Monoclonal antibody preparation for targeting TSLP

Abstract

The invention relates to a monoclonal antibody preparation targeting TSLP. A pharmaceutical composition containing a TSLP (thymic stromal lymphopoietin) antibody or an antigen binding fragment thereof comprises 50-400 mg / mL of the TSLP antibody or the antigen binding fragment thereof, and auxiliary materials. The invention also relates to a preparation and a kit containing the pharmaceutical composition, and application of the preparation and the kit in treatment of allergic inflammation or autoimmune diseases.

Description

A monoclonal antibody preparation targeting TSLP

[0001] This application is based on the application with CN application number 202310159488.1 and application date February 23, 2023, and claims its priority. The disclosed content of the CN application is hereby introduced as a whole into this application. Technical Field

[0002] The present application relates to the field of pharmaceutical preparations, and in particular to a monoclonal antibody preparation targeting TSLP. Background Art

[0003] Thymic stromal lymphopoietin (TSLP) is an inflammatory cytokine similar to IL-7. TSLP is secreted primarily by epithelial cells in the skin, lungs, thymus, and gastrointestinal tract in response to microorganisms, physical injury, or inflammatory cytokines such as IL-1β and TNF. Under pathological conditions such as inflammation, stromal cells, keratinocytes, dendritic cells (DCs), and mast cells can also secrete TSLP. TSLP plays a key role in the initial triggering of allergic and adaptive airway inflammation. Compared with healthy controls, TSLP is highly expressed in the airways of asthmatic patients, and its levels are directly correlated with the expression of TH2 cytokines and chemokines, as well as disease severity. TSLP can induce dendritic cell (DC) maturation and upregulate OX40L expression. The OX40-OX40L interaction participates in the polarization of TH2 cells induced by naive T cells. Following differentiation, DCs release cytokines such as IL-4, IL-5, and IL-13, triggering mast cell and eosinophil infiltration and a series of allergic inflammatory reactions, leading to pathological changes in the airways and causing asthma attacks. TSLP can effectively activate mast cells and natural killer T (NKT) cells, producing TH2 cytokines such as IL-13, exacerbating the occurrence and progression of airway inflammation.

[0004] The receptor for TSLP is a heterodimeric receptor complex composed of IL-7Rα and a unique TSLPR chain (CRFL2). Binding of the TSLP heterodimeric receptor leads to STAT5 activation and cell proliferation. DCs highly express TSLPR and IL-7Rα.

[0005] WO2021115240A1 discloses a fully human antibody capable of binding to human TSLP. The antibody has a high affinity for TSLP and can effectively block the proliferative effect of TSLP on Ba / F3 cells, as well as the ability of TSLP to activate PBMCs and secrete cytokines.

[0006] The preparation of therapeutic proteins such as antibodies, especially high-concentration preparations, faces technical challenges due to stability issues. The present invention aims to provide a high-concentration preparation of the aforementioned TSLP antibody with high stability.

[0007] Summary of the Invention

[0008] In one aspect, the present application provides a pharmaceutical composition containing a TSLP (thymic stromal lymphopoietin) antibody or an antigen-binding fragment thereof, which comprises 50-400 mg / mL of the TSLP antibody or the antigen-binding fragment thereof, and excipients.

[0009] In some embodiments, the TSLP antibody or antigen-binding fragment thereof comprises the following complementarity determining regions (CDRs):

[0010] CDR-H1 or a variant thereof, CDR-H2 or a variant thereof, and CDR-H3 or a variant thereof contained in the heavy chain variable region (VH) shown in SEQ ID NO: 12; and / or

[0011] CDR-L1 or a variant thereof, CDR-L2 or a variant thereof, and CDR-L3 or a variant thereof contained in the light chain variable region (VL) shown in SEQ ID NO: 13.

[0012] In some embodiments, the variant has one or more amino acid substitutions, deletions or additions (e.g., 1, 2, or 3 amino acid substitutions, deletions, or additions) compared to the CDR from which it is derived. In some embodiments, the substitutions are conservative substitutions.

[0013] In some embodiments, the TSLP antibody or antigen-binding fragment thereof comprises:

[0014] (I-1) VH and / or VL, as defined by the IMGT numbering system, wherein the VH comprises a CDR-H1 of SEQ ID NO: 1, a CDR-H2 of SEQ ID NO: 2, and a CDR-H3 of SEQ ID NO: 3; and / or,

[0015] The VL comprises a CDR-L1 having a sequence of SEQ ID NO: 4, a CDR-L2 having a sequence of SEQ ID NO: 5, and a CDR-L3 having a sequence of SEQ ID NO: 6;

[0016] (I-2) VH and / or VL, defined according to the AbM numbering system, wherein the VH comprises a CDR-H1 of SEQ ID NO: 7, a CDR-H2 of SEQ ID NO: 8, and a CDR-H3 of SEQ ID NO: 9; and / or,

[0017] The VL comprises a CDR-L1 having a sequence of SEQ ID NO: 10, a CDR-L2 having a sequence of SEQ ID NO: 11, and a CDR-L3 having a sequence of SEQ ID NO: 6;

[0018] or

[0019] (I-3) VH and / or VL, compared with the VH and / or VL described in any one of (I-1) or (I-2), at least one CDR contains a mutation, wherein the mutation is a substitution, deletion or addition of one or several amino acids or any combination thereof (for example, a substitution, deletion or addition of 1, 2 or 3 amino acids or any combination thereof).

[0020] In some embodiments, the substitutions are conservative substitutions.

[0021] In some embodiments, the TSLP antibody or antigen-binding fragment thereof binds human TSLP and / or monkey TSLP.

[0022] In some embodiments, the TSLP antibody or antigen-binding fragment thereof comprises:

[0023] (II-1) VH represented by SEQ ID NO: 12, and / or VL represented by any one of SEQ ID NO: 13;

[0024] (II-2) a VH having at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity compared to the VH in (II-1); and / or a VL having at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity compared to the VL in (II-1); or

[0025] (II-3) A VH having one or more amino acid substitutions, deletions or additions or any combination thereof (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof) compared to the VH in (II-1); and / or, a VL having one or more amino acid substitutions, deletions or additions or any combination thereof (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof) compared to the VL in (II-1); preferably, the substitutions are conservative substitutions.

[0026] In some embodiments, the TSLP antibody or antigen-binding fragment thereof comprises:

[0027] (III-1) VH of SEQ ID NO: 12 and VL of SEQ ID NO: 13;

[0028] (III-2) VH and VL, whose VH has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the VH and VL in (III-1); and / or, whose VL has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity; or

[0029] (III-3) VH and VL, compared to the VH and VL in (III-1), the VH has one or more amino acid substitutions, deletions, or additions, or any combination thereof (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, deletions, or additions, or any combination thereof); and / or the VL has one or more amino acid substitutions, deletions, or additions, or any combination thereof (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid substitutions, deletions, or additions, or any combination thereof). In some embodiments, the substitutions are conservative substitutions.

[0030] In some embodiments, the antibody or antigen-binding fragment thereof is a chimeric antibody, a humanized antibody, or a fully human antibody.

[0031] In some embodiments, the TSLP antibody or antigen-binding fragment thereof further comprises:

[0032] (i-1) a heavy chain constant region (CH) of a human immunoglobulin or a variant thereof; and / or

[0033] (i-2) a light chain constant region (CL) of a human immunoglobulin or a variant thereof,

[0034] wherein the variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% sequence identity compared to the wild-type sequence from which it is derived; or, the variant has one or more amino acid substitutions, deletions or additions or any combination thereof (e.g., at most 50, at most 45, at most 40, at most 35, at most 30, at most 25, at most 20, at most 15, at most 10 or at most 5 amino acid substitutions, deletions or additions or any combination thereof; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid substitutions, deletions or additions or any combination thereof) compared to the wild-type sequence from which it is derived; preferably, the substitutions are conservative substitutions.

[0035] In some embodiments, the heavy chain constant region is an IgG heavy chain constant region, such as an IgG1, IgG2, IgG3, or IgG4 heavy chain constant region. In some embodiments, the antibody or antigen-binding fragment thereof comprises a human IgG1 heavy chain constant region. In some embodiments, the light chain constant region is a kappa or lambda light chain constant region. In some embodiments, the antibody or antigen-binding fragment thereof comprises a human kappa light chain constant region.

[0036] In some embodiments, the heavy chain constant region or variant thereof comprises the CH set forth in SEQ ID NO: 14 or a variant thereof, which has up to 20 conservative amino acid substitutions (e.g., up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitutions) compared to SEQ ID NO: 14, or has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity compared to SEQ ID NO: 14.

[0037] In some embodiments, the light chain constant region or variant thereof comprises a light chain constant region (CL) as set forth in SEQ ID NO: 15, or a variant thereof, which has up to 20 conservative amino acid substitutions (e.g., up to 20, up to 15, up to 10, or up to 5 conservative amino acid substitutions; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 conservative amino acid substitutions) compared to SEQ ID NO: 15, or has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity compared to SEQ ID NO: 15.

[0038] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region (CH) set forth in SEQ ID NO: 14 and a light chain constant region (CL) set forth in SEQ ID NO: 15.

[0039] In some embodiments, the antibody comprises a heavy chain comprising VH set forth in SEQ ID NO:12 and CH set forth in SEQ ID NO:14, and a light chain comprising VL set forth in SEQ ID NO:13 and CL set forth in SEQ ID NO:15.

[0040] In some embodiments, the TSLP antibody comprises the heavy chain amino acid sequence of SEQ ID NO:16 and the light chain amino acid sequence of SEQ ID NO:17.

[0041] In some embodiments, the concentration of the TSLP antibody or antigen-binding fragment thereof is 100-350 mg / mL, for example 100-300 mg / mL, 100-250 mg / mL, 100-200 mg / mL, or 150-200 mg / mL, preferably 100-200 mg / mL, more preferably 150-200 mg / mL, and more preferably 135-165 mg / mL.

[0042] Herein, "x±n" describes the range of values ​​of a parameter, which includes a range of n above and below the value x. For example, the concentration of the TSLP antibody or its antigen-binding fragment is 150 mg / mL±15 mg / mL, which means that the concentration of the TSLP antibody or its antigen-binding fragment is 135 mg / mL to 165 mg / mL.

[0043] In some embodiments, the excipient is selected from one or more of the following: a buffer, a stabilizer, a surfactant, and an osmotic pressure regulator.

[0044] In some embodiments, the buffer is selected from histidine / histidine hydrochloride buffer, citric acid / citrate buffer and acetic acid / acetate buffer. In some embodiments, the buffer has a pH of 5.5-6.5, preferably 5.5-6.0, preferably 5.7-6.3, such as 5.5, 5.7, 6.0 or 6.3. In some embodiments, the buffer is 10-30 mM histidine / histidine hydrochloride buffer, more preferably 10.4-26.7 mM histidine / histidine hydrochloride buffer, such as 10 mM ± 2 mM or 20 mM ± 2 mM histidine / histidine hydrochloride buffer.

[0045] In some embodiments, the stabilizer is selected from one or more of the following: sodium chloride, sucrose, trehalose and amino acids or their salts (e.g., arginine or its salt, lysine or its salt, glycine, proline, arginine-glutamic acid). In some embodiments, the stabilizer is a combination of sucrose and arginine hydrochloride. In some embodiments, the concentration of each stabilizer is 15-200mM, for example, 50-200mM, 60-200mM, 50-120mM, or 60-120mM. In some embodiments, the concentration of the sucrose is 100-200mM, for example, 108-132mM; the concentration of the arginine hydrochloride is 45-120mM, for example, 54-66mM. In some embodiments, the stabilizer is a combination of 108-132mM sucrose and 54-66mM arginine hydrochloride.

[0046] In some embodiments, the surfactant is a nonionic surfactant, such as polysorbate 20, polysorbate 80, or poloxamer. In some embodiments, the surfactant is poloxamer, preferably poloxamer 188. In some embodiments, the concentration of the surfactant is 0.01 w / v%-0.1 w / v%, such as 0.01 w / v%-0.03 w / v%, 0.01 w / v%-0.05 w / v%, 0.02 w / v%-0.03 w / v%, 0.02 w / v%-0.05 w / v%, 0.02 w / v%-0.1 w / v%, 0.03 w / v%-0.05 w / v%, 0.03 w / v%-0.1 w / v%, or 0.05 w / v%-0.1 w / v%. In some embodiments, the surfactant is 0.01 w / v%-0.1 w / v% poloxamer 188, for example, 0.01 w / v%-0.03 w / v%, 0.01 w / v%-0.05 w / v%, 0.02 w / v%-0.03 w / v%, 0.02 w / v%-0.05 w / v%, 0.02 w / v%-0.1 w / v%, 0.03 w / v%-0.05 w / v%, 0.03 w / v%-0.1 w / v%, or 0.05 w / v%-0.1 w / v% poloxamer 188, preferably 0.045-0.055 w / v% poloxamer 188. As used herein, unless otherwise specified, "w / v%" refers to mass volume concentration, indicating the number of grams of solute per 100 ml of liquid, which can also be expressed as 10 g / L.

[0047] In some embodiments, the osmotic pressure regulator is sodium chloride. In some embodiments, the concentration of the osmotic pressure regulator is 20-130 mM, such as 40-130 mM, 60-130 mM; preferably, the osmotic pressure regulator is 54-66 mM sodium chloride.

[0048] In some embodiments, the pharmaceutical composition comprises 135-165 mg / mL of TSLP antibody, 18-22 mM histidine / histidine hydrochloride buffer at pH 5.7-6.3, 108-132 mM sucrose, 54-66 mM arginine hydrochloride, and 0.045-0.055 w / v % of poloxamer 188.

[0049] In some embodiments, the pharmaceutical composition comprises 150 mg / mL of TSLP antibody, 20 mM histidine / histidine hydrochloride buffer at pH 6.0, 120 mM sucrose, 60 mM arginine hydrochloride, and 0.05 w / v % of poloxamer 188.

[0050] In some embodiments, the pharmaceutical composition consists of 150 g / L TSLP antibody, 1.09 g / L histidine, 2.73 g / L histidine hydrochloride, 41.08 g / L sucrose, 12.64 g / L arginine hydrochloride and 0.5 g / L poloxamer 188.

[0051] In some embodiments, the pharmaceutical composition is an injection, such as a subcutaneous or intramuscular injection.

[0052] In some embodiments, the pharmaceutical composition is a solution.

[0053] In some embodiments, the pharmaceutical composition is a lyophilized powder.

[0054] In a second aspect, the present invention provides a preparation comprising the pharmaceutical composition according to any one of the first aspects, and a container containing the pharmaceutical composition.

[0055] In some embodiments, the container is a vial or a syringe.

[0056] In some embodiments, the formulation is a prefilled syringe or autoinjector pen.

[0057] In a third aspect, the present invention provides a kit comprising the pharmaceutical composition of any one of the first aspect, or the preparation of any one of the second aspect, and instructions for use.

[0058] In another aspect, the present invention provides use of the pharmaceutical composition of any one of the first aspect, the preparation of any one of the second aspect, or the kit of any one of the third aspect in the preparation of a medicament for preventing and / or treating allergic inflammation or autoimmune diseases.

[0059] In another aspect, the present invention provides the pharmaceutical composition of any one of the first aspect, the preparation of any one of the second aspect, or the kit of any one of the third aspect, for use in preventing and / or treating allergic inflammation or autoimmune diseases.

[0060] In another aspect, the present invention provides a method for preventing and / or treating allergic inflammation or autoimmune diseases, comprising administering to a subject in need thereof a preventive or therapeutically effective amount of the pharmaceutical composition of any one of the first aspect, the preparation of any one of the second aspect, or the kit of any one of the third aspect.

[0061] In some embodiments, the allergic inflammatory disease is selected from at least one of asthma, idiopathic pulmonary fibrosis, atopic dermatitis (AD), allergic conjunctivitis, allergic rhinitis (AR), Netherton syndrome, eosinophilic esophagitis (EOE), food allergy, allergic diarrhea, eosinophilic gastroenteritis, allergic bronchopulmonary aspergillosis (ABPA), allergic fungal sinusitis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), systemic sclerosis, keloids, ulcerative colitis, chronic sinusitis (CRS) and nasal polyps, chronic eosinophilic pneumonia, eosinophilic bronchitis, Churg-Strauss syndrome, eosinophilia, eosinophilic granulomatosis with polyangiitis, inflammatory bowel disease, urticaria, systemic mastocytosis, cutaneous mastocytosis, and recurrent idiopathic angioedema.

[0062] In some embodiments, the autoimmune disease is selected from the group consisting of diabetes, myasthenia gravis, gastritis, pemphigus, primary biliary cirrhosis, multiple sclerosis, lupus, colitis, rheumatoid arthritis, psoriasis, and thyroid disease.

[0063] In some embodiments, the use or method comprises the administration of the drug in combination with one or more additional therapeutic agents selected from, but not limited to, immunosuppressants (e.g., corticosteroids, nonsteroidal glucocorticoid receptor agonists, leukotriene D4 antagonists, leukotriene B4 antagonists, A2A agonists, A2B antagonists, dopamine receptor agonists, pirfenidone, nintedanib, or avB6 antagonists), bronchodilators (e.g., beta-2 adrenergic receptor agonists, muscarinic antagonists, short-acting beta2 receptor agonists, long-acting beta2 receptor agonists, short-acting anticholinergic drugs, methylxanthines), In some embodiments, the present invention may include but is not limited to: (a) an antagonist of IL-13, (b) an antagonist of IL-6, (c) an antagonist of IL-1, IL-33, IL-25, or TNF-α, (d) an anti-IgE antibody, (e.g., an anti-IL-13 antibody, an anti-IL31R antibody, an anti-IL13 antibody, an anti-endoglin antibody, an anti-IL1b antibody, another anti-TSLP antibody, or an anti-hTSLPR antibody), (e.g., an anti-histamine, an antitussive drug, or a leukotriene antagonist (e.g., montelukast, zafirlukast, or pranlukast), (e.g., a PDE4 inhibitor (e.g., roflumilast, xanthene), or a cough suppressant.

[0064] In some embodiments, the antibody or antigen-binding fragment, pharmaceutical composition, formulation, or kit antibody and the additional therapeutic agent are used simultaneously, separately, or sequentially.

[0065] Definition of terms

[0066] Unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the procedures in molecular genetics, nucleic acid chemistry, cell culture, biochemistry, cell biology, and the like used herein are conventional procedures widely used in the relevant fields. To facilitate a better understanding of the present invention, definitions and explanations of relevant terms are provided below.

[0067] As used herein, the term "antibody" refers to an immunoglobulin molecule typically consisting of two pairs of polypeptide chains, each pair having one light chain (LC) and one heavy chain (HC). Antibody light chains can be classified as kappa (κ) and lambda (λ) light chains. Heavy chains can be classified as μ, δ, γ, α, or ε, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. Within the light and heavy chains, the variable and constant regions are connected by a "J" region of approximately 12 or more amino acids, and the heavy chain also contains a "D" region of approximately 3 or more amino acids. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region consists of three domains (CH1, CH2, and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The light chain constant region consists of one domain, CL. The constant domains are not directly involved in the binding of antibodies to antigens, but exhibit a variety of effector functions, such as mediating the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The VH and VL regions can also be further subdivided into regions of high variability, called complementarity determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs arranged from amino terminus to carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions (VH and VL) of each heavy chain / light chain pair respectively form the antigen-binding site. The allocation of amino acids to each region or domain can follow various numbering systems known in the art.

[0068] The term "complementarity determining region" or "CDR" refers to the amino acid residues in the variable region of an antibody that are responsible for antigen binding. The variable regions of the heavy and light chains each contain three CDRs, designated CDR1, CDR2, and CDR3. The precise boundaries of these CDRs can be defined according to various numbering systems known in the art, for example, as defined in the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), the Chothia numbering system (Chothia & Lesk (1987) J. Mol. Biol. 196:901-917; Chothia et al. (1989) Nature 342:878-883), the IMGT numbering system (Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003), or the AbM numbering system (Martin ACR, Cheetham JC, Rees AR (1989) Modelling antibody hypervariable loops: A combined algorithm. Proc Natl Acad Sci USA 86:9268-9272). For a given antibody, a person skilled in the art will readily identify the CDRs defined by each numbering system. Furthermore, the correspondence between different numbering systems is well known to those skilled in the art (e.g., see Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003).

[0069] In the present invention, the CDRs contained in an antibody or antigen-binding fragment thereof can be identified according to various numbering systems known in the art, such as the Kabat, Chothia, IMGT, or AbM numbering systems. In certain embodiments, the CDRs contained in an antibody or antigen-binding fragment thereof are defined by the IMGT or AbM numbering systems.

[0070] The term "framework region" or "FR" residues refers to those amino acid residues in the variable region of an antibody other than the CDR residues as defined above.

[0071] The term "antigen-binding fragment" of an antibody refers to polypeptides that are fragments of an antibody, such as polypeptides that are fragments of a full-length antibody, which retain the ability to specifically bind to the same antigen bound by the full-length antibody and / or compete with the full-length antibody for specific binding to the antigen, and are also referred to as "antigen-binding portions." See generally, Fundamental Immunology, Ch. 7 (Paul, W., ed., 2nd ed., Raven Press, NY (1989), which is incorporated herein by reference in its entirety for all purposes. Antigen-binding fragments of antibodies can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Non-limiting examples of antigen-binding fragments include Fab fragments, Fab' fragments, F(ab)'2 fragments, F(ab)'3 fragments, Fd, Fv, scFv, di-scFv, (scFv)2, disulfide-stabilized Fv proteins ("dsFv"), single domain antibodies (sdAbs, nanobodies), and polypeptides that comprise at least a portion of an antibody sufficient to confer specific antigen-binding ability on the polypeptide. Engineered antibody variants are reviewed in Holliger et al., 2005; Nat Biotechnol, 23: 1126-1136.

[0072] As used herein, the term "excipient" refers to substances other than the active ingredient that are necessary for the preparation or formulation of a pharmaceutical formulation. These substances are generally required to be physiologically inactive and not to affect the efficacy, content determination, or stability of the drug in the pharmaceutical formulation. The primary purpose of adding excipients is to facilitate the preparation and clinical application of the formulation. Excipients used in the pharmaceutical compositions of the present invention are pharmaceutically acceptable and compatible with the active ingredient.

[0073] As used herein, the term "pharmaceutically acceptable" refers to carriers and / or excipients that are pharmacologically and / or physiologically compatible with the subject and the active ingredient, which are well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995), and include, but are not limited to, pH adjusters or buffers, stabilizers, surfactants, osmotic pressure regulators, preservatives, and the like. For example, pH adjusters or buffers include, but are not limited to, phosphate buffer, histidine / histidine hydrochloride buffer, citric acid / citrate buffer, acetic acid / acetate buffer. Surfactants include, but are not limited to, cationic, anionic, or nonionic surfactants, such as poloxamers, sorbitol esters, and the like. Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Osmotic pressure regulators include, but are not limited to, sugars, NaCl, and the like. Stabilizers have the meanings generally understood by those skilled in the art, and are capable of stabilizing the desired activity of the active ingredient in the drug, including but not limited to sodium glutamate, gelatin, SPGA, sugars (such as sorbitol, mannitol, starch, sucrose, lactose, dextran, or glucose), amino acids or their salts (such as glutamic acid, glycine, arginine or its salts, lysine or its salts, proline, arginine-glutamic acid), proteins (such as dried whey, albumin or casein) or their degradation products (such as lactalbumin hydrolysate), etc.

[0074] Preparations can be prepared into suitable forms according to the desired route of administration, and can be liquid suspensions and / or dry (lyophilized) powders, as well as other forms. Exemplary administration forms include hard or soft shell powder-filled uncoated or enteric-coated capsules, dissolving tablets, caplets, unencapsulated or encapsulated mini-tablets, multi-granules, lozenges (lozenges), pastilles (pastilles), granules, microspheres, nanoparticles, injectable liquid preparations, liquid pills, oral liquids, oral suspensions, syrups, elixirs, gels, bulk emulsions, aerosols, aerosols, microemulsions or nanoemulsions, liposomes or suppositories, etc. These preparations can be administered directly, or can also be prepared as added to the food or beverage of the experimenter, such as a dietary supplement.

[0075] As used herein, the term "administering" refers to using any various methods and delivery systems well known to those skilled in the art that the pharmaceutical composition of the present invention or preparation physics are introduced into individuality.Preferred routes of administration include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal column or other parenteral routes of administration, such as by injection or infusion.The pharmaceutical composition of the present invention and preparation are preferably administered parenterally, by injection, including but not limited to intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, intraepidermal, intraarticular, under the capsule, under the arachnoid membrane, in the spinal column, epidural and intrasternal injection and infusion and in vivo electroporation.Can also for example once, repeatedly and / or go through one or more extended periods and perform administration.

[0076] As used herein, "treatment" of a subject refers to any type of intervention or procedure performed on a subject, or the administration of a drug to a subject, with the purpose of reversing, alleviating, ameliorating, inhibiting, slowing, or preventing the onset, progression, development, severity, or recurrence of symptoms, complications, or conditions associated with a disease.

[0077] As used herein, the term "effective amount" refers to an amount sufficient to achieve, or at least partially achieve, a desired effect. For example, a prophylactic effective amount is an amount sufficient to prevent, arrest, or delay the onset of a disease; a therapeutic effective amount is an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. Determining such an effective amount is well within the capabilities of those skilled in the art. For example, an effective amount for therapeutic use will depend on the severity of the disease being treated, the overall state of the patient's own immune system, the patient's general condition such as age, weight, and sex, the mode of administration of the drug, and any other concurrently administered treatments.

[0078] As used herein, the term "subject" includes, but is not limited to, various animals, e.g., mammals, e.g., bovines, equines, ovines, porcines, canines, felines, lagomorphs, rodents (e.g., mice or rats), non-human primates (e.g., macaques or cynomolgus monkeys), or humans.

[0079] The pharmaceutical compositions of the present invention are "stable" in that the TSLP antibodies or antigen-binding fragments thereof contained therein remain stable under typical processing, storage and / or handling stressors, such as mechanical stress, thermal stress and / or freeze-thaw stress. Typically, the formulation remains stable after long-term storage at a specific temperature, after freeze-thaw cycles and / or after agitation. Typically, a "stable" protein shows minimal (or no) changes in secondary and tertiary structure, minimal (or no) degradation or aggregation, minimal (or no) signs of fragmentation and / or chemical modification (e.g., oxidation, reduction, deamidation), etc., and maintains the integrity of the protein's primary structure, such that it maintains its physical and chemical stability and biological activity during storage, even when subjected to stressors. In some embodiments, the antibody or antigen-binding fragment thereof changes by no more than 60%, preferably no more than 50%, no more than 20%, no more than 15%, no more than 10%, no more than 5%, no more than 2%, or no more than 1% of the total mass of the TSLP antibody compared to its initial mass before storage, freeze-thaw cycles or agitation stress testing. DETAILED DESCRIPTION

[0080] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. The following description of at least one exemplary embodiment is actually only illustrative and in no way limits the present invention and its application or use. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0081] Sequence information

[0082] The information of the sequences involved in the present invention is described in the table below.

[0083] The detection of various parameters in the examples, such as SEC-HPLC, IEC-HPLC, reduced CE-SDS, non-reduced CE-SDS, osmotic pressure, isoelectric point, color, clarity, insoluble particles, and visible foreign matter, can refer to the detection methods described in the general rules of the 2020 edition of the Chinese Pharmacopoeia. Viscosity was detected using an m-VROC microfluidic rheometer. Relative binding activity was detected using an enzyme-linked immunosorbent assay (ELISA). Biological activity was detected using a proliferation inhibition assay.

[0084] Experimental Example 1

[0085] The 43B1-H2L2 antibody (TSLP antibody, whose heavy chain is shown in SEQ ID NO: 16 and whose light chain is shown in SEQ ID NO: 17, and whose preparation is described in WO2021115240A1) has a molecular weight of approximately 145.4 kDa and a pI of 7.92. The 43B1-H2L2 antibody was formulated into the formulation shown in Table 1 and stored at 40°C for 28 days. The stability of the 43B1-H2L2 antibody was investigated in acetic acid / sodium acetate buffer, citric acid / sodium citrate buffer, and histidine / histidine hydrochloride buffer. The results are shown in Table 2.

[0086] Table 1 Preparation

[0087] Table 2 Experimental results

[0088] Note: 40℃28d means placed at 40℃ for 28 days, the same below.

[0089] The 43B1-H2L2 antibody is relatively stable in the histidine / histidine hydrochloride buffer system and is superior to the acetate buffer system and the citric acid buffer system.

[0090] Experimental Example 2

[0091] In this experiment, a 10mM histidine / histidine hydrochloride buffer system was used, with the pH adjusted to between 5.5 and 6.0. The 43B1-H2L2 antibody was formulated to a protein concentration of approximately 185 mg / ml. The composition is shown in Table 3. The experimental conditions were four freeze-thaw cycles at -20°C or 28 days at 40°C. The effects of arginine hydrochloride and arginine-glutamic acid combinations with polysorbate 20 on protein stability and viscosity were investigated. All parameters were measured using the same methods as previously described.

[0092] Table 3 Preparation

[0093] Table 4 Experimental results

[0094] Note: FT4X means four freeze-thaw cycles at -20°C.

[0095] The viscosity values ​​of formulations 2-1, 2-2, and 2-3 measured on day 0 were 33.5 cp, 13.6 cp, and 10.8 cp, respectively, indicating that in the above-mentioned histidine / histidine hydrochloride system, arginine-glutamic acid and arginine hydrochloride can reduce the viscosity of the antibody formulation, and arginine hydrochloride has a better viscosity-reducing effect.

[0096] In the above-mentioned histidine / histidine hydrochloride system, arginine-glutamic acid and arginine hydrochloride can maintain the freeze-thaw stability and high temperature stability of the 43B1-H2L2 antibody.

[0097] Experimental Example 3

[0098] In this experiment, a 10mM histidine / histidine hydrochloride buffer system was used, adjusted to a pH of approximately 6.0, to prepare the 43B1-H2L2 antibody at a protein concentration of 150 mg / ml. The composition is shown in Table 5. Experimental conditions included four freeze-thaw cycles at -70°C or storage at 40°C for 27 days to examine the effects of polysorbate 80 and various excipient combinations on protein stability and viscosity. All parameters were measured using the same methods as previously described.

[0099] Table 5 Preparation

[0100] Table 6 Experimental results

[0101] Note: 40℃27d means placed at 40℃ for 27 days.

[0102] The viscosity values ​​of formulation 3-1, formulation 3-2, formulation 3-3, formulation 3-4, formulation 3-5 and formulation 3-6 measured on day 0 were 7.2 cp, 7.0 cp, 7.6 cp, 7.8 cp, 8.5 cp and 17.3 cp, respectively, indicating that in the above formulations, the combination of arginine hydrochloride and various excipients can reduce the viscosity of the antibody preparations.

[0103] After four freeze-thaw cycles at -70°C, the appearance of each preparation in Table 5 remained clear and free of visible protein particles. The IEC-HPLC main peak and SEC-HPLC monomer purity indicators showed no significant difference compared with day 0, and there was no significant difference between the preparations. The freeze-thaw stability met the requirements.

[0104] After being placed at 40°C for 27 days, there was no significant difference in the stability of the preparations in Table 5. The IEC-HPLC main peak index was not significantly different from that on day 0. The SEC-HPLC monomer, non-reduced CE-SDS and reduced CE-SDS purity indexes were not significantly different from those on day 0. There was no significant difference among the preparations, and the stability met the requirements.

[0105] Experimental Example 4

[0106] In this experiment, a 20 mM histidine / histidine hydrochloride buffer system was used, adjusted to a pH of approximately 6.0, to prepare the 43B1-H2L2 antibody at a protein concentration of 150 mg / ml. The composition is shown in Table 7. The effects of polysorbate 80, polysorbate 20, and poloxamer 188 on protein stability and viscosity were investigated. The testing methods for these parameters were the same as above.

[0107] Table 7 Preparation

[0108] Table 8 Experimental results

[0109] The viscosity values ​​of formulations 4-1, 4-2, 4-3 and 4-4 measured on day 0 were 10.1 cp, 6.1 cp, 6.5 cp and 6.5 cp, respectively, indicating that in the above-mentioned histidine / histidine hydrochloride system, ≥60 mM arginine hydrochloride can meet the viscosity requirements of the formulations.

[0110] On day 0, the appearance of formulations 4-2, 4-3, and 4-4 was better than that of formulation 4-1. After being placed at 40°C for 28 days, it was observed that the appearance stability of formulation 4-4 was better than that of formulations 4-2 and 4-3, indicating that the stability of the formulations prepared with poloxamer 188 in appearance indicators was better than that of polysorbate 20 and polysorbate 80.

[0111] The results in Table 8 show that there is no significant difference in the stability of Formulation 4-2, Formulation 4-3 and Formulation 4-4, and all meet the quality requirements.

[0112] Experimental Example 5

[0113] In this experiment, a 20 mM histidine / histidine hydrochloride buffer system was used, adjusted to a pH of approximately 6.0, to prepare the 43B1-H2L2 antibody at a protein concentration of 150 mg / ml. The composition is shown in Table 9. The formulation was incubated at 40°C for 28 days to examine the effects of sodium chloride, glycine, and sucrose in combination with arginine hydrochloride and poloxamer 188 on protein stability and viscosity. All parameters were measured using the same methods as previously described.

[0114] Table 9 Preparation

[0115] Table 10 Experimental results

[0116] In this experiment, the viscosity of all three preparations was below 7.0 cp. After 28 days at 40°C, the appearance of the three preparations remained unchanged and met the requirements. There was no significant difference in the stability of the purity indicators.

[0117] Experimental Example 6

[0118] In this experiment, a 20 mM histidine / histidine hydrochloride buffer system was used to screen the concentration of poloxamer 188. The pH was adjusted to approximately 6.0. The 43B1-H2L2 antibody was formulated at a protein concentration of 150 mg / ml. The composition is shown in Table 11. The effects of different poloxamer 188 concentrations on protein stability were investigated, using the same testing methods as previously described.

[0119] Table 11 Preparation

[0120] Table 12 Experimental results

[0121] Note: AG4h means oscillation for 4 hours.

[0122] Preparation 6-1 showed no significant changes in appearance under the conditions of oscillation, freeze-thaw and 40°C inspection, meeting the requirements; there was no significant change in the purity indicators under the conditions of oscillation and freeze-thaw; under the conditions of 40°C inspection, the purity indicators decreased, but all met the requirements.

[0123] Under the conditions of oscillation, freeze-thaw and 40°C, the parameters of preparations 6-2, 6-3 and 6-4 showed no significant difference from those of preparation 6-1.

[0124] The effect of poloxamer 188 concentration between 0.01% and 0.10w / v% on the stability of the preparation was consistent and had no significant difference.

[0125] Test Example 7

[0126] The formulation of this experiment consists of antibody, histidine / histidine hydrochloride, arginine hydrochloride, sucrose, and poloxamer 188. The stability of the formulation was investigated when the pH value was between 5.7 and 6.3 and when the protein concentration, buffer salt, and excipient concentration changed.

[0127] Table 13 Preparation

[0128] Table 14 Experimental results

[0129] The appearance of preparation 7-1 met the requirements under the conditions of oscillation, freeze-thaw, 25°C and 40°C. The purity indicators all showed that the preparation was relatively stable, and the change in protein relative binding activity was less than 15%.

[0130] The other 8 groups of preparations (preparation 7-2 to preparation 7-9) in this experiment had no significant differences in various test indicators compared with preparation 7-1 under the test conditions of oscillation, freeze-thaw, 25°C and 40°C, and all met the requirements.

[0131] Experimental Conclusion

[0132] 1) The 43B1-H2L2 antibody concentration was 150 mg / ml, using a 20 mM histidine / histidine hydrochloride buffer system, pH 6.0, 60 mM arginine hydrochloride, 120 mM sucrose, and 0.05 w / v% poloxamer 188, which met the formulation stability requirements;

[0133] 2) Based on 1), with other conditions unchanged, there was no significant difference in the stability of the formulation when the pH value was between 5.7 and 6.3;

[0134] 3) Based on 1), with other conditions unchanged, when the histidine / histidine hydrochloride concentration was between 10.4 mM and 26.7 mM, there was no significant effect on the stability of the formulation;

[0135] 4) Based on 1), with other conditions unchanged, there was no significant difference in the stability of the formulation when the concentrations of the excipients arginine hydrochloride, sucrose, and poloxamer 188 fluctuated within a range of no more than 10%.

[0136] 5) Based on 1), when other conditions remain unchanged and the protein concentration fluctuates by no more than 10%, the viscosity is affected, but it meets the requirements, and there is no significant difference in other stability indicators.

[0137] Experimental Example 8

[0138] Prepare 43B1-H2L2 antibody injection: 43B1-H2L2 antibody 150 g / L, histidine 1.09 g / L, histidine hydrochloride 2.73 g / L, sucrose 41.08 g / L, arginine hydrochloride 12.64 g / L, and poloxamer 188 0.5 g / L. Package in injection vials and store upright and inverted at 5°C ± 3°C for long-term stability testing.

[0139] Experimental results

[0140] The 12-month inspection data showed that there was no significant change in color, visible foreign matter, clarity, insoluble particles, pH, and osmotic pressure molar concentration compared with the data in month 0, which met the requirements;

[0141] The protein content data in December compared with that in October showed a change of less than 4%;

[0142] From 0 to 12 months, the monomer content by SEC-HPLC did not change significantly and was not less than 99.0%. The main peak by IEC-HPLC did not change significantly and was not less than 65%. The content of heavy chain and light chain (HC+LC) by reduced CE-SDS did not change significantly and was not less than 97%. The main peak by non-reduced CE-SDS did not change significantly and was not less than 95%.

[0143] Compared with the data in October, the relative binding activity change in December did not exceed 10%, and the biological activity change did not exceed 10%, both of which met the requirements.

[0144] In summary, the 43B1-H2L2 antibody injection was stored at 5℃±3℃ for 12 months, and the sample was stable, with no significant changes in any of the investigated items.

[0145] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A pharmaceutical composition containing a TSLP (thymic stromal lymphopoietin) antibody or an antigen-binding fragment thereof, comprising 50-400 mg / mL of the TSLP antibody or the antigen-binding fragment thereof, and excipients.

2. The pharmaceutical composition of claim 1, wherein the TSLP antibody comprises the heavy chain amino acid sequence shown in SEQ ID NO: 16, and the light chain amino acid sequence shown in SEQ ID NO:

17.

3. The pharmaceutical composition of claim 1 or 2, wherein the concentration of the TSLP antibody or antigen-binding fragment thereof is 100-350 mg / mL, for example 100-300 mg / mL, 100-250 mg / mL, 100-200 mg / mL, or 150-200 mg / mL, preferably 100-200 mg / mL, more preferably 150-200 mg / mL, more preferably 135-165 mg / mL.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the excipient is selected from one or more of the following: a buffer, a stabilizer, a surfactant and an osmotic pressure regulator; Preferably, the buffer is selected from histidine / histidine hydrochloride buffer, citric acid / citrate buffer and acetic acid / acetate buffer; preferably, the buffer has a pH of 5.5-6.5, preferably 5.5-6.0, preferably 5.7-6.3, such as 5.5, 5.7, 6.0 or 6.3; preferably, the buffer is 10-30 mM histidine / histidine hydrochloride buffer, more preferably 10.4-26.7 mM histidine / histidine hydrochloride buffer, such as 10 mM ± 2 mM or 20 mM ± 2 mM histidine / histidine hydrochloride buffer; Preferably, the stabilizer is selected from one or more of the following: sodium chloride, sucrose, trehalose and amino acids or salts thereof (e.g., arginine or its salt, lysine or its salt, glycine, proline, arginine-glutamate); preferably, the stabilizer is a combination of sucrose and arginine hydrochloride; the concentration of each stabilizer is 15-200mM, such as 50-200mM, 60-200mM, 50-120mM, or 60-120mM; preferably, the concentration of sucrose is 100-200mM, such as 108-132mM; the concentration of arginine hydrochloride is 45-120mM, such as 54-66mM; preferably, the stabilizer is a combination of 108-132mM sucrose and 54-66mM arginine hydrochloride; Preferably, the surfactant is a nonionic surfactant, such as polysorbate 20, polysorbate 80 or poloxamer; preferably, the surfactant is poloxamer, preferably poloxamer 188; the concentration of the surfactant is 0.01w / v%-0.1w / v%, such as 0.01w / v%-0.03w / v%, 0.01w / v%-0.05w / v%, 0.02w / v%-0.03w / v%, 0.02w / v%-0.05w / v%, 0.02w / v%-0.1w / v%, 0.03w / v%-0.05w / v%, 0.03w / v%-0.1w / v%, or 0.05 w / v%-0.1w / v%; preferably, the surfactant is 0.01w / v%-0.1w / v% poloxamer 188, such as 0.01w / v%-0.03w / v%, 0.01w / v%-0.05w / v%, 0.02w / v%-0.03w / v%, 0.02w / v%-0.05w / v%, 0.02w / v%-0.1w / v%, 0.03w / v%-0.05w / v%, 0.03w / v%-0.1w / v%, or 0.05w / v%-0.1w / v% poloxamer 188, preferably 0.045-0.055w / v% poloxamer 188; Preferably, the osmotic pressure regulator is sodium chloride; preferably, the concentration of the osmotic pressure regulator is 20-130 mM, such as 40-130 mM, 60-130 mM; preferably, the osmotic pressure regulator is 54-66 mM sodium chloride.

5. The pharmaceutical composition of any one of claims 1 to 4, comprising 135-165 mg / mL of TSLP antibody, 18-22 mM histidine / histidine hydrochloride buffer at a pH of 5.7-6.3, 108-132 mM sucrose, 54-66 mM arginine hydrochloride, and 0.045-0.055 w / v% of poloxamer 188; Preferably, the pharmaceutical composition comprises 150 mg / mL of TSLP antibody, 20 mM histidine / histidine hydrochloride buffer at pH 6.0, 120 mM sucrose, 60 mM arginine hydrochloride and 0.05 w / v% poloxamer 188; Preferably, the pharmaceutical composition consists of 150 g / L TSLP antibody, 1.09 g / L histidine, 2.73 g / L histidine hydrochloride, 41.08 g / L sucrose, 12.64 g / L arginine hydrochloride and 0.5 g / L poloxamer 188.

6. The pharmaceutical composition according to any one of claims 1 to 5, which is an injection, such as a subcutaneous or intramuscular injection; Preferably, the pharmaceutical composition is a liquid solution; Preferably, the pharmaceutical composition is a lyophilized powder.

7. A preparation comprising the pharmaceutical composition according to any one of claims 1 to 6, and a container for containing the pharmaceutical composition; Preferably, the container is a vial or a syringe.

8. The preparation according to claim 7, which is in the form of a prefilled syringe or an autoinjector pen.

9. A kit comprising the pharmaceutical composition according to any one of claims 1 to 6, the preparation according to claim 7 or 8, and instructions for use.

10. Use of the pharmaceutical composition according to any one of claims 1 to 6, the preparation according to claim 7 or 8, or the kit according to claim 9 in the preparation of a medicament for preventing and / or treating allergic inflammation or autoimmune diseases; Preferably, the allergic inflammation is selected from at least one of asthma, idiopathic pulmonary fibrosis, atopic dermatitis (AD), allergic conjunctivitis, allergic rhinitis (AR) Netherton syndrome, eosinophilic esophagitis (EOE), food allergy, allergic diarrhea, eosinophilic gastroenteritis, allergic bronchopulmonary aspergillosis (ABPA), allergic fungal sinusitis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), systemic sclerosis, keloid, ulcerative colitis, chronic sinusitis (CRS) and nasal polyps, chronic eosinophilic pneumonia, eosinophilic bronchitis, Churg-Strauss syndrome, eosinophilia, eosinophilic granulomatosis with polyangiitis, inflammatory bowel disease, urticaria, systemic mastocytosis, cutaneous mastocytosis, and recurrent idiopathic angioedema; Optionally, the autoimmune disease is selected from the group consisting of diabetes, myasthenia gravis, gastritis, pemphigus, primary biliary cirrhosis, multiple sclerosis, lupus, colitis, rheumatoid arthritis, psoriasis and thyroid disease; Optionally, the use includes the combined administration of the drug with one or more additional therapeutic agents, the additional therapeutic agent being selected from but not limited to: immunosuppressants (e.g., corticosteroids, nonsteroidal glucocorticoid receptor agonists, leukotriene D4 antagonists, leukotriene B4 antagonists, A2A agonists, A2B antagonists, dopamine receptor agonists, pirfenidone nintedanib, or avB6 antagonists), bronchodilators (e.g., beta-2 adrenergic receptor agonists, muscarinic antagonists, short-acting beta2 receptor agonists, long-acting beta2 receptor agonists, short-acting anticholinergic drugs, methylxanthines, long-acting anticholinergic drugs), antagonists or antibodies to other cytokines or cytokine receptors (e.g., IL-13 antagonists, IL-6 antagonists, IL-1, IL-33, IL-25, or TNF-α antagonists, anti-IgE antibodies, anti-IL-13 antibodies, anti-IL31R antibodies, anti-IL13 antibodies, anti-endoglin antibodies, anti-IL1b antibodies, another anti-TSLP antibody, or anti-hTSLPR antibodies), antibiotics, radiation therapy, leukotriene antagonists (e.g., montelukast, zafirlukast, or pranosart), PDE4 inhibitors (e.g., roflumilast, xanthenes), antihistamines, or cough suppressants; Optionally, the antibody or antigen-binding fragment is administered simultaneously, separately or sequentially with an additional therapeutic agent.

11. A method for preventing and / or treating allergic inflammation or autoimmune diseases, comprising administering to a subject in need thereof a preventive or therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 6, the preparation according to claim 7 or 8, or the kit according to claim 9; Preferably, the allergic inflammation is selected from at least one of asthma, idiopathic pulmonary fibrosis, atopic dermatitis (AD), allergic conjunctivitis, allergic rhinitis (AR) Netherton syndrome, eosinophilic esophagitis (EOE), food allergy, allergic diarrhea, eosinophilic gastroenteritis, allergic bronchopulmonary aspergillosis (ABPA), allergic fungal sinusitis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), systemic sclerosis, keloid, ulcerative colitis, chronic sinusitis (CRS) and nasal polyps, chronic eosinophilic pneumonia, eosinophilic bronchitis, Churg-Strauss syndrome, eosinophilia, eosinophilic granulomatosis with polyangiitis, inflammatory bowel disease, urticaria, systemic mastocytosis, cutaneous mastocytosis, and recurrent idiopathic angioedema; Optionally, the autoimmune disease is selected from the group consisting of diabetes, myasthenia gravis, gastritis, pemphigus, primary biliary cirrhosis, multiple sclerosis, lupus, colitis, rheumatoid arthritis, psoriasis and thyroid disease; Optionally, the method comprises the step of administering one or more additional therapeutic agents in combination, wherein the additional therapeutic agent is selected from, but not limited to, immunosuppressants (e.g., corticosteroids, nonsteroidal glucocorticoid receptor agonists, leukotriene D4 antagonists, leukotriene B4 antagonists, A2A agonists, A2B antagonists, dopamine receptor agonists, pirfenidone, nintedanib, or avB6 antagonists), bronchodilators (e.g., beta-2 adrenergic receptor agonists, muscarinic antagonists, short-acting beta2 receptor agonists, long-acting beta2 receptor agonists, short-acting anticholinergics, methylxanthines, long-acting anti cholinergic drugs), antagonists or antibodies to other cytokines or cytokine receptors (e.g., IL-13 antagonists, IL-6 antagonists, IL-1, IL-33, IL-25, or TNF-α antagonists, anti-IgE antibodies, anti-IL-13 antibodies, anti-IL31R antibodies, anti-IL13 antibodies, anti-endoglin antibodies, anti-IL1b antibodies, another anti-TSLP antibody, or anti-hTSLPR antibodies), antibiotics, radiation therapy, leukotriene antagonists (e.g., montelukast, zafirlukast, or pranosart), PDE4 inhibitors (e.g., roflumilast, xanthenes), antihistamines, or cough suppressants; Optionally, the pharmaceutical composition, formulation, or kit antibody and the therapeutic agent are administered simultaneously, separately or sequentially.