Method for treating TNFα-related diseases

Abstract

The present invention relates to a method for treating TNFα-related diseases by subcutaneously administering an antibody (anti-TNFα antibody) or antigen-binding fragment thereof that binds to TNFα. In particular, the present invention relates to a method for treating TNFα-related diseases, the method comprising subcutaneously administering infliximab to rheumatoid arthritis patients without a history of anti-TNFα antibody (in particular, infliximab) administration.

Description

Methods to treat TNFα-related diseases

[0001] The present application relates to a method for treating TNFα-related diseases by administering an antibody that binds to TNFα (anti-TNFα antibody) subcutaneously. In particular, the present invention relates to a method for treating a disease comprising the step of administering infliximab subcutaneously to a rheumatoid arthritis patient who has no prior experience with the administration of an anti-TNFα antibody (particularly infliximab).

[0002] Infliximab is a type of chimeric monoclonal antibody capable of acting as a TNFα inhibitor, and is marketed as products such as Remsima, Remicade, and Renflexis. All of these products are manufactured as freeze-dried powders, which are typically administered to patients by re-dissolving and diluting them, and then injecting them intravenously according to the dosage and administration method for each disease.

[0003] Meanwhile, it has recently been known that infliximab can be administered subcutaneously (i.e., as a replacement) to patients who have been receiving infliximab intravenously. Although the disadvantages of intravenous administration (i.e., poor patient convenience, side effects due to invasiveness, etc.) are known, intravenous administration can still be considered as one of the treatment options for infliximab because it is well known that absorption into the body is slower when the drug is administered subcutaneously than when administered intravenously (Beate Bittner et al. Biodrugs, 32(5): 425-440, 2018).

[0004] However, TNFα-related diseases known as indications for infliximab (e.g., rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, etc.) are immune diseases that require long-term treatment, and patient adherence can affect the treatment response in these immune diseases. Unlike intravenous administration, subcutaneous administration can be self-administered by trained patients, and since it can shorten the administration time from 30 to 90 minutes for intravenous administration to 2 to 5 minutes, high adherence is expected.

[0005] Meanwhile, it is known that when infliximab is administered intravenously for rheumatoid arthritis, 3 mg / kg of infliximab (induction therapy) is administered at weeks 0, 2, and 6 of the start of treatment, followed by 3 mg / kg of infliximab (maintenance therapy) every 8 weeks thereafter. Additionally, regarding the therapeutic effect of subcutaneous infliximab administration, the effect is known only in patients who have already undergone induction therapy prior to subcutaneous administration, or who have started subcutaneous administration after receiving intravenous infliximab.

[0006] Therefore, when patients with TNFα-related diseases, such as rheumatoid arthritis, begin anti-TNFα antibody therapy with infliximab for the first time, administering it subcutaneously without induction therapy for the entire treatment period can improve patient compliance and convenience, and enhance therapeutic efficacy. However, it is unknown whether subcutaneous administration of anti-TNFα antibodies (particularly infliximab) alone demonstrates efficacy and safety equivalent to or superior to replacement therapy or intravenous administration of anti-TNFα antibodies. Furthermore, for antibody drugs to be suitable for subcutaneous administration, they must be stable liquid formulations containing high concentrations of antibodies; even for such products, the efficacy and safety of the formulation must be proven through clinical trials. However, since it is known that bioavailability decreases as the molecular weight of the substance intended for subcutaneous administration increases, developing products for subcutaneous administration and determining appropriate dosages and administration cycles is very difficult. In addition, when antibody proteins, which are macromolecular substances, are administered subcutaneously, a problem arises where bioavailability is reduced due to various factors within the skin tissue, such as blood vessels, lymphatic vessels, and proteolytic enzymes.

[0007] The applicant has developed a stable composition capable of exhibiting efficacy and safety equivalent to or superior to that of anti-TNFα antibody replacement administration or intravenous administration, and has perfected a subcutaneous administration regimen that can be used without induction therapy using said composition.

[0008] The problem that the present invention aims to solve is to provide a method for treating a TNFα-related disease comprising the step of administering a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof to a subject having a TNFα-related disease.

[0009] Another problem that the present invention aims to solve is to provide a pharmaceutical composition for treating TNFα-related diseases, characterized by containing an anti-TNFα antibody or an antigen-binding fragment thereof and being administered subcutaneously to a subject having a TNFα-related disease.

[0010] Another problem that the present invention aims to solve is to provide a kit comprising: a pharmaceutical composition comprising an anti-TNFα antibody or an antigen-binding fragment thereof; and instructions for administering the pharmaceutical composition subcutaneously to a subject having a TNFα-related disease to treat the TNFα-related disease.

[0011] Another problem that the present invention aims to solve is to provide a use of an anti-TNFα antibody or its antigen-binding fragment in the manufacture of a drug to be administered subcutaneously to a subject having a TNFα-related disease to treat the disease.

[0012] The present invention provides a method for treating a TNFα-related disease comprising the step of administering a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof to a subject having a TNFα-related disease, wherein the anti-TNFα antibody or an antigen-binding fragment thereof is administered subcutaneously to the subject at a dose of 40 to 300 mg at intervals of 1 to 8 weeks without an intravenous induction regimen.

[0013] Additionally, the present invention provides a pharmaceutical composition for treating TNFα-related diseases comprising an anti-TNFα antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition comprises (A) 90 to 180 mg / ml of the anti-TNFα antibody or its antigen-binding fragment; (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 comprising acetate, characterized by administering a dose of 40 to 300 mg of the anti-TNFα antibody or its antigen-binding fragment subcutaneously to a subject having a TNFα-related disease at intervals of 1 to 8 weeks without intravenous induction therapy.

[0014] Furthermore, the present invention provides a kit comprising (a) a pharmaceutical composition comprising an anti-TNFα antibody or an antigen-binding fragment thereof; and (b) instructions for administering a dose of 40 to 300 mg of the anti-TNFα antibody or an antigen-binding fragment thereof to a subject having a TNFα-related disease subcutaneously at intervals of 1 to 8 weeks without intravenous induction therapy.

[0015] In addition, the present invention provides a use of an anti-TNFα antibody or an antigen-binding fragment thereof for producing a drug that treats TNFα-related diseases by administering an anti-TNFα antibody or an antigen-binding fragment thereof to a subject at a dose of 40 to 300 mg subcutaneously at intervals of 1 to 8 weeks without intravenous induction therapy.

[0016] The above intravenous induction therapy may involve administering an anti-TNFα antibody or its antigen-binding fragment two or three times prior to subcutaneous administration.

[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, cetorizumab pegol, golimumab, and biosimilars thereof.

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

[0019] In one embodiment of the present invention, the anti-TNFα antibody may comprise a chimeric human-mouse IgG monoclonal antibody.

[0020] In one embodiment of the present invention, the anti-TNFα antibody may include a light chain variable region comprising a CDR1 domain having the amino acid sequence of SEQ ID NO. 1, a CDR2 domain having the amino acid sequence represented by YAS, and a CDR3 domain having the amino acid sequence of SEQ ID NO. 2; and a heavy chain variable region comprising a CDR1 domain having the amino acid sequence of SEQ ID NO. 3, a CDR2 domain having the amino acid sequence of SEQ ID NO. 4, and a CDR3 domain having the amino acid sequence of SEQ ID NO. 5.

[0021] In one embodiment of the present invention, the anti-TNFα antibody may include a light chain variable region comprising the amino acid sequence of SEQ ID NO. 6; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO. 7.

[0022] In one embodiment of the present invention, the anti-TNFα antibody may comprise a light chain having the amino acid sequence of SEQ ID NO. 8; and a heavy chain having the amino acid sequence of SEQ ID NO. 9.

[0023] In one embodiment of the present invention, the composition may comprise a surfactant; a sugar or a derivative thereof; and a buffer comprising acetate or histidine.

[0024] In one embodiment of the present invention, the composition may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture thereof as a surfactant.

[0025] In one embodiment of the present invention, the surfactant concentration of the composition may be 0.02 to 0.1% (w / v).

[0026] In one embodiment of the present invention, the composition may include sorbitol, mannitol, trehalose, sucrose, or a mixture thereof as a sugar or a derivative thereof.

[0027] In one embodiment of the present invention, the concentration of the sugar or its derivative in the composition may be 1 to 10% (w / v).

[0028] In one embodiment of the present invention, the composition may include acetate as a buffer.

[0029] In one embodiment of the present invention, the buffer concentration of the composition may be 1 to 50 mM.

[0030] In one embodiment of the present invention, the pH of the composition may be 4.0 to 5.5.

[0031] In one embodiment of the present invention, the composition may comprise (A) 90 to 220 mg / ml or 90 to 180 mg / ml of anti-TNFα antibody; (B) 0.02 to 0.1% (w / v) of polysorbate; (C) 1 to 10% (w / v) of sorbitol; and (D) 1 to 90 mM or 1 to 50 mM of a buffer comprising acetate or histidine.

[0032] In one embodiment of the present invention, the composition may not include aspartic acid, lysine, arginine, or a mixture thereof.

[0033] In one embodiment of the present invention, the composition may not include NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, K2SO4, or a mixture thereof.

[0034] In one embodiment of the present invention, the composition may not include a chelating agent.

[0035] In one embodiment of the present invention, the composition may have a viscosity of 0.5 cP to 10.0 cP after 1 month at a temperature of 40°C ± 2°C, or a viscosity of 0.5 cP to 5 cP after 6 months at a temperature of 5°C ± 3°C.

[0036] In one embodiment of the present invention, the composition may not undergo a reconstitution step, a dilution step, or both before use.

[0037] In one embodiment of the present invention, the composition may be filled into a pre-filled syringe or an auto-injector and administered to a subject.

[0038] In one embodiment of the present invention, the object may include a mammal.

[0039] In one embodiment of the present invention, the object may include a person.

[0040] In one embodiment of the present invention, the TNFα-related disease may include rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis. Additionally, the TNFα-related disease may be rheumatoid arthritis.

[0041] In one embodiment of the present invention, the antibody or its antigen-binding fragment may be administered subcutaneously in an amount of 40 to 300 mg.

[0042] In one embodiment of the present invention, the antibody or its antigen-binding fragment may be administered subcutaneously in an amount of 40 to 180 mg.

[0043] In one embodiment of the present invention, the antibody or its antigen-binding fragment may be administered subcutaneously in an amount of 40 mg, 60 mg, 80 mg, 90 mg, 120 mg, 180 mg, or 240 mg.

[0044] In one embodiment of the present invention, the antibody or its antigen-binding fragment may be administered subcutaneously in an amount of 40 to 120 mg.

[0045] In one embodiment of the present invention, the antibody or its antigen-binding fragment may be administered subcutaneously at a dose of 120 mg.

[0046] In one embodiment of the present invention, the antibody or its antigen-binding fragment may be administered in amounts of 40, 50, 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.

[0047] In one embodiment of the present invention, if the condition of the subject does not improve or the therapeutic response is lost, the dose of the anti-TNFα antibody or its antigen-binding fragment may be increased and administered subcutaneously.

[0048] In one embodiment of the present invention, when the TNFα-related disease is rheumatoid arthritis, an anti-TNFα antibody or an antigen-binding fragment thereof may be administered subcutaneously to the subject in a dose of 40 to 180 mg or 120 mg.

[0049] In one embodiment of the present invention, if the TNFα-related disease is one or more selected from the group consisting of ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis, an anti-TNFα antibody or an antigen-binding fragment thereof may be administered subcutaneously to the subject at a dose of 40 to 240 mg.

[0050] In one embodiment of the present invention, the antibody or its antigen-binding fragment may be administered subcutaneously at intervals of 1, 2, 3, 4, 5, 6, 7, or 8 weeks.

[0051] In one embodiment of the present invention, the antibody or its antigen-binding fragment may be administered subcutaneously at intervals of 2 or 4 weeks.

[0052] In one embodiment of the present invention, the antibody or its antigen-binding fragment may be administered subcutaneously at 2-week intervals.

[0053] In one embodiment of the present invention, the target for administration of the anti-TNFα antibody may include one or more characteristics selected from the following:

[0054] a) subjects with an insufficient response to disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate;

[0055] b) Subjects who have not previously been treated with methotrexate and other DMARDs;

[0056] c) Subjects who do not show an adequate response to conventional treatment and exhibit severe axial symptoms and elevated serological markers associated with inflammation;

[0057] d) subjects who do not respond adequately to systemic therapies including methotrexate, cyclosporine, or Psoralen ultraviolet A therapy (PVA), who do not tolerate such therapies, or for whom such treatments are contraindicated;

[0058] e) subjects who do not respond adequately to treatment with corticosteroids, 6-mercaptopurines, azathioprine, or immunosuppressants, who do not tolerate such treatment, or for whom such treatment is contraindicated; or

[0059] f) Subjects who do not respond to conventional treatment, including antibiotics, excretion, or immunosuppressive therapy.

[0060] In one embodiment of the present invention, the subject may be a patient with active rheumatoid arthritis who has shown an insufficient response to methotrexate monotherapy for more than 3 months.

[0061] In one embodiment of the present invention, the subject may be a patient who has not received the anti-TNFα antibody or its antigen-binding fragment prior to subcutaneous administration. Additionally, the subject may be a patient who has not received infliximab intravenously prior to subcutaneous administration.

[0062] In one embodiment of the present invention, a composition containing the anti-TNFα antibody or its antigen-binding fragment may be administered before or after administration, together with one or more administrations selected from the group consisting of infliximab, adalimumab, cetorizumab, pegol, golimumab, and biosimilars thereof.

[0063] In one embodiment of the present invention, the anti-TNFα antibody or its antigen-binding fragment may be administered before or after administration with one or more administrations selected from the group consisting of disease-relief antirheumatic drugs (DMARDs), steroids, and immunosuppressants. Specifically, the disease-relief antirheumatic drug (DMARD) may be selected from the group consisting of methotrexate (MTX), leflunomide, sulfasalazine, and hydroxychloroquine; the steroid may be selected from the group consisting of corticosteroids, glucocorticoids, cortisol, mineralocorticoids, and aldosterone; and the immunosuppressant may be selected from the group consisting of azathioprine, 6-mercaptopurine, cyclosporine A, tacrolimus, mycofenoric acid, bradinin, mTOR inhibitors, and anti-lymphocyte antibodies.

[0064] In one embodiment of the present invention, after subcutaneous administration to a subject, the lowest blood concentration (C) immediately before the next administration of the anti-TNFα antibody or its antigen-binding fragment trough ; It may be an administration method in which the minimum concentration immediately before the next application) is maintained at 0.01 μg / ml or higher.

[0065] In one embodiment of the present invention, a) in the case of a subject with rheumatoid arthritis, the trough blood concentration (C) of an anti-TNFα antibody or its antigen-binding fragment after subcutaneous administration trough b) maintained at 1 μg / ml or higher, and for subjects with one or more diseases selected from the group consisting of ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis, the trough blood concentration of the anti-TNFα antibody or its antigen-binding fragment after subcutaneous administration (C troughIt may be a method of administration in which ) is maintained at 5 μg / ml or higher.

[0066] In one embodiment of the present invention, after subcutaneous administration, the subject may have one or more characteristics selected from the following:

[0067] a) A decrease of at least 2.0 in DAS28 (Disease activity score in 28 joints); or

[0068] b) A decrease in CDAI (Crohn's disease activity index) of at least 70.

[0069] According to the treatment method, composition, kit, or use of the present invention, TNFα-related diseases can be treated by subcutaneously administering an anti-TNFα antibody or an antigen-binding fragment thereof.

[0070] In addition, the treatment method, composition, kit, or use according to the present invention provides the advantage of increased patient satisfaction through improved convenience and quality of life, as the administration time is reduced compared to intravenous injection and the time patients spend in the hospital is reduced.

[0071] Furthermore, the treatment method, composition, kit, or use according to the present invention is added as a new treatment option for anti-TNFα antibodies, such as infliximab, and provides the advantage of not causing burden or resistance to patients and healthcare workers due to drug changes.

[0072] Additionally, the treatment method, composition, kit, or use according to the present invention provides treatment convenience by administering the same dose of infliximab in fixed treatment cycles to patients with rheumatoid arthritis without induction therapy.

[0073] Figure 1 is a graph showing the overall plan of a clinical trial designed to evaluate the efficacy, pharmacokinetics, and safety of subcutaneous infliximab compared to a placebo group.

[0074] Figure 2 is a graph showing the trough blood concentration of infliximab 120 mg administered subcutaneously (SC) at 2-week intervals in rheumatoid arthritis patients obtained through PK simulation analysis, compared with the trough blood concentration of infliximab 3 mg / kg administered intravenously (IV) at 8-week intervals.

[0075] Figure 3 is a graph showing the area under the concentration-time curve (AUC) of infliximab 120 mg subcutaneously administered at 2-week intervals in rheumatoid arthritis patients obtained through PK simulation analysis, compared with the AUC of infliximab 3 mg / kg intravenously administered at 8-week intervals.

[0076] Figure 4 is a graph showing the DAS28 score obtained through exposure-response analysis when 120 mg of infliximab is administered subcutaneously at 2-week intervals, compared to the DAS28 score when 3 mg / kg of infliximab is administered intravenously at 8-week intervals.

[0077] Figure 5 is a graph showing the geometric mean ratio (GMR) and 90% confidence interval (CI) of DAS28 scores at 14 and 30 weeks for infliximab 120 mg subcutaneously administered at 2-week intervals and infliximab 3 mg / kg intravenously administered at 8-week intervals, obtained through exposure-response analysis.

[0078] Figure 6 is a graph comparing the probability of clinical response according to ACR20 criteria at week 14 for infliximab 120 mg administered subcutaneously (SC) at 2-week intervals and infliximab 3 mg / kg administered intravenously (IV) at 8-week intervals.

[0079] Figure 7 is a graph comparing the probability of clinical response according to ACR20 criteria at week 30 when infliximab 120 mg is administered subcutaneously (SC) at 2-week intervals and when infliximab 3 mg / kg is administered intravenously (IV) at 8-week intervals.

[0080] Figure 8 shows the characteristics (Figure 8a) and turbidity (Figure 8b) of a formulation containing a high concentration of infliximab after storing it at 5°C and 25°C for 0, 4, 8, or 12 weeks.

[0081] Figure 9 shows the results of measuring the antigen-binding ability of antibodies by ELISA (Figure 9a) and measuring the immunoglobulin content, heavy chain and light chain content by CE-SDS (Figures 9b and 9c) after storing formulations containing high concentrations of infliximab at 5°C and 25°C for 0, 4, 8, or 12 weeks.

[0082] Figure 10 shows the results of measuring peak values ​​by IEC-HPLC (Figure 10a) and confirming the number of particles by MFI (Figure 10b) after storing a formulation containing high concentrations of infliximab at 5°C and 25°C for 0, 4, 8, or 12 weeks.

[0083] Figure 11 shows the results of checking the number of particles using a HIAC particle counter after storing a formulation containing high concentrations of infliximab at 5°C and 25°C for 0, 4, 8, or 12 weeks.

[0084] The present invention relates to a method for treating a TNFα-related disease, comprising the step of subcutaneously administering a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof to a subject having a TNFα-related disease. The method may be characterized by subcutaneously administering an anti-TNFα antibody or an antigen-binding fragment thereof to the subject at a dose of 40 to 300 mg at intervals of 1 to 8 weeks.

[0085] To facilitate a better understanding of the present invention, the terms used in the present invention are defined below.

[0086] "TNFα" is intended to refer to a human cytokine that exists in a 17 kD secreted form and a 26 kD membrane-associated form, and whose biologically active form consists of a trimer non-covalently bound to a 17 kD molecule. The structure of TNFα is also described, for example, in the literature [References: 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].

[0087] "Antibody" refers to an immunoglobulin molecule composed of four polypeptide chains, in which two heavy chains and two light chains are connected to each other by disulfide bonds. Naturally occurring antibodies with other modified structures, such as camelid antibodies, are also included in this definition. Each heavy chain consists of a heavy chain variable region and a heavy chain constant region. The heavy chain constant region consists of three domains (CH1, CH2, and CH3). Each light chain consists of a light chain variable region and a light chain constant region. The light chain constant region consists of one domain (CL). The heavy chain variable region and the light chain variable region may be further subdivided into a supervariable region called the complementarity determining region (CDR), which is positioned together with a more conserved region called the backbone region (FR). Each heavy chain variable region and light chain variable region consists of 3 CDRs and 4 FRs, arranged in the following order from amino terminus to carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0088] "Antigen-binding fragment" refers to one or more fragments of an antibody that possess the ability to specifically bind to an antigen bound by the complete antibody. Exemplary antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv.

[0089] A "biosimilar" refers to a biological product that is very similar to a biological product (reference drug) approved by a drug regulatory agency and does not differ clinically significantly from the reference drug in terms of pharmacokinetics, safety, and efficacy.

[0090] “Biological preparations” or “biological products” refer to pharmaceuticals manufactured using materials or ingredients derived from humans or other living organisms that require special caution for public health and hygiene, and include biological preparations, genetically modified drugs, cell culture drugs, cell therapies, gene therapies, and other preparations recognized by the Minister of Food and Drug Safety.

[0091] "Administration" refers to the administration of a substance (e.g., anti-TNFα antibody) to achieve a therapeutic purpose (e.g., TNFα-related disease).

[0092] "TNFα-related disease" refers to local and / or systemic physiological diseases in which TNFα is a major mediator inducing the signs of the disease. The terms "TNFα-related disease," "disease treatable with anti-TNFα," and "disease in which TNFα activity is harmful" are used interchangeably herein.

[0093] “Subject” includes all human or non-human animals. The term “non-human animal” includes, but is not limited to, vertebrates, e.g., non-human primates, sheep, dogs, cats, rabbits, and ferrets; rodents, e.g., mice, rats, and guinea pigs; bird species, e.g., chickens; amphibians; and reptiles. In a preferred embodiment, the subject is a mammal, e.g., a non-human primate, sheep, dogs, cats, rabbits, ferrets, or rodents. In a more preferred embodiment, the subject is a human (person). The terms “subject,” “patient,” and “entity” are used interchangeably herein.

[0094] “C trough "(trough concentration)" or "trough blood concentration" refers to the trough blood concentration of the drug immediately before the next administration, and may mean the trough blood concentration of the drug predicted using a population pharmacokinetics model.

[0095] “DAS28 (Disease activity score in 28 joints)” is a method for evaluating the disease activity of rheumatoid arthritis (RA) using 28 joints.

[0096] “CDAI (Crohn's disease activity index)” is a research tool used to quantify symptoms in subjects with Crohn's disease.

[0097] The “PCDAI (Pediatric Crohn's Disease Activity Index)” is a research tool used to quantify symptoms of Crohn's disease in children and adolescents.

[0098] The “Mayo score” is a research tool used to quantify the symptoms of ulcerative colitis.

[0099] Disease-modifying anti-rheumatic drugs (DMARDs) are drugs or combinations thereof that are effective in relieving arthritis symptoms and slowing the progression of the disease. DMARDs block the release of chemicals by the immune system that attack joints and damage bones, tendons, ligaments, and cartilage. Specific types of DMARDs include methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide.

[0100] "Kit" refers to a packaged product containing components for administering the TNFα antibody of the present invention for the treatment of TNFα-related diseases. The kit preferably includes a container or box containing the components of the kit. The box or container is attached with a protocol or label approved by the Food and Drug Administration. The components of the present invention are contained within a plastic, polyethylene, polypropylene, ethylene, or propylene box or container. The container may be a tube or bottle with a lid. The kit may also include instructions for administering the TNFα antibody of the present invention.

[0101] Various aspects of the present invention are further described in detail herein.

[0102] The anti-TNFα antibody of the present invention or its antigen-binding fragment

[0103] In one embodiment of the present invention, the antibody may comprise a polyclonal antibody, a monoclonal antibody, a recombinant antibody, a single-strand antibody, a hybrid antibody, a chimeric antibody, a humanized antibody, or a fragment thereof. A chimeric antibody means an antibody comprising a heavy chain and light chain variable region sequence from one species and a constant region sequence from another species. In one embodiment of the present invention, the antibody may comprise a chimeric human-mouse IgG monoclonal antibody. The chimeric human-mouse IgG monoclonal antibody consists of a mouse heavy chain and light chain variable region and a human heavy chain and light chain constant region bound thereto. The chimeric human-mouse IgG monoclonal antibody may be prepared by a method known in the art. For example, in the case of infliximab, it may be prepared by the method described in U.S. Patent No. 6,284,471.

[0104] In one embodiment of the present invention, the antibody may include TNFα or an antibody that binds to an epitope of TNFα. As an antibody that binds to TNFα or an epitope of TNFα, one or more selected from the group consisting of infliximab, adalimumab, cetorizumab pegol, golimumab, and biosimilars thereof may be included. In one embodiment of the present invention, the antibody may include infliximab. In this specification, infliximab may be denoted as CT-P13.

[0105] In one embodiment of the present invention, the antibody or the antigen-binding fragment thereof may comprise a light chain variable region comprising a CDR1 domain having the amino acid sequence of SEQ ID NO. 1, a CDR2 domain having the amino acid sequence represented by YAS, and a CDR3 domain having the amino acid sequence of SEQ ID NO. 2; and a heavy chain variable region comprising a CDR1 domain having the amino acid sequence of SEQ ID NO. 3, a CDR2 domain having the amino acid sequence of SEQ ID NO. 4, and a CDR3 domain having the amino acid sequence of SEQ ID NO. 5.

[0106] In one embodiment of the present invention, the antibody or its antigen-binding fragment may include a light chain variable region comprising the amino acid sequence of SEQ ID NO. 6; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO. 7.

[0107] In one embodiment of the present invention, the antibody may comprise a light chain comprising the amino acid sequence of SEQ ID NO. 8; and a heavy chain comprising the amino acid sequence of SEQ ID NO. 9.

[0108] A composition or pharmaceutical composition containing the anti-TNFα antibody or an antigen-binding fragment thereof according to the present invention

[0109] In this document, the term "composition containing the anti-TNFα antibody of the present invention or its antigen-binding fragment" is used interchangeably with "stable liquid pharmaceutical preparation" and "pharmaceutical composition containing the anti-TNFα antibody or its antigen-binding fragment."

[0110] The composition according to the present invention may comprise (A) an antibody or an antigen-binding fragment thereof; (B) a surfactant; (C) a sugar or a derivative thereof; and (D) a buffer.

[0111] In the specification of this application, the term “not including” means not only that the component is not included at all, but also includes the meaning of substantially not including the component, that is, including it in a range that does not affect the activity of the antibody, the stability and viscosity of the liquid pharmaceutical formulation, for example, including it in an amount of 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.

[0112] (A) Antibody or its antigen-binding fragment

[0113] In one embodiment, the composition according to the present invention may include the anti-TNFα antibody of the present invention described above or an antigen-binding fragment thereof.

[0114] The concentration of the antibody or its antigen-binding fragment can 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 its antigen-binding fragment may be 10 to 220 mg / ml. In another embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment may be 50 to 220 mg / ml. In yet another embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment may be 80 to 220 mg / ml. In yet another embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment may be 90 to 220 mg / ml. In yet another embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment may be 90 to 180 mg / ml. In yet another embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment may be 90 to 145 mg / ml. In another embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment may be 110 to 130 mg / ml or 120 mg / ml. When the concentration of the antibody or its antigen-binding fragment is within the above range, excellent long-term stability and low viscosity can be exhibited while increasing the freedom of dosage and administration cycle according to the high content of the antibody or its antigen-binding fragment.

[0115] (B) Surfactant

[0116] Examples of surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate), polyoxyethylene alkyl ethers (e.g., Brij), alkylphenyl polyoxyethylene ethers (e.g., Triton-X), polyoxyethylene-polyoxypropylene copolymers (e.g., Poloxamer, Pluronic), sodium dodecyl sulfate (SDS), etc.

[0117] In one embodiment of the present 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 of these. In one embodiment of the present invention, the polysorbate may comprise polysorbate 20, polysorbate 80, or a mixture thereof. In another embodiment of the present invention, the polysorbate may comprise polysorbate 80.

[0118] In one embodiment of the present invention, the concentration of the surfactant can be freely adjusted within a range that does not adversely affect the stability and viscosity of the stable liquid pharmaceutical formulation according to the present invention. For example, the concentration of the surfactant may be 0.001 to 5% (w / v), 0.01 to 1% (w / v), or 0.02 to 0.1% (w / v). When the concentration of the surfactant is within the above range, excellent long-term stability and low viscosity can be exhibited.

[0119] (C) Sugar or sugar derivative

[0120] Sugars may include monosaccharides, disaccharides, oligosaccharides, polysaccharides, or a mixture of two or more of these. Examples of monosaccharides include glucose, fructose, galactose, etc., but are not limited thereto. Examples of disaccharides include sucrose, lactose, maltose, trehalose, etc., but are not limited thereto. Examples of oligosaccharides include fructooligosaccharides, galactooligosaccharides, mannan oligosaccharides, etc., but are not limited thereto. Examples of polysaccharides include starch, glycogen, cellulose, chitin, pectin, etc., but are not limited thereto.

[0121] Derivatives of sugars may include sugar alcohols, sugar acids, or mixtures thereof. Examples of sugar alcohols include, but are not limited to, glycerol, erythritol, threitol, arabitol, xylitol, ribitol, mannitol, sorbitol, galactitol, fucitol, iditol, inositol, bolemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, and polyglycitol. Examples of sugar acids include, but are not limited to, aldonic acids (glyceric acid, etc.), ulosonic acids (neuraminic acid, etc.), uronic acids (glucuronic acid, etc.), aldaric acids (tartaric acid, etc.).

[0122] In one embodiment of the present invention, the sugar or its derivative may include sorbitol, mannitol, trehalose, sucrose, or a mixture of two or more of these.

[0123] In one embodiment of the present invention, the concentration of the sugar or its derivative can be freely adjusted within a range that does not substantially affect the stability and viscosity of the liquid pharmaceutical formulation according to the present invention. For example, the concentration of the sugar or its derivative may be 0.1 to 30% (w / v), 1 to 20% (w / v), or 1 to 10% (w / v). When the concentration of the sugar or its derivative is within the above range, excellent long-term stability and low viscosity can be exhibited.

[0124] (D) Buffer

[0125] 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 include acetate or histidine. When both acetate and histidine are included as buffers, stability may be reduced.

[0126] In one embodiment of the present invention, the buffer may include acetate. Examples of acetate include, but are not limited to, sodium acetate, zinc acetate, aluminum acetate, ammonium acetate, and potassium acetate. An acid, for example, acetic acid, may be additionally included for pH adjustment. Including acetate as the buffer may be most preferable in terms of pH adjustment and stability.

[0127] In one embodiment of the present invention, the buffer may include histidine. When histidine is used as a buffer, histidine salts, such as histidine chloride, histidine acetate, histidine phosphate, histidine sulfate, etc., may be included. To adjust the pH, an acid, such as hydrochloric acid, acetic acid, phosphoric acid, sulfuric acid, etc., may be included.

[0128] In one embodiment of the present invention, the stable liquid pharmaceutical formulation may not contain citrate (citrate), phosphate (phosphate), or a mixture thereof.

[0129] In one embodiment of the present invention, the content of the buffer (or the anion of the buffer) can be freely adjusted within a range that does not substantially adversely affect the stability and viscosity of the liquid pharmaceutical formulation according to the present invention. For example, the content of the buffer or its anion may be 1 to 90 mM, 5 to 30 mM, or 10 to 25 mM. When the content of the buffer or its anion is within the above range, excellent long-term stability and low viscosity can be exhibited.

[0130] (E) pH

[0131] 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. When the pH is within the above range, excellent long-term stability and low viscosity can be exhibited. The pH can be adjusted using a buffer. In other words, if a buffer is included in a predetermined amount, the pH within the above range can be achieved without a separate pH adjuster. It may be difficult to achieve the above range of pH when citrate, phosphate, or a mixture thereof is used as a buffer. If an acid (e.g., hydrochloric acid) or a base (e.g., sodium hydroxide) is additionally included as a separate pH adjuster, the stability of the antibody may be reduced.

[0132] (F) Other ingredients

[0133] In one embodiment of the present invention, the stable liquid pharmaceutical formulation may not contain aspartic acid, lysine, arginine, or a mixture thereof. If these amino acids are included, the formulation may be in a solid state. In one embodiment of the present invention, the stable liquid pharmaceutical formulation may contain one or more of the remaining amino acids excluding the three types of amino acids mentioned above. In this case, the amino acid may be included in 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).

[0134] In another embodiment of the present invention, the stable liquid pharmaceutical formulation may contain taurine. In this case, the taurine may be included in 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).

[0135] In one embodiment of the present invention, a stable liquid pharmaceutical formulation may not include NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, K2SO4, etc. as metal salts. If these metal salts are included, precipitation may occur, the formulation may take on a gelatinous form, and stability may be poor.

[0136] In one embodiment of the present invention, the stable liquid pharmaceutical formulation may not contain a chelating agent (e.g., EDTA). If a chelating agent is included, the oxidation rate may increase.

[0137] In one embodiment of the present invention, the stable liquid pharmaceutical formulation may not contain a preservative. Examples of preservatives include octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl alcohol, benzyl alcohol, alkyl parabens, catechol, resorcinol, cyclohexanol, 3-pentanol, m-cresol, etc. Including a preservative may not help improve stability.

[0138] In one embodiment of the present invention, the stable liquid pharmaceutical formulation of the present invention may further include additives known in the art to the extent that they do not substantially affect the antibody activity, the stability of the formulation, and the low viscosity. For example, they may further include an aqueous carrier, an antioxidant, or a mixture of two or more of these. An aqueous carrier is a carrier that is pharmaceutically acceptable (i.e., safe and non-toxic when administered to humans) and useful for the preparation of a liquid pharmaceutical formulation. 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, etc. Antioxidants include, but are not limited to, ascorbic acid.

[0139] (G) "Stable" liquid pharmaceutical preparations

[0140] In the "stable" liquid pharmaceutical formulations of the present invention, the term "stable" means that the antibody according to the present invention substantially retains its physical stability and / or chemical stability and / or biological activity during the manufacturing process and / or storage. Various analytical techniques for measuring the stability of the antibody are readily available in the art.

[0141] Physical stability may be evaluated by methods known in the art, and such methods include measuring the apparent attenuation of light (absorption or optical density) of the sample. Such measurement of light attenuation relates to the turbidity of the formulation. In addition, regarding physical stability, 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., may be measured.

[0142] Chemical stability can be evaluated, for example, by detecting and quantifying the chemically altered form of the antibody. Chemical stability includes charge changes (e.g., occurring as a result of deamidation or oxidation) that can be evaluated, for example, by ion exchange chromatography. Regarding chemical stability, charge variants (acidic or basic peaks), etc., can be measured.

[0143] Biological activity can be evaluated by methods known in the art, for example, antigen binding affinity can be measured through ELISA.

[0144] In one embodiment of the present invention, the liquid pharmaceutical formulation can be stable for a long period of time.

[0145] In one embodiment of the present invention, the term "stable" liquid pharmaceutical formulation means a liquid pharmaceutical formulation satisfying one or more of the following.

[0146] Turbidity

[0147] - Absorbance A measured by a spectrophotometer after storage at 40℃±2℃ for 4 weeks 600 A liquid pharmaceutical preparation having 0 to 0.0300 or 0 to 0.0700;

[0148] - Absorbance A measured by a spectrophotometer after storage for 4 weeks under conditions of a temperature of 40℃±2℃, relative humidity of 75±5%, and a sealed environment 600 A liquid pharmaceutical preparation having 0 to 0.0300 or 0 to 0.0700;

[0149] Main component content (main peak)

[0150] - A liquid pharmaceutical preparation having an active ingredient content of 98% to 100% as measured by SE-HPLC after storage at 40℃±2℃ for 4 weeks;

[0151] - A liquid pharmaceutical preparation having an active ingredient content of 98 to 100% as measured by SE-HPLC after storage for 4 weeks under sealed conditions at a temperature of 40℃±2℃, relative humidity of 75±5%, and sealed conditions;

[0152] High molecular weight component (peak with retention time preceding the main peak (intact IgG))

[0153] - A liquid pharmaceutical preparation in which the high molecular weight component is 0 to 1.00% as measured by SE-HPLC after storage at 5℃±3℃ for 12 months;

[0154] - A liquid pharmaceutical preparation in which the high molecular weight component is 0 to 1.00% as measured by SE-HPLC after storage for 12 months at a temperature of 5℃±3℃ and under sealed conditions;

[0155] Low molecular weight component (peak with retention time later than the main peak (intact IgG))

[0156] - A liquid pharmaceutical preparation in which the low molecular weight component is 0 to 0.40% as measured by SE-HPLC after storage at a temperature of 5℃±3℃ for 12 months;

[0157] - A liquid pharmaceutical preparation in which the low molecular weight component is 0 to 0.40% as measured by SE-HPLC after storage for 12 months at a temperature of 5℃±3℃ and under sealed conditions;

[0158] Content of whole immunoglobulin G

[0159] - A liquid pharmaceutical preparation having an intact immunoglobulin G content (Intact IgG%) of 94.0% to 100% as measured by non-reducing CE-SDS after storage at 5℃±3℃ for 12 months;

[0160] - A liquid pharmaceutical preparation having an intact immunoglobulin G content (Intact IgG%) of 94.0% to 100% as measured by non-reducing CE-SDS after storage for 12 months at a temperature of 5℃±3℃ and under sealed conditions;

[0161] - A liquid pharmaceutical preparation having an intact immunoglobulin G content (Intact IgG%) of 94.0% to 100% as measured by non-reducing CE-SDS after storage at 40℃±2℃ for 4 weeks;

[0162] - A liquid pharmaceutical preparation having an intact immunoglobulin G content (Intact IgG%) of 94.0% to 100% as measured by non-reducing CE-SDS after storage for 4 weeks under conditions of a temperature of 40℃±2℃, a relative humidity of 75±5%, and a sealed environment;

[0163] Content of intact heavy and light chains

[0164] - A liquid pharmaceutical preparation having an intact heavy and light chain content (Intact HC+LC%) of 99.0% to 100% as measured by reduced CE-SDS after storage at a temperature of 5℃±3℃ for 12 months;

[0165] - A liquid pharmaceutical preparation 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℃±3℃ and under sealed conditions;

[0166] - A liquid pharmaceutical preparation having an intact heavy and light chain content (Intact HC+LC%) of 98.0% to 100% as measured by reduced CE-SDS after storage at 40℃±2℃ for 4 weeks;

[0167] - A liquid pharmaceutical preparation 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 under conditions of a temperature of 40℃±2℃, a relative humidity of 75±5%, and a sealed environment;

[0168] Number of insoluble foreign particles

[0169] - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (10.00 µm ≤, < 400.00 µm) measured by HIAC after storage at a temperature of 5℃±3℃ for 12 months is 0 to 1,000;

[0170] - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (10.00 μm ≤, < 400.00 μm) measured by HIAC after storage for 12 months at a temperature of 5℃±3℃ and under sealed conditions is 0 to 1,000;

[0171] - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (1.00 µm ≤, < 100.00 µm) measured by MFI after storage at a temperature of 40℃±2℃ for 4 weeks is 0 to 30,000;

[0172] - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (1.00 μm ≤, < 100.00 μm) measured by MFI after storage for 4 weeks under sealed conditions at a temperature of 40℃±2℃, a relative humidity of 75±5%, and a sealed state is 0 to 30,000;

[0173] - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (10.00 μm ≤, < 100.00 μm) measured by MFI after storage at a temperature of 40℃±2℃ for 4 weeks is 0 to 200;

[0174] - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (10.00 μm ≤, < 100.00 μm) measured by MFI after storage for 4 weeks under sealed conditions at a temperature of 40℃±2℃, a relative humidity of 75±5%, and a sealed state is 0 to 200;

[0175] - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (10.00 μm ≤, < 100.00 μm) measured by MFI after storage at a temperature of 40℃±2℃ for 6 weeks is 0 to 500;

[0176] - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (10.00 μm ≤, < 100.00 μm) measured by MFI after storage for 6 weeks under conditions of a temperature of 40℃±2℃, a relative humidity of 75±5%, and a sealed state is 0 to 500;

[0177] Oxidation rate

[0178] - A liquid pharmaceutical preparation having an oxidation rate of 0% to 2.5% of heavy chain Met 255 as measured by LC-MS after storage at 40℃±2℃ for 4 weeks;

[0179] - A liquid pharmaceutical preparation having an oxidation rate of 0% to 2.5% of heavy chain Met 255 as measured by LC-MS after storage for 4 weeks under conditions of a temperature of 40℃±2℃, a relative humidity of 75±5%, and a sealed environment;

[0180] Charge deformation body

[0181] - A liquid pharmaceutical preparation having an acid peak of 20% to 35% as measured by IEC-HPLC after storage at 40℃±2℃ for 4 weeks;

[0182] - A liquid pharmaceutical preparation having an acid peak of 20% to 35% as measured by IEC-HPLC after storage for 4 weeks under conditions of a temperature of 40℃±2℃, a relative humidity of 75±5%, and a sealed environment;

[0183] - A liquid pharmaceutical preparation having a basic peak of 33% to 40% as measured by IEC-HPLC after storage at 40℃±2℃ for 4 weeks;

[0184] - A liquid pharmaceutical preparation having a basic peak of 33% to 40% as measured by IEC-HPLC after storage for 4 weeks under conditions of a temperature of 40℃±2℃, a relative humidity of 75±5%, and a sealed environment;

[0185] TNFα binding affinity

[0186] - A liquid pharmaceutical preparation having a TNFα binding affinity of 80% to 120% as measured by ELISA after storage at 5℃±3℃ for 12 months; and

[0187] - A liquid pharmaceutical preparation having a TNFα binding affinity of 80% to 120% as measured by ELISA after storage for 12 months at a temperature of 5℃±3℃ and under sealed conditions.

[0188] In one embodiment of the present invention, the viscosity measured after one month at a temperature of 40°C ± 2°C may be 0.5 cP to 10.0 cP. In another embodiment of the present invention, the viscosity measured after six months at a temperature of 5°C ± 3°C may be 0.5 cP to 5.0 cP.

[0189] (H) Method for preparing a stable liquid pharmaceutical formulation

[0190] The stable liquid pharmaceutical formulation of the present invention can be prepared using known methods and is not limited to a specific method. For example, a liquid pharmaceutical formulation can be prepared by adjusting the pH while adding a buffer to a solution containing a surfactant and a sugar or a derivative thereof, and then adding an antibody to the mixed solution. Alternatively, a liquid pharmaceutical formulation can be prepared by preparing a solution containing some excipients at the final stage of a purification process and then adding the remaining components. For example, a liquid pharmaceutical formulation can be prepared by preparing a solution containing an antibody, a buffer, and a sugar or a derivative thereof at the final stage of a purification process, and then adding a surfactant to this solution.

[0191] In addition, the above formulation may not include a freeze-drying process during manufacturing or may include a freeze-drying process.

[0192] In cases where a freeze-drying process is not included, for example, the liquid pharmaceutical formulation of the present invention can be prepared and placed in a sealed container immediately after treatment such as sterilization.

[0193] In cases involving a freeze-drying process, for example, a liquid pharmaceutical formulation according to the present invention may be prepared by preparing and freeze-drying the liquid pharmaceutical formulation of the present invention, or by preparing, freeze-drying, and storing the liquid pharmaceutical formulation of the present invention, and then supplementing or replacing the components that have been removed or modified by freeze-drying and / or storage. Additionally, a liquid pharmaceutical formulation according to the present invention may be prepared by freeze-drying only the components from which the components that may be removed or modified by freeze-drying and / or storage have been excluded, or by freeze-drying only those components and storing them, and then adding the excluded components.

[0194] Korean Patent Application No. 10-2017-0081814 and Korean Patent Application No. 10-2018-0102233, previously filed by the applicant, are incorporated by reference into the specification of the present invention.

[0195] Treatment method for TNFα-related diseases of the present invention

[0196] The present invention provides a method for treating a TNFα-related disease, comprising the step of subcutaneously administering a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof to a subject having a TNFα-related disease.

[0197] In one embodiment of the present invention, the antibody may comprise one or more selected from the group consisting of infliximab, adalimumab, cetorizumab, pegol, golimumab, and biosimilars thereof.

[0198] In one embodiment of the present invention, the antibody may be infliximab.

[0199] In one embodiment of the present invention, the antibody may comprise a chimeric human-mouse IgG monoclonal antibody.

[0200] In one embodiment of the present invention, the antibody or the antigen-binding fragment thereof may comprise a light chain variable region comprising a CDR1 domain having the amino acid sequence of SEQ ID NO. 1, a CDR2 domain having the amino acid sequence represented by YAS, and a CDR3 domain having the amino acid sequence of SEQ ID NO. 2; and a heavy chain variable region comprising a CDR1 domain having the amino acid sequence of SEQ ID NO. 3, a CDR2 domain having the amino acid sequence of SEQ ID NO. 4, and a CDR3 domain having the amino acid sequence of SEQ ID NO. 5.

[0201] In one embodiment of the present invention, the antibody or its antigen-binding fragment may include a light chain variable region comprising the amino acid sequence of SEQ ID NO. 6; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO. 7.

[0202] In one embodiment of the present invention, the antibody may comprise a light chain comprising the amino acid sequence of SEQ ID NO. 8; and a heavy chain comprising the amino acid sequence of SEQ ID NO. 9.

[0203] In one embodiment of the present invention, the concentration of the antibody or its antigen-binding fragment may be 10 to 220 mg / ml, and may be 120 mg / ml.

[0204] The present invention also provides a method for treating a TNFα-related disease, comprising the step of subcutaneously administering to a subject a composition comprising (A) an anti-TNFα antibody or an antigen-binding fragment thereof; (B) a surfactant; (C) a sugar or a derivative thereof; and (D) a buffer.

[0205] In one embodiment of the present invention, the subject to whom the antibody or its antigen-binding fragment is administered may be a patient with active rheumatoid arthritis who has shown an insufficient response to methotrexate monotherapy for 3 months or more and / or a patient who has not received the anti-TNFα antibody or its antigen-binding fragment prior to subcutaneous administration. Additionally, the subject to whom the antibody or its antigen-binding fragment is administered may be a patient who has not received infliximab. Furthermore, the (A) anti-TNFα antibody or its antigen-binding fragment, (B) surfactant, (C) sugar or derivative thereof, and (D) buffer are as described above.

[0206] In one embodiment of the present invention, the surfactant (B) may include polysorbate, poloxamer, or a mixture thereof.

[0207] In one embodiment of the present invention, the surfactant (B) may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture of two or more of these.

[0208] In one embodiment of the present invention, the surfactant (B) may include polysorbate 80.

[0209] In one embodiment of the present invention, the concentration of the surfactant (B) may be 0.02 to 0.1% (w / v).

[0210] In one embodiment of the present invention, the (C) sugar comprises a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, or a mixture of two or more of these, and the derivative of the sugar may comprise a sugar alcohol, a sugar acid, or a mixture thereof.

[0211] In one embodiment of the present invention, the (C) sugar or its derivative may include sorbitol, mannitol, trehalose, sucrose, or a mixture of two or more of these.

[0212] In one embodiment of the present invention, the concentration of the (C) sugar or its derivative may be 1 to 10% (w / v).

[0213] In one embodiment of the present invention, the (D) buffer may include acetate or histidine.

[0214] In one embodiment of the present invention, the content of the (D) buffer may be 1 to 90 mM.

[0215] In one embodiment of the present invention, the pH of the composition may be 4.0 to 5.5.

[0216] In one embodiment of the present invention, the composition may not include aspartic acid, lysine, arginine, or a mixture thereof.

[0217] In one embodiment of the present invention, the composition may not include NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, K2SO4, or a mixture thereof.

[0218] In one embodiment of the present invention, the composition may not include a chelating agent.

[0219] In one embodiment of the present invention, the composition may not include a preservative.

[0220] In one embodiment of the present invention, the composition may further comprise an aqueous carrier, an antioxidant, or a mixture of two or more of these.

[0221] In one embodiment of the present invention, the composition may have a viscosity of 0.5 cP to 10.0 cP measured after 1 month at a temperature of 40℃±2℃, or a viscosity of 0.5 cP to 5.0 cP measured after 6 months at 5℃±3℃.

[0222] In one embodiment of the present invention, the composition may comprise (A) an anti-TNFα antibody or an antigen-binding fragment thereof, particularly a light chain variable region comprising a CDR1 domain having the amino acid sequence of SEQ ID NO. 1, a CDR2 domain having the amino acid sequence represented by YAS, and a CDR3 domain having the amino acid sequence of SEQ ID NO. 2; and a heavy chain variable region comprising a CDR1 domain having the amino acid sequence of SEQ ID NO. 3, a CDR2 domain having the amino acid sequence of SEQ ID NO. 4, and a CDR3 domain having the amino acid sequence of SEQ ID NO. 5; (B) a surfactant; (C) a sugar or a derivative thereof; and (D) a buffer comprising acetate or histidine.

[0223] In one embodiment of the present invention, the composition may comprise (A) 90 to 220 mg / ml or 90 to 180 mg / ml of an antibody or its antigen-binding fragment, comprising an anti-TNFα antibody or its antigen-binding fragment, in particular, a light chain variable region comprising a CDR1 domain having the amino acid sequence of SEQ ID NO. 1, a CDR2 domain having the amino acid sequence represented by YAS, and a CDR3 domain having the amino acid sequence of SEQ ID NO. 2; and a heavy chain variable region comprising a CDR1 domain having the amino acid sequence of SEQ ID NO. 3, a CDR2 domain having the amino acid sequence of SEQ ID NO. 4, and a CDR3 domain having the amino acid sequence of SEQ ID NO. 5; (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 90 mM or 1 to 50 mM of a buffer comprising acetate or histidine.

[0224] In one embodiment of the present invention, the composition may comprise (A) 90 to 220 mg / ml or 90 to 180 mg / ml of an antibody or its antigen-binding fragment, comprising an anti-TNFα antibody or its antigen-binding fragment, in particular, a light chain variable region comprising a CDR1 domain having the amino acid sequence of SEQ ID NO. 1, a CDR2 domain having the amino acid sequence represented by YAS, and a CDR3 domain having the amino acid sequence of SEQ ID NO. 2; and a heavy chain variable region comprising a CDR1 domain having the amino acid sequence of SEQ ID NO. 3, a CDR2 domain having the amino acid sequence of SEQ ID NO. 4, and a CDR3 domain having the amino acid sequence of SEQ ID NO. 5; (B) 0.02 to 0.1 % (w / v) of polysorbate; (C) 1 to 10 % (w / v) of sorbitol; and (D) 1 to 90 mM or 1 to 50 mM of a buffer comprising acetate.

[0225] In one embodiment of the present invention, the composition may be administered subcutaneously.

[0226] In one embodiment of the present invention, the composition may not undergo a reconstitution step, a dilution step, or both before use.

[0227] In one embodiment of the present invention, the composition may be filled into a sterile container or filled into a pre-filled syringe.

[0228] In one embodiment of the present invention, immediately before administering the composition to a subject, a portion of the composition filled in a sterile container or a pre-filled syringe may be subdivided into an administration dose for use. In one embodiment of the present invention, the stable composition may be filled into a pre-filled syringe before use.

[0229] In one embodiment of the present invention, the composition may be contained in an auto-injector or a syringe for subcutaneous administration before use.

[0230] TNFα-related diseases

[0231] In one embodiment of the present invention, the TNFα-related disease is selected from the group consisting of rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, neonatal hemolytic disease, inflammatory bowel disease, multiple sclerosis, prevention of organ transplant rejection, non-Hodgkin lymphoma, metastatic cancer, retinopathy of prematurity, ovarian cancer, gastric cancer, head and neck cancer, osteoporosis, paroxysmal nocturnal hemoglobinuria, invasive Candida infection, breast cancer, melanoma, chronic lymphocytic leukemia, acute myeloid leukemia, renal cell carcinoma, colorectal cancer, asthma, nasopharyngeal cancer, hemorrhagic shock, Staphylococcus aureus infection, and follicular lymphoma.

[0232] In one embodiment of the present invention, the TNFα-related disease may be a disease treatable with intravenous administration of infliximab.

[0233] In one embodiment of the present invention, the TNFα-related disease may be rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, or ankylosing spondylitis that can be treated with intravenous administration of infliximab.

[0234] In one embodiment of the present invention, the subject to administration of the anti-TNFα antibody is a subject with an insufficient response to disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate.

[0235] In one embodiment of the present invention, the subject to administration of the anti-TNFα antibody is a subject who has not previously been treated with methotrexate and other DMARDs.

[0236] In one embodiment of the present invention, the subject to administration of the anti-TNFα antibody is a subject exhibiting severe axial symptoms and elevated serological indicators associated with inflammation who does not show an adequate response to conventional treatment.

[0237] In one embodiment of the present invention, the subjects to whom the anti-TNFα antibody is administered are subjects who do not show an adequate response to systemic therapy including methotrexate, cyclosporine, or Psoralen ultraviolet A therapy (PUBA), who do not tolerate such therapy, or for whom such treatment methods are contraindicated.

[0238] In one embodiment of the present invention, the subjects to whom the anti-TNFα antibody is administered are those who do not show an adequate response to treatment with corticosteroids, 6-mercaptopurines, azathioprine, or immunosuppressants, who do not tolerate such treatment, or for whom such treatment methods are contraindicated.

[0239] In one embodiment of the present invention, the target for administration of the anti-TNFα antibody is a target that does not respond to conventional treatments including antibiotics, elimination therapy, or immunosuppressive therapy.

[0240] In one embodiment of the present invention, the subjects for administration of the anti-TNFα antibody may be patients with active disease who have at least 6 swollen joints out of 66 joints, at least 6 tender joints out of 68 joints, and who satisfy one of the following: high-sensitivity C-reactive protein (hsCRP) of 1.0 mg / dL or higher, or an erythrocyte sedimentation rate (ESR) of 28 mm / hour or higher, and / or patients who have received oral or parenteral methotrexate (MTX) treatment for at least 12 weeks and have stably maintained MTX administration for at least 4 weeks prior to initiating subcutaneous administration of the anti-TNFα antibody. In addition, the subjects for administration of the above anti-TNFα antibody may be patients with active rheumatoid arthritis who have shown an insufficient response to methotrexate monotherapy for more than 3 months and / or patients who have not received the above anti-TNFα antibody or its antigen-binding fragment prior to subcutaneous administration (in particular, patients who have not received infliximab intravenously).

[0241] In one embodiment of the present invention, the subjects receiving the anti-TNFα antibody may be (i) subjects with moderate to severely active Crohn's disease with a PCDAI greater than 30 points, ileocolonic Crohn's disease with a Simplified Endoscopic Activity Score for Crohn's Disease of 6 points or more, ileocolonic Crohn's disease with an endoscopic activity score of 4 points or more and at least one compartment ulcer score, and / or Crohn's disease diagnosed by radiology, biopsy, or endoscopy; and / or (ii) subjects with moderate to severely active ulcerative colitis with a modified Mayo score of 5 to 9 points and / or ulcerative colitis diagnosed by radiology, biopsy, or endoscopy.

[0242] In one embodiment of the present invention, the subjects to whom the anti-TNFα antibody is administered may be subjects who have received appropriate treatment with primary nutritional therapy and / or corticosteroids and / or immunosuppressants for active Crohn's disease but have not responded, have intolerance to the drugs, or have medical contraindications to them.

[0243] In one embodiment of the present invention, after subcutaneous administration, the subject may have one or more characteristics selected from the following:

[0244] a) A decrease of at least 2.0 in DAS28 (Disease Activity Score in 28 joints); or

[0245] b) A decrease in CDAI (Crohn's disease activity index) of at least 70.

[0246] Dosage and administration cycle

[0247] In one embodiment of the present invention, an anti-TNFα antibody or a binding fragment thereof may be administered in an amount of 10 to 300 mg. Specifically, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 mg may be administered subcutaneously.

[0248] In another embodiment of the present invention, the anti-TNFα antibody or its binding fragment may be administered subcutaneously in an amount of 40 to 180 mg or 90 to 180 mg. In another embodiment, the anti-TNFα antibody or its binding fragment may be administered subcutaneously in an amount of 40 to 300 mg or 90 to 300 mg. In another embodiment, the anti-TNFα antibody or its binding fragment may be administered subcutaneously in an amount of 120 to 240 mg or 120 mg.

[0249] In one embodiment of the present invention, the anti-TNFα antibody or its binding fragment may be administered subcutaneously in an amount of 40 to 120 mg, 40 to 100 mg, 80 to 100 mg, 110 to 130 mg, 170 to 190 mg, or 230 to 250 mg.

[0250] In one embodiment of the present invention, an anti-TNFα antibody or a binding fragment thereof may be administered subcutaneously to a subject with rheumatoid arthritis in an amount of 40 to 120 mg, 40 to 190 mg, 80 to 190 mg, 90 to 180 mg, 110 to 130 mg, 90 mg, 120 mg, or 180 mg.

[0251] In one embodiment of the present invention, an anti-TNFα antibody or a binding fragment thereof may be administered subcutaneously to subjects with ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis or ankylosing spondylitis in amounts of 40 to 120 mg, 40 to 250 mg, 80 to 250 mg, 110 to 250 mg, 110 to 130 mg, 120 to 240 mg, 140 to 160 mg, 170 to 190 mg, 230 mg to 250 mg, 120 mg, 150 mg, 180 mg, or 240 mg.

[0252] In one embodiment of the present invention, the anti-TNFα antibody or its binding fragment may be administered subcutaneously in an amount of 90 to 180 mg when the subject's body weight is less than 80 kg, and 190 to 270 mg when the subject's body weight is 80 kg or more.

[0253] The criteria for determining that a treatment response has been lost in Crohn's disease may be when the individual CDAI score increases by 70 points or more, and the total CDAI score is 220 or more.

[0254] The criteria for determining that the treatment response has been lost in ulcerative colitis may be that the subject meets condition a) and meets one or more of b) or c):

[0255] a) where the bleeding subscore increased by 1 point or more at the lowest score with an actual value greater than 1 point; and

[0256] b) In the lowest score where the actual value is 4 or more, if the Partial Mayo score increases by 2 or more; or

[0257] c) In the lowest score where the actual value exceeds 1 point, if the endoscopic subscore increases by 1 point or more.

[0258] In one embodiment of the present invention, if the subject's condition does not improve and the dose of the anti-TNFα antibody or its binding fragment is increased to 240 mg, it may be preferable not to increase the dose further. If a subject receiving a dose of 240 mg is administered a dose higher than that, liver damage caused by high concentrations of the drug may occur.

[0259] In one embodiment of the present invention, the dose increase of the anti-TNFα antibody or its binding fragment may be carried out after 5, 10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 32, and 35 weeks. More preferably, the dose increase may be carried out after 30 weeks. If the dose is increased before that, there may not be enough time to confirm the efficacy of the existing dose, and if the dose is increased after that, there may be side effects such as the subject's condition worsening.

[0260] In one embodiment of the present invention, the anti-TNFα antibody or its binding fragment may proceed directly to the maintenance regimen stage of administration without undergoing the induction regimen, which is a conventional antibody administration treatment method, and in such cases, a fixed cycle and a fixed dosage may be continuously maintained.

[0261] The "induction regimen" described in this invention refers to a process of initially exposing a patient to a drug, premised on securing a fixed dosage and administration cycle to enable the management of a stable maintenance regimen; it is a pre-medication act based on the subsequent "maintenance regimen." This refers to a treatment period intended to allow the drug within the patient to reach a threshold level, which is a constant and stable state. Terms synonymous with induction regimen include "introduction" regimen or "loading" regimen. The term "threshold" refers to the therapeutically effective level of the anti-TNFα antibody or its binding fragment within the patient. The threshold level is achieved by administering one or more induction doses during the induction phase of treatment. The threshold level of the anti-TNFα antibody can be achieved by administering the induction dose at any number of times. Once the threshold level is achieved, the "maintenance regimen" phase begins as the treatment phase. Since the treatment phase follows the induction phase, it begins once the threshold level is achieved. The term "intravenous induction therapy" as described in the present invention refers to administering a drug intravenously in advance to maintain a stable threshold level of the patient's blood drug concentration, thereby enabling the transition to a "maintenance therapy" stage. In one embodiment of the present invention, when a patient with a TNFα-related disease first starts anti-TNFα antibody treatment such as infliximab, the disease can be treated with only the initial subcutaneous administration without the inconvenience of induction therapy (intravenous administration) throughout the entire treatment period.

[0262] In one embodiment of the present invention, an anti-TNFα antibody or a binding fragment thereof may be administered subcutaneously at intervals of 1 to 8 weeks. Specifically, it may be administered subcutaneously 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.

[0263] In another embodiment of the present invention, an anti-TNFα antibody or a binding fragment thereof may be administered subcutaneously at weekly intervals.

[0264] In another embodiment of the present invention, the anti-TNFα antibody or its binding fragment may be administered subcutaneously at intervals of 2 to 4 weeks, preferably at intervals of 2 weeks.

[0265] In one embodiment of the present invention, after subcutaneous administration to a subject, the trough blood concentration (C) of the anti-TNFα antibody or its antigen-binding fragment trough ; The administration method may be one in which the minimum concentration immediately before the next application) is maintained at 0.01 μg / ml or higher. More specifically, it may be an administration method in which the concentration is maintained at 0.01 to 50 μg / ml, 0.01 to 45 μg / ml, 0.01 to 40 μg / ml, 0.01 to 35 μg / ml, 0.01 to 30 μg / ml, 0.01 to 25 μg / ml, 0.01 to 20 μg / ml, 0.01 to 15 μg / ml, 0.01 to 10 μg / ml, 0.01 to 6 μg / ml, 0.1 to 6 μg / ml, 5 μg / ml, or 1 μg / ml.

[0266] In one embodiment of the present invention, for a subject with rheumatoid arthritis, after subcutaneous administration to the subject, the trough blood concentration (C) of the anti-TNFα antibody or its antigen-binding fragment trough It may be a method of administration in which ) is maintained at 0.01 μg / ml or higher, 0.01 to 50 μg / ml, 0.01 to 40 μg / ml, 0.01 to 30 μg / ml, 1 to 40 μg / ml, or 1 μg / ml or higher. Preferably, the trough blood concentration (C) of an anti-TNFα antibody or its antigen-binding fragment against subjects with rheumatoid arthritis trough ) can be 1 μg / ml.

[0267] In one embodiment of the present invention, for a subject having one or more diseases selected from the group consisting of ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis, after subcutaneous administration to the subject, the trough blood concentration (C) of an anti-TNFα antibody or its antigen-binding fragment trough It may be a method of administration in which ) is maintained at 0.01 μg / ml or more, 0.01 to 60 μg / ml, 0.01 to 50 μg / ml, 0.01 to 45 μg / ml, 5 to 50 μg / ml, or 5 μg / ml or more.

[0268] Preferably, the trough blood concentration (C) of an anti-TNFα antibody or its antigen-binding fragment against inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn's disease. trough ) can be 5 μg / ml.

[0269] concomitant administration

[0270] Other bioagents or chemotherapy agents may be administered together with the anti-TNFα antibody or its antigen-binding fragment of the present invention. The administration is carried out simultaneously with, before, or after the administration of the anti-TNFα antibody or its antigen-binding fragment.

[0271] In one embodiment of the present invention, the bioagent administered in combination may include etanercept, infliximab, adalimumab, sertolizumab pegol, golimumab, or a combination thereof.

[0272] In one embodiment of the present invention, the chemotherapy agent administered in combination may include a disease-modifying antirheumatic drug (DMARD), a steroid, or an immunosuppressant.

[0273] In one embodiment of the present invention, the disease-relief antirheumatic drug (DMARD) administered in combination may include methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, or a combination thereof.

[0274] In one embodiment of the present invention, the steroid administered in combination may include a corticosteroid, a glucocorticoid, cortisol, a mineralocorticoid, aldosterone, or a combination thereof.

[0275] In one embodiment of the present invention, the immunosuppressant administered in combination may include azathioprine, 6-mercaptourein, cyclosporine A, tacrolimus, mycofenoric acid, bredinin, an mTOR inhibitor, an anti-lymphocyte antibody, or a combination thereof.

[0276] In one embodiment of the present invention, an antihistamine, hydrocortisone, paracetamol, and / or a non-sedating antihistamine may be co-administered with an anti-TNFα antibody or its antigen-binding fragment.

[0277] product

[0278] The present invention also provides a product comprising a composition containing an anti-TNFα antibody or a binding fragment thereof; and a container for containing said composition in a sealed state.

[0279] The composition containing the above-mentioned anti-TNFα antibody or its binding fragment is as described above.

[0280] In one embodiment of the present invention, the product may be a kit comprising a composition containing the anti-TNFα antibody or a binding fragment thereof.

[0281] In one embodiment of the present invention, the product may further include instructions for providing a method of use, a method of storage, or both of the composition containing the anti-TNFα antibody or its binding fragment. The method of use may include a treatment for a disease in which the activity of TNFα is harmful, and may include a route of administration, a dosage, and a time of administration.

[0282] In one embodiment of the present invention, the container may be formed from materials such as glass, polymer (plastic), metal, etc., but is not limited thereto. In one embodiment of the present invention, the container is a sterile container, bottle, vial, cartridge, syringe (pre-filled syringe, automatic syringe), or tube, but is not limited thereto. In one embodiment of the present invention, the container may be a glass or polymer vial, or a glass or polymer pre-filled syringe.

[0283] Specific product forms such as vials, cartridges, pre-filled syringes, and automatic syringes, and methods for filling the above-mentioned stable liquid pharmaceutical formulations into vials, cartridges, pre-filled syringes, automatic syringes, etc., can be easily obtained or practiced by those skilled in the art to which the present invention pertains. For example, U.S. Patents No. 4,861,335 and No. 6,331,174 disclose specific product forms and filling methods for pre-filled syringes. For example, U.S. Patents No. 5,085,642 and No. 5,681,291 disclose specific product forms and assembly methods for automatic syringes. Commercially available products as vials, cartridges, pre-filled syringes, automatic syringes, etc., may be used as is, or products specially manufactured by taking into account the physical properties, administration site, and dosage of the composition containing the anti-TNFα antibody or its binding fragment may be used.

[0284] 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 a single-dose or multi-dose container.

[0285] In one embodiment of the present invention, the product may include other tools necessary from a commercial and user perspective, such as needles, syringes, etc.

[0286] The present invention will be explained in detail below by way of examples. The following examples are merely for illustrating the present invention, and the scope of the present invention is not limited by the following examples.

[0287] Example 1. Evaluation of the efficacy and safety of subcutaneous injection of infliximab as a treatment regimen for patients with rheumatoid arthritis (RA).

[0288] Example 1-1. Clinical Protocol

[0289] This clinical trial is a randomized, placebo-controlled, parallel-group, double-blind, Phase 3 trial designed to evaluate the efficacy, pharmacokinetics, and safety of subcutaneous infliximab (infliximab SC) administered in combination with MTX and folic acid without induction therapy (IV) compared to a placebo group in patients with active rheumatoid arthritis who have shown an insufficient response to methotrexate (MTX) monotherapy over a period of 3 months or more, and its primary objective is to demonstrate the superiority of infliximab SC in terms of efficacy compared to the placebo group.

[0290] A total of 189 patients were subjects of the study (126 in the infliximab SC group and 63 in the placebo group). The study was designed so that patients would receive either 120 mg of infliximab or a placebo subcutaneously every other week starting from day 1, and all patients would receive 120 mg of infliximab starting from week 12. The overall plan of the clinical trial is shown in Figure 1.

[0291] Patients must meet all of the following criteria to be enrolled in this clinical trial.

[0292] Male or female patients aged 18 to 75

[0293] Patients diagnosed according to the 2010 ACR / EULAR diagnostic criteria for rheumatoid arthritis 24 weeks prior to the start date of study drug prescription (Day 1)

[0294] Patients with active disease who, at the time of screening, have 6 or more swollen joints out of 66 or 6 or more tender joints out of 68, and satisfy one of the following criteria: high-sensitivity C-reactive protein (hsCRP) of 1.0 mg / dL or higher or an erythrocyte sedimentation rate (ESR) of 28 mm / hour or higher.

[0295] Patients who have been receiving oral or parenteral methotrexate (MTX) treatment for at least 12 weeks and have maintained stable MTX administration in the range of 10 mg / week to 25 mg / week for at least 4 weeks prior to the start date of study drug prescription (Day 1).

[0296] Meanwhile, patients cannot be enrolled in the clinical trial if they meet any of the following criteria.

[0297] Patients who, prior to participating in the clinical trial, used biological or targeted synthetic disease-modifying antirheumatic drugs (DMARDs) (e.g., tofacitinib, baricitinib) that were under study or approved for the treatment of RA, or used tumor necrosis factor (TNF) α inhibitors for any purpose.

[0298] Patients who are allergic to any component of infliximab or other mouse and / or human proteins, or who are hypersensitive to immunoglobulin products

[0299] Patients with specific infections (tuberculosis / hepatitis, etc.) or medical conditions that restrict clinical participation. This clinical trial consists of three study periods, including a screening period, a blinded placebo-controlled period, and an open-label extension period.

[0300] Screening period: Screening is performed between -42 days and 0 days (maximum 6 weeks) prior to the first administration of infliximab SC.

[0301] Placebo-controlled period (weeks 0 to 12):

[0302] In the placebo-controlled period, only patients who meet all selection criteria and none of the exclusion criteria as of day 1 (week 0) are enrolled in the clinical trial and are randomly assigned to the infliximab 120 mg group and the placebo group in a 2:1 ratio before administration.

[0303] Randomization for administration assignment is stratified according to the following criteria:

[0304] * Weight at Day 1 (Week 0) (less than 90kg or 90kg or more)

[0305] * Disease activity score based on the Simplified Disease Activity Index (SDAI) during the screening period (26 or less or greater than 26)

[0306] A double-blind study design is used to maintain blindness of the study during the placebo-controlled period. During this period, a total of six injections of 120 mg of infliximab or placebo are administered subcutaneously every other week, and oral or parenteral MTX (10 to 25 mg) and folic acid (≥ 5 mg / week, oral dose) are administered concurrently during the study period. Additionally, the CT-P13 SC was formulated as a composition comprising 120 mg / ml of infliximab, acetate, sorbitol, polysorbate 80, and water for injection.

[0307] Open label extension period (weeks 12 to 52):

[0308] All patients who have completed the placebo-controlled period may enter the open-label extension period, during which all patients may receive 120 mg of infliximab subcutaneously every other week from week 12 to week 48. The open-label extension period continues until week 52.

[0309] The End of Study Visit (EOS) is conducted for patients who have completed all study treatments between 48 weeks and 52 weeks, which is 4 weeks after the last administration. All patients who discontinued study treatment early are encouraged to complete scheduled study visits regularly by 52 weeks for planned clinical evaluations (including safety evaluations, including efficacy and immunogenicity).

[0310] Example 1-2. Simulation results for determining the dosage of CT-P13 SC treatment in RA patients

[0311] A pharmacokinetic-pharmacodynamic (PK-PD) model for infliximab 120 mg subcutaneous injection every 2 weeks with induction therapy (IV) omitted (CT-P13SC) and infliximab 3 mg / kg intravenous injection every 8 weeks (CT-P13 IV) was established for the simulation of future dosages and the PK of each regimen, as well as for integration with a quantitative pharmacokinetic (PK) model to simulate the efficacy of the two regimens. Population PK analysis results and PK-PD modeling were based on infliximab intravenous or subcutaneous administration data in healthy adult subjects, adult patients with rheumatoid arthritis, adult patients with Crohn's disease, adult patients with ankylosing spondylitis (intravenous recipients only), and adult patients with ulcerative colitis (subcutaneous recipients only) (see EudraCT identification number 2013-003173-10, Clinicaltrials.gov identifiers NCT01220518, NCT01217086, NCT02096861, NCT03147248, NCT02883452, and NCT03446976).

[0312] PK simulation

[0313] The pharmacokinetic (PK) exposure of CT-P13 was simulated with bi-weekly (Q2W) dosing of CT-P13SC 120 mg from week 0 to week 30 without induction therapy, and with infliximab IV at 3 mg / kg administered at 8-week intervals (Q8W) from week 6 to week 30 following induction therapy at weeks 0 and 2. The estimated PK exposure parameters were based on the blood trough concentration (C trough ), area under the concentration-time curve (AUC) from 6 to 14 weeks, 14 to 22 weeks, and 22 to 30 weeks W6-14 ), AUC W14-22 and AUC W22-30 It included. Simulated blood trough concentration (C trough Week 14 was selected to represent the earliest PK results after the IV induction dose, and Week 30 was selected to represent steady-state PK results. In the case of administering CT-P13 SC 120 mg Q2W without an induction dose, C trough It gradually increased from week 0 to week 14 and reached a steady state at week 22, and was confirmed to exceed the minimum effective dose (1 µg / mL) throughout the entire period (see Fig. 2). When CT-P13 SC 120 mg Q2W was administered without induction therapy, the total exposure, measured by the area under the concentration-time curve (AUC), was generally equivalent to or superior to infliximab IV 3 mg / kg Q8W administration over the entire period (see Fig. 3).

[0314] Exposure-Response Analysis

[0315] Similar to the PK simulation, additional simulations were performed to investigate the clinical response according to the 28 joint disease activity scores (DAS28) and the American College of Rheumatology assessment index 20% improvement (ACR20) criteria after administration of CT-P13 SC 120 mg at 2-week intervals without induction therapy from week 0 to week 30, administration of infliximab IV 3 mg / kg at weeks 0 and 2, and administration at 8-week intervals from week 6 to week 30.

[0316] * DAS28 score simulation

[0317] In the development of the PK-PD model for the DAS28 score, the total concentration-time profile of CT-P13 was used as an efficacy factor. The DAS28 PK-PD model considered longitudinal measurements of the DAS28 score and applied time-varying concentration-time data through an indirect response model. This model [applied] summary measures of exposure (e.g., AUC or Cmax). trough It was designed not to be driven solely by ) but to comprehensively utilize all data through the entire concentration-time profile of CT-P13.

[0318] According to the simulation results, the expected DAS28 scores for SC administration were equivalent to or superior to IV administration from week 0 to week 30 (see Fig. 4), and the geometric mean ratio (GMR) and 90% confidence interval (CI) of DAS28 scores comparing SC and IV administration at all time points from week 6 to week 30 fell within the bioequivalence criteria range (0.80–1.25) for all 10 kg body weight intervals (see Fig. 5).

[0319] * ACR20 score simulation

[0320] Following DAS28, a simulation of the ACR20 response, another efficacy indicator for rheumatoid arthritis, was also conducted. The possibility of an ACR20 response was simulated based on the normalized AUC obtained at the dosing interval immediately prior to the clinical response evaluation for the CT-P13 120 mg subcutaneous administration group without induction therapy and the infliximab 3 mg / kg intravenous administration group with induction therapy at 8-week intervals.

[0321] In the analysis of clinical responses based on ACR20 criteria, AUC was used as an efficacy indicator because ACR20 is defined as a dichotomous outcome (respondents vs. non-responders). Therefore, a single summary measure of each drug exposure was required for the ACR20 analysis, and the normalized AUC obtained from the dosing interval immediately prior to the clinical response evaluation was selected as a measure reflecting the wholeness of each drug exposure.

[0322] The AUC was normalized to a common time interval, allowing for a fair assessment of the impact of exposure to each drug on clinical response despite the different dosing intervals of CT-P13 SC and infliximab IV administration. Accordingly, the probability of a positive response was expressed based on the total exposure of each drug during the dosing interval immediately preceding the evaluation.

[0323] The probability of clinical response according to the ACR20 criteria at week 14 is AUC W6-14 Reaction probability distribution and simulated AUC related to W6-14 It was diagrammed as shown in Figure 6. Overall, the median clinical response probability (95% predicted interval [PI]) according to the ACR20 criteria at week 14 was 0.71 (0.68 - 0.77), and by confirming that the graph shape and response rate of CT-P13 SC were equivalent to or superior to those of infliximab IV administration, it was confirmed that CT-P13 SC without induction therapy showed superior efficacy compared to the intravenous administration group.

[0324] The clinical response probability according to the Week 30 ACR20 criteria is the simulated AUC W22-30The values ​​and response probability distributions are shown in Figure 7. For CT-P13 SC 120 mg Q2W, the median clinical response probability (95% prediction interval [PI]) according to ACR20 criteria at week 30 was 0.89 (0.87 - 0.92).

[0325] For infliximab IV 3 mg / kg Q8W, the median response probability (95% PI) based on the same criteria was found to be 0.72 (0.69 - 0.79). The difference in clinical response between CT-P13 SC and CT-P13 IV administration observed at week 30 is due to the inclusion of the route as a binary covariate based on the difference in response probability by administration route observed at week 30 in the clinical trial, and the difference in response rates between SC and IV administration reflects the difference in drug delivery methods according to the route (Fig. 7). Consequently, as confirmed by the ACR20 response probability at week 30, it was finally confirmed that the CT-P13 120 mg subcutaneous administration group without induction therapy was equivalent to or superior to the infliximab 3 mg / kg intravenous administration group with induction therapy every 8 weeks (approved).

[0326] Example 2. Stability of the composition

[0327] In order to confirm whether the composition of CT-P13 SC administered subcutaneously in Example 1 above has excellent stability even when containing a high concentration of infliximab, a formulation having the composition of Table 1 below was prepared, and its stability was measured at temperatures of 5°C and 25°C after 0 weeks, 4 weeks, 8 weeks, and 12 weeks.

[0328] Antibody surfactant sugar alcohol buffer 220 mg / ml infliximab 0.05% w / v polysorbate 803.8% w / v sorbitol 90 mM acetate

[0329]

[0330] The formulation having the composition of Table 1 was confirmed to possess excellent stability, as there was minimal change in color and turbidity even after 12 weeks, and almost no change in color or turbidity occurred even when containing high concentration antibodies (Fig. 8). In addition, when the antigen binding ability of infliximab was measured by ELISA, there was no significant change, and when the immunoglobulin G content, heavy chain, and light chain content were measured by CE-SDS, the range of change after 12 months was not significant, indicating that the formulation having the composition of Table 1 has excellent stability (see Fig. 9). Furthermore, the high stability of the formulation was confirmed by the results of measuring the number of peaks and particles not visible to the naked eye after 12 months using an MFI analyzer or a HIAC particle counter (see Figs. 10 and 11).

Claims

1. A method for treating a TNFα-related disease comprising the step of administering a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof to a subject having a TNFα-related disease, wherein the anti-TNFα antibody or an antigen-binding fragment thereof is administered subcutaneously to the subject at a dose of 40 to 300 mg at intervals of 1 to 8 weeks without an intravenous induction regimen.

2. The method according to claim 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.

3. In paragraph 2, the method wherein the TNFα-related disease is rheumatoid arthritis.

4. The method of claim 1, wherein the intravenous induction therapy involves administering an anti-TNFα antibody or an antigen-binding fragment thereof two or three times prior to subcutaneous administration.

5. In any one of claims 1 to 4, the anti-TNFα antibody or its antigen-binding fragment is, A method comprising: a light chain variable region comprising a CDR1 domain having the amino acid sequence of SEQ ID NO. 1, a CDR2 domain having the amino acid sequence represented by YAS, and a CDR3 domain having the amino acid sequence of SEQ ID NO. 2; and a heavy chain variable region comprising a CDR1 domain having the amino acid sequence of SEQ ID NO. 3, a CDR2 domain having the amino acid sequence of SEQ ID NO. 4, and a CDR3 domain having the amino acid sequence of SEQ ID NO.

5.

6. A method according to any one of claims 1 to 5, wherein the anti-TNFα antibody or its antigen-binding fragment comprises: a light chain variable region comprising the amino acid sequence of SEQ ID NO. 6; and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO.

7.

7. A method according to any one of claims 1 to 4, wherein 40 mg, 60 mg, 80 mg, 90 mg, 120 mg, 180 mg, or 240 mg of an anti-TNFα antibody or an antigen-binding fragment thereof is administered subcutaneously to the subject.

8. A method according to claim 7, wherein 120 mg of the anti-TNFα antibody or its antigen-binding fragment is administered subcutaneously to the subject.

9. A method according to any one of claims 1 to 8, wherein an anti-TNFα antibody or an antigen-binding fragment thereof is administered subcutaneously to the subject at intervals of 1, 2, 3, 4, 5, 6, 7, or 8 weeks.

10. A method according to claim 9, wherein the anti-TNFα antibody or its antigen-binding fragment is administered subcutaneously to the subject at 2-week intervals.

11. A method according to any one of claims 1 to 10, wherein the subject is a patient with active rheumatoid arthritis who has shown an insufficient response to methotrexate monotherapy for 3 months or more.

12. A method according to any one of claims 1 to 11, wherein the subject is a patient who has not received the anti-TNFα antibody or its antigen-binding fragment prior to subcutaneous administration.

13. A method according to any one of claims 1 to 12, wherein the subject has one or more of the following characteristics after subcutaneous administration: a) A decrease of at least 2.0 in the DAS28 (Disease Activity Score in 28 joints); or b) A decrease in CDAI (Crohn's disease activity index) of at least 70.

14. In any one of claims 1 to 13, after subcutaneous administration to the subject, the trough blood concentration (C trough ; A method in which the minimum concentration immediately before the next application is maintained at 0.01 μg / ml or higher.

15. A method according to any one of claims 1 to 14, wherein the pharmaceutical composition 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 comprising acetate.

16. A pharmaceutical composition for treating TNFα-related diseases comprising an anti-TNFα antibody or an antigen-binding fragment thereof, wherein The above pharmaceutical composition comprises (A) 90 to 180 mg / ml of an anti-TNFα antibody or its antigen-binding fragment; (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, A pharmaceutical composition for treating TNFα-related diseases, characterized by subcutaneously administering an anti-TNFα antibody or its antigen-binding fragment at a dose of 40 to 300 mg to a subject with a TNFα-related disease at intervals of 1 to 8 weeks without intravenous induction therapy. 17.(a) A pharmaceutical composition comprising an anti-TNFα antibody or an antigen-binding fragment thereof; and (b) A kit containing instructions for administering 40 to 300 mg doses of an anti-TNFα antibody or its antigen-binding fragment subcutaneously at intervals of 1 to 8 weeks without intravenous induction therapy for the treatment of subjects with TNFα-related disease.

18. Use of an anti-TNFα antibody or its antigen-binding fragment to produce a drug for treating TNFα-related diseases, wherein the anti-TNFα antibody or its antigen-binding fragment is administered subcutaneously to a subject at a dose of 40 to 300 mg at intervals of 1 to 8 weeks without intravenous induction therapy.

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