Antibody injection

Abstract

The present invention provides an antibody injection, which comprises an anti-TSHR antibody, a stabilizer, and a surfactant. According to the present invention, by means of screening and optimization of the formulation formula, the physical and chemical stability of the anti-TSHR antibody injection is greatly improved. By means of high-temperature stability, accelerated stability, and long-term stability tests, it is confirmed that the formula is suitable for the anti-TSHR antibody, and it can be ensured that the product has good stability during storage, transportation, and use.

Description

An antibody injection

[0001] Cross-references to related applications

[0002] This application claims priority to an earlier application filed on January 22, 2025, with patent application number 202510103729.X and entitled "An Antibody Injection". The entire contents of the earlier application are incorporated herein by reference. Technical Field

[0003] This invention belongs to the field of biomedicine, and specifically relates to an antibody injection. Background Technology

[0004] The thyroid-stimulating hormone receptor (TSH receptor, TSHR) is mainly located on the lateral surface of basal cells of thyroid follicles, in the testes, and on the surface of orbital fibroblasts in patients with thyroid-associated ophthalmopathy. When it binds to thyroid-stimulating hormone (TSH) secreted by the pituitary gland, it stimulates the formation and release of thyroxine (T4) and triiodothyronine (T3). The levels of circulating T4 and T3, and the release of thyrotropin-releasing hormone (TRH) from the hypothalamus, control the release of TSH, thereby controlling the stimulation of the thyroid gland and the level of thyroid hormones in the serum (Szkudlinski MW, et al., 2002 supra).

[0005] Graves' disease (also known as diffuse toxic goiter, or GD) is an autoimmune thyroid disease (AITD) that causes hyperthyroidism, meaning the thyroid gland produces excessive amounts of thyroid hormones (T3, T4). The main clinical manifestations include hypermetabolic syndrome, diffuse goiter, ocular signs, skin lesions, and thyroid acromegaly. AITD patients often develop autoantibodies that bind to TSHR (Rees Smith B, et al 1988. Endocrine Reviews 9: 106-121), known as TRAb. There are two main types of TRAb: stimulatory and inhibitory. When stimulatory antibodies are present, the feedback control mechanism of thyroid function becomes ineffective, and patients exhibit clinical symptoms of thyroid overactivity, characterized by excessive serum thyroid hormones (T3, T4), a condition known as GD. Tab01 is a stimulatory human monoclonal antibody isolated from lymphocytes of GD patients, described in detail in WO2004 / 050708A2. In patients with AITD, the frequency of suppressive TRAb is lower than that of stimulating autoantibodies. Suppressive autoantibodies bind to TSHR, preventing TSH from binding to its receptor, but they are unable to stimulate TSHR activity. Therefore, the formation and secretion of thyroid hormones (T4 and T3) are greatly reduced, and these TRAb patients may present with clinical symptoms of hypothyroidism.

[0006] The researchers of this invention have developed a fully human monoclonal antibody against human thyroid-stimulating hormone receptor (TSHR), designated hAb01_G4P. This antibody specifically binds to TSHR expressed by fibroblasts, blocking the binding of thyroid-stimulating immunoglobulin (TSI) to TSHR, thereby achieving the antagonistic effect of TSHR. The hAb01_G4P monoclonal antibody can be used to treat diseases such as hyperthyroidism and exophthalmos.

[0007] However, antibody drugs not only need to achieve high purity during production, but also need to maintain structural stability during transportation, storage, and use. Insufficient stability of antibody drugs can lead to various chemical and physical degradations and structural changes, such as denaturation, aggregation, and precipitation. These degradation or unstable products can significantly impact the safety of biopharmaceuticals. In particular, some protein aggregates can trigger an immune response in the human body, which may reduce the efficacy of the biopharmaceutical in mild cases, and even cause death in severe cases. Therefore, polymers are considered a critical quality attribute (CQA) for biopharmaceutical safety, directly affecting the safety of antibody drug use. Therefore, it is essential to develop a novel antibody formulation to improve the stability of hAb01_G4P monoclonal antibody, thereby improving the uniformity and consistency of product quality and enhancing its stability during use. Summary of the Invention

[0008] To improve the above-mentioned technical problems, the present invention provides an antibody injection comprising an anti-TSHR antibody, a stabilizer, and a surfactant, wherein the stabilizer is sucrose, trehalose, mannitol, or sorbitol, and the surfactant is poloxamer 188, polysorbate 80, or polysorbate 20.

[0009] In one embodiment, the anti-TSHR antibody comprises VH CDR1, VH CDR2, and VH CDR3 contained in the heavy chain variable region (VH) as shown in SEQ ID NO: 7; and / or VL CDR1, VL CDR2, and VL CDR3 contained in the light chain variable region (VL) as shown in SEQ ID NO: 8.

[0010] In one embodiment, the anti-TSHR antibody comprises heavy chain variable regions (VH) of VH CDR1, VH CDR2 and VH CDR3 as shown in SEQ ID NOs: 1-3, respectively; and / or comprises light chain variable regions (VL) of VL CDR1, VL CDR2 and VL CDR3 as shown in SEQ ID NOs: 4-6, respectively.

[0011] In one embodiment, the anti-TSHR antibody comprises a heavy chain variable region and a light chain variable region, respectively, as shown in SEQ ID NO: 7 and / or 8.

[0012] In one embodiment, the anti-TSHR antibody comprises a heavy chain constant region and a light chain constant region, respectively, as shown in SEQ ID NO: 9 and / or 10.

[0013] In one embodiment, the anti-TSHR antibody comprises a heavy chain and a light chain with amino acid sequences as shown in SEQ ID NO: 11 and / or 12, respectively.

[0014] In one embodiment, the concentration of anti-TSHR antibody in the antibody injection is 50-150 mg / ml; preferably, the concentration of the antibody is 80-120 mg / ml; preferably, the concentration of the antibody is 50, 60, 70, 80, 90, 100, 110, 120, 130, 140 or 150 mg / ml, and any number between any two of these.

[0015] In one embodiment, the stabilizer is sucrose or trehalose at a concentration of about 50-100 mg / ml; preferably, the concentration of the sucrose or trehalose is about 60-90 mg / ml, for example 50, 60, 65, 70, 75, 80, 85, 90 or 100 mg / ml, and any number between any two.

[0016] In one embodiment, the stabilizer is mannitol or sorbitol at a concentration of about 30-60 mg / ml; for example, the concentration of mannitol or sorbitol is 30, 40, 45, 50, 55 or 60 mg / ml, and any number between any two.

[0017] In one embodiment, the surfactant is poloxamer 188, polysorbate 20, or polysorbate 80, at a concentration of 0.01-2 mg / ml; preferably, the concentration of the surfactant is about 0.2-1.5 mg / ml; preferably, the surfactant is 0.2-1.5 mg / ml of polysorbate 80, and more preferably, the surfactant is 0.8-1.2 mg / ml of polysorbate 80, for example, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5 mg / ml, and any number between any two of these values.

[0018] In one embodiment, the aforementioned antibody injection further comprises a buffer system selected from citrate buffer system, acetate buffer system, histidine buffer system, phosphate buffer system, succinate buffer system, and combinations thereof; preferably, the buffer system is selected from citrate buffer system, acetate buffer system, and histidine buffer system; preferably, the buffer system is an acetate buffer system.

[0019] In one embodiment, the acetate buffer system is prepared from a commonly used acetate buffer pair, such as an acetate-sodium acetate buffer system or an acetate-ammonium acetate buffer system. In one embodiment, the acetate buffer system is selected from an acetate-sodium acetate buffer system, specifically prepared from glacial acetic acid and anhydrous sodium acetate, glacial acetic acid and sodium acetate trihydrate, etc.

[0020] In one embodiment, the antibody injection has a pH of 4-6; preferably, the antibody injection has a pH of 4.5-5.5, for example, pH 4, 4.5, 5, 5.5, 6, or any number between two such numbers. The pH value is achieved by adding an appropriate amount of pH adjuster, which is a conventional pH adjuster such as hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, etc.

[0021] In one embodiment, the concentration of the buffer system is about 5-20 mmol / L; preferably, the concentration of the buffer system is about 8-12 mmol / L, for example, the buffer system is an 8, 9, 10, 11, or 12 mmol / L acetate buffer system, or any number between any two numbers.

[0022] In one embodiment, the buffer system is an acetate buffer system, the stabilizer is sucrose, and the surfactant is polysorbate 80.

[0023] In one embodiment, the antibody injection comprises an anti-TSHR antibody (hAb01_G4p monoclonal antibody protein) at a concentration of 50-150 mg / mL, sucrose at a concentration of 60-90 mg / mL, polysorbate 80 at a concentration of 0.5-1.5 mg / mL, and an acetate buffer system with a pH of 4.5-5.5.

[0024] In one embodiment, the antibody injection comprises 100 mg / mL of anti-TSHR antibody (hAb01_G4p monoclonal antibody protein), 60-90 mg / mL of sucrose, 0.8-1.2 mg / mL of polysorbate 80, and an acetate buffer system with a pH of 4.5-5.5.

[0025] In one embodiment, the antibody injection comprises an 8 mmol / L acetate buffer system, 60 mg / ml sucrose, 0.6 mg / ml polysorbate 80, 50 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5.

[0026] In one embodiment, the antibody injection comprises an 8 mmol / L acetate buffer system, 60 mg / ml sucrose, 0.8 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5.

[0027] In one embodiment, the antibody injection comprises a 12 mmol / L acetate buffer system, 90 mg / ml sucrose, 1.5 mg / ml polysorbate 80, 150 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5.

[0028] In one embodiment, the antibody injection comprises an 11 mmol / L acetate buffer system, 60 mg / ml sucrose, 0.7 mg / ml polysorbate 80, 120 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5.

[0029] In one embodiment, the antibody injection comprises a 9 mmol / L acetate buffer system, 67.5 mg / ml sucrose, 0.9 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5.

[0030] In one embodiment, the antibody injection comprises a 10 mmol / L acetate buffer system, 90 mg / ml sucrose, 1.3 mg / ml polysorbate 80, 130 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5.

[0031] In one embodiment, the antibody injection comprises an 8 mmol / L acetate buffer system, 60 mg / ml sucrose, 0.7 mg / ml polysorbate 80, 80 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5.

[0032] In one embodiment, the antibody injection comprises a 10 mmol / L acetate buffer system, 75 mg / ml sucrose, 1.0 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5.

[0033] In one embodiment, the antibody injection comprises an 11 mmol / L acetate buffer system, 80 mg / ml sucrose, 0.8 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5.

[0034] In one embodiment, the antibody injection comprises an 11 mmol / L acetate buffer system, 82.5 mg / ml sucrose, 1.1 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5.

[0035] In one embodiment, the antibody injection comprises a 10 mmol / L acetate buffer system, 70 mg / ml sucrose, 0.5 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5.

[0036] In one embodiment, the antibody injection comprises a 12 mmol / L acetate buffer system, 80 mg / ml sucrose, 1.2 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5.

[0037] In one embodiment, the antibody injection comprises a 12 mmol / L acetate buffer system, 90 mg / ml sucrose, 1.2 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5.

[0038] In the aforementioned embodiments, the acetate buffer system can be prepared from glacial acetic acid and sodium acetate trihydrate in a mass ratio of glacial acetic acid:sodium acetate trihydrate = 2:9.07. For example, a 10 mmol / L acetate buffer system contains 0.2 mg / ml of glacial acetic acid and 0.907 mg / ml of sodium acetate trihydrate.

[0039] In the aforementioned implementation scheme, the pH can be adjusted to 4.5–5.5 using sodium hydroxide.

[0040] In one embodiment, the mass ratio of sucrose to polysorbate 80 is 60-90:0.8-1.2.

[0041] In one embodiment, the osmolality of the antibody injection is 270-320 mOsmol / kg, for example 270, 276, 280, 286, 296, 306, 318 or 320 mOsmol / kg, and any number between any two.

[0042] On the other hand, this application provides the use of the aforementioned antibody injection in the preparation of a medicament for the prevention and / or treatment of autoimmune thyroid diseases.

[0043] In one implementation, the drug is used to prevent and / or treat autoimmune thyroid disease in a subject.

[0044] In one embodiment, the drug is prepared as a medicine box containing instructions for using the aforementioned drug.

[0045] In one implementation, the subject contains an autoantibody (e.g., a stimulatory TRAb) capable of activating TSHR.

[0046] In one implementation, the subject contains an autoantibody (e.g., a stimulating TRAb) capable of activating TSHR at levels exceeding a reference level (e.g., a healthy control level).

[0047] In one embodiment, the drug is not administered concurrently with, nor sequentially with, drugs or therapies for the prevention and / or treatment of hypothyroidism and / or subclinical hypothyroidism.

[0048] In one implementation, the medication for preventing and / or treating hypothyroidism and / or subclinical hypothyroidism includes levothyroxine tablets (Euthyrox), and / or the therapy for preventing and / or treating hypothyroidism and / or subclinical hypothyroidism includes administering levothyroxine tablets (Euthyrox) to the subject.

[0049] In one implementation, the drug is the only pharmaceutically active agent administered to the subject for the prevention and / or treatment of the autoimmune thyroid disease.

[0050] In one implementation, the subject contains an autoantibody (e.g., a stimulating TRAb) capable of activating TSHR.

[0051] In one implementation, the subject contains an autoantibody (e.g., a stimulating TRAb) capable of activating TSHR at levels exceeding a reference level (e.g., a healthy control level).

[0052] In one embodiment, the autoimmune thyroid disease is selected from: Graves' disease, Graves' ophthalmopathy, thyroid-associated ophthalmopathy, pretibial myxedema, Hashimoto's thyroiditis, thyroid cancer, and any combination thereof.

[0053] In one implementation, the autoimmune thyroid disease is Graves' disease.

[0054] In one implementation, the autoimmune thyroid disease is thyroid-associated ophthalmopathy.

[0055] In one implementation, administration of the drug does not cause the subject to develop hypothyroidism or subclinical hypothyroidism.

[0056] In one embodiment, the drug avoids one or more side effects caused by the administration of a TSHR inhibitor.

[0057] In one embodiment, the TSHR inhibitor is a TSHR-inhibiting antibody or antigen-binding fragment thereof other than the antibodies or antigen-binding fragments thereof that are capable of specifically binding TSHR as defined above.

[0058] In one implementation, the one or more side effects include causing the subject to develop hypothyroidism or subclinical hypothyroidism.

[0059] In one implementation, the aforementioned drug is administered to the subject via a route selected from the following:

[0060] Intravenous, intra-arterial, intraperitoneal, intramuscular, subcutaneous, intra-fat, and any combination thereof.

[0061] In one implementation, the aforementioned drug is administered to the subject via intravenous or subcutaneous injection.

[0062] In one implementation, the subject is selected from mammals.

[0063] In one implementation, the subject is a human being.

[0064] In one implementation, the aforementioned drug may be administered in combination with other pharmaceutically active agents (e.g., other drugs for treating autoimmune thyroid diseases such as Graves' disease or thyroid-associated ophthalmopathy), for example, simultaneously or sequentially.

[0065] In one implementation, the aforementioned drug may be administered in combination with an IGF1R antagonist or inhibitor and / or an additional TSHR antagonist or inhibitor, for example, simultaneously or sequentially.

[0066] In another aspect, the present invention provides an antibody injection for preparing a medicament for preventing and / or treating autoimmune thyroid diseases, comprising an anti-TSHR antibody, said anti-TSHR antibody comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively, and LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively;

[0067] Preferably, the anti-TSHR antibody comprises a heavy chain and a light chain with amino acid sequences as shown in SEQ ID NO: 11 and 12, respectively.

[0068] On the other hand, the present invention provides a method for preventing and / or treating autoimmune thyroid diseases, comprising administering an effective amount of the aforementioned antibody injection to a subject in need of such treatment.

[0069] In another aspect, the present invention provides an antibody injection for the aforementioned method of preventing and / or treating autoimmune thyroid diseases, comprising an anti-TSHR antibody, said anti-TSHR antibody comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively, and LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively;

[0070] Preferably, the anti-TSHR antibody comprises a heavy chain and a light chain with amino acid sequences as shown in SEQ ID NO: 11 and 12, respectively.

[0071] On the other hand, the present invention provides a method for preparing the aforementioned antibody injection, which is produced using conventional injection preparation processes in the art. In some embodiments, the components of the antibody injection are weighed, prepared, mixed, filtered for sterilization, and filled to obtain the antibody injection. Beneficial effects

[0072] This invention significantly improves the physical and chemical stability of anti-TSHR antibody injections through formulation screening and optimization. High-temperature stability, accelerated stability, and long-term stability tests confirm that the formulation is suitable for anti-TSHR antibodies and can ensure good stability of the product during storage, transportation, and use. Detailed Implementation

[0073] definition

[0074] This article uses the term "antibody injection," also known as a liquid antibody composition, to refer to an aqueous composition that is not reconstituted from a lyophilized substance, containing at least one anti-TSHR antibody or its antigen-binding fragment and at least one excipient (e.g., a stabilizer). This liquid pharmaceutical composition may contain other excipients (buffer systems, surfactants) and other active ingredients. This type of formulation is also called a "ready-to-use" formulation.

[0075] The term "stabilizer" refers to an agent that helps prevent the oxidation and aggregation of proteins in pharmaceutical compositions, particularly antibody injections, which have a short shelf life due to the susceptibility of proteins in aqueous solutions to oxidation and / or aggregation. Various analytical methods can be used to assess the stability of a given composition; for example, CEX-HPLC or SCX-HPLC can be used to assess the content of oxidation products (before the main peak) in the antibody injections of this disclosure, and SEC-HPLC can be used to assess the aggregation level in the antibody injections of this disclosure.

[0076] As used herein and unless otherwise stated, the terms “about” or “approximately” mean within 10% of a given value or range. Where an integer is required, the term means within 10% of a given value or range, rounded up or down to the nearest integer.

[0077] Compositions or methods described herein as “comprising” or “including” one or more named elements or steps are open-ended, meaning that the named elements or steps are necessary but other elements or steps may be added within the scope of the composition or method. In any composition or method disclosed herein, any known or disclosed equivalent of any named basic element or step may replace the element or step.

[0078] The term "antibody" in this document refers to the entire antibody and any antigen-binding portion or single chain thereof. Naturally occurring antibodies are glycoproteins comprising at least two heavy chains (H) and two light chains (L) linked together by disulfide bonds. Each heavy chain contains a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region contains three domains: CH1, CH2, and CH3. Each light chain contains a light chain variable region (VL) and a light chain constant region. The light chain constant region contains one domain, CL. The VH and VL regions can be further subdivided into multiple hypervariable regions, called hypervariable regions or complementarity-determining regions (CDRs), with more conserved regions called backbone regions (FRs). Each VH and VL contains three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus as follows: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen.

[0079] As used herein, “monoclonal antibody” refers to a population of identical antibodies, meaning that each individual antibody molecule in a population of monoclonal antibodies is identical to the others. This characteristic contrasts with that of a polyclonal population of antibodies, which contains antibodies with a variety of different sequences. Monoclonal antibodies can be prepared by a number of well-known methods (Smith et al. (2004) J. Clin. Pathol. 57, 912-917; and Nelson et al., J Clin Pathol (2000), 53, 111-117). For example, monoclonal antibodies can be prepared from immortalized B cells, for instance, by fusing with myeloma cells to generate hybridoma cell lines or by infecting B cells with a virus such as EBV. Recombinant technologies can also be used to prepare antibodies in vitro from a clonal population of host cells by transforming host cells with plasmids carrying artificial sequences of nucleotides encoding the antibody.

[0080] Sequence “identity” or “commonality” has a generally accepted meaning in the art, and the percentage of sequence similarity between two nucleic acid or polypeptide molecules or regions can be calculated using publicly available techniques. Sequence similarity can be measured along the full length of a polynucleotide or polypeptide or along a region of that molecule. Although many methods exist for measuring the similarity between two polynucleotides or polypeptides, the term “identity” is well known to those skilled in the art (Carrillo, H. & Lipman, D., SIAM J Applied Math 48:1073 (1988)).

[0081] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0082] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0083] In one embodiment of this application, the antibody injection comprises an antibody or its antigen-binding fragment capable of specifically binding to TSHR and a pharmaceutically acceptable carrier.

[0084] In one embodiment, the antibody or antigen-binding fragment thereof capable of specifically binding to TSHR comprises: VH CDR1, VH CDR2 and VH CDR3 contained in the heavy chain variable region (VH) as shown in SEQ ID NO: 7; and / or, VL CDR1, VL CDR2 and VL CDR3 contained in the light chain variable region (VL) as shown in SEQ ID NO: 8.

[0085] In one implementation, the CDRs are defined by the Kabat, IMGT, Chothia, or AbM numbering system.

[0086] In one embodiment, the antibody or its antigen-binding fragment capable of specifically binding to TSHR comprises:

[0087] (a) Heavy chain variable regions (VH) comprising VH CDR1, VH CDR2 and VH CDR3 as shown in SEQ ID NOs: 1-3 respectively; and / or

[0088] (b) light chain variable regions (VL) comprising VL CDR1, VL CDR2 and VL CDR3 as shown in SEQ ID NOs: 4-6 respectively.

[0089] In one implementation, the CDRs are defined by the Kabat numbering system.

[0090] In one embodiment, the antibody or antigen-binding fragment thereof capable of specifically binding to TSHR comprises a framework region sequence derived from human immunoglobulin.

[0091] In one embodiment, the antibody or antigen-binding fragment thereof capable of specifically binding to TSHR comprises a framework region contained in the amino acid sequence encoded by a human germline antibody gene. In one embodiment, the antibody or antigen-binding fragment thereof capable of specifically binding to TSHR comprises: a heavy chain framework region of a human heavy chain germline sequence, and / or, a light chain framework region of a human light chain germline sequence.

[0092] In one embodiment, the antibody or its antigen-binding fragment capable of specifically binding to TSHR comprises:

[0093] (1) Heavy chain variable region (VH), which contains the sequence shown in SEQ ID NO: 7 or a variant thereof; and / or,

[0094] (2) Light chain variable region (VL) comprising the sequence shown in SEQ ID NO: 8 or a variant thereof;

[0095] The variant has one or more amino acid substitutions, deletions, or additions (e.g., substitutions, deletions, or additions of 1, 2, 3, 4, or 5 amino acids) compared to its source sequence, or has a sequence identity of 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%, at least 99%, or 100%. In one embodiment, the substitution is a conservative substitution.

[0096] In one embodiment, the antibody or its antigen-binding fragment capable of specifically binding to TSHR comprises: a heavy chain variable region (VH) as shown in SEQ ID NO: 7 and a light chain variable region (VL) as shown in SEQ ID NO: 8.

[0097] In one embodiment, the antibody or antigen-binding fragment thereof capable of specifically binding to TSHR further comprises a constant region derived from mammalian (e.g., human) immunoglobulins.

[0098] In some embodiments, the antibody or antigen-binding fragment capable of specifically binding to TSHR comprises a heavy chain constant region of wild-type human immunoglobulin. In other embodiments, the antibody or antigen-binding fragment capable of specifically binding to TSHR comprises a variant of the heavy chain constant region of human immunoglobulin, the variant of which may have the same or substantially the same characteristics as its derived wild-type sequence. In one embodiment, the variant of the heavy chain constant region may have one or more conserved substitutions of amino acids compared to its derived sequence.

[0099] In one embodiment, the heavy chain of the antibody or its antigen-binding fragment capable of specifically binding to TSHR comprises a heavy chain constant region (CH) as shown in SEQ ID NO: 9, and / or, the light chain of the antibody or its antigen-binding fragment capable of specifically binding to TSHR comprises a light chain constant region (CL) as shown in SEQ ID NO: 10.

[0100] In one embodiment, the antibody or its antigen-binding fragment capable of specifically binding to TSHR comprises:

[0101] A heavy chain comprising the sequence shown in SEQ ID NO: 11, and / or a light chain comprising the sequence shown in SEQ ID NO: 12.

[0102] In one embodiment, the antibody or its antigen-binding fragment capable of specifically binding to TSHR comprises murine antibodies, humanized antibodies, chimeric antibodies, bispecific antibodies, or multispecific antibodies.

[0103] In one embodiment, the antibody specifically binding to TSHR is an anti-TSHR monoclonal antibody hAb01_G4p, which originates from patent application WO 2024 / 046384A1 (filed August 30, 2023), and patent applications PCT / CN2025 / 119435 (international filing date September 5, 2025, priority CN 202411253713.9, priority date September 6, 2024) and CN 202511270847.6 (filed September 5, 2025, priority CN202411253713.9, priority date September 6, 2024), the full text of which is incorporated herein by reference.

[0104] The VH CDRs and VL CDRs (defined by the Kabat numbering system) contained in the anti-TSHR monoclonal antibody hAb01_G4p are shown in SEQ ID NOs: 1-6; its heavy chain variable region and light chain variable region are shown in SEQ ID NO: 7 and 8, respectively; its full-length heavy chain and full-length light chain are shown in SEQ ID NO: 11 and 12, respectively.

[0105] The descriptions of the sequences involved in this application are provided in the table below.

[0106] Table 1 - Sequence Information Table

[0107] Based on the mechanism of action of hAb01_G4p, the administration route is subcutaneous injection, and the developed dosage form is an injection. Based on the properties of hAb01_G4p, excipients with different functions were initially selected for formulation screening studies. The buffer system is used to stabilize the pH of the formulation; the stabilizer utilizes the polyhydroxyl groups in the polyol molecule to protect the structural stability of the protein, increase protein solubility, and regulate the osmotic pressure of the product; the surfactant is used to prevent adsorption of the protein upon contact with the container surface during production and use, while also preventing protein polymerization.

[0108] The following describes the process of screening buffer systems, stabilizers and surfactants, adjusting osmotic molar concentration, optimizing formulations, confirming pH ranges, confirming excipient ranges and formula confirmation.

[0109] Methods for evaluating formulations include visual inspection, size exclusion chromatography (SEC-HPLC), cation exchange chromatography (CEX-HPLC), pH determination, protein content determination, differential scanning calorimetry (DSC), and reducing or non-reducing capillary electrophoresis (CE-SDS).

[0110] Example 1: Screening of Buffer Systems

[0111] Screening experiments were conducted using citrate, acetate, and histidine buffer systems. Different pH values ​​were set based on the varying buffer ranges of each system. Specifically, the stock solution was replaced with the corresponding buffer system, and the hAb01_G4p antibody protein concentration was 50 mg / ml. Stability was assessed at 40℃±2℃ / 75%RH±5%RH (i.e., temperature 40℃±2℃ and relative humidity 75%±5%, the same below) and 25℃±2℃ / 60%RH±5%RH. The assessment indicators included appearance, SEC-HPLC, CEX-HPLC, pH, protein content, DSC, and sampling points: T0, 1W, 2W, 3W, and 4W. After 4 weeks at 40℃±2℃ / 75%RH±5%RH, the results for appearance, pH, and protein content showed no significant changes in any of the buffer systems. SEC-HPLC and CEX-HPLC results also showed no significant differences between the buffer systems, with a generally consistent trend.

[0112] Based on the results of various investigations, a buffer system of 10 mmol / L acetate (pH 5.0) was selected for further screening in the formulation. The experimental results are summarized in Table 2.

[0113] Table 2 - Summary of Buffer System Test Results (40℃±2℃ / 75%RH±5%RH) Note: T0 is zero; W is the time unit, 1W = 1 week; Ace is the acetate buffer system, Cit is the citrate buffer system, and His is the histidine buffer system.

[0114] Example 2: Screening of stabilizers and surfactants

[0115] Protein stability is influenced not only by the type of buffer system and ion concentration, but also by the types of stabilizers and surfactants. In this embodiment, different stabilizer concentrations (preliminary selection based on osmolarity) and surfactant combinations were used. The stock solution was replaced with a 10 mmol / L acetate (pH 5.0) buffer system, and different proportions of stabilizers and surfactant combinations were added. The hAb01_G4p antibody protein concentration was adjusted to 100 mg / ml.

[0116] The stability of the samples was investigated at 40℃±2℃ / 75%RH±5%RH. The indicators tested included appearance, pH value, protein content, SEC-HPLC, CEX-HPLC, non-reduced CE-SDS, and reduced CE-SDS. Sampling points were T0, 1W, 2W, 3W, and 4W. After 4 weeks of storage under these conditions, the results for different stabilizers showed that the mannitol-containing formulation showed an increase in visible particles (white spots); the sorbitol formulation showed a faster rate of change on SEC-HPLC, while the sucrose and trehalose formulations showed slower rates of change; the CEX-HPLC, reduced CE-SDS, and non-reduced CE-SDS results showed consistent trends with no significant differences. Results of different surfactant tests showed that, compared to polysorbate 20 samples at the same concentration, the SEC main peak change rate was slower for polysorbate 80 samples, and the change in non-reducing CE-SDS electrophoresis purity was also slower. Given that the change rates of polysorbate 80 at different concentrations of 0.2, 0.6, and 1.0 mg / ml were not significantly different, lower concentrations of polysorbate 80 were preferred. Other indicators showed consistent trends across all formulations, with no significant differences. Under other conditions, the trends of the tested indicators were consistent across all formulations.

[0117] Based on the above experiments, sucrose or trehalose was selected as the preferred stabilizer for this product, with sucrose used as the stabilizer in subsequent screening. Polysorbate 80 was selected as the preferred surfactant for this product, with a minimum concentration tentatively set at 0.2 mg / ml. The test results are summarized in Table 3.

[0118] Table 3 - Summary of Screening Test Results for Stabilizers and Surfactants (40℃±2℃ / 75%RH±5%RH) Note: T0 is zero time; W is a unit of time, 1W = 1 week.

[0119] Ace is an acetate buffer system, Suc is sucrose, Sor is sorbitol, Tre is trehalose, Man is mannitol, PS80 is polysorbate 80, and PS20 is polysorbate 20.

[0120] Example 3: Adjustment of osmotic pressure molar concentration

[0121] Based on the stabilizer screening results, stabilizer samples of different concentrations (70 mg / ml sucrose, 75 mg / ml sucrose, and 80 mg / ml sucrose) were prepared, and their osmolar concentrations were measured. The data results are shown in Table 4.

[0122] Table 4 - Osmolar concentration data of sucrose at different concentrations

[0123] Since this product is administered via subcutaneous injection, its osmolality needs to be similar to that of human plasma (280–320 mOsmol / kg), and the above-mentioned sucrose concentrations meet these requirements.

[0124] Example 4: Prescription Optimization

[0125] When the aforementioned screened formulation samples underwent a stability study at 200 rpm / 5℃±3℃, a significant increase in the polymer content by SEC-HPLC, a decrease in the main peak content by SCX-HPLC, and an increase in the alkaline peak were observed after two weeks of oscillation. This suggests that there may be risks during transportation, and the formulation needs to be optimized and adjusted.

[0126] Formulas containing different concentrations of polysorbate 80 were prepared, with polysorbate 80 concentrations of 0.2 mg / ml, 0.4 mg / ml, 0.6 mg / ml, 0.8 mg / ml, and 1.0 mg / ml. Other components were fixed as follows: hAb01_G4p antibody protein concentration of 100 mg / ml, sucrose of 75 mg / ml, 10 mmol / L acetate buffer, and pH 5.0. After capping, the stability of the samples was investigated under shaking conditions of 200 rpm and 5℃±3℃. The indicators for investigation were appearance, pH value, insoluble particles, protein content, SEC-HPLC, SCX-HPLC, reduced CE-SDS, and non-reduced CE-SDS. Sampling points: T0, 1W, 2W, 3W, and 4W.

[0127] Experimental results showed that after 4 weeks of horizontal placement under shaking conditions at 200 rpm and 5℃±3℃, no significant changes were observed in appearance, pH value, protein content, and insoluble particulate matter in polysorbate 80 samples of different concentrations. SEC-HPLC results showed that the polymer content of 0.2 mg / ml and 0.4 mg / ml polysorbate 80 samples increased, with a maximum increase of 15.06%; while the polymer content of 0.6 mg / ml, 0.8 mg / ml, and 1.0 mg / ml polysorbate 80 samples showed no significant change. SCX-HPLC results showed that the main peak of 0.2 mg / ml and 0.4 mg / ml polysorbate 80 samples decreased, with a maximum decrease of 9.87%; while the main peak of 0.6 mg / ml, 0.8 mg / ml, and 1.0 mg / ml polysorbate 80 samples showed no significant change. CE-SDS reducing electrophoresis and CE-SDS non-reducing electrophoresis results showed that the trends of polysorbate 80 formulations of different concentrations were basically consistent.

[0128] Based on the results of various investigations, the preferred concentration of polysorbate 80 in the formulation was determined to be 0.5-1.5 mg / ml, with a further preferred concentration of 0.6-1.2 mg / ml. The experimental results are summarized in Table 5.

[0129] Table 5 - Summary of test results for prescription optimization oscillation conditions (200 rpm, 5℃±3℃) Note: T0 is zero time; W is a unit of time, 1W = 1 week.

[0130] Example 5: pH range confirmation

[0131] Based on the results of each screening step, the pH range was confirmed. Different samples with pH values ​​of 4.5, 4.8, 5.0, 5.3, and 5.5 were adjusted with sodium hydroxide and their stability was investigated at 40℃±2℃, 25℃±2℃, and 5℃±3℃. The indicators for investigation were appearance, protein content, pH value, insoluble particles, SEC-HPLC, SCX-HPLC, reduced CE-SDS, and non-reduced CE-SDS.

[0132] After being placed at 40℃±2℃ / 75%RH±5%RH for 30 days, with sampling points at 0, 5, 10, 15 and 30 days, the main peak of SCX-HPLC purity of samples with different pH values ​​decreased, and the decrease was within an acceptable range and the trend was consistent; there were no significant changes in SEC-HPCL purity, reduced CE-SDS, non-reduced CE-SDS purity and other items.

[0133] After being placed under accelerated conditions of 25℃±2℃ / 60%RH±5%RH for 2 months, and sampled at 0, 1 month, 2 months, 3 months and 6 months, the main peak of the SCX-HPLC purity of samples with different pH values ​​decreased slightly, and the decrease was within an acceptable range and the trend was consistent; there were no significant changes in the SEC-HPLC purity, reduced CE-SDS, non-reduced CE-SDS purity and others.

[0134] After being placed under long-term conditions of 5℃±3℃ for 18 months, with sampling points at 0, 3 months, 6 months, 9 months, 12 months, and 18 months, no significant changes were observed in the purity of SCX-HPLC, SEC-HPLC, reduced CE-SDS, non-reduced CE-SDS, and other parameters of samples with different pH values.

[0135] Based on the combined results of various experiments (the results of SEC-HPLC and SCX-HPLC are shown in Table 6-8), the pH range of the formulation was determined to be 4.5–5.5.

[0136] Table 6 - Stability Study Results of pH Range Confirmation Test (SEC-HPLC, SCX-HPLC) (40℃±2℃ / 75%RH±5%RH) Note: T0 is time zero; D is a unit of time, 5D = 5 days.

[0137] Table 7 - Stability Study Results of pH Range Confirmation Test (SEC-HPLC, SCX-HPLC) (25℃±2℃ / 60%RH±5%RH) Note: T0 is zero; M is a unit of time, 1M = 1 month.

[0138] Table 8 - Stability assessment results of pH range confirmation test using SEC-HPLC and SCX-HPLC (5℃±3℃) Note: T0 is zero; M is a unit of time, 1M = 1 month.

[0139] Example 6: Prescription Verification

[0140] Based on the results of comprehensive buffer system, stabilizer and surfactant screening tests, as well as osmotic pressure molar concentration adjustment tests, the range of each component in the formulation and the specific formulation were obtained, and stability verification was carried out.

[0141] The prescription contains the following components: 50-150 mg / mL of anti-TSHR antibody (hAb01_G4p monoclonal antibody protein), 60-90 mg / mL of sucrose, 0.5-1.5 mg / mL of polysorbate 80, an acetate buffer system with a concentration of approximately 8-12 mmol / L, and an appropriate amount of sodium hydroxide to adjust the pH to 4.5-5.5.

[0142] Specific prescription:

[0143] Prescription 1: 8 mmol / L acetate buffer system, 60 mg / ml sucrose, 0.6 mg / ml polysorbate 80, 50 mg / ml hAb01_G4p monoclonal antibody protein.

[0144] Prescription 2: 8 mmol / L acetate buffer system, 60 mg / ml sucrose, 0.8 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein.

[0145] Prescription 3: 12 mmol / L acetate buffer system, 90 mg / ml sucrose, 1.5 mg / ml polysorbate 80, 150 mg / ml hAb01_G4p monoclonal antibody protein.

[0146] Prescription 4: 11 mmol / L acetate buffer system, 60 mg / ml sucrose, 0.7 mg / ml polysorbate 80, 120 mg / ml hAb01_G4p monoclonal antibody protein.

[0147] Prescription 5: 9 mmol / L acetate buffer system, 67.5 mg / ml sucrose, 0.9 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein.

[0148] Prescription 6: 10 mmol / L acetate buffer system, 90 mg / ml sucrose, 1.3 mg / ml polysorbate 80, 130 mg / ml hAb01_G4p monoclonal antibody protein.

[0149] Prescription 7: 8 mmol / L acetate buffer system, 60 mg / ml sucrose, 0.7 mg / ml polysorbate 80, 80 mg / ml hAb01_G4p monoclonal antibody protein.

[0150] Prescription 8: 10 mmol / L acetate buffer system, 75 mg / ml sucrose, 1.0 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein.

[0151] Prescription 9: 11 mmol / L acetate buffer system, 80 mg / ml sucrose, 0.8 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein.

[0152] Prescription 10: 11 mmol / L acetate buffer system, 82.5 mg / ml sucrose, 1.1 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein.

[0153] Prescription 11: 10 mmol / L acetate buffer system, 70 mg / ml sucrose, 0.5 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein.

[0154] Prescription 12: 12 mmol / L acetate buffer system, 80 mg / ml sucrose, 1.2 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein.

[0155] Prescription 13: 12 mmol / L acetate buffer system, 90 mg / ml sucrose, 1.2 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein.

[0156] The above acetate buffer system is prepared using glacial acetic acid and sodium acetate trihydrate in a mass ratio of glacial acetic acid:sodium acetate trihydrate = 2:9.07. For example, a 10 mmol / L acetate buffer system contains 0.2 mg / ml glacial acetic acid and 0.907 mg / ml sodium acetate trihydrate. The pH is adjusted to 4.5–5.5 with sodium hydroxide.

[0157] Stability verification: Samples of formulations 2, 5, 8, 10, and 13 were extracted and their stability was investigated at 40℃±2℃, 25℃±2℃, and 5℃±3℃. The indicators for investigation were: appearance and visible foreign matter, insoluble particles, SEC-HPLC, SCX-HPLC, reduced CE-SDS, and non-reduced CE-SDS.

[0158] After being placed under high temperature conditions of 40℃±2℃ / 75%RH±5%RH for 30 days, with sampling points at 0, 5, 10, 15 and 30 days, the decrease in the main peak content of the SCX-HPLC purity of each formulation was within an acceptable range and the trend was consistent; there were no significant changes in the purity of reduced CE-SDS, non-reduced CE-SDS, and SEC-HPLC.

[0159] After being placed under accelerated conditions of 25℃±2℃ / 60%RH±5%RH for 6 months, with sampling points at 0, 1 month, 2 months, 3 months, and 6 months, the decrease in the main peak content of the SCX-HPLC purity of each formulation was within an acceptable range, and the rate of change was basically consistent; there were no significant changes in the SEC-HPLC purity, reduced CE-SDS, and non-reduced CE-SDS purity.

[0160] After being placed under long-term conditions of 5℃±3℃ for 18 months, with sampling points at 0, 3 months, 6 months, 9 months, 12 months, and 18 months, there were no significant changes in the purity of SCX-HPLC, SEC-HPLC, reduced CE-SDS, and non-reduced CE-SDS of each formulation.

[0161] Based on the results of high-temperature stability, accelerated stability, and long-term stability tests (as shown in Tables 9-11), the stability of the above formulation range was confirmed.

[0162] Table 9 - Summary of Component Range Confirmation Test Results (40℃±2℃ / 75%RH±5%RH) Note: T0 is zero time; D is a unit of time, 5D = 5 days.

[0163] Table 10 - Summary of Component Range Confirmation Test Results (25℃±2℃ / 60%RH±5%RH) Note: T0 is zero; M is a unit of time, 1M = 1 month.

[0164] Table 11 - Summary of Component Range Confirmation Test Results (5℃±3℃)

[0165] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An antibody injection comprising an anti-TSHR antibody, a stabilizer, and a surfactant, wherein the stabilizer is sucrose, trehalose, mannitol, or sorbitol, and the surfactant is poloxamer 188, polysorbate 80, or polysorbate 20.

2. The antibody injection according to claim 1, wherein the anti-TSHR antibody comprises VH CDR1, VH CDR2 and VH CDR3 contained in the heavy chain variable region (VH) as shown in SEQ ID NO: 7; and / or, VL CDR1, VL CDR2 and VL CDR3 contained in the light chain variable region (VL) as shown in SEQ ID NO: 8; Preferably, the anti-TSHR antibody comprises heavy chain variable regions (VH) of VH CDR1, VH CDR2 and VH CDR3 as shown in SEQ ID NOs: 1-3 respectively; and / or comprises light chain variable regions (VL) of VL CDR1, VL CDR2 and VL CDR3 as shown in SEQ ID NOs: 4-6 respectively; Preferably, the anti-TSHR antibody comprises a heavy chain variable region and a light chain variable region, respectively, as shown in SEQ ID NO: 7 and / or 8; Preferably, the anti-TSHR antibody comprises a heavy chain and a light chain with amino acid sequences as shown in SEQ ID NO: 11 and / or 12, respectively.

3. The antibody injection according to claim 1 or 2, wherein the concentration of anti-TSHR antibody in the antibody injection is 50-150 mg / ml; Preferably, the concentration of the antibody is 80-120 mg / ml; Preferably, the concentration of the antibody is 50, 60, 70, 80, 90, 100, 110, 120, 130, 140 or 150 mg / ml, or any number between any two of these values.

4. The antibody injection according to any one of claims 1-3, wherein the stabilizer is sucrose or trehalose at a concentration of about 50-100 mg / ml; preferably, the concentration of the sucrose or trehalose is about 60-90 mg / ml, for example 50, 60, 65, 70, 75, 80, 85, 90 or 100 mg / ml, and any number between any two of these.

5. The antibody injection according to any one of claims 1-4, wherein the surfactant is poloxamer 188, polysorbate 20, or polysorbate 80, at a concentration of 0.01-2 mg / ml; preferably, the concentration of the surfactant is about 0.2-1.5 mg / ml; preferably, the surfactant is 0.2-1.5 mg / ml of polysorbate 80, preferably, the surfactant is 0.8-1.2 mg / ml of polysorbate 80, for example 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5 mg / ml, and any number between any two of these values.

6. The antibody injection according to any one of claims 1-5, wherein the antibody injection further comprises a buffer system selected from citrate buffer system, acetate buffer system, histidine buffer system, phosphate buffer system, succinate buffer system, and combinations thereof; Preferably, the buffer system is selected from the citrate buffer system, the acetate buffer system, and the histidine buffer system; more preferably, the buffer system is the acetate buffer system. Preferably, the acetate buffer system is selected from the acetate-sodium acetate buffer system or the acetate-ammonium acetate buffer system; Preferably, the concentration of the buffer system is about 5-20 mmol / L; preferably, the concentration of the buffer system is about 8-12 mmol / L, for example, the buffer system is an 8, 9, 10, 11, or 12 mmol / L acetate buffer system, or any number between any two numbers.

7. The antibody injection according to any one of claims 1-6, wherein the pH of the antibody injection is 4-6; preferably, the pH of the antibody injection is 4.5-5.5, for example, pH is 4, 4.5, 5, 5.5, 6, or any number between any two numbers; the pH value is achieved by adding an appropriate amount of pH adjuster, wherein the pH adjuster is a conventional pH adjuster, such as hydrochloric acid, acetic acid, sodium hydroxide, potassium hydroxide, etc.

8. The antibody injection according to any one of claims 1-7, wherein the buffer system is an acetate-sodium acetate buffer system, the stabilizer is sucrose, and the surfactant is polysorbate 80.

9. The antibody injection according to any one of claims 1-8, wherein the antibody injection comprises an anti-TSHR antibody (hAb01_G4p monoclonal antibody protein) at a concentration of 50-150 mg / mL, sucrose at a concentration of 60-90 mg / mL, polysorbate 80 at a concentration of 0.5-1.5 mg / mL, and the buffer system is an acetate buffer system with a pH of 4.5-5.5; Preferably, the antibody injection comprises 100 mg / mL of anti-TSHR antibody (hAb01_G4p monoclonal antibody protein), 60-90 mg / mL of sucrose, 0.8-1.2 mg / mL of polysorbate 80, and an acetate buffer system with a pH of 4.5-5.

5. Preferably, the antibody injection comprises an 8 mmol / L acetate buffer system, 60 mg / ml sucrose, 0.6 mg / ml polysorbate 80, 50 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5; Preferably, the antibody injection comprises an 8 mmol / L acetate buffer system, 60 mg / ml sucrose, 0.8 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5; Preferably, the antibody injection comprises a 12 mmol / L acetate buffer system, 90 mg / ml sucrose, 1.5 mg / ml polysorbate 80, 150 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.

5. Preferably, the antibody injection comprises an acetate buffer system with a concentration of 11 mmol / L, 60 mg / ml sucrose, 0.7 mg / ml polysorbate 80, 120 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5; Preferably, the antibody injection comprises a 9 mmol / L acetate buffer system, 67.5 mg / ml sucrose, 0.9 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5; Preferably, the antibody injection comprises a 10 mmol / L acetate buffer system, 90 mg / ml sucrose, 1.3 mg / ml polysorbate 80, 130 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5; Preferably, the antibody injection comprises an 8 mmol / L acetate buffer system, 60 mg / ml sucrose, 0.7 mg / ml polysorbate 80, 80 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5; Preferably, the antibody injection comprises a 10 mmol / L acetate buffer system, 75 mg / ml sucrose, 1.0 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5; Preferably, the antibody injection comprises an acetate buffer system with a concentration of 11 mmol / L, 80 mg / ml sucrose, 0.8 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5; Preferably, the antibody injection comprises an acetate buffer system with a concentration of 11 mmol / L, 82.5 mg / ml sucrose, 1.1 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5; Preferably, the antibody injection comprises a 10 mmol / L acetate buffer system, 70 mg / ml sucrose, 0.5 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5; Preferably, the antibody injection comprises a 12 mmol / L acetate buffer system, 80 mg / ml sucrose, 1.2 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.5; Preferably, the antibody injection comprises a 12 mmol / L acetate buffer system, 90 mg / ml sucrose, 1.2 mg / ml polysorbate 80, 100 mg / ml hAb01_G4p monoclonal antibody protein, and a pH of 4.5–5.

5.

10. The antibody injection according to any one of claims 1-9, wherein the acetate buffer system may be prepared by glacial acetic acid and sodium acetate trihydrate in a mass ratio of glacial acetic acid: sodium acetate trihydrate = 2:9.07, and the pH may be adjusted to 4.5-5.5 by sodium hydroxide.

11. The antibody injection according to any one of claims 1-10, wherein the mass ratio of sucrose to polysorbate 80 in the antibody injection is 60-90:0.8-1.

2.

12. The antibody injection according to any one of claims 1-11, wherein the osmolality of the antibody injection is 270-320 mOsmol / kg, for example 270, 276, 280, 286, 296, 306, 318 or 320 mOsmol / kg, and any number between any two numbers.

13. Use of the antibody injection of any one of claims 1-12 in the preparation of a medicament for the prevention and / or treatment of autoimmune thyroid diseases; Preferably, the drug is used in subjects to prevent and / or treat autoimmune thyroid disease; Preferably, the drug is prepared as a medicine box, and the medicine box contains instructions for using the drug; Preferably, the subject contains an autoantibody (e.g., a stimulating TRAb) capable of activating TSHR; Preferably, the subject contains autoantibodies (e.g., stimulatory TRAb) that can activate TSHR at levels exceeding reference levels (e.g., healthy control levels); Preferably, the drug is not administered concurrently with or in combination with drugs or therapies for the prevention and / or treatment of hypothyroidism and / or subclinical hypothyroidism, nor is it administered sequentially with drugs or therapies for the prevention and / or treatment of hypothyroidism and / or subclinical hypothyroidism. Preferably, the medication for preventing and / or treating hypothyroidism and / or subclinical hypothyroidism includes levothyroxine tablets (Euthyrox), and / or the therapy for preventing and / or treating hypothyroidism and / or subclinical hypothyroidism includes: Levothyroxine tablets (Euthyrox) were administered to the subjects; Preferably, the drug is the only pharmaceutically active agent administered to the subject for the prevention and / or treatment of the autoimmune thyroid disease; Preferably, the subject contains an autoantibody (e.g., a stimulating TRAb) capable of activating TSHR; Preferably, the subject contains autoantibodies (e.g., stimulatory TRAb) that can activate TSHR at levels exceeding reference levels (e.g., healthy control levels); Preferably, the autoimmune thyroid disease is selected from: Graves' disease, Graves' ophthalmopathy, thyroid-associated ophthalmopathy, pretibial myxedema, Hashimoto's thyroiditis, thyroid cancer, and any combination thereof; Preferably, the autoimmune thyroid disease is Graves' disease; Preferably, the autoimmune thyroid disease is thyroid-associated ophthalmopathy; Preferably, administration of the drug will not cause hypothyroidism or subclinical hypothyroidism in the subject; Preferably, the drug avoids one or more side effects caused by the administration of TSHR inhibitors; Preferably, the TSHR inhibitor is a TSHR-inhibiting antibody or antigen-binding fragment other than the antibodies or antigen-binding fragments thereof that can specifically bind to TSHR as defined above; Preferably, the one or more side effects include causing the subject to develop hypothyroidism or subclinical hypothyroidism; Preferably, the drug is administered to the subject via a route selected from the following: Intravenous, intra-arterial, intraperitoneal, intramuscular, subcutaneous, intra-fat, and any combination thereof; Preferably, the drug is administered to the subject via intravenous or subcutaneous injection; Preferably, the subjects are selected from mammals; Preferably, the subject is a human being; Preferably, the drug can be administered in combination with other pharmaceutically active agents (e.g., other drugs for treating autoimmune thyroid diseases such as Graves' disease and thyroid-associated ophthalmopathy), for example, simultaneously or sequentially. Preferably, the drug can be administered in combination with an IGF1R antagonist or inhibitor and / or another TSHR antagonist or inhibitor, for example, simultaneously or sequentially.

14. An antibody injection for preparing a medicament for the prevention and / or treatment of autoimmune thyroid diseases, comprising an anti-TSHR antibody, said anti-TSHR antibody comprising HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and LCDR1, LCDR2 and LCDR3 with amino acid sequences as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively; Preferably, the anti-TSHR antibody comprises a heavy chain and a light chain with amino acid sequences as shown in SEQ ID NO: 11 and 12, respectively.

15. A method for preventing and / or treating autoimmune thyroid disease, comprising administering to a subject in need an effective amount of the antibody injection of any one of claims 1-12.

16. An antibody injection for the method of preventing and / or treating autoimmune thyroid disease, comprising an anti-TSHR antibody, said anti-TSHR antibody comprising HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and LCDR1, LCDR2 and LCDR3 with amino acid sequences as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively; Preferably, the anti-TSHR antibody comprises a heavy chain and a light chain with amino acid sequences as shown in SEQ ID NO: 11 and 12, respectively.

17. The method for preparing the antibody injection according to any one of claims 1-12, wherein the antibody is prepared using conventional injection preparation processes in the art; Preferably, the antibody injection is prepared by weighing, mixing, filtering and sterilizing, and filling each component.

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