Treatment methods for TNFα-related diseases

Abstract

The present invention relates to a method for treating TNFα-related diseases by subcutaneously administering an antibody that binds to TNFα (anti-TNFα antibody) or an antigen-binding fragment thereof. The treatment method, composition, kit, and use according to the present invention provide the advantages of shorter administration time and shorter hospital stays for patients compared to intravenous injection, thereby improving convenience and quality of life, and thereby increasing patient satisfaction.

Description

[Technical Field]

[0001] This application relates to a method for treating TNFα-related diseases by subcutaneously administering an antibody that binds to TNFα (anti-TNFα antibody). [Background technology]

[0002] Tumor necrosis factor alpha (TNFα) is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that form the acute phase response. TNFα is associated with a variety of diseases and disorders, including sepsis, infections, autoimmune diseases, and transplant rejection. TNFα promotes immune responses, which cause many clinical problems associated with autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, ulcerative colitis, adult Crohn's disease, childhood Crohn's disease, psoriasis, and psoriatic arthritis. These disorders can be treated with TNFα inhibitors.

[0003] Infliximab is a type of chimeric monoclonal antibody that can act as a TNFα inhibitor. Currently available products include Remsima, Remicade, and Renflexis. All of these products are manufactured as lyophilized powders, which are then redissolved and diluted and administered intravenously according to the dosage and administration method for each disease.

[0004] However, the aforementioned intravenous administration method requires patients to visit the hospital for medication, and the process, including waiting time, takes about 2 to 4 hours, which is a considerable burden or inconvenience for patients. Furthermore, there is the problem that the administration is limited to those who have received medical training.

[0005] Therefore, subcutaneous (SC) administration is proposed as an alternative route of administration. With appropriate training, patients can administer the drug themselves, and the administration time can be reduced from 30-90 minutes to 2-5 minutes.

[0006] Products developed and marketed for both intravenous and subcutaneous administration include Rituxan (Rituximab), Simponi (Golimumab), Herceptin (Trastuzumab), Actemra (Tocilizumab), and Xolair (Omalizumab), but there is currently no subcutaneous formulation of infliximab.

[0007] For subcutaneous administration, the formulation must be a stable liquid containing a high concentration of antibodies, and its efficacy and safety must be proven in clinical practice.

[0008] The applicant has demonstrated that subcutaneous administration of infliximab formulations provides efficacy and safety equivalent to conventional intravenous formulations, while improving convenience for patients and completing a subcutaneous administration therapy that enhances quality of life. [Overview of the project] [Problems that the invention aims to solve]

[0009] The problem that this invention aims to solve is to provide a therapeutic method for the treatment of TNFα-related diseases, which involves subcutaneously administering a pharmaceutical composition containing an anti-TNFα antibody or its antigen-binding fragment.

[0010] Another problem that the present invention aims to solve is to provide a pharmaceutical composition for the treatment of a disease treatable with an anti-TNFα antibody, which contains an anti-TNFα antibody or an antigen-binding fragment thereof and is administered subcutaneously to a subject.

[0011] Another problem that the present invention aims to solve is to provide a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof, and a kit including instructions for subcutaneous administration of the pharmaceutical composition to treat a disease treatable with the anti-TNFα antibody.

[0012] Another problem that the present invention aims to solve is to provide uses for anti-TNFα antibodies or their antigen-binding fragments in the manufacture of drugs that are administered subcutaneously to a subject and are used to treat diseases that are treatable with anti-TNFα antibodies. [Means for solving the problem]

[0013] The present invention provides a method for treating a disease treatable with an anti-TNFα antibody, comprising the step of subcutaneously administering a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof.

[0014] Furthermore, the present invention provides a pharmaceutical composition for the treatment of diseases treatable with anti-TNFα antibodies, which contains an anti-TNFα antibody or an antigen-binding fragment thereof and is administered subcutaneously to a target.

[0015] The present invention also provides (a) a pharmaceutical composition comprising an anti-TNFα antibody or an antigen-binding fragment thereof and a pharmaceutically acceptable carrier; and (b) a kit comprising instructions for subcutaneous administration of the pharmaceutical composition to treat a disease treatable with the anti-TNFα antibody.

[0016] Furthermore, the present invention provides uses for anti-TNFα antibodies or their antigen-binding fragments in the manufacture of pharmaceutical compositions for treating diseases that are administered subcutaneously to a target and are treatable with anti-TNFα antibodies.

[0017] In one embodiment of the present invention, the anti-TNFα antibody may comprise one or more selected from the group consisting of infliximab, adalimumab, certolizumab pegol, golimumab, and biosimilars thereof. In one embodiment of the present invention, the anti-TNFα antibody may be infliximab. In one embodiment of the present invention, the anti-TNFα antibody may include a chimeric human-mouse IgG monoclonal antibody.

[0018] In one embodiment of the present invention, the anti-TNFα antibody may include a light chain variable region containing a CDR1 domain having the amino acid sequence of SEQ ID NO: 1, a CDR2 domain having the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain having the amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region containing a CDR1 domain having the amino acid sequence of SEQ ID NO: 4, a CDR2 domain having the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain having the amino acid sequence of SEQ ID NO: 6.

[0019] In one embodiment of the present invention, the anti-TNFα antibody may include a light chain variable region containing the amino acid sequence of SEQ ID NO: 7; and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 8. In one embodiment of the present invention, the anti-TNFα antibody may include a light chain containing the amino acid sequence of SEQ ID NO: 9; and a heavy chain containing the amino acid sequence of SEQ ID NO: 10.

[0020] In one embodiment of the present invention, the composition may include a surfactant; a sugar or its derivative; and a buffer containing acetate or histidine. In one embodiment of the present invention, the composition may include, as the surfactant, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture thereof. In one embodiment of the present invention, the concentration of the surfactant in the composition may be 0.02 to 0.1% (w / v).

[0021] In one embodiment of the present invention, the composition may include, as the sugar or its derivative, sorbitol, mannitol, trehalose, sucrose, or a mixture thereof. In one embodiment of the present invention, the concentration of the sugar or its derivative in the composition may be 1 to 10% (w / v).

[0022] In one embodiment of the present invention, the composition may include acetate as the buffer. In one embodiment of the present invention, the concentration of the buffer in the composition may be 1 to 50 mM.

[0023] In one embodiment of the present invention, the pH of the composition may be 4.0 to 5.5.

[0024] In one embodiment of the present invention, the composition may contain (A) 90-180 mg / ml of anti-TNFα antibody; (B) 0.02-0.1% (w / v) of polysorbate; (C) 1-10% (w / v) of sorbitol; and (D) 1-50 mM of a buffer containing acetate or histidine.

[0025] In one embodiment of the present invention, the composition may not contain aspartic acid, lysine, arginine, or a mixture thereof. In one embodiment of the present invention, the composition may not contain NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, K2SO4, or a mixture thereof. In one embodiment of the present invention, the composition may not contain a chelating agent.

[0026] In one embodiment of the present invention, the composition may have a viscosity of 0.5 cp to 10.0 cp measured after 1 month at a temperature of 40°C ± 2°C, or a viscosity of 0.5 cp to 5 cp measured after 6 months at a temperature of 5°C ± 3°C.

[0027] In one embodiment of the present invention, the composition may not undergo a reconstitution step, a dilution step, or both steps before use.

[0028] In one embodiment of the present invention, the composition may be filled into a pre-filled syringe or an auto-injector and administered to a subject.

[0029] In one embodiment of the present invention, the subject may include mammals. In one embodiment of the present invention, the subject may include a human being.

[0030] In one embodiment of the present invention, an antibody or its antigen-binding fragment may be administered in a dose of 60 to 300 mg. In one embodiment of the present invention, the antibody or its antigen-binding fragment may be administered in doses of 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mg. In one embodiment of the present invention, an antibody or its antigen-binding fragment may be administered in a dose of 90 to 180 mg. In one embodiment of the present invention, an antibody or its antigen-binding fragment may be administered in an amount of 120 to 240 mg. In one embodiment of the present invention, the antibody or its antigen-binding fragment may be administered in an amount of 80-100 mg, 110-130 mg, 170-190 mg, or 230-250 mg. In one embodiment of the present invention, the antibody or its antigen-binding fragment may be administered in doses of 90 mg, 120 mg, 180 mg, or 240 mg. In one embodiment of the present invention, the antibody or its antigen-binding fragment may be administered in doses of 90 to 180 mg if the patient's weight is less than 80 kg, or 190 to 270 mg if the patient's weight is 80 kg or more.

[0031] In one embodiment of the present invention, an antibody or its antigen-binding fragment may be administered at intervals of 1 to 8 weeks. In one embodiment of the present invention, an antibody or its antigen-binding fragment may be administered at intervals of 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In one embodiment of the present invention, an antibody or its antigen-binding fragment may be administered at intervals of 2 or 4 weeks.

[0032] In one embodiment of the present invention, diseases treatable with anti-TNFα antibodies may include rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis vulgaris, psoriatic arthritis, and ankylosing spondylitis.

[0033] In one embodiment of the present invention, a patient to whom an anti-TNFα antibody is administered may have one or more characteristics selected from the following: a) Inadequate response to disease-modifying antirheumatic drugs (DMARDs), including methotrexate. b) No prior treatment history with methotrexate or other disease-modifying agents (DMARDs). c) Severe axial symptoms and elevated serological indicators related to inflammation are observed, and the patient does not respond adequately to conventional treatment. d) Unresponsive, contraindicated, or intolerant to systemic therapy including methotrexate, cyclosporine, or psoralen ultraviolet A therapy (PUVA). e) The patient does not respond adequately to, cannot tolerate, or is contraindicated for treatment with corticosteroids, 6-mercaptopurine, azathioprine, or immunosuppressants. f) Not responding to conventional treatments, including antibiotics, elimination therapies, or immunosuppressive therapy.

[0034] In one embodiment of the present invention, the patient may be a patient who has been intravenously administered an anti-TNFα antibody or its antigen-binding fragment at least once prior to subcutaneous administration. In one embodiment of the present invention, the patient may be a patient who has been intravenously administered 1 to 10 mg / kg of anti-TNFα antibody or its antigen-binding fragment in a single dose prior to subcutaneous administration.

[0035] In one embodiment of the present invention, the first subcutaneous administration may be performed 2 to 8 weeks after the last intravenous administration. In one embodiment of the present invention, the first subcutaneous administration may be performed four weeks after the last intravenous administration.

[0036] In one embodiment of the present invention, a composition containing an anti-TNFα antibody or its antigen-binding fragment may be administered simultaneously with, before or after, the administration of one or more selected from the group consisting of infliximab, adalimumab, certolizumab pegol, golimumab, and biosimilars thereof.

[0037] In one embodiment of the present invention, a composition containing an anti-TNFα antibody or its antigen-binding fragment may be administered simultaneously with, before, or after the administration of methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, or a combination thereof.

[0038] In one embodiment of the present invention, a patient after subcutaneous administration may have one or more characteristics selected from the following: a) The DAS28 (Disease Activity Score in 28 joints) decreased by at least 2.0. b) The CDAI (Crohn's disease activity index) decreased by at least 70 points. [Effects of the Invention]

[0039] The therapeutic method, composition, kit, or use according to the present invention can treat TNFα-related diseases by subcutaneously administering an anti-TNFα antibody or its antigen-binding fragment. Furthermore, the therapeutic method, composition, kit, or use according to the present invention offers the advantage of improved convenience and quality of life compared to intravenous injection, as it shortens the administration time and reduces the time patients spend in the hospital, thereby increasing patient satisfaction.

[0040] Furthermore, the therapeutic method, composition, kit, or use according to the present invention adds a new therapeutic option to infliximab, offering the advantage of not imposing any burden or resistance on patients or healthcare professionals who have previously received infliximab by intravenous injection, thus avoiding the need for a drug change. [Brief explanation of the drawing]

[0041] [Figure 1] Figure 1 shows an overview of the design of a clinical trial involving subcutaneous administration of infliximab in patients with rheumatoid arthritis (RA). [Figure 2] Figure 2 shows the design outline of a clinical trial involving subcutaneous administration of infliximab in patients with Crohn's disease (CD). [Modes for carrying out the invention]

[0042] The present invention relates to a method for treating a disease treatable with an anti-TNFα antibody, comprising the step of subcutaneously administering a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof.

[0043] To facilitate understanding of the present invention, the terms used herein are defined below. "TNFα" exists as a 17kD secreted form and a 26kD membrane-associated form, and its biologically active form is intended to refer to a human cytokine consisting of a trimer non-covalently bound to the 17kD molecule. The structure of TNFα is described, for example, in the literature [see: Pennica, D., et al. (1984) Nature 312:724-729; Davis, JM, et al. (1987) Biochemistry 26:1322-1326; and Jones, EY, et al. (1989) Nature 338:225-228].

[0044] An "antibody" refers to an immunoglobulin molecule consisting of four polypeptide chains, each containing two heavy chains and two light chains linked together by disulfide bonds. Other naturally occurring antibodies with altered structures, such as camelid antibodies, are also included in this definition. Each heavy chain consists of a heavy chain variable region and a heavy chain constant region. The heavy chain constant region consists of three domains (CH1, CH2, and CH3). Each light chain consists of a light chain variable region and a light chain constant region. The light chain constant region consists of one domain (CL). The heavy chain variable region and the light chain variable region are further subdivided into a hypervariable region called the complementarity-determining region (CDR), which is located along with a more conserved region called the framework region (FR). Each heavy chain variable region and light chain variable region consists of three CDRs and four FRs, which are arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0045] An "antigen-binding fragment" refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen bound by a complete antibody. Examples of antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv.

[0046] A "biosimilar" refers to a biological product that is very similar to an FDA-approved biological product (reference drug) and does not show any clinically significant differences from the reference product in terms of pharmacokinetics, pharmacodynamics, safety, and efficacy.

[0047] "Administration" refers to the act of administering a substance (e.g., an anti-TNFα antibody) to achieve a therapeutic objective (e.g., the treatment of TNFα-related diseases).

[0048] "TNFα-related disorders" refer to local and / or systemic physiological disorders in which TNFα is the primary mediating factor in inducing the symptoms of the disorder. The terms "TNFα-related disorders," "diseases treatable with anti-TNFα," and "diseases in which TNFα activity is harmful" are used interchangeably herein.

[0049] The term "subject" includes all humans and non-human animals. The term "non-human animals" includes, but is not limited to, vertebrates, e.g., non-human primates, sheep, dogs, cats, rabbits, and ferrets; rodents, e.g., mice, rats, and guinea pigs; birds, e.g., chickens; amphibians, and reptiles. In a preferred embodiment, the subject is a mammal, e.g., a non-human primate, sheep, dogs, cats, rabbits, ferrets, or rodents. In a more preferred embodiment, the subject is a human. The terms "subject," "patient," and "individual" are used interchangeably herein.

[0050] "IC50" is intended to refer to the concentration of an inhibitor required to suppress a desired biological outcome, for example, to neutralize cytotoxicity.

[0051] "Kit" refers to a packaged product containing components for administering the TNFα antibody of the present invention for the treatment of TNFα-related diseases. The kit preferably includes a container or box for holding the kit's components. The box or container is accompanied by a protocol or label approved by the Food and Drug Administration. The box or container contains the components of the present invention contained within a plastic, polyethylene, polypropylene, ethylene, or propylene container. The container may be a tube or bottle with a lid. The kit also includes instructions for administering the TNFα antibody of the present invention.

[0052] Various aspects of the present invention will be described in further detail. • The anti-TNFα antibody or its antigen-binding fragment of the present invention In one embodiment of the present invention, the antibody may include a polyclonal antibody, a monoclonal antibody, a recombinant antibody, a single-chain antibody, a hybrid antibody, a chimeric antibody, a humanized antibody, or fragments thereof. A chimeric antibody means an antibody that includes heavy chain and light chain variable region sequences from one species and a constant region sequence from another species. In one embodiment of the present invention, the antibody may include a chimeric human-mouse IgG monoclonal antibody. A chimeric human-mouse IgG monoclonal antibody consists of a mouse heavy chain and light chain variable region and a human heavy chain and light chain constant region bound thereto. A chimeric human-mouse IgG monoclonal antibody can be produced by methods known in the art. For example, infliximab can be produced by the method described in U.S. Patent No. 6,284,471.

[0053] In one embodiment of the present invention, the antibody may include TNFα or an antibody that binds to an epitope of TNFα. The antibody that binds to TNFα or an epitope of TNFα may include one or more selected from the group consisting of infliximab, adalimumab, certolizumab pegol, golimumab, and biosimilars thereof. In one embodiment of the present invention, the antibody may include infliximab.

[0054] In one embodiment of the present invention, the antibody or its antigen-binding fragment may include a light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 6.

[0055] In one embodiment of the present invention, the antibody or its antigen-binding fragment may include a light chain variable region containing the amino acid sequence of SEQ ID NO: 7 and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 8.

[0056] In one embodiment of the present invention, the antibody may include a light chain containing the amino acid sequence of SEQ ID NO: 9 and a heavy chain containing the amino acid sequence of SEQ ID NO: 10.

[0057] • A composition containing the anti-TNFα antibody or its antigen-binding fragment according to the present invention. In this specification, the term "composition containing the anti-TNFα antibody or its antigen-binding fragment of the present invention" is used interchangeably with "stable liquid pharmaceutical formulation."

[0058] The composition according to the present invention comprises (A) an antibody or an antigen-binding fragment thereof; (B) a surfactant; (C) a sugar or a derivative thereof; and (D) a buffering agent.

[0059] In the specification of this application, the term "does not contain" means that the component in question is not present at all. The term also means that the component in question is substantially absent, i.e., included in a manner that does not affect the antibody activity, the stability of the liquid pharmaceutical formulation, and the viscosity, for example, in an amount of 0-1% (w / v), 0-1 ppm (w / v), or 0-1 ppb (w / v) based on the total weight of the liquid pharmaceutical formulation.

[0060] (A) Antibody or its antigen-binding fragment In one embodiment, the composition according to the present invention may contain the anti-TNFα antibody of the present invention or its antigen-binding fragment as described above. The concentration of the antibody or its antigen-binding fragment may be freely adjusted within a range that does not substantially affect the stability and viscosity of the composition according to the present invention. In one embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment may be 10 to 200 mg / mL. In another embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment may be 50 to 200 mg / mL. In yet another embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment may be 80 to 150 mg / mL. In yet another embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment may be 90 to 145 mg / mL. In yet another embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment may be 110 to 130 mg / mL. If the concentration of the antibody or its antigen-binding fragment is within this range, the degree of freedom in dosage and administration cycle can be increased according to the high content of the antibody or its antigen-binding fragment, and excellent long-term stability and low viscosity can be achieved.

[0061] (B) Surfactants Examples of surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate), polyoxyethylene alkyl ethers (e.g., Brij), alkylphenyl polyoxyethylene ethers (e.g., Triton-X), polyoxyethylene-polyoxypropylene copolymers (e.g., Poloxamer, Pluronic), and sodium dodecyl sulfate (SDS).

[0062] In one embodiment of the present invention, the surfactant may include polyoxyethylene sorbitan fatty acid ester (polysorbate). The polysorbate may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture of two or more of these. In another embodiment of the present invention, the polysorbate may include polysorbate 20, polysorbate 80, or a mixture thereof.

[0063] In one embodiment of the present invention, the concentration of the surfactant may be freely adjusted within a range that does not adversely affect the stability and viscosity of the stable liquid pharmaceutical formulation according to the present invention. For example, the concentration of the surfactant may be 0.001 to 5% (w / v), 0.01 to 1% (w / v), or 0.02 to 0.1% (w / v). If the concentration of the surfactant is within this range, excellent long-term stability and low viscosity can be achieved.

[0064] (C) Sugar or sugar derivative The sugar may include monosaccharides, disaccharides, oligosaccharides, polysaccharides, or mixtures of two or more of these. Examples of monosaccharides include, but are not limited to, glucose, fructose, and galactose. Examples of disaccharides include, but are not limited to, sucrose, lactose, maltose, and trehalose. Examples of oligosaccharides include, but are not limited to, fructooligosaccharides, galactooligosaccharides, and mannanoligosaccharides. Examples of polysaccharides include, but are not limited to, starch, glycogen, cellulose, chitin, and pectin.

[0065] The sugar derivatives may include sugar alcohols, sugar acids, or mixtures thereof. Examples of sugar alcohols include, but are not limited to, glycerol, erythritol, treitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fusitol, isitol, inositol, boremitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, and polyglycitol. Examples of sugar acids include, but are not limited to, aldonic acid (such as glyceric acid), urosonic acid (such as neuraminic acid), uronic acid (such as glucuronic acid), and aldalic acid (such as tartaric acid).

[0066] In one embodiment of the present invention, the sugar or its derivative may include sorbitol, mannitol, trehalose, sucrose, or a mixture of two or more of these. In one embodiment of the present invention, the concentration of the sugar or its derivative may be freely adjusted within a range that does not substantially adversely affect the stability and viscosity of the liquid pharmaceutical formulation according to the present invention. For example, the concentration of the sugar or its derivative may be 0.1 to 30% (w / v), 1 to 20% (w / v), or 1 to 10% (w / v). If the concentration of the sugar or its derivative is within this range, excellent long-term stability and low viscosity can be achieved.

[0067] (D) Buffer

[0068] A buffer is a neutralizing substance that minimizes pH changes caused by acids or alkalis. Examples of buffers include phosphate, acetate, succinate, gluconate, glutamate, citrate, and histidine. In one embodiment of the present invention, the buffer may contain acetate or histidine. If both acetate and histidine are included as buffers, stability may decrease.

[0069] In one embodiment of the present invention, the buffer may include acetate. Examples of acetate include, but are not limited to, sodium acetate, zinc acetate, aluminum acetate, ammonium acetate, and potassium acetate. An acid, such as acetic acid, may be further included for pH adjustment. Including acetate as a buffer is most preferable in terms of pH adjustment and stability.

[0070] In one embodiment of the present invention, the buffer may contain histidine. When histidine is used as the buffer, histidine salts, such as histidine chloride, histidine acetate, histidine phosphate, histidine sulfate, etc., may be included. Acids, such as hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, etc., may be included for pH adjustment.

[0071] In one embodiment of the present invention, the stable liquid pharmaceutical formulation does not need to contain citrate, phosphate, or a mixture thereof.

[0072] In one embodiment of the present invention, the content of the buffer (or buffer anion) may be freely adjusted within a range that does not substantially adversely affect the stability and viscosity of the liquid pharmaceutical formulation according to the present invention. For example, the content of the buffer or its anion may be 1 to 50 mM, 5 to 30 mM, or 10 to 25 mM. If the content of the buffer or its anion is within this range, excellent long-term stability and low viscosity can be achieved.

[0073] (E) pH In one embodiment of the present invention, the pH of the stable liquid pharmaceutical composition may be 4.0 to 5.5 or 4.7 to 5.3. If the pH is within this range, excellent long-term stability and low viscosity can be achieved. The pH can be adjusted using a buffer. In other words, if a buffer is included in a predetermined amount, the pH can be within the aforementioned range without the need for a separate pH adjuster. When citrates, phosphates, or mixtures thereof are used as buffers, it may be difficult to achieve the pH within the aforementioned range. If an acid (e.g., hydrochloric acid) or a base (e.g., sodium hydroxide) is further included as a separate pH adjuster, the stability of the antibody may decrease.

[0074] (F) Other ingredients In one embodiment of the present invention, the stable liquid pharmaceutical formulation does not have to contain aspartic acid, lysine, arginine, or a mixture thereof. If these amino acids are included, the formulation may be in a solid state. In one embodiment of the present invention, the stable liquid pharmaceutical formulation may contain one or more of the remaining amino acids excluding the three amino acids mentioned above. In this case, the amino acids may be included in a range of 5% (w / v) or less, for example, in the range of 0.001 to 5% (w / v), 0.001 to 1% (w / v), 0.01 to 5% (w / v), 0.01 to 1% (w / v), 0.1 to 5% (w / v), or 0.1 to 1% (w / v).

[0075] In another embodiment of the present invention, the stable liquid pharmaceutical formulation may contain taurine. In this case, the taurine may be contained in a range of 5% (w / v) or less, for example, in the range of 0.001 to 5% (w / v), 0.001 to 1% (w / v), 0.01 to 5% (w / v), 0.01 to 1% (w / v), 0.1 to 5% (w / v), or 0.1 to 1% (w / v).

[0076] In one embodiment of the present invention, a stable liquid pharmaceutical formulation does not necessarily have to contain metal salts such as NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, and K2SO4. If these metal salts are included, precipitation may occur, and the formulation may take on a gelatinous form, reducing its stability.

[0077] In one embodiment of the present invention, the stable liquid pharmaceutical formulation does not need to contain a chelating agent (e.g., EDTA). If a chelating agent is included, the oxidation rate may increase.

[0078] In one embodiment of the present invention, a stable liquid pharmaceutical formulation may not contain preservatives. Examples of preservatives include octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl alcohol, benzyl alcohol, alkylparabens, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol. If preservatives are included, they may not contribute to improving stability.

[0079] In one embodiment of the present invention, the stable liquid pharmaceutical formulation of the present invention may further contain additives known in the art, provided that they do not substantially affect the antibody activity, the stability of the formulation, and the low viscosity. For example, it may further contain an aqueous carrier, an antioxidant, or a mixture of two or more of these. The aqueous carrier is a pharmaceutically acceptable (safe and non-toxic when administered to humans) carrier useful for the manufacture of liquid pharmaceutical formulations. Examples of aqueous carriers include, but are not limited to, sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), sterile salt aqueous solution, Ringer's solution, and dextrose. Examples of antioxidants include, but are not limited to, ascorbic acid.

[0080] (G) “Stable” liquid pharmaceutical formulations In the term "stable" in the present invention's "stable" liquid pharmaceutical formulations, the antibody according to the present invention substantially retains its physical stability and / or chemical stability and / or biological activity during the manufacturing process and / or storage. Various analytical techniques for measuring antibody stability are readily available in the art.

[0081] Physical stability can be evaluated by methods known in the art, which include measuring the apparent attenuation of light (absorption or optical density) of the sample. Such light attenuation measurements are related to the turbidity of the formulation. In addition, physical stability can be assessed by measuring the content of high molecular weight components, low molecular weight components, intact protein content, and the number of insoluble foreign particles.

[0082] Chemical stability can be evaluated, for example, by detecting and quantifying chemically altered forms of antibodies. Chemical stability also includes charge changes (e.g., those resulting from deamidation or oxidation) that can be evaluated by ion-exchange chromatography. Charge variants (acidic or basic peaks), etc., can also be measured to indicate chemical stability.

[0083] Biological activity can be evaluated by methods known in the art, for example, antigen binding affinity can be measured by ELISA.

[0084] In one embodiment of the present invention, the liquid pharmaceutical formulation can be stabilized over a long period of time. In one embodiment of the present invention, the term “stable” liquid pharmaceutical formulation means a liquid pharmaceutical formulation that satisfies one or more of the following conditions:

[0085] Turbidity - Absorbance A measured by spectrophotometer after storage at 40°C ± 2°C for 4 weeks. 600 However, liquid pharmaceutical preparations where the value is 0-0.0300 or 0-0.0700;

[0086] - Absorbance A measured by spectrophotometer after storage for 4 weeks at a temperature of 40°C ± 2°C, relative humidity of 75 ± 5%, and in a sealed environment. 600 However, liquid pharmaceutical preparations where the value is 0-0.0300 or 0-0.0700;

[0087] Main component content (main peak) - A liquid pharmaceutical preparation in which the main component, measured by SE-HPLC after storage at 40°C ± 2°C for 4 weeks, is 98% to 100%. - A liquid pharmaceutical preparation in which the main component, measured by SE-HPLC after being stored for 4 weeks at a temperature of 40°C ± 2°C, relative humidity of 75 ± 5%, and under sealed conditions, is 98-100%.

[0088] High molecular weight components (peaks with a retention time earlier than the main peak (intact IgG)) - A liquid pharmaceutical preparation in which the high molecular weight component, measured by SE-HPLC after storage at 5°C ± 3°C for 12 months, is 0-1.00%. - A liquid pharmaceutical preparation in which the high molecular weight component, measured by SE-HPLC after storage at 5°C ± 3°C under sealed conditions for 12 months, is 0-1.00%.

[0089] Low molecular weight components (peaks with a later retention time relative to the main peak (intact IgG)) - A liquid pharmaceutical preparation in which the low molecular weight component, measured by SE-HPLC after storage at 5°C ± 3°C for 12 months, is 0-0.40%; - A liquid pharmaceutical preparation in which the low molecular weight component, measured by SE-HPLC after storage at 5°C ± 3°C and under sealed conditions for 12 months, is 0-0.40%.

[0090] Content of intact immunoglobulin G - A liquid pharmaceutical preparation in which the intact immunoglobulin G content (Intact IgG%) measured by non-reducing CE-SDS after 12 months of storage at 5°C ± 3°C is 94.0% to 100%; - A liquid pharmaceutical preparation in which the intact immunoglobulin G content (Intact IgG%) measured by non-reducing CE-SDS after 12 months of storage at a temperature of 5°C ± 3°C under sealed conditions is 94.0% to 100%. - A liquid pharmaceutical preparation in which the intact immunoglobulin G content (Intact IgG%) measured by non-reducing CE-SDS after storage at 40°C ± 2°C for 4 weeks is 94.0% to 100%; - A liquid pharmaceutical preparation in which the intact immunoglobulin G content (Intact IgG%) measured by non-reducing CE-SDS after storage for 4 weeks at a temperature of 40℃±2℃, relative humidity of 75±5%, and under sealed conditions is 94.0% to 100%;

[0091] Content of intact heavy and light chains - A liquid pharmaceutical preparation in which the intact heavy and light chain content (Intact HC+ LC%), measured by reduced CE-SDS after storage at 5°C ± 3°C for 12 months, is 99.0% to 100%; - A liquid pharmaceutical preparation in which the intact heavy and light chain content (Intact HC+ LC%), measured by reduced CE-SDS after 12 months of storage at 5°C ± 3°C under sealed conditions, is 99.0% to 100%; - A liquid pharmaceutical preparation in which the intact heavy and light chain content (Intact HC+ LC%), measured by reduced CE-SDS after storage at 40°C ± 2°C for 4 weeks, is 98.0% to 100%; - A liquid pharmaceutical preparation in which the intact heavy and light chain content (Intact HC+ LC%), measured by reduced CE-SDS after storage for 4 weeks at a temperature of 40°C ± 2°C, relative humidity of 75 ± 5%, and sealed conditions, is 98.0% to 100%;

[0092] Number of insoluble foreign particles - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (10.00 μm ≤, <400.00 μm) measured by HIAC after storage at a temperature of 5°C ± 3°C for 12 months is between 0 and 1,000; - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (10.00 μm ≤, <400.00 μm) measured by HIAC after storage at a temperature of 5°C ± 3°C and sealed conditions for 12 months is between 0 and 1000; - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (1.00 μm ≤, <100.00 μm) measured by MFI after storage at 40°C ± 2°C for 4 weeks is between 0 and 30,000; - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (1.00 μm ≤, <100.00 μm) measured by MFI after storage for 4 weeks at a temperature of 40°C ± 2°C, relative humidity of 75 ± 5%, and sealed conditions is between 0 and 30,000; - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (10.00 μm ≤, <100.00 μm) measured by MFI after storage at 40°C ± 2°C for 4 weeks is between 0 and 200; - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (10.00 μm ≤, <100.00 μm) measured by MFI after storage for 4 weeks at a temperature of 40°C ± 2°C, relative humidity of 75 ± 5%, and sealed conditions is between 0 and 200; - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (10.00 μm ≤, <100.00 μm) measured by MFI after storage at 40°C ± 2°C for 6 weeks is between 0 and 500; - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (10.00 μm ≤, <100.00 μm) measured by MFI after storage for 6 weeks at a temperature of 40°C ± 2°C, relative humidity of 75 ± 5%, and sealed conditions is between 0 and 500;

[0093] oxidation rate - A liquid pharmaceutical preparation in which the oxidation rate of heavy chain Met255, measured by LC-MS after storage at 40°C ± 2°C for 4 weeks, is 0% to 2.5%. - A liquid pharmaceutical preparation in which the oxidation rate of heavy chain Met255, measured by LC-MS after storage for 4 weeks at a temperature of 40°C ± 2°C, relative humidity of 75 ± 5%, and sealed conditions, is 0% to 2.5%;

[0094] Charge variant - A liquid pharmaceutical preparation in which the acidic peak measured by IEC-HPLC after storage at 40°C ± 2°C for 4 weeks is 20% to 35%; - A liquid pharmaceutical preparation in which the acid peak measured by IEC-HPLC after storage for 4 weeks at a temperature of 40°C ± 2°C, relative humidity of 75 ± 5%, and sealed conditions is 20% to 35%; - A liquid pharmaceutical preparation in which the basic peak measured by IEC-HPLC after storage at 40°C ± 2°C for 4 weeks is 33% to 40%; - A liquid pharmaceutical preparation in which the basic peak measured by IEC-HPLC after storage for 4 weeks at a temperature of 40°C ± 2°C, relative humidity of 75 ± 5%, and sealed conditions is 33% to 40%;

[0095] TNFα binding affinity - A liquid pharmaceutical preparation having a TNFα binding affinity of 80% to 120% as measured by ELISA after being stored at a temperature of 5°C ± 3°C for 12 months; and - A liquid pharmaceutical formulation in which the binding affinity of TNFα, measured by ELISA after being stored for 12 months at a temperature of 5°C ± 3°C under sealed conditions, is 80% to 120%.

[0096] In one embodiment of the present invention, the viscosity measured after one month at a temperature of 40°C ± 2°C may be 0.5 cp to 10.0 cp. In another embodiment of the present invention, the viscosity measured after six months at a temperature of 5°C ± 3°C may be 0.5 cp to 5.0 cp.

[0097] (H) Method for producing a stable liquid pharmaceutical formulation The stable liquid pharmaceutical formulation of the present invention can be manufactured by known methods and is not limited to any particular method. For example, a liquid pharmaceutical formulation can be manufactured by adjusting the pH of a solution containing a surfactant and a sugar or its derivative while adding a buffer, and then adding an antibody to the mixed solution. Alternatively, a liquid pharmaceutical formulation can be manufactured by first producing a solution containing some excipients in the final stage of the purification process, and then adding the remaining components. For example, a liquid pharmaceutical formulation can be manufactured by first producing a solution containing an antibody, a buffer, and a sugar or its derivative in the final stage of the purification process, and then adding a surfactant to the solution.

[0098] Furthermore, the manufacturing process of the aforementioned formulation may or may not include a freeze-drying step. If the freeze-drying process is not included, for example, the liquid pharmaceutical formulation of the present invention can be manufactured and immediately placed in a sealed container after processing such as sterilization.

[0099] If the process includes a freeze-drying step, for example, the liquid pharmaceutical formulation of the present invention can be manufactured by producing and freeze-drying the liquid pharmaceutical formulation of the present invention, or by producing, freeze-drying and storing the liquid pharmaceutical formulation of the present invention, and then replenishing or replacing the components that have been removed or altered by freeze-drying and / or storage. Alternatively, the liquid pharmaceutical formulation of the present invention can be manufactured by freeze-drying only the components of the liquid pharmaceutical formulation of the present invention that have been excluded from the components that may be removed or altered by freeze-drying and / or storage, or by freeze-drying only those components and then storing them, and then adding the excluded components.

[0100] The applicant's previously filed patent, Korean Patent Application No. 10-2017-0081814, is incorporated by reference into the specification of this invention.

[0101] • A method for treating diseases treatable with the anti-TNFα antibody of the present invention. The present invention provides a method for treating a disease treatable with anti-TNFα, comprising the step of subcutaneously administering a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof.

[0102] In one embodiment of the present invention, the antibody may comprise one or more selected from the group consisting of infliximab, adalimumab, certolizumab pegol, golimumab, and biosimilars thereof. In one embodiment of the present invention, the antibody may include infliximab. In one embodiment of the present invention, the antibody may include a chimeric human-mouse IgG monoclonal antibody.

[0103] In one embodiment of the present invention, the antibody or its antigen-binding fragment may include a light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 6.

[0104] In one embodiment of the present invention, the antibody or its antigen-binding fragment may include a light chain variable region containing the amino acid sequence of SEQ ID NO: 7 and a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 8.

[0105] In one embodiment of the present invention, the antibody may include a light chain containing the amino acid sequence of SEQ ID NO: 9 and a heavy chain containing the amino acid sequence of SEQ ID NO: 10.

[0106] In one embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment may be 10 to 200 mg / mL.

[0107] The present invention also provides a method for treating a disease treatable with anti-TNFα, comprising the step of subcutaneously administering a composition comprising (A) an anti-TNFα antibody or an antigen-binding fragment thereof; (B) a surfactant; (C) a sugar or a derivative thereof; and (D) a buffering agent.

[0108] In one embodiment of the present invention, (B) the surfactant may include a polysorbate, a poloxamer, or a mixture thereof. In one embodiment of the present invention, (B) the surfactant may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture of two or more of these. In one embodiment of the present invention, (B) the surfactant may include polysorbate 80. In one embodiment of the present invention, the concentration of (B) surfactant may be 0.02 to 0.1% (w / v).

[0109] In one embodiment of the present invention, (C) sugar comprises monosaccharides, disaccharides, oligosaccharides, polysaccharides, or a mixture of two or more of these, and the sugar derivative may comprise sugar alcohols, sugar acids, or a mixture thereof. In one embodiment of the present invention, (C) sugar or its derivative may include sorbitol, mannitol, trehalose, sucrose, or a mixture of two or more of these. In one embodiment of the present invention, the concentration of (C) sugar or its derivative may be 1 to 10% (w / v).

[0110] In one embodiment of the present invention, (D) the buffer may include acetate or histidine. In one embodiment of the present invention, the content of (D) buffering agent may be 1 to 50 mM.

[0111] In one embodiment of the present invention, the pH of the composition may be 4.0 to 5.5.

[0112] In one embodiment of the present invention, the composition may not contain aspartic acid, lysine, arginine, or a mixture thereof. In one embodiment of the present invention, the composition may not contain NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, K2SO4, or a mixture thereof. In one embodiment of the present invention, the composition may not contain a chelating agent. In one embodiment of the present invention, the composition may not contain a preservative.

[0113] In one embodiment of the present invention, the composition may further contain an aqueous carrier, an antioxidant, or a mixture of two or more of these.

[0114] In one embodiment of the present invention, the composition may have a viscosity of 0.5 cp to 10.0 cp measured after one month at a temperature of 40°C ± 2°C, or a viscosity of 0.5 cp to 5.0 cp measured after six months at 5°C ± 3°C.

[0115] In one embodiment of the present invention, the composition may also include (A) an antibody or antigen-binding fragment thereof comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 6; (B) a surfactant; (C) a sugar or a derivative thereof; and (D) a buffer comprising acetate or histidine.

[0116] In one embodiment of the present invention, the composition may also contain (A) 90-180 mg / ml of an antibody or antigen-binding fragment thereof, comprising a light chain variable region including a CDR1 domain containing the amino acid sequence of SEQ ID NO: 1, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain containing the amino acid sequence of SEQ ID NO: 3; and a heavy chain variable region including a CDR1 domain containing the amino acid sequence of SEQ ID NO: 4, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain containing the amino acid sequence of SEQ ID NO: 6; (B) 0.02-0.1% (w / v) of a surfactant; (C) 1-10% (w / v) of a sugar or its derivative; and (D) 1-50 mM of a buffer containing acetate or histidine.

[0117] In one embodiment of the present invention, the composition may be administered subcutaneously.

[0118] In one embodiment of the present invention, the composition may not undergo a reconstitution step, a dilution step, or both steps before use. In one embodiment of the present invention, the stable composition may be filled into a pre-filled syringe before use. In one embodiment of the present invention, the composition may be contained in an auto-injector before use.

[0119] Diseases treatable with anti-TNFα antibodies In one embodiment of the present invention, the diseases treatable with anti-TNFα antibodies are selected from the group consisting of rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis vulgaris, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, neonatal hemolytic disease, inflammatory bowel disease, multiple sclerosis, organ transplant rejection, non-Hodgkin lymphoma, metastatic cancer, retinopathy of prematurity, ovarian cancer, gastric cancer, head and neck cancer, osteoporosis, paroxysmal nocturnal hemoglobinuria, invasive candidiasis, breast cancer, melanoma, chronic lymphocytic leukemia, acute myeloid leukemia, renal cell carcinoma, colon cancer, rectal cancer, asthma, nasopharyngeal cancer, hemorrhagic shock, Staphylococcus aureus infection, and follicular lymphoma.

[0120] In one embodiment of the present invention, a disease treatable with an anti-TNFα antibody may be a disease treatable with intravenous administration of infliximab.

[0121] In one embodiment of the present invention, diseases treatable with an anti-TNFα antibody may be rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis vulgaris, psoriatic arthritis, or ankylosing spondylitis, which can be treated by intravenous administration of infliximab.

[0122] In one embodiment of the present invention, the target population for administration of the anti-TNFα antibody is patients who have an insufficient response to disease-modifying antirheumatic drugs (DMARDs), including methotrexate.

[0123] In one embodiment of the present invention, the target population for administration of the anti-TNFα antibody is patients who have not received prior treatment with methotrexate or other disease-modifying agents (DMARDs).

[0124] In one embodiment of the present invention, the target population for administration of anti-TNFα antibodies is patients who do not respond adequately to conventional treatment and who exhibit severe axial symptoms and elevated serological indicators related to inflammation.

[0125] In one embodiment of the present invention, the target patients for administration of the anti-TNFα antibody are those who do not respond to, are contraindicated for, or are intolerant to systemic therapies including methotrexate, cyclosporine, or psoralen ultraviolet A therapy (PUVA).

[0126] In one embodiment of the present invention, the target patients for administration of the anti-TNFα antibody are those who do not respond adequately to, cannot tolerate, or for whom such treatments are contraindicated, with corticosteroids, 6-mercaptopurine, azathioprine, or immunosuppressants.

[0127] In one embodiment of the present invention, the target patients for administration of the anti-TNFα antibody are those who do not respond to conventional treatments, including antibiotics, efflux methods, or immunosuppressive therapy.

[0128] Dosage and administration interval In one embodiment of the present invention, the anti-TNFα antibody or its conjugated fragment may be administered in doses of 60 to 300 mg. Specifically, doses of 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mg may be administered.

[0129] In another embodiment of the present invention, the anti-TNFα antibody or its conjugated fragment may be administered in an amount of 90 to 180 mg. In yet another embodiment, the anti-TNFα antibody or its conjugated fragment may be administered in an amount of 120 to 240 mg. In yet another embodiment, the anti-TNFα antibody or its conjugated fragment may be administered in an amount of 120 to 240 mg.

[0130] In one embodiment of the present invention, the anti-TNFα antibody or its conjugated fragment may be administered in doses of 90 to 180 mg if the patient's weight is less than 80 kg, or 190 to 270 mg if the patient's weight is 80 kg or more.

[0131] In one embodiment of the present invention, an anti-TNFα antibody or its conjugated fragment may be administered at intervals of 1 to 8 weeks. Specifically, it may be administered at intervals of 1 week, 1.5 weeks, 2 weeks, 2.5 weeks, 3 weeks, 3.5 weeks, 4 weeks, 4.5 weeks, 5 weeks, 5.5 weeks, 6 weeks, 6.5 weeks, 7 weeks, 7.5 weeks, or 8 weeks.

[0132] In another embodiment of the present invention, the anti-TNFα antibody or its conjugated fragment may be administered at intervals of 2 to 4 weeks.

[0133] Pre-administration The procedure may include a step in which the anti-TNFα antibody or its antigen-binding fragment is administered intravenously, prior to the subcutaneous administration step of the anti-TNFα antibody or its binding fragment.

[0134] In one embodiment of the present invention, a step in which an anti-TNFα antibody or its antigen-binding fragment is administered intravenously at a dose of 1 to 10 mg / kg may be included prior to the subcutaneous administration step. Specifically, this may include a step in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / kg is administered intravenously.

[0135] In yet another embodiment of the present invention, a step of intravenous administration of 2 to 8 mg / kg of anti-TNFα antibody or its antigen-binding fragment may be included prior to the subcutaneous administration step. In yet another embodiment of the present invention, a step of intravenous administration of 3 to 5 mg / kg of anti-TNFα antibody or its antigen-binding fragment may be included prior to the subcutaneous administration step.

[0136] In one embodiment of the present invention, a step may be included in which an anti-TNFα antibody or its antigen-binding fragment is administered intravenously at intervals of 1 to 8 weeks prior to the subcutaneous administration step. Specifically, this may include a step in which the antibody is administered intravenously at intervals of 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 weeks.

[0137] In yet another embodiment of the present invention, a step may be included prior to the subcutaneous administration step in which an anti-TNFα antibody or its antigen-binding fragment is administered intravenously at intervals of 2 to 4 weeks.

[0138] In one embodiment of the present invention, a step is included in which an anti-TNFα antibody or its antigen-binding fragment is administered intravenously prior to the subcutaneous administration step, but the interval between the last intravenous administration and the first subcutaneous administration may be 1 to 8 weeks. Specifically, the step may include administration at intervals of 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 weeks.

[0139] In yet another embodiment of the present invention, a step is included prior to the subcutaneous administration step in which an anti-TNFα antibody or its antigen-binding fragment is administered intravenously, wherein the interval between the last intravenous administration and the first subcutaneous administration is 2 to 4 weeks.

[0140] Concomitant administration Other biological agents or chemotherapeutic agents may be administered together with the anti-TNFα antibody of the present invention or its antigen-binding fragment. The drug is administered simultaneously with, before, or after the administration of the anti-TNFα antibody or its antigen-binding fragment.

[0141] In one embodiment of the present invention, the biological agent administered concomitantly may include etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, or a combination thereof.

[0142] In one embodiment of the present invention, the chemotherapy agent administered in combination may include a disease-modifying antirheumatic drug (DMARD).

[0143] In one embodiment of the present invention, the chemotherapy agent administered in combination may include methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, or a combination thereof.

[0144] ·product The present invention also provides a product comprising a composition containing an anti-TNFα antibody or a conjugated fragment thereof, and a container for containing the composition in a sealed state.

[0145] The composition containing the anti-TNFα antibody or its conjugated fragment is as described above.

[0146] In one embodiment of the present invention, the container may be made of a material such as glass, polymer (plastic), or metal, but is not limited thereto. In one embodiment of the present invention, the container may be a bottle, vial, cartridge, syringe (pre-filled syringe, auto-injector), or tube, but is not limited thereto. In one embodiment of the present invention, the container may be a glass or polymer vial, or a glass or polymer pre-filled syringe.

[0147] The specific product forms of the vials, cartridges, pre-filled syringes, and auto-injectors, and the methods for filling the stable liquid pharmaceutical formulations into the vials, cartridges, pre-filled syringes, and auto-injectors, etc., can be readily obtained or implemented by any person with ordinary skill in the art to which the present invention belongs. For example, U.S. Patents 4,861,335 and 6,331,174 disclose specific product forms and filling methods for pre-filled syringes. For example, U.S. Patents 5,085,642 and 5,681,291 disclose specific product forms and assembly methods for auto-injectors. As for the vials, cartridges, pre-filled syringes, and auto-injectors, commercially available products may be used as is, or products that have been custom-made considering the physical properties of the composition containing the anti-TNFα antibody or its conjugated fragments, the administration site, the dosage, etc., may be used.

[0148] In one embodiment of the present invention, the inside of the container does not need to be coated with silicone oil. If it is coated with silicone oil, stability may be reduced. The container may be for single-dose or multiple-dose use.

[0149] In one embodiment of the present invention, the product may further include instructions providing a method of use, storage, or both of the method of use of the composition containing the anti-TNFα antibody or its conjugated fragment. The method of use may include the treatment of diseases in which TNFα activity is harmful, and may include the route of administration, the dosage, and the timing of administration.

[0150] In one embodiment of the present invention, the product may include other tools necessary from a commercial and user perspective, such as needles, syringes, and the like.

[0151] The present invention will be described in detail below with reference to examples. The following examples are for illustrative purposes only, and the scope of the present invention is not limited by these examples.

[0152] Example 1. Evaluation of the safety and efficacy of subcutaneous administration of infliximab in patients with rheumatoid arthritis (RA). This infliximab clinical trial is a randomized, multicenter, parallel-group, phase 1 / 3 study designed to evaluate the efficacy, pharmacokinetics, and safety of subcutaneous infliximab (infliximab SC) and intravenous infliximab (infliximab IV) in combination with methotrexate (MTX) monotherapy in patients with active rheumatoid arthritis who have not shown sufficient response to methotrexate monotherapy for more than 3 months. This clinical trial consists of two parts.

[0153] Part 1 is designed to determine the optimal dose of infliximab SC and the area under the steady-state concentration-time curve (AUC) between weeks 22 and 30. τ The optimal dose of infliximab SC corresponding to 3 mg / kg infliximab IV over the first 30 weeks was determined by this. The duration of the Part 1 clinical trial was up to 65 weeks, including screening (up to 3 weeks) and the final visit to the end of the clinical trial.

[0154] Part 2 is designed to demonstrate the non-inferiority of efficacy between infliximab SC and infliximab IV. It will demonstrate that infliximab SC is not inferior to infliximab IV in terms of efficacy, based on clinical response to the change from baseline in the Disease Activity Score in 28 joints (DAS28) (C-Reactive Protein [CRP]) at week 22. The dosage and dosing interval for infliximab SC in Part 2 was set at 120 mg every two weeks.

[0155] Part 1 Patients were eligible to enroll in this clinical trial if they met all of the following criteria. *The patient has active disease defined as having at least 6 swollen joints and tender joints out of 28 joints, and a serum C-reactive protein (CRP) concentration >0.6 mg / dL. *Patients had received treatment with methotrexate 12.5-25 mg / week (or 10-25 mg / week for patients in Korea) for at least 3 months prior to administration of the study drug (day 0), and continued to receive the same dose for the last 4 weeks.

[0156] Patients were ineligible to enroll in the clinical trial if they met any of the following criteria: *The patient has previously received biological agents for the treatment of rheumatoid arthritis (RA) and / or TNFα inhibitors for the treatment of other conditions. *Patients who are allergic to infliximab or any other murin and / or human protein excipients, or who have hypersensitivity to immunoglobulin products.

[0157] This clinical trial consisted of three clinical trial periods: screening, administration period, and completion of the clinical trial. Screening was conducted between 21 days and 1 day before the first dose of the study drug to assess patients' eligibility for the study. All tests were performed, including tests for hepatitis B, C, and human immunodeficiency virus (HIV-1, HIV-2) infection, urine and serum pregnancy tests in women of childbearing age, rheumatoid factor, anti-cyclic citrullinated peptide, 12-lead electrocardiogram, and laboratory tests. Interferon-gamma release assays (IGRA) and chest X-rays were also performed to exclude patients with tuberculosis.

[0158] All patients enrolled in the clinical trial received one dose of infliximab IV in weeks 0 and 2. Folic acid was administered concomitantly with MTX and the study drug to minimize or prevent adverse events related to MTX side effects, and patients were instructed to take it while maintaining the MTX dose from the start to the end of the clinical trial. In addition, to prevent hypersensitivity reactions to the study drug, patients could, at the discretion of the investigator, receive pre-medication 30 to 60 minutes before the start of administration of the study drug, including, but not limited to, antihistamines [2-4 mg chlorpheniramine equivalent dose], hydrocortisone, paracetamol, and / or non-sedating antihistamines [10 mg cetirizine equivalent dose].

[0159] After two complete doses were administered, patients without safety concerns were randomly assigned to either the infliximab SC or infliximab IV group 42 days prior to administration, at the discretion of the investigators. Randomization was stratified by country, serum CRP concentration at week 2 (≤0.6 mg / dL or >0.6 mg / dL), and body weight at week 6 (≤70 kg or >70 kg). A total of 50 patients with active rheumatoid arthritis were enrolled, of which 48 were randomly assigned to four clinical trial cohorts in a 1:1:1:1 ratio and received the study drug until week 54 (Table 1).

[0160] [Table 1]

[0161] Patients assigned to Cohort 1 received an additional seven doses of infliximab IV at week 6 and every eight weeks thereafter (weeks 14, 22, 30, 38, 46, and 54). Patients assigned to Cohorts 2, 3, and 4 received their first dose of infliximab SC at week 6, with additional doses of infliximab SC administered every two weeks until week 54. The initial dose assigned to all patients in Cohorts 2, 3, and 4 was adjusted to the optimal dose after dose verification. Subsequently, additional SC injections at the optimal dose were administered until week 54. Infliximab SC was administered by healthcare professionals during visits to each laboratory (weeks 6, 8, 10, 14, 22, 24, 26, 28, 30, 38, 46, and 54), while in other weeks (weeks 12, 16, 18, 20, 32, 34, 36, 40, 42, 44, 48, 50, and 52), patients could self-administer the injection if they had received training in the appropriate injection technique and the investigator deemed them suitable.

[0162] Patients visited the laboratory at predetermined time intervals for clinical evaluation and blood sampling. During each visit, patients were questioned about adverse events (AEs) and concomitant medications, and their clinical signs and symptoms of TB were monitored. Primary pharmacokinetic endpoints were evaluated during the maintenance phase from week 22 to week 30, secondary pharmacokinetic endpoints were evaluated during the administration period up to week 54, and blood samples for analysis, efficacy, disease progression (PD), and safety evaluations were collected and evaluated at the times indicated in the evaluation schedule.

[0163] End-of-clinical trial visits were conducted at the end of the maintenance phase or, if a patient dropped out, 8 weeks after the last dose. Every effort was made to ensure that all clinical trials were completed 8 weeks after the patient received their last dose.

[0164] Part 2 Part 2 was initiated based on the independent data safety monitoring committee's review of the PK modeling report data, including PK, efficacy, PD, and safety data for the first 30 weeks confirmed in Part 1.

[0165] Part 2 consisted of three clinical trial periods, including screening, a 24-week public period following a double-blind period up to week 30, and the end of the clinical trial. Screening was performed between 42 days and 0 days before the first dose of the study drug to assess patients' eligibility for the study. All tests were performed, including tests for hepatitis B, C, and human immunodeficiency virus (HIV-1, HIV-2) infection, urine and serum pregnancy tests in women of childbearing age, rheumatoid factor, anti-cyclic citrullinated peptide, 12-lead electrocardiogram, and laboratory tests. Interferon-gamma release assays (IGRA) and chest X-rays were also performed to exclude patients with tuberculosis.

[0166] All patients enrolled in the clinical trial received one dose of infliximab IV in weeks 0 and 2. Folic acid was administered concomitantly with MTX and the study drug to minimize or prevent adverse events related to MTX side effects, and patients were instructed to take it while maintaining the MTX dose from the start to the end of the clinical trial. To prevent hypersensitivity reactions to the study drug, patients could, at the discretion of the investigator, receive pre-medication 30–60 minutes prior to the start of administration of the study drug, including, but not limited to, antihistamines [2–4 mg chlorpheniramine equivalent dose], hydrocortisone, paracetamol, and / or non-sedating antihistamines [10 mg cetirizine equivalent dose].

[0167] After two complete doses were administered, patients without safety concerns were randomly assigned, at the discretion of the investigators, to receive either infliximab SC and placebo IV, or infliximab IV and placebo SC (PFS), administered via pre-filled syringe (PFS) 42 days prior to administration. Randomization was stratified by country, serum CRP concentration at week 2 (≤0.6 mg / dL or ≥0.6 mg / dL), and body weight at week 6 (≤100 kg or ≥100 kg). A minimum of 218 patients with active rheumatoid arthritis were randomly assigned in a 1:1 ratio to the two clinical trial groups, and the study drug was administered until week 54. A double placebo design was used to maintain blinding until week 30 (Table 2).

[0168] [Table 2]

[0169] Patients assigned to Group 1 received three additional doses of infliximab IV at week 6 and then every 8 weeks thereafter (weeks 14 and 22), while placebo SC was administered at week 6 and then every 2 weeks thereafter until week 28. Infliximab IV was then switched to infliximab SC (PFS) at week 30. Infliximab SC (PFS) was administered until week 54. Patients assigned to Group 2 received their first dose of infliximab SC (PFS) at week 6, followed by doses every 2 weeks until week 54. Placebo IV was administered at weeks 6, 14, and 22.

[0170] Infliximab SC (placebo SC during the double-blind period) was administered by healthcare professionals during visits to each study site (weeks 6, 14, 22, 24-28 [patients receiving visits for PK evaluation], 30, 38, 46, and 54). In all other weeks (weeks 8, 10, 12, 16, 18, 20, 24-28 [patients not receiving visits for PK evaluation], 32, 34, 36, 40, 42, 44, 48, 50, and 52), patients could self-administer the injection if they had received training in the appropriate injection technique and the study deemed it appropriate.

[0171] In certain countries, infliximab SC was self-administered every two weeks starting at week 46 using an auto-injector (AI). To assess the usability of infliximab SC (AI), diagnostic questionnaires, a self-administration diagnostic checklist, and a potential risk checklist were evaluated before and after self-administration.

[0172] The clinical evaluations, blood sampling, and clinical trial-specific visits in Part 2 were conducted in the same manner as in Part 1, with sampling and evaluation taking place at the times indicated in the evaluation schedule.

[0173] result 1-1. Safety Evaluation Summary of adverse events Safety assessments in Part 1 included secondary endpoints such as immunogenicity, monitoring of hypersensitivity reactions (including monitoring of delayed-type hypersensitivity reactions), measurement of vital signs (including blood pressure, heart rate and respiratory rate, and body temperature), body weight, interferon-gamma release assay, chest X-ray, infection status of hepatitis B, hepatitis C, and human immunodeficiency virus (HIV-1, HIV-2), physical examination findings, 12-lead electrocardiogram, adverse events (including serious adverse events), adverse events of special interest (infusion-related reactions / hypersensitivity reactions / anaphylactic reactions [medication-related reactions], delayed-type hypersensitivity reactions, injection site reactions, infections, and malignancies), signs and symptoms of tuberculosis, laboratory analysis, pregnancy tests, past medication history, and current concomitant medications, and local pain (assessed using a 10cm Visual Analogue Scale (VAS)).

[0174] The cumulative safety data for this study included adverse events (and serious adverse events) that occurred independently of the clinical drug up to the end of the clinical trial. A general summary of post-treatment adverse events that occurred during the maintenance phase (weeks 6-54) is shown in Table 3. Overall, 109 post-treatment adverse events occurred in 33 patients (68.8%), with 9 patients (69.2%) in the IV cohort (Cohort 1) and 24 patients (68.6%) in the SC cohorts as a whole (Cohorts 2, 3, and 4), showing a similar proportion in the SC cohorts as in the IV cohort. Furthermore, most post-treatment adverse events were grade 1 or 2, and of all post-treatment adverse events, 23 patients (47.9%) were considered to have been associated with the drug.

[0175] Serious adverse events after treatment occurred in a total of 6 patients (12.5%), with 1 patient (7.7%) in the IV cohort (Cohort 1) and 5 patients (14.3%) across all SC cohorts (Cohorts 2 and 4). No serious adverse events occurred in Cohort 3 of the SC cohorts. The severity of the serious adverse events was grade 2 or 3, and of these, 2 patients (16.7%) in Cohort 4 were reported as being related to the drug. Furthermore, of all serious adverse events after treatment, one patient (9.1%) in Cohort 2 discontinued treatment after week 30, and two patients (16.7%) in Cohort 3 discontinued treatment after week 30 and week 32, respectively, based on the researchers' judgment that these were significant medical incidents.

[0176] As adverse events following treatment, drug-related reactions, including infusion-related reactions, hypersensitivity, or anaphylaxis, occurred in a total of 4 patients (8.3%). This included 1 patient (7.7%) in the IV cohort (Cohort 1) and 3 patients (8.6%) in the entire SC cohort (Cohorts 2 and 3). In Cohort 4 of the SC cohort, no drug-related reactions, including infusion-related reactions, hypersensitivity, or anaphylaxis, occurred as adverse events following treatment. Since drug-related reactions to infliximab are associated with antibodies against the drug (ADA) (Remsima SmPC2017), the presence of antibodies against the drug (ADA) was investigated in patients who showed drug-related reactions. A total of 2 patients (1 each in Cohorts 1 and 2) showed positive reactions for both antibodies against the drug (ADA) and neutralizing antibodies (NAb). One patient in Cohort 2 received two doses of infliximab IV during weeks 0 and 2 of the dose-loading period, and a total of two doses of infliximab SC during weeks 6 and 8. Drug-related reactions occurred in weeks 6 and 8, and positive results were confirmed for antibodies to the drug and neutralizing antibodies in week 6 and at the end-of-trial visit (conducted 10 weeks after the week 8 visit). One patient in Cohort 1 experienced a drug-related reaction in week 38, and positive results were confirmed for antibodies to the drug and neutralizing antibodies in weeks 30 and 38, and at the end-of-trial visit (conducted 10 weeks after the week 38 visit).

[0177] Post-treatment adverse events (injection site reactions) occurred in a total of 5 patients (14.3%) across the entire SC cohort (cohorts 2, 3, and 4), all at a level of 1 or 2. No post-treatment adverse events (injection site reactions) were reported in cohort IV (cohort 1). The presence of antibodies to the drug (ADA) was also evaluated in patients who showed injection site reactions, and one of the five patients (cohort 2) tested positive for antibodies to the drug (ADA) and neutralizing antibodies (NAb) at the week 6 visit, one day before the injection site reaction occurred.

[0178] Post-treatment adverse events (infections) occurred in 5 patients (38.5%) in the IV cohort (Cohort 1) and in 13 patients (37.1%) across all SC cohorts (Cohorts 2, 3, and 4).

[0179] In the SC cohort (cohorts 2, 3, and 4), six patients (17.1%) discontinued administration of this drug due to adverse events after treatment. The reported adverse events were antiphospholipid syndrome, injection site reactions, drug-related reactions, pulmonary tuberculosis, and latent tuberculosis infection. No adverse events (infections) after treatment occurred in cohort IV. No deaths were reported during the clinical trial period.

[0180] [Table 3-1] [Table 3-2] *In each summary, if more than one adverse event was reported per patient, it was counted as one event, and only the most serious case was included in the calculation. Each event was considered to be associated only if a "Possible," "Probable," or "Definite" association was observed.

[0181] immunogenicity Generally, the proportion of patients testing positive for drug antibodies (ADA) was low in the SC cohort, and at week 54, most patients tested negative for drug antibodies (ADA). Furthermore, the proportion of patients testing positive for drug antibodies (ADA) tended to decrease with increasing SC doses. At week 54, the number of patients testing positive for drug antibodies (ADA) in cohorts 1 through 4 was 9 (69.2%), 4 (36.4%), 2 (16.7%), and 2 (16.7%), respectively (Table 4).

[0182] [Table 4-1] [Table 4-2] *Abbreviation: ADA, Antibody against drugs NAb, neutralizing antibody **Among patients who had never tested positive for antibodies against the drug or neutralizing antibodies before the 6th week of administration, we calculated the number of patients who tested positive for antibodies against the drug or neutralizing antibodies at least once after the 6th week of administration.

[0183] Visual Analog Scale (VAS) for assessing localized pain. The Visual Analog Scale (VAS) ranges from 0 to 100 mm, with higher scores indicating more severe pain. At the initial SC administration (week 6), slightly higher levels of localized pain were observed in the SC cohorts (cohorts 2, 3, and 4) compared to the IV cohort (cohort 1). However, as SC administration was repeated, localized pain gradually decreased, and slightly lower levels of pain were reported in the SC cohorts (cohorts 2, 3, and 4) than in the IV cohort (cohort 1). Within the SC cohorts, cohort 4, which required two administrations of SC 90 mg, showed more severe pain than the other two SC cohorts, but tended to report lower levels of pain than the IV cohort (cohort 1) (Table 5).

[0184] [Table 5-1] [Table 5-2]

[0185] 1-2. Evaluation of treatment effectiveness Disease activity as measured by DAS28 As an endpoint for secondary efficacy, DAS28 (C-reactive protein; CRP) and DAS28 (erythrocyte sedimentation rate; ESR) at weeks 2, 6, 14, 22, 30, and 54 compared to baseline were analyzed. The results showed no significant clinical differences between the three different doses of infliximab SC and infliximab IV cohorts, and actual values ​​tended to decrease over time.

[0186] Actual disease activity and changes from baseline, as measured by DAS28, are summarized in Tables 6 (CRP) and 7 (ESR). In each cohort, the mean disease activity scores measured by DAS28 at weeks 2, 6, 14, 22, 30, and 54 decreased compared to baseline. For DAS28(CRP), all SC cohorts showed lower DAS28 scores than the IV cohort from week 22, and for DAS28(ESR), from week 30. This is in contrast to the higher C scores shown in the SC cohort. trough This has been consistent.

[0187] [Table 6-1] [Table 6-2] [Table 6-3]

[0188] [Table 7-1] [Table 7-2] [Table 7-3]

[0189] EULAR response evaluation In the European League Against Rheumatism (EULAR) response assessment, classified based on DAS28(CRP), the proportion of patients showing a favorable response or severity response was similar across the treatment groups (Table 8). The results of the EULAR response assessment, classified based on DAS28(ESR), were also similar across the treatment groups (Table 9).

[0190] [Table 8-1] [Table 8-2]

[0191] [Table 9-1] [Table 9-2]

[0192] Percentage of patients who achieved a clinical response using ACR20 The proportion of patients meeting the clinical response criteria based on the ACR20 (American College of Rheumatology 20% improvement) classification from week 14 to week 54 was similar between the IV cohort (Cohort 1) and the SC cohorts (Cohorts 2, 3, and 4) (Table 10).

[0193] [Table 10]

[0194] Example 2. Modeling of subcutaneous administration of infliximab in patients with rheumatoid arthritis (RA). Building a PK-PD Model A pharmacokinetic-pharmacodynamic (PK-PD) model for subcutaneous administration (SC) of infliximab was established not only to simulate the PK of future dosages and regimens, but also for integration with a quantitative pharmacokinetic (PK) model to simulate the efficacy and safety of infliximab SC. The pharmacokinetic-pharmacodynamic model was based on infliximab intravenous administration data from healthy subjects, patients with ankylosing spondylitis (AS), rheumatoid arthritis (RA), and Crohn's disease (CD), and infliximab subcutaneous administration data from patients with Crohn's disease (CD), rheumatoid arthritis (RA), and healthy volunteers (Clinicaltrials.gov identifiers NCT01220518, NCT01217086, NCT02096861).

[0195] Based on the data described above, the PK-PD model can be used to simulate the results of subcutaneous administration of infliximab to patients with the indications for rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis vulgaris, psoriatic arthritis, or ankylosing spondylitis.

[0196] PK-PD modeling analysis was performed using a nonlinear mixed-effects modeling approach. Data analysis began with a one-compartment model including proportional elimination of the proportional error model, and the final model was a two-compartment model with linear elimination from the central compartment. All pharmacokinetic models were variable in terms of clearance (CL) and volume of distribution.

[0197] The final PK model is based on the area under the concentration-time curve (AUC) for each concentration-time curve in the infliximab clinical trial. tau ;area under the concentration-time curve) and minimum blood concentration (C trough; (the estimated value of the parameter at the minimum concentration immediately before the next application) was applied to each actual dose, dosage regimen, and route of administration to predict the profile, and the data were described by the median and 90% confidence interval. Additionally, additional simulations were performed to evaluate the efficacy for each body weight for a fixed dose, dosage regimen, and route of administration. The PK-PD modeling and simulation of the subcutaneous dose were performed using NONMEM v7.2.

[0198] Dose and regimen scenarios of subcutaneous (SC) dosage forms for modeling in patients with rheumatoid arthritis (RA) Based on the following simulation scenarios, the pharmacokinetic aspects were predicted, and based on this, the efficacy and safety were predicted, and it was compared and evaluated with the intravenous (IV) injection method of infliximab administered at a maintenance dose of 3 mg / kg at 8-week intervals (Table 11).

[0199]

Table 11

[0200] Estimated values of infliximab exposure parameters regarding SC dose and dosage regimen of infliximab by body weight in patients with rheumatoid arthritis Exposure pharmacokinetic parameters (AUC τ , C trough , and C max ) of the SC dose and dosage regimen of infliximab were simulated in 10-kg increments in the range of body weight from 50 to 130 kg, and the estimated values of the minimum blood concentration (C trough ), area under the concentration-time curve (AUC τ ) of infliximab exposure by body weight showed a correlation with the drug dose (Table 12).

[0201]

Table 12-1

[0202] Example 3. Evaluation of the safety and therapeutic effect of subcutaneous administration of infliximab in patients with Crohn's disease (CD) or ulcerative colitis (UC). This infliximab clinical trial is an open, randomized, multicenter, parallel-group, phase 1 study designed to evaluate the pharmacokinetics, efficacy, and safety of infliximab SC and infliximab IV in patients with active Crohn's disease or active ulcerative colitis up to week 54. The clinical trial consists of two parts.

[0203] Part 1 was designed to determine the optimal dose of infliximab SC in patients with Crohn's disease (CD), specifically the area under the steady-state concentration-time curve (AUC) between weeks 22 and 30. τ The optimal dose of infliximab SC corresponding to 5 mg / kg infliximab IV over the first 30 weeks was determined by this. The duration of the Part 1 clinical trial was up to 65 weeks, including screening (up to 3 weeks) and the final visit to the end of the clinical trial.

[0204] Part 2 was designed to confirm that infliximab SC is not pharmacokinetically inferior to infliximab IV in patients with Crohn's disease (CD) or ulcerative colitis (UC), and is demonstrated by the pre-dose concentration (C trough ) at week 22. The optimal dose and dosing interval of infliximab SC corresponding to 5 mg / kg infliximab IV in Part 2 were determined as follows by the independent Data Safety Monitoring Board (DSMB) based on the pharmacokinetic, efficacy, pharmacodynamic, and safety data over the first 30 weeks of Part 1. ● Patients weighing less than 80 kg: Administer infliximab SC 120 mg at 2-week intervals ● Patients weighing 80 kg or more: Administer infliximab SC 240 mg at 2-week intervals

[0205] Part 1 Patients could be enrolled in this clinical trial if they met all of the following criteria. * Suffering from active disease with a Crohn's Disease Activity Index (CDAI) score of 220 - 450 * Diagnosed with Crohn's disease at least 3 months prior to the first dose of the study drug * Treated for active Crohn's disease but showing no response, having no tolerance, or having medical contraindications despite receiving the appropriate full course of corticosteroid and / or immunosuppressive therapy

[0206] Patients could not be enrolled in the clinical trial if they met any of the following criteria. * Have been administered biological agents for the treatment of previous Crohn's disease or ulcerative colitis and / or TNFα inhibitors for the treatment of other diseases * Have an allergy to infliximab, any other murein and / or excipient of human proteins, or have hypersensitivity to immunoglobulin products *The patient must have an active enterobelostomy, retroperitoneal fistula, enterocutaneous fistula, or enterovaginal fistula within 6 months prior to the first dose of the study drug (Day 0). Based on the investigator's opinion, enterofolences without clinically significant symptoms and anal fistulas without drainage problems are acceptable. *The patient has undergone more than three small bowel resections prior to the first dose of the investigational drug (Day 0).

[0207] This clinical trial consisted of three clinical trial periods: screening, administration, and completion of the clinical trial. Screening was conducted between 21 days and 1 day before the first dose of the study drug to assess patients' eligibility for the study. All tests were performed, including tests for hepatitis B, C, and human immunodeficiency virus (HIV-1, HIV-2) infection, urine and serum pregnancy tests in women of childbearing age, colonoscopy, CRP, 12-lead electrocardiogram, and laboratory tests. Interferon-gamma release assays (IGRA) and chest X-rays were also performed to exclude patients with tuberculosis.

[0208] On week 0, day 0, patients who met all selection criteria and did not meet any exclusion criteria were enrolled in the clinical trial, and all enrolled patients received a single dose of infliximab IV twice, in week 0 and week 2. To prevent hypersensitivity reactions to the study drug, patients could, at the discretion of the investigator, receive pre-medication 30–60 minutes prior to the start of administration of the study drug, as follows (e.g., antihistamines [2–4 mg chlorpheniramine equivalent dose], hydrocortisone, paracetamol, and / or non-sedating antihistamines [10 mg cetirizine equivalent dose], but not limited to these).

[0209] After two complete doses were administered, patients without safety concerns were randomly assigned to either the infliximab SC or infliximab IV group 42 days prior to administration, at the discretion of the investigators. Randomization was stratified by region (Europe or non-Europe), current use of azathioprine, 6-mercaptopurine, or MTX for treatment, clinical response on CDAI-70 at week 6, and body weight at week 6 (≤70 kg or >70 kg). Forty-five patients with active Crohn's disease were enrolled, of which 44 were randomly assigned to four clinical trial cohorts in a 1:1:1:1 ratio and received the study drug until week 54 (Table 13).

[0210] [Table 13]

[0211] Patients assigned to Cohort 1 received an additional seven doses of infliximab IV at week 6 and every eight weeks thereafter (weeks 14, 22, 30, 38, 46, and 54). Patients assigned to Cohorts 2, 3, and 4 received their first dose of infliximab SC at week 6, with additional doses of infliximab SC administered every two weeks until week 54. The initial dose assigned to all patients in Cohorts 2, 3, and 4 was adjusted to the optimal dose after dose verification. Subsequently, additional SC injections at the optimal dose were administered until week 54. Infliximab SC was administered by healthcare professionals during visits to each laboratory (weeks 6, 8, 10, 14, 22, 24, 26, 28, 30, 38, 46, and 54), while in other weeks (weeks 12, 16, 18, 20, 32, 34, 36, 40, 42, 44, 48, 50, and 52), patients could self-administer the injection if they had received training in the appropriate injection technique and the investigator deemed them suitable.

[0212] Patients visited the laboratory at predetermined time intervals for clinical evaluation and blood sampling. During each visit, patients were questioned about adverse events (AEs) and concomitant medications, and their clinical signs and symptoms of TB were monitored. Primary pharmacokinetic endpoints were evaluated during the maintenance phase from week 22 to week 30, secondary pharmacokinetic endpoints were evaluated during the administration period up to week 54, and blood samples for analysis, efficacy, disease progression (PD), and safety evaluations were collected and evaluated at the times indicated in the evaluation schedule.

[0213] The final clinical trial visit was conducted 8 weeks after the end of the maintenance phase. However, if a patient discontinued the clinical trial, the visit was conducted 8 weeks after the last dose. In the case of patients who dropped out, all clinical trial procedures were performed on the day of or the day after the dropout, and every effort was made to complete all clinical trial procedures 8 weeks after the patient received their last dose.

[0214] Part 2 Part 2 will begin based on the review by the Independent Data Safety Monitoring Committee of the PK Modeling report data, including PK, efficacy, PD, and safety data for the first 30 weeks confirmed in Part 1.

[0215] Patients may be enrolled in Part 2 of this clinical trial if they meet all of the following criteria.

[0216] Patients with active Crohn's disease *Crohn's disease activity index (CDAI) score is between 220 and 450, indicating active disease. *Diagnosed with Crohn's disease at least 3 months prior to the first dose of the investigational drug. * Patients who have received treatment for active Crohn's disease but have not responded, cannot tolerate, or have medical contraindications to the appropriate full course of corticosteroid and / or immunosuppressant therapy. *Meets one or more of the following criteria - Serum CRP (C-reactive protein) concentration exceeds 0.5 mg / dL - Fecal calprotectin concentration exceeds 100 μg / g - Patients with ileocolonic Crohn's disease who have a colonoscopy (SES-CD) score of 6 or higher, or patients with ileal or colonic Crohn's disease who have a score of 4 or higher and at least one ulcer score.

[0217] Patients with active ulcerative colitis *Total Mayo score of 6-12, endoscopic examination score of 2 or higher, and active disease. *The patient was diagnosed with ulcerative colitis at least three months prior to the first dose of the investigational drug. * You have been treated for active ulcerative colitis, have not responded to, cannot tolerate, or have medical contraindications to common therapeutic agents such as corticosteroids and / or 6-mercaptopurine or azathioprine.

[0218] Patients who meet any of the following criteria will not be eligible to enroll in Part 2 of the clinical trial. *Previously received biological agents for the treatment of Crohn's disease or ulcerative colitis and / or TNFα inhibitors for the treatment of other diseases. * You have an allergy to infliximab, all other murin and / or human protein excipients, or you have hypersensitivity to immunoglobulin products. *Crohn's disease patients with active enterobelostomy, retroperitoneal fistula, enterocutaneous fistula, and enterovaginal fistula within 6 months prior to the first dose of the study drug (Day 0). At the discretion of the study, enterofistulas without clinically significant symptoms and anal fistulas without drainage problems are acceptable. *Crohn's disease patients who have undergone more than three small bowel resections prior to the first dose of the investigational drug (Day 0). * Ulcerative colitis patients who received corticosteroids or 5-aminosalicylic acid within two weeks prior to screening.

[0219] Part 2 consists of three clinical trial periods: screening, administration period, and end of clinical trial. Screening is conducted between 42 days and 0 days before the first administration of the test drug, and it evaluates the patient's eligibility for the study. All tests are performed, including urine and serum pregnancy tests in women of childbearing age, type B, C, and human immunodeficiency virus (HIV-1, HIV-2) infections, colonoscopy (for Crohn's disease patients), sigmoidoscopy (for ulcerative colitis patients), CRP, 12-lead electrocardiogram, clinical laboratory tests, etc. Also, an interferon-γ release assay (IGRA) and chest X-ray examination are performed to exclude tuberculosis patients.

[0220] On week 0, day 0, patients who meet all the selection criteria and do not fall under any of the exclusion criteria are enrolled in the clinical trial, and all enrolled patients are administered infliximab IV once per dose, twice over weeks 0 and 2. Patients can receive premedication at the discretion of the investigator as follows, 30 - 60 minutes before starting the administration of the test drug to prevent an allergic reaction to the test drug (e.g., antihistamine [2 - 4 mg chlorpheniramine equivalent dose], hydrocortisone, paracetamol, and / or non-sedating antihistamine [10 mg cetirizine equivalent dose], but not limited to these).

[0221] After two full doses are administered, patients with no safety concerns are randomly assigned to the infliximab SC or infliximab IV administration group 42 days before administration. The random assignment of administration is stratified by the current use of azathioprine, 6-mercaptopurine, or MTX for treatment, disease (Crohn's disease or ulcerative colitis), clinical response of Crohn's disease by CDAI-70 or clinical response of ulcerative colitis by partial Mayo score at week 6, and body weight at week 6 (< 80 kg or ≥ 80 kg). At least 130 patients with active Crohn's disease or active ulcerative colitis are randomly assigned to the two clinical trial groups at a 1:1 ratio, and the test drug is administered until week 54 (Table 14).

[0222]

Table 14

[0223] Patients assigned to Group 1 will receive an additional dose of infliximab IV at week 6 and then every 8 weeks thereafter (weeks 14 and 22) until week 22. From week 30, they will switch to infliximab SC, with the SC dose determined based on their body weight at week 30. This dose will be administered every two weeks until week 54. Patients assigned to Group 2 will receive a dose of infliximab SC determined based on their body weight at week 6, and this dose will be administered every two weeks from week 6 to week 54. Dose increases are permitted from week 30 onwards at the discretion of the investigator. Infliximab SC will be injected by healthcare professionals during visits to each study site (weeks 6, 14, 22, 24, 26, 28, 30, 38, 46, and 54). Patients may self-inject in other weeks if they have received appropriate injection training and the investigator deems them suitable.

[0224] Primary pharmacokinetic endpoints are evaluated at week 22, and secondary pharmacokinetic endpoints are evaluated during the maintenance phase from week 22 to week 30 and during the administration phase up to week 54. Blood samples for analysis, efficacy, PD, and safety assessments are collected and evaluated at the times indicated in the evaluation schedule.

[0225] The final clinical trial visit will be conducted two weeks after the end of the maintenance phase. However, if a patient discontinues the clinical trial after receiving SC, the visit will be conducted two weeks after the last dose. If a patient discontinues the clinical trial after receiving IV, the visit will be conducted eight weeks after the last dose. In the case of a patient who drops out, all clinical trial procedures will be performed on the day of or the day after the patient drops out, and all efforts will be made to ensure that all clinical trial procedures are completed at the predetermined time after the patient receives their last dose.

[0226] The clinical evaluation, blood sampling, and clinical trial-specific visits in Part 2 will be conducted in the same manner as in Part 1, with sampling and evaluation taking place at the times indicated in the evaluation schedule.

[0227] conclusion 3-1. Safety Evaluation Summary of adverse events The safety assessment included secondary endpoints in Part 1, which included immunogenicity, monitoring of hypersensitivity reactions (including monitoring of delayed-type hypersensitivity reactions), measurement of vital signs (including blood pressure, heart rate and respiratory rate, and body temperature), body weight, interferon-gamma release assay, chest X-ray, hepatitis B, hepatitis C, and human immunodeficiency virus (HIV-1, HIV-2) infection status, physical examination findings, 12-lead electrocardiogram, adverse events (including serious adverse events), adverse events of special interest (infusion-related reactions / hypersensitivity reactions / anaphylactic reactions [medication-related reactions], delayed-type hypersensitivity reactions, injection site reactions, infections, and malignancies), signs and symptoms of tuberculosis, laboratory analysis, pregnancy tests, past medication history, and current concomitant medications, as well as local pain (assessed using a 100mm Visual Analogue Scale (VAS)).

[0228] The cumulative safety data for this study includes data up to week 30, and a general summary of post-treatment adverse events that occurred during the maintenance phase (weeks 6-30) is shown in Table 15. Overall, 70 post-treatment adverse events occurred in 28 patients (63.6%), with 8 patients (61.5%) in the IV cohort (Cohort 1) and 20 patients (64.5%) in the entire SC cohort (Cohorts 2-4), showing similar proportions in both groups. Furthermore, most post-treatment adverse events were of grade 1 or 2, and 9 patients (20.5%) of all post-treatment adverse events were considered to be related to this drug.

[0229] Serious adverse events after treatment occurred in 8 patients (18.2%), including 2 patients (15.4%) in the IV cohort (Cohort 1) and 6 patients (19.4%) across the entire SC cohort (Cohorts 2-4). All of these were considered unrelated to the drug.

[0230] As adverse events after treatment, drug-related reactions such as infusion-related reactions, hypersensitivity, or anaphylaxis were reported in one patient in the IV cohort (Cohort 1) (Week 30, day of administration) and one patient in the SC cohort (Cohort 4) (Week 6, 2 days after administration). Since drug-related reactions to infliximab are associated with antibodies against the drug (ADA) (Remsima SmPC 2017), the presence of antibodies against the drug (ADA) was investigated in patients who showed drug-related reactions. Only one patient (IV cohort [Cohort 1]) showed a positive reaction for antibodies against the drug (ADA) and neutralizing antibodies (NAb). After administration during the dose-loading period, the IV formulation was administered at Weeks 6 and 14 during the maintenance phase, and a positive result was confirmed from Week 22, with an administration-related reaction occurring at Week 30.

[0231] Injection site reactions occurred as a post-treatment adverse event in four patients (12.9%) of the SC cohort (cohorts 2-4), all of which were at a grade 1 or 2 level. Patients who showed injection site reactions were also evaluated for the presence of antibodies to the drug (ADA), and two of the four patients tested positive for both ADA and neutralizing antibodies (NAb) during the clinical period.

[0232] Post-treatment adverse events included infection, which occurred in 2 patients (15.4%) in the IV cohort (Cohort 1) and 7 patients (22.6%) in the SC cohort (Cohorts 2-4).

[0233] In the IV cohort (Cohort 1), one patient (7.7%) discontinued administration of this drug due to adverse events after treatment, and in the SC cohort (Cohorts 2-4), four patients (12.9%) discontinued treatment. Of these, only one patient in Cohort 3 had a post-treatment adverse event considered to be related to this drug, and this adverse event was latent tuberculosis of grade 1.

[0234] Two deaths were reported during the clinical trial period (one in Cohort 1 and one in Cohort 3). In Cohort IV (Cohort 1), one patient experienced sudden cardiac death at home approximately one month after completing the 6th week of medication, but this was not reported to be related to the drug. This patient had hypertension and chronic heart failure. In Cohort SC (Cohort 3), one patient experienced sudden cardiac death at home on the night of the 30th week of medication, but this was also not reported to be related to the drug. This patient had chronic aortic calcification, diabetes mellitus, obesity, and metabolic syndrome.

[0235] [Table 15-1] [Table 15-2] *In each summary, if more than one adverse event was reported per patient, it was counted as one event, and only the most serious case was included in the calculation. Each event was considered to be associated only if a "Possible," "Probable," or "Definite" association was observed.

[0236] immunogenicity Generally, the proportion of patients testing positive for drug antibodies (ADA) was low in the SC cohort, and at week 30, most patients tested negative for drug antibodies (ADA). At week 30, the number of patients testing positive for drug antibodies (ADA) in cohorts 1 to 4 was 8 (61.5%), 0 (0.0%), 3 (25.0%), and 1 (12.5%), respectively (Table 16).

[0237] [Table 16] *Abbreviation: ADA, Antibody against drugs NAb, neutralizing antibody *Percentages per visit were calculated using the number of randomly assigned patients as the denominator. Denominator: Number of patients who tested negative for ADA in week 0 and week 6 Numerator: Number of patients who tested positive for ADA or NAb at least once in weeks 14 and 30.

[0238] Visual Analog Scale (VAS) for assessing localized pain. The Visual Analog Scale (VAS) ranges from 0 to 100 mm, with higher scores indicating more severe pain. Cohorts 3 and 4, which required two injections per visit, observed slightly higher levels of localized pain than the other cohorts. Overall, low levels of localized pain were observed in all cohorts (mean ≤21.05 mm) (Table 17).

[0239] [Table 17]

[0240] 3-2. Evaluation of Treatment Efficacy Disease activity as measured by CDAI As a secondary efficacy endpoint, analysis of CDAI (Crohn's disease activity index) scores at weeks 2, 6, 14, 22, and 30 compared to baseline revealed a tendency for actual values ​​to decrease over time in each cohort. The proportion of patients responding to the CDAI-70 criterion at week 6, one of the stratification variables for randomization, was slightly higher in cohort 2 than in the other cohorts, and care was taken to consider this when interpreting efficacy.

[0241] Table 18 summarizes the actual values ​​of disease activity and the change from baseline as measured by CDAI.

[0242] [Table 18-1] [Table 18-2]

[0243] Reaction evaluation based on CDAI-70 and CDAI-100 reaction criteria Based on the CDAI score, the proportion of patients who responded to the CDAI-70 response criterion (a decrease of 70 points or more in the CDAI score compared to the baseline value) was similar across each treatment group (Table 19). The proportion of patients who responded to the CDAI-100 response criterion (a decrease of 100 points or more in the CDAI score compared to the baseline value) was also similar across each treatment group (Table 20).

[0244] [Table 19]

[0245] [Table 20]

[0246] Evaluation of clinical remission The proportion of patients achieving clinical remission (CDAI absolute score less than 150) was similar across the treatment groups. A relatively high proportion of patients in Cohort 2 achieved clinical remission during the maintenance period (weeks 6-30), but six patients (54.5%) in Cohort 2 had already achieved clinical remission by week 6, and most patients maintained clinical remission until week 30 (Table 21).

[0247] [Table 21]

[0248] Example 4. Modeling of subcutaneous administration of infliximab in patients with Crohn's disease (CD). Building a PK-PD Model The procedure was carried out in the same manner as in Example 2. Dosage and regimen scenarios for subcutaneous (SC) formulations for modeling in patients with Crohn's disease (CD). Based on the following simulation scenarios, pharmacokinetic aspects were predicted, and based on these, efficacy and safety were predicted and compared with infliximab intravenous (IV) injection at a maintenance dose of 5 mg / kg every 8 weeks (Table 22).

[0249] [Table 22]

[0250] Estimated infliximab exposure parameters based on infliximab SC dosage and administration by body weight in Crohn's disease (CD) patients. The exposure pharmacokinetic parameters for infliximab SC dose and administration were simulated in 10kg increments within the body weight range of 50-130kg, and the lowest blood concentration (C) of SC exposure was determined. trough ), area under the concentration-time curve (AUC τ The estimated values ​​of ) showed a correlation with the drug dosage (Table 23).

[0251] [Table 23-1] [Table 23-2] [Table 23-3] [Table 23-4] (Note) This disclosure includes the following aspects: Item 1: A method for treating a TNFα-related disease, comprising the step of administering to a patient a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof, wherein the patient is subcutaneously administered a dose of 60 to 300 mg of the anti-TNFα antibody or its antigen-binding fragment at intervals of 1 to 8 weeks. Item 2: The method described in item 1, wherein TNFα-related diseases are selected from the group consisting of rheumatoid arthritis, ulcerative colitis, Crohn's disease, psoriasis vulgaris, psoriatic arthritis, and ankylosing spondylitis. Item 3: TNFα-related disease is rheumatoid arthritis, as described in item 2. Item 4: The method described in item 3, wherein the patient is administered a dose of 90-180 mg of anti-TNFα antibody or its antigen-binding fragment. Item 5: The method described in item 2, wherein TNFα-related diseases are selected from the group consisting of ulcerative colitis, Crohn's disease, psoriasis vulgaris, psoriatic arthritis, and ankylosing spondylitis. Item 6: The method described in item 5, wherein the patient is administered a dose of 120-240 mg of anti-TNFα antibody or its antigen-binding fragment. Item 7: The method according to item 1, wherein the patient is administered an anti-TNFα antibody or its antigen-binding fragment in doses of 80-100 mg, 110-130 mg, 170-190 mg, or 230-250 mg. Item 8: The method according to item 7, wherein the patient is administered a dose of 90 mg, 120 mg, 180 mg, or 240 mg of anti-TNFα antibody or its antigen-binding fragment. Item 9: The method according to item 1, further comprising the step of determining the dosage according to the patient's weight, wherein 90-180 mg of anti-TNFα antibody or its antigen-binding fragment is administered if the patient weighs less than 80 kg, and 190-270 mg if the patient weighs 80 kg or more. Item 10: The method according to item 1, wherein the patient is administered an anti-TNFα antibody or its antigen-binding fragment at intervals of 1, 2, 3, 4, 5, 6, 7, or 8 weeks. Item 11: The method according to item 10, wherein the patient is administered an anti-TNFα antibody or its antigen-binding fragment at intervals of 2 or 4 weeks. Item 12: The method described in item 1, in which an anti-TNFα antibody or its antigen-binding fragment is administered in combination with a disease-modifying antirheumatic drug (DMARD). Item 13: The method according to item 12, wherein the disease-modifying antirheumatic drug (DMARD) is selected from the group consisting of methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine. Item 14: The method according to item 1, wherein the patient is a patient who has received at least one intravenous administration of an anti-TNFα antibody or its antigen-binding fragment prior to subcutaneous administration. Item 15: The method according to item 14, wherein the patient is a patient who has been administered an anti-TNFα antibody or its antigen-binding fragment at a dose of 1 to 10 mg / kg per dose. Item 16: The method described in item 14, in which the first subcutaneous dose is administered 2 to 8 weeks after the last intravenous dose. Item 17: After subcutaneous administration to the patient, the lowest blood concentration (C) of anti-TNFα antibody or its antigen-binding fragment was determined. trough The method described in item 1, wherein the concentration is maintained at 3-16 μg / mL. Item 18: After subcutaneous administration to the patient, the lowest blood concentration (C) of anti-TNFα antibody or its antigen-binding fragment was determined. trough The method described in item 1, wherein the concentration is maintained at 9-32 μg / mL. Item 19: Patients who have received subcutaneous administration possess one or more of the following characteristics, as described in item 1: a) The DAS28 (Disease Activity Score in 28 joints) decreased by at least 2.0; or b) The CDAI (Crohn's disease activity index) decreased by at least 70 points. Item 20: Patients prior to subcutaneous administration possess one or more of the following characteristics, as described in item 1: a) Inadequate response to disease-modifying antirheumatic drugs (DMARDs), including methotrexate; b) No prior treatment history with methotrexate or other disease-modifying agents; c) Failure to respond adequately to conventional treatment, with severe axial symptoms and elevated serological indicators related to inflammation; or d) Unresponsive to, contraindicated for, or intolerant to systemic therapy including methotrexate, cyclosporine, or psoralen ultraviolet A therapy (PUVA). Item 21: Patients prior to subcutaneous administration possess one or more of the following characteristics, as described in item 1: a) The patient does not respond adequately to, cannot tolerate, or is contraindicated for treatment with corticosteroids, 6-mercaptopurine, azathioprine, or immunosuppressants; or b) Not responding to conventional treatments, including antibiotics, elimination therapies, or immunosuppressive therapy. Item 22: Anti-TNFα antibodies or their antigen-binding fragments are Light chain variable region including a CDR1 domain containing the amino acid sequence of SEQ ID NO: 1, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 2, and a CDR3 domain containing the amino acid sequence of SEQ ID NO: 3; and The method according to item 1, comprising a heavy chain variable region including a CDR1 domain containing the amino acid sequence of SEQ ID NO: 4, a CDR2 domain containing the amino acid sequence of SEQ ID NO: 5, and a CDR3 domain containing the amino acid sequence of SEQ ID NO: 6. Item 23: Anti-TNFα antibodies or their antigen-binding fragments are Light chain variable region containing the amino acid sequence of SEQ ID NO: 7; and The method according to item 1, comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 8. Item 24: Anti-TNFα antibodies or their antigen-binding fragments are Light chain containing the amino acid sequence of SEQ ID NO: 9; and The method according to item 1, comprising a heavy chain containing the amino acid sequence of SEQ ID NO: 10. Item 25: The anti-TNFα antibody is infliximab, as described in item 1. Item 26: A composition containing an anti-TNFα antibody or its antigen-binding fragment is the method according to item 1, comprising (A) 90-180 mg / ml of anti-TNFα antibody or its antigen-binding fragment; (B) 0.02-0.1% (w / v) of polysorbate; (C) 1-10% (w / v) of sorbitol; and (D) 1-50 mM of a buffer containing acetate. Item 27: The method according to item 1, wherein a composition containing an anti-TNFα antibody or its antigen-binding fragment is administered to a patient by being filled into a pre-filled syringe or auto-injector. Item 28: A pharmaceutical composition for the treatment of TNFα-related diseases containing an anti-TNFα antibody or its antigen-binding fragment, A pharmaceutical composition for the treatment of TNFα-related diseases, comprising subcutaneous administration of 60-300 mg of anti-TNFα antibody or its antigen-binding fragment at intervals of 1-8 weeks. Item 29: (a) A pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof; and (b) A kit comprising instructions for the subcutaneous administration of 60–300 mg of anti-TNFα antibody or its antigen-binding fragment at intervals of 1–8 weeks to treat patients with TNFα-related disease. Item 30: An application of anti-TNFα antibody or its antigen-binding fragment in the manufacture of a pharmaceutical composition for treating TNFα-related disease in patients, wherein a dose of 60-300 mg of anti-TNFα antibody or its antigen-binding fragment is administered subcutaneously at intervals of 1-8 weeks.

Claims

1. A pharmaceutical composition comprising infliximab for the treatment of TNFα-related disorders, wherein the infliximab is used to be administered subcutaneously to a patient at a dose of 120 mg every two weeks, and the TNFα-related disorder is characterized by being ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis vulgaris, or psoriatic arthritis.

2. The pharmaceutical composition according to claim 1, wherein the TNFα-related disease is ulcerative colitis or Crohn's disease.

3. The pharmaceutical composition according to claim 1 or 2, wherein the patient self-administers the pharmaceutical composition.

4. The pharmaceutical composition according to claim 1, which is used to administer to a patient who has received at least one intravenous dose of infliximab prior to subcutaneous administration.

5. The pharmaceutical composition according to claim 4, wherein the patient is a patient who has received intravenous administration of infliximab at least twice prior to subcutaneous administration.

6. The pharmaceutical composition according to claim 4, wherein each intravenous administration is performed 6 to 4 weeks before the subcutaneous administration.

7. The pharmaceutical composition according to claim 4, wherein the first subcutaneous administration is performed 2 to 8 weeks after the last intravenous administration.

8. The pharmaceutical composition according to claim 7, wherein the first subcutaneous administration is performed four weeks after the last intravenous administration.

9. The pharmaceutical composition according to claim 4, wherein the patient is a patient who has been intravenously administered infliximab at a dose of 1 to 10 mg / kg per dose.

10. The pharmaceutical composition according to claim 9, wherein the patient is a patient who has been intravenously administered infliximab at a dose of 3 to 5 mg / kg per dose.

11. The pharmaceutical composition according to claim 10, wherein the patient is a patient who has been intravenously administered infliximab at a dose of 5 mg / kg per dose, and the TNFα-related disease is ulcerative colitis or Crohn's disease.

12. The pharmaceutical composition according to claim 11, wherein the first subcutaneous administration is performed four weeks after the last intravenous administration.

13. After subcutaneous administration to the patient, the lowest blood concentration of infliximab (C) ｔｒｏｕｇｈ The pharmaceutical composition according to claim 1, wherein the concentration of ) is maintained at 3 to 16 μg / mL.

14. After subcutaneous administration to the patient, the lowest blood concentration of infliximab (C) ｔｒｏｕｇｈ The pharmaceutical composition according to claim 1, wherein the concentration of ) is maintained at 9 to 32 μg / mL.

15. The pharmaceutical composition according to claim 1, wherein a decrease of 70 or more in CDAI (Crohn's disease activity index) is observed in patients after subcutaneous administration.

16. Before subcutaneous administration, the patient has a pharmaceutical composition according to claim 1 having one or more of the following characteristics: a) Severe axial symptoms and elevated serological indicators related to inflammation that do not respond adequately to conventional treatment; or b) The patient is unresponsive, contraindicated, or intolerant to systemic therapy including cyclosporine or psoralen ultraviolet A therapy (PUVA).

17. Before subcutaneous administration, the patient has a pharmaceutical composition according to claim 1 having one or more of the following characteristics: a) The patient does not respond adequately to, cannot tolerate, or is contraindicated for treatment with corticosteroids, 6-mercaptopurine, azathioprine, or immunosuppressants; or b) Not responding to conventional treatments, including antibiotics, elimination therapies, or immunosuppressive therapy.

18. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is administered simultaneously with, before, or after the administration of one or more antibodies selected from the group consisting of adalimumab, etanercept, certolizumab pegol, golimumab, and biosimilars thereof.

19. The pharmaceutical composition according to claim 1, comprising (A) infliximab 90 to 180 mg / ml; (B) polysorbate 0.02 to 0.1% (w / v); (C) sorbitol 1 to 10% (w / v); and (D) a buffering agent containing acetate 1 to 50 mM.

20. The pharmaceutical composition according to claim 1, which is filled in a pre-filled syringe or an auto-injector.

21. (a) The pharmaceutical composition according to claim 1; and (b) Instructions for the subcutaneous administration of the pharmaceutical composition at a dose of 120 mg of infliximab every two weeks to treat patients suffering from ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis vulgaris, or psoriatic arthritis. A kit for subcutaneously administering a 120 mg dose of infliximab at two-week intervals to treat ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis vulgaris, or psoriatic arthritis.

22. Use of infliximab in the manufacture of the pharmaceutical composition described in claim 1.

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