Pharmaceutical composition containing antibody-drug conjugate of glucocorticoid

Abstract

A pharmaceutical composition containing an antibody-drug conjugate of glucocorticoid. Specifically, the present invention relates to a pharmaceutical composition, comprising an antibody-drug conjugate and a counterion. The pharmaceutical composition has good aerodynamic characteristics and is suitable for inhalation administration.

Description

A pharmaceutical composition of an antibody-drug conjugate containing glucocorticoid This application claims the priority of Chinese Patent Application No. 2023109382848 with the filing date of July 28, 2023. This application incorporates the full text of the above-mentioned Chinese patent application by reference. Technical Field This disclosure belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition of an antibody-drug conjugate containing glucocorticoid. Background Art Interleukin-4 (IL-4) consists of 153 amino acids and has a molecular weight of approximately 17 kDa. Initially, it was discovered because it could stimulate B cell proliferation and was named B cell stimulatory factor-1 (BSF-1). IL-4, like IL-13, belongs to the type I cytokine family and has a quaternary structure composed of a hydrophobic bundle core with 4α helices. IL-4 is secreted by TH2 cells and participates in TH2-mediated immune responses, having a wide range of biological activities, including stimulating the proliferation of T cells, mast cells, granulocytes, megakaryocytes, and erythrocytes. In addition, IL-4 can also stimulate B cells to express major histocompatibility complex class 2 molecules. IL-13 has approximately 30% amino acid sequence homology with IL-4 and multiple similar functions. Both IL-4 and IL-13 can promote B cell proliferation and jointly induce the transformation of IgM type into IgE with CD40 / CD40L co-stimulation. IL-4 promotes mast cell aggregation, upregulates the expression of high-affinity IgE receptors on mast cells and low-affinity IgE receptors CD23 (FcεRII) on B cells, upregulates the expression of vascular endothelial cell adhesion molecule (VCAM-1), and promotes the migration of eosinophils, T lymphocytes, monocytes, and basophils. Different from IL-13, IL-4 can promote the differentiation of naive T cells into TH2. IL-4 needs to bind to membrane receptors to exert its biological functions. Human interleukin-4 receptor (IL-4R) is a heterodimer formed by two polypeptide chains. One of the α chains has a high affinity for IL-4. Since the IL-4Rα chain plays a dominant role in the binding of IL-4 in the IL-4R complex, IL-4Rα is often used to replace IL-4R in many scientific studies and reports. IL-4R is expressed on a variety of cells such as human B cells, mast cells, eosinophils, basophils, macrophages / monocytes, DC cells, fibroblasts, airway epithelium and smooth muscle. IL-4Rα can form two types of receptor complexes with other subunits. In hematopoietic stem cells, the type I receptor mainly composed of IL-4Rα and γc is expressed. In non-hematopoietic stem cells, IL-4 mainly exerts its functions through the type II receptor composed of IL-4Rα and IL-13Rα1. The type II receptor is the common receptor for IL-4 and IL-13, and IL-13 binds to IL-13Rα1 to exert its functions. Both the type I receptor and the type II receptor transduce signals through the Jak / STAT pathway. IL-4Rα, γc and IL-13Rα1 bind to Jak1, Jak3 and Tyk2 respectively to activate the downstream pathway. IL-4 and IL-13 can also transduce signals through the insulin receptor substrate family (IRS), and finally activate PI3-K and NF-κB in the nucleus. Blocking IL-4R can inhibit the biological functions of both IL-4 and IL-13. Multiple studies have shown that IL-4 and IL-13 are associated with diseases related to TH2 immune responses. Atopic dermatitis (AD), also known as eczema or allergic dermatitis, is a common skin disease, mostly seen in children and adolescents, and often co-occurs with certain allergic diseases such as allergic rhinitis and asthma. Studies have found that the levels of TH2 factors IL-4, IL-5, IL-10 and IL-13 in AD patients increase, and the IgE level also increases. In addition, it has also been found that TH2 factors are related to the AD disease process. Mice overexpressing TH2 factors such as IL-4 and IL-13 show skin protection defects and symptoms similar to AD.

[0014]

[0015] . The elevated levels of IL-4 and IL-13 in AD patients hinder epidermal differentiation and the production of antimicrobial peptides. IL-4-deficient mice have a reduced occurrence of skin allergic inflammation. These studies suggest that blocking IL-4R may be effective in treating AD. Monoclonal antibodies against IL-4R have been marketed abroad and show good therapeutic effects on AD. IL-13 and IL-4 also play important roles in asthma. Asthma is a common pulmonary inflammatory disease characterized by airway hyperresponsiveness (AHR), mucus hypersecretion, fibrosis, and elevated IgE levels. Nonspecific stimuli such as cold air often exacerbate airway hyperresponsiveness. AHR and mucus hypersecretion lead to airway obstruction, which is the main cause of asthma mortality. TH2 factors play important roles in the asthma disease process. IL-4 and IL-13 are overexpressed in the bronchi and alveolar lavage fluid of asthma patients. Although IL-13 and IL-4 have some functional similarities, some studies have shown that IL-13 plays a more important role than other Th2 cytokines in the disease progression of asthma. IL-13 can promote the differentiation of goblet cells and fibrosis. Intratracheal injection of recombinant IL-13 into the airways of non-allergen-stimulated mice leads to airway inflammation, mucus hypersecretion, and airway hyperresponsiveness. Injection of soluble IL13Rα2 can prevent the occurrence of AHR, mucus hypersecretion, and pulmonary inflammation in mice. Injection of an IL-4Rα antibody in an asthma model can reduce AHR and eosinophils in the alveolar lavage fluid. Studies have shown that blocking IL-4Rα may be effective in treating asthma. Currently, several pharmaceutical companies in various countries are developing monoclonal antibodies against IL-4R, and related patent applications such as WO2010053751, WO2001092340, WO2008054606, WO2014031610, WO2020038454, etc. Glucocorticoids are also relatively effective drugs for treating allergic diseases, inflammation, etc. As representative glucocorticoids, cortisol, corticosterone, etc. are known glucocorticoids synthesized in vivo, as well as synthetic glucocorticoids such as dexamethasone, prednisone, prednisolone, and budesonide. These glucocorticoids are collectively called steroids due to their steroid structure and are used in the treatment of various diseases. However, due to their use, these steroids sometimes exhibit side effects such as steroid peptic ulcers, steroid purpura, steroid pancreatitis, steroid diabetes, steroid cataracts, and steroid glaucoma. An antibody-drug conjugate (ADC) refers to a monoclonal antibody or antibody fragment linked to a bioactive drug through a stable chemical linker compound. Most ADCs in preclinical and clinical development are used for oncology indications, where the cytotoxic payload targets cancer cells expressing the antigen. However, the delivery of bioactive small molecules mediated by ADCs to modulate pathogenic cell activity is also attractive for non-oncology indications, leading to the widespread application of this technology. The prior art has disclosed some drug conjugates of glucocorticoids, such as WO2017210471, WO2019106609, WO2019136487, etc. SUMMARY OF THE INVENTION The present disclosure provides a pharmaceutical composition comprising an antibody-drug conjugate and a counter ion, wherein the antibody-drug conjugate has a structure as shown in Formula I: Wherein: 25G7-Fab comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising: HCDR1 as shown in SEQ ID NO: 1 or SEQ ID NO: 12, HCDR2 as shown in SEQ ID NO: 2, HCDR3 as shown in SEQ ID NO: 3, the light chain variable region comprising: LCDR1 as shown in SEQ ID NO: 4, LCDR2 as shown in SEQ ID NO: 5, LCDR3 as shown in SEQ ID NO: 6; n is from 1 to 10. In some embodiments, the average drug loading (n) can range from the average number of glucocorticoid drugs conjugated to each 25G7-Fab. Non-limiting examples include an average number of glucocorticoid drugs conjugated to each 25G7-Fab of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and any range between these point values. For example, it can be 2 - 8, 2 - 7, 2 - 6, 2 - 5, 2 - 4, 3 - 4, 3 - 5, 3.5 - 4.7, 5 - 6, 5 - 7, 5 - 8, and 6 - 8. Exemplarily, the average drug loading (n) can be the mean of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. n is a decimal or an integer. In some embodiments, the 25G7-Fab has a heavy chain variable region as shown in SEQ ID NO: 8 and a light chain variable region as shown in SEQ ID NO: 7. In some embodiments, the 25G7-Fab has a heavy chain as shown in SEQ ID NO: 11 and a light chain as shown in SEQ ID NO: 10. The CDR sequences of 25G7-Fab are shown in Table 1: Table 1 CDR Sequences of 25G7-Fab The light chain variable region sequence of 25G7-Fab is as shown in SEQ ID NO: 7, and the heavy chain variable region sequence is as shown in SEQ ID NO: 8. hu25G7-A LCVR (hu25G7-A light chain variable region) SEQ ID NO: 7 hu25G7-VH (hu25G7 heavy chain variable region) SEQ ID NO: 8 The light chain sequence of 25G7-Fab is shown in SEQ ID NO: 10, and the heavy chain sequence is shown in SEQ ID NO: 11; the heavy chain sequence of hu25G7 is shown in SEQ ID NO: 9, and the light chain sequence is shown in SEQ ID NO: 10. hu25G7-IgG4 HC SEQ ID NO: 9 hu25G7-A LC SEQ ID NO: 10 hu25G7-24-IgG4 VH-CH1 SEQ ID NO: 11 In some embodiments, the concentration of the antibody-drug conjugate is 0.1 mg / mL - 50 mg / mL in terms of protein concentration. Non-limiting examples include 0.1 mg / mL, 0.5 mg / mL, 1.0 mg / mL, 1.5 mg / mL, 2.0 mg / mL, 2.5 mg / mL, 3.0 mg / mL, 3.5 mg / mL, 4.0 mg / mL, 4.5 mg / mL, 5.0 mg / mL, 6.0 mg / mL, 7.0 mg / mL, 8.0 mg / mL, 9.0 mg / mL, 10.0 mg / mL, 15.0 mg / mL, 20.0 mg / mL, 25.0 mg / mL, 30.0 mg / mL, 35.0 mg / mL, 40.0 mg / mL, 45.0 mg / mL, 50.0 mg / mL, and any range between these point values. In some embodiments, the concentration of the antibody-drug conjugate is 0.5 mg / mL - 10 mg / mL. In some embodiments, the concentration of the antibody-drug conjugate is 1 mg / mL - 5 mg / mL. In some embodiments, the counterions include but are not limited to sulfate, phosphate, malate, maleate, oxalate, citrate, succinate, fumarate, itaconate, chloride, bromide, etc. In some embodiments, the counterion is selected from one or more of sulfate, citrate, and chloride. In some embodiments, the counterion is selected from one or more of sodium citrate, sodium sulfate, zinc sulfate, magnesium sulfate, potassium sulfate, calcium sulfate, magnesium chloride, calcium chloride, and zinc chloride. In some embodiments, the counterion is sodium sulfate and / or sodium citrate. In some embodiments, the concentration of the counterion is 0.01 mg / mL - 10 mg / mL. Non-limiting examples include 0.01 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1.0 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2.0 mg / mL, 2.2 mg / mL, 2.4 mg / mL, 2.6 mg / mL, 2.8 mg / mL, 3.0 mg / mL, 4.0 mg / mL, 5.0 mg / mL, 6.0 mg / mL, 7.0 mg / mL, 8.0 mg / mL, 9.0 mg / mL, 10.0 mg / mL, and any range between these point values. In some embodiments, the concentration of the counterion is 0.05 mg / mL - 5 mg / mL. In some embodiments, the concentration of the counterion is 0.1 mg / mL - 2 mg / mL. In some embodiments, the pharmaceutical composition further comprises a protecting agent. In some embodiments, the protecting agent is selected from amino acids and / or sugars. In some embodiments, the amino acids include, but are not limited to, glycine, histidine, arginine, lysine, glutamic acid, alanine, valine, leucine, isoleucine, proline, tryptophan, phenylalanine, methionine, aspartic acid, etc. In some embodiments, the amino acid is glycine or histidine. In some embodiments, the concentration of the amino acid is 0.01 mg / mL - 10 mg / mL. Non-limiting examples include 0.01 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1.0 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2.0 mg / mL, 2.2 mg / mL, 2.4 mg / mL, 2.6 mg / mL, 2.8 mg / mL, 3.0 mg / mL, 4.0 mg / mL, 5.0 mg / mL, 6.0 mg / mL, 7.0 mg / mL, 8.0 mg / mL, 9.0 mg / mL, 10.0 mg / mL, and any range between these point values. In some embodiments, the concentration of the amino acid is 0.05 mg / mL - 5 mg / mL. In some embodiments, the concentration of the amino acid is 0.1 mg / mL - 2 mg / mL. The "sugar" of the present disclosure includes conventional compositions (CH 2 O) n and its derivatives, including monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, and the like. In some embodiments, the sugars include, but are not limited to, sorbitol, mannitol, xylitol, trehalose, lactose, fructose, maltose, sucrose, etc. In some embodiments, the sugar is trehalose. In some embodiments, the concentration of the sugar is 0.01 mg / mL - 10 mg / mL. Non-limiting examples include 0.01 mg / mL, 0.05 mg / mL, 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, 0.9 mg / mL, 1.0 mg / mL, 1.1 mg / mL, 1.2 mg / mL, 1.3 mg / mL, 1.4 mg / mL, 1.5 mg / mL, 1.6 mg / mL, 1.7 mg / mL, 1.8 mg / mL, 1.9 mg / mL, 2.0 mg / mL, 2.2 mg / mL, 2.4 mg / mL, 2.6 mg / mL, 2.8 mg / mL, 3.0 mg / mL, 4.0 mg / mL, 5.0 mg / mL, 6.0 mg / mL, 7.0 mg / mL, 8.0 mg / mL, 9.0 mg / mL, 10.0 mg / mL, and any range between these point values. In some embodiments, the concentration of the sugar is 0.05 mg / mL - 5 mg / mL. In some embodiments, the concentration of the sugar is 0.1 mg / mL - 2 mg / mL. In some embodiments, the pharmaceutical composition further comprises an organic solvent, which includes but is not limited to methanol, ethanol, 1-propanol, isopropanol, tert-butanol, butanol, acetone, acetonitrile, acetic acid, ethyl acetate, methyl ethyl ketone, methyl tert-butyl ether, dimethyl sulfoxide, etc. In some embodiments, the organic solvent is isopropanol. In some embodiments, the amount of the organic solvent is 0.1% - 50% v / v. Non-limiting examples include 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 11.0%, 12.0%, 13.0%, 14.0%, 15.0%, 20.0%, 25.0%, 30.0%, 35.0%, 40.0%, 45.0%, 50.0%, and any range between these point values. In some embodiments, the amount of the organic solvent is 0.5% - 30% v / v. In some embodiments, the amount of the organic solvent is 1% - 10% v / v. In some embodiments, the pH of the pharmaceutical composition is from 3.0 to 8.0. Non-limiting examples include 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, and any range between these point values. In some embodiments, the pH is from 4.5 to 6.0. In some embodiments, the pH is 5.0 or 5.5. In some embodiments, the pharmaceutical composition comprises: a) the antibody-drug conjugate at a protein concentration of 1 mg / mL to 5 mg / mL, b) a counterion at 0.1 mg / mL to 2 mg / mL, wherein the counterion is sodium citrate or sodium sulfate, c) an amino acid at 0.1 mg / mL to 2 mg / mL, wherein the amino acid is histidine or glycine, d) a sugar at 0.1 mg / mL to 2 mg / mL, wherein the sugar is trehalose, e) an organic solvent at 1% - 10% v / v, wherein the organic solvent is isopropanol; The pH of the pharmaceutical composition is from 4.5 to 5.5. The present disclosure also provides a lyophilized preparation containing an antibody-drug conjugate, wherein the preparation can form the pharmaceutical composition as described above after reconstitution. The present disclosure also provides a method for preparing a lyophilized preparation containing an antibody-drug conjugate, which includes the step of freeze-drying the pharmaceutical composition as described above. The present disclosure also provides a lyophilized preparation containing an antibody-drug conjugate, which is obtained by freeze-drying the pharmaceutical composition of the antibody-drug conjugate as described above. In some embodiments, the morphology of the lyophilized preparation is microspheres. In some embodiments, the aerodynamic particle size of the microspheres is from 0.01 to 10.0 μm. In some embodiments, the aerodynamic particle size of the microspheres is from 0.5 to 5 μm. The present disclosure also provides a reconstitution solution containing an antibody-drug conjugate, wherein the reconstitution solution is prepared by reconstituting the lyophilized preparation as described above. The present disclosure also provides a method for preparing the above-mentioned reconstituted solution, which includes the step of reconstituting the aforementioned lyophilized preparation, and the solution used for reconstitution is selected from, but not limited to, water for injection, physiological saline or glucose solution. The present disclosure also provides a pharmaceutical composition, which includes the aforementioned lyophilized preparation and a filler, and the filler includes, but is not limited to, trehalose, lactose, mannitol, glucose, sorbitol, dextran, etc. In some embodiments, the filler is trehalose. The present disclosure also provides an article, which includes a container, and the container contains the pharmaceutical composition, lyophilized preparation, reconstituted solution or dry powder preparation as described above. In some embodiments, the container is a neutral borosilicate glass vial for injection. The present disclosure also provides the use of the aforementioned pharmaceutical composition, lyophilized preparation, reconstituted solution or article in the preparation of a drug for treating or preventing an immune disease or disorder. The present disclosure also provides a method for treating or preventing an immune disease or disorder, and the method includes administering an effective amount or a prophylactically effective amount of the aforementioned pharmaceutical composition, lyophilized preparation, reconstituted solution or article to a subject. In some embodiments, the disease or disorder is selected from: asthma, nasal polyps, chronic rhinosinusitis, allergic skin diseases, eosinophilic esophagitis, chronic obstructive pulmonary disease, allergic rhinitis, arthritis, inflammatory diseases, allergic reactions, autoimmune lymphoproliferative syndrome, autoimmune hemolytic anemia, Barrett's esophagus, autoimmune uveitis, tuberculosis and kidney diseases. In some embodiments, the disease or disorder is selected from asthma or allergic skin diseases. Description of the Drawings Figure 1: Dose-response curve of the whole cell binding activity of the test protein to human IL-4Rα-expressing cells Figure 2: Dose-response curve of the blocking effect of the test protein on the IL-4 / IL-13 signaling pathway Figure 3: Endocytosis rate-time curve of the test protein in TF-1 cells Figure 4: Time-concentration curves of ADC-2 and free Budesonide in various tissues after intratracheal administration Figure 5: White blood cell and differential cell counts in bronchoalveolar lavage fluid in Test Example 6 Figure 6: White blood cell and differential cell counts in bronchoalveolar lavage fluid in Test Example 7 Figure 7: Scanning electron micrograph of inhaled dry powder formulation c Figure 8: Scanning electron micrograph of inhaled dry powder formulation f Terms To facilitate a better understanding of the present disclosure, certain technical and scientific terms are specifically defined below. Unless otherwise clearly defined herein, all other technical and scientific terms used herein shall have the meanings commonly understood by those of ordinary skill in the art to which the present disclosure pertains. The term “antibody-drug conjugate” refers to a ligand linked to a bioactive drug through a stable linker unit. In the present disclosure, an “antibody drug conjugate” (ADC) refers to a monoclonal antibody or antibody fragment linked to a bioactive glucocorticoid through a stable linker unit. The antibody or antibody fragment can bind to a glucocorticoid molecule containing a linker through a specific group therein (such as an interchain disulfide bond). The term “counterion” refers to a charged or charge-polarized molecule capable of initiating the formation of microparticles from macromolecules such as proteins, nucleic acids, lipids, or oligosaccharides. Whether a charged molecule is a counterion can be determined empirically based on parameters including, but not limited to, the protein species, pH, ionic strength, type of organic solvent used, and the presence of salts and other components such as active reagents. As provided and described herein, a counterion can be anionic or have a net negative charge or charge-polarized group, cationic or have a net positive charge or charge-polarized group, or zwitterionic and have negative and positive charges or charge-polarized groups. The terms “microparticle” and “microsphere” are interchangeable and refer to particles including macromolecules and delivering a reagent of interest, such as a drug or nutritional additive, to a subject, with a size range (average length, width, or diameter) of about or exactly 0.001 micrometers to about or exactly 500 micrometers. The reagent can be a macromolecule such as a protein, nucleic acid, lipid, or polysaccharide, or the macromolecule forming the microparticle can be a carrier for an active reagent such as a drug or nutritional additive. The microparticle can also include synthetic macromolecules including polymers such as polyethylene glycol (PEG), polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), and natural polymers such as albumin, gelatin, chitosan, and dextran. The “microparticle” described herein can include and can be prepared from a specific natural or synthetic macromolecule, or from more than one type of the same natural or synthetic macromolecule (such as more than one type of protein), or from a combination of more than one different type of natural or synthetic macromolecule (such as protein and nucleic acid or protein and synthetic polymer). The term “microparticle” used herein also generally refers to a particle in a solid form that is not the entire solution from which it is produced, although frozen and / or dried particles of solutions containing macromolecules are also contemplated herein. Rather, the microparticle used herein is generally an aggregate of a portion of the solution components, which includes salts, counterions, solvents, and other components, formed by methods including, but not limited to, precipitation, sedimentation, phase separation, and colloid formation. The method for determining monoclonal antibody molecular size variants (CE-SDS) of the present disclosure can adopt the ultraviolet detection method of sodium dodecyl sulfate capillary electrophoresis (CE-SDS). Under reducing and non-reducing conditions, according to the molecular weight, the purity of recombinant monoclonal antibody products can be quantitatively determined by capillary electrophoresis method (0542 of Chinese Pharmacopoeia 2015 Edition). In one embodiment of the present disclosure, the glucocorticoid is conjugated to the N-terminal amino group of the ligand and / or the ε-amino group of lysine residues through a linking unit. Generally, the number of drug molecules capable of conjugating with the antibody in the conjugation reaction will be less than the theoretical maximum value. The drug loading of the antibody-drug conjugate can be controlled by the following non-limiting methods, including: (1) Controlling the molar ratio of the linking reagent to the monoclonal antibody, (2) Controlling the reaction time and temperature, (3) Selecting different reaction reagents. The term "amino acid" refers to an organic compound whose molecular structure contains an amino group and a carboxyl group, and both the amino group and the carboxyl group are directly connected to the -CH- structure. The general formula is H2NCHRCOOH, where R is H, substituted or unsubstituted alkyl, etc. According to the position of the amino group linked to the carbon atom in the carboxylic acid, it can be divided into α, β, γ, δ, ε... -amino acids. In the biological world, the amino acids that make up natural proteins have their specific structural characteristics, that is, their amino groups are directly linked to the α-carbon atom, that is, α-amino acids, including glycine, alanine, valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, aspartic acid, histidine, asparagine, glutamic acid, lysine, glutamine, methionine, arginine, serine, threonine, cysteine, proline, etc. Non-natural amino acids such as citrulline. As is well known to those skilled in the art, non-natural amino acids do not constitute natural proteins and therefore do not participate in the synthesis of antibodies in the present disclosure. The three-letter codes and single-letter codes of amino acids used in the present disclosure are as described in J. biol. chem, 243, p3558 (1968). The term "antibody" refers to an immunoglobulin, which is a four - peptide chain structure composed of two identical heavy chains and two identical light chains connected by inter - chain disulfide bonds. The amino acid composition and arrangement order of the constant region of the immunoglobulin heavy chain are different, so its antigenicity is also different. Accordingly, immunoglobulins can be divided into five classes, or called isotypes of immunoglobulins, namely IgM, IgD, IgG, IgA, and IgE, and their corresponding heavy chains are μ chain, δ chain, γ chain, α chain, and ε chain respectively. The same class of Ig can be further divided into different subclasses according to the differences in the amino acid composition of its hinge region and the number and position of heavy - chain disulfide bonds. For example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4. The light chain is divided into κ chain or λ chain according to the difference in the constant region. Each of the five classes of Ig can have κ chain or λ chain. The sequences of approximately 110 amino acids near the N - terminal of the antibody heavy chain and light chain vary greatly, which is the variable region (Fv region); the remaining amino acid sequences near the C - terminal are relatively stable, which is the constant region. The variable region includes 3 hypervariable regions (HVRs) and 4 relatively conserved framework regions (FRs). The 3 hypervariable regions determine the specificity of the antibody and are also called complementarity - determining regions (CDRs). Each light - chain variable region (LCVR) and heavy - chain variable region (HCVR) is composed of 3 CDR regions and 4 FR regions, and the order arranged from the amino - terminal to the carboxyl - terminal is: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The 3 CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the 3 CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3. The antibodies of the present disclosure include murine antibodies, chimeric antibodies, humanized antibodies, and fully human antibodies, preferably humanized antibodies and fully human antibodies. The term "murine antibody" in the present disclosure refers to the preparation of antibodies in mice according to the knowledge and skills in the art. During the preparation, a test subject is injected with a specific antigen, and then hybridomas that express antibodies with the required sequence or functional characteristics are isolated. The term "chimeric antibody" is an antibody formed by fusing the variable region of a murine - derived antibody with the constant region of a human antibody, which can reduce the immune response induced by murine - derived antibodies. To establish a chimeric antibody, first establish a hybridoma that secretes murine - derived specific monoclonal antibodies, then clone the variable - region gene from the murine hybridoma cells, and then clone the constant - region gene of the human antibody as needed. Connect the murine variable - region gene with the human constant - region gene to form a chimeric gene and insert it into an expression vector, and finally express the chimeric antibody molecule in a eukaryotic system or a prokaryotic system. The term "humanized antibody", also known as CDR-grafted antibody, refers to an antibody produced by transplanting murine CDR sequences into the framework of the variable region of a human antibody, i.e., into framework sequences of different types of human germline antibody. It can overcome the heterologous reactions induced by chimeric antibodies due to the presence of a large amount of murine protein components. Such framework sequences can be obtained from public DNA databases including germline antibody gene sequences or from published references. For example, the germline DNA sequences of human heavy and light chain variable region genes can be found in the "VBase" germline sequence database (available on the Internet at www.mrccpe.com.ac.uk / vbase), as well as in Kabat, E.A. et al., 1991 Sequences of Proteins of Immunological Interest, 5th edition. To avoid a decrease in activity while reducing immunogenicity, the human antibody variable region framework sequences can be subjected to a minimum number of back mutations or revertant mutations to maintain activity. The humanized antibodies of the present disclosure also include humanized antibodies further affinity matured for CDRs by phage display. Literature further describing methods for humanization using murine antibodies includes, for example, Queen et al., Proc., Natl. Acad. Sci. USA, 88, 2869, 1991 and the methods of Winter and his colleagues [Jones et al., Nature, 321, 522 (1986), Riechmann, et al., Nature, 332, 323-327 (1988), Verhoeyen, et al., Science, 239, 1534 (1988)]. The terms "fully human antibody", "human antibody" or "completely human antibody", also known as "fully human monoclonal antibody", have variable and constant regions that are both of human origin, eliminating immunogenicity and toxic side effects. The development of monoclonal antibodies has gone through four stages, namely: murine monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies and fully human monoclonal antibodies. The present disclosure is for fully human monoclonal antibodies. The related techniques for preparing fully human antibodies mainly include: human hybridoma technology, EBV-transformed B lymphocyte technology, phage display technology, transgenic mouse antibody preparation technology and single B cell antibody preparation technology, etc. The term "antigen-binding fragment" refers to one or more fragments of an antibody that retain the ability to specifically bind an antigen. It has been shown that fragments of full-length antibodies can be used for the antigen-binding function of the antibody. Examples of binding fragments included in the "antigen-binding fragment" include (i) Fab fragment, a monovalent fragment composed of VL, VH, CL and CH1 domains; (ii) F(ab′)2 Fragments, including bivalent fragments of two Fab fragments linked by a disulfide bridge in the hinge region; (iii) Fd fragments consisting of VH and CH1 domains; (iv) Fv fragments consisting of VH and VL domains of a single arm of an antibody; (v) single domain or dAb fragments (Ward et al., (1989) Nature 341:544 - 546), which consist of VH domains; and (vi) isolated complementarity - determining regions (CDRs) or (vii) combinations of two or more isolated CDRs optionally linked by a synthetic linker. In addition, although the two domains VL and VH of the Fv fragment are encoded by separate genes, they can be linked by a synthetic linker using recombinant methods so that they can be produced as a single protein chain in which the VL and VH regions pair to form a monovalent molecule (referred to as single - chain Fv (scFv); see, for example, Bird et al. (1988) Science 242:423 - 426; and Huston et al. (1988) Proc. Natl. Acad. Sci USA 85:5879 - 5883). Such single - chain antibodies are also intended to be included in the term "antigen - binding fragment" of an antibody. Such antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened for functionality in the same manner as for intact antibodies. Antigen - binding portions can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact immunoglobulins. Antibodies can be antibodies of different isotypes, for example, IgG (e.g., IgG1, IgG2, IgG3, or IgG4 subtypes), IgA1, IgA2, IgD, IgE, or IgM antibodies. Fab is an antibody fragment with a molecular weight of approximately 50,000 and antigen - binding activity in the fragment obtained by treating an IgG antibody molecule with the protease papain (which cleaves the amino acid residue at position 224 of the H chain), where approximately the first half of the H - chain N - terminal side and the entire L - chain are bound together by a disulfide bond. F(ab′)2 is an antibody fragment with a molecular weight of approximately 100,000, antigen - binding activity, and containing two Fab regions linked at the hinge position, obtained by digesting the lower part of the two disulfide bonds in the IgG hinge region with the enzyme pepsin. Fab' is an antibody fragment with a molecular weight of approximately 50,000 and antigen - binding activity obtained by cleaving the disulfide bond in the hinge region of the above - mentioned F(ab′)2. In addition, the Fab′ can be produced by inserting the DNA encoding the Fab' fragment of an antibody into a prokaryotic expression vector or a eukaryotic expression vector and introducing the vector into a prokaryote or a eukaryote for expression of Fab'. The terms "single-chain antibody", "single-chain Fv", or "scFv" mean a molecule comprising an antibody heavy-chain variable domain (or region; VH) and an antibody light-chain variable domain (or region; VL) linked by a linker. Such scFv molecules can have the general structure: NH 2 -VL-linker-VH-COOH or NH 2 -VH-linker-VL-COOH. Suitable prior art linkers consist of repeated GGGGS amino acid sequences or variants thereof, for example variants using 1-4 repeats (Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90: 6444-6448). Other linkers that can be used in the present disclosure are described by Alfthan et al. (1995), Protein Eng. 8: 725-731, Choi et al. (2001), Eur. J. Immunol. 31: 94-106, Hu et al. (1996), Cancer Res. 56: 3055-3061, Kipriyanov et al. (1999), J. Mol. Biol. 293: 41-56, and Roovers et al. (2001), Cancer Immunol. The term "CDR" refers to one of the six hypervariable regions within the variable domain of an antibody that are primarily responsible for antigen binding. One of the most commonly used definitions of the six CDRs was provided by Kabat E.A. et al., (1991) Sequences of proteins of immunological interest. NIH Publication 91-3242). As used herein, the Kabat definition of CDR is only applied to CDR1, CDR2, and CDR3 (CDR L1, CDR L2, CDR L3 or L1, L2, L3) of the light chain variable domain, and CDR2 and CDR3 (CDR H2, CDR H3 or H2, H3) of the heavy chain variable domain. Generally, there are three CDRs (HCDR1, HCDR2, HCDR3) in each heavy chain variable region and three CDRs (LCDR1, LCDR2, LCDR3) in each light chain variable region. The amino acid sequence boundaries of CDRs can be determined using any of a variety of well-known schemes, including the "Kabat" numbering rule (see Kabat et al. (1991), "Sequences of Proteins of Immunological Interest", 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD), the "Chothia" numbering rule (see A1-Lazikani et al., (1997) JMB 273: 927-948), and the ImMunoGenTics (IMGT) numbering rule (see Lefranc M.P., Immunologist, 7, 132-136 (1999); Lefranc, M.P. et al., Dev. Comp. Immunol., 27, 55-77 (2003)), etc. For example, for the classical format, following the Kabat rule, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3); the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3). Following the Chothia rule, the CDR amino acid numbers in VH are 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3).By combining the CDR definitions of both Kabat and Chothia, the CDRs consist of amino acid residues 26 - 35 (HCDR1), 50 - 65 (HCDR2), and 95 - 102 (HCDR3) in human VH and amino acid residues 24 - 34 (LCDR1), 50 - 56 (LCDR2), and 89 - 97 (LCDR3) in human VL. Following the IMGT rules, the CDR amino acid residue numbering in VH is approximately 26 - 35 (CDR1), 51 - 57 (CDR2), and 93 - 102 (CDR3), and in VL is approximately 27 - 32 (CDR1), 50 - 52 (CDR2), and 89 - 97 (CDR3). Following the IMGT rules, the CDR regions of an antibody can be determined using the program IMGT / DomainGap Align. The term "antibody framework" refers to a part of the variable domain VL or VH that serves as a scaffold for the antigen - binding loops (CDRs) of that variable domain. In essence, it is the variable domain without CDRs. "Binding to IL - 4R" means the ability to interact with human IL - 4R (or its epitope, fragment). The term "antigen - binding site" herein refers to the three - dimensional spatial site recognized by the antibodies or antigen - binding fragments herein. The term "epitope" or "antigenic determinant" refers to the site on an antigen to which an immunoglobulin or antibody specifically binds. Epitopes typically include at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 contiguous or non - contiguous amino acids in a unique spatial conformation (see, e.g., Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, G.E. Morris, Ed. (1996)). The terms "specifically bind", "selectively bind", "selectively binds", and "specifically binds" refer to the binding of an antibody to an epitope on a pre - determined antigen. Generally, an antibody binds with an affinity (KD) of approximately less than 10 -7 M, e.g., approximately less than 10 -8 M, 10 -9 M or 10 -10 M or less. The term "nucleic acid molecule" refers to DNA molecules and RNA molecules. Nucleic acid molecules can be single - stranded or double - stranded, but are preferably double - stranded DNA. A nucleic acid is "operably linked" when placed into a functional relationship with another nucleic acid sequence. For example, if a promoter or enhancer affects the transcription of a coding sequence, then the promoter or enhancer is operably linked to the coding sequence. The term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it is linked. In one embodiment, the vector is a "plasmid", which refers to a circular double-stranded DNA loop to which additional DNA segments can be ligated. In another embodiment, the vector is a viral vector into which additional DNA segments can be ligated into the viral genome. The vectors disclosed herein are capable of autonomous replication in the host cells into which they have been introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors) or can integrate into the genome of the host cell after introduction into the host cell and thereby replicate along with the host genome (e.g., non-episomal mammalian vectors). Methods for the production and purification of antibodies and antigen-binding fragments are well known in the art, such as the Antibody Engineering Laboratory Manual from Cold Spring Harbor, Chapters 5-8 and 15. Antigen-binding fragments can also be prepared by conventional methods. The antibodies or antigen-binding fragments of the invention are genetically engineered to add one or more human FR regions to the non-human CDR regions. Human FR germline sequences can be obtained from the website of ImMunoGeneTics (IMGT) at http: / / imgt.cines.fr by aligning the IMGT human antibody variable region germline gene database and the MOE software, or from the Journal of Immunology, 2001 ISBN 012441351. The term "host cell" refers to a cell into which an expression vector has been introduced. Host cells can include bacterial, microbial, plant, or animal cells. Bacteria that are readily transformable include members of the enterobacteriaceae, such as strains of Escherichia coli or Salmonella; Bacillaceae such as Bacillus subtilis; Pneumococcus; Streptococcus; and Haemophilus influenzae. Suitable microorganisms include Saccharomyces cerevisiae and Pichia pastoris. Suitable animal host cell lines include CHO (Chinese hamster ovary cell line) and NS0 cells. The engineered antibodies or antigen-binding fragments thereof of the present disclosure can be prepared and purified by conventional methods. For example, the cDNA sequences encoding the heavy and light chains can be cloned and recombined into a GS expression vector. The recombinant immunoglobulin expression vector can be stably transfected into CHO cells. As a more recommended prior art, mammalian expression systems result in glycosylation of antibodies, especially at the highly conserved N-terminal sites in the Fc region. Positive clones are expanded in a serum-free medium in a bioreactor to produce antibodies. The culture broth secreting the antibodies can be purified by conventional techniques. For example, purification can be performed using an A or G Sepharose FF column with adjusted buffer. Non-specifically bound components are washed away. The bound antibodies are then eluted using a pH gradient method, and the antibody fragments are detected by SDS-PAGE and collected. The antibodies can be filtered and concentrated by conventional methods. Soluble mixtures and polymers can also be removed by conventional methods, such as molecular sieves and ion exchange. The resulting product needs to be immediately frozen, such as at -70 °C, or lyophilized. "Amino acid sequence identity" refers to the percentage of amino acid residues in a first sequence that are identical to the amino acid residues in a second sequence when the amino acid sequences are aligned and gaps are introduced as necessary to achieve the maximum percentage of sequence identity, and no conservative substitutions are considered part of the sequence identity. For the purpose of determining the percentage of amino acid sequence identity, the alignment can be achieved in a variety of ways within the skill of the art, such as using publicly available computer software, such as BLAST, BLAST-2, ALIGN, ALIGN-2, or Megalign (DNASTAR) software. Those skilled in the art can determine the parameters suitable for measuring the alignment, including any algorithms required to achieve the maximum alignment over the entire length of the sequences being compared. The term "anti-IL-4R antibody" or "antibody that binds to IL-4R" refers to an antibody that is capable of binding to IL-4R, for example, with sufficient affinity such that the antibody can be used as a therapeutic agent targeting IL-4R. The degree of binding of an anti-IL-4R antibody to an unrelated non-IL-4R protein can be less than, for example, about 10% of the binding of the antibody to IL-4R as measured by radioimmunoassay (RIA). In some embodiments, the antibody that binds to IL-4R has a dissociation constant (Kd) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, or ≤0.1 nM. The term "peptide" refers to a compound fragment between amino acids and proteins, formed by the linkage of two or more amino acid molecules through peptide bonds, and is a structural and functional fragment of proteins. Substances such as hormones and enzymes are essentially peptides. The term "sugar" refers to a biological macromolecule composed of the three elements C, H, and O, and can be divided into monosaccharides, disaccharides, polysaccharides, etc. "Pharmaceutical composition" refers to a mixture containing one or more of the antibody-drug conjugates described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to maintain the stability of the antibody active ingredient, facilitate administration to an organism, and facilitate absorption of the active ingredient and thus exert biological activity. In the present disclosure, "pharmaceutical composition" and "formulation" are not mutually exclusive. In the solution form of the pharmaceutical composition described in the present disclosure, unless otherwise specified, the solvent therein is water. "Lyophilized formulation" refers to a formulation or pharmaceutical composition obtained after a vacuum freeze-drying step of a pharmaceutical composition or a liquid or solution formulation in liquid or solution form. As used herein, the terms "about" and "approximately" mean that a numerical value is within an acceptable error range of a specific value determined by a person of ordinary skill in the art, and the numerical value depends in part on how it is measured or determined (i.e., the limitations of the measurement system). For example, in each practice in the art, "about" can mean within 1 or more than 1 standard deviation. Alternatively, "about" or "substantially comprises" can mean a range of up to 20%. In addition, particularly for biological systems or processes, the term can mean up to one order of magnitude or up to 5 times the numerical value. Unless otherwise specified, when a specific value appears in the present application and claims, the meaning of "about" or "substantially comprises" should be assumed to be within the acceptable error range of the specific value. In the present disclosure, the numerical values are instrument measurement values or calculated values after instrument measurement, and there is a certain degree of error. Generally speaking, plus or minus 10% is within a reasonable error range. Of course, it is necessary to consider the context in which the numerical value is used. For example, for the content of total impurities, the error of this numerical value after measurement does not exceed plus or minus 10%, and can be plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2% or plus or minus 1%, preferably plus or minus 5%. "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example, "optionally comprising 1-3 antibody heavy chain variable regions" means that the antibody heavy chain variable regions of a specific sequence may but need not be present. "Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1-3 hydrogen atoms, are independently replaced by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person of ordinary skill in the art can determine (by experiment or theory) what is possible or impossible to substitute without undue effort. For example, an amino group or a hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (such as an olefinic) bond. The preparation of conventional pharmaceutical compositions is described in the Chinese Pharmacopoeia. "Administering" and "treating" when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. "Administering" and "treating" can refer to, for example, therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Treating a cell includes the contact of a reagent with the cell, as well as the contact of a reagent with a fluid that contacts the cell. "Administering" and "treating" also mean treating a cell in vitro and ex vivo by a reagent, diagnostic, binding composition, or by another cell. "Treating" when applied to a human, veterinary, or research subject, refers to therapeutic treatment, prophylactic or preventive measures, research, and diagnostic applications. "Treatment" means administering to a patient an internal or external therapeutic agent, such as a composition comprising any one of the binding compounds of the present disclosure, the patient having one or more disease symptoms, and the therapeutic agent being known to have a therapeutic effect on these symptoms. Generally, the therapeutic agent is administered to the treated patient or population in an amount effective to alleviate one or more disease symptoms, to induce regression of such symptoms or to inhibit the development of such symptoms to any clinically measurable degree. The amount of a therapeutic agent effective to alleviate any particular disease symptom (also referred to as a "therapeutically effective amount") can vary depending on a variety of factors, such as the patient's disease state, age, and weight, as well as the ability of the drug to produce the desired effect in the patient. Whether a disease symptom has been alleviated can be evaluated by any clinical test method commonly used by a physician or other professional healthcare provider to assess the severity or progression of the symptom. Although the embodiments of the present disclosure (such as treatment methods or articles) may not be effective in alleviating each target disease symptom, they should alleviate the target disease symptoms in a statistically significant number of patients as determined by any statistical test method known in the art, such as the Student t-test, chi-square test, U test according to Mann and Whitney, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test. "Effective amount" includes an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical disease. An effective amount also means an amount sufficient to permit or facilitate a diagnosis. The effective amount for a particular patient or veterinary subject can vary depending on factors such as, for example, the condition to be treated, the overall health of the patient, the method of administration, route, and dosage, and the severity of side effects. The effective amount can be the maximum dose or dosing regimen that avoids significant side effects or toxic effects. "Replacement" refers to the replacement of the solvent system in which the antibody protein or antibody-drug conjugate is dissolved. For example, the high-salt or hypertonic solvent system containing the antibody protein or antibody-drug conjugate is replaced by the buffer system of the stable preparation through physical operation methods, so that the antibody protein or antibody-drug conjugate exists in the stable preparation. The so-called physical operation methods include, but are not limited to, ultrafiltration, dialysis, or redissolution after centrifugation. Detailed implementation manners The present disclosure will be further described below in conjunction with embodiments, but these embodiments are not intended to limit the scope of the present disclosure. For the experimental methods without specific conditions indicated in the embodiments of the present disclosure, they are generally carried out under conventional conditions, or according to the conditions recommended by the raw material or commodity manufacturers, such as referring to the "Antibody Technology Experimental Manual" and "Molecular Cloning Manual" published by Cold Spring Harbor Laboratory; or according to the conditions recommended by the raw material or commodity manufacturers. The reagents without specific sources indicated are conventional reagents purchased from the market. The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR measurement is performed using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer, and the measurement solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethylsilane (TMS). The MS measurement is performed using a Shimadzu 2010 Mass Spectrometer or an Agilent 6110A MSD mass spectrometer. The HPLC measurement is performed using a Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or an Agilent 1200 LC high-performance liquid chromatograph (Ultimate XB-C18 3.0*150mm chromatographic column or Xtimate C18 2.1*30mm chromatographic column 1). Chiral HPLC analysis was performed using Chiralpak IC-3 columns (100×4.6 mm I.D., 3 μm), Chiralpak AD-3 columns (150×4.6 mm I.D., 3 μm), Chiralpak AD-3 columns (50×4.6 mm I.D., 3 μm), Chiralpak AS-3 columns (150×4.6 mm I.D., 3 μm), Chiralpak AS-3 columns (100×4.6 mm I.D., 3 μm), ChiralCel OD-3 columns (150×4.6 mm I.D., 3 μm), ChiralCel OD-3 columns (100×4.6 mm I.D., 3 μm), ChiralCel OJ-H columns (150×4.6 mm I.D., 5 μm), and Chiralcel OJ-3 columns (150×4.6 mm I.D., 3 μm). For thin-layer chromatography, silica gel plates from Yantai Huanghai HSGF254 or Qingdao GF254 were used. The silica gel plates used for thin-layer chromatography (TLC) had a thickness of 0.15 mm - 0.2 mm, and those used for thin-layer chromatography separation and purification of products had a thickness of 0.4 mm - 0.5 mm. For column chromatography, silica gel from Yantai Huanghai with a mesh size of 100 - 200, 200 - 300, or 300 - 400 was generally used as the carrier. For chiral preparative columns, DAICEL CHIRALPAK IC (250 mm * 30 mm, 10 μm) or Phenomenex-Amylose-1 (250 mm * 30 mm, 5 μm) was used. For the CombiFlash rapid preparator, Combiflash Rf150 (TELEDYNE ISCO) was used. The average inhibition rate of kinases and the IC 50 value was measured using a NovoStar microplate reader (BMG Labtech, Germany). The known starting materials of the present disclosure can be synthesized by adopting or following methods known in the art, or can be purchased from companies such as ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals. Unless otherwise specified in the examples, the reactions can all be carried out under an argon or nitrogen atmosphere. An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of approximately 1 L. A hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of approximately 1 L. The pressure hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen gas generator or an HC2-SS hydrogenator. The hydrogenation reaction usually involves evacuating the air, filling with hydrogen gas, and repeating the operation three times. The microwave reaction uses a CEM Discover-S 908860 microwave reactor. Unless otherwise specified in the examples, the solution refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20 °C to 30 °C. The progress of the reaction in the examples was monitored by thin-layer chromatography (TLC). The developing agents used in the reaction, the eluent systems for column chromatography for purifying compounds, and the developing agent systems for thin-layer chromatography include: A: dichloromethane / methanol system; B: n-hexane / ethyl acetate system; C: petroleum ether / ethyl acetate system; D: petroleum ether / ethyl acetate / methanol. The volume ratio of the solvents was adjusted according to the polarity of the compounds, and a small amount of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment. Preparation of 1.0M Tris buffer pH = 8.30 ± 0.1: Weigh 6.0 g of tris in a 50 mL volumetric flask, add 40 mL of purified water, shake to dissolve, add 1.2 mL of concentrated hydrochloric acid dropwise, adjust the pH to 8.30, and then make up the volume to the mark with purified water. Preparation of Buffer A: In a 2.0 L container, add KH 2 PO4 (8.50 g), K 2 HPO4 (8.56 g), NaCl (5.86 g), and EDTA (1.50 g). Add 1.6 L of water for injection, stir for half an hour, and after complete dissolution, make up the volume to 2.0 L with water for injection. Measure the pH to be 6.30 ± 0.1. The meanings represented by the abbreviations used in the following experiments are as follows: DAST: diethylaminosulfur trifluoride; THF: tetrahydrofuran; NMP: N-methylpyrrolidone; DCM: dichloromethane; m-CPBA: meta-chloroperoxybenzoic acid; DIEA: N,N-diisopropylethylamine; TEA: triethylamine; Boc: tert-butoxycarbonyl; MeOH: methanol; Et 2 O: diethyl ether. The preparation and purification methods of the 25G7 and 7B10 antibodies in this application have been described in the patent document with the application number WO2020038454A1. The preparation methods of 25G7-Fab and ADC have been described in the patent document with the application number PCT / CN2023 / 073057. The entire contents of the foregoing application documents are incorporated into this disclosure. Example 1: Preparation of N-((10S)-10-benzyl-1-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-1,6,9,12,15-pentaoxo-3-oxo-5,8,11,14-tetraethylene glycol-16-yl)-1-(2-bromoacetamido)-3,6,9,12-tetraoxopentadecane-15-carboxamide (Compound 1) Step 1: Preparation of (((9H-fluoren-9-yl)methoxy)carbonyl)glycylglycyl-L-phenylalanine tert-butyl ester (Compound 1b) Compound 1a (5.14 g, 20.0 mmol, 1.0 eq) and L-phenylalanine tert-butyl ester hydrochloride (7.08 g, 20.0 mmol, 1.0 eq) were placed in a 250 mL three-necked flask, and anhydrous DMF (60 mL) was added to dissolve them. The mixture was cooled in an ice bath, and then HATU (9.12 g, 24.0 mmol, 1.2 eq) and DIEA (7.74 g, 60.0 mmol, 3.0 eq) were added. The reaction was maintained in the ice bath for 2 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, and concentrated under reduced pressure to obtain Compound 1b (11.5 g, 100% yield). The crude product could be directly used in the next step. MS(ESI): m / z 580.3 [M+Na] + 。 1 1H NMR (400 MHz, DMSO-d6) δ 8.21 - 8.16 (m, 1H), 8.12 - 8.05 (m, 1H), 7.91 - 7.87 (m, 2H), 7.72 - 7.68 (m, 2H), 7.64 - 7.59 (m, 1H), 7.44 - 7.38 (m, 2H), 7.36 - 7.25 (m, 4H), 7.23 - 7.18 (m, 3H), 4.41 - 4.18 (m, 4H), 3.76 - 3.72 (m, 2H), 3.68 - 3.61 (m, 2H), 2.98 - 2.89 (m, 2H), 2.69 (s, 2H), 1.30 (s, 9H). Step 2: Preparation of glycylglycyl-L-phenylalanine tert-butyl ester (Compound 1c) Compound 1b (5.57 g, 10.0 mmol, 1.0 eq) was placed in a 250 mL three-necked flask, dissolved in anhydrous DCM (60 mL), and cooled in an ice bath. Piperidine (8.5 g, 100.0 mmol, 10.0 eq) was slowly added. After the addition, the reaction mixture was stirred at room temperature for about 2 hours. The reaction solution was directly concentrated to dryness, and the crude product was purified by column chromatography to obtain compound 1c (2.70 g, 81% yield). MS (ESI): m / z 358.3 [M+H] + 。 Step 3) Preparation of (1-(9H-fluoren-9-yl)-3-oxo-2,7,10,13,16-pentaoxa-4-tetraethylene glycol-19-yloxy)glycylglycyl-L-phenylalanine tert-butyl ester (Compound 1d) The starting materials 1-(9H-fluoren-9-yl)-3-oxo-2,7,10,13,16-pentaoxa-4-tetraethylene glycol-19-oleic acid (1.0 g, 2.05 mmol, 1.0 eq; from Tonglai Biochemical) and 1c (0.69 g, 2.05 mmol, 1.0 eq) were added to a 100 mL three-necked flask, dissolved in anhydrous DMF (25 mL), and cooled in an ice bath. HATU (1.01 g, 2.67 mmol, 1.3 eq) and DIEA (529 mg, 4.10 mmol, 2.0 eq) were added, and the reaction was maintained in the ice bath for 1 hour. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried, and concentrated under reduced pressure to obtain compound 1d (1.60 g, 97% yield). MS (ESI): m / z 805.3 [M+H] + 。 Step 4) Preparation of (1-(9H-fluoren-9-yl)-3-oxo-2,7,10,13,16-pentaoxa-4-tetraethylene glycol-19-yloxy)glycylglycyl-L-phenylalanine (Compound 1e) Compound 1d (1.60 g, 1.99 mmol, 1.0 eq) was added to a 100 mL single-necked flask and dissolved in anhydrous dichloromethane (16 mL). Trifluoroacetic acid (8 mL) was added at room temperature, and the reaction mixture was stirred for 2 hours. The reaction solution was directly concentrated to dryness, dissolved in ethyl acetate, washed with saturated brine, dried, and concentrated under reduced pressure to obtain compound 1e (1.23 g, 83% yield); MS (ESI): m / z 749.3 [M+H] + 。 Preparation of (9H-Fluoren-9-yl)methyl (2-(((2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethoxy)methyl)amino)-2-oxoethyl)carbamate (Compound 1f) In a 100 mL three-necked flask, add the starting material budesonide (1.29 g, 3.0 mmol, 1.0 eq) and methyl (2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)acetamido)acetate (1.16 g, 3.15 mmol, 1.0 eq; prepared according to the method of the reference "Tetrahedron, 2018, 74(15), 1951 - 1956") and pyridinium p-toluenesulfonate (75 mg, 0.30 mmol, 0.1 eq). Add anhydrous tetrahydrofuran (20 mL) at room temperature and reflux for 4 hours. Directly concentrate the reaction solution to dryness, and purify the crude product by column chromatography to obtain 1f (0.54 g, 24% yield). MS(ESI): m / z 739.4 [M+H] + 。 1 H NMR(400 MHz, DMSO-d6) δ8.76 - 8.69(m, 1H), 7.91 - 7.84(m, 2H), 7.73 - 7.67(m, 2H), 7.63 - 7.57(m, 1H), 7.43 - 7.58(m, 2H), 7.35 - 7.23(m, 3H), 6.13(d, J = 7.5 Hz, 1H), 5.91(s, 2H), 5.15 - 4.97(m, 1H), 4.73 - 4.45(m, 5H), 4.30 - 4.09(m, 5H), 3.65 - 3.59(m, 2H), 2.29 - 2.21(m, 1H), 2.11 - 1.87(m, 2H), 1.74 - 1.21(m, 11H), 1.09 - 0.77(m, 8H). Step 6) Preparation of 2-Amino-N-((2-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethoxy)methyl)acetamide (Compound 1g) Place compound 1f (540 mg, 0.73 mmol, 1.0 eq) in a 25 mL single-necked flask, and dissolve it with anhydrous dichloromethane (10 mL). Cool in an ice bath, add DBU (167 mg, 1.10 mmol, 1.5 eq), and maintain stirring for 30 minutes. Add water and separate the layers. Extract the aqueous phase with dichloromethane twice, wash with saturated brine, and concentrate under reduced pressure to obtain compound 1g (450 mg, 100% yield). The crude product can be directly used in the next step of the reaction. MS(ESI): m / z 517.4 [M+H] + . Step 7) Preparation of (9H-Fluoren-9-yl)methyl ((10S)-10-benzyl-1-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-1,6,9,12,15,18-hexaoxo-3,21,24,27,30-pentaoxo-5,8,11,14,17-pentaaza-32-yl)carbamate (Compound 1h) Place compound 1g (0.45 g crude product, calculated as 0.73 mmol, 1.0 eq) and 1e (0.55 g, 0.73 mmol, 1.0 eq) in a 100 mL three-necked flask, and dissolve them with anhydrous DMF (9 mL). Cool in an ice bath, and then successively add HATU (361 mg, 0.95 mmol, 1.3 eq) and DIEA (189 mg, 1.46 mmol, 2.0 eq), and maintain stirring for 1 hour. Add water to the reaction solution, extract with dichloromethane twice, combine the organic phases, wash once with saturated brine, dry and concentrate under reduced pressure to obtain the crude product. Pulverize and purify the crude product in a mixed solvent of petroleum ether and ethyl acetate to obtain compound 1h (710 mg, 78% yield). MS(ESI): m / z 1269.7 [M+Na] + . Step 8) Preparation of 1-Amino-N-((10S)-10-benzyl-1-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-1,6,9,12,15-pentaoxo-3-oxo-5,8,11,14-tetraethylene glycol-16-yl-3,6,9,12-tetraoxopentadecane-15-carboxamide (Compound 1i) Compound 1h (350 mg, 0.28 mmol, 1.0 eq) was placed in a 25 mL single-necked flask and dissolved in anhydrous dichloromethane (10 mL). It was cooled in an ice bath, DBU (64 mg, 0.42 mmol, 1.5 eq) was added, and the reaction was stirred for 1 hour. The reaction solution was directly concentrated to dryness to obtain a crude product, which was then purified by column chromatography to obtain Compound 1i (289 mg, 89% yield). MS(ESI): m / z 1025.6 [M+H] + 。 Step 9) Preparation of N-((10S)-10-benzyl-1-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-1,6,9,12,15-pentaoxo-3-oxo-5,8,11,14-tetraethylene glycol-16-yl)-1-(2-bromoacetamido)-3,6,9,12-tetraoxopentadecane-15-carboxamide (Compound 1) Solid bromoacetic acid (35.2 mg, 0.127 mmol, 1.0 eq) and EEDQ (63 mg, 0.25 mmol, 2.0 eq) were placed in a 25 ml Schlenk-Tube and dissolved in anhydrous DMF (5 mL). The reaction was stirred at room temperature for 1 hour. Compound 1i (130 mg, 0.127 mmol, 1.0 eq) was dissolved in DMF (2 mL), and this solution was added dropwise to the active ester solution prepared above. After addition, the reaction was continued at room temperature for 2 hours. Water was added to the reaction system, and the mixture was extracted twice with ethyl acetate. The combined organic phases were washed with saturated brine, dried, and concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography to obtain Compound 1 (39 mg, 27% yield). MS(ESI): m / z 1145.5 / 1147.6 [M+1] + 。 1 H NMR(400 MHz, CDCl 3 ) δ 8.62 - 8.57 (m, 1H), 8.34 - 8.28 (m, 2H), 8.19 - 8.11 (m, 2H), 8.03 - 7.99 (m, 1H), 7.30 - 7.17 (m, 6H), 6.15 (d, J = 9.6 Hz, 1H), 5.92 (s, 2H), 5.18 - 5.03 (m, 1H), 4.72 - 4.47 (m, 5H), 4.29 - 4.15 (m, 2H), 3.78 - 3.42 (m, 27H), 3.27 - 3.21 (m, 2H), 3.06 - 2.84 (m, 2H), 2.41 - 2.28 (m, 3H), 2.06 - 1.73 (m, 2H), 1.60 - 1.24 (m, 10H), 1.01 - 0.82 (m, 8H). Example 2: N - ((10S)-10 - benzyl - 1 - ((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7 - hydroxy - 6a,8a - dimethyl - 4 - oxo - 10 - propyl - 1,2,4,6a,6b,7,8,8a,11a,12,12a,12b - dodecahydro - 8bH - naphtho[2′,1′:4,5]indeno[1,2 - d][1,3]dioxol - 8b - yl) - 1,6,9,12,15 - pentaoxo - 3 - oxo - 5,8,11,14 - tetraethylene glycol - 16 - yl) - 1 - (2,5 - dioxo - 2,5 - dihydro - 1H - pyrrol - 1 - yl) - 3,6,9,12 - tetraoxopentadecane - 15 - amide Preparation of (((9H - fluoren - 9 - yl)methoxy)carbonyl)glycylglycyl - L - phenylalanine (Compound 2a) Compound 1b (1.50 g, 2.69 mmol, 1.0 eq) was placed in a 100 mL single - necked flask and dissolved in a 1,4 - dioxane solution (20 mL) of 4M HCl. Stirring was maintained at room temperature for 4 hours until the raw material 1b was completely reacted. The reaction solution was directly concentrated to dryness to obtain Compound 1a (1.34 g, 100% yield). MS(ESI): m / z 502.3 [M+1] + Preparation of (9H-Fluoren-9-yl)methyl ((10S)-10-benzyl 1-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-1,6,9,12,15-pentaoxo-3-oxo-5,8,11,14-tetraethylene glycol 16-yl)carbamate (Compound 2b) Compound 2a (0.97 g, 1.63 mmol, 1.0 eq) and 1 g (1.0 g, 1.95 mmol, 1.2 eq) were placed in a 100 mL three-necked flask. DMF (20 mL) was added and the mixture was cooled in an ice bath. HATU (927 mg, 2.44 mmol, 1.5 eq) and DIEA (420 mg, 3.26 mmol, 2.0 eq) were added successively. After addition, the reaction was maintained in the ice bath for 1 - 2 hours. The reaction solution was concentrated and purified by column chromatography to obtain Compound 2b (860 mg, 53% yield). MS(ESI): m / z 1000.5[M + 1] + Preparation of (2S)-2-(2-(2-Aminoacetamido)acetamido-N-(2(((2((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-2-oxoethoxy)methyl)amino)-2-oxoethyl)-3-phenylpropanamide (Compound 2c) Compound 2b (860 mg, 0.86 mmol, 1.0 eq) was placed in a 25 mL single-necked flask and dissolved in anhydrous DMF (10 mL). It was cooled in an ice bath, and DBU (196 mg, 1.29 mmol, 1.5 eq) was added. The stirring reaction was maintained for 30 minutes. The reaction solution was directly concentrated and purified by column chromatography to obtain Compound 2c (485 mg, 72% yield). MS(ESI): m / z 778.4[M + 1] + Preparation of N-((10S)-10-Benzyl-1-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2′,1′:4,5]indeno[1,2-d][1,3]dioxol-8b-yl)-1,6,9,12,15-pentaoxo-3-oxo-5,8,11,14-tetraethylene glycol-16-yl)-1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,6,9,12-tetraoxopentadecane-15-carboxamide (Compound 2d) Compound 2c (480 mg, 0.62 mmol, 1.0 eq) and 1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3,6,9,12-tetraoxopentadecanoic acid (213 mg, 0.62 mmol, 1.0 eq; from Tonglai Biochemical) were placed in a 100 mL three-necked flask, and anhydrous DMF (10 mL) was added to dissolve them clearly. After cooling in an ice bath, HATU (352 mg, 0.93 mmol, 1.5 eq) and DIEA (159 mg, 1.23 mmol, 2.0 eq) were added successively, and the reaction was stirred for 1 hour. The reaction solution was directly concentrated and purified by column chromatography to obtain Compound 2d (360 mg, 53% yield). MS (ESI): m / z 1105.6 [M+1] + 1 H NMR (400 MHz, DMSO-d6) δ 8.61 - 8.56 (m, 1H), 8.32 - 8.26 (m, 1H), 8.22 - 8.13 (m, 2H), 8.03 - 7.96 (m, 1H), 7.39 - 7.20 (m, 6H), 7.02 (s, 2H), 6.17 - 6.13 (m, 1H), 5.92 (s, 2H), 5.16 - 4.99 (m, 1H), 4.76 - 4.40 (m, 6H), 4.29 - 4.16 (m, 2H), 3.64 - 3.19 (m, 26H), 3.09 - 3.02 (m, 1H), 2.86 - 2.79 (m, 1H), 2.41 - 2.26 (m, 3H), 2.12 - 1.90 (m, 2H), 1.78 - 1.25 (m, 10H), 1.03 - 0.83 (m, 8H). Example 3: Preparation Process of 25G7-Fab Protein The gene sequence of the synthetic antibody was subcloned into the pcDNA3.4 vector. The ligation product was transformed into Top10 competent cells, and positive clones were picked for expansion culture. The clones were inoculated into the medium for expansion culture, and plasmids containing the deoxyribonucleic acid sequence of the 25G7-Fab antibody were extracted in large quantities. Using liposome transfection, after mixing the expression plasmid with the transfection reagent, it was added to Expi 293 cells, and the cell culture was harvested after culturing in a constant temperature incubator for 5 days. The cell culture was centrifuged and the supernatant was taken, filtered to remove cell debris, and the clarified liquid was collected. A kappa select chromatography column was used to capture the target protein. The target protein was filtered, and the protein concentration was obtained by measuring the A280 absorbance value with a Nanodrop and dividing it by the extinction coefficient, and then multiplied by the volume to determine the final yield. SDS-PAGE, SEC-HPLC, and endotoxin detection were performed on the protein by gel electrophoresis and size exclusion chromatography, and the final product was 25G7-Fab. Example 4: Preparation process of AZD1402-TAG protein AZD1402-TAG (the protein sequence is from SEQ ID NO1 in patent WO2020200960A1. For the convenience of protein preparation and purification, a His tag was fused to the C-terminus of this sequence, and it was finally named AZD1402-TAG). AZD1402-TAG SEQ ID NO: 13 The coding gene sequence of the above protein was synthesized and subcloned into pcDNA3.4. After mixing the expression plasmid with the transfection reagent, it was incubated at 37°C for 15 minutes, and the mixture was added dropwise to the HEK293 cell solution. After culturing the cell solution in a shaker at 37°C for one week, the cell culture was centrifuged and the supernatant was taken. A nickel affinity chromatography column was equilibrated with a buffer without imidazole, then the protein sample was loaded by flowing through the nickel affinity chromatography column. After equilibration again with a buffer without imidazole, the protein bound to the column was eluted with a buffer containing a high concentration of imidazole. The eluted protein was transferred to a dialysis bag and dialyzed in 1×PBS to be replaced with a PBS storage buffer. After detection, the target protein was obtained. Example 5: Preparation of antibody-drug conjugate ADC-1 Preparation of BufferA: In a 2.0 L container, add KH 2 PO 4 (8.50 g), K 2 HPO 4 (8.56 g), NaCl (5.86 g) and EDTA (1.50 g), add 1.6 L of injection water, stir for half an hour, after complete dissolution, make up the volume to 2.0 L with injection water, and measure the pH to be 6.30 ± 0.1. At 37 °C, an aqueous solution of buffer A (0.05 M buffer aqueous solution with pH = 6.3; 10.0 mg / ml, 0.5 mL, 0.125 mmol) of antibody 25G7-Fab (heavy chain sequence as shown in SEQ ID NO: 11, light chain sequence as shown in SEQ ID NO: 10) was added with a prepared aqueous solution of tris(2-carboxyethyl)phosphine (TCEP) (2.5 mM, 100.0 μL, 0.250 mmol), placed in a water bath oscillator, and reacted with shaking at 37 °C for 3 hours, then the reaction was stopped. The reaction solution was cooled to 25 °C in a water bath. 1.0 M Tris buffer (50 μL) was added to the above reaction solution, and compound 1 (1.43 mg, 1.250 mmol) was dissolved in 25 μl of DMSO and added to the above reaction solution, placed in a water bath oscillator, and reacted with shaking at 25 °C for 3 hours, then the reaction was stopped. The reaction solution was desalted and purified using a Sephadex G25 gel column (elution phase: buffer A), and concentrated using an ultrafiltration tube to obtain a buffer A buffer solution of the title product ADC-1 (6.06 mg / mL, 0.60 mL), and stored frozen at 4 °C. [Corrected according to Rule 91 on 24.04.2025] Example 6: Preparation of antibody-drug conjugate ADC-2 At 37 °C, an aqueous solution of buffer A (0.05 M buffer aqueous solution with pH = 6.3; 10.0 mg / ml, 6.0 mL, 1.50 mmol) of antibody 25G7-Fab was added with a prepared aqueous solution of tris(2-carboxyethyl)phosphine (TCEP) (10.0 mM, 1.50 mL, 15.0 mmol), placed in a water bath oscillator, and reacted with shaking at 37 °C for 3 hours, then the reaction was stopped. The reaction solution was cooled to 25 °C in a water bath. Compound 2 (12.2 mg, 12.0 mmol) was dissolved in 300 μl of DMSO and added to the above reaction solution, placed in a water bath oscillator, and reacted with shaking at 25 °C for 3 hours, then the reaction was stopped. The reaction solution was desalted and purified using a Sephadex G25 gel column (elution phase: buffer A), and concentrated using an ultrafiltration tube to obtain a buffer A buffer solution of the title product ADC-2 (3.65 mg / mL, 12.8 mL), and stored frozen at 4 °C. Biological evaluation The following further describes and explains the present disclosure in combination with test examples, but these examples do not mean to limit the scope of the present disclosure. Test Example 1: Detection of the affinity of antibody-drug conjugate ADC-2 for human IL-4Rα protein 1. Tested protein Antibody-drug conjugate ADC-2, 25G7-Fab, AZD1402-TAG 2. Experimental methods Surface plasmon resonance (SPR) technology was used to detect the affinity of the antibody-drug conjugates ADC-2, 25G7-Fab, and AZD1402-TAG for the human IL-4Rα antigen protein. An SA sensor chip (Cytiva) was placed in a Biacore 8K (Cytiva), and the biotin-labeled human IL-4Rα protein (SinoBiological, CAT#10402-H08H-B) was captured on the SA sensor chip. The mobile phase used was HBS-EP+ buffer solution (10 mM HEPES, 150 mM NaCl, 3 mM EDTA, 0.05% surfactant P20). Each test protein was serially diluted 2-fold with HBS-EP+ buffer solution and used as an analyte for injection. The flow rate was set at 30 μL / min, and the detection time for ADC-2, 25G7-Fab, and AZD1402-TAG was 100 seconds for binding and 600 seconds for dissociation. Analysis was performed using Biacore 8K evaluation software (Cytiva) to obtain the affinity data of each test protein. 3. Experimental results Table 1 KD values of the affinity of the test proteins for binding to the human IL-4Rα protein As shown in Table 1, the KD value of ADC-2 binding to the human IL-4Rα antigen protein was 11.0 pM, slightly better than that of AZD1402-TAG and 25G7 - Fab. Test Example 2: Whole-cell binding activity of the antibody-drug conjugate ADC-2 to human IL-4Rα-expressing cells 1. Test proteins Antibody-drug conjugate ADC-2, 25G7-Fab, hu25G7 (heavy chain sequence as shown in SEQ ID NO: 9, light chain sequence as shown in SEQ ID NO: 10), AZD1402-TAG. 2. Experimental methods The TF-1 and Karpas 299 cell lines were identified to express IL-4Rα. After collecting the TF-1 and Karpas 299 cells in the logarithmic growth phase, they were counted and the cell density was adjusted to 1×10 5Cells were seeded into round-bottom 96-well plates at a density of [X] cells / well. The cells were incubated with different concentrations of anti-IL-4R antibodies (25G7, naked anti-25G7-Fab), antibody-drug conjugate ADC-2, and AZD1402-TAG at 4 °C for 45 minutes. After washing away the antibodies with FACS Buffer (PBS containing 2% FBS), fluorescently labeled secondary antibodies were added for staining. For 25G7-Fab, hu25G7, and ADC-2, FITC-conjugated anti-human IgG (Fab specific) secondary antibody (Sigma, CAT#F5512-1ML) was used. For AZD1402-TAG, FITC-conjugated anti-His antibody (GenScript, CAT#A01620) was used. The cells were incubated with the secondary antibody at 4 °C for 30 minutes, then washed twice with FACS Buffer, and analyzed by flow cytometry (BD, FACS Celesta). The results were analyzed using FlowJo (FlowJo, LLC) software. 3. Experimental Results Table 2 Whole-cell binding activity EC of the test proteins to human IL-4Rα-expressing cells 50 Value As shown in Figure 1 and Table 2, the EC 50 value of ADC-2 binding to TF-1 cells was 0.107 nM, comparable to that of naked anti-25G7-Fab and hu25G7. The binding of AZD1402-TAG to TF-1 cells was strong, but due to different detection antibodies, the data was not comparable to that of ADC-2, 25G7-Fab, etc. Test Example 3: Blocking effect of antibody-drug conjugate ADC-2 on the IL-4 / IL-13 signaling pathway 1. Test Proteins Antibody-drug conjugate ADC-2, 25G7-Fab. 2. Experimental Method The activation of STAT6 is a key step in the activation of the IL-4 / IL-13 signaling pathway. In this example, the blocking effect of ADC-2 on the IL-4 / IL-13 signaling pathway was evaluated using the HEK-Blue TM IL-4 / IL-13 reporter cell line. This cell line was purchased from Invivogen (Cat#hkb-i1413), which overexpresses the human STAT6 gene and a secreted alkaline phosphatase reporter gene (Secreted alkaline phosphatase, SEAP) induced by phosphorylated STAT6. The activation level of the IL-4 / IL-13 signaling pathway can be evaluated by detecting the content of SEAP secreted in the cell culture supernatant using the SEAP substrate QUANTI-Blue. Collect HEK-Blue cells in the logarithmic growth phase TM After collecting IL-4 / IL-13 cells, adjust the density to 5×10 5 cells / ml, add 100 μL per well to a 96-well flat-bottom culture plate, and culture at 37 °C, 5% CO 2 for 24 hours. Then add 20 μL of serially diluted test protein and 20 μL of recombinant human IL-4 or IL-13 to each well. Place the cell culture plate in an incubator at 37 °C, 5% CO 2 and continue to incubate for 20 - 24 hours. After the culture is completed, take out the cell culture plate, aspirate 20 μL of cell culture supernatant from each well and transfer it to another 96-well plate. Add 180 μL / well of QUANTI-Blue chromogenic solution preheated at 37 °C. After incubating at 37 °C for 1 hour, measure the absorbance at a wavelength of 620 nm. 3. Experimental results Table 3 IC 50 values of the test protein's blocking effect on the IL-4 / IL-13 signaling pathway As shown in Figure 2 and Table 3, each test protein has a blocking effect on the activation of STAT6 induced by recombinant human IL-4 and IL-13. The IC 50 value of ADC-2 blocking the IL-4 signaling pathway is 0.68 nM, which is close to the IC 50 value of 0.61 nM of 25G7-Fab; the IC 50 value of ADC-2 blocking the IL-13 signaling pathway is 10.60 nM, which is comparable to the IC 50 value of 14.59 nM of 25G7-Fab. Test Example 4: Endocytic activity of antibody-drug conjugate ADC-2 in TF-1 cells 1. Test proteins Antibody-drug conjugate ADC-2, 25G7-Fab, hu25G7, AZD1402-TAG. 2. Experimental method Collect TF-1 cells in good growth state, adjust the density to 1×10 6 cells / mL, add 100 μL / well to a 96-well cell culture plate and place it at 4 °C. Add each test protein at a final concentration of 2 nM, incubate at 4 °C for 1 hour, then put it into a cell culture incubator at 4 °C for minutes, 5% CO 2Continue the culture under the conditions, set up a culture plate at each time point, take out the culture plate at different incubation times during the period, wash it with FACS buffer and centrifuge, and then add a fluorescently labeled secondary antibody for incubation. 25G7-Fab, hu25G7 and ADC-2 were labeled with an FITC-conjugated anti-human IgG (Fab specific) secondary antibody, and AZD1402-TAG was labeled with an FITC-conjugated anti-His antibody. Incubate the cells with the secondary antibody at 4 °C for 30 minutes, then wash twice with FACS Buffer and detect with a flow cytometer (BD, FACS Celesta). The test results were analyzed using FlowJo (FlowJo, LLC) software. The formula for calculating the endocytosis rate at a specific time point is: (gMFI Test Ab at time X -gMFI ISO Ab at time X ) / (gMFI Test Ab at time zero -gMFI ISO Ab at time zero )*100% 3. Experimental results The experimental results are shown in Figure 3. Endocytosis signals of each test protein could be detected in TF-1 cells. The endocytosis activities of ADC-2 and hu25G7 were comparable, and the endocytosis rate within 3 hours was about 70%; the endocytosis of 25G7-Fab was faster and the endocytosis rate was also higher. Compared with AZD1402-TAG, the endocytosis rate and endocytosis percentage of ADC-2, 25G7-Fab and hu25G7 were significantly better than those of AZD1402-TAG, reaching a plateau at about 2 hours, and the endocytosis activity of ADC-2 was slightly weaker than that of 25G7-Fab. Test Example 5: Pharmacokinetic test of antibody-drug conjugate ADC-2 in a mouse model 1. Test protein Antibody-drug conjugate ADC-2 2. Experimental method 2.1 Experimental animals C57BL6 / J mice, 8 weeks old, male, Cyagen Biosciences (Suzhou) Inc. 2.2 Administration operation for mice Mice were administered drugs by intratracheal (i.t.) aerosolization. At different time points after administration, 300 - 400 μL of blood was collected from the mandible. After standing for 2 hours, it was centrifuged at 7500 rpm at 4°C for 10 minutes, and the serum was collected. After blood collection, the mice were anesthetized and fixed. The neck muscles of the mice were bluntly dissected to expose the trachea. The trachea was opened horizontally, and an irrigation needle was slowly inserted. The pre - drawn 4°C pre - cooled physiological saline was slowly pushed into the lung tissue for irrigation, and bronchoalveolar lavage fluid (BALF) was collected. A total of 3 irrigations were performed. The first two times were irrigated with 300 μL of physiological saline respectively, and the third time was irrigated with 400 μL. The collected bronchoalveolar lavage fluid was centrifuged at 1000 rpm at 4°C for 10 minutes, and the supernatant was collected. After euthanizing the mice, the thoracic cavity of the mice was opened, and the complete mouse lung tissue was separated and collected. The blood stains on the surface of the lung tissue were washed off with PBS. After blotting the surface PBS with a tissue paper, the lung tissue was weighed. The lung tissue was placed in a 2 - mL centrifuge tube, 1 mL of cell lysate (CST, #9803) was added, and it was ground with a homogenizer (Shanghai Jing Xin, Tissuelyser - 48) at 60 Hz for 2 minutes, then centrifuged at 10,000×g at 4°C for 10 minutes. The supernatant was the lung tissue homogenate, and the protein concentration of the homogenate was detected (Pierce, 23227). The serum, BALF, and lung tissue homogenate were stored at - 80°C. The drug administration protocol is shown in Table 4, and the sampling protocol is shown in Table 5. Table 4 Drug Administration Protocol Table 5 Sampling Protocol 2.3 Detection of ADC - 2 Content (1) Coating: Dilute the antigen hIL - 4Rα to 1 μg / mL with carbonate buffer (Acro, ILR - H5221), add 100 μL to each well of the ELISA plate, and incubate overnight at 4°C (16 - 18 h). (2) Plate washing: The ELISA plate was restored to room temperature, and each well was washed with 300 μL of 0.05% PBST (PBS + 0.05% Tween 20) buffer, and the plate was washed 3 times in total. (3) Blocking: Add 300 μL of PBS containing 3% BSA to each well, and incubate with shaking at 400 rpm at room temperature for 2 h. (4) Plate washing: Add 300 μL of 0.05% PBST to each well and wash the plate 3 times. (5) Sample incubation: Add 100 μL of diluted serum, BALF, or lung tissue homogenate to the ELISA plate, and incubate with shaking at 400 rpm at room temperature for 1.5 h. (6) Plate washing: Add 300 μL of 0.05% PBST to each well and wash the plate 3 times. (7) Detection: Dilute the detection antibody (Invitrogen, A18811) 10,000 times with Assay buffer (0.05% PBST containing 0.5% BSA), add 100 μL to each well of the ELISA plate, and incubate on a shaker at 400 rpm at room temperature for 1 h. (8) Plate washing: Add 300 μL of 0.05% PBST to each well and wash the plate 3 times. (9) Color development: Add 100 μL of TMB substrate (Sera care, 5120 - 0080) to each well and incubate at room temperature for 15 min. (10) Termination: Add 100 μL of substrate reaction termination solution (Solarbio, C1058) to each well and measure the absorbance at a wavelength of 620 nm. 2.4 Detection of free Budesonide content Take 30 μL of serum, BALF or lung tissue homogenate, add 30.0 μL of internal standard working solution (5.00 ng / mL Budesonide - D8) and 120 μL of acetonitrile, vortex for 1 min, centrifuge at 13,000 rpm at 4 °C for 5 min, take 100 μL of the supernatant into a 96 - well plate, add 100 μL of 0.3% FA dilution solution, incubate on a shaker at 1,000 rpm at room temperature for 15 min, and take 20 μL for LC - MS / MS analysis (Shimadzu, Japan, Shimadzu liquid chromatography system; AB Sciex, Triple Quad 6500 + type triple quadrupole tandem mass spectrometer). 3. Experimental results The pharmacokinetic parameters of the antibody - drug conjugate ADC - 2 and free Budesonide are shown in Table 6, and the concentration - time curves are shown in Figure 4. Table 6 PK parameters of ADC - 2 and free Budesonide The experimental results show that after intratracheal administration of the antibody - drug conjugate ADC - 2, the drug is mainly distributed in serum and BALF, and the serum exposure is low. The exposure of Budesonide in each tissue is very low. Test Example 6: In vivo efficacy of ADC - 2 in an OVA - induced mouse asthma model 1. Test articles Antibody - drug conjugate ADC - 2, 25G7 - Fab, AZD1402 - TAG, Budesonide. 2. Experimental methods 2.1 Experimental animals IL - 4 hu / hu - IL - 4Rα hu / hu double - transgenic C57BL6 / J mice, 8 weeks old, female, Cyagen Biosciences (Suzhou) Inc. 2.2 Mouse Administration Operation The animals were randomly divided into normal control animals and model animals. On Day 0, 7, and 14, 100 μL of PBS solution containing 200 μg OVA (Sigma, A5503) was intraperitoneally injected, and aluminum hydroxide of equal volume was used as an adjuvant to sensitize the mice. From Day 21 to 27, the mice inhaled an aerosol solution of 3% OVA once a day for 35 min each time. Starting from Day 21, half an hour before inhaling the OVA aerosol solution, the mice received intratracheal aerosol administration. The specific dosing regimen is shown in Table 7. On Day 28, after the mice were euthanized, the neck muscles of the mice were bluntly dissected to expose the trachea. The trachea was opened transversely, and an irrigation needle was slowly inserted. The pre-loaded 4°C pre-cooled physiological saline was slowly pushed into the lung tissue for irrigation, and the bronchoalveolar lavage fluid was collected. A total of 3 irrigations were performed, with the first two times using 300 μL of physiological saline for irrigation and the third time using 400 μL for irrigation. After centrifugation at 1,000 rpm for 10 min at 4°C, the cell pellet was resuspended in 350 μL of pre-cooled physiological saline, and white blood cells and differential cell counts were performed using an automated hematology analyzer. Table 7 Dosing Regimen 2.3 Experimental Indexes The number of white blood cells and differential cells in BALF. 2.4 Statistical Analysis Unless otherwise specified, the comparison between the two groups of cell counts was performed using one-way ANOVA test, and p < 0.05 was defined as having a statistically significant difference. 3. Experimental Results The experimental results are shown in Figure 5. Compared with the model group, at equimolar doses, the antibody-drug conjugate ADC-2 significantly reduced the number of white blood cells, eosinophils, and neutrophils in BALF, and also had a certain inhibitory effect on the number of monocytes. Its drug efficacy was better than AZD1402-TAG, and significantly better than 25G7-Fab and Budesonide. ADC-2 demonstrated the synergistic effect of 25G7-Fab and Budesonide in terms of drug efficacy. Test Example 7: Dose Exploration of the In Vivo Efficacy of ADC-2 in an OVA-Induced Mouse Asthma Model 1. Test Substances Antibody-drug conjugate ADC-2, AZD1402-TAG, Budesonide. 2. Experimental Methods 2.1 Experimental Animals IL-4 hu / hu-IL-4Rα hu / hu double transgenic C57BL6 / J mice, 8 weeks old, female, Cyagen (Suzhou) Biosciences Co., Ltd. 2.2 Mouse drug administration operation The drug administration and BALF sampling operations are the same as those in Test Example 6. The specific drug administration plan is shown in Table 8. Table 8 Drug administration plan 2.3 Experimental indicators The number of white blood cells and classified cells in BALF. 2.4 Statistical analysis Unless otherwise specified, the comparison between the two groups of cell counts was performed using one-way ANOVA test, and p < 0.05 was defined as having statistically significant differences. 3. Experimental results The experimental results are shown in Figure 6. Compared with the model group, 10 μg of ADC-2 could significantly reduce the number of eosinophils in the alveolar lavage fluid, which was equivalent to AZD1402-TAG and slightly better than budesonide at a far higher clinical equivalent dose. In addition, the inhibitory ability of 10 μg of ADC-2 on the number of white blood cells was also very significant, and it also had a certain degree of inhibition on the number of monocytes and neutrophils. These results indicate that a 1 / 10 molar dose of ADC-2 can achieve the same efficacy as AZD1402-TAG. Example 7: Preparation of inhaled dry powder a-d Table 9 Composition of prescriptions a-d Preparation process: 1) Prepare the excipient solution by adding water according to the prescription composition in Table 9, add the prescribed amount of ADC-2 buffer solution (prepared in Example 6), gently stir evenly, add the prescribed amount of isopropanol, and gently stir evenly (the pH can be adjusted with hydrochloric acid as needed); 2) Freeze-dry. The particle size was measured using a SYMPATEC particle size analyzer, with a dispersion pressure of 4 bar. The particle size results are shown in Table 10. Table 10 Geometric particle size measurement results of inhaled dry powder a-c The prepared drug-containing inhaled dry powder was filled into transparent HPMC capsules (No. 3), with a filling amount of 10 mg. The capsule samples were subjected to APSD testing using the NGI impactor of COPLEY Company according to the regulations of the General Rules 0951 [Method for Determining the Aerodynamic Characteristics of Fine Particles of Inhalation Preparations] in the Fourth Part of the Chinese Pharmacopoeia 2015 Edition. The APSD distribution results at each level were input into the CITDAS version 3.10 software (COPLEY) to obtain values such as FPF (<5 μm), MMAD, and GSD. The results are shown in Table 11. Table 11 Test results of the aerodynamic particle size (APSD) of inhaled dry powder The samples were placed under different stability test conditions, and the drug stability was analyzed by the method of SEC (size exclusion chromatography). The results are shown in Table 12. The results show that the monomer decline of Formulations c and d was the smallest during the stability process, and the addition of sodium citrate in the formulation made the macromolecular properties more stable. Results of the determination of the purity of the active ingredient (SEC) (%) Example 8: Preparation of inhalation dry powders e, f, and g The same formulation composition and preparation method as in Formulation b of Example 7 were used, with the difference being the adjustment of the dosage of the organic solvent as shown in Table 13. Table 13 Dosages of water and isopropanol for preparing inhalation dry powders e, f, and g The particle size was measured using a SYMPATEC particle size analyzer at a dispersion pressure of 4 bar. The particle size results are shown in Table 14. Results of the geometric particle size determination of inhalation dry powders e, f, and g Example 9: Preparation of inhalation dry powders h - k The same formulation and freeze - drying process as in Example 7 were used to prepare the inhalation powder according to the formulation composition in Table 15. Composition of Formulations h - k The particle size was measured using a SYMPATEC particle size analyzer at a dispersion pressure of 4 bar. The particle size results are shown in Table 16. The results show that when the drug concentration was increased from 2 mg / ml to 3.5 mg / ml, the geometric particle size changed little. Results of the geometric particle size determination of inhalation dry powders h - k The method for determining the aerodynamic particle size was the same as in Example 7, and the APSD results are shown in Table 17. The results show that when the drug concentration changed within the range of 2 - 3.5 mg / ml, the aerodynamic particle size results such as FPF and MMAD were not significantly affected. Test results of the aerodynamic particle size (APSD) of inhalation dry powders Example 10: Observation of the morphology of inhalation dry powders The morphology of inhalation dry powders c and f was observed using a scanning electron microscope (SEM). The results are shown in Figures 7 and 8. It can be seen that both inhalation dry powders c and f are aggregates of several nanoscale smooth spheres. Example 11: Preparation of inhalation dry powders of different specifications Preparation of inhaled dry powder m (0.4 mg specification): Weigh histidine, sodium citrate and 0.06 mg of trehalose in the amounts prescribed in Table 18, add water to prepare an excipient solution, add the ADC-2 buffer solution (prepared in Example 6) in the prescribed amount, gently stir evenly, add isopropanol in the prescribed amount, and gently stir evenly. Prepare the lyophilized powder using the same lyophilization process as in Example 7, and then add the remaining prescribed amount of trehalose as a filler and fill it into hypromellose hollow capsules. Preparation of inhaled dry powder n (2 mg specification): Using the same formulation and lyophilization process as in Example 7, prepare inhaled powder m according to the prescription composition in Table 18 and directly fill it into hypromellose hollow capsules. Composition of Prescriptions m and n in Table 18 The method for measuring the aerodynamic particle size is the same as that in Example 7, and the APSD results are shown in Table 19. Table 19 Test Results of Aerodynamic Particle Size (APSD) of Inhaled Dry Powder

Claims

1. A pharmaceutical composition comprising an antibody drug conjugate and a counterion, wherein the antibody drug conjugate has a structure as shown in Formula I: in: 25G7-Fab comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: HCDR1 as shown in SEQ ID NO:1 or SEQ ID NO:12, HCDR2 as shown in SEQ ID NO:2, and HCDR3 as shown in SEQ ID NO:3, and the light chain variable region comprises: LCDR1 as shown in SEQ ID NO:4, LCDR2 as shown in SEQ ID NO:5, and LCDR3 as shown in SEQ ID NO:6; n is 1 to 10.

2. The pharmaceutical composition according to claim 1, wherein the 25G7-Fab has a heavy chain variable region as shown in SEQ ID NO: 8, and a light chain variable region as shown in SEQ ID NO:

7.

3. The pharmaceutical composition according to claim 1 or 2, wherein the 25G7-Fab has a heavy chain as shown in SEQ ID NO: 11, and a light chain as shown in SEQ ID NO:

10.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the concentration of the antibody drug conjugate is 0.1 mg / mL-50 mg / mL, preferably 0.5 mg / mL-10 mg / mL, more preferably 1 mg / mL-5 mg / mL, in terms of protein concentration.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the counterion is selected from one or more of sulfate, phosphate, malate, maleate, oxalate, citrate, succinate, fumarate, itaconate, chloride and bromide, preferably one or more of sulfate, citrate and chloride, more preferably one or more of sodium citrate, sodium sulfate, zinc sulfate, magnesium sulfate, potassium sulfate, calcium sulfate, magnesium chloride, calcium chloride and zinc chloride, most preferably sodium sulfate and / or sodium citrate.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the concentration of the counterion is 0.01 mg / mL-10 mg / mL, preferably 0.05 mg / mL-5 mg / mL, more preferably 0.1 mg / mL-2 mg / mL.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition further comprises a protective agent.

8. The pharmaceutical composition according to claim 7, wherein the protective agent is selected from amino acids and / or sugars.

9. The pharmaceutical composition according to claim 8, wherein the amino acid is selected from one or more of glycine, histidine, arginine, lysine, glutamic acid, alanine, valine, leucine, isoleucine, proline, tryptophan, phenylalanine, methionine, and aspartic acid, more preferably glycine or histidine.

10. The pharmaceutical composition according to claim 8 or 9, wherein the concentration of the amino acid is 0.01 mg / mL-10 mg / mL, preferably 0.05 mg / mL-5 mg / mL, more preferably 0.1 mg / mL-2 mg / mL.

11. The pharmaceutical composition according to claim 8, wherein the sugar is selected from one or more of sorbitol, mannitol, xylitol, trehalose, lactose, fructose, maltose and sucrose, preferably trehalose. 12 . The pharmaceutical composition according to claim 11 , wherein the concentration of the sugar is 0.01 mg / mL-10 mg / mL, preferably 0.05 mg / mL-5 mg / mL, more preferably 0.1 mg / mL-2 mg / mL.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the pharmaceutical composition further comprises an organic solvent, wherein the organic solvent is preferably one or more of methanol, ethanol, 1-propanol, isopropanol, tert-butyl alcohol, butanol, acetone, acetonitrile, acetic acid, ethyl acetate, methyl ethyl ketone, methyl tert-butyl ether and dimethyl sulfoxide, more preferably isopropanol.

14. The pharmaceutical composition according to claim 13, wherein the amount of the organic solvent is 0.1%-50% v / v, preferably 0.5%-30% v / v, more preferably 1%-10% v / v.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the pH of the pharmaceutical composition is 3.0-8.0, preferably 4.5-6.

0.

16. The pharmaceutical composition according to any one of claims 1 to 15, comprising: a) 1 mg / mL to 5 mg / mL of the antibody-drug conjugate, based on protein concentration, b) 0.1 mg / mL to 2 mg / mL of a counterion, wherein the counterion is sodium citrate or sodium sulfate, c) 0.1 mg / mL to 2 mg / mL of an amino acid, wherein the amino acid is histidine or glycine, d) 0.1 mg / mL to 2 mg / mL of sugar, wherein the sugar is trehalose, e) 1%-10% v / v of an organic solvent, wherein the organic solvent is isopropanol; The pH of the pharmaceutical composition is 4.5-6.

0.

17. A lyophilized preparation containing an antibody drug conjugate, wherein the lyophilized preparation is obtained by freeze-drying the pharmaceutical composition according to any one of claims 1 to 16.

18. A reconstituted solution containing an antibody drug conjugate, wherein the reconstituted solution is prepared by reconstituted the lyophilized preparation according to claim 17.

19. A pharmaceutical composition comprising the lyophilized preparation according to claim 17, and a filler, wherein the filler is selected from one or more of trehalose, lactose, mannitol, glucose, sorbitol, and dextran, preferably trehalose.

20. A product comprising a container containing the pharmaceutical composition of any one of claims 1 to 16, the lyophilized preparation of claim 17, the reconstituted solution of claim 18 or the dry powder preparation of claim 19.

21. Use of the pharmaceutical composition according to any one of claims 1 to 16, the lyophilized preparation according to claim 17, the reconstituted solution according to claim 18, the dry powder preparation according to claim 19 or the product according to claim 20 in the preparation of a medicament for treating or preventing an immune disease or condition, wherein the disease or condition is preferably asthma, nasal polyps, chronic sinusitis, allergic skin disease, eosinophilic esophagitis, chronic obstructive pulmonary disease, allergic rhinitis, arthritis, inflammatory disease, allergic reaction, autoimmune lymphoproliferative syndrome, autoimmune hemolytic anemia, Barrett's esophagus, autoimmune uveitis, tuberculosis and nephropathy, more preferably asthma or allergic skin disease.

Images