WO2024222838A1 - Pharmaceutical composition comprising drug conjugate containing glucocorticoid receptor agonist - Google Patents

Abstract

A pharmaceutical composition comprising a drug conjugate containing a glucocorticoid receptor agonist, comprising an antibody drug conjugate, a buffering agent, sugar, and a surfactant, wherein the antibody drug conjugate has the following structure: formula (I).

Description

A pharmaceutical composition containing a drug conjugate of a glucocorticoid receptor agonist Technical Field

The present invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition containing a drug conjugate of a glucocorticoid receptor agonist.

Background Art

Rheumatoid arthritis (RA) is a common type of arthritis and an autoimmune disease with an incidence rate of 0.3-1% in the population. If not treated in time, it can lead to bone destruction and joint damage. There are a variety of proinflammatory cytokines involved in the pathogenesis of RA, such as tumor necrosis factor-α (TNFα), interleukins such as IL-1, IL-6, IL-8, etc. Therefore, inhibiting the production of proinflammatory cytokines or blocking their physiological effects is a hot topic in the current RA research field. In recent years, many newly developed biological agents can control the progression of the disease by blocking or downregulating the activity of proinflammatory cytokines, such as TNFα inhibitors, anti-IL-6R antibodies, etc. It is currently believed that among the many cytokines of RA inflammatory reactions, TNFα is one of the most important proinflammatory cytokines, which plays an important role in the development of RA, local inflammatory reactions and tissue damage. Currently, the TNFα inhibitors approved by the US FDA include: soluble receptor antagonist - Etanercept, human-mouse chimeric antibody - Infliximab, fully human monoclonal antibody - Adalimumab, ), fully human monoclonal antibody Golimumab and PEGylated humanized Fab' fragment Certolizumab pegol. Despite their clinical success, TNFα inhibitors are still limited by the maximum efficacy they can achieve in patients, and more powerful and effective therapeutic agents need to be identified and developed. Patients treated with TNFα inhibitors may also develop immunogenic responses to the therapeutic agents, thereby limiting their effectiveness.

Glucocorticoid receptor agonists are also relatively effective medicines for treating rheumatoid arthritis. As representative glucocorticoid receptor agonists, glucocorticoid receptor agonists made in vivo by known cortisol, corticosterone, etc. and synthetic glucocorticoid receptor agonists such as dexamethasone, prednisone, and prednisolone. These glucocorticoid receptor agonists are owing to having steroid structure, and therefore are generally referred to as steroids, and are applied in the treatment of various diseases. But these steroids, due to their use, sometimes show side effects such as steroid peptic ulcer, steroid purpura, steroid pancreatitis, steroid diabetes, steroid cataract, steroid glaucoma.

Antibody drug conjugates (ADCs) are monoclonal antibodies or antibody fragments linked to biologically active drugs via stable chemical linker compounds. Most ADCs in preclinical and clinical development are used for oncology indications, where cytotoxic payloads target 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.

ADC has a more complex heterogeneous structure than antibodies, thus posing greater challenges to ADC preparations for therapeutic purposes. As of March 2022, a total of 14 ADCs have been approved worldwide. Considering stability issues, all ADC preparations are currently in the form of lyophilized powders rather than solutions.

Summary of the invention

The present disclosure provides a pharmaceutical composition comprising an antibody drug conjugate, a buffer, a sugar and a surfactant, wherein the antibody drug conjugate has a structure as shown in formula (I):

in:

Ab is adalimumab;

n is 1 to 10;

Wherein, based on the total amount of the antibody-drug conjugate, the content of the component with a compound DAR of 4 in the antibody-drug conjugate is greater than 80%.

In some embodiments, the range of average drug load (n) can be the average number of glucocorticoid receptor agonist drugs bound to each adalimumab antibody, and non-limiting examples include the average number of glucocorticoid receptor agonist drugs bound to each antibody as 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, n is 1 to 8, or 3 to 5.

In some embodiments, based on the total amount of the antibody drug conjugate, the content of the component with a compound DAR of 4 in the antibody drug conjugate is greater than 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%. The more components with a compound DAR of 4, the more conducive to the stability of the formulation.

In some embodiments, the buffer is selected from acetate buffer, citrate buffer, histidine buffer and succinate buffer. In some embodiments, the buffer is selected from acetic acid-sodium acetate, histidine-acetic acid, histidine-histidine hydrochloride, citric acid-sodium citrate, succinic acid-histidine and succinic acid-sodium succinate.

In some embodiments, the pH of the pharmaceutical composition is 3.5 to 6.0, 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 and 6.0, and any value between these points. In some embodiments, the pH is between 3.5 and 5.5, or the pH is between 3.7 and 5.2.

In some embodiments, the buffer concentration in the pharmaceutical composition is 1 mM to 50 mM, non-limiting examples include 1 mM, 3 mM, 5 mM, 10 mM, 12 mM, 15 mM, 16 mM, 17 mM, 18 mM, 19 mM, 20 mM, 30 mM, 40 mM, 50 mM and any range between these points; in some embodiments, the buffer and concentration are 1 mM to 30 mM; in some embodiments, the buffer and concentration are 5 mM to 20 mM; in some embodiments, the buffer and concentration is 15 mM.

In some embodiments, the pharmaceutical composition further comprises a surfactant. It can be selected from polysorbate, poloxamer, polyhydroxyalkylene, Triton, sodium dodecyl sulfate, sodium lauryl sulfate, sodium octyl glucoside, lauryl-sulfobetaine, myristyl-sulfobetaine, linoleyl-sulfobetaine, stearyl-sulfobetaine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine, stearyl-sarcosine, linoleyl-betaine, myristyl-betaine, cetyl-betaine, lauryl amide Propyl-betaine, cocamidopropyl-betaine, linoleamidopropyl-betaine, myristamidopropyl-betaine, palmitamidopropyl-betaine, isostearamidopropyl-betaine, myristamidopropyl-dimethylamine, palmitamidopropyl-dimethylamine, isostearamidopropyl-dimethylamine, methyl cocoyl sodium, methyl oleyl taurate sodium, polyethylene glycol, polypropylene glycol and copolymers of ethylene and propylene glycol, etc. In some embodiments, the surfactant is a poloxamer or a polysorbate, such as poloxamer 188, polysorbate 20, polysorbate 80.

In some embodiments, the concentration of the surfactant in the pharmaceutical composition is 0.01 mg/mL to 10 mg/mL, or 0.1 mg/mL to 8 mg/mL, or 0.3 mg/mL to 5 mg/mL. In some embodiments, the concentration of the surfactant is 1 mg/mL. Non-limiting examples include 0.02 mg/mL, 0.05 mg/mL, 0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4 mg/mL, 0.5 mg/mL, 0.6 mg/mL, 0.7 mg/mL, 0.8 mg/mL, 0.9 mg/mL, 1.0 mg /mL, 1.1 mg/mL, 1.2 mg/mL, 1.3 mg/mL, 1.4 mg/mL, 1.5 mg/mL, 1.6 mg/mL, 1.7 mg/mL, 1.8 mg/mL, 1.9 mg/mL, 2.0 mg/mL, 2.2 mg/mL, 2.4 mg/mL, 2.6 mg/mL, 2.8 mg/mL, 3.0 mg/mL, 4.0 mg/mL, 5.0 mg/mL, 6.0 mg/mL, 7.0 mg/mL, 8.0 mg/mL, 9.0 mg/mL, 10.0 mg/mL, and any range between these points.

In some embodiments, the aforementioned pharmaceutical composition further comprises sugar. The "sugar" disclosed herein comprises conventional compositions ( _CH2O ) _n and derivatives thereof, including monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, and the like. The sugar may be selected from glucose, sucrose, trehalose, α, α-trehalose dihydrate, lactose, fructose, maltose, dextran, glycerol, erythritol, glycerol, arabitol, sylitol, sorbitol, mannitol, melibiose, melezitose, raffinose, mannotriose, stachyose, maltose, lactulose, maltulose, sorbitol, maltitol, lactitol, iso-maltulose, and the like. In some embodiments, the sugar is sucrose.

In some embodiments, the concentration of sugar in the aforementioned pharmaceutical composition is 25 mg/mL to 150 mg/mL, or 30 mg/mL to 120 mg/mL, non-limiting examples include 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 45 mg/mL, 50 mg/mL, 55 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, 100 mg/mL, 110 mg/mL, 120 mg/mL, 130 mg/mL, 140 mg/mL, 150 mg/mL, 160 mg/mL, 170 mg/mL, 180 mg/mL and any range between these points. In some embodiments, the concentration is 80 mg/mL.

In some embodiments, the aforementioned pharmaceutical composition further comprises amino acids, such as amino acids other than histidine for buffering, for enhancing the stability of the drug. Available amino acids include, but are not limited to, glycine, arginine, methionine, proline, lysine, and the like.

In some embodiments, the concentration of the amino acid in the aforementioned pharmaceutical composition is 1 mg/mL to 100 mg/mL, non-limiting examples include 6 mg/mL, 6.5 mg/mL, 7 mg/mL, 7.2 mg/mL, 7.6 mg/mL, 7.8 mg/mL, 8 mg/mL, 8.5 mg/mL, 9 mg/mL, 10 mg/mL, 10.2 mg/mL, 11 mg/mL, 12 mg/mL, 13 mg/mL, 14 mg/mL, 15 mg/mL, 20 mg/mL, 25 mg/mL, 30 mg/mL, 35 mg/mL, 40 mg/mL, 45 mg/mL, 50 mg/mL, 60 mg/mL, 70 mg/mL, 80 mg/mL, 90 mg/mL, 100 mg/mL and any range between these points.

In some embodiments, the pharmaceutical composition of the present disclosure does not contain amino acids other than histidine for buffering. In some embodiments, the pharmaceutical composition of the present disclosure has excellent stability and does not require the addition of additional amino acids.

In some embodiments, the concentration of the antibody drug conjugate in the pharmaceutical composition is 1 mg/mL to 200 mg/mL based on protein concentration. Non-limiting examples include 1 mg/mL, 10 mg/mL, 11 mg/mL, 12 mg/mL, 13 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL, 17 mg/mL, 18 mg/mL, 19 mg/mL, 20 mg/mL, 21 mg/mL, 22 mg/mL, 23 mg/mL, 24 mg/mL, 25 mg/mL, 26 mg/mL, 27 mg/mL, 28 mg/mL, 29 mg/mL, 30 mg/mL, 40 In some embodiments, the concentration of the antibody drug conjugate is 10 mg/mL to 180 mg/mL, 30 mg/mL to 180 mg/mL, or 50 mg/mL to 150 mg/mL, based on protein concentration. The term "based on protein concentration" refers to the concentration of the antibody portion in the antibody drug conjugate.

In some embodiments, the pharmaceutical composition comprises:

(a) based on protein concentration, 10 mg/mL to 180 mg/mL of the antibody drug conjugate, (b) 0.1 mg/mL to 8 mg/mL of poloxamer or polysorbate, (c) 25 mg/mL to 150 mg/mL of sucrose, and (d) 1 mM to 50 mM succinate-histidine buffer; the pH of the pharmaceutical composition is 3.5 to 5.5,

Wherein, based on the total amount of the antibody-drug conjugate, the content of the component with a compound DAR of 4 in the antibody-drug conjugate is greater than 85%.

In some embodiments, the pharmaceutical composition comprises:

(a) based on protein concentration, 10 mg/mL to 180 mg/mL of the antibody drug conjugate, (b) 0.3 mg/mL to 5 mg/mL of poloxamer or polysorbate, (c) 30 mg/mL to 120 mg/mL of sucrose, and (d) 5 mM to 20 mM succinate-histidine buffer; the pH of the pharmaceutical composition is 3.7 to 5.2,

Wherein, based on the total amount of the antibody-drug conjugate, the content of the component with a compound DAR of 4 in the antibody-drug conjugate is greater than 85%.

In some embodiments, the pharmaceutical composition comprises:

(a) based on protein concentration, 100 mg/mL of the antibody-drug conjugate, (b) 1 mg/mL of poloxamer, (c) 80 mg/mL of sucrose, and (d) 15 mM of succinate-histidine buffer; the pH of the pharmaceutical composition is 5.0,

Wherein, based on the total amount of the antibody-drug conjugate, the content of the component with a compound DAR of 4 in the antibody-drug conjugate is greater than 85%.

In some embodiments, any of the foregoing pharmaceutical compositions is a liquid preparation. The liquid preparation or the reconstituted preparation disclosed herein has good stability. Further, a stable liquid preparation includes a liquid preparation that exhibits desired characteristics after being stored at a temperature of 40° C. for 1 month.

In some embodiments, the antibody drug conjugate monomer measured by HP-SEC after storage of the pharmaceutical composition of the present disclosure at 2-8°C for 3 months is ≥96%, such as ≥97%, ≥98% or ≥99%.

In some embodiments, the pharmaceutical compositions of the present disclosure show no more than 10%, such as no more than 5% or no more than 3%, aggregation or degradation of the antibody drug conjugate as measured by HP-SEC after the formulation is stored at 2-8°C for 3 months.

In some embodiments, the % antibody drug conjugate monomer measured by HP-SEC after storage of the pharmaceutical composition of the present disclosure at 2-8°C for 6 months is ≥96%, such as ≥97%, ≥98% or ≥99%.

In some embodiments, the pharmaceutical compositions of the present disclosure show no more than 10%, such as no more than 5% or no more than 3%, aggregation or degradation of the antibody drug conjugate as measured by HP-SEC after the formulation is stored at 2-8°C for 6 months.

In some embodiments, the % antibody drug conjugate monomer measured by HP-SEC after storage of the pharmaceutical composition of the present disclosure at 25° C. for 3 months is ≥96%, such as ≥97%, ≥98% or ≥99%.

In some embodiments, the pharmaceutical compositions of the present disclosure show no more than 10%, such as no more than 5% or no more than 3%, aggregation or degradation of the antibody drug conjugate as measured by HP-SEC after the formulation is stored at 25°C for 3 months.

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.

In some embodiments, the lyophilized formulation is stable at 40°C for at least 7 days, at least 14 days, at least 28 days, or at least 30 days.

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.

The present disclosure also provides a method for preparing a lyophilized formulation containing an antibody drug conjugate, which comprises the step of freeze-drying the pharmaceutical composition as described above.

The present disclosure also provides a reconstitution solution containing an antibody drug conjugate, wherein the reconstitution solution is prepared by The lyophilized preparation described above was reconstituted to obtain the above-mentioned product.

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 lyophilized preparations disclosed herein can maintain good stability.

The present disclosure also provides a product, which includes a container, wherein the pharmaceutical composition, lyophilized preparation or reconstituted solution as described above is contained in the container. In some embodiments, the container is a neutral borosilicate glass tube injection bottle.

The antibody-drug conjugates and/or pharmaceutical compositions comprising the antibody-drug conjugates described in the present disclosure can be used to lyse cells expressing surface TNFα (in vitro or in vivo) and/or to treat diseases or conditions characterized by increased TNFα (e.g., increased TNFα in synovial fluid). In certain embodiments, the antibody-drug conjugates and/or compositions can be used to inhibit cytokine release (in vitro or in vivo) and/or to treat autoimmune or inflammatory diseases. In certain embodiments, the antibody-drug conjugates and/or compositions are used to treat Crohn's disease. In certain embodiments, the antibody-drug conjugates and/or compositions are used to treat ulcerative colitis. In certain embodiments, the antibody-drug conjugates and/or compositions are used to treat rheumatoid arthritis (RA). In certain embodiments, the antibody-drug conjugates and/or compositions are used to treat juvenile idiopathic arthritis (JA). In certain embodiments, the antibody-drug conjugates and/or compositions are used to treat psoriatic arthritis (PsA). In certain embodiments, the antibody-drug conjugate and/or composition is used to treat spondyloarthropathies, such as ankylosing spondylitis (AS) or axial spondyloarthritis (axSpA). In certain embodiments, the antibody-drug conjugate and/or composition is used to treat adult Crohn's disease (CD). In certain embodiments, the antibody-drug conjugate and/or composition is used to treat pediatric Crohn's disease. In certain embodiments, the antibody-drug conjugate and/or composition is used to treat ulcerative colitis (UC). In certain embodiments, the antibody-drug conjugate and/or composition is used to treat plaque psoriasis (Ps). In certain embodiments, the antibody-drug conjugate and/or composition is used to treat hidradenitis suppurativa (HS). In certain embodiments, the antibody-drug conjugate and/or composition is used to treat uveitis. In certain embodiments, the antibody-drug conjugate and/or composition is used to treat Behcet's disease. In certain embodiments, the antibody-drug conjugate and/or composition is used to treat psoriasis, including plaque psoriasis.

As is well known to those skilled in the art, one, some or all of the features of the various embodiments described in the present disclosure may be further combined to form other embodiments of the present disclosure. The above embodiments of the present disclosure and other embodiments obtained by combination are further described by the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure provides a pharmaceutical composition that is more conducive to production and administration and has stable performance. Among them, the undesirable instability may include any one or more of the following: aggregation, deamidation (e.g., Asn deamidation), oxidation (e.g., Met oxidation), isomerization (e.g., Asp isomerization), clipping/hydrolysis/fragmentation (e.g., hinge region fragmentation), succinimide formation, unpaired cysteine, dissociation of toxins, etc. The pharmaceutical composition described in the present disclosure can remain stable for a long time in a liquid state.

the term

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

“Antibody-drug conjugates (ADCs) are antibodies that are linked to biologically active cytotoxins or small molecule drugs with cell-killing activity through a linker unit.

“Drug loading” or “drug loading” is also called the drug-to-antibody ratio (DAR), which is the amount of drug coupled to each antibody in the ADC.

"Compound drug loading" or "compound DAR" refers to the specific amount of drug conjugated to each antibody in the ADC. Exemplary, the drug loading can be a value of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. For example, the compound drug loading is an integer from 1 to 10.

"Average drug loading" or "average drug loading" is also called average DAR, which is the average number of drugs coupled to each antibody in the ADC. It can be, for example, in the range of 1 to 10 drugs coupled to each antibody, and in certain embodiments, in the range of 1 to 8 drugs coupled to each antibody, preferably 2-8, 2-7, 2-6, 2-5, 2-4, 3-4, 3-5, 5-6, 5-7, 5-8 and 6-8. Exemplarily, the drug loading can be the average of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. For example, the average drug loading is an integer or decimal from 1 to 10.

The term "linker unit" or "connection fragment" or "connection unit" refers to a chemical structure fragment or bond that is connected to an antibody or its antigen-binding fragment at one end and to a drug at the other end, and can also be connected to other linkers before being connected to the drug.

Linkers, including extenders, spacers, and amino acid units, can be synthesized by methods known in the art, such as those described in US20050238649A1. The linker can be a "cleavable linker" that facilitates release of the drug in the cell. For example, an acid-labile linker (e.g., hydrazone), a protease-sensitive (e.g., peptidase-sensitive) linker, a photolabile linker, a dimethyl linker, or a disulfide-containing linker can be used (Chari et al., Cancer Research 52: 127-131 (1992); U.S. Patent No. 5,208,020).

The term "drug linker fragment" or "drug-linker fragment" refers to a fragment formed by linking a drug to a linker unit, which can be linked to an antibody via the other end of the linker unit.

The glucocorticoid receptor agonist drug loading may be controlled by the following non-limiting methods, including:

(1) Control the molar ratio of the drug linker fragment and the monoclonal antibody,

(2) Control the reaction time and temperature,

(3) Select different reaction reagents.

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 "antibody" described in the present disclosure is used in the broadest sense and covers various antibody structures, including but not limited to full-length antibodies and antibody fragments (or antigen-binding fragments, or antigen-binding portions), as long as they exhibit the desired antigen-binding activity. Generally, a natural complete antibody consists of a tetrapeptide chain structure formed by two identical heavy chains and two identical light chains connected by interchain disulfide bonds.

The engineered antibodies or antigen-binding fragments disclosed herein can be prepared and purified by conventional methods. The cDNA sequences of the heavy chain and light chain can be cloned and recombined into the GS expression vector. The recombinant immunoglobulin expression vector can stably transfect CHO cells. As a more recommended existing technology, the mammalian expression system will lead to glycosylation of antibodies, especially at the highly conserved N-terminal site of the Fc region. Positive clones are expanded in serum-free 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 the pH gradient method, and the antibody fragments are detected by SDS-PAGE and collected. The antibodies can be filtered and concentrated by conventional methods. Soluble mixtures and polymers can also be removed by conventional methods, such as molecular sieves and ion exchange. The obtained product should be immediately frozen, such as -70°C, or freeze-dried.

"Buffer" refers to a buffer that tolerates pH changes through the action of its acid-base conjugate components. Examples of buffers that control pH in an appropriate range include acetate, succinate, gluconate, histidine, oxalate, lactate, phosphate, citrate, tartrate, fumarate, glycylglycine, and other organic acid buffers.

"Histidine buffer" is a buffer containing histidine. Examples of histidine buffers include histidine-histidine hydrochloride, histidine-histidine acetate, histidine-histidine phosphate, histidine-histidine sulfate and the like, preferably histidine-histidine hydrochloride buffer. Histidine-histidine hydrochloride buffer can be prepared from histidine and hydrochloric acid, or from histidine and histidine hydrochloride.

"Citrate buffer" is a buffer including citrate ions. Examples of citrate buffers include citric acid-sodium citrate, citric acid-potassium citrate, citric acid-calcium citrate, citric acid-magnesium citrate, and the like. A preferred citrate buffer is citric acid-sodium citrate.

"Succinate buffer" is a buffer comprising succinate ions. Examples of succinate buffers include succinic acid-succinic acid sodium salt, succinic acid-succinic acid potassium salt, succinic acid-succinic acid calcium salt, etc. A preferred succinic acid buffer is succinic acid-succinic acid sodium salt. Exemplarily, the succinic acid-succinic acid sodium salt can be prepared from succinic acid and sodium hydroxide, or from succinic acid and succinic acid sodium salt.

"Phosphate buffer" is a buffer including phosphate ions. Examples of phosphate buffers include disodium hydrogen phosphate-sodium dihydrogen phosphate, disodium hydrogen phosphate-potassium dihydrogen phosphate, disodium hydrogen phosphate-citric acid, and the like. A preferred phosphate buffer is disodium hydrogen phosphate-sodium dihydrogen phosphate.

"Acetate buffer" is a buffer including acetate ions. Examples of acetate buffers include acetate-sodium acetate, histidine-histidine acetate, acetate-potassium acetate, acetate-calcium acetate, acetate-magnesium acetate, etc. A preferred acetate buffer is acetate-sodium acetate.

"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 specific value determined by a person of ordinary skill in the art, which value depends in part on how it is measured or determined (i.e., the limits of the measurement system). For example, "about" can mean within 1 or more than 1 standard deviation in each practice in the art. Alternatively, "about" or "substantially including" can mean a range of up to 20%. In addition, particularly for biological systems or processes, the term can mean up to an order of magnitude or up to 5 times the value. Unless otherwise stated, when a specific value appears 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%.

The pharmaceutical composition disclosed herein can achieve a stable effect: a pharmaceutical composition in which the antibody drug conjugate substantially retains its physical stability and/or chemical stability and/or biological activity after storage; preferably, the pharmaceutical composition substantially retains its physical and chemical stability and its biological activity after storage. The storage period is generally selected based on the predetermined shelf life of the pharmaceutical composition. There are currently a variety of analytical techniques for measuring the stability of proteins or antibody drug conjugates, which can measure the stability after storage at a selected temperature for a selected period of time.

A stable formulation is one in which no significant changes are observed when stored at a refrigerated temperature (2-8°C) for at least 3 months, preferably 6 months, and more preferably 1 year. In addition, a stable liquid formulation includes a liquid formulation that exhibits desired characteristics after being stored at a temperature of 25°C for a period of 1 month, 2 months, or 3 months. Further, a stable liquid formulation includes a liquid formulation that exhibits desired characteristics after being stored at a temperature of 40°C for a period of 10 days, 20 days, or 1 month. A typical example of stability: As measured by SEC-HPLC, usually no more than about 10%, preferably no more than about 5%, of the antibody drug conjugate monomers aggregate or degrade. By visual analysis, the formulation is a pale yellow, nearly colorless, clear liquid or colorless, or clear to slightly milky white. The concentration, pH, and weight-gram molecular osmotic pressure concentration of the formulation have no more than ±10% variation. A decrease of no more than about 10%, preferably no more than about 5%, is usually observed. Aggregation of no more than about 10%, preferably no more than about 5%, is usually formed.

The antibody drug conjugate "retains its physical stability" in the pharmaceutical formulation if it shows no significant increase in aggregation, precipitation and/or denaturation as measured after visual inspection of color and/or clarity, or by UV light scattering, size exclusion chromatography (SEC) and dynamic light scattering (DLS). Changes in protein conformation can be evaluated by fluorescence spectroscopy (which determines protein tertiary structure) and by FTIR spectroscopy (which determines protein secondary structure).

An antibody drug conjugate "retains its chemical stability" in a pharmaceutical formulation if the antibody drug conjugate does not show significant chemical alteration. By detecting and quantifying chemically altered forms of the protein, Chemical stability can be assessed. Degradation processes that often change the chemical structure of a protein include hydrolysis or truncation (assessed by methods such as size exclusion chromatography and CE-SDS), oxidation (assessed by methods such as peptide mapping coupled to mass spectrometry or MALDI/TOF/MS), deamidation (assessed by methods such as ion exchange chromatography, capillary isoelectric focusing, peptide mapping, isoaspartate measurement), and isomerization (assessed by measuring isoaspartate content, peptide mapping, etc.).

An antibody drug conjugate "retains its biological activity" in a pharmaceutical formulation if the biological activity of the antibody drug conjugate at a given time is within a predetermined range of the biological activity exhibited when the pharmaceutical formulation is prepared.

"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.

The term "carrier" is used for the drugs disclosed herein and refers to a system that can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug, and deliver the drug to the targeted organ. The drug carrier release and targeting system can reduce drug degradation and loss, reduce side effects, and improve bioavailability. For example, polymer surfactants that can be used as carriers can self-assemble to form various forms of aggregates due to their unique amphiphilic structure, and preferred examples are micelles, microemulsions, gels, liquid crystals, vesicles, etc. These aggregates have the ability to encapsulate drug molecules and have good permeability to membranes, and can be used as excellent drug carriers.

"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 disease symptoms in the patient or population being treated, to induce regression of such symptoms or to inhibit the progression 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 disease state, age, and weight of the patient, and the ability of the drug to produce the desired therapeutic effect in the patient. The amount of therapeutic agent administered may be determined by any clinical assessment routinely used by a physician or other health care professional to evaluate the severity or progression of the symptom. Detection methods can evaluate whether disease symptoms have been alleviated. Although the embodiments of the present disclosure (e.g., treatment methods or products) may not be effective in alleviating each target disease symptom, they should alleviate the target disease symptoms in a statistically significant number of patients as determined by any statistical test 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 a symptom or condition 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 condition to be treated, the patient's general health, the method, route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosage 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 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, such as the Antibody Technology Laboratory Manual and the Molecular Cloning Manual published by the Cold Spring Harbor Laboratory; or under the conditions recommended by the raw material or product manufacturer. Reagents that do not specify specific sources are conventional reagents purchased from the market.

The antibody drug conjugate shown in formula (I) described herein can be prepared according to the method of WO2022166779.

The equipment used in the preparation and testing process and the calculation method of the results are as follows:

SEC Size Exclusion Chromatography:

An analytical method that separates solutes based on the relative relationship between the pore size of the gel and the coil size of the polymer sample molecule.

SEC% (SEC monomer content percentage) = A monomer/A total × 100% (A monomer is the peak area of the main peak monomer in the sample, and A total is the sum of all peak areas). ΔSEC% = SEC% of the preparation before stability placement - SEC% of the preparation after stability placement.

SEC instrument: Agilent 1260; column: waters, XBridge Protein BEH SEC (300×7.8mm 3.5μm)

R-CE capillary gel electrophoresis:

A method of electrophoresis in which the gel is moved into a capillary tube as a supporting medium and the samples are separated according to their molecular weight at a certain voltage.

R-CE% = A main peak/A total × 100% (A main peak is the peak area of the light chain main peak + the heavy chain main peak in the sample, and A total is the sum of all peak areas.) ΔR-CE% = R-CE% of the preparation before stability placement - R-CE% of the preparation after stability placement.

CE test instrument: Sciex PA800 plus

Osmolality determination:

The freezing point method is used to determine osmotic pressure. It is based on the fact that the freezing point depression value is proportional to the molar concentration of the solution. It uses a highly sensitive temperature sensing element to measure the freezing point of the solution and convert the electricity into osmotic pressure. Instrument manufacturer: Loser, model OM815.

Protein concentration:

The protein used in the following examples is an antibody-drug conjugate ADC represented by formula (I).

Instrument for determining protein concentration: UV-visible spectrophotometer, model: Nano Drop One.

The protein concentration of the test article was calculated using the following formula:
A _246nm = (C _drug × E _drug-246 + C _mAb × E _mAb-246 ) × l
A _280nm = (C _drug × E _drug-280 + C _mAb × E _mAb-280 ) × l

Right now:

Where, A _246nm : the average absorbance of a single sample of the test solution at a wavelength of 246nm when the optical path is 1cm;

A _280nm : The average absorbance of a single sample of the test solution at a wavelength of 280nm when the optical path is 1cm;

E _mAb-280 : The mass extinction coefficient of the protein at a wavelength of 280 nm is 1.463 g ^-1 cm ^-1 L;

E _mAb-246 : The mass extinction coefficient of the protein at a wavelength of 246 nm is 0.619 g ^-1 cm ^-1 L;

R: the ratio of the toxin extinction coefficient at 246nm and 280nm, which is 5.20;

C _mAb : protein concentration, mg/mL;

l: optical path length, cm (the optical path here is 1 cm).

If the test solution is diluted, the protein concentration is: C (mg/mL) = C _mAb × N, where N is the dilution factor.

Free toxin determination (RP-UPLC reverse phase method):

The protein in the sample was removed by ACN precipitation, the supernatant was taken and dried with nitrogen, and then re-dissolved. The toxins in the sample were separated according to their different polarities, and the toxin content in the sample was calculated by the linear equation formula of toxin standard concentration-peak area fitting.

Measuring instrument: waters ACQuity H-class UPLC;

Column: Waters BioResolve RP mAb Polyphenyl, 2.7μm, 4.6*100mm

Example 1. Screening of adjuvants and surfactants for mixed DAR4 formulations

The antibody drug conjugate shown in formula (I) was prepared according to the method of WO2022166779 to obtain an ADC with an average DAR value of approximately 4.0, which was a mixture of DAR 0 to DAR 8, wherein the content of the DAR4 component was approximately 70%.

This antibody drug conjugate showed obvious phase separation in the range of 5.0＜pH＜7.5. When pH≤5.0 and pH≥7.5, the sample appearance was relatively good. The 15mM Tris-HCl system was selected for excipient and surfactant concentration screening. The specific prescription information is shown in Table 1.

Table 1 Excipient and surfactant screening prescription design table

The prepared samples were filtered and aseptically filled into 2R vials. The samples were placed at 25°C, shaken at 300 rpm for 3 days, frozen and thawed at -35°C/room temperature for 5 cycles, and tested at 40°C-1W and 40°C-2W. The stability test results are shown in Table 2.

Table 2 Screening results of excipients and surfactants

Note 1: CY = light yellow; SO = strong opalescence; P+ (a small amount of particles);

Note 2: F1, F2 and F3 are samples from different sources, so their DARs are different;

Based on the results of appearance, SEC, RCE and DAR, F1-F3 produced a small amount of particles after 5 cycles of freeze-thaw. Considering that the ADC sample dosage form was lyophilized powder, the F2 and F3 samples were lyophilized. After reconstitution, the two groups of prescriptions showed strong opalescence and produced a large number of particles, indicating that the stability of ADC was poor after being made into lyophilized products in 15mM Tris-HCl pH8.0 system.

Example 2. pH screening of mixed DAR4 formulations and screening of surfactant types and concentrations

According to the results of excipient and surfactant screening and freeze-drying reconstitution in the 15 mM Tris-HCl system and the DAR value distribution and pI distribution of ADC, the histidine-histidine hydrochloride pH 6.0 system was selected for surfactant type and concentration screening. At the same time, a fine screening in the pH 5.7-6.3 range was carried out based on 100 mM Arg-HCl + 4% sucrose + 0.1% PF68. The specific prescription design is shown in Table 3.

Table 3 pH fine screening and surfactant type and concentration screening prescription design table

The prepared samples were filtered and aseptically filled into 2R vials. The samples were placed at 25°C, shaken at 300 rpm for 3 days, frozen and thawed at -35°C/room temperature for 5 cycles, and at 40°C-1W and 40°C-2W. The stability test results are shown in Table 4.

Table 4 pH fine screening and surfactant type and concentration screening results

Note: CY = light yellow; SO = strong opalescence; P+ (a small amount of particles);

Based on the appearance, SEC, RCE and DAR results, the purity test items of each prescription changed slightly, all within the acceptable range. A small amount of particles appeared in F5 (0.2% PF68) after 5 rounds of freeze-thaw, and no particles were produced in the other prescriptions. Therefore, the pH/buffer was finally determined to be 15mM histidine-histidine hydrochloride pH6.0 system, the excipients were 100mM Arg-HCl+4% sucrose, and the surfactant was 0.1% PF68. At the same time, in the 15mM histidine-histidine hydrochloride system, the excipients were 100mM Arg-HCl+4% sucrose, and the surfactant was 0.1% PF68, the pH fluctuated in the range of 5.7-6.3, which had no significant effect on the stability of the preparation, and the preparation showed good robustness. The sample was freeze-dried to obtain a freeze-dried preparation of mixed DAR4. The freeze-dried product has a good appearance and good stability.

Example 3. Pure DAR4 formulation pH/Buffer and ADC concentration screening

The DAR 4 component in the mixture of DAR 0 to DAR 8 was separated and purified by an anion exchange chromatography column (filler: Poros 50HQ, eluent: phosphate buffered saline + Tris + citric acid / phosphate buffered saline + Tris + citric acid + sodium chloride) to obtain a purified antibody drug conjugate of formula (I), wherein the content of DAR4 component was 96%. The preparation of the antibody drug conjugate (ADC) of formula (I) was prepared according to the composition of Table 5.

Table 5 pH/Buffer and ADC concentration screening prescription design table

The prepared samples were filtered and aseptically filled into 2R vials. The samples were placed at 25°C and shaken at 300 rpm for 3 days (15 mM His-HCl pH 5.5 was not placed under shaking conditions due to sample quantity limitations), -35°C/room temperature freeze-thaw for 5 cycles, 40°C for 1W, and 40°C for 2W. The stability test results are shown in Table 6.

Table 6 pH/Buffer and ADC concentration screening results

Note: CL = colorless; LO = slightly opalescent; N/A = not detected;

Based on the results of appearance, SEC, and RCE, the pure DAR4 ADC samples had good stability in 15 mM His-HCl pH 5.5 and pH 6.0 systems. The F1-F4 samples were freeze-dried, and the freeze-dried products had good appearance without collapse and shrinkage, but a large number of fine particles appeared in the samples after reconstitution.

Example 4. Pure DAR4 Preparation pH/Buffer and Excipient Screening

According to the results of pH/Buffer and ADC concentration screening, the Arg-HCl concentration and the pH of the formulation system were lowered, and 15mM Succinic pH 5.0 and 15mM His-HCl pH 5.5 systems were selected for excipient screening. The specific prescription design is shown in Table 7.

Table 7 pH/Buffer and excipient screening prescription design table

The prepared samples were filtered and aseptically filled into 2R vials. The samples were placed at 25°C, shaken at 300 rpm for 3 days, frozen and thawed at -35°C/room temperature for 5 cycles, and at 40°C for 2W and 40°C for 4W. The stability test results are shown in Table 8.

Table 8 pH/Buffer and excipient screening results

Note: CL = colorless; T = clear; LO = slightly opalescent;

Based on the results of appearance, SEC, and RCE, the ADC samples have good stability in both 15mM Succinic pH 5.0 and 15mM His-HCl pH 5.5 systems. Comparing F1 (15mM Succinic pH 5.0 + 8% Sucrose) and F2 (15mM Succinic pH 5.0 + 30mM Arg-HCl + 4% Sucrose), the purity of F1 without Arg-HCl has no significant difference compared with F2, and the appearance has been significantly improved.

Example 5. pH Screening of Pure DAR4 Formulations

According to the results of pH/Buffer and excipient screening, the 15 mM Succinic-His system was selected, the excipient was 8% Sucrose, and the pH range was 5.0-6.0 for pH fine screening. The specific prescription design is shown in Table 9.

Table 9 pH fine sieve prescription design table

The prepared samples were filtered and aseptically filled into 2R vials. The samples were placed at 25°C, shaken at 300 rpm for 3 days, frozen and thawed at -35°C/room temperature for 5 cycles, and at 40°C for 2W and 40°C for 4W. The stability test results are shown in Table 10.

Table 10 pH fine screening results

Note: CL = colorless; T = clear; LO = slightly opalescent;

Based on the results of appearance, SEC, and RCE, the ADC samples have good stability in the 15mM Succinic-His pH 5.0-6.0 system. The appearance of the low pH F1 formulation is improved compared to F2 and F3.

Example 6. Confirmation of pure DAR4 formulation prescription

According to the results of pH/Buffer and excipient screening, 15mM Succinic-His (pH 5.0), 80g/L sucrose, 1g/L poloxamer 188, 100mg/mL ADC were selected for prescription investigation. The prepared samples were filtered and aseptically filled into 2R vials. The samples were placed at 40℃ for 2W and 40℃ for 4W. The stability results are shown in Table 11.

Table 11 Prescription confirmation results

Note: CL = colorless; T-LO = clear to slightly opalescent; LOD = limit of detection;

Based on the results of appearance, SEC, and RCE, the liquid preparation prepared by increasing the ADC concentration to 100 mg/mL in the 15 mM Succinic-His pH 5.0 system still had good stability.

Example 7. Study on the stability of ADC preparations

The stability of the pure DAR4 liquid preparation of Example 6 was investigated, and the results are shown in the following table.

Table 12 Stability results of pure DAR4 ADC formulations

The stability of the lyophilized preparation of mixed DAR4 prepared in Example 2 was investigated. The results are shown in the following table.

Table 13 Mixed DAR4 ADC formulation stability results

The results showed that the mixed DAR4-50mg/ml lyophilized preparation and the pure DAR4-100mg/ml liquid preparation had good stability at 25℃3M and 5℃6M. Comparing the appearance of the reconstituted liquid preparation and the lyophilized preparation, the pure DAR4 preparation was still a colorless clear liquid even at a higher concentration of 100mg/ml. The mixed DAR4 lyophilized preparation was reconstituted at a concentration of 50mg/ml, without particles, but with strong opalescence, indicating that the purified DAR4 ADC can be made into a high-concentration liquid preparation and can be stably stored without lyophilization.

Claims (17)

1. A pharmaceutical composition comprising an antibody-drug conjugate, a buffer, a sugar and a surfactant, wherein the antibody-drug conjugate has a structure as shown in formula (I):
   

   in:

   Ab is adalimumab;

   n is 1 to 10, preferably 1 to 8, more preferably 3 to 5;

   Wherein, based on the total amount of the antibody-drug conjugate, the content of the component with a compound DAR of 4 in the antibody-drug conjugate is greater than 80%, preferably greater than 85%, and more preferably greater than 90%.
2. The pharmaceutical composition according to claim 1, wherein the pH of the pharmaceutical composition is 3.5 to 6.0, preferably the pH is 3.5 to 5.5, and more preferably the pH is 3.7 to 5.2.
3. The pharmaceutical composition according to claim 1, wherein the buffer is selected from citrate buffer, histidine buffer and succinate buffer, more preferably histidine-histidine hydrochloride, citrate-sodium citrate, succinate-histidine and succinate-sodium succinate.
4. The pharmaceutical composition according to claim 3, wherein the concentration of the buffer is 1 mM to 50 mM, preferably 1 mM to 30 mM, more preferably 15 mM.
5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the surfactant is polysorbate or poloxamer.
6. The pharmaceutical composition according to claim 5, wherein the surfactant concentration is 0.01 mg/mL to 10 mg/mL, preferably 0.1 mg/mL to 8 mg/mL, and more preferably 0.3 mg/mL to 5 mg/mL.
7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the sugar is sucrose.
8. The pharmaceutical composition according to claim 7, wherein the sugar concentration is 25 mg/mL to 150 mg/mL, preferably 30 mg/mL to 120 mg/mL, and more preferably 80 mg/mL.
9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutical composition does not contain amino acids other than histidine for buffering.
10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the pharmaceutical composition is a liquid preparation.
11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the concentration of the antibody drug conjugate is 1 mg/mL to 200 mg/mL based on protein concentration,

    Preferably, the concentration of the antibody drug conjugate is 10 mg/mL to 180 mg/mL in terms of protein concentration.

    More preferably, the concentration of the antibody drug conjugate is 50 mg/mL to 150 mg/mL based on protein concentration.
12. The pharmaceutical composition according to any one of claims 1 to 11, comprising:

    (a) based on protein concentration, 10 mg/mL to 180 mg/mL of the antibody drug conjugate, (b) 0.1 mg/mL to 8 mg/mL of poloxamer or polysorbate, (c) 25 mg/mL to 150 mg/mL of sucrose, and (d) 1 mM to 50 mM succinate-histidine buffer; the pH of the pharmaceutical composition is 3.5 to 5.5,

    Wherein, based on the total amount of the antibody-drug conjugate, the content of the component with a DAR of 4 in the antibody-drug conjugate is greater than 90%;

    Preferably, the pharmaceutical composition comprises:

    (a) based on protein concentration, 10 mg/mL to 180 mg/mL of the antibody drug conjugate, (b) 0.3 mg/mL to 5 mg/mL of poloxamer or polysorbate, (c) 30 mg/mL to 120 mg/mL of sucrose, and (d) 5 mM to 20 mM succinate-histidine buffer; the pH of the pharmaceutical composition is 3.7 to 5.2,

    Wherein, based on the total amount of the antibody-drug conjugate, the content of the component with a DAR of 4 in the antibody-drug conjugate is greater than 90%;

    More preferably, the pharmaceutical composition comprises:

    (a) based on protein concentration, 100 mg/mL of the antibody-drug conjugate, (b) 1 mg/mL of poloxamer, (c) 80 mg/mL of sucrose, and (d) 15 mM of succinate-histidine buffer; the pH of the pharmaceutical composition is 5.0,

    Wherein, based on the total amount of the antibody-drug conjugate, the content of the component with a compound DAR of 4 in the antibody-drug conjugate is greater than 90%.
13. A lyophilized preparation containing an antibody drug conjugate, wherein the lyophilized preparation can form the pharmaceutical composition according to any one of claims 1 to 12 after being reconstituted.
14. 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 12.
15. A reconstituted solution containing an antibody drug conjugate, wherein the reconstituted solution is prepared by reconstituted the lyophilized preparation according to claim 13 or 14.
16. A product comprising a container containing the pharmaceutical composition according to any one of claims 1 to 12, the lyophilized preparation according to claim 13 or 14, or the reconstituted solution according to claim 15.
17. Use of the pharmaceutical composition according to any one of claims 1 to 12, the lyophilized preparation according to claim 13 or 14, the reconstituted solution according to claim 15 or the preparation according to claim 16 in the preparation of a medicament for treating an immune disease, wherein the immune disease is preferably selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, adult Crohn's disease, pediatric Crohn's disease, ulcerative colitis, suppurative hidradenitis, uveitis, Behcet's disease, spondyloarthropathies and psoriasis.