Pharmaceutical composition comprising Anti-PD-1 antibody and second antibody

Abstract

The present invention belongs to the field of biomedicine, and relates to a pharmaceutical composition comprising an anti-PD-1 antibody and a second antibody, wherein the second antibody is an anti-TIM-3 antibody. In addition, the present invention also relates to a preparation method for the pharmaceutical composition and the use of the pharmaceutical composition in the preparation of a medicine for treating diseases in a subject.

Description

Pharmaceutical composition comprising an anti-PD-1 antibody and a second antibody Technical Field

[0001] The present disclosure belongs to the field of biomedicine, and specifically relates to a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof and a second antibody or an antigen-binding fragment thereof, and uses thereof. Background Art

[0002] PD-1 (Programmed death-1) is primarily expressed by activated T and B lymphocytes, and its ligands include PD-L1 and PD-L2. Binding of PD-1 to its ligand inhibits T cell activation and proliferation, downregulating the secretion of T cell immunostimulatory cytokines, thereby suppressing T cell immune responses and promoting T cell apoptosis. PD-1 is highly expressed on tumor-infiltrating lymphocytes, and its ligand is also upregulated on the surface of various tumor cells. Therefore, anti-PD-1 antibodies, by blocking the binding of PD-1 to its ligand, can interrupt the immunosuppressive signaling pathway and enhance the body's endogenous anti-tumor immune response.

[0003] T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), also known as hepatitis A virus cellular receptor 2 (HAVCR2), is a member of the TIM family of immunoregulatory proteins. TIM-3 is selectively expressed on the surface of activated Th1 cells and is also expressed on myeloid cells, dendritic cells, natural killer (NK) cells, macrophages, and a variety of tumor cells. TIM-3 has multiple ligands, including galectin 9, phosphatidylserine (PtdSer), high mobility group box 1 (HMGB1), and carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1). TIM-3 negatively regulates the body's immune response, preventing damage from excessive immune or autoimmune responses. However, multiple lines of evidence indicate that TIM-3 protein and / or mRNA expression is upregulated in various tumor tissues and tumor-associated immune cells, participating in tumor immune escape and immune responses, and promoting tumor progression.

[0004] Anti-PD-1 antibodies can be administered in combination with anti-TIM-3 antibodies, but administration of both antibodies requires multiple doses at different time points. Therefore, a single formulation containing both antibodies will improve patient convenience and reduce drug resistance. Because each antibody has unique physical and chemical properties, such as surface-exposed residues, breakable sites, glycation sites, deamidation sites, surface charge distribution, isoelectric point, aggregation tendency, solubility, etc., unique formulation excipients are required to maintain the stability of each antibody, making it difficult to determine a single formulation.

[0005] SUMMARY OF THE INVENTION

[0006] The present disclosure provides a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof and a second antibody or an antigen-binding fragment thereof. In some embodiments, the second antibody or an antigen-binding fragment thereof is an anti-TIM-3 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-PD-1 antibody or an antigen-binding fragment thereof and the anti-TIM-3 antibody or an antigen-binding fragment thereof are present in the pharmaceutical composition at a fixed dose ratio.

[0007] In some embodiments, the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:1-30, 1:1-20, 1:1-18, 1:1-15, 1:1-12, 1:1-10, 1:1-9, 1:1-7.5, 1:1-6, 1:1-5, 1:1-4.5, 1:1-3, 1:1-2 or 1:1-1.5.

[0008] The present disclosure also provides a lyophilized preparation, wherein the lyophilized preparation is obtained by freeze-drying the pharmaceutical composition of the present disclosure.

[0009] The present disclosure also provides a lyophilized preparation, wherein the lyophilized preparation can form the pharmaceutical composition of the present disclosure after reconstitution.

[0010] The present disclosure also provides a medicine kit, wherein the medicine kit comprises the pharmaceutical composition of the present disclosure. The present disclosure also provides a vial, wherein the vial comprises the pharmaceutical composition of the present disclosure.

[0011] The present disclosure also provides a syringe, wherein the syringe comprises the pharmaceutical composition of the present disclosure. The present disclosure also provides an intravenous bag, wherein the intravenous bag comprises the pharmaceutical composition of the present disclosure.

[0012] The present disclosure also provides a method for preparing the pharmaceutical composition and lyophilized formulation of the present disclosure.

[0013] The present disclosure also provides a method for treating a disease in a subject, the method comprising administering to the subject a pharmaceutical composition or lyophilized formulation of the present disclosure. The present disclosure also provides a method for treating a disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or lyophilized formulation of the present disclosure. In some embodiments, the disease includes cancer and infectious diseases.

[0014] The present disclosure also provides a method for enhancing an immune response in a subject, the method comprising administering to the subject a pharmaceutical composition or lyophilized formulation of the present disclosure. The present disclosure also provides a method for enhancing an immune response in a subject, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition or lyophilized formulation of the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] FIG1 shows an ELISA assay for the binding of h50B5 to CHO-S-HuTIM-3 cells that highly express human TIM-3;

[0016] FIG2 shows the promoting effect of h50B5 on IFN-γ secretion in MLR;

[0017] FIG3 shows the blood drug concentration curve of h50B5 after a single intravenous injection in the HCC827 lung cancer human immune reconstitution mouse (PBMC-NCG) subcutaneous transplant tumor model.

[0018] Detailed Description of the Invention

[0019] Explanation of terms

[0020] In order to make the present disclosure more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise explicitly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the present disclosure belongs.

[0021] The term "buffer" refers to a pharmaceutically acceptable buffer, and refers to a substance that helps maintain the pH of a pharmaceutical composition within a desired pH range. Buffers suitable for use in the present disclosure include phosphate buffers, acetate buffers, citrate buffers, Tris buffers, or histidine buffers. Furthermore, mixtures of two or more buffers may also be used. Preferably, the buffer suitable for use in the present disclosure is a histidine buffer.

[0022] The term "phosphate buffer" refers to a buffer containing phosphate ions. Examples of phosphate buffers include sodium phosphate buffers, potassium phosphate buffers, and the like. 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).

[0023] The term "acetate buffer" refers to a buffer containing acetate ions. Examples of acetate buffers include potassium acetate buffer, ammonium acetate buffer, sodium acetate buffer, and the like. Sodium acetate buffer can be prepared using acetic acid and sodium acetate or a hydrate thereof (e.g., anhydrous sodium acetate or sodium acetate trihydrate).

[0024] The term "citrate buffer" refers to a buffer containing citrate ions. Examples of citrate buffers include sodium citrate buffer, potassium citrate buffer, calcium citrate buffer, and the like. Sodium citrate buffer can be prepared using citric acid and sodium citrate or a hydrate thereof (e.g., trisodium citrate dihydrate).

[0025] The term "histidine buffer" is a buffer comprising histidine ions. Examples of histidine buffers include histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, histidine-acetate buffer, histidine-phosphate buffer, etc. Histidine-histidine hydrochloride buffer can be prepared using histidine (e.g., L-histidine) and histidine hydrochloride or its hydrate (e.g., histidine hydrochloride monohydrate), or using histidine hydrochloride or its hydrate (e.g., histidine hydrochloride monohydrate). Histidine-hydrochloride buffer can be prepared using histidine (e.g., L-histidine) and further adjusted with hydrochloric acid to pH. Histidine-acetate buffer can be prepared using histidine (e.g., L-histidine) and further adjusted with acetic acid to pH. Histidine-phosphate buffer can be prepared using histidine (e.g., L-histidine) and further adjusted with phosphoric acid to pH.

[0026] 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.

[0027] The term "antioxidant" refers to a substance that can prevent, slow down or reduce the oxidation of an active ingredient (eg, an antibody) in a pharmaceutical composition.

[0028] The term "isotonic agent" refers to a substance that helps maintain the osmotic pressure of a pharmaceutical composition at or near physiological osmotic pressure.

[0029] The term "excipient" refers to any ingredient other than the active ingredient. The choice of excipient will depend, to a large extent, on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. As used herein, "pharmaceutically acceptable excipients" include, but are not limited to, excipients, diluents, fillers, binders, chelating agents, disintegrants, solubilizers, stabilizers, colorants, flavorings, surfactants, emulsifiers, buffers, or encapsulating materials.

[0030] The term "stable" pharmaceutical composition refers to a pharmaceutical composition in which the active ingredient (e.g., an antibody) substantially maintains its physical stability and / or chemical stability and / or biological activity when stored therein. A variety of techniques for measuring the stability and biological activity of active ingredients are available in the art, for example, as reviewed in Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, NY, Pubs. (1991) Jones, A. Adv. Drug Delivery Rev. 10: 29-90 (1993). Stability can be measured at a selected temperature and other storage conditions for a selected time period. For example, if the active ingredient does not show a significant increase in aggregation, precipitation, and / or denaturation after visual inspection of color and / or clarity, or as measured by UV light scattering, size exclusion chromatography (SEC), and differential scanning calorimetry (DSC), then the active ingredient "retains its physical stability" in the pharmaceutical composition. An active ingredient (e.g., an antibody) "retains its chemical stability" in a pharmaceutical composition if it does not exhibit significant chemical changes. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the antibody. Processes that alter the chemical structure of an antibody include hydrolysis or truncation (which can be assessed by methods such as size exclusion chromatography and SDS-PAGE), oxidation (which can be assessed by methods such as peptide mapping in combination with mass spectrometry or MALDI / TOF / MS), deamidation (which can be assessed by methods such as ion exchange chromatography, capillary isoelectric focusing, peptide mapping, isoaspartate measurement), and isomerization (which can be assessed by measuring isoaspartate content, peptide mapping, etc.). An active ingredient (e.g., an antibody) "retains its biological activity" in a pharmaceutical composition over a given period of time if the biological activity over that period of time is within a predetermined range of the biological activity exhibited when the pharmaceutical composition was prepared, which can be determined by antigen binding assays.

[0031] "High molecular weight impurities" or "aggregates" are a general term for impurities with a molecular weight greater than that of the target active ingredient (eg, antibody).

[0032] As used herein, 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, 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 the amino terminus to the 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 host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. At the same time, as will be appreciated by those skilled in the art, special "whole antibodies," such as nanobodies, have only heavy (H) chains and no light (L) chains.

[0033] 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 "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, and immunoconjugates comprising the antigen-binding fragment are also encompassed by the term antigen-binding fragment.

[0034] A "chimeric antibody" is an antibody having at least a portion of a heavy chain variable region and at least a portion of a light chain variable region derived from one species, and at least a portion of a constant region derived from another species. For example, in one embodiment, a chimeric antibody may comprise a murine variable region and a human constant region.

[0035] A "humanized antibody" is an antibody that contains complementary determining regions (CDRs) derived from a non-human antibody and framework and constant regions derived from a human antibody. For example, an anti-TIM-3 antibody and an anti-PD-1 antibody may contain CDRs derived from one or more murine antibodies and human framework and constant regions. Additional anti-TIM-3 antibodies or variants thereof comprising the HCDRs and LCDRs provided herein may be generated using any human framework sequence and are also encompassed by the present disclosure. Additional anti-PD-1 antibodies or variants thereof comprising the HCDRs and LCDRs provided herein may be generated using any human framework sequence and are also encompassed by the present disclosure.

[0036] 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.

[0037] The term "fixed dose ratio" refers to that two or more different antibodies or antigen-binding fragments thereof in a single pharmaceutical composition are present in a specific (fixed) ratio relative to each other in the pharmaceutical composition, and the ratio is the fixed dose ratio. In some embodiments, the fixed dose ratio is based on the mass (e.g., mg) of the antibody or antigen-binding fragment thereof. In certain embodiments, the fixed dose ratio is based on the concentration (e.g., mg / mL) of the antibody or antigen-binding fragment thereof.

[0038] Herein, "multiples / fractions" refer to multiples or fractions of a parameter / value. For example, multiples of 200 mg include 400 mg (2 times), 600 mg (3 times), 800 mg (4 times), and 1000 mg (5 times); fractions of 200 mg include 20 mg (1 / 10), 25 mg (1 / 8), 40 mg (1 / 5), 50 mg (1 / 4), and 100 mg (1 / 2).

[0039] 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.

[0040] "Therapeutically effective amount" or "therapeutically effective dose" refers to any amount of a drug that protects a subject from the onset of disease or promotes disease regression, which can be demonstrated by a reduction 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 subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by measuring the activity of the agent in in vitro assays.

[0041]

[00146] 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.

[0042] As used herein, the terms "subject," "patient," or "subject" are used interchangeably. "Subject," "patient," or "subject" 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, patient, or subject is a mammal. In some embodiments, the subject, patient, or subject is a mouse. In some embodiments, the subject, patient, or subject is a human.

[0043] The articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. For example, "a pharmaceutical composition" refers to one pharmaceutical composition or more than one pharmaceutical composition.

[0044] As used herein, "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" can mean within one or more standard deviations, as practiced in the art. Alternatively, "about" can mean a range of up to ±5%, for example, within ±2%, ±1%, or ±0.5% of the range of a given specific value. When specific values ​​or parameters are given herein or in the claims, they are assumed to be modified by "about" unless otherwise indicated.

[0045] As used herein, unless the context dictates otherwise, the words "comprising," "including," and "containing" will be understood to mean including the recited step or element or group of steps or elements but not excluding any other step or element or group of steps or elements. "Consisting of" means including and limited to what follows the phrase "consisting of." Thus, the phrase "consisting of" means that the listed elements are required or essential, and no other elements may be present. "Consisting essentially of" means including any element listed after the phrase and is limited to other elements that do not interfere with or contribute to the activity or action of the listed elements. Thus, the phrase "consisting essentially of" means that the listed elements are required or essential, but other elements are optional and may be present or absent depending on whether they affect the activity or action of the listed elements.

[0046] As described herein, any concentration range, percentage range, ratio range, or integer range should be understood to include the value of any integer within the range, and where appropriate, fractions thereof (such as tenths and hundredths of integers), unless otherwise indicated.

[0047] Pharmaceutical composition

[0048] The present disclosure provides a pharmaceutical composition comprising an anti-PD-1 antibody or an antigen-binding fragment thereof and a second antibody or an antigen-binding fragment thereof. In some embodiments, the second antibody or an antigen-binding fragment thereof is an anti-TIM-3 antibody or an antigen-binding fragment thereof.

[0049] As used herein, a "pharmaceutical composition" includes two or more antibodies or antigen-binding fragments thereof, wherein the two or more antibodies or antigen-binding fragments thereof are formulated together and stored as a combination product in a single vial or container (e.g., an injection device), rather than being formulated and stored separately and then mixed before administration or administered separately. The purpose of a pharmaceutical composition is to make the active ingredients (e.g., two or more antibodies or antigen-binding fragments thereof) suitable for manufacture and / or administration to a patient and to maintain biological activity and / or stability during storage and subsequent use.

[0050] In some embodiments, the pharmaceutical composition of the present disclosure is an injection. In some embodiments, the injection includes but is not limited to a non-lyophilized water-soluble preparation or a water-soluble preparation reconstituted from a lyophilized preparation.

[0051] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof and the anti-TIM-3 antibody or antigen-binding fragment thereof are present in the pharmaceutical composition at a fixed dose ratio. In some embodiments, the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical composition is 1:1-30, 1:1-20, 1:1-18, 1:1-15, 1:1-12, 1:1-10, 1:1-9, 1:1-7.5, 1:1-6, 1:1-5, 1:1-4.5, 1:1-3, 1:1-2, or 1:1-1.5. In some embodiments, the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical composition is 1:1-6. In some embodiments, the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment in the pharmaceutical composition is 30:1, 20:1, 18:1, 15:1, 12:1, 10:1, 9:1, 7.5:1, 6:1, 5:1, 4.5:1, 3:1, 2:1, 1.5:1, 1:1, 1:1.5, 1:2, 1:3, 1:4.5, 1:5, 1:6, 1:7.5, 1:9, 1:10, 1:12, 1:15, 1:18, 1:20 or 1:30. In some embodiments, the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical composition is 1:1, 1:1.5, 1:2, 1:3, 1:4.5, 1:5, 1:6, 1:7.5, 1:9, 1:10, 1:12, 1:15, 1:18, 1:20, or 1:30. In some embodiments, the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical composition is 1:1.5, 1:3, 1:4.5, 1:6, 1:7.5, or 1:9. In some embodiments, the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical composition is 1:2, 1:3, 1:6, or 1:7.5. In some embodiments, the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical composition is 1:2, 1:3, or 1:6. In some embodiments, the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical composition is 1:6.

[0052] In some embodiments, the fixed dose ratio is the mass ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical composition.

[0053] In some embodiments, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100-200 mg, or multiples / fractions thereof, for example, 100 mg, or 200 mg, or multiples / fractions thereof. In some embodiments, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples / fractions thereof. In some embodiments, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg or multiples / fractions thereof. In some embodiments, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or 200 mg. In some embodiments, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg.

[0054] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof has a mass of 100-2400 mg, 100-1800 mg, 300-1800 mg, 600-1500 mg, or 600-1200 mg, or any multiple or fraction thereof, such as 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 2000 mg, or 2400 mg, or multiples or fractions thereof. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof has a mass of 300 mg or multiples or fractions thereof. In some embodiments, the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg, 900 mg, or 1200 mg. In some embodiments, the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg.

[0055] In some embodiments, the pharmaceutical composition comprises 100-200 mg, or any multiple / fraction thereof of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 100-2400 mg, 100-1800 mg, 300-1800 mg, 600-1500 mg, or 600-1200 mg, or any multiple / fraction thereof of an anti-TIM-3 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises 100 mg, or 200 mg, or multiples thereof of an anti-PD-1 antibody or antigen-binding fragment thereof, and 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 2000 mg, or 2400 mg, or multiples thereof of an anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises 200 mg, or multiples thereof of an anti-PD-1 antibody or antigen-binding fragment thereof, and 300 mg, 600 mg, 900 mg, 1200 mg, 1500 mg, or 1800 mg, or multiples thereof of an anti-TIM-3 antibody or antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises 200 mg or a multiple / fraction of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 600 mg, 1200 mg, or 1500 mg, or a multiple / fraction thereof of an anti-TIM-3 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises 200 mg or a multiple / fraction of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 600 mg, or 1200 mg, or a multiple / fraction thereof of an anti-TIM-3 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises 100 mg or a multiple / fraction of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 300 mg, 600 mg, 750 mg, or 900 mg, or a multiple / fraction thereof of an anti-TIM-3 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises 100 mg or a multiple / fraction of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 300 mg or 600 mg, or a multiple / fraction thereof of an anti-TIM-3 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises 100 mg or 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 600 mg or 1200 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises 100 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 600 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof.

[0056] In some embodiments, the fixed dose ratio is the concentration ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof in the pharmaceutical composition.

[0057] In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 1-100 mg / mL, 1-80 mg / mL, 2-60 mg / mL, 3-30 mg / mL, 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL. In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof includes, but is 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, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, or 80 mg / mL, or a range formed by any two of the foregoing values. In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5 mg / mL. In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 8 mg / mL. In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 10 mg / mL. In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 15 mg / mL. In some embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 20 mg / mL.

[0058] In some embodiments, the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 1-200 mg / mL, 3-180 mg / mL, 6-120 mg / mL, 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In some embodiments, the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof includes, but is not limited to, 3 mg / mL, 6 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 120 mg / mL, 150 mg / mL, or 180 mg / mL, or a range formed by any two of the foregoing values. In some embodiments, the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 15 mg / mL. In some embodiments, the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 24 mg / mL. In some embodiments, the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30 mg / mL. In some embodiments, the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 45 mg / mL. In some embodiments, the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 48 mg / mL. In some embodiments, the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 60 mg / mL. In some embodiments, the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 90 mg / mL.

[0059] In some embodiments, the pharmaceutical composition comprises 1-100 mg / mL, 1-80 mg / mL, 2-60 mg / mL, 3-30 mg / mL, 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 1-200 mg / mL, 3-180 mg / mL, 6-120 mg / mL, 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL of an anti-TIM-3 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL of an anti-TIM-3 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises 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, 20 mg / mL, 21 mg / mL, 22 mg / mL, 23 mg / mL, 24 mg / mL, 25 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, or 80 mg / mL. 0 mg / mL of an anti-PD-1 antibody, or an antigen-binding fragment thereof, and 3 mg / mL, 6 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 120 mg / mL, 150 mg / mL, or 180 mg / mL of an anti-TIM-3 antibody, or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises 5 mg / mL, 8 mg / mL, 10 mg / mL, or 15 mg / mL of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 15 mg / mL, 24 mg / mL, 30 mg / mL, 45 mg / mL, 48 mg / mL, 60 mg / mL, or 90 mg / mL of an anti-TIM-3 antibody or an antigen-binding fragment thereof.In some embodiments, the pharmaceutical composition comprises 5 mg / mL or 10 mg / mL of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 15 mg / mL, 30 mg / mL, or 60 mg / mL of an anti-TIM-3 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises 5 mg / mL of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 30 mg / mL of an anti-TIM-3 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical composition comprises 5 mg / mL of an anti-PD-1 antibody or an antigen-binding fragment thereof, and 15 mg / mL of an anti-TIM-3 antibody or an antigen-binding fragment thereof.

[0060] The pharmaceutical compositions of the present disclosure may further comprise one or more pharmaceutically acceptable excipients, such as buffers, stabilizers, diluents, chelating agents, and surfactants.

[0061] The pharmaceutical composition of the present disclosure further comprises a buffer. In some embodiments, the buffer comprises a histidine buffer, an acetate buffer, a Tris buffer, a phosphate buffer, and / or a citrate buffer. In some embodiments, the buffer comprises a histidine buffer and / or an acetate buffer. In some embodiments, the buffer comprises a histidine buffer.

[0062] In some embodiments, the histidine buffer can be a histidine-histidine hydrochloride buffer, a histidine-hydrochloric acid buffer, a histidine-acetate buffer, or a histidine-phosphate buffer. In some embodiments, the histidine buffer can be a histidine-acetate buffer. In some embodiments, the acetate buffer can be a sodium acetate buffer, a potassium acetate buffer, or an ammonium acetate buffer. In some embodiments, the phosphate buffer can be a sodium phosphate buffer or a potassium phosphate buffer. In some embodiments, the citrate buffer can be a sodium citrate buffer, a potassium citrate buffer, or a calcium citrate buffer.

[0063] In some embodiments, the concentration of the buffer is 1-100mM, 2-80mM, 5-60mM, 10-40mM, or 10-20mM. In some embodiments, the concentration of the buffer includes but is not limited to: 5mM, 10mM, 11mM, 12mM, 13mM, 14mM, 15mM, 16mM, 17mM, 18mM, 19mM, 20mM, 21mM, 22mM, 23mM, 24mM, 25mM, 26mM, 27mM, 28mM, 29mM, 30mM, 32mM, 34mM, 36mM, 38mM, 40mM, 50mM, or 60mM, or a range formed by any two of the above values. In some embodiments, the concentration of the buffer is 10mM. In some embodiments, the concentration of the buffer is 20mM. In some embodiments, the buffer comprises a histidine buffer. In some embodiments, the buffer comprises a histidine-acetate buffer.

[0064] In some embodiments, the pH of the buffer is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5. 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, or a range formed by any two of the above values. 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. In some embodiments, the pH of the buffer is 6.2. In some embodiments, the pH of the buffer is 6.5.

[0065] The pharmaceutical composition of the present disclosure also includes a stabilizer. In some embodiments, the stabilizer includes 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), and / or a salt (e.g., sodium chloride). In some embodiments, the stabilizer includes mannitol, sorbitol, trehalose, sucrose, maltose, lactose, lysine, glycine, proline, arginine or a pharmaceutically acceptable salt thereof and / or sodium chloride. In some embodiments, the stabilizer includes a sugar alcohol (e.g., sorbitol) or a disaccharide (e.g., sucrose or trehalose). In some embodiments, the stabilizer includes sucrose.

[0066] In some embodiments, the concentration of the stabilizer is 1-400 mg / mL, 10-300 mg / mL, 20-200 mg / mL, 40-200 mg / mL, 40-180 mg / mL, 60-180 mg / mL, or 70-170 mg / mL. In some embodiments, the concentration of the stabilizer includes but is not limited to: 10 mg / mL, 20 mg / mL, 24 mg / mL, 30 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 54 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 80 mg / mL, 85 mg / mL, 89 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 113 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 154

[0014] In some embodiments, the present invention provides an intravenous infusion of at least one molecule of the present invention and / or a mixture of at least one molecule of the present invention. The intravenous infusion of at least one molecule of the present invention may be in the form of a 1% to 2% iodine-containing compound or a mixture of at least one molecule of the present invention.

[0014] In some embodiments, the intravenous infusion of at least one molecule of the present invention may be in the form of a 1% to 2% iodine-containing compound or a mixture of at least one molecule of the present invention.In some embodiments, the concentration of the stabilizer includes but is not limited to: 10.3 mg / mL, 13.7 mg / mL, 17.1 mg / mL, 20.5 mg / mL, 27.4 mg / mL, 30.8 mg / mL, 34.2 mg / mL, 34.5 mg / mL, 37.7 mg / mL, 41.1 mg / mL, 44.5 mg / mL, 47.9 mg / mL, 51.3 mg / mL, 54.8 mg / mL, 58.2 mg / mL, 61.6 mg / mL, 68.5 mg / mL, 71.9 mg / mL, 75.3 mg / mL, 78.7 mg / mL , 82.2mg / mL, 85.6mg / mL, 92.4mg / mL, 95.8mg / mL, 99.3mg / mL, 102.7mg / mL, 106.1mg / mL, 108.1mg / mL, 109.5mg / mL, 116.4mg / mL, 119.8m g / mL, 123.2mg / mL, 126.7mg / mL, 130.1mg / mL, 133.5mg / mL, 136.9mg / mL, 140.3mg / mL, 143.8mg / mL, 147.2mg / mL, 150.6mg / mL, 157.5mg / mL, 160.9mg / mL, 164.3mg / mL, 167.7mg / mL, 171.2mg / mL, 174.6mg / mL, 181.4mg / mL, 184.8mg / mL, 188.3mg / mL, 191.7mg / mL, 195.1mg / m L, 198.5mg / mL, 205.4mg / mL, 208.8mg / mL, 212.2mg / mL, 215.6mg / mL, 219.1mg / mL, 222.5mg / mL, 225.9mg / mL, 229.3mg / mL, 232.8mg / mL, In some embodiments, the concentration of the stabilizer is 80-164.3 mg / mL. In some embodiments, the concentration of the stabilizer is 80 mg / mL. In some embodiments, the concentration of the stabilizer is 85 mg / mL.In some embodiments, the concentration of the stabilizer is 85.6 mg / mL. In some embodiments, the concentration of the stabilizer is 100 mg / mL. In some embodiments, the concentration of the stabilizer is 164 mg / mL. In some embodiments, the concentration of the stabilizer is 164.3 mg / mL. In some embodiments, the stabilizer comprises sucrose.

[0067] In some embodiments, the concentration of the stabilizer is 30mM-960mM, 60mM-720mM, 120mM-480mM, 240mM-480mM, 210mM-270mM, 230mM-250mM, 450mM-510mM, or 470mM-490mM. In some embodiments, the concentration of the stabilizer is 100-800mM, 200-700mM, 300-600mM, 400-500mM, or 470-490mM. In some embodiments, the concentration of the stabilizer includes but is not limited to: 30mM, 60mM, 90mM, 100mM, 120mM, 150mM, 160mM, 175mM, 180mM, 200mM, 210mM, 230mM, 234mM, 240mM, 250mM, 270mM, 300mM, 330mM, 360mM, 390mM, 400mM, 420mM, 450mM, In some embodiments, the concentration of the stabilizer is 470mM, 480mM, 490mM, 500mM, 510mM, 526mM, 540mM, 550mM, 570mM, 600mM, 630mM, 660mM, 690mM, 700mM, 720mM, 750mM, 780mM, 800mM, 810mM, 840mM, 870mM, 900mM, 930mM, or 960mM, or a range formed by any two of the above values. In some embodiments, the concentration of the stabilizer is 200-500mM. In some embodiments, the concentration of the stabilizer is 230-480mM. In some embodiments, the concentration of the stabilizer is 400-500mM. In some embodiments, the concentration of the stabilizer is 230mM. In some embodiments, the concentration of the stabilizer is 234mM. In some embodiments, the concentration of the stabilizer is 240 mM. In some embodiments, the concentration of the stabilizer is 300 mM. In some embodiments, the concentration of the stabilizer is 480 mM. In some embodiments, the stabilizer comprises sucrose.

[0068] Pharmaceutical composition of the present disclosure also includes surfactant. In some embodiments, the surfactant is a nonionic surfactant. In some embodiments, the surfactant includes polysorbate (for example, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85), poloxamer (for example, poloxamer 181, poloxamer 188, poloxamer 407) and / or polyethylene glycol etc. In some embodiments, the surfactant includes polysorbate (for example, polysorbate 80 or polysorbate 20). In some embodiments, the surfactant includes polysorbate 80.

[0069] In some embodiments, the concentration of the surfactant is 0.01-3 mg / mL, 0.04-2 mg / mL, 0.08-1.6 mg / mL, 0.1-1.2 mg / mL, 0.1-1 mg / mL, 0.2-0.8 mg / mL, or 0.4-0.8 mg / mL. In some embodiments, the concentration of the surfactant includes but is not limited to: 0.01 mg / mL, 0.04 mg / mL, 0.06 mg / mL, 0.08 mg / mL, 0.1 mg / mL, 0.15 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, 1 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, or 2 mg / mL, or a range formed by any two of the above values. In some embodiments, the concentration of the surfactant is 0.2 mg / mL. In some embodiments, the concentration of the surfactant is 0.4 mg / mL. In some embodiments, the concentration of the surfactant is 0.5 mg / mL. In some embodiments, the concentration of the surfactant is 0.6 mg / mL. In some embodiments, the concentration of the surfactant is 0.8 mg / mL.In some embodiments, the surfactant comprises polysorbate 80.

[0070] In some embodiments, the pH of the pharmaceutical composition of the present disclosure is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5. In some embodiments, the pH of the pharmaceutical composition of the present disclosure 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, or a range formed by any two of the above values. In some embodiments, the pH of the pharmaceutical composition is 5.5. In some embodiments, the pH of the pharmaceutical composition of the present disclosure is 5.8. In some embodiments, the pH of the pharmaceutical composition of the present disclosure is 6. In some embodiments, the pH of the pharmaceutical composition of the present disclosure is 6.2. In some embodiments, the pH of the pharmaceutical composition of the present disclosure is 6.5.

[0071] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) a buffer, (c) a stabilizer, and (d) a surfactant; wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:1-9, 1:1-7.5, 1:1-6, 1:1-5, 1:1-4.5, 1:1-3, 1:1-2 or 1:1-1.5 (e.g., 1:1-7.5 or 1:1-6). In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) a buffer, (c) a stabilizer, and (d) a surfactant; wherein the fixed dose ratio of the anti-PD-1 antibody or an antigen-binding fragment thereof to the anti-TIM-3 antibody or an antigen-binding fragment thereof is 1:1.5, 1:3, 1:4.5, 1:6, 1:7.5, or 1:9 (e.g., 1:2, 1:3, 1:6, or 1:7.5). In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) a buffer, (c) a stabilizer, and (d) a surfactant; wherein the fixed dose ratio of the anti-PD-1 antibody or an antigen-binding fragment thereof to the anti-TIM-3 antibody or an antigen-binding fragment thereof is 1:3, 1:6, or 1:7.5. In such specific embodiments, the concentration of the anti-PD-1 antibody or its antigen-binding fragment is 1-100 mg / mL, 1-80 mg / mL, 2-60 mg / mL, 3-30 mg / mL, 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or its antigen-binding fragment is 1-200 mg / mL, 3-180 mg / mL, 6-120 mg / mL, 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In such specific embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In such specific embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 15-60 mg / mL.In a specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30-60 mg / mL. In a specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30 mg / mL. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100-200 mg, or any multiple / fraction thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 100-2400 mg, 100-1800 mg, 300-1800 mg, 600-1500 mg, or 600-1200 mg, or any multiple / fraction thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600-1500 mg, or 600-1200 mg, or multiples thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg, 1200 mg, or 1500 mg, or multiples thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg, 600 mg, 750 mg, or 900 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg or 600 mg, or multiples / fractions thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg.

[0072] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 1-100 mM buffer (e.g., acetate buffer or histidine buffer), (c) 1-400 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) 0.01-3 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20 ); wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof is 1:1-9, 1:1-7.5, 1:1-6, 1:1-5, 1:1-4.5, 1:1-3, 1:1-2 or 1:1-1.5 (e.g., 1:1-7.5 or 1:1-6), and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 1-100 mM buffer (e.g., acetate buffer or histidine buffer), (c) 1-400 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) 0.01-3 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:1.5, 1:3, 1:4.5, 1:6, 1:7.5 or 1:9 (e.g., 1:2, 1:3, 1:6 or 1:7.5), and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 1-100 mM buffer (e.g., a histidine buffer), (c) 1-400 mg / mL stabilizer (e.g., sucrose), and (d) 0.01-3 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:2, 1:3, 1:6 or 1:7.5, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.In such specific embodiments, the concentration of the anti-PD-1 antibody or its antigen-binding fragment is 1-100 mg / mL, 1-80 mg / mL, 2-60 mg / mL, 3-30 mg / mL, 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or its antigen-binding fragment is 1-200 mg / mL, 3-180 mg / mL, 6-120 mg / mL, 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In specific embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In specific embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 15-60 mg / mL. In specific embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30-60 mg / mL. In specific embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30 mg / mL. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100-200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 100-2400 mg, 100-1800 mg, 300-1800 mg, 600-1500 mg, or 600-1200 mg, or multiples / fractions thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600-1500 mg, or 600-1200 mg, or multiples / fractions thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg, 1200 mg, or 1500 mg, or multiples / fractions thereof.In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg, 600 mg, 750 mg, or 900 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg or 600 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg.

[0073] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) a 2-80 mM buffer (e.g., an acetate buffer or a histidine buffer), (c) a 10-300 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) a 0.04-2 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20). ); wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof is 1:1-9, 1:1-7.5, 1:1-6, 1:1-5, 1:1-4.5, 1:1-3, 1:1-2 or 1:1-1.5 (e.g., 1:1-7.5 or 1:1-6), and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 2-80 mM buffer (e.g., acetate buffer or histidine buffer), (c) 10-300 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) 0.04-2 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof is 1:1.5, 1:3, 1:4.5, 1:6, 1:7.5 or 1:9 (e.g., 1:2, 1:3, 1:6 or 1:7.5), and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 2-80 mM buffer (e.g., a histidine buffer), (c) 10-300 mg / mL stabilizer (e.g., sucrose), and (d) 0.04-2 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:2, 1:3, 1:6 or 1:7.5, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.In such specific embodiments, the concentration of the anti-PD-1 antibody or its antigen-binding fragment is 1-100 mg / mL, 1-80 mg / mL, 2-60 mg / mL, 3-30 mg / mL, 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or its antigen-binding fragment is 1-200 mg / mL, 3-180 mg / mL, 6-120 mg / mL, 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 15-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30 mg / mL. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100-200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 100-2400 mg, 100-1800 mg, 300-1800 mg, 600-1500 mg, or 600-1200 mg, or multiples / fractions thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600-1500 mg, or 600-1200 mg, or multiples / fractions thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg, 1200 mg, or 1500 mg, or multiples / fractions thereof.In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg, 600 mg, 750 mg, or 900 mg, or multiples thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg or 600 mg, or multiples thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg.

[0074] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) a 5-60 mM buffer (e.g., an acetate buffer or a histidine buffer), (c) a 20-200 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) a 0.08-1.6 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20). 0); wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:1-9, 1:1-7.5, 1:1-6, 1:1-5, 1:1-4.5, 1:1-3, 1:1-2 or 1:1-1.5 (e.g., 1:1-7.5 or 1:1-6), and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 5-60 mM buffer (e.g., acetate buffer or histidine buffer), (c) 20-200 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) 0.08-1.6 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof is 1:1.5, 1:3, 1:4.5, 1:6, 1:7.5 or 1:9 (e.g., 1:2, 1:3, 1:6 or 1:7.5), and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 5-60 mM buffer (e.g., a histidine buffer), (c) 20-200 mg / mL stabilizer (e.g., sucrose), and (d) 0.08-1.6 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:2, 1:3, 1:6 or 1:7.5, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.In such specific embodiments, the concentration of the anti-PD-1 antibody or its antigen-binding fragment is 1-100 mg / mL, 1-80 mg / mL, 2-60 mg / mL, 3-30 mg / mL, 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or its antigen-binding fragment is 1-200 mg / mL, 3-180 mg / mL, 6-120 mg / mL, 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 15-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30 mg / mL. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100-200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 100-2400 mg, 100-1800 mg, 300-1800 mg, 600-1500 mg, or 600-1200 mg, or multiples / fractions thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600-1500 mg, or 600-1200 mg, or multiples / fractions thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg, 1200 mg, or 1500 mg, or multiples / fractions thereof.In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg, 600 mg, 750 mg, or 900 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg or 600 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg.

[0075] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) a 10-40 mM buffer (e.g., an acetate buffer or a histidine buffer), (c) a 40-200 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) a 0.1-1.2 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20). 0); wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:1-9, 1:1-7.5, 1:1-6, 1:1-5, 1:1-4.5, 1:1-3, 1:1-2 or 1:1-1.5 (e.g., 1:1-7.5 or 1:1-6), and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-40 mM buffer (e.g., acetate buffer or histidine buffer), (c) 40-200 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) 0.1-1.2 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof is 1:1.5, 1:3, 1:4.5, 1:6, 1:7.5 or 1:9 (e.g., 1:2, 1:3, 1:6 or 1:7.5), and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-40 mM buffer (e.g., a histidine buffer), (c) 40-200 mg / mL stabilizer (e.g., sucrose), and (d) 0.1-1.2 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:2, 1:3, 1:6 or 1:7.5, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.In such specific embodiments, the concentration of the anti-PD-1 antibody or its antigen-binding fragment is 1-100 mg / mL, 1-80 mg / mL, 2-60 mg / mL, 3-30 mg / mL, 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or its antigen-binding fragment is 1-200 mg / mL, 3-180 mg / mL, 6-120 mg / mL, 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 15-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30 mg / mL. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100-200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 100-2400 mg, 100-1800 mg, 300-1800 mg, 600-1500 mg, or 600-1200 mg, or multiples / fractions thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600-1500 mg, or 600-1200 mg, or multiples / fractions thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg, 1200 mg, or 1500 mg, or multiples / fractions thereof.In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg, 600 mg, 750 mg, or 900 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg or 600 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg.

[0076] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) a 10-40 mM buffer (e.g., an acetate buffer or a histidine buffer), (c) a 40-180 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) a 0.1-1 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20). ); wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof is 1:1-9, 1:1-7.5, 1:1-6, 1:1-5, 1:1-4.5, 1:1-3, 1:1-2 or 1:1-1.5 (e.g., 1:1-7.5 or 1:1-6), and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-40 mM buffer (e.g., acetate buffer or histidine buffer), (c) 40-180 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) 0.1-1 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof is 1:1.5, 1:3, 1:4.5, 1:6, 1:7.5 or 1:9 (e.g., 1:2, 1:3, 1:6 or 1:7.5), and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-40 mM buffer (e.g., a histidine buffer), (c) 40-180 mg / mL stabilizer (e.g., sucrose), and (d) 0.1-1 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:2, 1:3, 1:6 or 1:7.5, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.In such specific embodiments, the concentration of the anti-PD-1 antibody or its antigen-binding fragment is 1-100 mg / mL, 1-80 mg / mL, 2-60 mg / mL, 3-30 mg / mL, 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or its antigen-binding fragment is 1-200 mg / mL, 3-180 mg / mL, 6-120 mg / mL, 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 15-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30 mg / mL. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100-200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 100-2400 mg, 100-1800 mg, 300-1800 mg, 600-1500 mg, or 600-1200 mg, or multiples / fractions thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600-1500 mg, or 600-1200 mg, or multiples / fractions thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg, 1200 mg, or 1500 mg, or multiples / fractions thereof.In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg, 600 mg, 750 mg, or 900 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg or 600 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg.

[0077] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) a 10-20 mM buffer (e.g., an acetate buffer or a histidine buffer), (c) a 60-180 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) a 0.2-0.8 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20). 0); wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:1-9, 1:1-7.5, 1:1-6, 1:1-5, 1:1-4.5, 1:1-3, 1:1-2 or 1:1-1.5 (e.g., 1:1-7.5 or 1:1-6), and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM buffer (e.g., acetate buffer or histidine buffer), (c) 60-180 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) 0.2-0.8 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof is 1:1.5, 1:3, 1:4.5, 1:6, 1:7.5 or 1:9 (e.g., 1:2, 1:3, 1:6 or 1:7.5), and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM buffer (e.g., a histidine buffer), (c) 60-180 mg / mL stabilizer (e.g., sucrose), and (d) 0.2-0.8 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:2, 1:3, 1:6 or 1:7.5, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.In such specific embodiments, the concentration of the anti-PD-1 antibody or its antigen-binding fragment is 1-100 mg / mL, 1-80 mg / mL, 2-60 mg / mL, 3-30 mg / mL, 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or its antigen-binding fragment is 1-200 mg / mL, 3-180 mg / mL, 6-120 mg / mL, 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 15-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30 mg / mL. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100-200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 100-2400 mg, 100-1800 mg, 300-1800 mg, 600-1500 mg, or 600-1200 mg, or multiples / fractions thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600-1500 mg, or 600-1200 mg, or multiples / fractions thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg, 1200 mg, or 1500 mg, or multiples / fractions thereof.In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg, 600 mg, 750 mg, or 900 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg or 600 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg.

[0078] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) a 10-20 mM buffer (e.g., an acetate buffer or a histidine buffer), (c) a 70-170 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) a 0.4-0.8 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20). 0); wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:1-9, 1:1-7.5, 1:1-6, 1:1-5, 1:1-4.5, 1:1-3, 1:1-2 or 1:1-1.5 (e.g., 1:1-7.5 or 1:1-6), and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM buffer (e.g., acetate buffer or histidine buffer), (c) 70-170 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) 0.4-0.8 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof is 1:1.5, 1:3, 1:4.5, 1:6, 1:7.5 or 1:9 (e.g., 1:2, 1:3, 1:6 or 1:7.5), and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM buffer (e.g., a histidine buffer), (c) 70-170 mg / mL stabilizer (e.g., sucrose), and (d) 0.4-0.8 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:2, 1:3, 1:6 or 1:7.5, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.In such specific embodiments, the concentration of the anti-PD-1 antibody or its antigen-binding fragment is 1-100 mg / mL, 1-80 mg / mL, 2-60 mg / mL, 3-30 mg / mL, 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or its antigen-binding fragment is 1-200 mg / mL, 3-180 mg / mL, 6-120 mg / mL, 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 15-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30 mg / mL. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100-200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 100-2400 mg, 100-1800 mg, 300-1800 mg, 600-1500 mg, or 600-1200 mg, or multiples / fractions thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600-1500 mg, or 600-1200 mg, or multiples / fractions thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg, or multiples / fractions thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg, 1200 mg, or 1500 mg, or multiples / fractions thereof.In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg, 600 mg, 750 mg, or 900 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg or 600 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg.

[0079] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-40 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 40-200 mg / mL sucrose (e.g., 80 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL or 16 The invention relates to an agent comprising: (a) 0.1-1.2 mg / mL polysorbate 80 (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, or 0.8 mg / mL polysorbate 80); wherein the fixed dose ratio of the anti-PD-1 antibody, or antigen-binding fragment thereof, to the anti-TIM-3 antibody, or antigen-binding fragment thereof, is 1:2, 1:3, 1:6, or 1:7.5, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-40 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 40-180 mg / mL sucrose (e.g., 80 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL or 1 The invention relates to an agent comprising: (a) 0.1-1 mg / mL polysorbate 80 (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, or 0.8 mg / mL polysorbate 80); wherein the fixed dose ratio of the anti-PD-1 antibody, or antigen-binding fragment thereof, to the anti-TIM-3 antibody, or antigen-binding fragment thereof, is 1:2, 1:3, 1:6, or 1:7.5, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5. In such specific embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In such specific embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 15-60 mg / mL.In a specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30-60 mg / mL. In a specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30 mg / mL. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600-1500 mg, or 600-1200 mg, or multiples thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg, 1200 mg, or 1500 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg, 600 mg, 750 mg, or 900 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg or 600 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg.

[0080] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 60-180 mg / mL sucrose (e.g., 80 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL or 16 The invention relates to an agent comprising: (a) 0.2-0.8 mg / mL polysorbate 80 (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, or 0.8 mg / mL polysorbate 80); wherein the fixed dose ratio of the anti-PD-1 antibody, or antigen-binding fragment thereof, to the anti-TIM-3 antibody, or antigen-binding fragment thereof, is 1:2, 1:3, 1:6, or 1:7.5, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 60-180 mg / mL sucrose (e.g., 80 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL, 400 mg / mL, 20 ... g / mL or 164.3 mg / mL sucrose), and (d) 0.2-0.8 mg / mL polysorbate 80 (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, or 0.8 mg / mL polysorbate 80); wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:6, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5. In the specific embodiment, the concentration of the anti-PD-1 antibody or its antigen-binding fragment is 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or its antigen-binding fragment is 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or its antigen-binding fragment is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or its antigen-binding fragment is 15-60 mg / mL.In a specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30-60 mg / mL. In a specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30 mg / mL. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600-1500 mg, or 600-1200 mg, or multiples thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg, 1200 mg, or 1500 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg, 600 mg, 750 mg, or 900 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg or 600 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg.

[0081] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 70-170 mg / mL sucrose (e.g., 80 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL), mL or 164.3 mg / mL sucrose), and (d) 0.4-0.8 mg / mL polysorbate 80 (e.g., 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof is 1:2, 1:3, 1:6 or 1:7.5, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 70-170 mg / mL sucrose (e.g., 80 mg / mL, 85.6 mg / mL, 100 mg / mL , 164 mg / mL or 164.3 mg / mL sucrose), and (d) 0.4-0.8 mg / mL polysorbate 80 (e.g., 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof is 1:6, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 80-164.3 mg / mL sucrose (e.g., 80 mg / mL, 85.6 mg / mL, 100 mg / mL, L, 164 mg / mL or 164.3 mg / mL sucrose), and (d) 0.4-0.8 mg / mL polysorbate 80 (e.g., 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof is 1:6, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 20 mM histidine buffer (e.g., 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 80-164.3 mg / mL sucrose (e.g., 80 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL, or 164.3 mg / mL sucrose), and (d) 0.8 mg / mL polysorbate 80; wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:6, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 200-500 mM sucrose (e.g., 230 mM, 234 mM, 400 mM, 450 mM or 480 mM). 0 mM sucrose), and (d) 0.4-0.8 mg / mL polysorbate 80 (e.g., 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof is 1:2, 1:3, 1:6 or 1:7.5, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-acetate buffer), (c) 230-480 mM sucrose (e.g., 230 mM, 234 mM, 400 mM, 450 mM or 480 mM sucrose), and (d) 0.4-0.8 mg / mL polysorbate 80 (e.g., 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:6, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 20 mM histidine buffer (e.g., 20 mM histidine-acetate buffer), (c) 230-480 mM sucrose (e.g., 230 mM, 234 mM, 400 mM, 450 mM or 480 mM sucrose), and (d) 0.8 mg / mL polysorbate 80; wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:6, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 20 mM histidine buffer (e.g., 20 mM histidine-acetate buffer), (c) 400-500 mM sucrose (e.g., 480 mM sucrose), and (d) 0.8 mg / mL polysorbate 80; wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:6, and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5. In such specific embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In such specific embodiments, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 15-60 mg / mL.In a specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30-60 mg / mL. In a specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30 mg / mL. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600-1500 mg, or 600-1200 mg, or multiples thereof. In a specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 200 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg, 1200 mg, or 1500 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg, 600 mg, 750 mg, or 900 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg or multiples thereof, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 300 mg or 600 mg, or multiples thereof. In the specific embodiment, the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100 mg, and the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 600 mg.

[0082] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 200 mg or multiples / fractions thereof of an anti-PD-1 antibody or an antigen-binding fragment thereof and 600 mg, or 1200 mg, or multiples / fractions thereof of an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 60-180 mM g / mL sucrose (e.g., 80 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL or 164.3 mg / mL sucrose), and (d) 0.2-0.8 mg / mL polysorbate 80 (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); wherein the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 200 mg or multiples / fractions thereof of an anti-PD-1 antibody or an antigen-binding fragment thereof and 600 mg, or 1200 mg, or multiples / fractions thereof of an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 70 -170 mg / mL sucrose (e.g., 80 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL, or 164.3 mg / mL sucrose), and (d) 0.4-0.8 mg / mL polysorbate 80 (e.g., 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, or 0.8 mg / mL polysorbate 80); wherein the pharmaceutical composition has a pH of 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 200 mg or multiples / fractions thereof of an anti-PD-1 antibody or an antigen-binding fragment thereof and 600 mg, or 1200 mg, or multiples / fractions thereof of an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10 mM or 20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 80 mg / mL or 164.3 mg / mL sucrose, and (d) 0.4 mg / mL or 0.8 mg / mL polysorbate 80; wherein the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 15-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30 mg / mL.

[0083] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 100 mg or multiples / fractions thereof of an anti-PD-1 antibody or an antigen-binding fragment thereof and 600 mg or multiples / fractions thereof of an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 60- 180 mg / mL sucrose (e.g., 80 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL or 164.3 mg / mL sucrose), and (d) 0.2-0.8 mg / mL polysorbate 80 (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); wherein the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 100 mg or multiples / fractions thereof of an anti-PD-1 antibody or an antigen-binding fragment thereof and 600 mg or multiples / fractions thereof of an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 70-170 mM g / mL sucrose (e.g., 80 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL or 164.3 mg / mL sucrose), and (d) 0.4-0.8 mg / mL polysorbate 80 (e.g., 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); wherein the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 100 mg or multiples / fractions thereof of an anti-PD-1 antibody or an antigen-binding fragment thereof and 600 mg or multiples / fractions thereof of an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 80-164.3 The invention relates to a pharmaceutical composition comprising: (a) 0.4-0.8 mg / mL sucrose (e.g., 80 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL or 164.3 mg / mL sucrose), and (b) 0.4-0.8 mg / mL polysorbate 80 (e.g., 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); wherein the pharmaceutical composition has a pH of 5.5 to 6.5, or 5.8 to 6.5.In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 90-110 mg or multiples / fractions thereof of an anti-PD-1 antibody or antigen-binding fragment thereof and 540-660 mg or multiples / fractions thereof of an anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 15-25 mM histidine buffer (e.g., 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 150-180 mg / mL sucrose (e.g., 164.3 mg / mL sucrose), and (d) 0.7-0.9 mg / mL polysorbate 80 (e.g., 0.8 mg / mL polysorbate 80); wherein the pH of the pharmaceutical composition is 5.3 to 6.3, 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 100 mg or multiples / fractions thereof of an anti-PD-1 antibody or antigen-binding fragment thereof and 600 mg or multiples / fractions thereof of an anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 230-480 mM sucrose (e.g., 230 mM, 234 mM, 400 mM, 450 mM or 480 mM sucrose), and (d) 0.4-0.8 mg / mL polysorbate 80 (e.g., 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); wherein the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 100 mg or multiples / fractions thereof of an anti-PD-1 antibody or antigen-binding fragment thereof and 600 mg or multiples / fractions thereof of an anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 20 mM histidine buffer (e.g., 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 80-164.3 mg / mL sucrose (e.g., 80 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL, or 164.3 mg / mL sucrose), and (d) 0.8 mg / mL polysorbate 80; wherein the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 100 mg or multiples / fractions thereof of an anti-PD-1 antibody or antigen-binding fragment thereof and 600 mg or multiples / fractions thereof of an anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 20 mM histidine buffer (e.g., 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 230-480 mM sucrose (e.g., 230 mM, 234 mM, 400 mM, 450 mM or 480 mM sucrose), and (d) 0.8 mg / mL polysorbate 80; wherein the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 100 mg or multiples / fractions thereof of an anti-PD-1 antibody or an antigen-binding fragment thereof and 600 mg or multiples / fractions thereof of an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10 mM or 20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 80 mg / mL or 164.3 mg / mL sucrose, and (d) 0.4 mg / mL or 0.8 mg / mL polysorbate 80; wherein the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 100 mg or multiples / fractions thereof of an anti-PD-1 antibody or an antigen-binding fragment thereof and 600 mg or multiples / fractions thereof of an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10 mM or 20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 234 mM or 480 mM sucrose, and (d) 0.4 mg / mL or 0.8 mg / mL polysorbate 80; wherein the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5. In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 90-110 mg or multiples / fractions thereof of an anti-PD-1 antibody or antigen-binding fragment thereof and 540-660 mg or multiples / fractions thereof of an anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 15-25 mM histidine buffer (e.g., 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 450-510 mM sucrose (e.g., 480 mM sucrose), and (d) 0.7-0.9 mg / mL polysorbate 80 (e.g., 0.8 mg / mL polysorbate 80); wherein the pH of the pharmaceutical composition is 5.3 to 6.3, 5.5 to 6.5, or 5.8 to 6.5.In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 15-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5-10 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30-60 mg / mL. In the specific embodiment, the concentration of the anti-PD-1 antibody or antigen-binding fragment thereof is 5 mg / mL, and the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 30 mg / mL.

[0084] In some specific embodiments, the pharmaceutical composition of the present disclosure comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) a buffer, (c) a stabilizer, and (d) a surfactant.

[0085] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 1-100 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 1-200 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 1-100 mM buffer (e.g., acetate buffer or histidine buffer), (c) 1-400 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) 0.01-3 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5.

[0086] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 1-80 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 3-180 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 2-80 mM buffer (e.g., acetate buffer or histidine buffer), (c) 10-300 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) 0.04-2 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5.

[0087] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 2-60 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 6-120 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 5-60 mM buffer (e.g., acetate buffer or histidine buffer), (c) 20-200 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) 0.08-1.6 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5.

[0088] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 3-30 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 10-90 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-40 mM buffer (e.g., acetate buffer or histidine buffer), (c) 40-200 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) 0.1-1.2 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5.

[0089] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 3-20 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 15-90 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-40 mM buffer (e.g., acetate buffer or histidine buffer), (c) 40-180 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) 0.1-1 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5.

[0090] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5-20 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 15-60 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM buffer (e.g., acetate buffer or histidine buffer), (c) 60-180 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) 0.2-0.8 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5.

[0091] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5-15 mg / mL, or 5-10 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 30-60 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM buffer (e.g., acetate buffer or histidine buffer), (c) 70-170 mg / mL stabilizer (e.g., sorbitol or sucrose), and (d) 0.4-0.8 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); and the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5.

[0092] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 1-100 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 1-200 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 1-100 mM buffer (e.g., histidine buffer), (c) 1-400 mg / mL stabilizer (e.g., sucrose), and (d) 0.01-3 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0093] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 1-80 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 3-180 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 2-80 mM buffer (e.g., histidine buffer), (c) 10-300 mg / mL stabilizer (e.g., sucrose), and (d) 0.04-2 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0094] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 2-60 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 6-120 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 5-60 mM buffer (e.g., histidine buffer), (c) 20-200 mg / mL stabilizer (e.g., sucrose), and (d) 0.08-1.6 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0095] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 3-30 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 10-90 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-40 mM buffer (e.g., histidine buffer), (c) 40-200 mg / mL stabilizer (e.g., sucrose), and (d) 0.1-1.2 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0096] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 3-20 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 15-90 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-40 mM buffer (e.g., histidine buffer), (c) 40-180 mg / mL stabilizer (e.g., sucrose), and (d) 0.1-1 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0097] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5-20 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 15-60 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM buffer (e.g., histidine buffer), (c) 60-180 mg / mL stabilizer (e.g., sucrose), and (d) 0.2-0.8 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0098] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5-15 mg / mL, or 5-10 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 30-60 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM buffer (e.g., histidine buffer), (c) 70-170 mg / mL stabilizer (e.g., sucrose), and (d) 0.4-0.8 mg / mL surfactant (e.g., polysorbate 80 or polysorbate 20); and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0099] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 3-30 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 5 mg / mL, 8 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, or 30 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof) and 10-90 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof (e.g., 15 mg / mL, 24 mg / mL, 30 mg / mL, 45 mg / mL, 48 mg / mL, 60 mg / mL, or 90 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof), (b) 10-40 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 40-200 mg / mL sucrose (e.g., 80 mg / mL, 85 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL or 164.3 mg / mL sucrose), and (d) 0.1-1.2 mg / mL polysorbate 80 (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0100] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 3-20 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 5 mg / mL, 8 mg / mL, 10 mg / mL, 15 mg / mL, or 20 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof) and 15-90 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof (e.g., 15 mg / mL, 24 mg / mL, 30 mg / mL, 45 mg / mL, 48 mg / mL, 60 mg / mL, or 90 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof), (b) 10-40 mM histidine buffer (e.g., , 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 40-180 mg / mL sucrose (e.g., 80 mg / mL, 85 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL or 164.3 mg / mL sucrose), and (d) 0.1-1 mg / mL polysorbate 80 (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0101] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5-20 mg / mL anti-PD-1 antibody or its antigen-binding fragment (e.g., 5 mg / mL, 8 mg / mL, 10 mg / mL, 15 mg / mL, or 20 mg / mL anti-PD-1 antibody or its antigen-binding fragment) and 15-60 mg / mL anti-TIM-3 antibody or its antigen-binding fragment (e.g., 15 mg / mL, 24 mg / mL, 30 mg / mL, 45 mg / mL, 48 mg / mL, or 60 mg / mL anti-TIM-3 antibody or its antigen-binding fragment), (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 60-180 mg / mL sucrose (e.g., 80 mg / mL, 85 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL or 164.3 mg / mL sucrose), and (d) 0.2-0.8 mg / mL polysorbate 80 (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0102] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5-10 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 5 mg / mL, 8 mg / mL, or 10 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof) and 15-60 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof (e.g., 15 mg / mL, 24 mg / mL, 30 mg / mL, 45 mg / mL, 48 mg / mL, or 60 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof), (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, In some embodiments, the pharmaceutical composition comprises: (a) a histidine-HCl buffer, or a histidine-acetate buffer), (c) 60-180 mg / mL sucrose (e.g., 80 mg / mL, 85 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL, or 164.3 mg / mL sucrose), and (d) 0.2-0.8 mg / mL polysorbate 80 (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, or 0.8 mg / mL polysorbate 80); and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0103] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5-15 mg / mL, or 5-10 mg / mL anti-PD-1 antibody or its antigen-binding fragment (e.g., 5 mg / mL, 8 mg / mL, 10 mg / mL or 15 mg / mL anti-PD-1 antibody or its antigen-binding fragment) and 15-60 mg / mL anti-TIM-3 antibody or its antigen-binding fragment (e.g., 15 mg / mL, 30 mg / mL, 45 mg / mL, 48 mg / mL or 60 mg / mL anti-TIM-3 antibody or its antigen-binding fragment), (b) 10-20 mM histidine buffer (e.g., 10 In some embodiments, the pharmaceutical composition comprises (a) 20 mM or 20 mM histidine-histidine hydrochloride buffer, (b) 70-170 mg / mL sucrose (e.g., 80 mg / mL, 85 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL or 164.3 mg / mL sucrose), and (c) 70-170 mg / mL sucrose (e.g., 80 mg / mL, 85 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL or 164.3 mg / mL sucrose), and (d) 0.4-0.8 mg / mL polysorbate 80 (e.g., 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0104] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5-10 mg / mL anti-PD-1 antibody or its antigen-binding fragment (e.g., 5 mg / mL, 8 mg / mL or 10 mg / mL anti-PD-1 antibody or its antigen-binding fragment) and 15-60 mg / mL anti-TIM-3 antibody or its antigen-binding fragment (e.g., 15 mg / mL, 24 mg / mL, 30 mg / mL, 45 mg / mL, 48 mg / mL or 60 mg / mL anti-TIM-3 antibody or its antigen-binding fragment), (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine- In some embodiments, the pharmaceutical composition comprises: (a) a histidine hydrochloride buffer, a histidine-hydrochloride buffer, or a histidine-acetate buffer), (c) 80-164.3 mg / mL sucrose (e.g., 80 mg / mL, 85 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL or 164.3 mg / mL sucrose), and (d) 0.4-0.8 mg / mL polysorbate 80 (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0105] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5-10 mg / mL anti-PD-1 antibody or its antigen-binding fragment (e.g., 5 mg / mL, 8 mg / mL or 10 mg / mL anti-PD-1 antibody or its antigen-binding fragment) and 30-60 mg / mL anti-TIM-3 antibody or its antigen-binding fragment (e.g., 30 mg / mL, 45 mg / mL, 48 mg / mL or 60 mg / mL anti-TIM-3 antibody or its antigen-binding fragment), (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer). granules), (c) 70-170 mg / mL sucrose (e.g., 80 mg / mL, 85 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL, or 164.3 mg / mL sucrose) or 200-500 mM sucrose (e.g., 230 mM, 234 mM, 400 mM, 450 mM, or 480 mM sucrose), and (d) 0.4-0.8 mg / mL polysorbate 80 (e.g., 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, or 0.8 mg / mL polysorbate 80); and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0106] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5-10 mg / mL anti-PD-1 antibody or its antigen-binding fragment (e.g., 5 mg / mL, 8 mg / mL or 10 mg / mL anti-PD-1 antibody or its antigen-binding fragment) and 30-60 mg / mL anti-TIM-3 antibody or its antigen-binding fragment (e.g., 30 mg / mL, 45 mg / mL, 48 mg / mL or 60 mg / mL anti-TIM-3 antibody or its antigen-binding fragment), (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride), acid buffer, histidine-HCl buffer, or histidine-acetate buffer), (c) 80-164.3 mg / mL sucrose (e.g., 80 mg / mL, 85 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL, or 164.3 mg / mL sucrose), and (d) 0.4-0.8 mg / mL polysorbate 80 (e.g., 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, or 0.8 mg / mL polysorbate 80); and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0107] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5-10 mg / mL anti-PD-1 antibody or its antigen-binding fragment (e.g., 5 mg / mL, 8 mg / mL, or 10 mg / mL anti-PD-1 antibody or its antigen-binding fragment) and 30-60 mg / mL anti-TIM-3 antibody or its antigen-binding fragment (e.g., 30 mg / mL, 45 mg / mL, 48 mg / mL, or 60 mg / mL anti-TIM-3 antibody or its antigen-binding fragment), (b) 10-20 mM histidine buffer (e.g., 10 In some embodiments, the pharmaceutical composition comprises (a) 20 mM or 20 mM histidine-histidine hydrochloride buffer, (b) 230-480 mM sucrose (e.g., 230 mM, 234 mM, 400 mM, 450 mM or 480 mM sucrose), and (c) 230-480 mM sucrose (e.g., 230 mM, 234 mM, 400 mM, 450 mM or 480 mM sucrose), and (d) 0.4-0.8 mg / mL polysorbate 80 (e.g., 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); and the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0108] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5 mg / mL of anti-PD-1 antibody or its antigen-binding fragment and 15 mg / mL of anti- TIM-3 antibody or antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 60-180 mg / mL sucrose (e.g., 80 mg / mL, 85 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL, or 164.3 mg / mL sucrose), and (d) 0.2-0.8 mg / mL polysorbate 80 (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, or 0.8 mg / mL polysorbate 80); the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0109] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 8 mg / mL anti-PD-1 antibody or antigen-binding fragment thereof and 24 mg / mL anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 60-180 mg / mL sucrose (e.g., 80 mg / mL sucrose). In some embodiments, the pharmaceutical composition comprises (a) 0.2-0.8 mg / mL of sucrose (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); and (b) 0.2-0.8 mg / mL of polysorbate 80 (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0110] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 8 mg / mL anti-PD-1 antibody or antigen-binding fragment thereof and 48 mg / mL anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 60-180 mg / mL sucrose (e.g., 80 mg / mL sucrose). In some embodiments, the pharmaceutical composition comprises (a) 0.2-0.8 mg / mL of sucrose (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); and (b) 0.2-0.8 mg / mL of polysorbate 80 (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0111] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 10 mg / mL anti-PD-1 antibody or antigen-binding fragment thereof and 30 mg / mL anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 60-180 mg / mL sucrose (e.g., 80 mg / mL sucrose). / mL, 85 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL or 164.3 mg / mL sucrose), and (d) 0.2-0.8 mg / mL polysorbate 80 (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0112] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 10 mg / mL anti-PD-1 antibody or antigen-binding fragment thereof and 60 mg / mL anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 60-180 mg / mL sucrose (e.g., 80 mg / mL sucrose). / mL, 85 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL or 164.3 mg / mL sucrose), and (d) 0.2-0.8 mg / mL polysorbate 80 (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0113] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 10 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 60 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 20 mM histidine buffer (e.g., 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 80 mg / mL sucrose, and (d) 0.2 mg / mL polysorbate 80; the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5 (e.g., 5.5, 5.8, 6, 6.2, or 6.5).

[0114] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5 mg / mL anti-PD-1 antibody or antigen-binding fragment thereof and 30 mg / mL anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 60-180 mg / mL sucrose (e.g., 80 mg / mL sucrose). In some embodiments, the pharmaceutical composition comprises (a) 0.2-0.8 mg / mL of sucrose (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); and (b) 0.2-0.8 mg / mL of polysorbate 80 (e.g., 0.2 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL or 0.8 mg / mL polysorbate 80); the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0115] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5 mg / mL anti-PD-1 antibody or antigen-binding fragment thereof and 30 mg / mL anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 80-164.3 mg / mL sucrose (e.g., 80 mg / mL, 85 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL, or 164.3 mg / mL sucrose), and (d) 0.4-0.8 mg / mL polysorbate 80 (e.g., 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, or 0.8 mg / mL polysorbate 80); the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0116] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5 mg / mL anti-PD-1 antibody or antigen-binding fragment thereof and 30 mg / mL anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 10-20 mM histidine buffer (e.g., 10 mM or 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 230-480 mM sucrose (e.g., 230 mM, 234 mM, 400 mM, 450 mM, or 480 mM sucrose), and (d) 0.4-0.8 mg / mL polysorbate 80 (e.g., 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, or 0.8 mg / mL polysorbate 80); the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5.

[0117] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5 mg / mL anti-PD-1 antibody or antigen-binding fragment thereof and 30 mg / mL anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 20 mM histidine buffer (e.g., 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 80-164.3 mg / mL sucrose (e.g., 80 mg / mL, 85 mg / mL, 85.6 mg / mL, 100 mg / mL, 164 mg / mL, or 164.3 mg / mL sucrose), and (d) 0.8 mg / mL polysorbate 80; the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5 (e.g., 5.5, 5.8, 6, 6.2, or 6.5).

[0118] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 4-6 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 5 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof) and 24-36 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof (e.g., 30 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof), (b) 15-25 mM histidine buffer (e.g., 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 150-180 mg / mL sucrose (e.g., 164.3 mg / mL sucrose), and (d) 0.7-0.9 mg / mL polysorbate 80 (e.g., 0.8 mg / mL polysorbate 80); the pH of the pharmaceutical composition is 5.3 to 6.3, 5.5 to 6.5, or 5.8 to 6.5 (e.g., 5.8).

[0119] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 30 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 20 mM histidine buffer (e.g., 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 164.3 mg / mL sucrose, and (d) 0.8 mg / mL polysorbate 80; the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5 (e.g., 5.5, 5.8, 6, 6.2, or 6.5).

[0120] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 30 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 20 mM histidine buffer (e.g., 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 230-480 mM sucrose (e.g., 230 mM, 234 mM, 400 mM, 450 mM or 480 mM sucrose), and (d) 0.8 mg / mL polysorbate 80; the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5 (e.g., 5.5, 5.8, 6, 6.2 or 6.5).

[0121] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 4-6 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 5 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof) and 24-36 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof (e.g., 30 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof), (b) 15-25 mM histidine buffer (e.g., 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 450-510 mM sucrose (e.g., 480 mM sucrose), and (d) 0.7-0.9 mg / mL polysorbate 80 (e.g., 0.8 mg / mL polysorbate 80); the pH of the pharmaceutical composition is 5.3 to 6.3, 5.5 to 6.5, or 5.8 to 6.5 (e.g., 5.8).

[0122] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 30 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 20 mM histidine buffer (e.g., 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 480 mM sucrose, and (d) 0.8 mg / mL polysorbate 80; the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5 (e.g., 5.5, 5.8, 6, 6.2, or 6.5).

[0123] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 30 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10 mM histidine buffer (e.g., 10 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 164.3 mg / mL sucrose, and (d) 0.8 mg / mL polysorbate 80; the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5 (e.g., 5.5, 5.8, 6, 6.2, or 6.5).

[0124] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 30 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 20 mM histidine buffer (e.g., 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 80 mg / mL sucrose, and (d) 0.8 mg / mL polysorbate 80; the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5 (e.g., 5.5, 5.8, 6, 6.2, or 6.5).

[0125] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 30 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 20 mM histidine buffer (e.g., 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 80 mg / mL sucrose, and (d) 0.4 mg / mL polysorbate 80; the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5 (e.g., 5.5, 5.8, 6, 6.2, or 6.5).

[0126] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 15 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 20 mM histidine buffer (e.g., 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 80 mg / mL sucrose, and (d) 0.4 mg / mL polysorbate 80; the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5 (e.g., 5.5, 5.8, 6, 6.2, or 6.5).

[0127] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 15 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 20 mM histidine buffer (e.g., 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 80 mg / mL sucrose, and (d) 0.8 mg / mL polysorbate 80; the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5 (e.g., 5.5, 5.8, 6, 6.2, or 6.5).

[0128] In some embodiments, the pharmaceutical composition of the present disclosure comprises: (a) 5 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 15 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 20 mM histidine buffer (e.g., 20 mM histidine-histidine hydrochloride buffer, histidine-hydrochloride buffer, or histidine-acetate buffer), (c) 164.3 mg / mL sucrose, and (d) 0.8 mg / mL polysorbate 80; the pH of the pharmaceutical composition is 5.5 to 6.5, or 5.8 to 6.5 (e.g., 5.5, 5.8, 6, 6.2, or 6.5).

[0129] In some embodiments, the pharmaceutical compositions of the present disclosure can be stably stored at 2-8°C for at least about 1 week, at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 1 year, or at least about 2 years. In some embodiments, the pharmaceutical compositions of the present disclosure can be stably stored at 25°C for at least about 1 week, at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 1 year, or at least about 2 years. In some embodiments, the pharmaceutical compositions of the present disclosure can be stably stored at 40°C for at least about 1 week, at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, at least about 9 months, at least about 1 year, or at least about 2 years.

[0130] Lyophilized preparations

[0131] The present disclosure also provides a lyophilized formulation comprising an anti-PD-1 antibody or an antigen-binding fragment thereof and a second antibody or an antigen-binding fragment thereof. In some embodiments, the second antibody or an antigen-binding fragment thereof is an anti-TIM-3 antibody or an antigen-binding fragment thereof.

[0132] The present disclosure also provides a method for preparing the lyophilized formulation, which includes the step of freeze-drying the pharmaceutical composition of the present disclosure. In some embodiments, the freeze-drying is carried out according to methods well 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 of removing water from the pharmaceutical composition of the present disclosure is applicable to the present disclosure. It will be understood by those skilled in the art that in the pharmaceutical field, lyophilized formulations typically have a residual moisture content of about 0.1 to 5% (w / v) and are present as a powder or a physically stable cake.

[0133] The present disclosure also provides a lyophilized preparation comprising an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, wherein the lyophilized preparation is prepared by the aforementioned method for preparing a lyophilized preparation.

[0134] The present disclosure also provides a lyophilized formulation comprising an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, which, upon reconstitution, can 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 dextrose injection. In the present disclosure, "reconstitution" and "reconstitution" are used interchangeably.

[0135] Anti-PD-1 antibodies or antigen-binding fragments thereof

[0136] In some embodiments, the anti-PD-1 antibodies or antigen-binding fragments thereof described herein comprise: a heavy chain CDR1 (HCDR1) having an amino acid sequence as set forth in SEQ ID NO: 11, a HCDR2 having an amino acid sequence as set forth in SEQ ID NO: 12, a HCDR3 having an amino acid sequence as set forth in SEQ ID NO: 13, a light chain CDR1 (LCDR1) having an amino acid sequence as set forth in SEQ ID NO: 14, a LCDR2 having an amino acid sequence as set forth in SEQ ID NO: 15, and a LCDR3 having an amino acid sequence as set forth in SEQ ID NO: 16. In some embodiments, the anti-PD-1 antibodies or antigen-binding fragments thereof comprise: HCDR1, HCDR2, and HCDR3 in the heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 17, and LCDR1, LCDR2, and LCDR3 in the light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 18. The CDR sequences of the anti-PD-1 antibodies or antigen-binding fragments thereof are shown in Table 1-1.

[0137] Table 1-1. CDR sequences of anti-PD-1 antibodies or antigen-binding fragments thereof

[0138] 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 1-1, 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 definitions known in the art, such as AbM, Kabat, CCG, Chothia, IMGT, or Contact).

[0139] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region set forth in SEQ ID NO: 17. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region set forth in SEQ ID NO: 18. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 17, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 17, and a light chain variable region having the amino acid sequence of SEQ ID NO: 18. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-PD-1 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 17, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 18.

[0140] In some embodiments, the anti-PD-1 antibodies or antigen-binding fragments thereof described in the present disclosure comprise 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 amino acid sequence of SEQ ID NO: 11, HCDR2 comprises the amino acid sequence of SEQ ID NO: 12, HCDR3 comprises the amino acid sequence of SEQ ID NO: 13, LCDR1 comprises the amino acid sequence of SEQ ID NO: 14, LCDR2 comprises the amino acid sequence of SEQ ID NO: 15, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 16, and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 17. NO:17 has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:18.

[0141] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment may further comprise an immunoglobulin constant region, or a fragment, analog, variant or derivative of the constant region. In some embodiments, the constant region comprises a heavy chain constant region and a light chain constant region. In some embodiments, the heavy chain constant region is from a human immunoglobulin heavy chain, such as IgG1, IgG2, IgG3 and IgG4 or other classes of immunoglobulin heavy chains, preferably IgG1 heavy chains. In some embodiments, the light chain constant region is from a human immunoglobulin light chain, such as a kappa light chain or a lambda light chain of a human immunoglobulin. In some embodiments, the constant region may comprise any modification described in the text, such as insertion, deletion, substitution or chemical modification of amino acids. In some embodiments, the constant region comprises a mutation that alters effector function. In some embodiments, any amino acid residue in the constant region may be substituted with an amino acid residue of any allotype.

[0142] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises the heavy chain set forth in SEQ ID NO: 19. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises the light chain set forth in SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19, and a light chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 19, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 20. In some specific embodiments, the heavy chain amino acid sequence of the anti-PD-1 antibody or antigen-binding fragment thereof is as set forth in SEQ ID NO: 19, and the light chain amino acid sequence is as set forth in SEQ ID NO: 20. The terminal amino acid K of SEQ ID NO: 19 may or may not be present.

[0143] The entire contents of the CN106977602A patent application document are incorporated herein by reference.

[0144] Anti-TIM-3 antibodies or antigen-binding fragments thereof

[0145] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof described herein comprises: a HCDR1 of the amino acid sequence set forth in SEQ ID NO: 1 or 21, a HCDR2 of the amino acid sequence set forth in SEQ ID NO: 2 or 22, a HCDR3 of the amino acid sequence set forth in SEQ ID NO: 3 or 23, a LCDR1 of the amino acid sequence set forth in SEQ ID NO: 4 or 24, a LCDR2 of the amino acid sequence set forth in SEQ ID NO: 5 or 25, and a LCDR3 of the amino acid sequence set forth in SEQ ID NO: 6 or 26. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises: a HCDR1 of the amino acid sequence set forth in SEQ ID NO: 1, a HCDR2 of the amino acid sequence set forth in SEQ ID NO: 2, a HCDR3 of the amino acid sequence set forth in SEQ ID NO: 3, a LCDR1 of the amino acid sequence set forth in SEQ ID NO: 4, a LCDR2 of the amino acid sequence set forth in SEQ ID NO: 5, and a LCDR3 of the amino acid sequence set forth in SEQ ID NO: 6. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises: a HCDR1 having an amino acid sequence as set forth in SEQ ID NO:21, a HCDR2 having an amino acid sequence as set forth in SEQ ID NO:22, a HCDR3 having an amino acid sequence as set forth in SEQ ID NO:23, a LCDR1 having an amino acid sequence as set forth in SEQ ID NO:24, a LCDR2 having an amino acid sequence as set forth in SEQ ID NO:25, and a LCDR3 having an amino acid sequence as set forth in SEQ ID NO:26. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises: HCDR1, HCDR2, and HCDR3 in the heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO:7, and LCDR1, LCDR2, and LCDR3 in the light chain variable region having an amino acid sequence as set forth in SEQ ID NO:8. The CDR sequences of the anti-TIM-3 antibodies or antigen-binding fragments thereof are shown in Tables 1-2.

[0146] Table 1-2. CDR sequences of anti-TIM-3 antibodies or antigen-binding fragments thereof

[0147] 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 Tables 1-2 have shown CDR sequences (wherein the CDR regions shown in SEQ ID NOs: 1-6 are defined by the AbM numbering system), when referring to antibodies defined by specific CDR sequences disclosed herein, the scope of the antibodies also encompasses antibodies defined by CDR sequences converted to any other numbering system (e.g., one or more combinations of the definitions of Kabat, Chothia, CCG, IMGT, or Contact, which are well known in the art). For example, an anti-TIM-3 antibody or antigen-binding fragment thereof comprising the following amino acid sequence: HCDR1 of the amino acid sequence set forth in SEQ ID NO: 1, HCDR2 of the amino acid sequence set forth in SEQ ID NO: 2, HCDR3 of the amino acid sequence set forth in ARRYYGYDAMDY (SEQ ID NO: 31), LCDR1 of the amino acid sequence set forth in SEQ ID NO: 4, LCDR2 of the amino acid sequence set forth in SEQ ID NO: 5, and LCDR3 of the amino acid sequence set forth in SEQ ID NO: 6 is also encompassed within the scope of the anti-TIM-3 antibodies or antigen-binding fragments thereof of the present disclosure.

[0148] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7 or 27. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 8 or 28. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region set forth in SEQ ID NO: 7. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a light chain variable region set forth in SEQ ID NO: 8. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7 or 27, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 8 or 28. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 and a light chain variable region having the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region having the amino acid sequence of SEQ ID NO: 27 and a light chain variable region having the amino acid sequence of SEQ ID NO: 28. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-TIM-3 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 7, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 8.In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-TIM-3 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 27, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 28.

[0149] In some embodiments, the anti-TIM-3 antibodies or antigen-binding fragments thereof described herein comprise 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 amino acid sequence of SEQ ID NO: 1, HCDR2 comprises the amino acid sequence of SEQ ID NO: 2, HCDR3 comprises the amino acid sequence of SEQ ID NO: 3, LCDR1 comprises the amino acid sequence of SEQ ID NO: 4, LCDR2 comprises the amino acid sequence of SEQ ID NO: 5, and LCDR3 comprises the amino acid sequence of SEQ ID NO: 6, and the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 7. NO:7 having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical, and the light chain variable region comprises an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identical to SEQ ID NO:8.

[0150] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof may further comprise an immunoglobulin constant region, or a fragment, analog, variant, or derivative of the constant region. In some embodiments, the constant region comprises a heavy chain constant region and a light chain constant region. In some embodiments, the heavy chain constant region is derived from a human immunoglobulin heavy chain, such as IgG1, IgG2, IgG3, and IgG4 or other classes of immunoglobulin heavy chains, preferably IgG4 heavy chains. In some embodiments, the light chain constant region is derived from a human immunoglobulin light chain, such as a kappa light chain or a lambda light chain of a human immunoglobulin. In some embodiments, the constant region may comprise any modification described herein, such as insertion, deletion, substitution, or chemical modification of amino acids. In some embodiments, the constant region comprises a mutation that alters effector function. In some embodiments, any amino acid residue in the constant region may be substituted with an amino acid residue of any allotype.

[0151] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 9 or 29. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a light chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10 or 30. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises the heavy chain set forth in SEQ ID NO: 9. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises the light chain set forth in SEQ ID NO: 10. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 9 or 29, and a light chain having an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10 or 30. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain having the amino acid sequence of SEQ ID NO: 9 and a light chain having the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises a heavy chain having the amino acid sequence of SEQ ID NO: 29 and a light chain having the amino acid sequence of SEQ ID NO: 30. In some specific embodiments, the amino acid sequence of the heavy chain of the anti-TIM-3 antibody or antigen-binding fragment thereof is as set forth in SEQ ID NO: 9, and the amino acid sequence of the light chain is as set forth in SEQ ID NO: 10. In some specific embodiments, the amino acid sequence of the heavy chain of the anti-TIM-3 antibody or antigen-binding fragment thereof is as set forth in SEQ ID NO: 29, and the amino acid sequence of the light chain is as set forth in SEQ ID NO: 30.The terminal amino acid K of SEQ ID NOs: 9 and 29 may be present or absent.

[0152] In some embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof of the present disclosure is mAb 50B5 or an antigen-binding fragment thereof described in the patent application document with publication number CN112566936A, or a chimeric antibody or an antigen-binding fragment thereof of mAb 50B5, or a humanized antibody or an antigen-binding fragment thereof of mAb 50B5.

[0153] In other embodiments, the anti-TIM-3 antibody or antigen-binding fragment thereof disclosed herein is mAb 15B4 or an antigen-binding fragment thereof described in the patent application document with publication number CN112566936A, or a chimeric antibody or an antigen-binding fragment thereof of mAb 15B4, or a humanized antibody or an antigen-binding fragment thereof of mAb 15B4.

[0154] The entire contents of the CN112566936A patent application document are incorporated herein by reference.

[0155] Preparation method of pharmaceutical composition

[0156] The present disclosure relates to any method of preparing the pharmaceutical composition of the present disclosure.

[0157] In some embodiments, the present disclosure provides a method for preparing a pharmaceutical composition of the present disclosure, comprising: mixing a pharmaceutical composition comprising an anti-TIM-3 antibody or antigen-binding fragment thereof with a pharmaceutical composition comprising an anti-PD-1 antibody or antigen-binding fragment thereof in a desired ratio. In some embodiments, the pharmaceutical composition of the antibody or antigen-binding fragment thereof comprises the antibody or antigen-binding fragment thereof and a buffer, and optionally, further comprises a stabilizer and a surfactant.

[0158] In some embodiments, the present disclosure provides a method for preparing a pharmaceutical composition of the present disclosure, comprising: contacting an anti-TIM-3 antibody or antigen-binding fragment thereof with a buffer, a stabilizer, and a surfactant, contacting an anti-PD-1 antibody or antigen-binding fragment thereof with a buffer, a stabilizer, and a surfactant, and mixing the two in a desired ratio. In some embodiments, the step of contacting the antibody or antigen-binding fragment thereof with the buffer, the stabilizer, and the surfactant comprises displacing the antibody or antigen-binding fragment thereof into the buffer, and then adding the surfactant and stabilizer, wherein the surfactant and stabilizer are added in no particular order.

[0159] It is understood that the preparation method of the present disclosure may further include the steps of sterilizing and packaging the prepared pharmaceutical composition (e.g., packaging into vials). The present disclosure does not specifically limit the sterilization method, and membrane filtration may be used but is not limited thereto.

[0160] In some embodiments, the buffer comprises a phosphate buffer, a histidine buffer, an acetate buffer, and / or a citrate buffer. In some embodiments, the stabilizer comprises a sugar alcohol, a disaccharide, a monosaccharide, an amino acid, and / or a salt. In some embodiments, the surfactant comprises a polysorbate, a poloxamer, and / or a polyethylene glycol.

[0161] use

[0162] The present disclosure provides a method for treating a disease in a subject, the method comprising administering a pharmaceutical composition or lyophilized formulation of the present disclosure to the subject. The present disclosure provides a method for treating a disease in a subject, the method comprising administering a therapeutically effective amount of a pharmaceutical composition or lyophilized formulation of the present disclosure to the subject. The present disclosure also provides the use of the pharmaceutical composition and lyophilized formulation of the present disclosure in the preparation of a medicament for treating a disease in a subject.

[0163] The present disclosure provides a method for enhancing an immune response in a subject, the method comprising administering a pharmaceutical composition or lyophilized formulation of the present disclosure to the subject. The present disclosure provides a method for enhancing an immune response in a subject, the method comprising administering a therapeutically effective amount of a pharmaceutical composition or lyophilized formulation of the present disclosure to the subject. The present disclosure also provides the use of the pharmaceutical composition and lyophilized formulation of the present disclosure in the preparation of a medicament for enhancing an immune response in a subject.

[0164] The present disclosure provides a method for inducing or enhancing an anti-tumor immune response, comprising administering a pharmaceutical composition or lyophilized formulation of the present disclosure to a subject. The present disclosure provides a method for inducing or enhancing an anti-tumor immune response, comprising administering a therapeutically effective amount of a pharmaceutical composition or lyophilized formulation of the present disclosure to a subject. The present disclosure also provides the use of the pharmaceutical composition and lyophilized formulation of the present disclosure in the preparation of a medicament for inducing or enhancing an anti-tumor immune response.

[0165] The present disclosure provides a method for treating cancer in a subject, the method comprising administering to the subject a pharmaceutical composition or lyophilized formulation of the present disclosure. The present disclosure provides a method for treating cancer in a subject, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition or lyophilized formulation of the present disclosure. The present disclosure also provides use of the pharmaceutical composition and lyophilized formulation of the present disclosure in the preparation of a medicament for treating cancer in a subject.

[0166] The term "cancer" is the name of a disease in which the cells of the body become abnormal and divide and grow uncontrollably. In some embodiments, the cancer is a recurrent, refractory, metastatic, and / or advanced cancer. In some embodiments, the cancer is a non-solid tumor. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer includes but is not limited to head and neck cancer, nasopharyngeal cancer, oral cancer, esophageal cancer, lung cancer, liver cancer, colon cancer, colorectal cancer, kidney cancer, endometrial cancer, cervical cancer, glioblastoma, bladder cancer, breast cancer, ovarian cancer, fallopian tube cancer, prostate cancer, anal cancer, testicular cancer, vaginal cancer, stomach cancer, gastroesophageal junction cancer, pancreatic cancer, bone cancer, thyroid cancer, skin cancer, nervous system tumors, sarcomas, myeloma, bile duct cancer, gallbladder cancer, soft tissue sarcomas, lymphomas, and hematologic tumors.

[0167] In some embodiments, the head and neck cancer comprises head and neck squamous cell carcinoma. In some embodiments, the esophageal cancer comprises esophageal squamous cell carcinoma. In some embodiments, the lung cancer comprises small cell lung cancer and non-small cell lung cancer. In some embodiments, the liver cancer comprises hepatocellular carcinoma. In some embodiments, the kidney cancer comprises renal cell carcinoma. In some embodiments, the bladder cancer comprises urothelial carcinoma. In some embodiments, the skin cancer comprises melanoma.

[0168] In some embodiments, the lymphoma comprises Hodgkin lymphoma and non-Hodgkin lymphoma. In some embodiments, the lymphoma comprises T-cell non-Hodgkin lymphoma or B-cell non-Hodgkin lymphoma. In some embodiments, the non-Hodgkin lymphoma comprises primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, peripheral T-cell lymphoma, mantle cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, marginal zone lymphoma, and / or AIDS-related B-cell lymphoma.

[0169] In some embodiments, the bloodstream comprises myeloma, leukemia, myelodysplastic syndrome, myelofibrosis, and B-cell malignancies. In some embodiments, the leukemia comprises acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and chronic myelomonocytic leukemia.

[0170] In some embodiments, the pharmaceutical compositions or lyophilized formulations of the present disclosure can be administered together with cancer therapeutics known in the art.

[0171] The present disclosure provides a method for treating an infectious disease of a subject, the method comprising administering a pharmaceutical composition or lyophilized preparation of the present disclosure to the subject. The present disclosure provides a method for treating an infectious disease of a subject, the method comprising administering a therapeutically effective amount of a pharmaceutical composition or lyophilized preparation of the present disclosure to the subject. The present disclosure also provides the use of the pharmaceutical composition and lyophilized preparation of the present disclosure in the preparation of a medicament for treating an infectious disease. In some embodiments, the infectious disease is a disease caused by organisms such as bacteria, fungi, parasites, viruses or other pathogens, including but not limited to AIDS, viral hepatitis, viral pneumonia, hand, foot and mouth disease, meningitis, measles, etc. In some embodiments, the pharmaceutical composition or lyophilized preparation of the present disclosure can be administered together with infectious disease therapeutic agents known in the art, such as vaccines.

[0172] The pharmaceutical compositions and lyophilized formulations of the present disclosure 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.

[0173] In some embodiments, pharmaceutical compositions of the present disclosure and lyophilized formulations are suitable for parenteral administration. In some embodiments, pharmaceutical compositions of the present disclosure and lyophilized formulations are suitable for intravenous, intramuscular, intraperitoneal, subcutaneous, epidermal, spinal, intralesional injection or infusion. In some embodiments, pharmaceutical compositions of the present disclosure and lyophilized formulations are suitable for topical administration, inhalation, oral administration or administration by sustained release or delayed release delivery systems. In some embodiments, pharmaceutical compositions of the present disclosure, lyophilized formulations, and the reconstituted solution of lyophilized formulations 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.

[0174] Medical devices, kits, and vials

[0175] The present disclosure also provides a product comprising a container containing a pharmaceutical composition or lyophilized formulation of the present disclosure. The product of the present disclosure may also include instructions for using the pharmaceutical composition or lyophilized formulation of the present disclosure for treating a disease. The container is a single chamber (containing a pharmaceutical composition or lyophilized formulation comprising an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof).

[0176] The present disclosure also provides a medicine box or vial comprising a pharmaceutical composition or lyophilized formulation of the present disclosure. The medicine box and vial of the present disclosure may also include instructions for the use of the pharmaceutical composition or lyophilized formulation of the present disclosure in treating a disease. The vial is a single chamber (containing a pharmaceutical composition or lyophilized formulation comprising an anti-PD-1 antibody or its antigen-binding fragment and an anti-TIM-3 antibody or its antigen-binding fragment).

[0177] The present disclosure also provides a medical device comprising a pharmaceutical composition or lyophilized formulation of the present disclosure. The medical device of the present disclosure may also include instructions for use of the pharmaceutical composition or lyophilized formulation of the present disclosure in treating a disease. In some embodiments, the medical device includes a syringe and an intravenous bag. The syringe or intravenous bag is a single-chamber (containing a pharmaceutical composition or lyophilized formulation comprising an anti-PD-1 antibody or its antigen-binding fragment and an anti-TIM-3 antibody or its antigen-binding fragment).

[0178] In some embodiments, the disease comprises cancer. In some embodiments, the cancer is recurrent, refractory, metastatic and / or advanced cancer. In some embodiments, the cancer is a non-solid tumor. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer includes but is not limited to head and neck cancer, nasopharyngeal cancer, oral cancer, esophageal cancer, lung cancer, liver cancer, colon cancer, colorectal cancer, kidney cancer, endometrial cancer, cervical cancer, glioblastoma, bladder cancer, breast cancer, ovarian cancer, fallopian tube cancer, prostate cancer, anal cancer, testicular cancer, vaginal cancer, gastric cancer, gastroesophageal junction cancer, pancreatic cancer, bone cancer, thyroid cancer, skin cancer, nervous system tumors, sarcomas, myeloma, bile duct cancer, gallbladder cancer, soft tissue sarcomas, lymphomas and hematological tumors.

[0179] In some embodiments, the head and neck cancer comprises head and neck squamous cell carcinoma. In some embodiments, the esophageal cancer comprises esophageal squamous cell carcinoma. In some embodiments, the lung cancer comprises small cell lung cancer and non-small cell lung cancer. In some embodiments, the liver cancer comprises hepatocellular carcinoma. In some embodiments, the kidney cancer comprises renal cell carcinoma. In some embodiments, the bladder cancer comprises urothelial carcinoma. In some embodiments, the skin cancer comprises melanoma.

[0180] In some embodiments, the lymphoma comprises Hodgkin lymphoma and non-Hodgkin lymphoma. In some embodiments, the lymphoma comprises T-cell non-Hodgkin lymphoma or B-cell non-Hodgkin lymphoma. In some embodiments, the non-Hodgkin lymphoma comprises primary mediastinal large B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, peripheral T-cell lymphoma, mantle cell lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, cutaneous T-cell lymphoma, cutaneous B-cell lymphoma, marginal zone lymphoma, and / or AIDS-related B-cell lymphoma.

[0181] In some embodiments, the bloodstream comprises myeloma, leukemia, myelodysplastic syndrome, myelofibrosis, and B-cell malignancies. In some embodiments, the leukemia comprises acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and chronic myelomonocytic leukemia.

[0182] In some embodiments, the disease includes an infectious disease. In some embodiments, the infectious disease is a disease caused by organisms such as bacteria, fungi, parasites, viruses, or other pathogens, including but not limited to AIDS, viral hepatitis, viral pneumonia, hand, foot and mouth disease, meningitis, measles, etc.

[0183] The pharmaceutical compositions of the present disclosure can be provided in any desired volume. In some embodiments, the pharmaceutical compositions of the present disclosure are present in a single cavity of a container, vial, syringe, or intravenous bag with a fill volume of 1 ml, 2 ml, 5 ml, 10 ml, or 20 ml. In some embodiments, the pharmaceutical compositions of the present disclosure are present in a single cavity of a container, vial, syringe, or intravenous bag with a fill volume of 30 ml or 40 ml. In some embodiments, the container, vial, syringe, or intravenous bag contains 100 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof and 600 mg of an anti-TIM-3 antibody or an antigen-binding fragment thereof.

[0184] The present disclosure also provides the following specific implementation schemes, but the protection scope of the present disclosure is not limited thereto:

[0185] Embodiment 1. A pharmaceutical composition comprising (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) a buffer, (c) a stabilizer, and (d) a surfactant.

[0186] Embodiment 2. The pharmaceutical composition of embodiment 1, wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-TIM-3 antibody or antigen-binding fragment thereof is 1:1-30, 1:1-20, 1:1-18, 1:1-15, 1:1-12, 1:1-10, 1:1-9, 1:1-7.5, 1:1-6, 1:1-5, 1:1-4.5, 1:1-3, 1:1-2 or 1:1-1.5.

[0187] Embodiment 3. The pharmaceutical composition of embodiment 1 or 2, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is at a concentration of 1-100 mg / mL, 1-80 mg / mL, 2-60 mg / mL, 3-30 mg / mL, 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL.

[0188] Embodiment 4. The pharmaceutical composition of any one of Embodiments 1-3, wherein the concentration of the anti-TIM-3 antibody or antigen-binding fragment thereof is 1-200 mg / mL, 3-180 mg / mL, 6-120 mg / mL, 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL.

[0189] Embodiment 5. The pharmaceutical composition according to any one of Embodiments 1-4, wherein the mass of the anti-PD-1 antibody or antigen-binding fragment thereof is 100-200 mg, or any multiple / fraction thereof.

[0190] Embodiment 6. The pharmaceutical composition according to any one of Embodiments 1-5, wherein the mass of the anti-TIM-3 antibody or antigen-binding fragment thereof is 100-2400 mg, 100-1800 mg, 300-1800 mg, 600-1500 mg, or 600-1200 mg, or any multiple / fraction thereof.

[0191] Embodiment 7. The pharmaceutical composition according to any one of embodiments 1-6, wherein the buffer comprises a histidine buffer, an acetate buffer, a Tris buffer, a phosphate buffer and / or a citrate buffer.

[0192] Embodiment 8. The pharmaceutical composition of any one of embodiments 1-7, wherein the concentration of the buffer is 1-100 mM, 2-80 mM, 5-60 mM, 10-40 mM, or 10-20 mM.

[0193] Embodiment 9. The pharmaceutical composition according to any one of embodiments 1-8, wherein the pharmaceutical composition comprises 1-100 mM, 2-80 mM, 5-60 mM, 10-40 mM, or 10-20 mM histidine buffer.

[0194] Embodiment 10. The pharmaceutical composition according to any one of embodiments 1-9, wherein the stabilizer comprises mannitol, sorbitol, trehalose, sucrose, maltose, lactose, lysine, glycine, proline, arginine or a pharmaceutically acceptable salt thereof and / or sodium chloride.

[0195] Embodiment 11. The pharmaceutical composition of any one of Embodiments 1-10, wherein the concentration of the stabilizer is 1-400 mg / mL, 10-300 mg / mL, 20-200 mg / mL, 40-200 mg / mL, 40-180 mg / mL, 60-180 mg / mL, or 70-170 mg / mL.

[0196] Embodiment 12. The pharmaceutical composition of any one of Embodiments 1-11, wherein the pharmaceutical composition comprises 1-400 mg / mL, 10-300 mg / mL, 20-200 mg / mL, 40-200 mg / mL, 40-180 mg / mL, 60-180 mg / mL, or 70-170 mg / mL of sucrose.

[0197] Embodiment 13. The pharmaceutical composition according to any one of embodiments 1-12, wherein the surfactant comprises polysorbate 80 or polysorbate 20.

[0198] Embodiment 14. The pharmaceutical composition of any one of Embodiments 1-13, wherein the concentration of the surfactant is 0.01-3 mg / mL, 0.04-2 mg / mL, 0.08-1.6 mg / mL, 0.1-1.2 mg / mL, 0.1-1 mg / mL, 0.2-0.8 mg / mL, or 0.4-0.8 mg / mL.

[0199] Embodiment 15. The pharmaceutical composition of any one of Embodiments 1-14, wherein the pharmaceutical composition comprises 0.01-3 mg / mL, 0.04-2 mg / mL, 0.08-1.6 mg / mL, 0.1-1.2 mg / mL, 0.1-1 mg / mL, 0.2-0.8 mg / mL, or 0.4-0.8 mg / mL of polysorbate 80.

[0200] Embodiment 16. The pharmaceutical composition of any one of Embodiments 1-15, wherein the pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5, or 5.8 to 6.5.

[0201] Embodiment 17. The pharmaceutical composition according to any one of Embodiments 1-16, wherein the pharmaceutical composition comprises:

[0202] (a) an anti-PD-1 antibody or antigen-binding fragment thereof and an anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 1-100 mM histidine buffer, (c) 1-400 mg / mL sucrose, and (d) 0.01-3 mg / mL polysorbate 80 or polysorbate 20; wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-LAG-3 antibody or antigen-binding fragment thereof is 1:2, 1:3, 1:6 or 1:7.5, and the pH of the pharmaceutical composition is 5.5 to 6.5;

[0203] (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM histidine buffer, (c) 60-180 mg / mL sucrose, and (d) 0.2-0.8 mg / mL polysorbate 80; wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-LAG-3 antibody or its antigen-binding fragment is 1:2, 1:3, 1:6 or 1:7.5, and the pH of the pharmaceutical composition is 5.5 to 6.5;

[0204] (a) an anti-PD-1 antibody or antigen-binding fragment thereof and an anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 10-20 mM histidine buffer, (c) 80-164.3 mg / mL sucrose, and (d) 0.4-0.8 mg / mL polysorbate 80; wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-LAG-3 antibody or antigen-binding fragment thereof is 1:6, and the pH of the pharmaceutical composition is 5.5 to 6.5;

[0205] (a) an anti-PD-1 antibody or antigen-binding fragment thereof and an anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 20 mM histidine buffer, (c) 80-164.3 mg / mL sucrose, and (d) 0.8 mg / mL polysorbate 80; wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-LAG-3 antibody or antigen-binding fragment thereof is 1:6, and the pH of the pharmaceutical composition is 5.5 to 6.5;

[0206] (a) 90-110 mg or multiples / fractions thereof of an anti-PD-1 antibody or antigen-binding fragment thereof and 540-660 mg or multiples / fractions thereof of an anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 15-25 mM histidine buffer, (c) 150-180 mg / mL sucrose, and (d) 0.7-0.9 mg / mL polysorbate 80, and the pH of the pharmaceutical composition is 5.3 to 6.3; or

[0207] (a) 90-110 mg or multiples / fractions thereof of an anti-PD-1 antibody or an antigen-binding fragment thereof and 540-660 mg or multiples / fractions thereof of an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 15-25 mM histidine buffer, (c) 450-510 mM sucrose, and (d) 0.7-0.9 mg / mL polysorbate 80, and the pH of the pharmaceutical composition is 5.3 to 6.3.

[0208] Embodiment 18. The pharmaceutical composition according to any one of embodiments 1-17, wherein the pharmaceutical composition comprises:

[0209] (a) 1-100 mg / mL anti-PD-1 antibody or antigen-binding fragment thereof and 1-200 mg / mL anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 1-100 mM histidine buffer, (c) 1-400 mg / mL sucrose, and (d) 0.01-3 mg / mL polysorbate 80 or polysorbate 20, and the pH of the pharmaceutical composition is 5.5 to 6.5;

[0210] (a) 5-10 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 15-60 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM histidine buffer, (c) 60-180 mg / mL sucrose, and (d) 0.2-0.8 mg / mL polysorbate 80, and the pH of the pharmaceutical composition is 5.5 to 6.5;

[0211] (a) 5-10 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 15-60 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM histidine buffer, (c) 80-164.3 mg / mL sucrose, and (d) 0.4-0.8 mg / mL polysorbate 80, and the pH of the pharmaceutical composition is 5.5 to 6.5;

[0212] (a) 5 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 30 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 20 mM histidine buffer, (c) 80-164.3 mg / mL sucrose, and (d) 0.8 mg / mL polysorbate 80, and the pH of the pharmaceutical composition is 5.5 to 6.5;

[0213] (a) 4-6 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 24-36 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 15-25 mM histidine buffer, (c) 150-180 mg / mL sucrose, and (d) 0.7-0.9 mg / mL polysorbate 80, and the pH of the pharmaceutical composition is 5.3 to 6.3; or

[0214] (a) 4-6 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 24-36 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 15-25 mM histidine buffer, (c) 450-510 mM sucrose, and (d) 0.7-0.9 mg / mL polysorbate 80, and the pH of the pharmaceutical composition is 5.3 to 6.3.

[0215] Embodiment 19. The pharmaceutical composition of any one of Embodiments 1-18, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a HCDR1 with the amino acid sequence set forth in SEQ ID NO: 11, a HCDR2 with the amino acid sequence set forth in SEQ ID NO: 12, a HCDR3 with the amino acid sequence set forth in SEQ ID NO: 13, a LCDR1 with the amino acid sequence set forth in SEQ ID NO: 14, a LCDR2 with the amino acid sequence set forth in SEQ ID NO: 15, and a LCDR3 with the amino acid sequence set forth in SEQ ID NO: 16.

[0216] Embodiment 20. The pharmaceutical composition of any one of Embodiments 1-19, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 17, and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18.

[0217] Embodiment 21. The pharmaceutical composition of any one of Embodiments 1-20, wherein the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a heavy chain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 19, and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 20.

[0218] Embodiment 22. The pharmaceutical composition according to any one of Embodiments 1 to 21, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises: a HCDR1 of the amino acid sequence set forth in SEQ ID NO: 1, a HCDR2 of the amino acid sequence set forth in SEQ ID NO: 2, a HCDR3 of the amino acid sequence set forth in SEQ ID NO: 3, a LCDR1 of the amino acid sequence set forth in SEQ ID NO: 4, a LCDR2 of the amino acid sequence set forth in SEQ ID NO: 5, and a LCDR3 of the amino acid sequence set forth in SEQ ID NO: 6; or a HCDR1 of the amino acid sequence set forth in SEQ ID NO: 21, a HCDR2 of the amino acid sequence set forth in SEQ ID NO: 22, a HCDR3 of the amino acid sequence set forth in SEQ ID NO: 23, a LCDR1 of the amino acid sequence set forth in SEQ ID NO: 24, a LCDR2 of the amino acid sequence set forth in SEQ ID NO: 25, and a LCDR3 of the amino acid sequence set forth in SEQ ID NO: 26.

[0219] Embodiment 23. The pharmaceutical composition of any one of Embodiments 1-22, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 7, and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 8; or a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 27, and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 28.

[0220] Embodiment 24. The pharmaceutical composition of any one of Embodiments 1-23, wherein the anti-TIM-3 antibody or antigen-binding fragment thereof comprises: a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 9, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 10; or a heavy chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 29, and a light chain having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 30.

[0221] Embodiment 25. A lyophilized preparation, wherein the lyophilized preparation is obtained by freeze-drying the pharmaceutical composition according to any one of Embodiments 1-24; or the lyophilized preparation can form the pharmaceutical composition according to any one of Embodiments 1-24 after reconstitution.

[0222] Embodiment 26. A vial, wherein the vial contains the pharmaceutical composition of any one of Embodiments 1-24 or the lyophilized formulation of Embodiment 25.

[0223] Embodiment 27. Use of the pharmaceutical composition of any one of Embodiments 1-24 or the lyophilized formulation of Embodiment 25 in the preparation of a medicament for treating a disease in a subject.

[0224] Embodiment 28. The use according to embodiment 27, wherein the disease comprises cancer and an infectious disease; optionally, the cancer is recurrent, refractory, metastatic and / or advanced cancer.

[0225] Embodiment 29. The use according to embodiment 28, wherein the cancer comprises head and neck cancer, nasopharyngeal cancer, oral cancer, esophageal cancer, lung cancer, liver cancer, colon cancer, colorectal cancer, kidney cancer, endometrial cancer, cervical cancer, glioblastoma, bladder cancer, breast cancer, ovarian cancer, fallopian tube cancer, prostate cancer, anal cancer, testicular cancer, vaginal cancer, gastric cancer, gastroesophageal junction cancer, pancreatic cancer, bone cancer, thyroid cancer, skin cancer, nervous system tumors, sarcoma, myeloma, bile duct cancer, gallbladder cancer, soft tissue sarcoma, lymphoma and hematological tumors.

[0226] Embodiment 30. The use according to any one of embodiments 27 to 29, wherein the pharmaceutical composition or lyophilized formulation is suitable for parenteral administration.

[0227] Embodiment 31. A method of treating a disease in a subject, the method comprising administering to the subject the pharmaceutical composition of any one of embodiments 1-24 or the lyophilized formulation of embodiment 25.

[0228] Embodiment 32. The method according to embodiment 31, wherein the disease comprises cancer and an infectious disease; optionally, the cancer is recurrent, refractory, metastatic and / or advanced cancer.

[0229] Embodiment 33. The method of embodiment 32, wherein the cancer comprises head and neck cancer, nasopharyngeal cancer, oral cancer, esophageal cancer, lung cancer, liver cancer, colon cancer, colorectal cancer, kidney cancer, endometrial cancer, cervical cancer, glioblastoma, bladder cancer, breast cancer, ovarian cancer, fallopian tube cancer, prostate cancer, anal cancer, testicular cancer, vaginal cancer, gastric cancer, gastroesophageal junction cancer, pancreatic cancer, bone cancer, thyroid cancer, skin cancer, nervous system tumors, sarcoma, myeloma, bile duct cancer, gallbladder cancer, soft tissue sarcoma, lymphoma, and hematologic tumors.

[0230] Embodiment 34. The method according to any one of embodiments 31-33, wherein the pharmaceutical composition or lyophilized formulation is suitable for parenteral administration.

[0231] Embodiment 35. The method of any one of embodiments 31-34, wherein the pharmaceutical composition or lyophilized formulation is administered to the subject in a therapeutically effective amount.

[0232] The present disclosure is further illustrated by the following examples, which should not be construed as further limiting.The contents of all references, Genbank records, patents, and published patent applications cited in this disclosure are expressly incorporated herein by reference. Example

[0233] The heavy chain amino acid sequence of the anti-TIM-3 antibody h50B5 in the Examples is shown in SEQ ID NO: 9, and the light chain amino acid sequence is shown in SEQ ID NO: 10. The heavy chain amino acid sequence of the anti-PD-1 antibody 14C12H1L1 in the Examples is shown in SEQ ID NO: 19, and the light chain amino acid sequence is shown in SEQ ID NO: 20. The heavy chain amino acid sequence of TSR022 in the Examples is shown in SEQ ID NO: 32, and the light chain amino acid sequence is shown in SEQ ID NO: 33.

[0234] Example 1 Binding of Anti-TIM-3 Antibodies to Human TIM-3

[0235] Human TIM-3 (R&D) recombinant protein was coated in an ELISA 96-well plate (Greiner), and different concentrations of anti-TIM-3 antibody h50B5 (100,000 ng / mL, 30,000 ng / mL, 10,000 ng / mL, 3,000 ng / mL, 1,000 ng / mL, 300 ng / mL, 100 ng / mL, 30 ng / mL, 10 ng / mL, 30 ng / mL, 10 ng / mL, 3 ng / mL) were added and incubated at 37°C for 1 hour. After washing the 96-well plate with PBS (pH 7.4), Goat anti-human Ig kappa chain-HRP conjugate (Millipore) was added and incubated at 37°C for 1 hour. The HRP substrate o-phenylenediamine dihydrochloride (OPD) was added, and the reaction was terminated with H2SO4. The OD value was measured at a wavelength of 450 nm using a full-function microplate reader Synergy H4 (BioTek). The binding EC value was calculated based on the OD value. 50 .

[0236] The results showed that the anti-TIM-3 antibody h50B5 had a strong binding affinity with human TIM-3 protein and 50 was 291.0±14.1ng / mL, and the maximum binding E max (OD 450 ) is 0.52±0.03.

[0237] The human TIM-3 gene was transfected into CHO-S cells and cultured in Dynamis AGT medium (containing 4 mM glutamate and 3 μg / mL Puromycin) at 37° C. in an incubator containing 5% CO 2 in air to obtain CHO-S-HuTIM-3 cells. Different concentrations of h50B5 or TSR022 (300000ng / mL, 100000ng / mL, 30000ng / mL, 10000ng / mL, 3000ng / mL, 1000ng / mL, 300ng / mL, 100ng / mL, 30ng / mL, 10ng / mL) were incubated with CHO-S-HuTIM-3 cells at 4°C for 1 hour, and then Goat anti-human Ig kappa chain-HRP conjugate was added and incubated at 37°C for 1 hour. Finally, HRP substrate OPD was added, and the reaction was terminated with H2SO4. The OD value was measured at a wavelength of 450nm using a full-function microplate reader Synergy H4. The binding EC was calculated based on the OD value. 50 .

[0238] As shown in Figure 1, h50B5 binds strongly to CHO-S-HuTIM-3 cells that highly express human TIM-3 and binds to EC 50 and the maximum combined E max (OD 450 ) were 1456.0±338.0 ng / mL and 0.21±0.03; the EC values ​​of TSR022 binding to CHO-S-HuTIM-3 cells were 50 and the maximum combined E max (OD 450 ) were 6815.5±166.2 ng / mL and 0.26±0.05, respectively. The binding activity of h50B5 was stronger than that of TSR022.

[0239] Example 2 Effect of anti-TIM-3 antibodies on IFN-γ secretion in mixed lymphocyte reaction (MLR)

[0240] CD14 was isolated from human PBMC (prepared in-house) using a CD14 magnetic bead isolation kit (Miltenyi Biotec). + After the mononuclear cells were cultured, they were induced with GM-CSF (Xiamen Tebao Bioengineering Co., Ltd.) for 7 days to differentiate into mature dendritic cells (DCs); CD4 + CD4 T cell magnetic bead isolation kit (Miltenyi Biotec) was used to isolate CD4 T cells from human PBMCs. + T cells, then CD4 +T cells were mixed with mature DCs and incubated for 5 days with varying concentrations of h50B5 or TSR022 (100 μg / mL, 10 μg / mL, and 1 μg / mL). A blank control (no antibody) was also established. The cells were then aspirated and the IFN-γ content was measured using an IFN-γ assay kit (Cisbio).

[0241] As shown in Figure 2, after DC cells were induced to mature, they were incubated with allogeneic CD4 + T cells interact with each other, and h50B5 can significantly promote the secretion of IFN-γ in MLR, with activity superior to TSR022.

[0242] Example 3 Effect of anti-TIM-3 antibodies on tumor-infiltrating lymphocytes in subcutaneous transplanted tumors of lung cancer HCC827 human immune reconstitution mice (PBMC-NCG)

[0243] NCG mice were subcutaneously inoculated with HCC827 cells (Cell Bank of the Chinese Academy of Sciences), 8×10 6 cells / mouse. When the tumor grows to 100-150 mm 3 , intravenous injection of human PBMC (Shanghai Ausells Biotechnology (Shanghai) Co., Ltd., catalog number PB004F), 6×10 6 cells / mouse. On the second day, h50B5 or hIgG4 (dosage was 10 mg / kg) was injected intravenously. Blood was collected from the mouse orbits at different time points (5 min, 4 h, 24 h, 48 h, 72 h, 96 h, 168 h) after administration, and serum was separated to detect drug concentration. Orbital blood was collected from 6 mice at each time point. 72 hours after administration, groups 1 and 3 were dissected; 168 hours after administration, groups 2 and 4 were dissected. Tumor tissues were taken from each group, tumor infiltrating lymphocytes (TILs) were separated, and human CD45 was analyzed by flow cytometry. + 、CD3 + 、CD4 + 、CD8 + Cell ratio. The experimental design is shown in Table 2-1. min represents minutes, and h represents hours.

[0244] Table 2-1. Experimental design

[0245] As shown in Table 2-2, 168 hours after tumor-bearing mice were intravenously injected with h50B5 (10 mg / kg), CD8 + / CD3 + The proportion of T cells was significantly higher in the hIgG4 group (46.9±6.9% vs 31.1±6.9%, P<0.01), and CD8 + / CD4 +The proportion of T cells was significantly higher than that in the hIgG4 group (112.7±32.1% vs 60.2±11.3%, P<0.01), indicating that h50B5 can promote the proliferation of CD8 T cells in HCC827 subcutaneous transplanted tumor tissues. + T cell infiltration, significantly increased CD3 + CD8 T cells + As shown in Figure 3, after a single intravenous injection of 50B5 (10 mg / kg) into tumor-bearing mice, the serum concentration of h50B5 gradually decreased over time. 168 hours after administration, the serum concentration of h50B5 still reached 29.4±2.3 μg / mL. The Cmax was 150.3 μg / mL, and the AUC 0-168 h 8142.0 h·μg·mL -1 .

[0246] Table 2-2. Effects of a single intravenous injection of h50B5 or hIgG4 on the proportions of various T cell subsets in TILs of subcutaneous transplanted tumors in human immune reconstituted mice (PBMC-NCG) with lung cancer HCC827

[0247] Mean ± SD; **P < 0.01 vs hIgG4 group.

[0248] Example 4 Preparation of buffer and detection method of pharmaceutical composition

[0249] Preparation of buffer

[0250] Histidine-histidine hydrochloride buffer: prepared from L-histidine and histidine hydrochloride monohydrate. For example, 20 mM histidine-histidine hydrochloride buffer (pH 6.0) can be prepared from about 1.36 g / L histidine and about 2.35 g / L histidine hydrochloride monohydrate.

[0251] Acetic acid-sodium acetate buffer: prepared from acetic acid and sodium acetate trihydrate. For example, 20 mM acetic acid-sodium acetate buffer (pH 6.0) can be prepared from about 2.60 g / L sodium acetate trihydrate and about 0.15 g / L acetic acid (37%).

[0252] Histidine-HCl buffer: prepared with L-histidine and adjusted to the target pH with hydrochloric acid. For example, 20 mM histidine-HCl buffer (pH 5.8) can be prepared with about 3.1 g / L L-histidine and adjusted to pH 5.8 with hydrochloric acid.

[0253] Histidine-acetate buffer: prepared with L-histidine and adjusted to the target pH with acetic acid. For example, 20 mM histidine-acetate buffer (pH 5.8) can be prepared with about 3.1 g / L L-histidine and adjusted to pH 5.8 with acetic acid.

[0254] Detection method

[0255] Size exclusion chromatography (SEC-UPLC): used to determine the purity of antibodies in samples, using Thermo Vanquish F high performance liquid chromatography, ACQUITY UPLC Protein BEH SEC Column ( 1.7μm, 4.6*300mm) as the chromatographic column, ACQUITY UPLC Protein BEH SEC Guard Column ( A pre-column (1.7 μm, 4.6 x 30 mm) was used. Elution was performed with a 50 mmol / L phosphate-200 mmol / L sodium chloride solution (pH 7.0) as the mobile phase. Detection was at a wavelength of 280 nm. Peak area percentages of high-molecular-weight impurities and immunoglobulin monomers were calculated using the area normalization method.

[0256] Unfolding temperature (Tm): The unfolding temperature (Tm) of the samples was analyzed using MicroCal VP-Capillary DSC (Malvern). The samples were diluted to a concentration of 1 mg / mL with the following program: scan start temperature at 20°C, scan end temperature at 110°C, and heating rate at 60°C / h.

[0257] Aggregation temperature (Tagg): The aggregation temperature (Tagg) of the sample was analyzed using Dynaproplate Reader III (Wyatt). The sample was added to a 384-well sample plate, sealed with a sealing film, and then the 384-well sample plate was centrifuged to remove bubbles. The test was then performed using the following procedure: the temperature was raised from 35°C to 85°C, and the scanning time was 5 seconds.

[0258] Binding activity to TIM-3 was assessed using an enzyme-linked immunosorbent assay (ELISA): 2 μg / mL TIM-3 protein (ACRO, TM3-H5229) was coated in a 96-well plate at 100 μL / well and incubated overnight at 2-8°C. After washing the 96-well plate, 250 μL of blocking buffer (3% BSA in PBS) was added to each well and incubated at 25°C for 2 hours. After washing the 96-well plate, serial dilutions of the reference and test samples (initial concentration 1000 ng / mL, 4-fold serial dilutions, 8 dilutions total) were added, along with a blank control, and incubated at 25°C for 2 hours. After washing the 96-well plate, 100 μL / well of HRP-conjugated goat anti-human antibody (PekinElmer, NEF802001EA, diluted according to the manufacturer's instructions) was added and incubated at 25°C for 1 hour. After washing the 96-well plate, add 100 μL of TMB to each well and incubate at 25°C in the dark for 5 minutes. Finally, add 1M H2SO4 to stop color development. After standing at room temperature for 5 minutes, detect using a microplate reader. Use 650 nm as the reference wavelength and measure the absorbance at 450 nm. Record the measurement results. 50 Value / test sample EC 50 value)×100%.

[0259] Binding activity to PD-1 was detected using an enzyme-linked immunosorbent assay (ELISA): 2 μg / mL PD-1 protein (Sinobiological, 10377-H08H) was coated in a 96-well plate at 100 μL / well and incubated overnight at 2-8°C. After washing the 96-well plate, 250 μL of blocking buffer (3% BSA in PBS) was added to each well and incubated at 25°C for 2 hours. After washing the 96-well plate, serial dilutions of the reference and test products (initial concentration 1000 ng / mL, 4-fold serial dilutions, a total of 7 dilutions) were added, along with a blank control, and incubated at 25°C for 2 hours. After washing the 96-well plate, HRP-conjugated goat anti-human antibody (PekinElmer, NEF802001EA, diluted according to the manufacturer's instructions) was added at 100 μL / well and incubated at 25°C for 1 hour. After washing the 96-well plate, add 100 μL of TMB to each well and incubate at 25°C in the dark for 5 minutes. Finally, add 1M H2SO4 to stop color development. After standing at room temperature for 5 minutes, detect using a microplate reader. Use 650 nm as the reference wavelength and measure the absorbance at 450 nm. Record the measurement results. 50 Value / test sample EC 50 value)×100%.

[0260] Dynamic light scattering (DLS) was used to detect particle size. A nanoparticle size analyzer (Malvern, ZEN3600) was used for detection. The sample was slowly added to a clean sample cell and allowed to stand for 15 minutes to remove bubbles. The test was then performed. The test type was size. Each sample was measured three times in a cycle, and the average value was taken as the result.

[0261] Example 5 Screening of pharmaceutical compositions

[0262] The anti-TIM-3 antibody h50B5 was replaced by ultrafiltration into the buffer listed in Table 3-1. After the replacement, the solution was concentrated and then surfactants and stabilizers were added according to Table 3-1 to obtain an h50B5 stock solution. The anti-PD-1 antibody 14C12H1L1 was replaced by ultrafiltration into the buffer listed in Table 3-1 and a 14C12H1L1 stock solution was prepared using the same method. The h50B5 and 14C12H1L1 stock solutions were mixed in the appropriate proportions to obtain a pharmaceutical composition containing 60 mg / mL of h50B5 and 10 mg / mL of 14C12H1L1. The pharmaceutical composition was sterilized by filtration through a 0.22 μm filter and dispensed into vials, stoppered, and capped.

[0263] The pharmaceutical composition shown in Table 3-1 was subjected to Tm and Tagg testing. The test results are shown in Table 3-2. The results indicate that the pharmaceutical composition exhibits good conformational and colloidal stability within the pH range of 5.5-7.0. The pharmaceutical composition shown in Table 3-1 was stored at 40°C for one month and at 2-8°C for one month, respectively. The SEC-UPLC test results are shown in Table 3-3.

[0264] Table 3-1. Components of the pharmaceutical composition

[0265] Table 3-2. Tm and Tagg test results of pharmaceutical compositions

[0266] Table 3-3. SEC-UPLC test results of pharmaceutical compositions

[0267] Example 6 Screening of pharmaceutical compositions

[0268] The anti-TIM-3 antibody h50B5 was replaced by ultrafiltration into the buffer listed in Table 4-1. After the replacement, the solution was concentrated, and then a surfactant and stabilizer were added according to Table 4-1 to obtain an h50B5 stock solution. The anti-PD-1 antibody 14C12H1L1 was replaced by ultrafiltration into the buffer listed in Table 4-1, and then a 14C12H1L1 stock solution was prepared using the same method. The h50B5 and 14C12H1L1 stock solutions were mixed in the appropriate proportions to obtain a pharmaceutical composition containing 30 mg / mL of h50B5 and 5 mg / mL of 14C12H1L1. The pharmaceutical composition was sterilized by filtration through a 0.22 μm filter and dispensed into vials, stoppered, and capped.

[0269] The pharmaceutical compositions shown in Table 4-1 were subjected to Tm and Tagg testing. The test results are shown in Table 4-2. The results show that pharmaceutical composition F5 has the lowest Tagg value. The pharmaceutical compositions shown in Table 4-1 were stored at 40°C for one month, 25°C for one month, and 2-8°C for one month, respectively. The SEC-UPLC test results are shown in Table 4-3.

[0270] Table 4-1. Components of the pharmaceutical composition

[0271] Table 4-2. Tm and Tagg test results of pharmaceutical compositions

[0272] Table 4-3. SEC-UPLC test results of pharmaceutical compositions

[0273] The anti-TIM-3 antibody h50B5 was replaced by ultrafiltration into the buffer listed in Table 5-1. After the replacement, the solution was concentrated, and then a surfactant and stabilizer were added according to Table 5-1 to obtain an h50B5 stock solution. The anti-PD-1 antibody 14C12H1L1 was replaced by ultrafiltration into the buffer listed in Table 5-1, and then a 14C12H1L1 stock solution was prepared using the same method. The h50B5 and 14C12H1L1 stock solutions were mixed in the appropriate proportions to obtain a pharmaceutical composition containing 30 mg / mL of h50B5 and 5 mg / mL of 14C12H1L1. The pharmaceutical composition was sterilized by filtration through a 0.22 μm filter and dispensed into vials, stoppered, and capped.

[0274] The pharmaceutical compositions shown in Table 5-1 were stored at 40°C for one month, 25°C for one month, and 2-8°C for one month. The SEC-UPLC analysis results are shown in Table 5-2, and the DLS particle size and binding activity analysis results are shown in Table 5-4. The pharmaceutical compositions shown in Table 5-1 were shaken at 25°C for five days and ten days, respectively. The SEC-UPLC analysis results are shown in Table 5-3. The results showed that the pharmaceutical compositions maintained good stability within the sucrose concentration range of 80 mg / mL to 164.3 mg / mL and the polysorbate 80 concentration range of 0.4 mg / mL to 0.8 mg / mL.

[0275] Table 5-1. Components of the pharmaceutical composition

[0276] Table 5-2. SEC-UPLC test results of pharmaceutical compositions

[0277] Table 5-3. SEC-UPLC test results of pharmaceutical compositions

[0278] Table 5-4. DLS particle size and binding activity test results of pharmaceutical compositions

[0279] Example 7 Screening of pharmaceutical compositions

[0280] The anti-TIM-3 antibody h50B5 was replaced by ultrafiltration into the buffer listed in Table 6-1. After replacement, the solution was concentrated and then surfactants and stabilizers were added according to Table 6-1 to obtain an h50B5 stock solution. The anti-PD-1 antibody 14C12H1L1 was replaced by ultrafiltration into the buffer listed in Table 6-1 and a 14C12H1L1 stock solution was prepared using the same method. Furthermore, a blank stock solution containing no antibody was prepared by adding buffer, surfactants, and stabilizers according to Table 6-1. The h50B5 stock solution, 14C12H1L1 stock solution, and the blank stock solution were mixed in the appropriate proportions to obtain a pharmaceutical composition containing 15 mg / mL of h50B5 and 5 mg / mL of 14C12H1L1. The pharmaceutical composition was sterilized by filtration through a 0.22 μm filter and dispensed into vials, stoppered, and capped.

[0281] The pharmaceutical composition shown in Table 6-1 was placed at 40°C for 1 month, 25°C for 1 month, and 2-8°C for 1 month, respectively. The SEC-UPLC test results are shown in Table 6-2.

[0282] Table 6-1. Components of the pharmaceutical composition

[0283] Table 6-2. SEC-UPLC test results of pharmaceutical compositions

[0284] Although the present disclosure has been described in conjunction with one or more embodiments, it should be understood that the present disclosure not only covers these embodiments, but is also intended to cover all alternatives, modifications and equivalents included in the spirit and scope of the appended claims. All documents cited herein are fully incorporated herein by reference.

Claims

1. A pharmaceutical composition comprising (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) a buffer, (c) a stabilizer, and (d) a surfactant, wherein: The anti-PD-1 antibody or antigen-binding fragment thereof comprises: HCDR1 of the amino acid sequence shown in SEQ ID NO: 11, HCDR2 of the amino acid sequence shown in SEQ ID NO: 12, HCDR3 of the amino acid sequence shown in SEQ ID NO: 13, LCDR1 of the amino acid sequence shown in SEQ ID NO: 14, LCDR2 of the amino acid sequence shown in SEQ ID NO: 15, and LCDR3 of the amino acid sequence shown in SEQ ID NO: 16; The anti-TIM-3 antibody or antigen-binding fragment thereof comprises: HCDR1 of the amino acid sequence shown in SEQ ID NO: 1, HCDR2 of the amino acid sequence shown in SEQ ID NO: 2, HCDR3 of the amino acid sequence shown in SEQ ID NO: 3, LCDR1 of the amino acid sequence shown in SEQ ID NO: 4, LCDR2 of the amino acid sequence shown in SEQ ID NO: 5, and LCDR3 of the amino acid sequence shown in SEQ ID NO: 6; or HCDR1 of the amino acid sequence shown in SEQ ID NO: 21, HCDR2 of the amino acid sequence shown in SEQ ID NO: 22, HCDR3 of the amino acid sequence shown in SEQ ID NO: 23, LCDR1 of the amino acid sequence shown in SEQ ID NO: 24, LCDR2 of the amino acid sequence shown in SEQ ID NO: 25, and LCDR3 of the amino acid sequence shown in SEQ ID NO:

26.

2. The pharmaceutical composition according to claim 1, wherein The anti-PD-1 antibody or its antigen-binding fragment and the anti-TIM-3 antibody or its antigen-binding fragment are present in the pharmaceutical composition at a fixed dose ratio, and the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-TIM-3 antibody or its antigen-binding fragment is 1:1-30, 1:1-20, 1:1-18, 1:1-15, 1:1-12, 1:1-10, 1:1-9, 1:1-7.5, 1:1-6, 1:1-5, 1:1-4.5, 1:1-3, 1:1-2 or 1:1-1.5; Optionally, the concentration of the anti-PD-1 antibody or its antigen-binding fragment is 1-100 mg / mL, 1-80 mg / mL, 2-60 mg / mL, 3-30 mg / mL, 3-20 mg / mL, 5-20 mg / mL, 5-15 mg / mL, or 5-10 mg / mL; and / or the concentration of the anti-TIM-3 antibody or its antigen-binding fragment is 1-200 mg / mL, 3-180 mg / mL, 6-120 mg / mL, 10-90 mg / mL, 15-90 mg / mL, 15-60 mg / mL, or 30-60 mg / mL.

3. The pharmaceutical composition according to claim 1 or 2, wherein The buffer comprises a histidine buffer, an acetate buffer, a Tris buffer, a phosphate buffer and / or a citrate buffer; Optionally, the concentration of the buffer is 1-100 mM, 2-80 mM, 5-60 mM, 10-40 mM or 10-20 mM.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein The pharmaceutical composition comprises 1-100 mM, 2-80 mM, 5-60 mM, 10-40 mM or 10-20 mM histidine buffer.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein The stabilizer comprises mannitol, sorbitol, trehalose, sucrose, maltose, lactose, lysine, glycine, proline, arginine or a pharmaceutically acceptable salt thereof and / or sodium chloride; Optionally, the concentration of the stabilizer is 1-400 mg / mL, 10-300 mg / mL, 20-200 mg / mL, 40-200 mg / mL, 40-180 mg / mL, 60-180 mg / mL or 70-170 mg / mL.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein The pharmaceutical composition comprises 1-400 mg / mL, 10-300 mg / mL, 20-200 mg / mL, 40-200 mg / mL, 40-180 mg / mL, 60-180 mg / mL or 70-170 mg / mL of sucrose.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein The surfactant comprises polysorbate 80 or polysorbate 20; Optionally, the concentration of the surfactant is 0.01-3 mg / mL, 0.04-2 mg / mL, 0.08-1.6 mg / mL, 0.1-1.2 mg / mL, 0.1-1 mg / mL, 0.2-0.8 mg / mL or 0.4-0.8 mg / mL.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein The pharmaceutical composition comprises 0.01-3 mg / mL, 0.04-2 mg / mL, 0.08-1.6 mg / mL, 0.1-1.2 mg / mL, 0.1-1 mg / mL, 0.2-0.8 mg / mL or 0.4-0.8 mg / mL of polysorbate 80.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein The pH of the pharmaceutical composition is 5 to 7, 5.5 to 7, 5.5 to 6.5 or 5.8 to 6.

5.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein The pharmaceutical composition comprises: (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 1-100 mM histidine buffer, (c) 1-400 mg / mL sucrose, and (d) 0.01-3 mg / mL polysorbate 80 or polysorbate 20; wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-LAG-3 antibody or its antigen-binding fragment is 1:2, 1:3, 1:6 or 1:7.5, and the pH of the pharmaceutical composition is 5.5 to 6.5; (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) a 10-20 mM histidine buffer, (c) 60-180 mg / mL sucrose, and (d) 0.2-0.8 mg / mL polysorbate 80; wherein the fixed dose ratio of the anti-PD-1 antibody or antigen-binding fragment thereof to the anti-LAG-3 antibody or antigen-binding fragment thereof is 1:2, 1:3, 1:6 or 1:7.5, and the pH of the pharmaceutical composition is 5.5 to 6.5; (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM histidine buffer, (c) 80-164.3 mg / mL sucrose, and (d) 0.4-0.8 mg / mL polysorbate 80; wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-LAG-3 antibody or its antigen-binding fragment is 1:6, and the pH of the pharmaceutical composition is 5.5 to 6.5; (a) an anti-PD-1 antibody or an antigen-binding fragment thereof and an anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 20 mM histidine buffer, (c) 80-164.3 mg / mL sucrose, and (d) 0.8 mg / mL polysorbate 80; wherein the fixed dose ratio of the anti-PD-1 antibody or its antigen-binding fragment to the anti-LAG-3 antibody or its antigen-binding fragment is 1:6, and the pH of the pharmaceutical composition is 5.5 to 6.5; (a) 1-100 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 1-200 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 1-100 mM histidine buffer, (c) 1-400 mg / mL sucrose, and (d) 0.01-3 mg / mL polysorbate 80 or polysorbate 20, and the pH of the pharmaceutical composition is 5.5 to 6.5; (a) 5-10 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 15-60 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 10-20 mM histidine buffer, (c) 60-180 mg / mL sucrose, and (d) 0.2-0.8 mg / mL polysorbate 80, and the pH of the pharmaceutical composition is 5.5 to 6.5; (a) 5-10 mg / mL anti-PD-1 antibody or antigen-binding fragment thereof and 15-60 mg / mL anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 10-20 mM histidine buffer, (c) 80-164.3 mg / mL sucrose, and (d) 0.4-0.8 mg / mL polysorbate 80, and the pH of the pharmaceutical composition is 5.5 to 6.5; (a) 5 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 30 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 20 mM histidine buffer, (c) 80-164.3 mg / mL sucrose, and (d) 0.8 mg / mL polysorbate 80, and the pH of the pharmaceutical composition is 5.5 to 6.5; (a) 4-6 mg / mL anti-PD-1 antibody or antigen-binding fragment thereof and 24-36 mg / mL anti-TIM-3 antibody or antigen-binding fragment thereof, (b) 15-25 mM histidine buffer, (c) 150-180 mg / mL sucrose, and (d) 0.7-0.9 mg / mL polysorbate 80, and the pH of the pharmaceutical composition is 5.3 to 6.3; or (a) 4-6 mg / mL anti-PD-1 antibody or an antigen-binding fragment thereof and 24-36 mg / mL anti-TIM-3 antibody or an antigen-binding fragment thereof, (b) 15-25 mM histidine buffer, (c) 450-510 mM sucrose, and (d) 0.7-0.9 mg / mL polysorbate 80, and the pH of the pharmaceutical composition is 5.3 to 6.

3.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein The anti-PD-1 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 17, and a light chain variable region having an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 18; Optionally, the anti-PD-1 antibody or antigen-binding fragment thereof comprises: a heavy chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 19, and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO:

20.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein The anti-TIM-3 antibody or antigen-binding fragment thereof comprises: a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 7, and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 8; or a heavy chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 27, and a light chain variable region having an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 28; Optionally, the anti-TIM-3 antibody or antigen-binding fragment thereof comprises: a heavy chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 9, and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 10; or a heavy chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO: 29, and a light chain having an amino acid sequence that is at least 95% identical to the amino acid sequence shown in SEQ ID NO:

30.

13. A freeze-dried preparation, wherein: The lyophilized preparation is obtained by freeze-drying the pharmaceutical composition according to any one of claims 1 to 12; or the lyophilized preparation can form the pharmaceutical composition according to any one of claims 1 to 12 after being reconstituted.

14. A vial, wherein: The vial contains the pharmaceutical composition according to any one of claims 1 to 12 or the lyophilized preparation according to claim 13.

15. Use of the pharmaceutical composition according to any one of claims 1 to 12 or the lyophilized preparation according to claim 13 in the preparation of a medicament for treating a disease in a subject; Optionally, the disease includes cancer and infectious disease; Optionally, the cancer is recurrent, refractory, metastatic and / or advanced cancer; Optionally, the cancer includes head and neck cancer, nasopharyngeal cancer, oral cancer, esophageal cancer, lung cancer, liver cancer, colon cancer, colorectal cancer, kidney cancer, endometrial cancer, cervical cancer, glioblastoma, bladder cancer, breast cancer, ovarian cancer, fallopian tube cancer, prostate cancer, anal cancer, testicular cancer, vaginal cancer, gastric cancer, gastroesophageal junction cancer, pancreatic cancer, bone cancer, thyroid cancer, skin cancer, nervous system tumors, sarcoma, myeloma, bile duct cancer, gallbladder cancer, soft tissue sarcoma, lymphoma and hematological tumors.

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