Pharmaceutical composition of drug conjugate containing glucocorticoid receptor stimulant

Abstract

A pharmaceutical composition of a drug conjugate containing a glucocorticoid receptor agonist comprises an antibody drug conjugate, a buffer agent, sugar and a surfactant, and 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

[0001] The present disclosure belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing a glucocorticoid receptor agonist-drug conjugate. Background Art

[0002] 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. A variety of proinflammatory cytokines are involved in the pathogenesis of RA, such as tumor necrosis factor-α (TNFα) and interleukins such as IL-1, IL-6, and IL-8. Therefore, inhibiting the production of proinflammatory cytokines or blocking their physiological effects is currently a hot topic in the field of RA research. 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 and anti-IL-6R antibodies. 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, ), the fully human monoclonal antibody golimumab, and the pegylated humanized Fab' fragment certolizumab pegol. Despite their clinical success, TNFα inhibitors remain limited by their maximum efficacy in patients, necessitating the identification and development of more potent and effective therapeutic agents. Patients treated with TNFα inhibitors may also develop immunogenic responses to the therapeutic agents, limiting their effectiveness.

[0003] Glucocorticoid receptor agonists are also comparatively effective medicines for the treatment of rheumatoid arthritis. As representative glucocorticoid receptor agonists, the glucocorticoid receptor agonists made in vivo by known cortisol, corticosterone, and the synthetic glucocorticoid receptor agonists such as dexamethasone, prednisone, and prednisolone. These glucocorticoid receptor agonists are owing to having a steroid structure, and are therefore 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.

[0004] Antibody drug conjugates (ADCs) are monoclonal antibodies or antibody fragments linked to a bioactive drug via a stable chemical linker compound. Most ADCs in preclinical and clinical development are for oncology indications, where the cytotoxic payload targets cancer cells expressing the antigen. However, modulating 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.

[0005] ADCs have a more complex heterogeneous structure than antibodies, posing greater challenges to their formulation for therapeutic purposes. As of March 2022, a total of 14 ADCs have been approved worldwide. Due to stability issues, all ADC formulations are currently in the form of lyophilized powders rather than solutions.

[0006] Summary of the Invention

[0007] 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):

[0008] in:

[0009] Ab is adalimumab;

[0010] n is 1 to 10;

[0011] 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 80%.

[0012] 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 an average number of glucocorticoid receptor agonist drugs bound to each antibody of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and any range between these point values. For example, it can be 2-8, 2-7, 2-6, 2-5, 2-4, 3-4, 3-5, 3.5 to 4.7, 5-6, 5-7, 5-8 and 6-8. Exemplary, the average drug load (n) can be an average 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.

[0013] 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.

[0014] 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.

[0015] In some embodiments, the pH of the pharmaceutical composition is between 3.5 and 6.0, non-limiting examples of which 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 range therebetween. In some embodiments, the pH is between 3.5 and 5.5, or between 3.7 and 5.2.

[0016] 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 concentration is 1 mM to 30 mM; in some embodiments, the buffer concentration is 5 mM to 20 mM; in some embodiments, the buffer concentration is 15 mM.

[0017] 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, sodium methyl cocoyl, sodium methyl oleyl taurate, polyethylene glycol, polypropylene glycol and copolymers of ethylene and propylene glycol, etc. In some embodiments, the surfactant is a poloxamer or polysorbate, such as poloxamer 188, polysorbate 20, polysorbate 80.

[0018] 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 therebetween.

[0019] In some embodiments, the aforementioned pharmaceutical composition further comprises sugar. The "sugar" of the present disclosure comprises the conventional composition (CH2O) nand derivatives thereof, including monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, and the like. The sugar can be selected from glucose, sucrose, trehalose, α,α-trehalose dihydrate, lactose, fructose, maltose, dextran, glycerol, erythritol, glycerol, arabitol, sylitol, sorbitol, mannitol, milibiose, melezitose, raffinose, mannotriose, stachyose, maltose, lactulose, maltulose, sorbitol, maltitol, lactitol, iso-maltulose, and the like. In some embodiments, the sugar is sucrose.

[0020] 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 therebetween. In some embodiments, the concentration is 80 mg / mL.

[0021] 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.

[0022] 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 of which 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 therebetween.

[0023] 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.

[0024] 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 of which 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 calculated based on protein concentration, ranging from 10 mg / mL to 180 mg / mL, or from 30 mg / mL to 180 mg / mL, or from 50 mg / mL to 150 mg / mL. The term "calculated based on protein concentration" refers to the concentration of the antibody portion of the antibody drug conjugate.

[0025] In some embodiments, the pharmaceutical composition comprises:

[0026] (a) 10 mg / mL to 180 mg / mL of the antibody drug conjugate, based on protein concentration, (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,

[0027] 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 85%.

[0028] In some embodiments, the pharmaceutical composition comprises:

[0029] (a) 10 mg / mL to 180 mg / mL of the antibody drug conjugate, based on protein concentration, (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,

[0030] 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 85%.

[0031] In some embodiments, the pharmaceutical composition comprises:

[0032] (a) 100 mg / mL of the antibody drug conjugate, based on protein concentration, (b) 1 mg / mL of poloxamer, (c) 80 mg / mL of sucrose, and (d) 15 mM succinate-histidine buffer; the pH of the pharmaceutical composition is 5.0,

[0033] 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 85%.

[0034] In some embodiments, any of the aforementioned pharmaceutical compositions is a liquid formulation. The liquid formulation or the reconstituted formulation disclosed herein has good stability. Furthermore, a stable liquid formulation includes a liquid formulation that exhibits desired characteristics after storage at a temperature of 40°C or above for one month.

[0035] In some embodiments, the antibody drug conjugate monomer content of the pharmaceutical compositions described herein is ≥96%, eg, ≥97%, ≥98%, or ≥99%, as measured by HP-SEC after storage at 2-8°C for 3 months.

[0036] In some embodiments, the pharmaceutical compositions of the present disclosure exhibit 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 storage of the formulation at 2-8°C for 3 months.

[0037] In some embodiments, the % antibody drug conjugate monomer measured by HP-SEC after storage of the pharmaceutical compositions of the present disclosure at 2-8°C for 6 months is ≥96%, eg, ≥97%, ≥98%, or ≥99%.

[0038] In some embodiments, the pharmaceutical compositions of the present disclosure exhibit 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 storage of the formulation at 2-8°C for 6 months.

[0039] In some embodiments, the pharmaceutical compositions of the present disclosure have a % antibody drug conjugate monomer measured by HP-SEC of ≥96%, eg, ≥97%, ≥98%, or ≥99% after storage at 25°C for 3 months.

[0040] 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 storage of the formulation at 25°C for 3 months.

[0041] The present disclosure also provides a lyophilized formulation containing an antibody drug conjugate, wherein the formulation can form the pharmaceutical composition described above after reconstitution.

[0042] 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.

[0043] The present disclosure also provides a lyophilized formulation comprising an antibody drug conjugate, wherein the lyophilized formulation is obtained by freeze-drying the pharmaceutical composition of the antibody drug conjugate as described above.

[0044] 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.

[0045] The present disclosure also provides a reconstituted solution containing an antibody drug conjugate, wherein the reconstituted solution is prepared by reconstituted the lyophilized formulation as described above.

[0046] The present disclosure also provides a method for preparing the aforementioned reconstituted solution, which comprises the step of reconstituted the aforementioned lyophilized preparation, wherein the solution used for reconstitution is selected from but not limited to water for injection, physiological saline or glucose solution.

[0047] The lyophilized formulations disclosed herein can maintain good stability.

[0048] The present disclosure also provides a product, comprising a container, wherein the container is filled with the pharmaceutical composition, lyophilized preparation or reconstituted solution as described above. In some embodiments, the container is a neutral borosilicate glass tube injection bottle.

[0049] The antibody-drug conjugates and / or pharmaceutical compositions comprising the antibody-drug conjugates disclosed herein 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 conjugates and / or compositions are used to treat spondyloarthropathies, such as ankylosing spondylitis (AS) or axial spondyloarthritis (axSpA). In certain embodiments, the antibody-drug conjugates and / or compositions are used to treat adult Crohn's disease (CD). In certain embodiments, the antibody-drug conjugates and / or compositions are used to treat pediatric Crohn's disease. In certain embodiments, the antibody-drug conjugates and / or compositions are used to treat ulcerative colitis (UC). In certain embodiments, the antibody-drug conjugates and / or compositions are used to treat plaque psoriasis (Ps). In certain embodiments, the antibody-drug conjugates and / or compositions are used to treat hidradenitis suppurativa (HS). In certain embodiments, the antibody-drug conjugates and / or compositions are used to treat uveitis. In certain embodiments, the antibody-drug conjugates and / or compositions are used to treat Behcet's disease. In certain embodiments, the antibody-drug conjugates and / or compositions are used to treat psoriasis, including plaque psoriasis.

[0050] As is well known to those skilled in the art, one, some or all of the features of the various embodiments described in this 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 in detail below.

[0051] Detailed Description of the Invention

[0052] The present disclosure provides a pharmaceutical composition that is more convenient for production and administration and exhibits stable performance. Undesirable instabilities 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 ​​residues, and toxin dissociation. The pharmaceutical composition described herein can remain stable in a liquid state for extended periods of time.

[0053] the term

[0054] 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 skilled in the art to which the present disclosure belongs.

[0055] Antibody drug conjugates (ADCs) are antibodies that are linked to biologically active cytotoxins or small molecule drugs with cell-killing activity through a linker.

[0056] “Drug loading” or “drug loading” is also called the drug-to-antibody ratio (DAR), which refers to the amount of drug conjugated to each antibody in the ADC.

[0057] "Compound drug loading" or "Compound DAR" refers to the specific amount of drug conjugated to each antibody in the ADC. Exemplary drug loadings can be values ​​of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. For example, a compound drug loading is an integer from 1 to 10.

[0058] The "average drug loading" or "average drug loading," also known as the average DAR, is the average number of drugs conjugated per antibody in the ADC. It can range, for example, from 1 to 10 drugs conjugated per antibody, and in certain embodiments, from 1 to 8 drugs conjugated per antibody, preferably selected from 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, or 10. For example, the average drug loading is an integer or decimal between 1 and 10.

[0059] 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.

[0060] 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., a hydrazone), a protease-sensitive (e.g., a 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).

[0061] 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 through the other end of the linker unit.

[0062] The glucocorticoid receptor agonist drug loading can be controlled by the following non-limiting methods, including:

[0063] (1) Control the molar ratio of the drug linker fragment and the monoclonal antibody,

[0064] (2) Control reaction time and temperature,

[0065] (3) Select different reaction reagents.

[0066] The three letter and one letter codes for amino acids used in this disclosure are as described in J. biol. chem, 243, p3558 (1968).

[0067] The term "antibody" as used herein is used in the broadest sense and encompasses 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. Typically, a natural intact antibody consists of a tetrapeptide chain structure consisting of two identical heavy chains and two identical light chains connected by interchain disulfide bonds.

[0068] The engineered antibodies or antigen-binding fragments disclosed herein can be prepared and purified using 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 preferred existing technology, mammalian expression systems result in glycosylation of antibodies, particularly at the highly conserved N-terminal site in 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 using conventional techniques. For example, purification can be 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 should be immediately frozen, such as at -70°C, or freeze-dried.

[0069] "Buffer" refers to a buffer that tolerates changes in pH through the action of its acid-base conjugate components. Examples of buffers that control pH within an appropriate range include acetate, succinate, gluconate, histidine, oxalate, lactate, phosphate, citrate, tartrate, fumarate, glycylglycine, and other organic acid buffers.

[0070] "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, with histidine-histidine hydrochloride buffer being preferred. Histidine-histidine hydrochloride buffer can be prepared from histidine and hydrochloric acid, or from histidine and histidine hydrochloride.

[0071] "Citrate buffer" is a buffer comprising 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.

[0072] A "succinate buffer" is a buffer comprising succinate ions. Examples of succinate buffers include succinic acid-sodium succinate, succinic acid-potassium succinate, succinic acid-calcium succinate, and the like. A preferred succinate buffer is succinic acid-sodium succinate. For example, the succinic acid-sodium succinate can be prepared from succinic acid and sodium hydroxide, or from succinic acid and sodium succinate.

[0073] "Phosphate buffer" is a buffer containing 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.

[0074] An "acetate buffer" is a buffer comprising acetate ions. Examples of acetate buffers include acetic acid-sodium acetate, histidine-histidine acetate, acetic acid-potassium acetate, acetic acid-calcium acetate, acetic acid-magnesium acetate, and the like. A preferred acetate buffer is acetic acid-sodium acetate.

[0075] A "pharmaceutical composition" refers to a mixture containing one or more antibody-drug conjugates described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to maintain the stability of the antibody active ingredient, facilitate administration to an organism, and promote absorption of the active ingredient, thereby exerting its biological activity.

[0076] In the present disclosure, "pharmaceutical composition" and "formulation" are not mutually exclusive.

[0077] Unless otherwise specified, the solvent in the solution form of the pharmaceutical composition described in the present disclosure is water.

[0078] "Lyophilized formulation" refers to a pharmaceutical composition in liquid or solution form or a formulation or pharmaceutical composition obtained after a liquid or solution formulation has been subjected to a vacuum freeze-drying step.

[0079] As used herein, the terms "about" and "approximately" refer to values ​​that are within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how it is measured or determined (i.e., the limits of the measurement system). For example, in each practice in the art, "about" can mean within 1 or more than 1 standard deviation. Alternatively, "about" or "substantially comprising" 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 indicated, when a specific value appears in the application and claims, the meaning of "about" or "substantially comprising" should be assumed to be within an acceptable error range for that specific value.

[0080] The numerical values ​​in this disclosure are instrumental measurements or calculated values ​​after instrumental measurement, and are subject to a certain degree of error. Generally speaking, a value within a reasonable error range of plus or minus 10% is within the reasonable error range. Of course, the context in which the numerical value is used must be considered. For example, the total impurity content, which is a value with an error variation 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%.

[0081] The pharmaceutical compositions disclosed herein can achieve a stable effect: the antibody drug conjugates therein substantially retain their physical stability and / or chemical stability and / or biological activity after storage; preferably, the pharmaceutical compositions substantially retain their physical and chemical stability and their biological activity after storage. The storage period is generally selected based on the intended shelf life of the pharmaceutical composition. Currently, there are various analytical techniques for measuring the stability of protein or antibody drug conjugates after storage at a selected temperature for a selected period of time.

[0082] A stable formulation is one in which no significant changes are observed after storage at refrigerated temperatures (2-8°C) for at least 3 months, preferably 6 months, and more preferably 1 year. Additionally, stable liquid formulations include those that exhibit the desired characteristics after storage at 25°C for periods of time, including 1 month, 2 months, or 3 months. Furthermore, stable liquid formulations include those that exhibit the desired characteristics after storage at 40°C for periods of time, including 10 days, 20 days, or 1 month. Typical examples of stability include: typically no more than about 10%, preferably no more than about 5%, of the antibody drug conjugate monomers aggregate or degrade as measured by SEC-HPLC. Visually, the formulation is a pale yellow, nearly colorless, clear liquid, or colorless, or clear to slightly opalescent. The concentration, pH, and osmolality of the formulation vary by no more than ±10%. A decrease of no more than about 10%, preferably no more than about 5%, is typically observed. Aggregates typically form no more than about 10%, preferably no more than about 5%.

[0083] 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 by 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 assessed by fluorescence spectroscopy (which determines protein tertiary structure) and by FTIR spectroscopy (which determines protein secondary structure).

[0084] An antibody drug conjugate "retains its chemical stability" in a pharmaceutical formulation if it does not show significant chemical changes. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the protein. 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 with 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.).

[0085] 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.

[0086] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally comprising 1-3 antibody heavy chain variable regions" means that the antibody heavy chain variable region of the specified sequence may but need not be present.

[0087] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0088] The preparation of conventional pharmaceutical compositions can be found in the Chinese Pharmacopoeia.

[0089] The term "carrier" as used in the context of the present invention refers to a system that can alter the way a drug enters the human body and its distribution within the body, control the rate of drug release, and deliver the drug to a targeted organ. Drug carrier release and targeting systems can reduce drug degradation and loss, reduce side effects, and improve bioavailability. For example, polymeric surfactants that can be used as carriers can self-assemble to form various forms of aggregates due to their unique amphiphilic structure, preferably micelles, microemulsions, gels, liquid crystals, vesicles, and the like. These aggregates have the ability to encapsulate drug molecules while also having good membrane permeability, making them excellent drug carriers.

[0090] "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 contacting 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, therapeutic, pharmacokinetics, diagnostics, research and experimental procedures. Treatment of cells includes contacting an agent with a cell, and contacting an agent with a fluid, wherein the fluid is in contact with the cell. "Administering" and "treating" also mean treating, for example, a cell in vitro and ex vivo, by an agent, a diagnostic, a binding composition or by another cell. "Treatment" as applied to a human, veterinary or research subject, refers to therapeutic treatment, prophylactic or preventative measures, research and diagnostic applications.

[0091] "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 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 a therapeutic agent effective to alleviate any specific disease symptom (also referred to as a "therapeutically effective amount") can 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 symptoms of the disease have been alleviated can be assessed by any clinical test method commonly used by a physician or other health care professional to assess the severity or progression of the symptoms. Although embodiments of the present disclosure (e.g., methods of treatment 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.

[0092] An "effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to permit 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 overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0093] "Displacement" refers to the replacement of the solvent system in which the antibody protein or antibody drug conjugate is dissolved. For example, the high-salt or hypertonic solvent system containing the antibody protein or antibody drug conjugate is replaced by a physical manipulation using the buffer system of the stabilizing formulation, thereby allowing the antibody protein or antibody drug conjugate to be present in the stabilizing formulation. Such physical manipulations include, but are not limited to, ultrafiltration, dialysis, or reconstitution followed by centrifugation. DETAILED DESCRIPTION

[0094] The present disclosure is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present disclosure. Experimental methods in the examples herein where specific conditions are not specified generally follow conventional conditions, such as those in the Cold Spring Harbor Laboratory's "Antibody Techniques Laboratory Manual" and "Molecular Cloning Manual," or according to the conditions recommended by the raw material or product manufacturer. Reagents where the specific source is not specified are commercially available.

[0095] The antibody drug conjugates described herein as shown in formula (I) can be prepared according to the method of WO2022166779.

[0096] The equipment used in the preparation and testing process and the calculation method of the results are as follows:

[0097] SEC size exclusion chromatography:

[0098] 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 molecules.

[0099] SEC% (SEC monomer content percentage) = A monomer / A total × 100% (A monomer is the peak area of ​​the main peak monomer in the sample, A total is the sum of all peak areas). ΔSEC% = SEC% of the preparation before stability placement - SEC% of the preparation after stability placement.

[0100] SEC instrument: Agilent 1260; columns: waters, XBridge Protein BEH SEC (300×7.8mm 3.5μm)

[0101] R-CE capillary gel electrophoresis:

[0102] A method of electrophoresis in which gel is transferred to a capillary tube as a supporting medium and samples are separated according to their molecular weight at a certain voltage.

[0103] 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.

[0104] CE measurement instrument: Sciex PA800 plus

[0105] Osmolality determination:

[0106] The freezing point method determines osmotic pressure based on the proportional relationship between freezing point depression and the molar concentration of a solution. It uses a highly sensitive temperature sensor to measure the freezing point of a solution and converts the electrical charge into osmotic pressure. Instrument manufacturer: Loser, model OM815.

[0107] Protein concentration:

[0108] The protein used in the following examples is the antibody-drug conjugate ADC represented by formula (I).

[0109] The protein concentration was determined using a UV-visible spectrophotometer, model: Nano Drop One.

[0110] The protein concentration of the test sample 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

[0111] Right now:

[0112] Where A 246nm : The average absorbance of a single sample of the test solution at a wavelength of 246 nm when the optical path length is 1 cm;

[0113] A 280nm : The average absorbance of a single sample of the test solution at a wavelength of 280 nm when the optical path length is 1 cm;

[0114] E mAb-280 : The mass extinction coefficient of the protein at a wavelength of 280nm is 1.463g -1 cm -1 L;

[0115] E mAb-246 : The mass extinction coefficient of the protein at a wavelength of 246 nm is 0.619 g -1 cm -1 L;

[0116] R: the ratio of the toxin extinction coefficient at 246 nm to that at 280 nm, which is 5.20;

[0117] C mAb : protein concentration, mg / mL;

[0118] l: optical path length, cm (the optical path here is 1 cm).

[0119] If the test solution is diluted, the protein concentration is: C (mg / mL) = C mAb ×N, where N is the dilution multiple.

[0120] Determination of free toxin (RP-UPLC reverse phase method):

[0121] The protein in the sample was removed by ACN precipitation, the supernatant was dried with nitrogen and then redissolved, the toxins in the sample were separated according to their polarity, and the toxin content in the sample was calculated by the linear equation formula of toxin standard concentration-peak area fitting.

[0122] Measurement instrument: Waters ACQuity H-class UPLC;

[0123] Column: Waters BioResolve RP mAb Polyphenyl, 2.7μm, 4.6*100mm

[0124] Example 1. Screening of mixed DAR4 formulation excipients and surfactants

[0125] The antibody drug conjugate of formula (I) was prepared according to the method of WO2022166779 to obtain an ADC with an average DAR value of approximately 4.0, which is a mixture of DAR 0 to DAR 8, wherein the content of the DAR4 component is approximately 70%.

[0126] This antibody-drug conjugate exhibited significant phase separation within the pH range of 5.0 < pH < 7.5. The sample's appearance remained relatively good at pH ≤ 5.0 and pH ≥ 7.5. A 15 mM Tris-HCl system was selected for excipient and surfactant concentration screening. Specific formulation information is shown in Table 1.

[0127] Table 1 Excipient and surfactant screening formula design table

[0128] The prepared samples were filtered and aseptically filled into 2R vials. The samples were shaken at 300 rpm at 25°C for 3 days, frozen and thawed at -35°C / room temperature for 5 cycles, and then frozen at 40°C for 1 week and 40°C for 2 weeks. The stability test results are shown in Table 2.

[0129] Table 2 Screening results of excipients and surfactants

[0130] Note 1: CY = pale yellow; SO = strong opalescence; P+ (a small amount of particles);

[0131] Note 2: F1, F2, and F3 are samples from different sources, so their DARs are different;

[0132] Based on the appearance, SEC, RCE and DAR results, F1 to F3 all produced a small amount of particles after 5 freeze-thaw cycles. Considering that the ADC sample dosage form was lyophilized powder, the samples of formulations F2 and F3 were lyophilized. After reconstitution, the two groups of formulations showed strong opalescence and produced a large number of particles, indicating that the stability of the ADC was poor after being made into lyophilized products in the 15mM Tris-HCl pH8.0 system.

[0133] Example 2. pH screening of mixed DAR4 formulations and screening of surfactant types and concentrations

[0134] Based on the results of excipient and surfactant screening and lyophilization and reconstitution of the 15 mM Tris-HCl system, as well as the DAR value distribution and pI distribution of the 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 range of 5.7-6.3 was performed based on 100 mM Arg-HCl + 4% sucrose + 0.1% PF68. The specific formulation design is shown in Table 3.

[0135] Table 3 pH fine screening and surfactant type and concentration screening prescription design table

[0136] The prepared samples were filtered and aseptically filled into 2R vials. The samples were shaken at 300 rpm at 25°C for 3 days, frozen and thawed at -35°C / room temperature for 5 cycles, and then frozen at 40°C for 1 week and 40°C for 2 weeks. The stability test results are shown in Table 4.

[0137] Table 4 pH fine screening and surfactant type and concentration screening results

[0138] Note: CY = pale yellow; SO = strong opalescence; P+ (a small amount of particles);

[0139] Based on the appearance, SEC, RCE and DAR results, the purity test items of each formulation changed slightly, all within the acceptable range. A small amount of particles appeared in F5 (0.2% PF68) after 5 cycles of freeze-thaw, while no particles were produced in the other formulations. Therefore, the pH / buffer was finally determined to be a 15mM histidine-histidine hydrochloride pH 6.0 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.

[0140] Example 3. Pure DAR4 Formulation pH / Buffer and ADC Concentration Screening

[0141] The DAR 4 component from the mixture of DARs 0 to 8 was separated and purified using 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 the DAR 4 component was 96%. An antibody-drug conjugate (ADC) formulation of formula (I) was prepared according to the composition in Table 5.

[0142] Table 5 pH / Buffer and ADC concentration screening prescription design table

[0143] The prepared samples were filtered and aseptically filled into 2R vials. The samples were shaken at 300 rpm at 25°C for 3 days (the 15 mM His-HCl pH 5.5 formulation was not shaken due to sample size limitations), followed by five cycles of freeze-thaw at -35°C / room temperature, and then at 40°C for 1 week and 2 weeks. Stability testing results are shown in Table 6.

[0144] Table 6 pH / Buffer and ADC concentration screening results

[0145] Note: CL = colorless; LO = slightly opalescent; N / A = not detected;

[0146] Based on appearance, SEC, and RCE results, the pure DAR4 ADC samples showed good stability in both 15 mM His-HCl (pH 5.5) and pH 6.0. Samples F1-F4 were freeze-dried, and the lyophilized products showed good appearance with no bottom collapse. However, upon reconstitution, a large number of fine particles appeared in the samples.

[0147] Example 4. pH / Buffer and Excipient Screening of Pure DAR4 Formulations

[0148] Based on the results of pH / Buffer and ADC concentration screening, the Arg-HCl concentration and the pH of the formulation system were lowered, and 15 mM Succinic pH 5.0 and 15 mM His-HCl pH 5.5 systems were selected for excipient screening. The specific formulation design is shown in Table 7.

[0149] Table 7 pH / Buffer and excipient screening prescription design table

[0150] The prepared samples were filtered and aseptically filled into 2R vials. The samples were shaken at 300 rpm at 25°C for 3 days, freeze-thawed at -35°C / room temperature for 5 cycles, and then frozen at 40°C for 2 weeks and 4 weeks. The stability test results are shown in Table 8.

[0151] Table 8 pH / Buffer and excipient screening results

[0152] Note: CL = colorless; T = clear; LO = slightly opalescent;

[0153] Based on appearance, SEC, and RCE results, the ADC samples exhibited good stability in both 15mM Succinic Acid pH 5.0 and 15mM His-HCl pH 5.5 systems. Comparison of F1 (15mM Succinic Acid pH 5.0 + 8% Sucrose) and F2 (15mM Succinic Acid pH 5.0 + 30mM Arg-HCl + 4% Sucrose) revealed no significant difference in purity between the F1 formulation without Arg-HCl and the F2 formulation, while significantly improving appearance.

[0154] Example 5. pH screening of pure DAR4 formulations

[0155] Based on the results of pH / Buffer and excipient screening, a 15 mM Succinic-His system was selected, with an excipient of 8% Sucrose and a pH range of 5.0-6.0 for pH fine screening. The specific formulation design is shown in Table 9.

[0156] Table 9 pH fine sieve prescription design table

[0157] The prepared samples were filtered and aseptically filled into 2R vials. The samples were shaken at 300 rpm at 25°C for 3 days, subjected to five cycles of freeze-thaw at -35°C / room temperature, and then subjected to 2 weeks at 40°C and 4 weeks at 40°C. Stability tests were performed as shown in Table 10.

[0158] Table 10 pH fine screening results

[0159] Note: CL = colorless; T = clear; LO = slightly opalescent;

[0160] Based on the appearance, SEC, and RCE results, the ADC samples exhibited good stability in the 15mM Succinic-His pH 5.0-6.0 system. The appearance of the low-pH F1 formulation was improved compared to F2 and F3.

[0161] Example 6. Confirmation of the pure DAR4 formulation prescription

[0162] Based on the pH / buffer and excipient screening results, a formulation containing 15 mM Succinic-His (pH 5.0), 80 g / L sucrose, 1 g / L Poloxamer 188, and 100 mg / mL ADC was selected for formulation investigation. The prepared sample was filtered and aseptically filled into 2R vials. The sample was then stored at 40°C for 2 weeks and 40°C for 4 weeks. Stability testing results are shown in Table 11.

[0163] Table 11 Prescription confirmation results

[0164] Note: CL = colorless; T-LO = clear to slightly opalescent; LOD = limit of detection;

[0165] Based on the appearance, SEC, and RCE results, the liquid preparation prepared by increasing the ADC concentration to 100 mg / mL in a 15 mM Succinic-His pH 5.0 system still had good stability.

[0166] Example 7. Study on the stability of ADC preparations

[0167] The stability of the pure DAR4 liquid formulation of Example 6 was investigated, and the results are shown in the following table.

[0168] Table 12 Stability results of pure DAR4 ADC formulations

[0169] The stability of the lyophilized preparation of mixed DAR4 prepared in Example 2 was investigated. The results are shown in the following table.

[0170] Table 13 Mixed DAR4 ADC formulation stability results

[0171] Results showed that both the mixed DAR4-50mg / ml lyophilized formulation and the pure DAR4-100mg / ml liquid formulation exhibited excellent stability at 25°C (3M) and 5°C (6M). Comparing the appearance of the reconstituted liquid and lyophilized formulations, the pure DAR4 formulation remained a colorless, clear liquid even at a higher concentration of 100mg / ml. Reconstituted mixed DAR4 lyophilized formulations at a concentration of 50mg / ml showed no particle formation but exhibited a strong opalescence, demonstrating that the purified DAR4 ADC can be formulated into a high-concentration liquid formulation and can be stored stably without lyophilization.

Claims

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 3.5 to 5.5, more preferably 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. A 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, in, 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.

Images