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 containing an antibody-drug conjugate of glucocorticoid This application claims the priority of Chinese patent application No. 2023109382848 filed on July 28, 2023. This application cites the entire text of the above Chinese patent application. Technical Field The present invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition containing an antibody-drug conjugate of a glucocorticoid. Background Art Interleukin-4 (IL-4) consists of 153 amino acids and has a molecular weight of approximately 17 kDa. Initially, IL-4 was discovered because it could stimulate B cell proliferation and was named B cell stimulating factor-1 (BSF-1). IL-4, like IL-13, belongs to the type I cytokine family and has a quaternary structure consisting of a hydrophobic core of 4 α helices. IL-4 is secreted by TH2 cells and participates in TH2-mediated immune responses. It has 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 and IL-4 have approximately 30% amino acid sequence homology and multiple similar functions. Both IL-4 and IL-13 can promote B cell proliferation and induce the conversion of IgM type to IgE in combination with CD40 / CD40L co-stimulation. IL-4 promotes mast cell aggregation, upregulates the expression of mast cell high-affinity IgE receptor and B cell low-affinity IgE receptor CD23 (FcεRII), upregulates the expression of vascular endothelial cell adhesion molecule (VCAM-1), and promotes the migration of eosinophils, T lymphocytes, monocytes and basophils. Unlike 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 function. Human interleukin receptor (IL-4R) is a heterodimer formed by two polypeptide chains, one of which is an α chain with 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, including 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, type I receptors composed of IL-4Rα and γc are mainly expressed. In non-hematopoietic stem cells, IL-4 mainly exerts its effects through type II receptors composed of IL-4Rα and IL-13Rα1. Type II receptor is a common receptor for IL-4 and IL-13. IL-13 binds to IL-13Rα1 to exert its function. Both type I and type II receptors transduce signals through the Jak / STAT pathway. IL-4Rα, γc and IL-13Rα1 bind to Jak1, Jak3 and Tyk2 respectively to activate downstream pathways. IL-4 and IL-13 can also transduce signals through the insulin receptor substrate family (IRS), ultimately activating PI3-K and NF-κB in the nucleus. Blocking IL-4R can inhibit the biological functions of both IL-4 and IL-13. Many studies have shown that IL-4 and IL-13 are related to diseases related to TH2 immune response. Atopic dermatitis (AD), also known as atopic dermatitis or genetic allergic dermatitis, is a common dermatological disease, more common in children and adolescents, and often complicated by certain genetic allergic diseases such as allergic rhinitis and asthma. Studies have found that TH2 factors IL-4, IL-5, IL- In addition, it was found that TH2 factors are related to the progression of AD, and mice overexpressing TH2 factors such as IL-4 and IL-13 showed skin protection defects and AD-like symptoms.

[0014]

[0015] . Elevated levels of IL-4 and IL-13 in AD patients hinder epidermal differentiation and the production of antimicrobial peptides. IL-4-deficient mice reduce the occurrence of skin allergic inflammation. These studies show that blocking IL-4R may be effective in treating AD. Anti-IL-4R monoclonal antibodies have been marketed abroad and have shown good therapeutic effects on AD. IL-13 and IL-4 also play an important role in asthma. Asthma is a common pulmonary inflammatory disease characterized by airway hyperresponsiveness (AHR), excessive mucus secretion, fibrosis and elevated IgE levels. Nonspecific stimuli such as cold air often lead to aggravated airway hyperresponsiveness. AHR and excessive mucus secretion lead to airway obstruction, which is the main cause of death in asthma. TH2 factors play an important role in the progression of asthma. Bronchial and alveolar lavage fluid of asthmatic patients overexpress IL-4 and IL-13. Although IL-13 and IL-4 have certain functional similarities, some studies have shown that IL-13 plays a more important role in the progression of asthma than other Th2 cytokines. IL-13 can promote goblet cell differentiation and fibrosis. Injection of recombinant IL-13 into the airways of mice that have not been stimulated by allergens will lead to airway inflammation, excessive mucus secretion and airway hyperresponsiveness. Injection of soluble IL13Rα2 can prevent the occurrence of AHR, excessive mucus secretion and lung inflammation in mice. Injection of IL-4Rα antibody in asthma model can reduce AHR and eosinophils in bronchoalveolar lavage fluid. The study suggests that blocking IL-4Rα may be effective in treating asthma. Currently, many pharmaceutical companies in various countries are developing monoclonal antibodies targeting IL-4R. Relevant patent applications include WO2010053751, WO2001092340, WO2008054606, WO2014031610, WO2020038454, etc. Glucocorticoid is also the comparatively effective medicine for treating allergic diseases, inflammation etc. As representative glucocorticoid, known cortisol, corticosterone etc. are made in vivo glucocorticoid and dexamethasone, prednisone, prednisolone, budesonide etc. synthetic glucocorticoid.These glucocorticoids are owing to having steroid structure, therefore are generally referred to as steroids, are applied in the treatment of various diseases.But these steroids, due to its use, sometimes show the side effects such as steroid peptic ulcer, steroid purpura, steroid pancreatitis, steroid diabetes, steroid cataract, steroid glaucoma etc. Antibody drug conjugate (ADC) refers to a monoclonal antibody or antibody fragment connected to a biologically active 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 antigens. However, modulation of pathogenic cell activity through ADC-mediated delivery of bioactive small molecules is also attractive for non-oncology indications, leading to the widespread application of this technology. The prior art has disclosed some glucocorticoid drug conjugates, such as WO2017210471, WO2019106609, WO2019136487, etc. Summary of the invention The present disclosure provides 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, 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, LCDR3 as shown in SEQ ID NO: 6; n is 1 to 10. In some embodiments, the range of average drug load (n) can be the average number of glucocorticoid drugs bound to each 25G7-Fab, and non-limiting examples include the average number of glucocorticoid drugs bound to each 25G7-Fab being 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 load (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 sequence of 25G7-Fab is shown in Table 1: Table 1 CDR sequences of 25G7-Fab The light chain variable region sequence of 25G7-Fab is shown in SEQ ID NO: 7, and the heavy chain variable region sequence is shown in SEQ ID NO: 8 shown. 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 counterions are selected from one or more of sulfate, citrate and chloride. In some embodiments, the counterions are 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 counterions are 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 In some embodiments, the concentration of the counter ion is 0.05 mg / mL to 5 mg / mL. In some embodiments, the concentration of the counter ion is 0.1 mg / mL to 2 mg / mL. In some embodiments, the pharmaceutical composition further comprises a protective agent. In some embodiments, the protective agent is selected from amino acids and / or sugars. In some embodiments, the amino acid includes but is 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, and 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 In some embodiments, the concentration of the amino acid is 0.05 mg / mL to 5 mg / mL. In some embodiments, the concentration of the amino acid is 0.1 mg / mL to 2 mg / mL. The "sugar" of the present disclosure comprises the general composition (CH2O) n and their derivatives, including monosaccharides, disaccharides, trisaccharides, polysaccharides, Sugar alcohol, reducing sugar, non-reducing sugar, etc. In some embodiments, the sugar includes but is 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. In some embodiments, the sugar concentration is 0.05mg / mL-5mg / mL. In some embodiments, the sugar concentration is 0.1mg / mL-2mg / mL. In some embodiments, the pharmaceutical composition further comprises an organic solvent, including but 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, and 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 3.0-8.0, 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 points. In some embodiments, the pH is 4.5-6.0. In some embodiments, the pH is 5.0 or 5.5. In some embodiments, the pharmaceutical composition comprises: 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 a 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 4.5-5.5. The present disclosure also provides a lyophilized formulation containing an antibody drug conjugate, wherein the formulation 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, comprising: The pharmaceutical composition is subjected to a freeze-drying step. The present disclosure also provides a lyophilized preparation comprising an antibody drug conjugate, wherein the lyophilized preparation is obtained by freeze-drying the pharmaceutical composition of the antibody drug conjugate as described above. In some embodiments, the lyophilized preparation is in the form of microspheres. In some embodiments, the aerodynamic particle size of the microspheres is 0.01-10.0 μm. In some embodiments, the aerodynamic particle size of the microspheres is 0.5-5 μm. The present disclosure also provides a reconstituted solution containing an antibody drug conjugate, wherein the reconstituted solution is prepared by reconstituted the lyophilized preparation as described above. The present disclosure also provides a method for preparing the above-mentioned reconstituted solution, which comprises the step of reconstituted the above-mentioned 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 comprises the aforementioned lyophilized preparation and a filler, wherein 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 a product, which includes a container, wherein the pharmaceutical composition, lyophilized preparation, reconstituted solution or dry powder preparation as described above is contained in the container. In some embodiments, the container is a neutral borosilicate glass tube injection bottle. The present disclosure also provides use of the aforementioned pharmaceutical composition, lyophilized preparation, reconstituted solution or product in the preparation of a medicament 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, the method comprising administering an effective amount or a preventive effective amount of the aforementioned pharmaceutical composition, lyophilized preparation, reconstituted solution or preparation to a subject. In some embodiments, the disease or condition is selected from: asthma, nasal polyps, chronic sinusitis, 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 disease. In some embodiments, the disease or condition is selected from asthma or allergic skin diseases. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1: Dose-response curve of whole-cell binding activity of the tested proteins 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: Internalization rate-time curve of the tested 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 cell type count in bronchoalveolar lavage fluid of test case 6 Figure 6: White blood cell and cell type count in bronchoalveolar lavage fluid of test case 7 Figure 7: SEM image of inhaled dry powder formulation c Figure 8: SEM image of inhaled dry powder formulation f the term In order to make the present disclosure more easily understood, certain technical and scientific terms are specifically defined below. It is intended that all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The term "antibody-drug conjugate" refers to a ligand connected to a biologically active drug through a stable linking unit. In the present disclosure, "antibody-drug conjugate" (ADC) refers to a monoclonal antibody or antibody fragment connected to a biologically active glucocorticoid through a stable linking unit. The antibody or antibody fragment can be combined with a glucocorticoid molecule containing a linker through a specific group therein (e.g., an interchain disulfide bond). The term "counterion" refers to a charged or charge-polarized molecule that is capable of initiating microparticle formation from macromolecules such as proteins, nucleic acids, lipids, or oligosaccharides. Whether a charged molecule is a counterion can be empirically determined based on parameters including, but not limited to, the type of protein, pH, ionic strength, the type of organic solvent used, and the presence of salts and other ingredients such as active agents. As provided and described herein, a counterion can be anionic or a group with a net negative charge or charge polarization, cationic or a group with a net positive charge or charge polarization, or zwitterionic and a group with negative and positive charges or charge polarization. The term "microparticle" is interchangeable with "microsphere" and refers to particles that include macromolecules and deliver an agent of interest, such as a drug or nutritional supplement to a subject, and whose size range (average length, width or diameter) is about or exactly 0.001 micrometer to about or exactly 500 micrometers. The agent 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 agent, such as a drug or nutritional supplement. The microparticle can also include synthetic macromolecules, including polymers, such as polyethylene glycol (PEG), polylactic acid (PLA), polylactic-co-glycolic acid (PLGA) and natural polymers, such as albumin, gelatin, chitosan and dextran. The "microparticles" 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 a protein and a nucleic acid or a protein and a synthetic polymer). The term "microparticle" as used herein also generally refers to a particle that is not a solid form of the entire solution from which it is produced, although frozen and / or dried particles of solutions containing macromolecules are also contemplated herein. Rather, a microparticle as used herein is generally a collection of a portion of the components of a solution, including salts, counterions, solvents and other ingredients, formed by processes including, but not limited to, precipitation, sedimentation, phase separation and colloid formation. The monoclonal antibody molecular size variant determination method (CE-SDS) disclosed in the present invention can adopt the sodium dodecyl sulfate capillary electrophoresis (CE-SDS) ultraviolet detection method to quantitatively determine the purity of the recombinant monoclonal antibody product according to the capillary electrophoresis method (2015 edition of the "Chinese Pharmacopoeia" 0542) based on the molecular weight under reducing and non-reducing conditions. In one embodiment of the present disclosure, the glucocorticoid is coupled to the N-terminal amino group of the ligand and / or the ε-amino group of the lysine residue via a linker. Generally, the number of drug molecules that can be coupled to the antibody in the coupling reaction will be less than the theoretical maximum value. The loading capacity of the antibody-drug conjugate can be controlled by the following non-limiting methods, including: (1) Control the molar ratio of the linking reagent and the monoclonal antibody, (2) Control the reaction time and temperature, (3) Select different reaction reagents. The term "amino acid" refers to an organic compound that contains an amino group and a carboxyl group in its molecular structure, 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. Depending on the position of the amino group attached 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 constituting natural proteins have their specific structural characteristics, that is, their amino groups are directly connected to the α-carbon atom, i.e., 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 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 one letter codes for amino acids used in this disclosure are as described in J. biol. chem, 243, p3558 (1968). The term "antibody" refers to immunoglobulin, which is a tetrapeptide chain structure composed of two identical heavy chains and two identical light chains connected by interchain disulfide bonds. The amino acid composition and arrangement order of the constant region of the immunoglobulin heavy chain are different, so their antigenicity is also different. Based on this, immunoglobulins can be divided into five categories, or immunoglobulin isotypes, namely IgM, IgD, IgG, IgA and IgE, and their corresponding heavy chains are μ chain, 6 chain, γ chain, α chain, and ε chain respectively. The same class of Ig can be divided into different subclasses according to the difference in the amino acid composition of its hinge region and the number and position of the disulfide bonds of the heavy chain, such as 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 types of Ig can have κ chain or λ chain. The sequences of about 110 amino acids near the N-terminus of the antibody heavy and light chains vary greatly, which is the variable region (Fv region); the remaining amino acid sequences near the C-terminus are relatively stable, which is the constant region. The variable region includes three hypervariable regions (HVRs) and four relatively conservative framework regions (FRs). The three hypervariable regions determine the specificity of the antibody, also known as the complementarity determining regions (CDRs). Each light chain variable region (LCVR) and heavy chain variable region (HCVR) consists of three CDR regions and four FR regions, arranged in the order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3. The antibodies disclosed herein include murine antibodies, chimeric antibodies, humanized antibodies and fully human antibodies, with humanized antibodies and fully human antibodies being preferred. The term "murine antibody" in this disclosure refers to antibodies prepared in mice according to the knowledge and skills in the art. When preparing, a test subject is injected with a specific antigen, and then a hybridoma expressing an antibody with the desired sequence or functional characteristics is isolated. The term "chimeric antibody" refers to an antibody formed by fusing the variable region of a mouse antibody with the constant region of a human antibody, which can reduce the immune response induced by the mouse antibody. To establish a chimeric antibody, it is necessary to first establish a hybridoma that secretes mouse-specific monoclonal antibodies, then clone the variable region gene from the mouse hybridoma cells, and then clone the constant region gene of the human antibody as needed, connect the mouse variable region gene with the human constant region gene into a chimeric gene, and then 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 the mouse CDR sequence into the human antibody variable region framework, that is, different types of human germline antibody framework sequences. The heterologous reaction induced by chimeric antibodies due to carrying a large amount of mouse protein components can be overcome. Such framework sequences can be obtained from public DNA databases including germline antibody gene sequences or published references. For example, the germline DNA sequences of human heavy chain and light chain variable region genes can be found in the "VBase" human germline sequence database (available on the Internet www.mrccpe.com.ac.uk / vbase), and in Kabat, EA et al., 1991 Sequences of Proteins of Immunological Interest, 5th edition. In order to avoid the decrease in activity caused by the decrease in immunogenicity, the human antibody variable region framework sequence can be subjected to minimal reverse mutation or back mutation to maintain activity. The humanized antibodies disclosed in the present invention also include humanized antibodies after further affinity maturation of CDR by phage display. References further describing methods for humanizing mouse antibodies include, for example, Queen et al., Proc., Natl. Acad. Sci. USA, 88, 2869, 1991 and the methods of Winter and 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", "fully human antibody" or "completely human antibody", also known as "fully human monoclonal antibody", are antibodies whose variable and constant regions are both human, 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 a fully human monoclonal antibody. The relevant technologies for the preparation of fully human antibodies mainly include: human hybridoma technology, EBV-transformed B lymphocyte technology, phage display technology (phage display), transgenic mouse antibody preparation technology (transgenic mouse) 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 to an antigen. It has been shown that fragments of a full-length antibody can be used to perform the antigen-binding function of an antibody. Examples of binding fragments included in "antigen-binding fragments" include (i) Fab fragments, monovalent fragments consisting of VL, VH, CL and CH1 domains; (ii) F(ab')2 fragments, bivalent fragments comprising two Fab fragments connected by a disulfide bridge on the hinge region; (iii) Fd fragments consisting of VH and CH1 domains; (iv) Fv fragments consisting of the 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 a VH domain; and (vi) isolated complementarity determining regions (CDRs) or (vii) combinations of two or more isolated CDRs, optionally connected by synthetic linkers. In addition, although the two domains VL and VH of the Fv fragment are encoded by separate genes, they can be connected by synthetic linkers using recombinant methods, so that they can be produced as a single protein chain in which the VL and VH regions are paired to form a monovalent molecule (called 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 technology or by enzymatic or chemical cleavage of intact immunoglobulins. The antibodies can be of different isotypes, for example, IgG (eg, IgG1, IgG2, IgG3, or IgG4 subtype), IgA1, IgA2, IgD, IgE, or IgM antibodies. Fab is prepared by treating IgG antibody fragments with the protease papain (which cleaves amino acid residue 224 of the H chain). Among the fragments obtained, an antibody fragment having a molecular weight of about 50,000 and having antigen-binding activity is obtained, in which about half of the N-terminal side of the H chain and the entire L chain are bound together by a disulfide bond. F(ab')2 is an antibody fragment having a molecular weight of about 100,000 and antigen-binding activity, obtained by digesting the portion below two disulfide bonds in the hinge region of IgG with the enzyme pepsin and comprising two Fab regions linked at the hinge position. Fab' is an antibody fragment having a molecular weight of about 50,000 and having antigen-binding activity obtained by cleaving the disulfide bond of the hinge region of the above-mentioned F(ab')2. Furthermore, the Fab' fragment of the antibody can be produced by inserting a DNA encoding the Fab' fragment into a prokaryotic expression vector or a eukaryotic expression vector and introducing the vector into a prokaryotic or eukaryotic organism to express the Fab'. The term "single-chain antibody", "single-chain Fv" or "scFv" means a molecule comprising an antibody heavy chain variable domain (or region; VH) and an antibody light chain variable domain (or region; VL) connected by a linker. Such scFv molecules may have the general structure: NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH. Suitable prior art linkers consist of repeated GGGGS amino acid sequences or variants thereof, for example using variants with 1-4 repeats (Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90: 6444-6448). Other linkers useful 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 that mainly contribute to antigen binding in the variable domain of an antibody. One of the most commonly used definitions of the six CDRs is provided by Kabat EA 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. Typically, 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 a CDR can be determined using any of a variety of well-known schemes, including the "Kabat" numbering convention (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 convention (see Al-Lazikani et al., (1997) JMB 273:927-948), and the ImMunoGenTics (IMGT) numbering convention (see Lefranc MP, Immunologist, 7, 132-136 (1999); Lefranc, MP 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 residues in VH are numbered 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. The IMGT convention was followed. Then, the CDR amino acid residues in VH are numbered approximately as 26-35 (CDR1), 51-57 (CDR2) and 93-102 (CDR3), and the CDR amino acid residues in VL are numbered approximately as 27-32 (CDR1), 50-52 (CDR2) and 89-97 (CDR3). Following the IMGT rules, the CDR regions of antibodies can be determined using the program IMGT / DomainGap Align. The term "antibody framework" refers to a portion of a variable domain VL or VH that serves as a scaffold for the antigen binding loops (CDRs) of the variable domain. Essentially, it is a variable domain without CDRs. "Binding to IL-4R" means being able to interact with human IL-4R (or its epitope, fragment). The term "antigen binding site" herein refers to the three-dimensional site recognized by the antibody or antigen binding fragment herein. The term "epitope" or "antigenic determinant" refers to the site on an antigen to which an immunoglobulin or antibody specifically binds. An epitope typically includes at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 continuous or non-continuous 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 "specific binding", "selective binding", "selectively binds" and "specifically binds" refer to the binding of an antibody to a predetermined epitope on an antigen. -7 M, for example: approximately less than 10 -8 M, 10 -9 M or 10 -10 Binds with an affinity (KD) of 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 it is placed in 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 connected thereto. In one embodiment, the vector is a "plasmid", which refers to a circular double-stranded DNA loop into which other DNA segments can be connected. In another embodiment, the vector is a viral vector, in which other DNA segments can be connected to the viral genome. The vector disclosed herein can be autonomously replicated in the host cell introduced therein (e.g., bacterial vectors and additional mammalian vectors with a bacterial origin of replication) or can be integrated into the genome of the host cell after being introduced into the host cell, thereby replicating with the host genome (e.g., non-additional mammalian vectors). Methods for producing and purifying antibodies and antigen-binding fragments are well known in the prior art, such as the Cold Spring Harbor Manual of Antibody Laboratory Technology, 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 region. Human FR germline sequences can be obtained from the ImMunoGeneTics (IMGT) website http: / / imgt.cines.fr by comparing the IMGT human antibody variable region germline gene database and MOE software, or from the Journal of Immunoglobulins, 2001 ISBN012441351. The term "host cell" refers to a cell into which an expression vector has been introduced. Host cells may include bacteria, microorganisms, plants or animal cells. Easily transformed bacteria include members of the family 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 disclosed herein can be prepared and purified by conventional methods. For example, cDNA sequences encoding heavy and light chains can be cloned and recombined into GS expression vectors. The recombinant immunoglobulin expression vector can be stably transfected into CHO cells. As a more recommended prior art, mammalian expression systems lead to glycosylation of antibodies, especially at the highly conserved N-terminal site of the Fc region. Positive clones are expanded in serum-free culture medium in a bioreactor to produce antibodies. The culture fluid that secretes antibodies can be purified by conventional techniques. For example, purification is performed using an A or G Sepharose FF column containing an 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 using conventional methods. Soluble mixtures and polymers can also be removed using conventional methods, such as molecular sieves and ion exchange. The resulting product must 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, while aligning the amino acid sequences and, if necessary, introducing gaps to achieve maximum sequence identity percentage, and not considering any conservative substitutions as part of the sequence identity. For the purpose of determining the percentage of amino acid sequence identity, alignment can be achieved in a variety of ways within the scope of the art, for example, 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 alignment, including any algorithm required to achieve maximum alignment over the full length of the compared sequences. 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, e.g., with sufficient affinity, such that the antibody can be used as a therapeutic agent targeting IL-4R. The extent of binding of the anti-IL-4R antibody to unrelated, non-IL-4R proteins can be less than about 10% of the binding of the antibody to IL-4R as measured, e.g., 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. It is composed of two or more amino acid molecules connected to each other by peptide bonds. It is a structural and functional fragment of protein. Hormones, enzymes, etc. are essentially peptides. The term "sugar" refers to a biological macromolecule composed of three elements: C, H, and O, which can be divided into monosaccharides, disaccharides, and polysaccharides. "Pharmaceutical composition" means a mixture containing one or more 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, promote administration to the organism, and facilitate the absorption of the active ingredient to exert biological activity. In the present disclosure, "pharmaceutical composition" and "formulation" are not mutually exclusive. The pharmaceutical compositions described in the present disclosure are in the form of solutions, and unless otherwise specified, the solvent therein is water. "Lyophilized preparation" refers to a pharmaceutical composition in liquid or solution form or a preparation or pharmaceutical composition obtained after a liquid or solution preparation has been subjected to a vacuum freeze-drying step. As used herein, the terms "about" and "approximately" refer to values ​​within an acceptable error range for a particular value determined by one of ordinary skill in the art, which depends in part on how it is measured or determined (i.e., the limitations of the measurement system). For example, "about" can mean within 1 or more than 1 standard deviation per practice in the art. Alternatively, "about" or "substantially comprising" can mean a range of up to 20%. Furthermore, particularly with respect to biological systems or processes, the term can mean up to one number. Unless otherwise stated, when specific values ​​appear in the application and claims, the meaning of "about" or "substantially including" should be assumed to be within an acceptable error range for the specific value. The numerical values ​​in this disclosure are instrumental measurements or calculated values ​​after instrumental measurements, and there is a certain degree of error. Generally speaking, plus or minus 10% is within the reasonable error range. Of course, the context in which the numerical value is used needs to be considered. For example, the total impurity content, which is a value with an error change of no more than plus or minus 10% after measurement, 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 event or environment described later can but need not occur, and the description includes occasions where the event or environment occurs or does not occur. For example, "optionally comprising 1-3 antibody heavy chain variable regions" means that the antibody heavy chain variable region of a specific sequence can but does not have to be present. "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds. The preparation of conventional pharmaceutical compositions is described in the Chinese Pharmacopoeia. "Administering" and "treating" as applied to an animal, a human, a laboratory subject, a cell, a tissue, an organ, or a biological fluid, refers to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, a human, a subject, a cell, a tissue, an organ, or a biological fluid. "Administering" and "treating" can refer to, for example, treatment, pharmacokinetics, diagnosis, research, and experimental procedures. Treatment of cells includes contact of an agent with a cell, and contact of an agent with a fluid, wherein the fluid is in contact with the cell. "Administering" and "treating" also mean in vitro and ex vivo treatment of, for example, a cell by an agent, a diagnostic, a combination composition, or by another cell. "Treatment" as applied to humans, veterinary medicine, or research subjects refers to therapeutic treatment, prophylactic or preventative measures, research and diagnostic applications. "Treatment" means administering an internal or external therapeutic agent, such as a composition comprising any of the binding compounds of the present disclosure, to a patient who has one or more symptoms of a disease for which the therapeutic agent is known to have a therapeutic effect. Typically, the therapeutic agent is administered in an amount effective to alleviate one or more symptoms of the disease in the treated patient or population to induce regression of such symptoms or inhibit the development of such symptoms to any clinically measurable degree. The amount of therapeutic agent effective to alleviate any specific disease symptom (also referred to as a "therapeutically effective amount") may vary according to a variety of factors, such as the patient's disease state, age, and weight, and the ability of the drug to produce the desired therapeutic effect in the patient. Whether the disease symptom has been alleviated can be evaluated by any clinical test method commonly used by physicians or other professional health care personnel to evaluate the severity or progression of the symptom. Although embodiments of the present disclosure (e.g., treatment methods or articles of manufacture) may not be effective in alleviating every symptom of the target disease, they should alleviate the target disease symptoms in a statistically significant number of patients as determined by any statistical test known in the art, such as Student's t-test, chi-square test, U test according to Mann and Whitney, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test. An "effective amount" includes an amount sufficient to ameliorate or prevent symptoms or conditions of a medical disease. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the type of The condition being treated, the patient's overall health, the method and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or administration regimen that avoids significant side effects or toxic effects. "Displacement" refers to the replacement of the solvent system for dissolving the antibody protein or antibody drug conjugate, for example, using the buffer system of the stable preparation to replace the high salt or hypertonic solvent system containing the antibody protein or antibody drug conjugate by physical manipulation, so that the antibody protein or antibody drug conjugate is present in the stable preparation. The so-called physical manipulation method includes but is not limited to ultrafiltration, dialysis or centrifugation followed by re-dissolution. DETAILED DESCRIPTION The present disclosure is further described below in conjunction with the examples, but these examples are not intended to limit the scope of the present disclosure. Experimental methods in the examples of the present disclosure that do not specify specific conditions are usually carried out under conventional conditions, or under conditions recommended by raw material or product manufacturers, such as the Antibody Technology Laboratory Manual and Molecular Cloning Manual published by Cold Spring Harbor Laboratory; or under conditions recommended by raw material or product manufacturers. Reagents that do not specify specific sources are conventional reagents purchased from the market. NMR shift (δ) was 10 -6 The NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, and the solvent used was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS). MS was measured using a Shimadzu 2010 Mass Spectrometer or an Agilent 6110A MSD mass spectrometer. HPLC determination was performed using Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent 1200 LC high pressure liquid chromatograph (Ultimate XB-C18 3.0*150mm column or Xtimate C18 2.1*30mm column1. Chiral HPLC analysis was performed using Chiralpak IC-3 100×4.6mm ID, 3um, Chiralpak AD-3 150×4.6mm ID, 3um, Chiralpak AD-3 50×4.6mm ID, 3um, Chiralpak AS-3 150×4.6mm ID, 3um, Chiralpak AS-3 100×4.6mm ID, 3μm, ChiralCel OD-3 150×4.6mm ID.3um, Chiralcel OD-3 100×4.6mm ID, 3μm, ChiralCel OJ-H 150×4.6mm ID.5um, Chiralcel OJ-3 150×4.6mm ID, 3um chromatographic column; thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specification of silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification of thin layer chromatography separation and purification product is 0.4mm~0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier. The chiral preparative column used was DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um) or Phenomenex-Amylose-1 (250 mm*30 mm, 5 um). The CombiFlash rapid preparation instrument used was Combiflash Rf150 (TELEDYNE ISCO). Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany). The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies. Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere. Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L. Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L. The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator. The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times. The microwave reaction was carried out using 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, 20°C to 30°C. The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of 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 solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment. Preparation of 1.0M Tris buffer pH=8.30±0.1: Weigh 6.0 g of tris into 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 to volume with purified water. Preparation of Buffer A: In a 2.0L container, add KH2PO4 (8.50g), K2HPO4 (8.56g), NaCl (5.86g) and EDTA (1.50g), add 1.6L of water for injection, stir for half an hour, and after complete dissolution, dilute to 2.0L with water for injection. The pH is measured to be 6.30±0.1. The abbreviations used in the following experiments have the following meanings: DAST: diethylaminosulfur trifluoride; THF: tetrahydrofuran; NMP: N-methylpyrrolidone; DCM: dichloromethane; m-CPBA: m-chloroperbenzoic acid; DIEA: N,N-diisopropylethylamine; TEA: triethylamine; Boc: tert-butyloxycarbonyl, MeOH: methanol; Et2O: diethyl ether. The preparation and purification methods of 25G7 and 7B10 antibodies in this application have been recorded in the patent document with application number WO2020038454A1, and the preparation methods of 25G7-Fab and ADC have been recorded in the patent document with application number PCT / CN2023 / 073057. All contents of the aforementioned application documents are introduced into the present 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-bromoacetylamino)-3,6,9,12-tetraoxopentadecane-15-amide (Compound 1) Step 1) (((9H-fluoren-9-yl)methoxy)carbonyl)glycylglycyl-L-phenylalanine tert-butyl ester (Compound 1b) Preparation 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. Ice-cooled, HATU (9.12 g, 24.0 mmol, 1.2 eq) and DIEA (7.74 g, 60.0 mmol, 3.0 eq) were added, and the reaction was kept in an ice bath for 2 hours. Water was added to the reaction solution, and ethyl acetate was extracted. 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 can be directly used in the next step. MS (ESI): m / z 580.3 [M+Na] + . 1 H NMR (400MHz, 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, anhydrous DCM (60 mL) was added to dissolve, and then cooled in an ice bath. Piperidine (8.5 g, 100.0 mmol, 10.0 eq) was slowly added, and after the addition, the 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-pentaoxo-4-tetraethylene glycol-19-oxy)glycylglycyl-L-phenylalanine tert-butyl ester (Compound 1d) Add raw materials 1-(9H-fluorene-9-yl)-3-oxo-2,7,10,13,16-pentaoxo-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) into a 100 mL three-necked flask, add anhydrous DMF (25 mL) to dissolve, and cool in an ice bath. Add HATU (1.01 g, 2.67 mmol, 1.3 eq) and DIEA (529 mg, 4.10 mmol, 2.0 eq), and keep the reaction in an ice bath for 1 hour. Add water to the reaction solution, extract with ethyl acetate, wash with saturated brine, dry and concentrate 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-pentaoxo-4-tetraethylene glycol-19-oxy)glycylglycyl-L-phenylalanine (Compound 1e) Compound 1d (1.60 g, 1.99 mmol, 1.0 eq) was added to a 100 mL single-mouth bottle, and anhydrous dichloromethane (16 mL) was added to dissolve. Trifluoroacetic acid (8 mL) was added at room temperature, and the reaction was stirred for 2 hours. The reaction solution was directly concentrated to dryness, ethyl acetate was added to dissolve, 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] + . Step 5 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]dioxolan-8b-yl)-2-oxoethoxy)methyl)amino)-2-oxoethyl)carbamate (Compound 1f) The raw materials budesonide (1.29 g, 3.0 mmol, 1.0 eq) and (2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)acetamido)acetate (1.16 g, 3.15 mmol, 1.0 eq; prepared by the method of reference "Tetrahedron, 2018, 74 (15), 1951-1956") and p-toluenesulfonic acid pyridinium salt (75 mg, 0.30 mmol, 0.1 eq) were added to a 100 mL three-necked flask. Anhydrous tetrahydrofuran (20 mL) was added at room temperature and the mixture was heated under reflux for 4 hours. The reaction solution was directly concentrated to dryness, and the crude product was purified by column chromatography to obtain 1f (0.54 g, 24% yield). MS (ESI): m / z 739.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) 68.76-8.69 (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=7.5Hz, 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]dioxolan-8b-yl)-2-oxoethoxy)methyl)acetamide (Compound 1g) Compound 1f (540 mg, 0.73 mmol, 1.0 eq) was placed in a 25 mL single-mouth bottle, and anhydrous dichloromethane (10 mL) was added to dissolve. Cooled in an ice bath, DBU (167 mg, 1.10 mmol, 1.5 eq) was added, and the reaction was stirred for 30 minutes. Water was added to separate, and the aqueous phase was extracted twice with dichloromethane, washed with saturated brine, and concentrated under reduced pressure to obtain compound 1g (450 mg, 100% yield). The crude product can be directly used in the next step 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]dioxolan-8b-yl)-1,6,9,12,15,18-hexaoxo-3,21,24,27,30-pentaoxo-5,8,11,14,17-pentahydrotriacontan-32-yl)carbamate (Compound 1h) Compound 1g (0.45g crude product, equivalent to 0.73mmol, 1.0eq) and 1e (0.55g, 0.73mmol, 1.0eq) were placed in a 100mL three-necked flask, and anhydrous DMF (9mL) was added to dissolve. Ice bath cooling was followed by the addition of HATU (361mg, 0.95mmol, 1.3eq) and DIEA (189mg, 1.46mmol, 2.0eq), and the reaction was stirred for 1 hour. Water was added to the reaction solution, and the mixture was extracted twice with dichloromethane. The organic phases were combined, washed once with saturated brine, dried and concentrated under reduced pressure to obtain a crude product. The crude product was purified by slurrying in a mixed solvent of petroleum ether and ethyl acetate to obtain compound 1h (710mg, 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-polytetraethylene glycol-16-yl-3,6,9,12-tetraoxopentadecane-15-amide (Compound 1i) Compound 1h (350 mg, 0.28 mmol, 1.0 eq) was placed in a 25 mL single-necked bottle, and anhydrous dichloromethane (10 mL) was added to dissolve. Cool in an ice bath, and DBU (64 mg, 0.42 mmol, 1.5 eq) was added. The reaction was stirred for 1 hour. The reaction solution was then 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-bromoacetylamino)-3,6,9,12-tetraoxopentadecane-15-amide (Compound 1) Bromoacetic acid solid (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 anhydrous DMF (5 mL) was added to dissolve. 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 the solution was added dropwise to the active ester solution prepared above, and the reaction was maintained at room temperature for 2 hours. Water was added to the reaction system, and ethyl acetate was extracted twice. The organic phases were combined, 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 (400MHz, CDCl3) δ8.62-8.57 (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=9.6Hz, 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), 3.06-2.8 4(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). Embodiment 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 Step 1) 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-mouth bottle, and 4 M HCl 1,4-dioxane solution (20 mL) was added to dissolve. Stirring was maintained at room temperature for 4 hours until the reaction of raw material 1b was complete. 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] + Step 2 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 1g (1.0 g, 1.95 mmol, 1.2 eq) were placed in a 100 mL three-necked flask. DMF (20 mL) was added and 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 in sequence. After the addition was complete, the reaction was maintained in an 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] + Step 3 Preparation of (2S)-2-(2-(2-aminoacetylamino)acetylamino-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 bottle, and anhydrous DMF (10 mL) was added to dissolve it. The mixture was cooled in an ice bath, and DBU (196 mg, 1.29 mmol, 1.5 eq) was added, and the reaction was stirred 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] + Step 4) N-((10S)-10-benzyl-1-((6aR,6bS,7S,8aS,8bS,11aR,12aS,12bS)-7-hydroxy-6a,8a-dimethyl-4-oxo-10-propyl-1-1,2,4,6a,6b,7,8,8a,11a,12,12a,12b-dodecahydro-8bH-naphtho[2′,1 Preparation of 4,5-dioxo-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 (Compound 2d) Compound 2c (480 mg, 0.62 mmol, 1.0 eq) and 1-(2,5-dioxy-2,5-dihydro-1H-pyrrol-1-yl)-3,6,9,12-tetraoxoglutaric acid-15-oleic 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. 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 in sequence, 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 (400MHz, DMSO-d6) 68.61-8.56 (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: 25G7-Fab protein preparation process The gene sequence of the synthetic antibody was subcloned into the pcDNA3.4 vector. The ligation product was transformed into Top10 competent cells, and the positive clones were picked for expansion and culture. The clones were inoculated in the culture medium for expansion and culture, and the plasmid containing the DNA sequence of the 25G7-Fab antibody was extracted in large quantities. The expression plasmid was mixed with the transfection reagent by liposome transfection, added to Expi 293 cells, and the cell culture was harvested after 5 days of culture in a constant temperature incubator. The cell culture was centrifuged and the supernatant was taken, the cell debris was filtered to remove the clear liquid, and the target protein was captured using a kappa select chromatography column. The target protein was filtered, and the A280 absorbance value was measured by Nanodrop and divided by the extinction coefficient to obtain the protein concentration, which was multiplied by the volume to determine the final yield. The protein was subjected to SDS-PAGE, SEC-HPLC and endotoxin detection by gel electrophoresis and size exclusion chromatography, and the final product was 25G7-Fab. Example 4: AZD1402-TAG protein preparation process AZD1402-TAG (the protein sequence comes from SEQ ID NO1 in patent WO2020200960A1. In order to facilitate protein preparation and purification, a His tag was fused to the C-terminus of the sequence and 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. The expression plasmid was mixed with the transfection reagent and incubated at 37°C for 15 minutes. The mixture was added dropwise to the HEK293 cell solution. After the cell solution was cultured on a shaker at 37°C for one week, the cell culture was centrifuged and the supernatant was taken. The nickel affinity chromatography column was equilibrated with an imidazole-free buffer, and then the protein sample was passed through the nickel affinity chromatography column for loading. After equilibration with an imidazole-free buffer again, the column-bound protein 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 and replaced with PBS storage buffer. After detection, the target protein was obtained. Example 5: Preparation of Antibody Drug Conjugate ADC-1 Preparation of Buffer A: In a 2.0L container, add KH2PO4 (8.50g), K2HPO4 (8.56g), NaCl (5.86g) and EDTA (1.50g), add 1.6L water for injection, stir for half an hour, and after complete dissolution, dilute to 2.0L with water for injection. The pH is measured to be 6.30±0.1. At 37°C, a prepared aqueous solution of tris(2-carboxyethyl)phosphine (TCEP) (2.5 mM, 100.0 uL, 0.250 mmol) was added to a buffer A aqueous solution (0.05 M buffer solution at 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) and placed in a water bath shaker, and the reaction was oscillated at 37°C for 3 hours to stop the reaction. The reaction solution was cooled to 25°C using a water bath. 1.0M Tris buffer (50uL) was added to the above reaction solution, and compound 1 (1.43mg, 1.250mmol) was dissolved in 25ul DMSO, added to the above reaction solution, placed in a water bath shaker, and oscillated at 25°C for 3 hours to stop the reaction. 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 the buffer A buffer (6.06mg / mL, 0.60mL) of the title product ADC-1, which was stored frozen at 4°C. Example 6: Preparation of Antibody Drug Conjugate ADC-2 At 37°C, add the prepared aqueous solution of tris(2-carboxyethyl)phosphine (TCEP) (10.0 mM, 1.50 mL, 15.0 mmol) to the buffer A buffer solution (0.05 M buffer solution with pH=6.3; 10.0 mg / ml, 6.0 mL, 1.50 mmol) of antibody 25G7-Fab, place in a water bath shaker, shake at 37°C for 3 hours, and stop the reaction. Cool the reaction solution to 25°C in a water bath. Compound 2 (12.2 mg, 12.0 mmol) was dissolved in 300 ul DMSO, added to the above reaction solution, placed in a water bath shaker, and oscillated at 25°C for 3 hours to stop the reaction. The reaction solution was desalted using a Sephadex G25 gel column. The title product ADC-2 in buffer A (3.65 mg / mL, 12.8 mL) was purified (elution phase: buffer A) and concentrated using an ultrafiltration tube and stored in a frozen state at 4°C. Biological evaluation The present disclosure is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present disclosure. Test Example 1: Affinity detection of antibody drug conjugate ADC-2 and human IL-4Rα protein 1. Test protein Antibody drug conjugate ADC-2, 25G7-Fab, AZD1402-TAG 2. Experimental methods Surface plasmon resonance (SPR) was used to detect the affinity of antibody-drug conjugates ADC-2, 25G7-Fab and AZD1402-TAG to human IL-4Rα antigen protein. SA sensor chip (Cytiva) was placed in Biacore 8K (Cytiva), and human IL-4Rα protein (SinoBiological, CAT#10402-H08H-B) labeled with Biotin was captured on the SA sensor chip. The mobile phase was HBS-EP+ buffer solution (10mM HEPES, 150mM NaCl, 3mM EDTA, 0.05% surfactant P20). Each test protein was diluted 2 times with HBS-EP+ buffer solution and injected as an analyte. The flow rate was set to 30μL / min. The detection time of ADC-2, 25G7-Fab and AZD1402-TAG was 100 seconds for binding and 600 seconds for dissociation. Biacore 8K evaluation software (Cytiva) was used for analysis to obtain the affinity data of each tested protein. 3. Experimental results Table 1 Affinity KD values ​​of the tested proteins binding to human IL-4Rα protein The results are shown in Table 1. The KD value of ADC-2 binding to human IL-4Rα antigen protein was 11.0 pM, which was slightly better than that of AZD1402-TAG and 25G7. - Fab. Test Example 2: Whole-cell binding activity of antibody-drug conjugate ADC-2 with human IL-4Rα expressing cells 1. Test protein Antibody drug conjugate ADC-2, 25G7-Fab, hu25G7 (the heavy chain sequence is shown in SEQ ID NO: 9, the light chain sequence is shown in SEQ ID NO: 10), AZD1402-TAG. 2. Experimental methods TF-1 and Karpas 299 cell lines were identified to express IL-4Rα. TF-1 and Karpas 299 cells in the logarithmic growth phase were collected, counted, and the cell density was adjusted to 1×10 5Cells / well were inoculated into a round-bottom 96-well plate. 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, and the antibodies were washed away with FACS Buffer (PBS containing 2% FBS). Fluorescently labeled secondary antibodies were used for staining. 25G7-Fab, hu25G7 and ADC-2 were stained with FITC-conjugated anti-human IgG (Fab specific) secondary antibodies (Sigma, CAT#F5512-1ML), and AZD1402-TAG was stained with FITC-conjugated anti-His antibody (GenScript, CAT#A01620). The cells were incubated with the secondary antibodies at 4°C for 30 minutes, then washed twice with FACS Buffer, and detected by flow cytometry (BD, FACS Celesta). The detection results were analyzed using FlowJo (FlowJo, LLC) software. 3. Experimental results Table 2 EC binding activity of the tested proteins to whole-cell human IL-4Rα expressing cells 50 value The results are shown in Figure 1 and Table 2. ADC-2 binds to the EC of TF-1 cells. 50 The value was 0.107nM, which was comparable to naked antibody 25G7-Fab and hu25G7. AZD1402-TAG had a strong binding effect on TF-1 cells, but due to the different detection antibodies, the data were not comparable with ADC-2, 25G7-Fab, etc. Test Example 3: Blocking effect of antibody drug conjugate ADC-2 on IL-4 / IL-13 signaling pathway 1. Test protein Antibody drug conjugate ADC-2, 25G7-Fab. 2. Experimental methods STAT6 activation 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 determined by HEK-Blue TM The IL-4 / IL-13 reporter gene cell line was evaluated. The cells were purchased from Invivogen (Cat#hkb-i1413), in which the human STAT6 gene and the secreted alkaline phosphatase reporter gene (Secreted alkaline phosphatase, SEAP) induced by phosphorylated STAT6 were overexpressed. The SEAP substrate QUANTI-Blue was used to detect the content of SEAP secreted in the cell culture supernatant to evaluate the activation level of the IL-4 / IL-13 signaling pathway. HEK-Blue in the logarithmic growth phase TM After IL-4 / IL-13 cells were collected, the density was adjusted to 5×10 5 cells / ml, 100 μL per well was added to a 96-well flat-bottom culture plate, and cultured at 37°C, 5% CO2 for 24 hours, and then 20 μL of gradient diluted test protein and 20 μL of recombinant human IL-4 or IL-13 were added to each well, and the cell culture plate was placed in a 37°C, 5% CO2 incubator for further incubation for 20 to 24 hours. After the culture was completed, the cell culture plate was removed, 20 μL of cell culture supernatant was aspirated from each well and transferred to another 96-well plate, 180 μL / well of QUANTI-Blue colorimetric solution preheated at 37°C was added, and after incubation at 37°C for 1 hour, the light absorption value at a wavelength of 620 nm was detected. 3. Experimental results Table 3 IC of the tested proteins blocking the IL-4 / IL-13 signaling pathway 50 value The results are shown in Figure 2 and Table 3. Each of the tested proteins had a blocking effect on the activation of STAT6 induced by recombinant human IL-4 and IL-13. The IC of ADC-2 blocking the IL-4 signaling pathway was 50 The value was 0.68 nM, which is similar to the IC 50 The value is close to 0.61nM; the IC value of ADC-2 blocking IL-13 signaling pathway 50 The value was 10.60 nM, which is comparable to the IC 50 The value is equivalent to 14.59nM. Test Example 4: Endocytosis activity of antibody drug conjugate ADC-2 in TF-1 cells 1. Test protein Antibody drug conjugate ADC-2, 25G7-Fab, hu25G7, AZD1402-TAG. 2. Experimental methods The TF-1 cells with good growth status were collected and the density was adjusted to 1×10 6cells / mL, 100 μL / well was added to a 96-well cell culture plate and placed at 4°C, and each test protein was added at a final concentration of 2 nM. After incubation at 4°C for 1 hour, it was placed in a cell culture incubator at 4°C for minutes and continued to be cultured under 5% CO2. A single culture plate was set at each time point. During the period, the culture plate was taken out according to different incubation times, washed with FACS buffer and centrifuged, and then fluorescently labeled secondary antibodies were added for incubation. 25G7-Fab, hu25G7 and ADC-2 were labeled with FITC-conjugated anti-human IgG (Fab-specific) secondary antibodies, and AZD1402-TAG was labeled with FITC-conjugated anti-His antibodies. The cells were incubated with the secondary antibody at 4°C for 30 minutes, then washed twice with FACS Buffer, and detected by flow cytometry (BD, FACS Celesta). The detection 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. Each tested protein can detect its endocytosis signal in TF-1 cells. The endocytosis activity of ADC-2 and hu25G7 is comparable, with an endocytosis rate of about 70% within 3 hours; 25G7-Fab has a faster endocytosis and a higher endocytosis rate. Compared with AZD1402-TAG, the endocytosis rate and endocytosis rate of ADC-2, 25G7-Fab and hu25G7 are significantly better than AZD1402-TAG, reaching a platform in about 2 hours, and the endocytosis activity of ADC-2 is slightly weaker than that of 25G7-Fab. Test Example 5: Pharmacokinetic test of antibody drug conjugate ADC-2 in mouse model 1. Test protein Antibody Drug Conjugate ADC-2 2. Experimental methods 2.1 Experimental animals C57BL6 / J mice, 8 weeks old, male, Saiye (Suzhou) Biotechnology Co., Ltd. 2.2 Drug administration in mice Mice received intratracheal aerosol administration (it), and 300-400 μL of blood was collected from the jaw at different time points after administration. After standing for 2 hours, the blood was centrifuged at 7500 rpm and 4°C for 10 minutes to collect serum. After being drunk and fixed, the neck muscles of the mice were bluntly separated to expose the trachea. The trachea was opened laterally, and the lavage needle was slowly inserted. The pre-drawn 4°C pre-cooled saline was slowly pushed into the lung tissue for lavage, and the alveolar lavage fluid (BALF) was collected. A total of 3 lavages were performed, with 300 μL of saline used for the first two lavages and 400 μL used for the third lavage. The collected alveolar lavage fluid was centrifuged at 1000 rpm and 4°C for 10 minutes, and the supernatant was collected. After euthanizing the mice, the mouse chest cavity was opened, the complete mouse lung tissue was separated and collected, the blood stains on the surface of the lung tissue were washed off with PBS, and the lung tissue was weighed after the surface PBS was dried with a paper towel. The lung tissue was placed in a 2 mL centrifuge tube, 1 mL of cell lysis buffer (CST, #9803) was added, and the homogenizer (Shanghai Jing Xin, Tissuelyser-48) was used to grind for 2 min at 60 Hz, and then centrifuged at 10,000 × g at 4 ° C for 10 min. The supernatant was the lung tissue homogenate, and the protein concentration of the homogenate was detected (Pierce, 23227). Serum, BALF and lung tissue homogenate were stored at -80 ° C. The dosing regimen is shown in Table 4, and the sampling regimen is shown in Table 5. Table 4 Dosage regimen Table 5 Sampling plan 2.3 ADC-2 content detection (1) Coating: Dilute the antigen hIL-4Rα to 1 μg / mL (Acro, ILR-H5221) with carbonate buffer, add 100 μL to each well of the ELISA plate, and incubate at 4°C overnight (16-18 h). (2) Washing: The ELISA plate was returned to room temperature, and 300 μL of 0.05% PBST (PBS+0.05% Tween20) buffer was added to each well for washing. The plate was washed 3 times in total. (3) Blocking: Add 300 μL of PBS containing 3% BSA to each well and incubate at room temperature at 400 rpm for 2 h. (4) Washing: Add 300 μL of 0.05% PBST to each well and wash the plate three times. (5) Sample incubation: Add 100 μL of diluted serum, BALF or lung tissue homogenate to the ELISA plate and incubate at room temperature at 400 rpm for 1.5 h. (6) Washing: Add 300 μL of 0.05% PBST to each well and wash the plate three times. (7) Detection: The detection antibody (Invitrogen, A18811) was diluted 10,000-fold with assay buffer (0.05% PBST containing 0.5% BSA) and added to the ELISA plate, 100 μL per well, and incubated at room temperature for 1 h with shaking at 400 rpm. (8) Washing: Add 300 μL of 0.05% PBST to each well and wash the plate three times. (9) Color development: Add 100 μL 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 detect the light absorbance at a wavelength of 620 nm. 2.4 Detection of free Budesonide content 30 μL of serum, BALF or lung tissue homogenate was taken, 30.0 μL of internal standard working solution (5.00 ng / mL budesonide-D8) and 120 μL of acetonitrile were added, vortexed for 1 min, centrifuged at 13,000 rpm and 4 °C for 5 min, 100 μL of supernatant was taken to a 96-well plate, 100 μL of 0.3% FA diluent was added, and the plate was shaken at 1,000 rpm and incubated at room temperature for 15 min. 20 μL was taken for LC-MS / MS analysis (Shimadzu, Shimadzu liquid chromatography system; AB Sciex, Triple Quad 6500, Shimadzu, Japan) + triple quadrupole tandem mass spectrometer). 3. Experimental results The pharmacokinetic parameters of 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 showed that after intratracheal administration of antibody-drug conjugate ADC-2, the drug was mainly distributed in serum and BALF, with low serum exposure. The exposure of Budesonide in various tissues was very low. Test Example 6: In vivo efficacy of ADC-2 in OVA-induced mouse asthma model 1. Test substance 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, Saiye (Suzhou) Biotechnology Co., Ltd. 2.2 Drug administration in mice The animals were randomly divided into normal control animals and modeling animals. On Day 0, 7 and 14, 100 μL of PBS solution containing 200 μg OVA (Sigma, A5503) was intraperitoneally injected, and the mice were sensitized using an equal volume of aluminum hydroxide as an adjuvant. On Day 21-27, the mice inhaled a 3% OVA aerosol solution once a day for 35 minutes each time. Starting on 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 separated to expose the trachea. The trachea was opened laterally, and the lavage needle was slowly inserted. The pre-drawn 4°C pre-cooled saline was slowly pushed into the lung tissue for lavage, and the alveolar lavage fluid was collected. A total of 3 lavages were performed, with 300 μL of saline used for the first two lavages and 400 μL used for the third lavage. The cells were centrifuged at 1,000 rpm and 4°C for 10 min. The cell pellet was resuspended with 350 μL of pre-cooled saline and then centrifuged with an automatic blood flow analyzer. The white blood cell and cell type analysis were performed by liquid analyzer. Table 7 Dosage regimen 2.3 Experimental indicators The number of white blood cells and cell types in BALF. 2.4 Statistical analysis Unless otherwise specified, the cell counts between the two groups were compared using the one-way ANOVA test, and p < 0.05 was defined as a statistically significant difference. 3. Experimental results The experimental results are shown in Figure 5. Compared with the modeling group, at an equimolar dose, the antibody-drug conjugate ADC-2 significantly reduced the number of leukocytes, eosinophils and neutrophils in BALF, and also inhibited the number of monocytes to a certain extent. The efficacy was better than AZD1402-TAG, and significantly better than 25G7-Fab and Budesonide. ADC-2 showed the synergistic effect of 25G7-Fab and Budesonide in terms of efficacy. Test Example 7: Dose exploration of the in vivo efficacy of ADC-2 in the OVA-induced mouse asthma model 1. Test substance 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, Saiye (Suzhou) Biotechnology Co., Ltd. 2.2 Drug administration in mice The drug administration and BALF sampling operations were the same as those in Test Example 6. The specific drug administration scheme is shown in Table 8. Table 8 Dosage regimen 2.3 Experimental indicators The number of white blood cells and cell types in BALF. 2.4 Statistical analysis Unless otherwise specified, the cell counts between the two groups were compared using the one-way ANOVA test, and p < 0.05 was defined as a statistically significant difference. 3. Experimental results The experimental results are shown in Figure 6. Compared with the modeling group, 10μg ADC-2 can significantly reduce the number of eosinophils in the alveolar lavage fluid, which is equivalent to AZD1402-TAG and slightly better than budesonide, which is far higher than the clinical equivalent dose. In addition, 10μg ADC-2 also has a very significant ability to inhibit the number of white blood cells, and also has a certain degree of inhibition on the number of monocytes and neutrophils. These results show that a 1 / 10 molar dose of ADC-2 can achieve an efficacy equivalent to that of AZD1402-TAG. Example 7: Preparation of inhalation dry powder ad Table 9 Composition of prescription ad Preparation process: 1) Add water to prepare an auxiliary material solution according to the prescription composition in Table 9, add the prescription amount of ADC-2 buffer (prepared in Example 6), gently stir evenly, add the prescription amount of isopropanol, and gently stir evenly (the pH can be adjusted with hydrochloric acid as needed); 2) Freeze drying. 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 determination results of inhaled dry powder ac The prepared drug-containing inhalation dry powder was filled into transparent HPMC capsules (No. 3) with a loading volume of 10 mg. The capsule samples were subjected to APSD testing using the NGI impactor of COPLEY Company in accordance with the provisions of the General Rules 0951 [Aerodynamic Properties of Fine Particles of Inhalation Preparations] of the 2015 edition of the Chinese Pharmacopoeia. The APSD distribution results at all levels were input into the CITDAS version 3.10 software (COPLEY) to obtain the FPF (<5μm), MMAD, GSD and other values. The results are shown in Table 11. Table 11 Inhaled dry powder aerodynamic particle size (APSD) test results The samples were placed under different stability test conditions, and the drug stability analysis was performed by SEC (size exclusion chromatography), and the results are shown in Table 12. The results showed that the monomer decrease in formulations c and d was the smallest during the stability process, and the addition of sodium citrate to the formulation made the macromolecular properties more stable. Table 12 Active ingredient purity determination (SEC) results (%) Example 8: Preparation of inhalation dry powders e, f, and g The same formulation composition and preparation method as formulation b in Example 7 were adopted, except that the amount of the organic solvent was adjusted, as shown in Table 13. Table 13 Amounts of water and isopropanol used in preparing inhalation dry powder e, f, g 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 14. Table 14 Geometric particle size measurement results of inhaled dry powder e, f, g Example 9: Preparation of dry powder hk for inhalation The same preparation and freeze-drying process as in Example 7 was used to prepare inhalation powder according to the prescription composition in Table 15. Table 15 Composition of prescription h~k 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 16. The results showed that the geometric particle size did not change much when the drug concentration increased from 2 mg / ml to 3.5 mg / ml. Table 16 Geometric particle size determination results of inhaled dry powder h~k The aerodynamic particle size determination method was the same as in Example 7, and the APSD results are shown in Table 17. The results showed that the drug concentration within the range of 2 to 3.5 mg / ml had little effect on the aerodynamic particle size results such as FPF and MMAD. Table 17 Inhaled dry powder aerodynamic particle size (APSD) test results Example 10: Observation of dry powder morphology after inhalation The morphology of inhalation dry powders c and f was observed using a scanning electron microscope (SEM), and the results are shown in Figures 7 and 8. It can be seen that inhalation dry powders c and f are both composed of several nano-scale smooth spheres. Example 11: Preparation of dry powder for inhalation of different specifications Preparation of inhalation dry powder m (0.4 mg): weigh the amount of histidine, sodium citrate and 0.06 mg trehalose, add water to prepare an auxiliary material solution, add the prescribed amount of ADC-2 buffer (prepared in Example 6), gently stir evenly, add the prescribed amount of isopropanol, and gently stir evenly. Prepare a lyophilized powder using the same lyophilization process as Example 7, add the remaining prescribed amount of trehalose as a filler, and fill it into hollow capsules of hypromellose. Preparation of inhalation dry powder n (2 mg specification): The same preparation and lyophilization process as in Example 7 was adopted to prepare inhalation powder m according to the prescription composition in Table 18, and directly filled into HPMC hollow capsules. Table 18 Composition of prescription m and n The aerodynamic particle size determination method is the same as in Example 7, and the APSD results are shown in Table 19. Table 19 Inhaled dry powder aerodynamic particle size (APSD) test results

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.

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