable region set forth in SEQ ID NO: 18.

[0100] In some embodiments, the anti-LAG-3 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, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, wherein HCDR1 comprises the sequence of SEQ ID NO:1, HCDR2 comprises the sequence of SEQ ID NO:2, HCDR3 comprises the sequence of SEQ ID NO:3, LCDR1 comprises the sequence of SEQ ID NO:4, LCDR2 comprises the sequence of SEQ ID NO:5, and LCDR3 comprises the sequence of SEQ ID NO:6, and the heavy chain variable region comprises the sequence of SEQ ID NO:7. NO:7 having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.99% or 100%) identity, and the light chain variable region comprises a sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.99% or 100%) identity to SEQ ID NO:8.

[0101] In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof is an IgG1, IgG2, or IgG4 antibody or a variant thereof.

[0102] In some embodiments, the heavy chain of the anti-LAG-3 antibody, or antigen-binding fragment thereof, comprises the sequence set forth in SEQ ID NO: 9 or 19, or a sequence that is at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.99%, or 100%) identical to SEQ ID NO: 9 or 19. In some embodiments, the sequence of the heavy chain of the anti-LAG-3 antibody, or antigen-binding fragment thereof, differs from that of SEQ ID NO: 9 or 19 in no more than 10, optionally no more than 8, 7, 6, 5, 4, or 3 residues, optionally wherein the different residues are conservative amino acid substitutions. In some embodiments, the heavy chain of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the sequence set forth in SEQ ID NO:9, or a sequence at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.99%, or 100%) identical to SEQ ID NO:9. In some embodiments, the heavy chain of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the sequence set forth in SEQ ID NO: 19, or a sequence at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.99%, or 100%) identical to SEQ ID NO: 19. The terminal amino acid K of SEQ ID NOs: 9 and 19 may or may not be present.

[0103] In some embodiments, the light chain of the anti-LAG-3 antibody, or antigen-binding fragment thereof, comprises the sequence of SEQ ID NO: 10 or 20, or a sequence that is at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.99%, or 100%) identical to SEQ ID NO: 10 or 20. In some embodiments, the sequence of the light chain of the anti-LAG-3 antibody, or antigen-binding fragment thereof, differs from SEQ ID NO: 10 or 20 in no more than 10, optionally no more than 8, 7, 6, 5, 4, or 3 residues, optionally wherein the different residues are conservative amino acid substitutions. In some embodiments, the light chain of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the sequence of SEQ ID NO: 10, or a sequence at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.99%, or 100%) identical to SEQ ID NO: 10. In some embodiments, the light chain of the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the sequence of SEQ ID NO:20, or a sequence at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.99%, or 100%) identical to SEQ ID NO:20.

[0104] In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain set forth in SEQ ID NO: 9 or 19 and a light chain set forth in SEQ ID NO: 10 or 20. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain set forth in SEQ ID NO: 9 and a light chain set forth in SEQ ID NO: 10. In some embodiments, the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain set forth in SEQ ID NO: 19 and a light chain set forth in SEQ ID NO: 20. The terminal amino acid K in SEQ ID NOs: 9 and 19 may or may not be present.

[0105] The anti-LAG-3 antibody disclosed herein is a fully human anti-lymphocyte activation gene 3 (LAG-3) monoclonal antibody disclosed in Chinese invention patent application CN201780074499.2 (filing date: October 13, 2017). For the purposes of the present embodiments, the entire contents of Chinese invention patent application CN201780074499.2 are hereby incorporated by reference.

[0106] "Conservative substitutions" refer to amino acid changes that result in the replacement of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. In any embodiment of the present disclosure, in a preferred aspect, the conservative substitution residues are selected from the following conservative substitution table, optionally with the preferred substitution residues shown in Table B.

[0107] Table B. Conservative Substitution Table

[0108] Preparation method

[0109] The present disclosure also provides a method for preparing the pharmaceutical composition of the present disclosure, comprising the steps of: mixing the anti-LAG-3 antibody or antigen-binding fragment thereof, a buffer, a stabilizer, and a surfactant to prepare the pharmaceutical composition.

[0110] In some embodiments, the preparation method further comprises the step of sterilizing the mixture obtained by mixing. It is understood that the present disclosure does not particularly limit the sterilization method, and membrane filtration can be used but is not limited to it.

[0111] During the preparation process, there is no particular limitation on the mixing method and order of the components.

[0112] In some embodiments, the method for preparing a pharmaceutical composition of the present disclosure comprises: mixing the anti-LAG-3 antibody or antigen-binding fragment thereof, a buffer, and a stabilizer to prepare a mixture 1; and mixing the mixture 1 with a surfactant to prepare the pharmaceutical composition. Optionally, the step of preparing the mixture 1 comprises: replacing the anti-LAG-3 antibody or antigen-binding fragment thereof with the buffer and stabilizer by ultrafiltration, and optionally concentrating the mixture to prepare the mixture 1.

[0113] In some embodiments, the method for preparing a pharmaceutical composition of the present disclosure comprises: mixing the anti-LAG-3 antibody or antigen-binding fragment thereof and a buffer to prepare a mixture 1; and then mixing the mixture 1, the stabilizer, and the surfactant to prepare the pharmaceutical composition. Optionally, the step of preparing the mixture 1 comprises: replacing the anti-LAG-3 antibody or antigen-binding fragment thereof with the buffer by ultrafiltration, and optionally concentrating the mixture to prepare the mixture 1.

[0114] It is understood that the method for preparing the pharmaceutical composition of the present disclosure further includes the step of subpackaging the prepared pharmaceutical composition (for example, into vials).

[0115] Lyophilized preparations

[0116] The present disclosure also provides a lyophilized formulation, which is obtained by freeze-drying the pharmaceutical composition of the present disclosure. In some embodiments, the freeze-drying is carried out according to methods known in the art, including but not limited to the steps of pre-freezing, primary drying, and secondary drying. It will be understood by those skilled in the art that any method for removing water from the pharmaceutical composition of the present disclosure is applicable to the present disclosure.

[0117] The present disclosure also provides a lyophilized formulation, which can be reconstituted to form the pharmaceutical composition of the present disclosure. In some embodiments, the solution used for reconstitution includes but is not limited to water for injection, sodium chloride injection, Ringer's solution or glucose injection.

[0118] Products

[0119] The present disclosure also provides a product comprising the pharmaceutical composition or lyophilized formulation of the present disclosure. In some embodiments, the product of the present disclosure comprises a container containing the pharmaceutical composition or lyophilized formulation of the present disclosure.

[0120] The pharmaceutical composition or product disclosed herein can be stably stored for a long time at -80°C to room temperature.

[0121] In one embodiment, the pharmaceutical compositions or preparations of the present disclosure can be stably stored at about 2°C to about 8°C, e.g., stably stored for at least 24 months, e.g., stably stored for at least 10 days, at least 20 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, or longer at about 2°C, about 3°C, about 4°C, about 5°C, about 6°C, about 7°C, about 8°C.

[0122] In one embodiment, the pharmaceutical compositions or preparations of the present disclosure can be stably stored at 25° C., e.g., stably stored for at least 12 months (e.g., at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months).

[0123] In one embodiment, the pharmaceutical compositions or preparations of the present disclosure can be stably stored under light conditions, for example, stably stored for at least 1 month (e.g., at least 1 day, at least 3 days, at least 5 days, at least 9 days, at least 11 days, at least 13 days, at least 15 days, at least 17 days, at least 19 days, at least 21 days, at least 23 days, at least 25 days, at least 27 days, at least 29 days, at least 31 days).

[0124] In one embodiment, the pharmaceutical compositions or preparations of the present disclosure can be stably stored at 40° C., for example, stably stored for at least 1 month (e.g., at least 1 day, at least 3 days, at least 5 days, at least 9 days, at least 11 days, at least 13 days, at least 15 days, at least 17 days, at least 19 days, at least 21 days, at least 23 days, at least 25 days, at least 27 days, at least 29 days, at least 31 days).

[0125] In one embodiment, the pharmaceutical compositions or preparations of the present disclosure can be stably stored at 25° C. under shaking conditions, e.g., stably stored for at least 10 days (e.g., at least 1 day, at least 3 days, at least 5 days, at least 9 days, at least 10 days, at least 13 days, at least 15 days, at least 17 days, at least 19 days, at least 20 days, at least 23 days, at least 25 days, at least 27 days, at least 29 days, at least 31 days).

[0126] use

[0127] The present disclosure also provides a method for treating a disease in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition, lyophilized formulation, or product of the present disclosure. The present disclosure also provides use of the pharmaceutical composition, lyophilized formulation, or product of the present disclosure in the preparation of a medicament for treating a disease in a subject.

[0128] The present disclosure also provides a method for enhancing an immune response in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition, lyophilized formulation, or product of the present disclosure. The present disclosure also provides use of the pharmaceutical composition, lyophilized formulation, or product of the present disclosure in the preparation of a medicament for enhancing an immune response in a subject.

[0129] In some embodiments, the subject has cancer or an infectious disease. In some embodiments, the subject is at risk of developing cancer or an infectious disease.

[0130] The present disclosure also provides a method for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition, lyophilized formulation, or product of the present disclosure. The present disclosure also provides use of the pharmaceutical composition, lyophilized formulation, or product of the present disclosure in the preparation of a medicament for treating cancer in a subject.

[0131] The term "cancer" is the name for a disease in which the cells of the body become abnormal and divide without control. In some embodiments, the cancer is a relapsed, refractory, metastatic, and / or advanced cancer. In some embodiments, the cancer is a non-solid tumor. In some embodiments, the cancer is a blood tumor. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a leukemia (e.g., acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, HTLV-associated T-cell leukemia), lymphoma (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, small lymphocytic lymphoma, HTLV-associated T-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma), myeloma, melanoma, lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), bladder cancer, head Neck cancer (e.g., head and neck squamous cell carcinoma), ovarian cancer, oral cancer, esophageal cancer, gastroesophageal junction cancer, gastric cancer, colorectal cancer, renal cell carcinoma, Merkel cell carcinoma, sarcoma (e.g., fibrosarcoma), glioma, glioblastoma, meningeal cancer, liver cancer (e.g., hepatocellular carcinoma), nasopharyngeal cancer, prostate cancer, breast cancer, pancreatic cancer, endometrial cancer, biliary tract cancer, urinary system cancer, bone cancer, cervical cancer, thyroid cancer, anal cancer, gallbladder cancer, thymic cancer, MSI-high tumors, HPV and HIV-associated cancers.

[0132] The present disclosure also provides a method for treating an infectious disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition, lyophilized formulation, or product of the present disclosure. The present disclosure also provides the use of a pharmaceutical composition, lyophilized formulation, or product of the present disclosure in the preparation of a medicament for treating an infectious disease in a subject. In some embodiments, the infectious disease is caused by an organism such as bacteria, fungi, parasites, viruses, or other pathogens.

[0133] The pharmaceutical compositions, lyophilized formulations, or products disclosed herein can be administered according to methods known in the art. In some embodiments, the lyophilized formulation requires reconstitution prior to administration to obtain a reconstituted solution of the lyophilized formulation. In some embodiments, reconstitution can be performed with water for injection, sodium chloride injection, Ringer's solution, or dextrose injection.

[0134] In some embodiments, pharmaceutical compositions, lyophilized formulations or products of the present disclosure are suitable for parenteral administration. In some embodiments, pharmaceutical compositions, lyophilized formulations and products of the present disclosure are suitable for intravenous, intramuscular, intraperitoneal, subcutaneous, epidermal, spinal, intralesional injection or infusion. In some embodiments, pharmaceutical compositions, lyophilized formulations and products of the present disclosure are suitable for topical administration, inhalation, oral administration or administration by sustained release or delayed release delivery systems. In some embodiments, pharmaceutical compositions, lyophilized formulations, and the reconstituted solution of the lyophilized formulations of the present disclosure can be diluted with a suitable diluent before administration. In some embodiments, water for injection, sodium chloride injection, Ringer's solution or glucose injection can be diluted.

[0135] In some embodiments, the pharmaceutical compositions, lyophilized formulations or products of the present disclosure can be administered alone or in combination with other drugs, for example, they can be administered together with cancer therapeutic agents known in the art, such as immunostimulants, biotherapeutics, chemotherapeutics, anti-tumor agents, anti-angiogenic agents or radiation therapy.

[0136] The embodiments of the present disclosure will be described in detail below with reference to the examples. It should be understood that these examples are only used to illustrate the present disclosure and are not used to limit the scope of the present disclosure. For experimental methods in the following examples where specific conditions are not specified, reference should be made to the guidance given in this disclosure, and may also be made according to the experimental manuals or conventional conditions in this field, or according to the conditions recommended by the manufacturer, or with reference to experimental methods known in the art. In the following examples, the measurement parameters of the raw material components may have slight deviations within the range of weighing accuracy unless otherwise specified. For temperature and time parameters, acceptable deviations caused by instrument test accuracy or operating accuracy are allowed.

[0137] The present disclosure also provides the following specific embodiments, but the scope of the present disclosure is not limited thereto:

[0138] Embodiment 1. A pharmaceutical composition comprising an anti-LAG-3 antibody or antigen-binding fragment thereof, a buffer, a stabilizer, and a surfactant; wherein,

[0139] The anti-LAG-3 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, and HCDR3 in the heavy chain variable region of SEQ ID NO:7, and LCDR1, LCDR2, and LCDR3 in the light chain variable region of SEQ ID NO:8; or HCDR1, HCDR2, and HCDR3 in the heavy chain variable region of SEQ ID NO:17, and LCDR1, LCDR2, and LCDR3 in the light chain variable region of SEQ ID NO:18.

[0140] Embodiment 2. The pharmaceutical composition of embodiment 1, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof is present at a concentration of 1-50 mg / mL, 2-50 mg / mL, 5-40 mg / mL, 10-40 mg / mL, or 10-30 mg / mL.

[0141] Embodiment 3. The pharmaceutical composition of embodiment 2, wherein the concentration of the anti-LAG-3 antibody or antigen-binding fragment thereof is 10 mg / mL, 20 mg / mL, or 30 mg / mL.

[0142] Embodiment 4. The pharmaceutical composition according to any one of embodiments 1-3, wherein the buffer comprises a histidine buffer, an acetate buffer, a Tris buffer, a phosphate buffer, or a citrate buffer.

[0143] Embodiment 5. The pharmaceutical composition according to embodiment 4, wherein the buffer comprises an acetate buffer, preferably, the acetate buffer is a sodium acetate buffer.

[0144] Embodiment 6. The pharmaceutical composition according to any one of embodiments 1-5, wherein the concentration of the buffer is 1-150 mmol / L, 1-120 mmol / L, 2-100 mmol / L, 5-80 mmol / L, 10-60 mmol / L or 10-40 mmol / L.

[0145] Embodiment 7. The pharmaceutical composition of embodiment 6, wherein the concentration of the buffer is 10 mg / mL, 20 mg / mL, 30 mg / mL, or 40 mg / mL.

[0146] Embodiment 8. The pharmaceutical composition according to any one of embodiments 1-7, wherein the stabilizer comprises trehalose or proline.

[0147] Embodiment 9. The pharmaceutical composition of any one of embodiments 1-8, wherein the concentration of the stabilizer is 1-200 mg / mL, 5-100 mg / mL, 10-80 mg / mL, 15-60 mg / mL, 10-60 mg / mL, or 15-55 mg / mL.

[0148] Embodiment 10. The pharmaceutical composition of embodiment 9, wherein the concentration of the stabilizer is 20-55 mg / mL.

[0149] Embodiment 11. The pharmaceutical composition according to any one of embodiments 1-8, wherein the concentration of the stabilizer is 1-800 mmol / L, 10-600 mmol / L, 15-500 mmol / L, 20-400 mmol / L, 50-400 mmol / L, or 50-350 mmol / L.

[0150] Embodiment 12. The pharmaceutical composition according to embodiment 11, wherein the concentration of the stabilizer is 150-350 mmol / L.

[0151] Embodiment 13. The pharmaceutical composition according to any one of embodiments 1-12, wherein the surfactant comprises polysorbate, preferably, the surfactant comprises polysorbate 20 or polysorbate 80.

[0152] Embodiment 14. The pharmaceutical composition of any one of embodiments 1-13, wherein the concentration of the surfactant is 0.02-2 mg / mL, 0.04-1.5 mg / mL, 0.06-1 mg / mL, 0.08-0.8 mg / mL, 0.1-0.5 mg / mL, or 0.1-0.3 mg / mL.

[0153] Embodiment 15. The pharmaceutical composition of embodiment 14, wherein the concentration of the surfactant is 0.1 mg / mL, 0.2 mg / mL, or 0.3 mg / mL.

[0154] Embodiment 16. The pharmaceutical composition of any one of Embodiments 1-15, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the HCDR1 of SEQ ID NO: 1, the HCDR2 of SEQ ID NO: 2, the HCDR3 of SEQ ID NO: 3, the LCDR1 of SEQ ID NO: 4, the LCDR2 of SEQ ID NO: 5, and the LCDR3 of SEQ ID NO: 6; or the HCDR1 of SEQ ID NO: 11, the HCDR2 of SEQ ID NO: 12, the HCDR3 of SEQ ID NO: 13, the LCDR1 of SEQ ID NO: 14, the LCDR2 of SEQ ID NO: 15, and the LCDR3 of SEQ ID NO: 16.

[0155] Embodiment 17. The pharmaceutical composition of any one of Embodiments 1-16, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the heavy chain variable region set forth in SEQ ID NO:7 and the light chain variable region set forth in SEQ ID NO:8, or the heavy chain variable region set forth in SEQ ID NO:17 and the light chain variable region set forth in SEQ ID NO:18.

[0156] Embodiment 18. The pharmaceutical composition of any one of Embodiments 1-17, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the heavy chain of SEQ ID NO: 9 and the light chain of SEQ ID NO: 10, or the heavy chain of SEQ ID NO: 19 and the light chain of SEQ ID NO: 20.

[0157] Embodiment 19. The pharmaceutical composition of any one of Embodiments 1-18, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises HCDR1 set forth in SEQ ID NO: 1, HCDR2 set forth in SEQ ID NO: 2, HCDR3 set forth in SEQ ID NO: 3, LCDR1 set forth in SEQ ID NO: 4, LCDR2 set forth in SEQ ID NO: 5, and LCDR3 set forth in SEQ ID NO: 6.

[0158] Embodiment 20. The pharmaceutical composition of any one of embodiments 1-19, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region set forth in SEQ ID NO: 7 and a light chain variable region set forth in SEQ ID NO: 8.

[0159] Embodiment 21. The pharmaceutical composition of any one of Embodiments 1-20, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises the heavy chain shown in SEQ ID NO: 9 and the light chain shown in SEQ ID NO: 10.

[0160] Embodiment 22. A pharmaceutical composition according to any one of embodiments 1-21, wherein the pharmaceutical composition comprises: (a) 1-50 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 1-150 mmol / L buffer, (c) stabilizer, and (d) 0.02-2 mg / mL surfactant, and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.8.

[0161] Embodiment 23. A pharmaceutical composition according to any one of embodiments 1-22, wherein the pharmaceutical composition comprises: (a) 1-50 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 1-150 mmol / L acetate buffer or citrate buffer, (c) a stabilizer comprising trehalose or proline, and (d) 0.02-2 mg / mL polysorbate 80 or polysorbate 20, and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.8.

[0162] Embodiment 24. A pharmaceutical composition according to any one of embodiments 1-23, wherein the pharmaceutical composition comprises: (a) 1-50 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 1-150 mmol / L acetate buffer, (c) a stabilizer comprising 1-200 mg / mL trehalose or 1-800 mmol / L proline, and (d) 0.02-2 mg / mL polysorbate 20, and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.8.

[0163] Embodiment 25. A pharmaceutical composition according to any one of embodiments 1-24, wherein the pharmaceutical composition comprises: (a) 20 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 20 mmol / L sodium acetate buffer, (c) 50 mg / mL trehalose or 300 mmol / L proline, and (d) 0.2 mg / mL polysorbate 20, and the pH of the pharmaceutical composition is 5-6, 5.2-5.8 or 5.5-5.8; optionally, the pH of the pharmaceutical composition is 5.5.

[0164] Embodiment 26. A pharmaceutical composition according to any one of embodiments 1-25, wherein the pharmaceutical composition comprises: (a) 20 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 20 mmol / L sodium acetate buffer, (c) 50 mg / mL trehalose, and (d) 0.2 mg / mL polysorbate 20, and the pH of the pharmaceutical composition is 5.5-5.8; optionally, the pH of the pharmaceutical composition is 5.5.

[0165] Embodiment 27. A pharmaceutical composition according to any one of embodiments 1-25, wherein the pharmaceutical composition comprises: (a) 20 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 20 mmol / L sodium acetate buffer, (c) 300 mmol / L proline, and (d) 0.2 mg / mL polysorbate 20, and the pH of the pharmaceutical composition is 5.5-5.8; optionally, the pH of the pharmaceutical composition is 5.5.

[0166] Embodiment 28. A lyophilized preparation, wherein the lyophilized preparation is obtained by freeze-drying the pharmaceutical composition according to any one of embodiments 1-27, or the lyophilized preparation can form the pharmaceutical composition according to any one of embodiments 1-27 after reconstitution.

[0167] Embodiment 29. A product, wherein the product comprises the pharmaceutical composition of any one of embodiments 1-27 or the lyophilized formulation of embodiment 28.

[0168] Embodiment 30. Use of the pharmaceutical composition of any one of Embodiments 1-27, the lyophilized formulation of Embodiment 28, or the preparation of Embodiment 29 in the preparation of a medicament for treating cancer.

[0169] Embodiment 31. The use according to embodiment 30, wherein the cancer is a hematological tumor or a solid tumor.

[0170] Embodiment 32. The use according to embodiment 30 or 31, wherein the cancer is recurrent, refractory, metastatic and / or advanced cancer.

[0171] Embodiment 33. The use according to any one of embodiments 30-32, wherein the cancer is leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, myeloma, melanoma, non-small cell lung cancer, small cell lung cancer, bladder cancer, head and neck cancer, ovarian cancer, oral cancer, esophageal cancer, gastroesophageal junction cancer, gastric cancer, colorectal cancer, renal cell carcinoma, Merkel cell carcinoma, sarcoma, glioma, glioblastoma, meningeal cancer, hepatocellular carcinoma, nasopharyngeal cancer, prostate cancer, breast cancer, pancreatic cancer, endometrial cancer, biliary tract cancer, urinary system cancer, bone cancer, cervical cancer, thyroid cancer, anal cancer, gallbladder cancer, thymic cancer, MSI-high tumors or HPV and HIV-related cancers.

[0172] Embodiment 34. The use according to any one of embodiments 30-33, wherein the pharmaceutical composition is for parenteral administration.

[0173] Embodiment 35. The use according to any one of embodiments 30-34, wherein the pharmaceutical composition is administered together with a cancer therapeutic agent.

[0174] Embodiment 36. The use according to embodiment 35, wherein the cancer therapeutic agent comprises an immunostimulatory agent, a biotherapeutic agent, a chemotherapeutic agent, an anti-tumor agent, an anti-angiogenic agent, or radiation therapy.

[0175] Example

[0176] CHO cells were transfected with a vector containing the gene encoding the heavy chain (SEQ ID NO: 9) and the light chain (SEQ ID NO: 10) of an anti-LAG-3 antibody. The CHO cells were cultured, and the cell culture supernatant was purified by a standard purification method to obtain the anti-LAG-3 antibody described in the following examples, which has the heavy chain variable region set forth in SEQ ID NO: 7 and the light chain variable region set forth in SEQ ID NO: 8.

[0177] The English codes and corresponding abbreviations in the following embodiments are as follows: SEC-HPLC is size exclusion high performance liquid chromatography; CGE is capillary gel electrophoresis; iCIEF is whole-column imaging capillary isoelectric focusing; CIEX is cation exchange chromatography; MFI is microfluidic imaging; kDa is kilodaltons; A2 is the second virial coefficient.

[0178] Example 1

[0179] A pharmaceutical composition comprising an anti-LAG-3 antibody and a buffer was prepared according to Table 1. The preparation steps included replacing the anti-LAG-3 antibody into the buffer by ultrafiltration to a final concentration of 20 mg / mL. After uniform mixing, the composition was sterilized by filtration through a 0.22 μm filter membrane, and dispensed into vials, which were stoppered and capped.

[0180] The second virial coefficient (A2) of the pharmaceutical compositions was determined using the CG-MALS method developed by ProJect Pharmaceutics. Pharmaceutical compositions with higher A2 values ​​were screened out (A2 < 0 indicates mutual attraction between molecules, and A2 > 0 indicates mutual repulsion between molecules). The A2 value test results are shown in Table 2.

[0181] Table 1. Composition of the pharmaceutical composition

[0182] Table 2. Test results

[0183] The results showed that when the concentration of anti-LAG-3 antibody was 20 mg / mL, the A2 value in the pharmaceutical composition containing citrate buffer (corresponding to F2 and F3) was the lowest, indicating that the attractive force between proteins was dominant, which was not conducive to the stability of the anti-LAG-3 antibody; the A2 value in the pharmaceutical composition containing acetate buffer (corresponding to F1) was higher, indicating that the repulsive force between proteins was dominant, which was conducive to the stability of the anti-LAG-3 antibody.

[0184] Example 2

[0185] A pharmaceutical composition comprising an anti-LAG-3 antibody, a buffer, and a stabilizer was prepared according to Table 3. The preparation steps included: replacing the anti-LAG-3 antibody into the buffer and stabilizer by ultrafiltration to a final concentration of 20 mg / mL; mixing thoroughly; and sterilizing by filtration through a 0.22 μm filter membrane. The composition was then dispensed into vials and capped.

[0186] The CG-MALS method of ProJect Pharmaceutics was used to determine the second virial coefficient (A2) values ​​of the pharmaceutical compositions, and pharmaceutical compositions with higher second virial coefficient (A2) values ​​were screened out (A2 < 0 indicates mutual attraction between molecules, and A2 > 0 indicates mutual repulsion between molecules). The A2 value test results are shown in Table 4.

[0187] Table 3. Composition of the pharmaceutical composition

[0188] Table 4. Test results

[0189] The results showed that in 20 mmol / L acetate buffer (pH 5.5), the A2 values ​​of the pharmaceutical compositions containing sodium chloride (corresponding to F1a-b1, F1a-b4, F1a-b5 and F1a-b8) were all <0, and the attraction between proteins was dominant, indicating that sodium chloride was not conducive to the stability of anti-LAG-3 antibodies; the A2 values ​​of the pharmaceutical compositions containing 2-5% (w / v) trehalose (corresponding to F1a-b2 and F1a-b3) and the pharmaceutical compositions containing 150-300 mmol / L proline (corresponding to F1a-b6 and F1a-b7) were higher, and the repulsion between proteins was dominant, indicating that trehalose and proline were conducive to the stability of anti-LAG-3 antibodies.

[0190] Example 3

[0191] A pharmaceutical composition comprising an anti-LAG-3 antibody, a buffer, a stabilizer, and a surfactant was prepared according to Table 5. The preparation steps included: replacing the anti-LAG-3 antibody into the buffer and stabilizer by ultrafiltration, concentrating the mixture after the replacement, and then adding polysorbate 20 according to Table 5 to a final concentration of 20 mg / mL of the anti-LAG-3 antibody. After uniform mixing, the mixture was sterilized by filtration through a 0.22 μm filter membrane, and dispensed into vials, which were stoppered and capped.

[0192] Pharmaceutical composition samples were frozen at -80°C for at least 1 hour and then thawed at room temperature in the dark until completely thawed. This constituted one cycle. Freeze-thaw cycle samples were prepared after 0, 3, and 6 freeze-thaw cycles to assess freeze-thaw cycle (FT) stability. After freeze-thaw cycles, the pharmaceutical compositions were tested for SEC-HPLC, non-reducing CGE, iCIEF, and MFI. Specific data are shown in Tables 6.1 and 6.2.

[0193] Table 5. Composition of the pharmaceutical composition

[0194] Note: “-” means none.

[0195] Table 6.1. Test results I

[0196] Note: “-” means not tested.

[0197] Table 6.2. Test results II

[0198] Note: “-” means not tested.

[0199] The results showed that after freeze-thaw cycles, there was no significant change in the visible foreign matter, anti-LAG-3 antibody content, non-reduced CGE and iCIEF results in all pharmaceutical compositions; SEC-HPLC test results showed that the pharmaceutical compositions without any stabilizer (corresponding to F1a and F1a-c1) had the largest increase in high molecular weight impurities; compared with the pharmaceutical compositions without polysorbate 20 (corresponding to F1a, F1a-b3 and F1a-b7), the number of insoluble particles (2-100 μm) in the pharmaceutical compositions containing polysorbate 20 (corresponding to F1a-c1, F1a-b3-c1 and F1a-b7-c1) was significantly reduced; compared with the pharmaceutical composition containing only polysorbate 20 (corresponding to F1a-c1), the number of insoluble particles (2-100 μm) in the pharmaceutical compositions containing trehalose or proline (corresponding to F1a-b3-c1 and F1a-b7-c1) was significantly reduced.

[0200] Example 4

[0201] A pharmaceutical composition comprising an anti-LAG-3 antibody, a buffer, a stabilizer, and a surfactant was prepared according to Table 7. The preparation steps included: replacing the anti-LAG-3 antibody into the buffer and stabilizer by ultrafiltration, concentrating the composition after the replacement, and then adding polysorbate 20 according to Table 7 to a final concentration of 20 mg / mL of the anti-LAG-3 antibody. After uniform mixing, the composition was sterilized by filtration through a 0.22 μm filter membrane, and dispensed into vials, which were stoppered and capped.

[0202] The stability at -80°C was used as a control to investigate the long-term stability at 2-8°C, the accelerated stability at 20-25°C, and the light stability. The shaking stability at 25°C was also investigated.

[0203] Table 7. Composition of the pharmaceutical composition

[0204] The pharmaceutical compositions F1a-b3-c1 and F1a-b7-c1 were subjected to long-term 2-8°C, accelerated 25°C and light stability tests. The results are shown in Figures 1, 2, 3, 4, 5, 6, 7 and 8.

[0205] (1) Long-term stability study at 2-8℃

[0206] The pharmaceutical compositions F1a-b3-c1 and F1a-b7-c1 were stored at 2-8°C for 24 months. The SEC-HPLC, non-reducing CGE, and CIEX results are shown in Figures 1 to 3, respectively.

[0207] Results showed no significant changes or differences in pH, anti-LAG-3 antibody concentration, osmolarity, or SEC-HPLC results between F1a-b3-c1 and F1a-b7-c1. Non-reducing CGE analysis revealed a slight decrease in monomer content during storage for both F1a-b3-c1 and F1a-b7-c1, with no significant differences between the two pharmaceutical compositions. CIEX analysis revealed a slight decrease in monomer content and an increase in basic peaks for both F1a-b3-c1 and F1a-b7-c1 during storage, with no significant differences between the two pharmaceutical compositions. Long-term stability studies at 2-8°C demonstrated that pharmaceutical compositions F1a-b3-c1 and F1a-b7-c1 remained stable for at least 24 months at 2-8°C.

[0208] (2) Accelerated stability test at 25°C

[0209] The pharmaceutical compositions F1a-b3-c1 and F1a-b7-c1 were stored at 25±2°C for 12 months. The SEC-HPLC, non-reducing CGE, and CIEX results are shown in Figures 4 to 6, respectively.

[0210] The results showed that there were no significant changes or differences in the pH value, anti-LAG-3 antibody concentration, osmotic pressure molar concentration and other results of F1a-b3-c1 and F1a-b7-c1; SEC-HPLC determination showed that the main peak content of F1a-b3-c1 and F1a-b7-c1 decreased during storage, and F1a-b7-c1 was slightly better than F1a-b3-c1; non-reducing CGE determination showed that the monomer content of F1a-b3-c1 and F1a-b7-c1 decreased during storage, and F1a-b3-c1 was slightly better than F1a-b7-c1; CIEX determination showed that the monomer content of F1a-b3-c1 and F1a-b7-c1 decreased during storage, and there was no significant difference between the two pharmaceutical compositions.

[0211] (3) Light stability study

[0212] Pharmaceutical compositions F1a-b3-c1 and F1a-b7-c1 were irradiated at room temperature for one month. The SEC-HPLC and non-reducing CGE results are shown in Figures 7 and 8, respectively.

[0213] The results showed that: by visual inspection, F1a-b3-c1 and F1a-b7-c1 were both yellow clear solutions, and there was no difference between the two pharmaceutical compositions; by SEC-HPLC, the main peak content of F1a-b3-c1 and F1a-b7-c1 was reduced, and F1a-b3-c1 was superior to F1a-b7-c1; by non-reducing CGE determination, the monomer content of F1a-b3-c1 and F1a-b7-c1 was reduced, F1a-b3-c1 is superior to F1a-b7-c1; peptide mapping analysis of the irradiated pharmaceutical compositions showed that compared with the unirradiated pharmaceutical compositions, the deamidation of the anti-LAG-3 antibodies in F1a-b3-c1 and F1a-b7-c1 did not increase, while the M (methionine), H (histidine), and W (tryptophan) oxidation sites of the anti-LAG-3 antibodies increased significantly, among which the oxidation of F1a-b3-c1 was lower than that of F1a-b7-c1.

[0214] (4) Shaking stability test at 25℃

[0215] The pharmaceutical composition F1a-b3-c1 was shaken at 250 rpm at 25±2°C for 10 days. The results showed that there were no significant changes or differences in the pH value, anti-LAG-3 antibody concentration, SEC-HPLC results, and other results of F1a-b3-c1. F1a-b3-c1 was stable at 25±2°C and 250 rpm (see Table 8).

[0216] Table 8. Test results

[0217] Example 5

[0218] The pharmaceutical composition provided in this embodiment is shown in Table 9 below. The preparation method refers to Example 4, and the long-term stability at 2-8°C, accelerated stability at 20-25°C, light stability, and shaking stability at 25°C were investigated.

[0219] Table 9. Composition of the pharmaceutical composition

[0220] Example 6

[0221] The pharmaceutical composition provided in this embodiment is shown in Table 10 below. The preparation method refers to Example 4, and the long-term stability at 2-8°C, accelerated stability at 20-25°C, light stability, and shaking stability at 25°C were examined.

[0222] Table 10. Composition of the pharmaceutical composition

[0223] The various technical features of the above-mentioned implementation modes and examples can be combined in any appropriate manner. In order to make the description concise, not all possible combinations of the various technical features in the above-mentioned implementation modes and examples are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of the description in this specification.

[0224] The embodiments described above only express several implementation methods of the present disclosure, which are convenient for understanding the technical solutions of the present disclosure in a specific and detailed manner, but they cannot be understood as limiting the scope of protection of the disclosed patent. It should be pointed out that for ordinary technicians in this field, without departing from the concept of the present disclosure, several variations and improvements can be made, which all fall within the scope of protection of the present disclosure. In addition, it should be understood that after reading the above teaching content of the present disclosure, those skilled in the art can make various changes or modifications to the present disclosure, and the equivalent forms obtained also fall within the scope of protection of the present disclosure. It should also be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided by the present disclosure are all within the scope of protection of the claims attached to the present disclosure. Therefore, the scope of protection of the patent disclosed herein shall be based on the content of the attached claims, and the description and drawings can be used to explain the content of the claims.

Claims

1. A pharmaceutical composition, wherein the pharmaceutical composition comprises an anti-LAG-3 antibody or an antigen-binding fragment thereof, a buffer, a stabilizer and a surfactant; wherein, The anti-LAG-3 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2 and HCDR3 in the heavy chain variable region of SEQ ID NO:7, and LCDR1, LCDR2 and LCDR3 in the light chain variable region of SEQ ID NO:8; or HCDR1, HCDR2 and HCDR3 in the heavy chain variable region of SEQ ID NO:17, and LCDR1, LCDR2 and LCDR3 in the light chain variable region of SEQ ID NO:

18.

2. The pharmaceutical composition of claim 1, wherein the concentration of the anti-LAG-3 antibody or antigen-binding fragment thereof is 1-50 mg / mL, 2-50 mg / mL, 5-40 mg / mL, 10-40 mg / mL or 10-30 mg / mL.

3. The pharmaceutical composition of claim 2, wherein the concentration of the anti-LAG-3 antibody or antigen-binding fragment thereof is 10 mg / mL, 20 mg / mL, or 30 mg / mL.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the buffer comprises a histidine buffer, an acetate buffer, a Tris buffer, a phosphate buffer or a citrate buffer.

5. The pharmaceutical composition according to claim 4, wherein the buffer comprises an acetate buffer, preferably, the acetate buffer is a sodium acetate buffer.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the concentration of the buffer is 1-150 mmol / L, 1-120 mmol / L, 2-100 mmol / L, 5-80 mmol / L, 10-60 mmol / L or 10-40 mmol / L.

7. The pharmaceutical composition of claim 6, wherein the concentration of the buffer is 10 mg / mL, 20 mg / mL, 30 mg / mL, or 40 mg / mL.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the stabilizer comprises trehalose or proline.

9. The pharmaceutical composition according to any one of claims 1-8, wherein the concentration of the stabilizer is 1-200 mg / mL, 5-100 mg / mL, 10-80 mg / mL, 15-60 mg / mL, 10-60 mg / mL, or 15-55 mg / mL.

10. The pharmaceutical composition according to claim 9, wherein the concentration of the stabilizer is 20-55 mg / mL.

11. The pharmaceutical composition according to any one of claims 1-8, wherein the concentration of the stabilizer is 1-800 mmol / L, 10-600 mmol / L, 15-500 mmol / L, 20-400 mmol / L, 50-400 mmol / L, or 50-350 mmol / L.

12. The pharmaceutical composition according to claim 11, wherein the concentration of the stabilizer is 150-350 mmol / L.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the surfactant comprises polysorbate, preferably, the surfactant comprises polysorbate 20 or polysorbate 80.

14. The pharmaceutical composition according to any one of claims 1-13, wherein the concentration of the surfactant is 0.02-2 mg / mL, 0.04-1.5 mg / mL, 0.06-1 mg / mL, 0.08-0.8 mg / mL, 0.1-0.5 mg / mL, or 0.1-0.3 mg / mL.

15. The pharmaceutical composition according to claim 14, wherein the concentration of the surfactant is 0.1 mg / mL, 0.2 mg / mL or 0.3 mg / mL.

16. The pharmaceutical composition of any one of claims 1-15, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2, HCDR3 shown in SEQ ID NO: 3, LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6; or HCDR1 shown in SEQ ID NO: 11, HCDR2 shown in SEQ ID NO: 12, HCDR3 shown in SEQ ID NO: 13, LCDR1 shown in SEQ ID NO: 14, LCDR2 shown in SEQ ID NO: 15, and LCDR3 shown in SEQ ID NO:

16.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region set forth in SEQ ID NO:7 and a light chain variable region set forth in SEQ ID NO:8, or a heavy chain variable region set forth in SEQ ID NO:17 and a light chain variable region set forth in SEQ ID NO:

18.

18. The pharmaceutical composition of any one of claims 1-17, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain as shown in SEQ ID NO: 9 and a light chain as shown in SEQ ID NO: 10, or a heavy chain as shown in SEQ ID NO: 19 and a light chain as shown in SEQ ID NO:

20.

19. The pharmaceutical composition of any one of claims 1-18, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2, HCDR3 shown in SEQ ID NO: 3, LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO:

6.

20. The pharmaceutical composition of any one of claims 1-19, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region shown in SEQ ID NO:7 and a light chain variable region shown in SEQ ID NO:

8.

21. The pharmaceutical composition of any one of claims 1-20, wherein the anti-LAG-3 antibody or antigen-binding fragment thereof comprises a heavy chain as shown in SEQ ID NO:9 and a light chain as shown in SEQ ID NO:

10.

22. The pharmaceutical composition of any one of claims 1-21, wherein the pharmaceutical composition comprises: (a) 1-50 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 1-150 mmol / L buffer, (c) stabilizer, and (d) 0.02-2 mg / mL surfactant, and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.

8.

23. The pharmaceutical composition of any one of claims 1-22, wherein the pharmaceutical composition comprises: (a) 1-50 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 1-150 mmol / L acetate buffer or citrate buffer, (c) a stabilizer comprising trehalose or proline, and (d) 0.02-2 mg / mL polysorbate 80 or polysorbate 20, and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.

8.

24. The pharmaceutical composition of any one of claims 1-23, wherein the pharmaceutical composition comprises: (a) 1-50 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 1-150 mmol / L acetate buffer, (c) a stabilizer comprising 1-200 mg / mL trehalose or 1-800 mmol / L proline, and (d) 0.02-2 mg / mL polysorbate 20, and the pH of the pharmaceutical composition is 5-7, 5-6.5, 5-6, 5.2-5.8, or 5.5-5.

8.

25. The pharmaceutical composition according to any one of claims 1-24, wherein the pharmaceutical composition comprises: (a) 20 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 20 mmol / L sodium acetate buffer, (c) 50 mg / mL trehalose or 300 mmol / L proline, and (d) 0.2 mg / mL polysorbate 20, and the pH of the pharmaceutical composition is 5-6, 5.2-5.8 or 5.5-5.8; optionally, the pH of the pharmaceutical composition is 5.

5.

26. The pharmaceutical composition according to any one of claims 1-25, wherein the pharmaceutical composition comprises: (a) 20 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 20 mmol / L sodium acetate buffer, (c) 50 mg / mL trehalose, and (d) 0.2 mg / mL polysorbate 20, and the pH of the pharmaceutical composition is 5.5-5.8; optionally, the pH of the pharmaceutical composition is 5.

5.

27. The pharmaceutical composition according to any one of claims 1-25, wherein the pharmaceutical composition comprises: (a) 20 mg / mL anti-LAG-3 antibody or antigen-binding fragment thereof, (b) 20 mmol / L sodium acetate buffer, (c) 300 mmol / L proline, and (d) 0.2 mg / mL polysorbate 20, and the pH of the pharmaceutical composition is 5.5-5.8; optionally, the pH of the pharmaceutical composition is 5.

5.

28. A lyophilized preparation, wherein the lyophilized preparation is obtained by freeze-drying the pharmaceutical composition according to any one of claims 1 to 27, or the lyophilized preparation can form the pharmaceutical composition according to any one of claims 1 to 27 after being reconstituted.

29. A product, wherein the product comprises the pharmaceutical composition according to any one of claims 1 to 27 or the lyophilized preparation according to claim 28.

30. Use of the pharmaceutical composition of any one of claims 1 to 27, the lyophilized preparation of claim 28 or the preparation of claim 29 in the preparation of a medicament for treating cancer.

31. The use according to claim 30, wherein the cancer is a hematological tumor or a solid tumor.

32. The use according to claim 30 or 31, wherein the cancer is a relapsed, refractory, metastatic and / or advanced cancer.

33. The use according to any one of claims 30-32, wherein the cancer is leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myeloma, melanoma, non-small cell lung cancer, small cell lung cancer, bladder cancer, head and neck cancer, ovarian cancer, oral cancer, esophageal cancer, gastroesophageal junction cancer, gastric cancer, colorectal cancer, renal cell carcinoma, Merkel cell carcinoma, sarcoma, glioma, glioblastoma, meningeal cancer, hepatocellular carcinoma, nasopharyngeal cancer, prostate cancer, breast cancer, pancreatic cancer, endometrial cancer, biliary tract cancer, urinary system cancer, bone cancer, cervical cancer, thyroid cancer, anal cancer, gallbladder cancer, thymic cancer, MSI-high tumors or HPV and HIV-related cancers.

34. The use according to any one of claims 30 to 33, wherein the pharmaceutical composition is for parenteral administration.

35. The use according to any one of claims 30-34, wherein the pharmaceutical composition is administered together with a cancer therapeutic agent.

36. The use according to claim 35, wherein the cancer therapeutic agent comprises an immunostimulant, a biotherapeutic agent, a chemotherapeutic agent, an anti-tumor agent, an anti-angiogenic agent or radiation therapy.

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