Method for treating TNFα-related disease

Abstract

To provide a therapeutic method in which a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof is subcutaneously administered to a subject for the treatment of a TNFα-related disease; to provide the pharmaceutical composition; and to provide a kit containing the pharmaceutical composition; as well as to provide use of an anti-TNFα antibody or antigen-binding fragment thereof in the manufacture of a medicament to be administered subcutaneously to a subject to treat a disease treatable with an anti-TNFα antibody.SOLUTION: The present invention relates to a method for treating a TNFα-related disease by subcutaneously administering an antibody (anti-TNFα antibody) or an antigen-binding fragment thereof that binds to TNFα. The treatment method, composition, kit or use thereof according to the present invention provides an advantage of increased patient satisfaction, through the improvement of convenience and enhancement of the quality of life, by reducing the time taken for administration compared to intravenous injections and decreasing the time that patients stay in a hospital.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present application relates to a method for treating TNFα-related disorders by subcutaneous administration of 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, pediatric 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 freeze-dried powder, which is then redissolved and diluted before being administered intravenously according to the dosage and administration method for each disease.

[0004] However, the intravenous administration method described above requires the patient to visit a hospital for administration, and takes about 2 to 4 hours including waiting time, which is a considerable burden and inconvenience for the patient. In addition, there is a problem that the administering personnel is limited to those who have received medical education.

[0005] Therefore, subcutaneous (SC) administration has been proposed as an alternative route of administration, which, with appropriate training, can be self-administered by patients and can reduce administration times from 30-90 minutes to 2-5 minutes.

[0006] Products that have been developed and are commercially available as subcutaneous formulations as well as intravenous formulations include Rituxan (Rituximab), Simponi (Golimumab), Herceptin (Trastuzumab), Actemra (Tocilizumab), and Xolair (Omalizumab), but there is no subcutaneous formulation of Infliximab yet.

[0007] Subcutaneous administration requires a liquid formulation that is stable while containing a high concentration of the antibody, and its efficacy and safety must be demonstrated in clinical trials.

[0008] The applicant has demonstrated that subcutaneous administration of an infliximab formulation has efficacy and safety equivalent to that of conventional intravenous formulations, and has completed a subcutaneous administration therapy that improves the convenience of administration for patients and their quality of life. Summary of the Invention [Problem to be solved by the invention]

[0009] The problem to be solved by the present invention is to provide a therapeutic method for treating a TNFα-related disease, comprising subcutaneously administering to a subject a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof.

[0010] Another problem to be solved by the present invention is to provide a pharmaceutical composition for treating 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 to be solved by the present invention is to provide a kit comprising a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof and instructions for administering the pharmaceutical composition subcutaneously to a subject to treat a disease treatable with an anti-TNFα antibody.

[0012] Another problem to be solved by the present invention is to provide use of an anti-TNFα antibody or an antigen-binding fragment thereof in the manufacture of a medicament for subcutaneous administration to a subject to treat a disease treatable with an anti-TNFα antibody. [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 to a subject a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof.

[0014] The present invention also provides a pharmaceutical composition for treating a disease treatable with an anti-TNFα antibody, comprising an anti-TNFα antibody or an antigen-binding fragment thereof and administered subcutaneously to a subject.

[0015] The invention also provides a kit comprising: (a) a pharmaceutical composition comprising an anti-TNFα antibody or antigen-binding fragment thereof and a pharma- ceutical acceptable carrier; and (b) instructions for administering the pharmaceutical composition subcutaneously to a subject to treat a disease treatable with an anti-TNFα antibody.

[0016] The invention also provides the use of an anti-TNFα antibody, or an antigen-binding fragment thereof, in the manufacture of a pharmaceutical composition to be administered subcutaneously to a subject for treating a disease treatable with an anti-TNFα antibody.

[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 invention, the anti-TNFα antibody may be infliximab. In one embodiment of the invention, the anti-TNFα antibody may comprise a chimeric human-mouse IgG monoclonal antibody.

[0018] In one embodiment of the present invention, the anti-TNFα antibody may comprise 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.

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

[0020] In one embodiment of the invention, the composition may comprise a surfactant; a sugar or a derivative thereof; and a buffer comprising acetate or histidine. In one embodiment of the invention, the composition may comprise, as a surfactant, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or mixtures 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 invention, the composition may comprise, as sugar or derivative thereof, sorbitol, mannitol, trehalose, sucrose, or mixtures thereof. In one embodiment of the present invention, the concentration of the sugar or its derivative in the composition may be 1-10% (w / v).

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

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

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

[0025] In one embodiment of the invention, the composition may be free of aspartic acid, lysine, arginine, or mixtures thereof. In one embodiment of the invention, the composition comprises NaCl, KCl, NaF, KBr, NaBr, Na 2 SO 4 , NaSCN, K 2 SO 4 Or, it may not contain a mixture of these. In one embodiment of the invention, the composition may be free of 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 one month at a temperature of 40°C ± 2°C, or a viscosity of 0.5 cp to 5 cp measured after six months at a temperature of 5°C ± 3°C.

[0027] In one embodiment of the invention, the composition does not have to undergo a reconstitution step, a dilution step, or both steps prior to use.

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

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

[0030] In one embodiment of the invention, the antibody or antigen-binding fragment thereof may be administered in an amount of 60-300 mg. In one embodiment of the invention, the antibody or antigen-binding fragment thereof may be administered at 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 invention, 90-180 mg of the antibody or antigen-binding fragment thereof may be administered. In one embodiment of the invention, 120-240 mg of the antibody or antigen-binding fragment thereof may be administered. In one embodiment of the invention, the antibody or antigen-binding fragment thereof may be administered at 80-100 mg, 110-130 mg, 170-190 mg, or 230-250 mg. In one embodiment of the invention, the antibody or antigen-binding fragment thereof may be administered at 90 mg, 120 mg, 180 mg, or 240 mg. In one embodiment of the invention, the antibody or antigen-binding fragment thereof may be administered at 90-180 mg if the patient weighs less than 80 kg, and at 190-270 mg if the patient weighs 80 kg or more.

[0031] In one embodiment of the invention, the antibody or antigen-binding fragment thereof may be administered at 1-8 week intervals. In one embodiment of the invention, the antibody or antigen-binding fragment thereof may be administered at 1, 2, 3, 4, 5, 6, 7, or 8 week intervals. In one embodiment of the invention, the antibody or antigen-binding fragment thereof may be administered at two or four week intervals.

[0032] In one embodiment of the invention, diseases treatable with anti-TNFα antibodies may include rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, 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 anti rheumatic drugs (DMARDs), including methotrexate. b) No history of methotrexate or other DMARDs. c) There are severe axial symptoms and elevated serologic indicators associated with inflammation that do not respond adequately to standard treatments. d) Failure to respond to, contraindication to, or intolerance to systemic therapy, including methotrexate, cyclosporine, or psoralen ultraviolet A therapy (PUVA). e) Failure to adequately respond to or intolerance of treatment with corticosteroids, 6-mercaptopurine, azathioprine, or immunosuppressants, or such treatment is contraindicated. f) Failure to respond to standard treatments including antibiotics, excretion techniques, or immunosuppressive therapy.

[0034] In one embodiment of the present invention, the patient may have received at least one intravenous dose of an anti-TNFα antibody or an antigen-binding fragment thereof prior to subcutaneous administration. In one embodiment of the present invention, the patient may be a patient who has received an anti-TNFα antibody or an antigen-binding fragment thereof intravenously at a dose of 1 to 10 mg / kg per administration prior to subcutaneous administration.

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

[0036] In one embodiment of the invention, a composition containing an anti-TNFα antibody or antigen-binding fragment thereof may be administered simultaneously with, prior to, or after 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 invention, a composition containing an anti-TNFα antibody or antigen-binding fragment thereof may be administered simultaneously with, prior to, or following administration of methotrexate, leflunomide and sulfasalazine, hydroxychloroquine, or a combination thereof.

[0038] In one embodiment of the invention, the patient following subcutaneous administration may have one or more characteristics selected from the following: a) DAS28 (Disease Activity Score in 28 joints) decreased by at least 2.0. b) Crohn's disease activity index (CDAI) decreased by at least 70 points. Effect 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 an antigen-binding fragment thereof. Furthermore, the therapeutic method, composition, kit, or use according to the present invention has the advantage of improving convenience and quality of life, thereby increasing patient satisfaction, since the administration time is shorter than that of intravenous injection and the patient's stay in the hospital is reduced.

[0040] Furthermore, the therapeutic method, composition, kit, or use of the present invention is added as a new treatment option for infliximab, and also offers the advantage of not imposing a burden or resistance associated with changing medication on patients and medical professionals who have traditionally administered infliximab by intravenous injection. [Brief description of the drawings]

[0041] [Figure 1] FIG. 1 shows the design outline for a clinical trial of subcutaneous infliximab in patients with rheumatoid arthritis (RA). [Diagram 2] Figure 2 shows the design outline of a clinical trial of subcutaneous infliximab in patients with Crohn's disease (CD). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

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

[0043] In order that the present invention may be more readily understood, certain terms used herein are defined below. "TNFα" is intended to refer to a human cytokine that exists as a 17 kD secreted form and a 26 kD membrane associated form, the biologically active form of which consists of a trimer non-covalently linked to the 17 kD 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] "Antibody" refers to an immunoglobulin molecule consisting of four polypeptide chains, two heavy chains and two light chains, interconnected by disulfide bonds. Naturally occurring antibodies with other 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 and light chain variable regions are further subdivided into hypervariable regions called complementarity determining regions (CDRs) arranged together with more conserved regions called framework regions (FRs). Each heavy and light chain variable region consists of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

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

[0046] "Biosimilar" means a biological product that is so similar to an FDA-approved biological product (reference drug) that it has no clinically significant differences from the reference drug in terms of pharmacokinetics, pharmacodynamics, safety, and efficacy.

[0047] "Administering" refers to giving a substance (eg, an anti-TNFα antibody) to achieve a therapeutic objective (eg, treatment of a TNFα-related disorder).

[0048] "TNFα-related disease" refers to a local and / or systemic physiological disease in which TNFα is the primary mediator inducing disease manifestations. The terms "TNFα-related disease", "anti-TNFα-treatable disease" and "disease in which TNFα activity is detrimental" are used interchangeably herein.

[0049] A "subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates, such as non-human primates, sheep, dogs, cats, rabbits, and ferrets, rodents, such as mice, rats, and guinea pigs, birds, such as chickens, amphibians, and reptiles. In a preferred embodiment, the subject is a mammal, such as a non-human primate, sheep, dog, cat, rabbit, ferret, or rodent. 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 inhibitor required to inhibit a desired biological outcome, e.g., neutralize cytotoxicity.

[0051] A "kit" refers to a packaged product containing components for administering a TNFα antibody of the invention for the treatment of a TNFα-related disorder. The kit preferably includes a container or box that holds the components of the kit. The box or container is affixed with a Food and Drug Administration approved protocol or labeling. The box or container contains the components of the 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 invention.

[0052] Various aspects of the invention will now be described in further detail. The anti-TNFα antibody or antigen-binding fragment thereof 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 a fragment thereof. A chimeric antibody refers to an antibody that includes heavy and light chain variable region sequences from one species and constant region sequences 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 mouse heavy and light chain variable regions and human heavy and light chain constant regions bound thereto. A chimeric human-mouse IgG monoclonal antibody may be produced by a method known in the art. For example, in the case of infliximab, it may be produced by the method described in U.S. Pat. No. 6,284,471.

[0053] In one embodiment of the present invention, the antibody may include an antibody that binds to TNFα or 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 antigen-binding fragment thereof may comprise 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 invention, the antibody or antigen-binding fragment thereof may comprise: a light chain variable region comprising the amino acid sequence of SEQ ID NO:7; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:8.

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

[0057] A composition comprising the anti-TNFα antibody or its antigen-binding fragment of the present invention As used herein, the term "composition containing the anti-TNFα antibody or antigen-binding fragment thereof of the present invention" is used interchangeably with "stable liquid pharmaceutical formulation."

[0058] The composition of 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 the present application, the term "free" means that the component is not contained at all. The term also means that the component is substantially free of the component, that is, the component is contained to an extent that does not affect the activity of the antibody, the stability, and the viscosity of the liquid pharmaceutical formulation, for example, at 0 to 1% (w / v), 0 to 1 ppm (w / v), or 0 to 1 ppb (w / v) based on the total weight of the liquid pharmaceutical formulation.

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

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

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

[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 0.001-5% (w / v), 0.01-1% (w / v), or 0.02-0.1% (w / v). When the concentration of the surfactant is within this range, excellent long-term stability and low viscosity can be exhibited.

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

[0065] The sugar derivative may include a sugar alcohol, a sugar acid, or a mixture thereof. Examples of sugar alcohols include, but are not limited to, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, polyglycitol, and the like. Examples of sugar acids include, but are not limited to, aldonic acids (such as glyceric acid), urosonic acids (such as neuraminic acid), uronic acids (such as glucuronic acid), aldaric acids (such as tartaric acid), and the like.

[0066] In one embodiment of the present invention, the sugar or derivative thereof may include sorbitol, mannitol, trehalose, sucrose, or a mixture of two or more thereof. 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 0.1-30% (w / v), 1-20% (w / v), or 1-10% (w / v). When the concentration of the sugar or its derivative is within this range, it can exhibit excellent long-term stability and low viscosity.

[0067] (D) Buffer

[0068] A buffer is a neutralizing substance that minimizes changes in pH caused by acids or alkalis, and 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. When both acetate and histidine are included as a buffer, 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, potassium acetate, etc. An acid, such as acetic acid, may be further included for pH adjustment. It is most preferable to include acetate as a buffer from the viewpoints 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 may be free of citrate, phosphate, or mixtures thereof.

[0072] In one embodiment of the present invention, the content of the buffering agent (or the anion of the buffering agent) 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 buffering agent or its anion may be 1 to 50 mM, 5 to 30 mM, or 10 to 25 mM. When the content of the buffering agent or its anion is within this range, excellent long-term stability and low viscosity can be exhibited.

[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, it can exhibit excellent long-term stability and low viscosity. The pH can be adjusted using a buffer. In other words, when a buffer is contained at a predetermined content, it can exhibit a pH in the above range without a separate pH adjuster. When citrate, phosphate, or a mixture thereof is used as a buffer, it may be difficult to exhibit a pH in the above range. When an acid (e.g., hydrochloric acid) or a base (e.g., sodium hydroxide) is further contained as a separate pH adjuster, the stability of the antibody may be reduced.

[0074] (F) Other Ingredients In one embodiment of the present invention, the stable liquid pharmaceutical formulation may not contain aspartic acid, lysine, arginine, or a mixture thereof. When these amino acids are contained, 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 above three types of amino acids. In this case, the amino acids may be contained within a range of 5% (w / v), for example, a range of 0.001 to 5% (w / v), a range of 0.001 to 1% (w / v), a range of 0.01 to 5% (w / v), a range of 0.01 to 1% (w / v), a range of 0.1 to 5% (w / v), or a range of 0.1 to 1% (w / v).

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

[0076] In one embodiment of the present invention, the stable liquid pharmaceutical formulation contains metal salts such as NaCl, KCl, NaF, KBr, NaBr, Na 2 SO 4 , NaSCN, K 2 SO 4 etc. If these metal salts are included, precipitation phenomena may occur and the formulation may have a gelatinous form, reducing stability.

[0077] In one embodiment of the present invention, the stable liquid pharmaceutical formulation may be free of chelating agents (e.g., EDTA), which may increase the rate of oxidation.

[0078] In one embodiment of the present invention, the 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, alkyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, m-cresol, etc. If preservatives are included, they may not be useful for 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 within the scope of not substantially adversely affecting the activity of the antibody, the stability of the formulation, and the low viscosity. For example, the formulation may further contain an aqueous carrier, an antioxidant, or a mixture of two or more of these. The aqueous carrier is a carrier that is pharma- ceutical acceptable (safe and non-toxic when administered to humans) and 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 saline solution, Ringer's solution, dextrose, and the like. Examples of antioxidants include, but are not limited to, ascorbic acid, and the like.

[0080] (G) "Stable" Liquid Pharmaceutical Formulations The term "stable" in the context of a "stable" liquid pharmaceutical formulation of the invention means that the antibody of the invention substantially retains its physical stability and / or chemical stability and / or biological activity during the manufacturing process and / or upon storage / preservation. A variety of analytical techniques for measuring antibody stability are readily available in the art.

[0081] Physical stability can be assessed by methods known in the art, including measuring the apparent attenuation of light (absorbance or optical density) of a sample. Such light attenuation measurements are related to the turbidity of the formulation. Physical stability can also be measured by measuring the content of high molecular weight components, the content of low molecular weight components, the amount of intact protein, the number of insoluble foreign particles, etc.

[0082] Chemical stability can be assessed, for example, by detecting and quantifying chemically altered forms of the antibody. Chemical stability includes charge changes (e.g., occurring as a result of deamidation or oxidation), which can be assessed, for example, by ion exchange chromatography. For chemical stability, charge variants (acidic or basic peaks), etc. can be measured.

[0083] Biological activity can be assessed 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 stable for an extended period of time. In one embodiment of the present invention, the term "stable" liquid pharmaceutical formulation refers to a liquid pharmaceutical formulation that meets one or more of the following:

[0085] Turbidity - Absorbance A measured by a spectrophotometer after storing at 40°C ± 2°C for 4 weeks 600 is 0 to 0.0300 or 0 to 0.0700;

[0086] - Absorbance A measured by a spectrophotometer after storing for 4 weeks under sealed conditions at a temperature of 40°C ± 2°C and a relative humidity of 75 ± 5% 600 is 0 to 0.0300 or 0 to 0.0700;

[0087] Content of main component (main peak) - a liquid pharmaceutical preparation having a content of 98%-100% of the active ingredient as determined by SE-HPLC after storage at a temperature of 40°C ± 2°C for 4 weeks; - a liquid pharmaceutical preparation having a content of 98-100% of the main ingredient as measured by SE-HPLC after storage for 4 weeks under sealed conditions at a temperature of 40°C ± 2°C and a relative humidity of 75 ± 5%;

[0088] High molecular weight components (peaks whose retention times are ahead of the main peak (intact IgG)) - a liquid pharmaceutical formulation having 0-1.00% of high molecular weight components as measured by SE-HPLC after storage for 12 months at a temperature of 5°C ± 3°C; - a liquid pharmaceutical formulation having a high molecular weight component content of 0-1.00% as measured by SE-HPLC after storage at a temperature of 5°C ± 3°C and under sealed conditions for 12 months;

[0089] Low molecular weight components (peaks whose retention times are later than the main peak (intact IgG)) - a liquid pharmaceutical formulation having 0-0.40% low molecular weight components as measured by SE-HPLC after storage for 12 months at a temperature of 5°C ± 3°C; - a liquid pharmaceutical formulation having a low molecular weight component content of 0-0.40% as measured by SE-HPLC after storage at a temperature of 5°C ± 3°C and under sealed conditions for 12 months;

[0090] Intact immunoglobulin G content - a liquid pharmaceutical formulation having a content of intact immunoglobulin G (Intact IgG%) between 94.0% and 100% as measured by non-reduced CE-SDS after storage for 12 months at a temperature of 5°C ± 3°C; - a liquid pharmaceutical formulation having an intact immunoglobulin G content (Intact IgG%) of 94.0% to 100% as measured by non-reduced CE-SDS after storage for 12 months at a temperature of 5°C ± 3°C and under sealed conditions; - a liquid pharmaceutical formulation having a content of intact immunoglobulin G (Intact IgG%) between 94.0% and 100% as measured by non-reduced CE-SDS after storage for 4 weeks at a temperature of 40°C ± 2°C; - a liquid pharmaceutical formulation having an intact immunoglobulin G content (Intact IgG%) of 94.0% to 100% as measured by non-reduced CE-SDS after storage for 4 weeks at a temperature of 40°C ± 2°C, a relative humidity of 75 ± 5% and under sealed conditions;

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

[0092] Insoluble foreign particle count - liquid pharmaceutical preparations having a number of insoluble foreign particles (10.00 μm ≦, < 400.00 μm) between 0 and 1,000 particles, measured by HIAC after storage for 12 months at a temperature of 5 °C ± 3 °C; - liquid pharmaceutical preparations having a number of insoluble foreign particles (10.00 μm ≦, < 400.00 μm) between 0 and 1000 particles, measured by HIAC after storage at a temperature of 5 ° C ± 3 ° C and under closed conditions for 12 months; - a liquid pharmaceutical formulation having a number of insoluble foreign particles (1.00 μm ≦, <100.00 μm) between 0 and 30,000 particles, measured by MFI after storage for 4 weeks at a temperature of 40°C ± 2°C; - a liquid pharmaceutical formulation having a number of insoluble foreign particles (1.00 μm ≦, <100.00 μm) between 0 and 30,000 particles as measured by MFI after storage for 4 weeks at a temperature of 40°C ± 2°C, a relative humidity of 75 ± 5% and under closed conditions; - a liquid pharmaceutical formulation having a number of insoluble foreign particles (10.00 μm ≦, <100.00 μm) between 0 and 200 particles, measured by MFI, after storage for 4 weeks at a temperature of 40 °C ± 2 °C; - a liquid pharmaceutical formulation having a number of insoluble foreign particles (10.00 μm ≦, <100.00 μm) between 0 and 200 particles as measured by MFI after storage for 4 weeks at a temperature of 40°C ± 2°C, a relative humidity of 75 ± 5% and under sealed conditions; - a liquid pharmaceutical formulation having a number of insoluble foreign particles (10.00 μm ≦, <100.00 μm) between 0 and 500 particles, measured by MFI, after storage for 6 weeks at a temperature of 40°C ± 2°C; - a liquid pharmaceutical formulation having a number of insoluble foreign particles (10.00 μm ≦, <100.00 μm) between 0 and 500 particles as measured by MFI after storage for 6 weeks at a temperature of 40°C ± 2°C, a relative humidity of 75 ± 5% and under closed conditions;

[0093] oxidation rate - a liquid pharmaceutical formulation having an oxidation rate of heavy chain Met255 between 0% and 2.5%, measured by LC-MS after storage for 4 weeks at a temperature of 40°C ± 2°C; - a liquid pharmaceutical formulation having an oxidation rate of heavy chain Met255 between 0% and 2.5%, as measured by LC-MS after storage for 4 weeks at a temperature of 40°C ± 2°C, a relative humidity of 75 ± 5% and under sealed conditions;

[0094] Charge variants - a liquid pharmaceutical formulation having an acidic peak of 20% to 35% as measured by IEC-HPLC after storage for 4 weeks at a temperature of 40°C ± 2°C; - a liquid pharmaceutical formulation having an acidic peak of 20%-35% as measured by IEC-HPLC after storage for 4 weeks at a temperature of 40°C ± 2°C, a relative humidity of 75 ± 5% and under sealed conditions; - a liquid pharmaceutical formulation having a basic peak of 33%-40% as measured by IEC-HPLC after storage at a temperature of 40°C ± 2°C for 4 weeks; - a liquid pharmaceutical formulation having a basicity peak of 33%-40% as measured by IEC-HPLC after storage for 4 weeks at a temperature of 40°C ± 2°C, a relative humidity of 75 ± 5% and under sealed conditions;

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

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

[0097] (H) Method for producing a stable liquid pharmaceutical formulation The stable liquid pharmaceutical formulation of the present invention can be produced by a known method and is not limited to a specific method. For example, a buffer is added to a solution containing a surfactant and a sugar or a derivative thereof to adjust the pH, and then an antibody is added to the mixed solution to produce a liquid pharmaceutical formulation. In addition, in the final stage of the purification process, a solution containing a part of the excipients is produced, and then the remaining components are added to produce a liquid pharmaceutical formulation. For example, in the final stage of the purification process, a solution containing an antibody, a buffer, and a sugar or a derivative thereof is produced, and then a surfactant is added to the solution to produce a liquid pharmaceutical formulation.

[0098] Furthermore, the preparation may or may not include a freeze-drying step during production. In the case where the freeze-drying step is not included, for example, the liquid pharmaceutical formulation of the present invention can be produced and immediately placed in a sealed container after treatment such as sterilization.

[0099] In the case where a lyophilization step is included, for example, after the liquid pharmaceutical formulation of the present invention is produced and lyophilized, or after the liquid pharmaceutical formulation of the present invention is produced and lyophilized and stored / preserved, the components removed or altered by lyophilization and / or storage / preservation can be supplemented or replaced to produce the liquid pharmaceutical formulation of the present invention. Also, the liquid pharmaceutical formulation of the present invention can be produced by lyophilizing only the components of the liquid pharmaceutical formulation of the present invention excluding the components that may be removed or altered by lyophilization and / or storage / preservation, or by lyophilizing only the components and storing / preserving, and then adding the excluded components.

[0100] The applicant's previously filed patent, Korean Patent Application No. 10-2017-0081814, is incorporated herein by reference.

[0101] Methods 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 to a subject a pharmaceutical composition containing an anti-TNFα antibody or antigen-binding fragment thereof.

[0102] In one embodiment of the 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 invention, the antibody may comprise infliximab. In one embodiment of the invention, the antibody may comprise a chimeric human-mouse IgG monoclonal antibody.

[0103] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may comprise 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 invention, the antibody or antigen-binding fragment thereof may comprise: a light chain variable region comprising the amino acid sequence of SEQ ID NO:7; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:8.

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

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

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

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

[0109] In one embodiment of the present invention, the (C) sugar may include a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, or a mixture of two or more thereof, and the sugar derivative may include a sugar alcohol, a sugar acid, or a mixture thereof. In one embodiment of the present invention, (C) sugar or a derivative thereof may include sorbitol, mannitol, trehalose, sucrose, or a mixture of two or more thereof. In one embodiment of the present invention, the concentration of (C) the sugar or a derivative thereof may be 1 to 10% (w / v).

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

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

[0112] In one embodiment of the invention, the composition may be free of aspartic acid, lysine, arginine, or mixtures thereof. In one embodiment of the invention, the composition comprises NaCl, KCl, NaF, KBr, NaBr, Na 2 SO 4 , NaSCN, K 2 SO 4 , or a mixture thereof. In one embodiment of the invention, the composition may be free of a chelating agent. In one embodiment of the invention, the composition may be free of preservatives.

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

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

[0115] In one embodiment of the present invention, the composition may comprise: (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 comprise: (A) 90 to 180 mg / ml of 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) 0.02 to 0.1% (w / v) of a surfactant; (C) 1 to 10% (w / v) of a sugar or a derivative thereof; and (D) 1 to 50 mM of a buffer containing acetate or histidine.

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

[0118] In one embodiment of the invention, the composition does not need to undergo a reconstitution step, a dilution step, or both steps prior to use. In one embodiment of the invention, the stable composition may be loaded into a pre-filled syringe prior to use. In one embodiment of the invention, the composition may be contained within an auto-injector prior to use.

[0119] Diseases treatable with anti-TNFα antibodies In one embodiment of the invention, the disease treatable with an anti-TNFα antibody is 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's 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 carcinoma, hemorrhagic shock, Staphylococcus aureus infection, and follicular lymphoma.

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

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

[0122] In one embodiment of the present invention, the subject to administration of an anti-TNFα antibody is a patient who has an inadequate response to disease-modifying anti rheumatic drugs (DMARDs), including methotrexate.

[0123] In one embodiment of the present invention, the subjects for administration of the anti-TNFα antibody are patients who have not previously been treated with methotrexate or other DMARDs.

[0124] In one embodiment of the present invention, anti-TNFα antibodies are administered to patients with severe axial symptoms and elevated serologic indicators associated with inflammation who do not respond adequately to conventional treatments.

[0125] In one embodiment of the invention, anti-TNFα antibodies are administered to patients who do not respond to, are contraindicated for, or have intolerance to systemic therapies, including methotrexate, cyclosporine, or psoralen ultraviolet A therapy (PUVA).

[0126] In one embodiment of the invention, the anti-TNFα antibody is administered to a patient who has not adequately responded to or is unable to tolerate treatment with corticosteroids, 6-mercaptopurine, azathioprine, or immunosuppressants, or in whom such treatment is contraindicated.

[0127] In one embodiment of the invention, anti-TNFα antibodies are administered to patients who have not responded to standard treatments, including antibiotics, depuration, or immunosuppressive therapy.

[0128] Dosage and interval In one embodiment of the present invention, the anti-TNFα antibody or binding fragment thereof may be administered at 60 to 300 mg, specifically 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.

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

[0130] In one embodiment of the present invention, the anti-TNFα antibody or binding fragment thereof may be administered at 90-180 mg if the patient weighs less than 80 kg, and at 190-270 mg if the patient weighs 80 kg or more.

[0131] In one embodiment of the present invention, the anti-TNFα antibody or binding fragment thereof may be administered at intervals of 1 to 8 weeks, specifically 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 invention, the anti-TNFα antibody or binding fragment thereof may be administered at 2-4 week intervals.

[0133] Premedication The step of administering the anti-TNFα antibody or antigen-binding fragment thereof subcutaneously may include a step in which the anti-TNFα antibody or antigen-binding fragment thereof is administered intravenously.

[0134] In one embodiment of the present invention, the subcutaneous administration step may include a step of intravenously administering 1 to 10 mg / kg of an anti-TNFα antibody or an antigen-binding fragment thereof, specifically, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / kg.

[0135] In yet another embodiment of the present invention, the subcutaneous administration step may include a step of intravenously administering 2 to 8 mg / kg of an anti-TNFα antibody or an antigen-binding fragment thereof. In yet another embodiment of the present invention, the subcutaneous administration step may include a step of intravenously administering 3 to 5 mg / kg of an anti-TNFα antibody or an antigen-binding fragment thereof.

[0136] In one embodiment of the present invention, the subcutaneous administration step may include a step of intravenously administering the anti-TNFα antibody or antigen-binding fragment thereof at intervals of 1 to 8 weeks, specifically 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, the subcutaneous administration step may include a step of intravenously administering the anti-TNFα antibody or antigen-binding fragment thereof at 2-4 week intervals.

[0138] In one embodiment of the present invention, the subcutaneous administration step may include a step of intravenously administering the anti-TNFα antibody or antigen-binding fragment thereof, and may include a step in which the interval between the last intravenous administration and the first subcutaneous administration is 1 to 8 weeks, specifically, a step in which the administration is performed 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, the subcutaneous administration step includes a step of intravenously administering an anti-TNFα antibody or an antigen-binding fragment thereof, and may include a step in which the interval between the final intravenous administration and the first subcutaneous administration is 2 to 4 weeks.

[0140] Coadministration Other biologics or chemotherapeutic agents may be administered together with the anti-TNFα antibodies or antigen-binding fragments thereof of the present invention. The administration may be simultaneous with, prior to, or subsequent to administration of an anti-TNFα antibody or antigen-binding fragment thereof.

[0141] In one embodiment of the invention, the co-administered biologic may include Etanercept, Infliximab, Adalimumab, Certolizumab pegol, Golimumab, or combinations thereof.

[0142] In one embodiment of the invention, the co-administered chemotherapeutic agents may include disease-modifying antirheumatic drugs (DMARDs).

[0143] In one embodiment of the invention, the co-administered chemotherapeutic agents may include Methotrexate, Leflunomide, Sulfasalazine, Hydroxychloroquine, or combinations thereof.

[0144] ·product The present invention also provides an article of manufacture comprising a composition comprising an anti-TNFα antibody or binding fragment thereof; and a container containing the composition in a sealed state.

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

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

[0147] The specific product forms of the vial, cartridge, prefilled syringe, auto-injector, etc., and the method of filling the stable liquid pharmaceutical formulation into the vial, cartridge, prefilled syringe, auto-injector, etc., can be easily obtained or carried out by a person having ordinary skill in the art to which the present invention belongs. For example, U.S. Patent Nos. 4,861,335 and 6,331,174 disclose specific product forms and filling methods of prefilled syringes. For example, U.S. Patent Nos. 5,085,642 and 5,681,291 disclose specific product forms and assembly methods of auto-injectors. The vial, cartridge, prefilled syringe, auto-injector, etc. may be a commercialized product as it is, or may be a product individually custom-made in consideration of the physical properties, administration site, dosage, etc. of the composition containing the anti-TNFα antibody or its binding fragment.

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

[0149] In one embodiment of the invention, the article of manufacture may further comprise instructions providing a method of use, storage, or both, of a composition containing the anti-TNFα antibody or binding fragment thereof, the method of use including a method of treating a disease in which TNFα activity is detrimental, and may include a route of administration, dosage, and timing of administration.

[0150] In one embodiment of the invention, the product may include other paraphernalia necessary from a commercial and user standpoint, such as needles, syringes, etc.

[0151] The present invention will now be described in more detail with reference to the following examples, which are provided for illustrative purposes only and are not intended to limit the scope of the present invention.

[0152] Example 1. Evaluation of safety and efficacy of subcutaneous administration of infliximab in patients with rheumatoid arthritis (RA) The 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) versus intravenous infliximab (infliximab IV) when administered in combination with methotrexate (MTX) and folic acid in patients with active rheumatoid arthritis who have not responded adequately to MTX monotherapy for at least 3 months. The trial consists of two parts.

[0153] Part 1 was designed to identify the optimal dose of infliximab SC and to evaluate the area under the steady-state concentration-time curve (AUC) between weeks 22 and 30. τ ) identified the optimal dose of infliximab SC equivalent to 3 mg / kg infliximab IV over the first 30 weeks. The duration of the Part 1 clinical trial was up to 65 weeks, including screening (up to 3 weeks) through the end-of-study visit.

[0154] Part 2 is designed to demonstrate non-inferiority of efficacy between SC and IV infliximab. The efficacy of SC infliximab is demonstrated by clinical response according to change from baseline in Disease Activity Score in 28 joints (DAS28) (C-Reactive Protein, CRP) at week 22. The dose and interval of SC infliximab in part 2 was set to 120 mg every 2 weeks.

[0155] Part 1 Patients were eligible to enroll in this clinical trial if they met all of the following criteria: *Having active disease defined as at least 6 swollen and tender joints out of 28 joints and a serum C-reactive protein (CRP) concentration >0.6 mg / dL * Patients had been receiving methotrexate at 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), with the same dose being administered for the last 4 weeks.

[0156] Patients were not eligible to enroll in the clinical trial if they met any of the following criteria: *Previously received biologics for the treatment of RA and / or TNFα inhibitors for the treatment of other diseases. *Patients with known allergy to infliximab or any other murine and / or human protein excipients or hypersensitivity to immune globulin products.

[0157] The study consisted of three clinical trial periods: screening, treatment, and end of study. Screening took place between 21 days and 1 day before the first dose of study drug to assess patients' eligibility for the study. All tests were performed, including tests for HIV-B, HIV-C, and human immunodeficiency virus (HIV-1, HIV-2) infection, urine and serum pregnancy tests in women of childbearing potential, rheumatoid factor, anti-cyclic citrullinated peptide, 12-lead electrocardiogram, and clinical laboratory tests. Interferon-gamma release assays (IGRAs) and chest x-rays were also performed to exclude tuberculosis patients.

[0158] All patients enrolled in the clinical trial received one dose of infliximab IV at weeks 0 and 2. Folic acid was administered in combination with MTX and the study drug to minimize or prevent adverse events related to the side effects of MTX, and patients were instructed to maintain the MTX dose from the start of the clinical trial to the end of the trial. In addition, patients were allowed to receive premedication at the discretion of the investigator 30 to 60 minutes before starting the study drug administration to prevent hypersensitivity reactions to the study drug (e.g., antihistamines [2 to 4 mg chlorpheniramine equivalent doses], hydrocortisone, paracetamol, and / or nonsedating antihistamines [10 mg cetirizine equivalent doses], but not limited to these).

[0159] Patients who received two complete doses and had no safety concerns were randomized to receive either SC or IV infliximab 42 days prior to dosing, based on investigator discretion. 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 whom 48 were randomized in a 1:1:1:1 ratio to four clinical trial cohorts and received study drug through week 54 (Table 1).

[0160] [Table 1]

[0161] Patients randomized to cohort 1 received seven additional doses of infliximab IV at week 6 and every 8 weeks thereafter (weeks 14, 22, 30, 38, 46, and 54). For patients randomized to cohorts 2, 3, and 4, the first dose of infliximab SC was administered at week 6, and additional doses of infliximab SC were administered every 2 weeks until week 54. The dose originally assigned to all patients in cohorts 2, 3, and 4 was adjusted to the optimal dose after dose confirmation. Additional SC injections at the optimal dose were then administered until week 54. Infliximab SC was injected by healthcare professionals during each study site visit (weeks 6, 8, 10, 14, 22, 24, 26, 28, 30, 38, 46, and 54), and patients were able to self-inject during the other weeks (weeks 12, 16, 18, 20, 32, 34, 36, 40, 42, 44, 48, 50, and 52) if they were trained in the proper injection technique and deemed this appropriate by the study personnel.

[0162] Patients visited the study site at pre-determined intervals for clinical evaluations and blood sampling. At each visit, patients were questioned about adverse events (AEs) and concomitant medications and were monitored for clinical signs and symptoms of TB. Primary pharmacokinetic endpoints were assessed during the maintenance phase from Weeks 22 to 30, secondary pharmacokinetic endpoints were assessed during treatment up to Week 54, and analytical blood samples, efficacy, PD, and safety assessments were collected and evaluated at the time points described in the evaluation schedule.

[0163] The end-of-study visit occurred at the end of the maintenance phase or 8 weeks after the last dose if the patient dropped out. Every effort was made to end all trials 8 weeks after the patient received their last dose.

[0164] Part 2 Part 2 was initiated based on an Independent Data Safety Monitoring Committee review of reported PK modeling data, including PK, efficacy, PD, and safety data over the first 30 weeks identified in Part 1.

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

[0166] All patients enrolled in the clinical trial received one dose of infliximab IV at weeks 0 and 2. Folic acid was administered in combination with MTX and the study drug to minimize or prevent adverse events related to the side effects of MTX, and patients were instructed to maintain the MTX dose throughout the clinical trial. Patients were allowed to premedicate at the discretion of the investigator 30-60 minutes prior to the start of study drug administration to prevent hypersensitivity reactions to the study drug, as follows (e.g., but not limited to, antihistamines [2-4 mg chlorpheniramine equivalent dose], hydrocortisone, paracetamol, and / or nonsedating antihistamines [10 mg cetirizine equivalent dose]).

[0167] Patients who had received two complete doses and had no safety concerns, at the investigator's discretion, were randomized to receive infliximab SC or placebo IV, or infliximab IV or placebo SC, administered via a pre-filled syringe (PFS) 42 days prior to dosing. 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). At least 218 patients with active rheumatoid arthritis were randomized in a 1:1 ratio to the two clinical trial arms and received study medication through week 54. A double placebo design was used to maintain blinding through week 30 (Table 2).

[0168] [Table 2]

[0169] Patients randomized to arm 1 received three additional doses of infliximab IV at week 6 and then every 8 weeks (weeks 14 and 22) until week 22, and placebo SC at week 6 and then every 2 weeks until week 28. Infliximab IV was then switched to infliximab SC (PFS) at week 30. Infliximab SC (PFS) was administered until week 54. Patients randomized to arm 2 received their first dose of infliximab SC (PFS) at week 6, then 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 injected by medical personnel during visits to each study site (weeks 6, 14, 22, 24-28 [patients visiting for PK assessment], 30, 38, 46, and 54), and patients were trained in the proper injection technique and could self-inject if deemed appropriate by the investigator during all other weeks (weeks 8, 10, 12, 16, 18, 20, 24-28 [patients not visiting for PK assessment], 32, 34, 36, 40, 42, 44, 48, 50, and 52).

[0171] In selected countries, SC infliximab was self-administered by auto-injector (AI) every 2 weeks from week 46. To evaluate the usability of SC infliximab (AI), a diagnostic questionnaire, a diagnostic checklist for self-administration, and a checklist of potential risks were assessed before and after self-administration.

[0172] Clinical evaluations, blood sampling, and clinical trial type visits in Part 2 were conducted similarly to those in Part 1, with samples collected and evaluated at the times described in the evaluation schedule.

[0173] result 1-1.Safety evaluation Summary of adverse events Safety evaluations included secondary endpoints in Part 1, including immunogenicity, monitoring of hypersensitivity reactions (including monitoring of delayed hypersensitivity reactions), vital sign measurements (including blood pressure, heart and respiratory rates, and temperature), weight, interferon-gamma release assay, chest x-ray, HIV-B, HIV-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 / hypersensitivity / anaphylactic reactions [medication-related reactions], delayed hypersensitivity reactions, injection site reactions, infections, and malignancies), signs and symptoms of tuberculosis, laboratory analyses, pregnancy tests, past and current concomitant medications, and local pain (assessed using a 10-cm visual analogue scale (VAS)).

[0174] The cumulative safety data for this study included adverse events (and serious adverse events) that occurred without correlation to clinical drug up until the end of study visit. 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 (68.8%) patients, 9 (69.2%) in the IV cohort (cohort 1) and 24 (68.6%) in the overall SC cohort (cohorts 2, 3, and 4), with similar rates in the overall SC cohort compared to the IV cohort. Most post-treatment adverse events were grade 1 or 2, and a total of 23 (47.9%) patients were considered to be drug-related of all post-treatment adverse events.

[0175] A total of six (12.5%) patients experienced serious post-treatment adverse events, one (7.7%) in the IV cohort (Cohort 1) and five (14.3%) in the SC cohorts (Cohorts 2 and 4). No serious post-treatment adverse events occurred in Cohort 3 of the SC cohorts. The level of serious post-treatment adverse events was grade 2 or 3, and two (16.7%) patients in Cohort 4 reported events that were considered to be related to the drug. Of all serious post-treatment adverse events, one (9.1%) patient in Cohort 2 and two (16.7%) patients in Cohort 3 discontinued treatment after Week 30 and Week 32, respectively, due to the investigator's judgment that they were serious medical events.

[0176] Medication-related adverse events after treatment, such as infusion-related reactions, hypersensitivity, or anaphylaxis, occurred in a total of four patients (8.3%), one patient (7.7%) in the IV cohort (cohort 1) and three patients (8.6%) in the entire SC cohort (cohorts 2 and 3). In the SC cohort, no medication-related adverse events after treatment, such as infusion-related reactions, hypersensitivity, or anaphylaxis, occurred in cohort 4. Because infliximab medication-related reactions are associated with antibodies against the drug (ADA) (Remsima SmPC2017), patients who showed medication-related reactions were investigated for the presence or absence of antibodies against the drug (ADA). A total of two patients (one each in cohorts 1 and 2) showed positive reactions to antibodies against the drug (ADA) and neutralizing antibodies (NAb). One patient in cohort 2 received two doses of IV infliximab at weeks 0 and 2 of the dose-loading period and two doses of SC infliximab at weeks 6 and 8. A dose-related reaction occurred at weeks 6 and 8, with positive drug-specific and neutralizing antibodies at week 6 and the End of Study Visit (10 weeks after the week 8 visit). One patient in cohort 1 developed a dose-related reaction at week 38, with positive drug-specific and neutralizing antibodies at weeks 30, 38, and the End of Study Visit (10 weeks after the week 38 visit).

[0177] A total of five patients (14.3%) in the SC cohort (Cohorts 2, 3, and 4) experienced post-treatment adverse events (injection site reactions), all of which were grade 1 or grade 2. No post-treatment adverse events (injection site reactions) were reported in the IV cohort (Cohort 1). Patients who experienced injection site reactions were also evaluated for the presence of antibodies to the drug (ADA), 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 occurrence of the injection site reaction.

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

[0179] Six patients (17.1%) in the SC cohort (cohorts 2, 3, and 4) discontinued treatment due to adverse events after treatment, including antiphospholipid syndrome, injection site reactions, medication-related reactions, pulmonary tuberculosis, and latent tuberculosis infection. No posttreatment adverse events (infections) occurred in the IV cohort. No deaths were reported during the clinical trial.

[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 event was counted. Events were considered to be related only if a "possible," "probable," or "definite" relationship was observed.

[0181] immunogenicity In general, the proportion of patients with ADA positivity was low in the SC cohort, and most patients were ADA negative at week 54. The proportion of patients with ADA positivity tended to decrease with increasing SC dose. The number of patients with ADA positivity at week 54 was 9 (69.2%), 4 (36.4%), 2 (16.7%), and 2 (16.7%) in cohorts 1 to 4, respectively (Table 4).

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

[0183] Localized pain assessment using a visual analogue scale (VAS) The visual analog scale (VAS) ranged from 0 to 100 mm, with higher scores indicating more severe pain. At the first SC administration (week 6), slightly higher levels of local site pain were observed in the SC cohorts (cohorts 2, 3, and 4) than in the IV cohort (cohort 1). However, as SC administrations were repeated, local site pain gradually decreased, with the SC cohorts (cohorts 2, 3, and 4) reporting slightly lower levels of pain than the IV cohort (cohort 1). Among the SC cohorts, cohort 4, which had to receive two doses of the SC 90 mg formulation, showed more 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 effects Disease activity measured by DAS28 As secondary efficacy endpoints, DAS28 (C reactive protein; CRP) and DAS28 (erythrocyte sedimentation rate; ESR) were analyzed at weeks 2, 6, 14, 22, 30, and 54 compared to baseline, and it was found that there were no clinically significant differences between the three different doses of infliximab SC and infliximab IV cohorts, with actual values ​​tending to decrease over time.

[0186] The actual values ​​and changes from baseline in disease activity measured by DAS28 are summarized in Table 6 (CRP) and Table 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. All SC cohorts showed lower DAS28 scores than the IV cohort from week 22 for DAS28 (CRP) and week 30 for DAS28 (ESR), which is consistent with the higher CRP scores shown in the SC cohort. trough This is consistent.

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

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

[0189] EULAR response assessment The proportion of patients with a good or severe response in the EULAR (European League Against Rheumatism) response assessment, classified according to DAS28 (CRP), was similar between treatment groups (Table 8). The results of the EULAR response assessment, classified according to DAS28 (ESR), were also similar between treatment groups (Table 9).

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

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

[0192] Proportion of patients achieving an ACR20 clinical response The proportion of patients who achieved a clinical response based on the American College of Rheumatology 20% improvement (ACR20) classification criteria from weeks 14 to 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) PK-PD model construction A pharmacokinetic-pharmacodynamic (PK-PD) model for subcutaneous (SC) infliximab was established for integration with a quantitative pharmacokinetic (PK) model to simulate the efficacy and safety of SC infliximab as well as to simulate the PK of future doses and regimens. The PK-PD model was based on data from intravenous infliximab in healthy subjects, patients with ankylosing spondylitis (AS), patients with rheumatoid arthritis (RA), and Crohn's disease (CD), and data from SC infliximab in patients with Crohn's disease (CD), patients with rheumatoid arthritis (RA), and healthy volunteers (Clinicaltrials.gov identifiers NCT01220518, NCT01217086, NCT02096861).

[0195] The PK-PD model constructed based on the above data can be used to simulate the results of subcutaneous administration of infliximab to patients with the indicated conditions (rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, or ankylosing spondylitis).

[0196] PK-PD modeling analysis was performed using a nonlinear mixed-effects modeling approach. Data analysis began with a 1-compartment model with proportional elimination of proportional error model, and the final model was a 2-compartment model with linear elimination from the central compartment. All pharmacokinetic models were parameterized in terms of clearance (CL) and volume of distribution.

[0197] The final PK model was designed to estimate the area under the concentration-time curve (AUC tau ;area under the concentration-time curve) and minimum blood concentration (C trough(minimum concentration immediately before the next application) parameter estimates were applied to each actual dose, regimen, and route of administration to predict profiles, and the data are described by median and 90% confidence intervals. Additional simulations were performed to evaluate the efficacy of each weight group for a fixed dose, regimen, and route of administration. PK-PD modeling and simulations for the subcutaneous dose were performed with NONMEM v7.2.

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

[0199] [Table 11]

[0200] Estimates of infliximab exposure parameters for weight-specific SC infliximab doses and administration regimens in patients with rheumatoid arthritis Exposure pharmacokinetic parameters (AUC τ , C trough , and C max The minimum blood concentration (C) of infliximab SC exposure was simulated for subjects with body weight ranging from 50 to 130 kg in 10 kg increments. trough ), area under the concentration-time curve (AUC τ ) estimates correlated with drug dose (Table 12).

[0201] [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5] [Table 12-6]

[0202] Example 3. Evaluation of 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 versus infliximab IV in patients with active Crohn's disease or active ulcerative colitis through 54 weeks. The trial consists of two parts.

[0203] Part 1 was designed to identify the optimal dose of infliximab SC in patients with Crohn's disease (CD) and to evaluate the area under the steady-state concentration-time curve (AUC τ ) identified the optimal dose of infliximab SC equivalent to 5 mg / kg infliximab IV over the first 30 weeks. The duration of the Part 1 clinical trial was up to 65 weeks, including screening (up to 3 weeks) through the end-of-study visit.

[0204] Part 2 was designed to confirm that SC infliximab was non-inferior pharmacokinetically to IV infliximab in patients with Crohn's disease (CD) or ulcerative colitis (UC) and to assess baseline concentrations (C trough The optimal dose and dosing interval of infliximab SC, equivalent to 5 mg / kg infliximab IV in Part 2, was determined by an independent Data Safety Monitoring Board (DSMB) based on the pharmacokinetic, efficacy, pharmacodynamic, and safety data over the first 30 weeks of Part 1, as follows: Patients weighing less than 80 kg: Infliximab SC 120 mg administered every 2 weeks Patients weighing 80 kg or more: Infliximab SC 240 mg every 2 weeks

[0205] Part 1 Patients were eligible to enroll in this clinical trial if they met all of the following criteria: * Crohn's Disease Activity Index (CDAI) score of 220-450 means you have active disease * Patients must have been diagnosed with Crohn's disease at least 3 months prior to the first administration of the study drug. *Has been treated for active Crohn's disease and has not responded to, is not tolerated by, or has medical contraindications to, a full course of corticosteroid and / or immunosuppressant therapy

[0206] Patients were not eligible to enroll in the clinical trial if they met any of the following criteria: *Previously received biologics for the treatment of Crohn's disease or ulcerative colitis and / or TNFα inhibitors for the treatment of other diseases *Allergy to infliximab or any other murine and / or human protein excipients, or hypersensitivity to immunoglobulin products *Active enterovesical, retroperitoneal, enterocutaneous, or enterovaginal fistula within 6 months prior to the first administration of study drug (Day 0). In the opinion of the investigator, enteric fistulas without clinically significant symptoms and anal fistulas without drainage problems were acceptable. *Having had more than 3 small bowel resections prior to first dose of study drug (Day 0)

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

[0208] At week 0, day 0, patients who met all inclusion criteria and none of the exclusion criteria were enrolled in the clinical trial, and all enrolled patients received one dose of infliximab IV twice, at week 0 and week 2. Patients were allowed to receive premedication at the investigator's discretion 30-60 minutes before starting study drug administration to prevent hypersensitivity reactions to the study drug, as follows (e.g., but not limited to, antihistamines [2-4 mg chlorpheniramine equivalent dose], hydrocortisone, paracetamol, and / or nonsedating antihistamines [10 mg cetirizine equivalent dose]).

[0209] Patients who received two complete doses and had no safety concerns were randomized to receive either SC or IV infliximab 42 days prior to dosing, based on investigator discretion. Randomization was stratified by region (Europe or non-Europe), current use of azathioprine, 6-mercaptopurine, or MTX for treatment, clinical response by 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 patients were randomized in a 1:1:1:1 ratio to four clinical trial cohorts and received study drug through week 54 (Table 13).

[0210] [Table 13]

[0211] Patients randomized to cohort 1 received seven additional doses of infliximab IV at week 6 and every 8 weeks thereafter (weeks 14, 22, 30, 38, 46, and 54). For patients randomized to cohorts 2, 3, and 4, the first dose of infliximab SC was administered at week 6, and additional doses of infliximab SC were administered every 2 weeks until week 54. The dose originally assigned to all patients in cohorts 2, 3, and 4 was adjusted to the optimal dose after dose confirmation. Additional SC injections at the optimal dose were then administered until week 54. Infliximab SC was injected by healthcare professionals during each study site visit (weeks 6, 8, 10, 14, 22, 24, 26, 28, 30, 38, 46, and 54), and patients were able to self-inject during the other weeks (weeks 12, 16, 18, 20, 32, 34, 36, 40, 42, 44, 48, 50, and 52) if they were trained in the proper injection technique and deemed this appropriate by the study personnel.

[0212] Patients visited the study site at pre-determined intervals for clinical evaluations and blood sampling. At each visit, patients were questioned about adverse events (AEs) and concomitant medications and were monitored for clinical signs and symptoms of TB. Primary pharmacokinetic endpoints were assessed during the maintenance phase from Weeks 22 to 30, secondary pharmacokinetic endpoints were assessed during treatment up to Week 54, and analytical blood samples, efficacy, PD, and safety assessments were collected and evaluated at the time points described in the evaluation schedule.

[0213] The end-of-study visit was 8 weeks after the end of the maintenance phase, or 8 weeks after the last dose if the patient discontinued the study. For patients who dropped out, all study procedures were performed on the dropout date or the day after dropout, and every effort was made to end all studies 8 weeks after the patient received their last dose.

[0214] Part 2 Part 2 will be initiated based on an Independent Data Safety Monitoring Committee review of reported PK modeling data, including PK, efficacy, PD, and safety data over the first 30 weeks identified in Part 1.

[0215] Patients may enroll 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 of 220-450 means you have active disease * Patients have been diagnosed with Crohn's disease for at least 3 months prior to the first administration of the study drug. *Has been treated for active Crohn's disease and has not responded to, is not tolerated by, or has medical contraindications to, a full course of corticosteroid and / or immunosuppressant therapy *Meet one or more of the following criteria: - Serum CRP (C-reactive protein) concentration exceeds 0.5 mg / dL - Fecal calprotectin concentration >100μg / g - A colonoscopy (SES-CD) score of ≥ 6 in patients with ileocolonic Crohn's disease or ≥ 4 in patients with ileocolonic Crohn's disease with at least one ulcer

[0217] Patients with active ulcerative colitis *Total Mayo score 6-12, endoscopy score ≥2, and active disease * Patients have been diagnosed with ulcerative colitis for at least 3 months prior to the first administration of the study drug. *Those who have been treated for active ulcerative colitis and have not responded to, are intolerant to, or have medical contraindications to common treatments such as corticosteroids and / or 6-mercaptopurine or azathioprine

[0218] Patients were ineligible to enroll in Part 2 of the clinical trial if they met any of the following criteria: *Previously received biologics for the treatment of Crohn's disease or ulcerative colitis and / or TNFα inhibitors for the treatment of other diseases *Allergy to infliximab or any other murine and / or human protein excipients, or hypersensitivity to immunoglobulin products *Patients with Crohn's disease who have active enterovesical, retroperitoneal, enterocutaneous, or enterovaginal fistulas within 6 months prior to the first administration of study drug (Day 0). In the opinion of the investigator, enterovesical fistulas without clinically significant symptoms and anal fistulas without drainage problems were acceptable. *Patients with Crohn's disease who had undergone more than three small bowel resections prior to the first administration of study drug (Day 0) *Patients with ulcerative colitis who received corticosteroids or 5-aminosalicylic acid within 2 weeks prior to screening

[0219] Part 2 consists of three clinical trial periods: screening, dosing, and end of clinical trial. Screening will be performed between 42 days and 0 days before the first dose of study drug to assess the patient's eligibility for the study. All tests will be performed, including for B, C, and human immunodeficiency virus (HIV-1, HIV-2) infection, urine and serum pregnancy tests in women of childbearing potential, colonoscopy (for Crohn's disease patients) and rectosigmoidoscopy (for ulcerative colitis patients), CRP, 12-lead electrocardiogram, and clinical laboratory tests. Also, interferon-gamma release assay (IGRA) and chest x-ray to exclude tuberculosis patients will be performed.

[0220] At week 0, day 0, patients who meet all inclusion criteria and none of the exclusion criteria will be enrolled in the clinical trial and all enrolled patients will receive one dose of infliximab IV on two occasions, at week 0 and week 2. Patients may be premedicated 30-60 minutes prior to initiating study drug administration, at the investigator's discretion, to prevent hypersensitivity reactions to the study drug, as follows (e.g., but not limited to, antihistamines [2-4 mg chlorpheniramine equivalent dose], hydrocortisone, paracetamol, and / or non-sedating antihistamines [10 mg cetirizine equivalent dose]).

[0221] Patients who receive two full doses and, at the investigator's discretion, are free of safety concerns will be randomized to receive either SC or IV infliximab 42 days prior to dosing. Randomization will be stratified by current use of azathioprine, 6-mercaptopurine, or MTX, disease (Crohn's disease or ulcerative colitis), clinical response at Week 6 by CDAI-70 for Crohn's disease or partial Mayo score for ulcerative colitis, and body weight at Week 6 (<80 kg or ≥80 kg). A minimum of 130 patients with active Crohn's disease or active ulcerative colitis will be randomized 1:1 into the two clinical trial arms and will receive study medication through Week 54 (Table 14).

[0222] [Table 14]

[0223] Patients randomized to arm 1 will receive additional IV infliximab at week 6 and every 8 weeks thereafter (weeks 14 and 22) until week 22, then will switch to SC infliximab at week 30, with the dose of SC based on body weight at week 30. This dose will be administered every 2 weeks until week 54. Patients randomized to arm 2 will receive SC infliximab at a dose based on body weight at week 6, with this dose administered every 2 weeks from week 6 through week 54. Dose escalation will be allowed after week 30 at the investigator's discretion. SC infliximab will be injected by medical personnel at each study site visit (weeks 6, 14, 22, 24, 26, 28, 30, 38, 46, and 54) and may be self-injected by patients during other weeks if they have been properly trained in the injection technique and the investigator deems it appropriate.

[0224] The primary pharmacokinetic endpoint will be assessed at Week 22, and the secondary pharmacokinetic endpoints will be assessed during the maintenance phase from Weeks 22 to 30 and during the treatment period through Week 54. Blood samples for analysis, efficacy, PD, and safety assessments will be collected and evaluated at the times described in the evaluation schedule.

[0225] The end of study visit will be 2 weeks after the end of the maintenance phase, unless the patient discontinues after an SC dose, in which case the end of the study visit will be 2 weeks after the last dose, or 8 weeks after the last dose if the patient discontinues after an IV dose. For patients who drop out, all study procedures will be performed on the dropout date or the day after dropout, and every effort will be made to terminate all study visits at the appointed time after the patient receives their last dose.

[0226] Clinical evaluations, blood sampling, and clinical trial type visits in Part 2 will be conducted similarly to Part 1, with sampling and evaluations occurring at the times outlined in the evaluation schedule.

[0227] conclusion 3-1. Safety evaluation Summary of adverse events Safety evaluations included secondary endpoints in Part 1, including immunogenicity, monitoring of hypersensitivity reactions (including monitoring of delayed hypersensitivity reactions), vital sign measurements (including blood pressure, heart and respiratory rates, and temperature), weight, interferon-gamma release assay, chest x-ray, HIV-B, HIV-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 / hypersensitivity / anaphylactic reactions [medication-related reactions], delayed hypersensitivity reactions, injection site reactions, infections, and malignancies), signs and symptoms of tuberculosis, laboratory analyses, pregnancy tests, past and current concomitant medications, and local pain (assessed using a 100-mm visual analogue scale (VAS)).

[0228] Cumulative safety data for this study included 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 (63.6%) patients, with similar rates in both groups, including 8 (61.5%) in the IV cohort (cohort 1) and 20 (64.5%) in the overall SC cohort (cohorts 2-4). Most post-treatment adverse events were grade 1 or 2, and 9 (20.5%) of all post-treatment adverse events were considered drug-related.

[0229] Post-treatment serious adverse events occurred in 8 (18.2%) patients: 2 (15.4%) in the IV cohort (cohort 1) and 6 (19.4%) in the overall SC cohort (cohorts 2-4), all of which were considered unrelated to the drug.

[0230] As for adverse events after treatment, medication-related reactions, including 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). Because infliximab medication-related reactions are associated with antibodies to the drug (ADA) (Remsima SmPC 2017), patients who showed medication-related reactions were investigated for the presence or absence of antibodies to the drug (ADA). Only one patient (IV cohort [cohort 1]) showed a positive reaction to antibodies to the drug (ADA) and neutralizing antibodies (NAb). After administration during the dose loading period, the patient was administered the IV formulation at weeks 6 and 14 during the maintenance phase, and positive results were confirmed from week 22. An administration-related reaction occurred at week 30.

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

[0232] Post-treatment adverse events including infection 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] One patient (7.7%) in the IV cohort (cohort 1) and four patients (12.9%) in the SC cohorts (cohorts 2-4) discontinued treatment due to post-treatment adverse events. Only one patient in cohort 3 had a post-treatment adverse event that was considered related to the drug, and the adverse event was grade 1 latent tuberculosis.

[0234] Two deaths were reported during the clinical trial (one each in cohort 1 and cohort 3). One patient in the IV cohort (cohort 1) experienced sudden cardiac death at home approximately one month after completing the 6th week of dosing, which was reported to be unrelated to the drug. The patient had hypertension and chronic heart failure. One patient in the SC cohort (cohort 3) experienced sudden cardiac death at home the evening of the 30th week of dosing, which was reported to be unrelated to the drug. The patient had chronic aortic calcification, diabetes, 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 event was counted. Events were considered to be related only if a "possible," "probable," or "definite" relationship was observed.

[0236] immunogenicity In general, the proportion of patients testing positive for antibodies to drugs (ADA) was low in the SC cohort, with most patients testing negative for antibodies to drugs (ADA) at week 30. The numbers of patients testing positive for antibodies to drugs (ADA) at week 30 were 8 (61.5%), 0 (0.0%), 3 (25.0%), and 1 (12.5%) in cohorts 1 to 4, respectively (Table 16).

[0237] [Table 16] *Abbreviation: ADA, antibody to drug NAb, neutralizing antibody *Percentages by visit were calculated using the number of patients randomized as the denominator. Denominator: Number of patients who were ADA negative at weeks 0 and 6 Numerator: Number of patients who were ADA or NAb positive at least once during weeks 14 and 30

[0238] Localized pain assessment using a visual analogue scale (VAS) The visual analog scale (VAS) ranged from 0 to 100 mm, with higher scores indicating more severe pain. Slightly higher levels of local site pain were observed in cohorts 3 and 4, who had to receive two injections per visit, than in the other cohorts. Overall, low levels of local site pain were observed in all cohorts (mean 21.05 mm or less) (Table 17).

[0239] [Table 17]

[0240] 3-2. Evaluation of treatment efficacy Disease activity 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 with baseline confirmed a trend toward a decrease in actual values ​​over time in each cohort. The proportion of patients who responded to the CDAI-70 criteria at week 6, one of the randomization stratification variables, was slightly higher in cohort 2 than in the other cohorts, and caution was exercised in interpreting efficacy taking this into account.

[0241] The actual disease activity measured by the CDAI and the change from baseline are summarized in Table 18.

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

[0243] Response evaluation based on CDAI-70 and CDAI-100 response criteria Based on CDAI score, the proportion of patients who responded to the CDAI-70 response criteria (patients with a CDAI score reduction of 70 points or more compared to baseline) was similar between treatment groups (Table 19). The proportion of patients who responded to the CDAI-100 response criteria (patients with a CDAI score reduction of 100 points or more compared to baseline) was also similar between treatment groups (Table 20).

[0244] [Table 19]

[0245] [Table 20]

[0246] Assessment of clinical remission The proportion of patients who achieved clinical remission (CDAI absolute score <150) was similar between treatment groups. A relatively high proportion of patients achieved clinical remission in cohort 2 during the maintenance period (weeks 6–30), with 6 (54.5%) patients in cohort 2 already achieving clinical remission at 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) PK-PD model construction The procedure was the same as in Example 2. Dose and regimen scenarios for subcutaneous (SC) dosage forms for modeling in patients with Crohn's disease (CD) Pharmacokinetic aspects were predicted based on the following simulation scenario, and efficacy and safety were predicted based on this, and compared with infliximab intravenous (IV) administration of a maintenance dose of 5 mg / kg every 8 weeks (Table 22).

[0249] [Table 22]

[0250] Infliximab exposure parameter estimates for weight-specific infliximab SC doses and administration regimens in patients with Crohn's disease (CD) The exposure pharmacokinetic parameters of infliximab SC dose and administration were simulated in 10 kg increments in the body weight range of 50 to 130 kg. trough ), area under the concentration-time curve (AUC τ ) estimates correlated with drug dose (Table 23).

[0251] [Table 23-1] [Table 23-2] [Table 23-3] [Table 23-4]

[0252] (Additional Note) The present 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 a dose of 60 to 300 mg of the anti-TNFα antibody or an antigen-binding fragment thereof is administered subcutaneously to the patient at intervals of 1 to 8 weeks. Item 2: The method according to Item 1, wherein the TNFα-related disease is selected from the group consisting of rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis. Item 3: The method according to Item 2, wherein the TNFα-related disease is rheumatoid arthritis. Item 4: The method according to Item 3, wherein the patient is administered a dose of 90 to 180 mg of an anti-TNFα antibody or an antigen-binding fragment thereof. Item 5: The method according to Item 2, wherein the TNFα-related disease is selected from the group consisting of ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis. Item 6: The method according to Item 5, wherein the patient is administered a dose of 120 to 240 mg of an anti-TNFα antibody or an antigen-binding fragment thereof. Item 7: The method according to Item 1, wherein the patient is administered a dose of 80 to 100 mg, 110 to 130 mg, 170 to 190 mg, or 230 to 250 mg of an anti-TNFα antibody or an antigen-binding fragment thereof. Term 8: The method of term 7, wherein the patient is administered a dose of 90 mg, 120 mg, 180 mg, or 240 mg of an anti-TNFα antibody or antigen-binding fragment thereof. Item 9: The method according to Item 1, further comprising a step of determining the dosage depending on the patient's body weight, in which 90 to 180 mg of the anti-TNFα antibody or its antigen-binding fragment is administered if the patient weighs less than 80 kg, and 190 to 270 mg of the anti-TNFα antibody or its antigen-binding fragment is administered if the patient weighs 80 kg or more. Item 10: The method of item 1, wherein the patient is administered the anti-TNFα antibody or antigen-binding fragment thereof at 1, 2, 3, 4, 5, 6, 7, or 8 week intervals. Item 11: The method of item 10, wherein the patient is administered an anti-TNFα antibody or antigen-binding fragment thereof at 2 or 4 week intervals. Paragraph 12: The method of paragraph 1, wherein the anti-TNFα antibody or antigen-binding fragment thereof 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 has received at least one intravenous dose of an anti-TNFα antibody or an antigen-binding fragment thereof prior to subcutaneous administration. Item 15: The method according to Item 14, wherein the patient is administered an anti-TNFα antibody or an antigen-binding fragment thereof at a single dose of 1 to 10 mg / kg. Item 16: The method according to Item 14, wherein the first subcutaneous administration is administered 2 to 8 weeks after the last intravenous administration. Item 17: The minimum blood concentration (C trough Item 1. The method according to item 1, wherein the concentration of 3 to 16 μg / mL is maintained at 3 to 16 μg / mL. Item 18: The minimum blood concentration (C trough Item 1. The method according to item 1, wherein the concentration of 9 to 32 μg / mL is maintained at 9 to 32 μg / mL. Item 19: The method according to item 1, wherein the patient after subcutaneous administration has one or more of the following characteristics: a) A decrease of at least 2.0 in the Disease Activity Score in 28 joints (DAS28); or b) Crohn's disease activity index (CDAI) decreased by at least 70 points. Item 20: The method of item 1, wherein the patient prior to subcutaneous administration has one or more of the following characteristics: a) inadequate response to disease-modifying anti rheumatic drugs (DMARDs), including methotrexate; b) no history of treatment with methotrexate or other DMARDs; c) Failure to respond adequately to standard treatments and the presence of severe axial symptoms and elevated serologic indicators associated with inflammation; or d) Failure to respond to, contraindication to, or intolerance to systemic therapy, including methotrexate, cyclosporine, or psoralen ultraviolet A therapy (PUVA). Item 21: The method according to Item 1, wherein the patient prior to subcutaneous administration has one or more of the following characteristics: a) has not responded adequately to or is not tolerated by treatment with corticosteroids, 6-mercaptopurine, azathioprine, or immunosuppressants, or such treatment is contraindicated; or b) Failure to respond to standard treatments including antibiotics, excretion techniques, or immunosuppressive therapy. Item 22: The anti-TNFα antibody or antigen-binding fragment thereof is 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 The method according to item 1, comprising 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. Item 23: The anti-TNFα antibody or antigen-binding fragment thereof A light chain variable region comprising the amino acid sequence of SEQ ID NO:7; and The method according to item 1, comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:8. Item 24: The anti-TNFα antibody or antigen-binding fragment thereof A light chain comprising the amino acid sequence of SEQ ID NO:9; and The method of claim 1, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:10. Paragraph 25: The method of paragraph 1, wherein the anti-TNFα antibody is infliximab. Item 26: The method according to Item 1, wherein the composition containing an anti-TNFα antibody or an antigen-binding fragment thereof comprises: (A) 90 to 180 mg / ml of an anti-TNFα antibody or an antigen-binding fragment thereof; (B) 0.02 to 0.1% (w / v) of polysorbate; (C) 1 to 10% (w / v) of sorbitol; and (D) 1 to 50 mM of a buffer containing acetate. Item 27: The method of item 1, wherein the composition containing the anti-TNFα antibody or antigen-binding fragment thereof is administered to the patient in a pre-filled syringe or auto-injector. Item 28: A pharmaceutical composition for treating a TNFα-related disease, comprising an anti-TNFα antibody or an antigen-binding fragment thereof, A pharmaceutical composition for treating TNFα-related diseases, comprising subcutaneously administering a dose of 60 to 300 mg of an anti-TNFα antibody or an antigen-binding fragment thereof at intervals of 1 to 8 weeks. Item 29: (a) a pharmaceutical composition comprising an anti-TNFα antibody or an antigen-binding fragment thereof; and (b) A kit comprising instructions for administering a dose of 60 to 300 mg of an anti-TNFα antibody or antigen-binding fragment thereof subcutaneously at intervals of 1 to 8 weeks to treat a patient with a TNFα-related disorder. Item 30: Use of an anti-TNFα antibody or an antigen-binding fragment thereof in the manufacture of a pharmaceutical composition for administration to a patient to treat a TNFα-related disease, wherein a dose of 60 to 300 mg of the anti-TNFα antibody or an antigen-binding fragment thereof is administered subcutaneously at intervals of 1 to 8 weeks.

[0253] Sequence Listing [ka] [ka] [ka] [ka]

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Claims

1. A pharmaceutical composition for the treatment of rheumatoid arthritis, comprising infliximab, The aforementioned infliximab is used to be administered subcutaneously to patients at a dose of 120 mg every two weeks. The patient in question is a patient who has received at least one intravenous dose of infliximab prior to the subcutaneous administration. A pharmaceutical composition characterized in that the intravenous administration is performed four weeks prior to the subcutaneous administration.

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

3. The pharmaceutical composition according to claim 1, wherein the patient is a patient who has been administered infliximab intravenously at least twice prior to the subcutaneous administration.

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

5. The pharmaceutical composition according to claim 4, wherein the patient is a patient who has been intravenously administered the infliximab at a dose of 3 to 5 mg / kg per dose.

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

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

8. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is administered in combination with a disease-modifying antirheumatic drug (DMARD).

9. The pharmaceutical composition according to claim 8, wherein the disease-modifying antirheumatic drug (DMARD) is selected from the group consisting of methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine.

10. The pharmaceutical composition according to claim 1, wherein the DAS28 (Disease Activity Score in 28 joints) decreases by at least 2.0 in the patient after subcutaneous administration.

11. The pharmaceutical composition according to claim 1, wherein the patient before subcutaneous administration has one or more of the following characteristics: a) The patient has an inadequate response to disease-modifying antirheumatic drugs (DMARDs), including methotrexate; b) The patient has no history of treatment with methotrexate and other DMARDs; or c) The patient is unresponsive to, contraindicated for, or intolerant to methotrexate.

12. 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.

13. (A) 90 to 180 mg / mL of the infliximab; (B) 0.02–0.1% (w / v) polysorbate; (C) 1-10% (w / v) sorbitol; and (D) A buffer containing acetate in a concentration of 1 to 50 mM; A pharmaceutical composition according to claim 1, comprising:

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

15. A kit for the treatment of rheumatoid arthritis, for subcutaneous administration of infliximab 120 mg at two-week intervals to a patient, wherein the patient has received at least one intravenous administration of infliximab prior to the subcutaneous administration, and the intravenous administration was performed four weeks prior to the subcutaneous administration. (a) The pharmaceutical composition according to claim 1; and (b) Instructions for administering the pharmaceutical composition subcutaneously at a dose of 120 mg of infliximab every two weeks to treat a patient having rheumatoid arthritis, wherein the patient has received at least one intravenous dose of infliximab prior to the subcutaneous administration, and the intravenous dose is administered four weeks prior to the subcutaneous administration. A kit that includes this.

16. Use of infliximab in the manufacture of the pharmaceutical composition according to Claim 1.

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