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) that binds to TNFα or an antigen-binding fragment thereof. A treatment method, a composition, a kit, or a use according to the present invention provides the advantage that administration time is reduced compared to intravenous injections and the amount of time that patients stay in hospitals is reduced, and thus patient satisfaction is increased through improved convenience and improved quality of life. In particular, the present invention has the advantage of providing a therapeutic agent that is highly effective in improving medication convenience, disease treatment effects, growth disorders, and the like with respect to pediatric / adolescent patients suffering from autoimmune diseases.

Description

Methods for treating TNFα-related diseases

[0001] The present application relates to a method for treating a TNFα-related disease by subcutaneously administering an antibody that binds to TNFα (anti-TNFα antibody).

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

[0003] Meanwhile, inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease, among autoimmune diseases, is known to develop in young adults, and approximately 25% of IBD patients develop it before the age of 20. The prevalence of IBD is increasing worldwide, and the prevalence of IBD in children and adolescents in the United States is known to be 100 to 200 per 100,000 children and adolescents. Furthermore, 10 to 40% of children and adolescents with IBD experience growth disorders, and the younger the age of onset of IBD, the higher the likelihood of surgery due to complications and disease recurrence. Autoimmune diseases such as inflammatory bowel disease can be treated using TNFα inhibitors, and early treatment of autoimmune diseases in children and adolescents is known to improve treatment outcomes, reduce height and weight loss, and improve skeletal and other developmental delays. However, currently in the United States, the only TNFα inhibitors approved for the treatment of pediatric and adolescent IBD are infliximab, which is administered intravenously, and adalimumab, which is administered subcutaneously.

[0004] The above infliximab is a type of chimeric monoclonal antibody that can act as a TNFα inhibitor. Remsima, Remicade, and Renflexis are commercially available, but all of these products are manufactured as lyophilized powder, which is reconstituted and diluted and administered to patients by intravenous injection according to the dosage and route of administration for each disease. However, intravenous administration requires patients to visit a hospital for administration, and it takes 2-4 hours including waiting time, which causes significant burden and inconvenience in daily life. In addition, there is a problem that the person administering it is limited to medically trained people. Therefore, subcutaneous (SC) administration is proposed as an alternative administration route. SC administration can be administered by trained patients on their own, and can shorten the administration time from 30-90 minutes to 2-5 minutes. Nonetheless, subcutaneous infliximab is not currently marketed in many countries, including the United States, as a treatment for pediatric and adolescent autoimmune diseases (e.g., IBD).

[0005] Meanwhile, antibody drugs must be stable liquid formulations containing high concentrations of antibodies to be suitable for subcutaneous administration, and even for such products, the efficacy and safety of the formulation must be proven through clinical trials.

[0006] However, it is known that the bioavailability of a substance to be administered subcutaneously decreases as the molecular weight of the substance increases. Therefore, it is very difficult to develop a product for subcutaneous administration and determine the appropriate dosage / administration cycle. In addition, when antibody proteins, which are high molecular weight substances, are administered subcutaneously, the bioavailability decreases due to various factors such as blood vessels and lymphatic vessels in the skin tissue and proteolytic enzymes. Furthermore, the thicker the stratum corneum of the skin epithelium, the more it hinders the absorption of the substance to be administered subcutaneously, and the larger the body surface area to body weight, the more it excessively promotes the absorption of the substance to be administered subcutaneously.

[0007] Therefore, the subcutaneous administration dose and / or administration cycle of antibody proteins for treating patients in children and / or adolescents, who are known to have a large body surface area relative to body weight, cannot be applied in the same manner as the subcutaneous administration dose and / or administration cycle of antibody proteins for adults, and the administration dose / administration cycle must be carefully determined by considering various factors.

[0008] The present applicant has completed a subcutaneous administration regimen that exhibits equivalent efficacy and safety to intravenous administration of an anti-TNFα antibody, such as infliximab, when administered subcutaneously, thereby enhancing administration convenience and improving the quality of life of patients, for example, pediatric and / or adolescent patients (i.e., pediatric-adolescent patients).

[0009] The problem to be solved by the present invention is to provide a treatment method for treating a TNFα-related disease by subcutaneously administering a pharmaceutical composition containing an anti-TNFα antibody or an antigen-binding fragment thereof to a subject, particularly a subject aged 20 years or younger, preferably a child or adolescent.

[0010] Another problem to be solved by the present invention is to provide a pharmaceutical composition for treating a TNFα-related disease, which comprises an anti-TNFα antibody or an antigen-binding fragment thereof and is administered subcutaneously to a subject, particularly a subject under 20 years of age, preferably a child or adolescent.

[0011] Another problem to be solved by the present invention is to provide a kit comprising a pharmaceutical composition comprising an anti-TNFα antibody or an antigen-binding fragment thereof; and instructions directing subcutaneous administration of the pharmaceutical composition to a subject, particularly a subject under 20 years of age, preferably a child or adolescent, for treating a TNFα-related disease.

[0012] Another problem to be solved by the present invention is to provide a use of an anti-TNFα antibody or an antigen-binding fragment thereof in the manufacture of a medicament for treating a TNFα-related disease by subcutaneously administering the medicament to a subject, particularly a subject under 20 years of age, preferably a child or adolescent.

[0013] 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, particularly a subject aged 20 years or younger, preferably a child or adolescent.

[0014] The present invention also provides a pharmaceutical composition for treating a TNFα-related disease, which comprises an anti-TNFα antibody or an antigen-binding fragment thereof and is administered subcutaneously to a subject, particularly a subject aged 20 years or younger, preferably a child or adolescent.

[0015] The present invention also provides a kit comprising (a) a pharmaceutical composition comprising an anti-TNFα antibody or an antigen-binding fragment thereof and a pharmaceutically acceptable carrier; and (b) instructions directing subcutaneous administration of the pharmaceutical composition to a subject, particularly a subject 20 years of age or younger, preferably a child or adolescent, for treating a TNFα-related disorder.

[0016] The present invention also provides the use of an anti-TNFα antibody or an antigen-binding fragment thereof in the manufacture of a pharmaceutical composition for treating a TNFα-related disease by subcutaneous administration to a subject.

[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, certoizumab 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 comprise a light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence represented by YAS, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 2; and a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 4, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 5.

[0021] In one embodiment of the present invention, the anti-TNFα antibody may comprise 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 comprising the amino acid sequence of SEQ ID NO: 8; and a heavy chain comprising 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 comprise 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 the sugar or derivative thereof.

[0027] In one embodiment of the present invention, the concentration of 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 comprise acetate as a buffering agent.

[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 an 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 comprise aspartic acid, lysine, arginine or mixtures thereof.

[0033] In one embodiment of the present invention, the composition may not include NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, K2SO4 or mixtures 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, prior to 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 subject may comprise a mammal.

[0039] In one embodiment of the present invention, the subject may include a human.

[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.

[0041] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may be administered subcutaneously at a dose of 40 to 300 mg.

[0042] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may be administered subcutaneously at a dose of 40 to 180 mg.

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

[0044] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may be administered subcutaneously at a dose of 40 to 120 mg.

[0045] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may be administered at 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.

[0046] In one embodiment of the present invention, the subject may be a human being aged 20 years or younger, 19 years or younger, 18 years or younger, 17 years or younger, 2 to 18 years, 2 to 17 years, or 6 to 17 years, or a child or adolescent. In one embodiment of the present invention, if the subject's condition does not improve or the therapeutic response is lost, the dose of the anti-TNFα antibody or antigen-binding fragment thereof may be increased and administered subcutaneously.

[0047] In one embodiment of the present invention, when the TNFα-related disease is rheumatoid arthritis, the subject may be administered subcutaneously an anti-TNFα antibody or an antigen-binding fragment thereof at a dose of 40 to 180 mg.

[0048] In one embodiment of the present invention, when the TNFα-related disease is at least one selected from the group consisting of ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis, the subject may be subcutaneously administered 40 to 240 mg of an anti-TNFα antibody or an antigen-binding fragment thereof. In one embodiment of the present invention, when the subject having the TNFα-related disease is 20 years old or younger, 19 years old or younger, 18 years old or younger, 17 years old or younger, 2 to 18 years old, 2 to 17 years old, or 6 to 17 years old, or a child or adolescent, the subject may be subcutaneously administered 40 to 120 mg of an anti-TNFα antibody or an antigen-binding fragment thereof. Preferably, the TNFα-related disease may be at least one disease selected from the group consisting of ulcerative colitis and Crohn's disease.

[0049] In one embodiment of the present invention, when the subject weighs less than 80 kg, the antibody or antigen-binding fragment thereof may be administered subcutaneously in an amount of 90 to 180 mg, and when the subject weighs 80 kg or more, in an amount of 190 to 270 mg.

[0050] In one embodiment of the present invention, when the subject's body weight is 40 kg or more and / or is 20 years old or younger, 19 years old or younger, 18 years old or younger, 17 years old or younger, 2 to 18 years old, 2 to 17 years old, or 6 to 17 years old or a child-adolescent, 60 to 120 mg of the anti-TNFα antibody or antigen-binding fragment thereof may be administered subcutaneously, and when the subject's body weight is 40 kg or less, 40 to 60 mg of the anti-TNFα antibody or antigen-binding fragment thereof may be administered subcutaneously. Preferably, the TNFα-related disease may be one or more diseases selected from the group consisting of ulcerative colitis and Crohn's disease.

[0051] In one embodiment of the present invention, if the subject's body weight is 40 kg or more, 120 mg of an anti-TNFα antibody or an antigen-binding fragment thereof may be administered subcutaneously 5 times, and then 60 mg of an anti-TNFα antibody or an antigen-binding fragment thereof may be administered subcutaneously from the 6th administration. Preferably, the TNFα-related disease may be one or more diseases selected from the group consisting of ulcerative colitis and Crohn's disease.

[0052] In one embodiment of the present invention, if the subject's body weight is 40 kg or less, 60 mg of an anti-TNFα antibody or an antigen-binding fragment thereof may be administered subcutaneously 5 times, and then 40 mg of an anti-TNFα antibody or an antigen-binding fragment thereof may be administered subcutaneously from the 6th administration. Preferably, the TNFα-related disease may be one or more diseases selected from the group consisting of ulcerative colitis and Crohn's disease. In one embodiment of the present invention, the antibody or an antigen-binding fragment thereof may be administered at intervals of 1 to 8 weeks.

[0053] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may be administered subcutaneously at intervals of 1, 2, 3, 4, 5, 6, 7 or 8 weeks.

[0054] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may be administered subcutaneously at intervals of 2 or 4 weeks.

[0055] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may be administered subcutaneously at two-week intervals.

[0056] In one embodiment of the present invention, the subject of anti-TNFα antibody administration may comprise one or more characteristics selected from:

[0057] a) Subjects with an inadequate response to disease-modifying anti rheumatic drugs (DMARDs), including methotrexate;

[0058] b) Subjects who have not previously been treated with methotrexate or other DMARDs;

[0059] c) Subjects with severe inflammatory symptoms and elevated serum markers associated with inflammation who do not respond adequately to conventional treatment;

[0060] d) Subjects who have not responded adequately to systemic therapy, including methotrexate, cyclosporine, or psoralen ultraviolet A therapy (PUVA), are intolerant to such therapy, or for whom such treatment is contraindicated;

[0061] e) Those who do not respond adequately to treatment with corticosteroids, 6-mercaptopurine, azathioprine or immunosuppressants, are intolerant to such treatment or are contraindicated in such treatment; or

[0062] f) Subjects who do not respond to conventional treatment including antibiotics, excretion, or immunosuppressive therapy.

[0063] In one embodiment of the present invention, the subject may be a subject who has received intravenous administration of an anti-TNFα antibody or antigen-binding fragment thereof at least once prior to subcutaneous administration.

[0064] In one embodiment of the present invention, the subject may be a subject who has received two or three intravenous administrations of an anti-TNFα antibody or antigen-binding fragment thereof prior to subcutaneous administration.

[0065] In one embodiment of the present invention, a) in the case of a subject having rheumatoid arthritis, the anti-TNFα antibody or antigen-binding fragment thereof may be administered intravenously twice before subcutaneous administration, and b) in the case of a subject having at least one disease selected from the group consisting of ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis, the anti-TNFα antibody or antigen-binding fragment thereof may be administered intravenously twice or three times before subcutaneous administration.

[0066] In one embodiment of the present invention, the subject may be a subject who received two intravenous administrations of the anti-TNFα antibody or antigen-binding fragment thereof at weeks 0 and 2, or a subject who received three intravenous administrations at weeks 0, 2, and 6, prior to subcutaneous administration.

[0067] In one embodiment of the present invention, the subject may be a subject who has received an intravenous administration of 1 to 10 mg / kg per dose of an anti-TNFα antibody or antigen-binding fragment thereof prior to subcutaneous administration.

[0068] In one embodiment of the present invention, the subject may be a subject who has received an intravenous administration of 3 to 5 mg / kg per dose of an anti-TNFα antibody or antigen-binding fragment thereof prior to subcutaneous administration.

[0069] In one embodiment of the present invention, a) a subject having rheumatoid arthritis disease may be intravenously administered 3 mg / kg per dose of an anti-TNFα antibody or an antigen-binding fragment thereof, and b) a subject having at least one disease selected from the group consisting of ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis may be intravenously administered 5 mg / kg per dose of an anti-TNFα antibody or an antigen-binding fragment thereof.

[0070] In one embodiment of the present invention, the first subcutaneous administration may be performed 2 to 8 weeks after the last intravenous administration.

[0071] In one embodiment of the present invention, the first subcutaneous administration may be performed four weeks after the last intravenous administration.

[0072] In one embodiment of the present invention, a composition containing an anti-TNFα antibody or an antigen-binding fragment thereof can be administered together with, before, or after administration of one or more selected from the group consisting of infliximab, adalimumab, certoizumab pegol, golimumab, and biosimilars thereof.

[0073] In one embodiment of the present invention, the anti-TNFα antibody or antigen-binding fragment thereof may be administered together with, before, or after administration of any one or more selected from the group consisting of disease-modifying antirheumatic drugs (DMARDs), steroids, and immunosuppressants. Specifically, the disease-modifying antirheumatic drugs (DMARDs) may be selected from the group consisting of Methotrexate, 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, mycophenoric acid, bradynin, mTOR inhibitors, and antilymphocyte antibodies.

[0074] 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 antigen-binding fragment thereof trough ; It may be a method of administration in which the minimum concentration immediately before the next application) is maintained at 0.01 μg / ml or more.

[0075] In one embodiment of the present invention, a) in a subject having rheumatoid arthritis disease, the lowest blood concentration (C) of the anti-TNFα antibody or antigen-binding fragment thereof after subcutaneous administration trough ) is maintained at 1 μg / ml or more, and b) in 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 (C) of the anti-TNFα antibody or antigen-binding fragment thereof after subcutaneous administration trough ) may be an administration method that maintains the concentration at 5 μg / ml or higher.

[0076] In one embodiment of the present invention, after subcutaneous administration, the subject may have one or more characteristics selected from:

[0077] a) DAS28 (Disease activity score in 28 joints) decrease of at least 2.0; or

[0078] b) CDAI (Crohn's disease activity index) decreases by at least 70.

[0079] In one embodiment of the present invention, the kit may comprise (a) a pharmaceutical composition comprising an anti-TNFα antibody or an antigen-binding fragment thereof; and (b) instructions directing subcutaneous administration of the anti-TNFα antibody or an antigen-binding fragment thereof at a dose of 40 to 300 mg at intervals of 1 to 8 weeks for the treatment of a subject having a TNFα-related disease.

[0080] In one embodiment of the present invention, the use of an anti-TNFα antibody or an antigen-binding fragment thereof for preparing a medicament for treating a TNFα-related disease when administered to a subject may be a use in which a dose of 40 to 300 mg of the anti-TNFα antibody or an antigen-binding fragment thereof is administered subcutaneously at intervals of 1 to 8 weeks.

[0081] According to the treatment method, composition, kit, or use of the present invention, a TNFα-related disease can be treated by subcutaneously administering an anti-TNFα antibody or an antigen-binding fragment thereof. In addition, the treatment method, composition, kit, or use of the present invention provides the advantage of increasing patient satisfaction through improved convenience and quality of life by reducing the administration time compared to intravenous injection and reducing the time patients stay in the hospital. Furthermore, the present invention has the advantage of providing a therapeutic agent with excellent effects in improving the convenience of taking medication, disease treatment effect, and growth disorders, etc., for patients who develop an autoimmune disease in childhood or adolescence.

[0082] In addition, 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 and resistance due to drug change to patients and healthcare workers who were previously administered infliximab by intravenous injection.

[0083] Figure 1 is a simulation graph showing the median (predicted interval 5-95 percentile) of blood infliximab concentrations versus time by weight class when infliximab was administered intravenously at 5 mg / kg at weeks 0, 2, and 6, and then subcutaneously every two weeks starting from week 10 in patients with Crohn's disease and ulcerative colitis.

[0084] Figure 2 shows the appearance (Figure 2a) and turbidity (Figure 2b) of a formulation containing high concentrations of infliximab after storage at 5°C and 25°C for 0, 4, 8, or 12 weeks.

[0085] Figure 3 shows the results of measuring the antigen binding ability of antibodies by ELISA after storing a formulation containing high concentrations of infliximab at 5°C and 25°C for 0, 4, 8, or 12 weeks (Figure 3a) and measuring the immunoglobulin content, heavy chain, and light chain contents by CE-SDS (Figures 3b and 3c).

[0086] Figure 4 shows the results of measuring the peak value by IEC-HPLC (Figure 4a) and confirming the number of particles by MFI (Figure 4b) after storing a formulation containing high concentration of infliximab at 5°C and 25°C for 0, 4, 8, or 12 weeks.

[0087] Figure 5 shows the results of counting 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.

[0088] 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, particularly a subject aged 20 years or younger, preferably a child or adolescent.

[0089] To facilitate a better understanding of the present invention, terms used in the present invention are defined below.

[0090] "TNFα" is intended to refer to a human cytokine that exists as a 17 kD secreted form and a 26 kD membrane associated form, the biologically active form of which is composed of a trimer noncovalently bound to a 17 kD molecule. The structure of TNFα is also described, for example, in the literature [see, e.g., 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].

[0091] "Antibody" refers to an immunoglobulin molecule composed of four polypeptide chains, each of which consists of two heavy chains and two light chains linked by disulfide bonds. Naturally occurring antibodies with other altered structures, such as camelid antibodies, are also included in this definition. Each heavy chain consists of a heavy chain variable region and a heavy chain constant region. The heavy chain constant region is composed 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 is composed of a single domain (CL). The heavy and light chain variable regions can be further subdivided into hypervariable regions, called complementarity determining regions (CDRs), which are arranged alongside more conserved regions, called framework regions (FRs). Each heavy chain variable region and light chain variable region consists of three CDRs and four FRs, which are arranged in the following order from amino terminus to carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0092] "Antigen-binding fragment" refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen that is bound by a complete antibody. Exemplary antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv.

[0093] “Biosimilar” means a biological product that is highly similar to a biological product (reference drug) approved by a pharmaceutical regulatory agency and has no clinically significant differences from the reference drug in terms of pharmacokinetics, safety, and efficacy.

[0094] “Biological preparations” or “biological products” refer to pharmaceuticals manufactured using raw materials or ingredients derived from humans or other organisms, which require special precautions in terms of public health and hygiene, and include biological preparations, recombinant genetically modified drugs, cell culture drugs, cell therapy products, gene therapy products, and other preparations recognized by the Commissioner of the Ministry of Food and Drug Safety.

[0095] “Administration” refers to the administration of a substance (e.g., an anti-TNFα antibody) to achieve a therapeutic purpose (e.g., a TNFα-related disease).

[0096] "TNFα-associated disease" refers to a local and / or systemic physiological condition in which TNFα is the primary mediator inducing the symptoms of the condition. The terms "TNFα-associated disease," "disease treatable with anti-TNFα," and "disease in which TNFα activity is detrimental" are used interchangeably herein.

[0097] "Subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, cats, rabbits, and ferrets, rodents such as mice, rats, and guinea pigs, avian species such as chickens, amphibians, and reptiles. In a preferred embodiment, the subject is a mammal such as a non-human primate, sheep, dogs, cats, rabbits, ferrets, or rodents. In a more preferred embodiment, the subject is a human (human). The terms "subject," "patient," and "individual" are used interchangeably herein.

[0098] "IC50" is intended to refer to the concentration of inhibitor required to inhibit a desired biological outcome, for example, to neutralize cytotoxic activity.

[0099] “C trough“(trough concentration)” or “trough blood concentration” refers to the lowest blood concentration of the drug immediately before the next dose, and may refer to the lowest blood drug concentration predicted using a population pharmacokinetic model.

[0100] “DAS28 (Disease activity score in 28 joints)” is a disease activity assessment method for rheumatoid arthritis (RA) using 28 joints.

[0101] “CDAI (Crohn's disease activity index)” is a research tool used to quantify symptoms in subjects with Crohn's disease.

[0102] “PCDAI (Pediatric Crohn's Disease Activity Index)” is a research tool used to quantify symptoms in children and adolescents with Crohn's disease.

[0103] The “Mayo score” is a research tool used to quantify symptoms in subjects with ulcerative colitis.

[0104] Disease-modifying antirheumatic drugs (DMARDs) are medications or combinations of medications that are effective in relieving arthritis symptoms and slowing the progression of the disease. DMARDs block the release of chemicals that cause the immune system to attack joints and damage bone, tendons, ligaments, and cartilage. Specific DMARD classes include methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide.

[0105] A "kit" refers to a packaged product comprising components for administering a TNFα antibody of the present invention for the treatment of a TNFα-related disorder. The kit preferably includes a container or box for holding the components of the kit. The box or container is accompanied by a Food and Drug Administration-approved protocol or label. The components of the present invention are contained within a plastic, polyethylene, polypropylene, ethylene, or propylene box or container. The container may be a capped tube or bottle. The kit also includes instructions for administering the TNFα antibody of the present invention.

[0106] Various aspects of the present invention are further described in detail herein.

[0107] - Anti-TNFα antibody of the present invention or antigen-binding fragment thereof

[0108] In one embodiment of the present invention, the antibody may include a polyclonal antibody, a monoclonal antibody, a recombinant antibody, a single-chain antibody, a hybrid antibody, a chimeric antibody, a humanized antibody, or a fragment thereof. A chimeric antibody refers to an antibody comprising heavy and light chain variable region sequences from one species and constant region sequences from another species. In one embodiment of the present invention, the antibody may include a chimeric human-mouse IgG monoclonal antibody. A chimeric human-mouse IgG monoclonal antibody is composed of mouse heavy and light chain variable regions and human heavy and light chain constant regions linked thereto. A chimeric human-mouse IgG monoclonal antibody can be produced by a method known in the art. For example, infliximab can be produced by the method described in U.S. Patent No. 6,284,471.

[0109] In one embodiment of the present invention, the antibody may include TNFα or an antibody that binds to an epitope of TNFα. The antibody may include one or more selected from the group consisting of infliximab, adalimumab, certoizumab pegol, golimumab, and biosimilars thereof. In one embodiment of the present invention, the antibody may include infliximab. In the present specification, infliximab may be referred to as CT-P13.

[0110] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may comprise a light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence represented by YAS, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 2; and a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 4, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 5.

[0111] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may comprise 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.

[0112] 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.

[0113] - Composition containing the anti-TNFα antibody of the present invention or an antigen-binding fragment thereof

[0114] As used herein, the term “composition containing the anti-TNFα antibody or antigen-binding fragment thereof of the present invention” is used interchangeably with “stable liquid pharmaceutical preparation”.

[0115] A 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.

[0116] The term “not including” in the specification of the present application means not including the component at all. In addition, the term encompasses not substantially including the component, i.e. including the component in an amount that does not affect the activity of the antibody, the stability and viscosity of the liquid pharmaceutical preparation, for example, including the component 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 preparation.

[0117] (A) an antibody or antigen-binding fragment thereof;

[0118] In one embodiment, the composition according to the present invention may comprise the anti-TNFα antibody of the present invention or an antigen-binding fragment thereof as described above.

[0119] The concentration of the antibody or antigen-binding fragment thereof 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 antigen-binding fragment thereof may be 10 to 220 mg / ml. In another embodiment of the present invention, the concentration of the antibody or antigen-binding fragment thereof may be 50 to 220 mg / ml. In yet another embodiment of the present invention, the concentration of the antibody or antigen-binding fragment thereof may be 80 to 220 mg / ml. In yet another embodiment of the present invention, the concentration of the antibody or antigen-binding fragment thereof may be 90 to 220 mg / ml. In yet another embodiment of the present invention, the concentration of the antibody or antigen-binding fragment thereof may be 90 to 180 mg / ml. In yet another embodiment of the present invention, the concentration of the antibody or antigen-binding fragment thereof may be 90 to 145 mg / ml. In another embodiment of the present invention, the concentration of the antibody or antigen-binding fragment thereof may be 110 to 130 mg / ml. When the concentration of the antibody or antigen-binding fragment thereof is within this range, the degree of freedom in administration dosage and administration cycle can be increased depending on the high content of the antibody or antigen-binding fragment thereof, while exhibiting excellent long-term stability and low viscosity.

[0120] (B) Surfactant

[0121] Examples of surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters (e.g., polysorbates), polyoxyethylene alkyl ethers (e.g., Brij), alkylphenyl polyoxyethylene ethers (e.g., Triton-X), polyoxyethylene-polyoxypropylene copolymers (e.g., Poloxamer, Pluronic), sodium dodecyl sulfate (SDS), and the like.

[0122] In one embodiment of the present invention, the surfactant may include polyoxyethylene sorbitan fatty acid ester (polysorbate). The polysorbate may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture of two or more thereof. In one embodiment of the present invention, the polysorbate may include polysorbate 20, polysorbate 80, or a mixture thereof. In another embodiment of the present invention, the polysorbate may include polysorbate 80.

[0123] 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 preparation 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 this range, excellent long-term stability and low viscosity can be exhibited.

[0124] (C) sugar or sugar derivative

[0125] The sugar may include a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, or a mixture of two or more thereof. Examples of monosaccharides include, but are not limited to, glucose, fructose, and galactose. Examples of disaccharides include, but are not limited to, sucrose, lactose, maltose, and trehalose. Examples of oligosaccharides include, but are not limited to, fructooligosaccharides, galactooligosaccharides, and mannan-oligosaccharides. Examples of polysaccharides include, but are not limited to, starch, glycogen, cellulose, chitin, and pectin.

[0126] The sugar derivatives 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, volemitol, isomalt, maltitol, lactitol, maltotriitol, maltotetraitol, and polyglycitol. Examples of sugar acids include, but are not limited to, aldonic acid (e.g., glyceric acid), ulosonic acid (e.g., neuraminic acid), uronic acid (e.g., glucuronic acid), and aldaric acid (e.g., tartaric acid).

[0127] 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 thereof.

[0128] 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 adversely affect the stability and viscosity of the liquid pharmaceutical preparation according to the present invention. For example, the concentration of the sugar or its derivative can 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 this range, excellent long-term stability and low viscosity can be exhibited.

[0129] (D) Buffer

[0130] A buffer is a neutralizing substance that minimizes changes in pH caused by acids or alkalis. Examples of buffers include phosphate, acetate, succinate, gluconate, glutamate, citrate, and histidine. In one embodiment of the present invention, the buffer may include acetate or histidine. If both acetate and histidine are included as buffers, stability may be reduced.

[0131] In one embodiment of the present invention, the buffer may include acetate. Examples of acetate include, but are not limited to, sodium acetate, zinc acetate, aluminum acetate, ammonium acetate, and potassium acetate. An acid, such as acetic acid, may be additionally included to adjust pH. Including acetate as the buffer may be most preferred in terms of pH adjustment and stability.

[0132] In one embodiment of the present invention, the buffer may include histidine. When histidine is used as the buffer, a histidine salt, such as histidine chloride, histidine acetate, histidine phosphate, or histidine sulfate, may be included. For pH adjustment, an acid, such as hydrochloric acid, acetic acid, phosphoric acid, or sulfuric acid, may be included.

[0133] In one embodiment of the present invention, the stable liquid pharmaceutical preparation may not contain citrate, phosphate, or a mixture thereof.

[0134] 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 preparation 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 this range, excellent long-term stability and low viscosity can be exhibited.

[0135] (E) pH

[0136] 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 this range, excellent long-term stability and low viscosity can be exhibited. The pH can be adjusted using a buffer. In other words, when a buffer is included in a predetermined amount, the pH within the above range can be maintained without a separate pH adjusting agent. When citrate, phosphate, or a mixture thereof is used as a buffer, it may be difficult to maintain the pH within the above range. When an acid (e.g., hydrochloric acid) or a base (e.g., sodium hydroxide) is additionally included as a separate pH adjusting agent, the stability of the antibody may be reduced.

[0137] (F) Other ingredients

[0138] In one embodiment of the present invention, the stable liquid pharmaceutical preparation may not contain aspartic acid, lysine, arginine, or a mixture thereof. If it contains these amino acids, the preparation may be in a solid state. In one embodiment of the present invention, the stable liquid pharmaceutical preparation may contain one or more of the remaining amino acids excluding the three amino acids. In this case, the amino acid may be contained in an amount of 5% (w / v), for example, in a range of 0.001 to 5% (w / v), in a range of 0.001 to 1% (w / v), in a range of 0.01 to 5% (w / v), in a range of 0.01 to 1% (w / v), in a range of 0.1 to 5% (w / v), or in a range of 0.1 to 1% (w / v).

[0139] In another embodiment of the present invention, the stable liquid pharmaceutical preparation may contain taurine. In this case, the taurine may be contained in an amount of less than 5% (w / v), for example, in an amount of 0.001 to 5% (w / v), in an amount of 0.001 to 1% (w / v), in an amount of 0.01 to 5% (w / v), in an amount of 0.01 to 1% (w / v), in an amount of 0.1 to 5% (w / v), or in an amount of 0.1 to 1% (w / v).

[0140] In one embodiment of the present invention, the stable liquid pharmaceutical preparation may not contain metal salts such as NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, K2SO4, etc. If these metal salts are contained, precipitation may occur, the preparation may have a gelatinous shape, and stability may be poor.

[0141] In one embodiment of the present invention, the stable liquid pharmaceutical formulation may not include a chelating agent (e.g., EDTA). If a chelating agent is included, the oxidation rate may increase.

[0142] In one embodiment of the present invention, the stable liquid pharmaceutical preparation may not include a preservative. Examples of preservatives include octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl alcohol, benzyl alcohol, alkyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, m-cresol, and the like. Including a preservative may not help improve stability.

[0143] In one embodiment of the present invention, the stable liquid pharmaceutical preparation of the present invention may further comprise additives known in the art, as long as they do not substantially adversely affect the activity of the antibody, the stability of the preparation, and the low viscosity of the preparation. For example, the preparation may further comprise an aqueous carrier, an antioxidant, or a mixture of two or more thereof. An aqueous carrier is a carrier that is pharmaceutically acceptable (i.e., safe and non-toxic when administered to humans) and useful in the manufacture of a liquid pharmaceutical preparation. Examples of aqueous carriers include, but are not limited to, sterile water for injection (SWFI), bacteriostatic water for injection (BWFI), sterile saline solution, Ringer's solution, dextrose, and the like. Antioxidants include, but are not limited to, ascorbic acid, and the like.

[0144] (G) “Stable” liquid pharmaceutical preparations

[0145] The term "stable" in the "stable" liquid pharmaceutical formulation of the present invention means that the antibody according to the present invention substantially retains its physical stability, chemical stability, and / or biological activity during the manufacturing process and / or during storage. Various analytical techniques for measuring antibody stability are readily available in the art.

[0146] Physical stability can be assessed by methods known in the art, including measuring the apparent attenuation of light (absorbance or optical density) in a sample. This attenuation measurement is related to the turbidity of the formulation. Additionally, physical stability can be assessed by measuring the content of high-molecular-weight components, the content of low-molecular-weight components, the amount of intact protein, and the number of insoluble foreign particles.

[0147] Chemical stability can be assessed, for example, by detecting and quantifying chemically altered forms of the antibody. Chemical stability includes charge changes (e.g., resulting from deamidation or oxidation), which can be assessed, for example, by ion exchange chromatography. Charge variants (acidic or basic peaks) can be measured for chemical stability.

[0148] Biological activity can be assessed by methods known in the art, for example, antigen binding affinity can be measured by ELISA.

[0149] In one embodiment of the present invention, the liquid pharmaceutical preparation can be stable for a long period of time.

[0150] In one embodiment of the present invention, the term “stable” liquid pharmaceutical preparation means a liquid pharmaceutical preparation that satisfies one or more of the following:

[0151] Turbidity

[0152] - Absorbance A measured with a spectrophotometer after storage for 4 weeks at a temperature of 40℃±2℃ 600 Liquid pharmaceutical preparations having a viscosity of 0 to 0.0300 or 0 to 0.0700;

[0153] - Absorbance A measured with a spectrophotometer after storage for 4 weeks at a temperature of 40°C±2°C, a relative humidity of 75±5%, and in an airtight condition. 600 Liquid pharmaceutical preparations having a viscosity of 0 to 0.0300 or 0 to 0.0700;

[0154] Main ingredient content (main peak)

[0155] - A liquid pharmaceutical preparation containing 98% to 100% of the active ingredient as measured by SE-HPLC after storage at a temperature of 40°C±2°C for 4 weeks;

[0156] - A liquid pharmaceutical preparation containing 98 to 100% of the active ingredient as measured by SE-HPLC after storage for 4 weeks under sealed conditions at a temperature of 40°C±2°C and a relative humidity of 75±5%;

[0157] High molecular weight component (peak with a retention time earlier than the main peak (intact IgG))

[0158] - A liquid pharmaceutical preparation containing 0 to 1.00% of high molecular weight components as measured by SE-HPLC after storage for 12 months at a temperature of 5℃±3℃;

[0159] - A liquid pharmaceutical preparation having 0 to 1.00% of high molecular weight components as measured by SE-HPLC after storage for 12 months at a temperature of 5°C±3°C and in a sealed condition;

[0160] Low molecular weight component (peak with a retention time later than the main peak (intact IgG))

[0161] - Liquid pharmaceutical preparations containing 0 to 0.40% of low molecular weight components as measured by SE-HPLC after storage for 12 months at a temperature of 5℃±3℃;

[0162] - Liquid pharmaceutical preparations containing 0 to 0.40% of low molecular weight components as measured by SE-HPLC after storage for 12 months at a temperature of 5°C±3°C and in sealed conditions;

[0163] Content of intact immunoglobulin G

[0164] - 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°C±3°C;

[0165] - 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°C±3°C and in a sealed condition;

[0166] - 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 a temperature of 40°C±2°C for 4 weeks;

[0167] - 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 at a temperature of 40°C±2°C, a relative humidity of 75±5%, and in a sealed condition;

[0168] Content of intact heavy and light chains

[0169] - A liquid pharmaceutical preparation having an intact heavy and light chain content (Intact HC+LC%) of 99.0% to 100% as measured by reducing CE-SDS after storage for 12 months at a temperature of 5℃±3℃;

[0170] - A liquid pharmaceutical preparation having an intact heavy and light chain content (Intact HC+LC%) of 99.0% to 100% as measured by reducing CE-SDS after storage for 12 months at a temperature of 5°C±3°C and in a sealed condition;

[0171] - A liquid pharmaceutical preparation having an intact heavy and light chain content (Intact HC+LC%) of 98.0% to 100% as measured by reducing CE-SDS after storage at a temperature of 40°C±2°C for 4 weeks;

[0172] - A liquid pharmaceutical preparation having an intact heavy and light chain content (Intact HC+LC%) of 98.0% to 100% as measured by reducing CE-SDS after storage for 4 weeks at a temperature of 40°C±2°C, a relative humidity of 75±5%, and in an airtight condition;

[0173] Number of insoluble foreign particles

[0174] - A liquid pharmaceutical preparation having 0 to 1,000 insoluble foreign particles (10.00㎛≤, <400.00㎛) measured by HIAC after storage for 12 months at a temperature of 5℃±3℃;

[0175] - A liquid pharmaceutical preparation having 0 to 1,000 insoluble foreign particles (10.00㎛≤, <400.00㎛) measured by HIAC after storage for 12 months at a temperature of 5℃±3℃ and in a sealed condition;

[0176] - A liquid pharmaceutical preparation having a number of insoluble foreign particles (1.00㎛≤, <100.00㎛) of 0 to 30,000 as measured by MFI after storage for 4 weeks at a temperature of 40℃±2℃;

[0177] - A liquid pharmaceutical preparation having a number of insoluble foreign particles (1.00㎛≤, <100.00㎛) of 0 to 30,000 as measured by MFI after storage for 4 weeks under a temperature of 40℃±2℃, a relative humidity of 75±5%, and a sealed condition;

[0178] - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (10.00㎛≤, <100.00㎛) measured by MFI is 0 to 200 after storage for 4 weeks at a temperature of 40℃±2℃;

[0179] - A liquid pharmaceutical preparation having 0 to 200 insoluble foreign particles (10.00㎛≤, <100.00㎛) measured by MFI after storage for 4 weeks under sealed conditions at a temperature of 40℃±2℃, a relative humidity of 75±5%;

[0180] - A liquid pharmaceutical preparation in which the number of insoluble foreign particles (10.00㎛≤, <100.00㎛) measured by MFI after storage for 6 weeks at a temperature of 40℃±2℃ is 0 to 500;

[0181] - A liquid pharmaceutical preparation having 0 to 500 insoluble foreign particles (10.00㎛≤, <100.00㎛) measured by MFI after storage for 6 weeks under a temperature of 40℃±2℃, a relative humidity of 75±5%, and a sealed condition;

[0182] Oxidation rate

[0183] - A liquid pharmaceutical preparation having an oxidation rate of heavy chain Met 255 of 0% to 2.5% as measured by LC-MS after storage at a temperature of 40°C±2°C for 4 weeks;

[0184] - A liquid pharmaceutical preparation having an oxidation rate of heavy chain Met 255 of 0% to 2.5% as measured by LC-MS after storage for 4 weeks at a temperature of 40°C±2°C, a relative humidity of 75±5%, and in a sealed condition;

[0185] charge transformant

[0186] - A liquid pharmaceutical preparation having an acid peak of 20% to 35% as measured by IEC-HPLC after storage at a temperature of 40°C±2°C for 4 weeks;

[0187] - A liquid pharmaceutical preparation having an acid peak of 20% to 35% as measured by IEC-HPLC after storage for 4 weeks at a temperature of 40°C±2°C, a relative humidity of 75±5%, and in a sealed condition;

[0188] - A liquid pharmaceutical preparation having a basicity peak of 33% to 40% as measured by IEC-HPLC after storage at a temperature of 40℃±2℃ for 4 weeks;

[0189] - A liquid pharmaceutical preparation having a basicity peak of 33% to 40% as measured by IEC-HPLC after storage for 4 weeks at a temperature of 40°C±2°C, a relative humidity of 75±5%, and in a sealed condition;

[0190] TNFα binding affinity

[0191] - A liquid pharmaceutical preparation having a TNFα binding affinity of 80% to 120% as measured by ELISA after storage at a temperature of 5°C±3°C for 12 months; and

[0192] - 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°C±3°C and in a sealed condition.

[0193] In one embodiment of the present invention, the viscosity measured after one month at a temperature of 40°C±2°C may be from 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 from 0.5 cP to 5.0 cP.

[0194] (H) Method for manufacturing a stable liquid pharmaceutical preparation

[0195] The stable liquid pharmaceutical preparation of the present invention can be prepared using known methods, and is not limited to a specific method. For example, a liquid pharmaceutical preparation can be prepared by adjusting the pH by adding a buffer to a solution containing a surfactant and a sugar or its derivative, and then adding an antibody to the mixed solution. Furthermore, a liquid pharmaceutical preparation can be prepared by preparing a solution containing some excipients in the final stage of the purification process and then adding the remaining ingredients. For example, a liquid pharmaceutical preparation can be prepared by preparing a solution containing an antibody, a buffer, and a sugar or its derivative in the final stage of the purification process and then adding a surfactant to the solution.

[0196] Additionally, the formulation may not include a freeze-drying process during manufacture or may include a freeze-drying process.

[0197] If a freeze-drying process is not included, for example, the liquid pharmaceutical preparation of the present invention can be prepared and placed in a sealed container immediately after sterilization or other treatment.

[0198] In the case where a freeze-drying process is included, for example, after preparing and freeze-drying the liquid pharmaceutical preparation of the present invention, or after preparing and freeze-drying and storing / storing the liquid pharmaceutical preparation of the present invention, the components removed or modified by freeze-drying and / or storage / storage can be supplemented or replaced to prepare the liquid pharmaceutical preparation according to the present invention. In addition, the liquid pharmaceutical preparation according to the present invention can be prepared by freeze-drying only the components from which components that can be removed or modified by freeze-drying and / or storage / storage are excluded, or after freeze-drying and storing / storing only those components, and then adding the excluded components.

[0199] 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.

[0200] - Method for treating TNFα-related diseases of the present invention

[0201] 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, particularly a subject aged 20 years or younger, preferably a child or adolescent.

[0202] In one embodiment of the present invention, the antibody may comprise at least one selected from the group consisting of infliximab, adalimumab, certoizumab pegol, golimumab, and biosimilars thereof.

[0203] In one embodiment of the present invention, the antibody may comprise infliximab.

[0204] In one embodiment of the present invention, the antibody may comprise a chimeric human-mouse IgG monoclonal antibody.

[0205] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may comprise a light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence represented by YAS, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 2; and a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 4, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 5.

[0206] In one embodiment of the present invention, the antibody or antigen-binding fragment thereof may comprise 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.

[0207] 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.

[0208] In one embodiment of the present invention, the concentration of the antibody or antigen-binding fragment thereof may be 10 to 220 mg / ml.

[0209] The present invention also provides a method for treating a TNFα-related disease, comprising 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.

[0210] In one embodiment of the present invention, the subject to whom the antibody or antigen-binding fragment thereof is administered may be a subject / patient having a TNFα-related disease who is 20 years of age or younger, 19 years of age or younger, 18 years of age or younger, 17 years of age or younger, 2 to 18 years of age, 2 to 17 years of age, or 6 to 17 years of age. In addition, the subject / patient may be referred to herein as a pediatric-adolescent patient.

[0211] The above (A) anti-TNFα antibody or antigen-binding fragment thereof, (B) surfactant, (C) sugar or derivative thereof, and (D) buffer are as described above.

[0212] In one embodiment of the present invention, (B) the surfactant may include polysorbate, poloxamer or a mixture thereof.

[0213] In one embodiment of the present invention, the (B) surfactant may include polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, or a mixture of two or more thereof.

[0214] In one embodiment of the present invention, (B) the surfactant may include polysorbate 80.

[0215] In one embodiment of the present invention, the concentration of the (B) surfactant may be 0.02 to 0.1% (w / v).

[0216] In one embodiment of the present invention, (C) the sugar may include a monosaccharide, a disaccharide, an oligosaccharide, a polysaccharide, or a mixture of two or more thereof, and the sugar derivative may include a sugar alcohol, a sugar acid, or a mixture thereof.

[0217] In one embodiment of the present invention, (C) the sugar or derivative thereof may include sorbitol, mannitol, trehalose, sucrose or a mixture of two or more thereof.

[0218] In one embodiment of the present invention, the concentration of (C) sugar or its derivative may be 1 to 10% (w / v).

[0219] In one embodiment of the present invention, the (D) buffer may include acetate or histidine.

[0220] In one embodiment of the present invention, the content of the (D) buffer may be 1 to 90 mM.

[0221] In one embodiment of the present invention, the pH of the composition may be 4.0 to 5.5.

[0222] In one embodiment of the present invention, the composition may not contain aspartic acid, lysine, arginine or mixtures thereof.

[0223] In one embodiment of the present invention, the composition may not contain NaCl, KCl, NaF, KBr, NaBr, Na2SO4, NaSCN, K2SO4 or mixtures thereof.

[0224] In one embodiment of the present invention, the composition may not include a chelating agent.

[0225] In one embodiment of the present invention, the composition may not contain a preservative.

[0226] In one embodiment of the present invention, the composition may further comprise an aqueous carrier, an antioxidant, or a mixture of two or more thereof.

[0227] In one embodiment of the present invention, the composition may have a viscosity of 0.5 cp to 10.0 cp measured after 1 month at a temperature of 40°C±2°C, or a viscosity of 0.5 cp to 5.0 cp measured after 6 months at 5°C±3°C.

[0228] In one embodiment of the present invention, the composition may comprise (A) an anti-TNFα antibody or an antigen-binding fragment thereof, particularly, an antibody or an antigen-binding fragment thereof, comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence represented by YAS, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 2; and a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 4, and a CDR3 domain comprising 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.

[0229] 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 anti-TNFα antibody or antigen-binding fragment thereof, particularly an antibody or antigen-binding fragment thereof, comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence represented by YAS, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 2; and a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 4, and a CDR3 domain comprising 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 derivative thereof; and (D) 1 to 90 mM or 1 to 50 mM of a buffer comprising acetate or histidine.

[0230] 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 anti-TNFα antibody or antigen-binding fragment thereof, particularly an antibody or antigen-binding fragment thereof, comprising a light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence represented by YAS, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 2; and a heavy chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 3, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 4, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 5; (B) 0.02 to 0.1 % (w / v) polysorbate; (C) 1 to 10 % (w / v) sorbitol; and (D) 1 to 90 mM or 1 to 50 mM of a buffer comprising acetate.

[0231] In one embodiment of the present invention, the composition can be administered subcutaneously.

[0232] In one embodiment of the present invention, the composition may not undergo a reconstitution step, a dilution step, or both, prior to use.

[0233] In one embodiment of the present invention, the composition may be filled in a sterile container or filled in a pre-filled syringe.

[0234] 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 pre-filled syringe may be divided into a single dose and used. In one embodiment of the present invention, the stable composition may be filled into a pre-filled syringe prior to use.

[0235] In one embodiment of the present invention, the composition may be included in an auto-injector or a subcutaneous injection syringe prior to use.

[0236] TNFα-related diseases

[0237] 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, hemolytic disease of the newborn, inflammatory bowel disease, multiple sclerosis, prevention of organ transplant rejection, non-Hodgkin's lymphoma, metastatic cancer, retinopathy of prematurity, ovarian cancer, gastric cancer, head and neck cancer, osteoporosis, paroxysmal nocturnal hemoglobinuria, invasive 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.

[0238] In one embodiment of the present invention, the TNFα-related disease may be a disease treatable by intravenous administration of infliximab.

[0239] 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, which can be treated with intravenous administration of infliximab.

[0240] In one embodiment of the present invention, the TNFα-related disease may be a disease that develops in a person aged 20 years or younger, 19 years or younger, 18 years or younger, 17 years or younger, 2 to 18 years, 2 to 17 years, or 6 to 17 years.

[0241] In one embodiment of the present invention, the subject of anti-TNFα antibody administration is a subject who has an inadequate response to disease-modifying anti rheumatic drugs (DMARDs), including methotrexate.

[0242] In one embodiment of the present invention, the subject receiving anti-TNFα antibody administration is a subject who has not previously been treated with methotrexate or other DMARDs.

[0243] In one embodiment of the present invention, the subject of anti-TNFα antibody administration is a subject who does not respond adequately to conventional treatment and exhibits severe inflammatory symptoms and elevated serum indices related to inflammation.

[0244] In one embodiment of the present invention, the subject receiving the anti-TNFα antibody is a subject who does not respond adequately to systemic therapy including methotrexate, cyclosporine, or psoralen ultraviolet A therapy (PUVA), is intolerant to such therapy, or is contraindicated in such treatment methods.

[0245] In one embodiment of the present invention, the subject receiving anti-TNFα antibody administration is a subject who does not show an adequate response to treatment with a corticosteroid, 6-mercaptopurine, azathioprine, or immunosuppressant, or is intolerant to such treatment, or for whom such treatment is contraindicated.

[0246] In one embodiment of the present invention, the subject of anti-TNFα antibody administration is a subject who does not respond to conventional treatments including antibiotics, excretion methods, or immunosuppressive treatments.

[0247] In one embodiment of the present invention, the subject of administration of the anti-TNFα antibody may be a subject having (i) moderately to severely active CD with a PCDAI score of greater than 30, ileo-colonic Crohn's disease with a Simplified Endoscopic Activity Score for Crohn's Disease score of 6 or higher, ileo-colonic Crohn's disease with an endoscopic activity score of 4 or higher and an ulcer score in at least one compartment, and / or Crohn's disease diagnosed through radiography, biopsy, or endoscopic examination; and / or (ii) moderately to severely active ulcerative colitis with a modified Mayo score of 5 to 9 and / or ulcerative colitis diagnosed through radiography, biopsy, or endoscopic examination.

[0248] In one embodiment of the present invention, the subject of anti-TNFα antibody administration may be a subject who has received appropriate treatment with primary nutritional therapy and / or corticosteroids and / or immunosuppressants for active Crohn's disease but has not responded, is intolerant, or has a medical contraindication thereto.

[0249] In one embodiment of the present invention, after subcutaneous administration, the subject may have one or more characteristics selected from:

[0250] a) a decrease in DAS28 (Disease Activity Score in 28 joints) of at least 2.0; or

[0251] b) CDAI (Crohn's disease activity index) decreases by at least 70.

[0252] Dosage and administration cycle

[0253] In one embodiment of the present invention, the anti-TNFα antibody or 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.

[0254] In another embodiment of the present invention, the anti-TNFα antibody or binding fragment thereof may be administered subcutaneously in a dose of 40 to 180 mg or 90 to 180 mg. In another embodiment, the anti-TNFα antibody or binding fragment thereof may be administered subcutaneously in a dose of 40 to 300 mg or 90 to 300 mg. In another embodiment, the anti-TNFα antibody or binding fragment thereof may be administered subcutaneously in a dose of 120 to 240 mg.

[0255] In one embodiment of the present invention, the anti-TNFα antibody or binding fragment thereof can be administered subcutaneously at 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.

[0256] In one embodiment of the present invention, the anti-TNFα antibody or binding fragment thereof may be administered subcutaneously to a subject suffering from rheumatoid arthritis at a dose 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.

[0257] In one embodiment of the present invention, the anti-TNFα antibody or binding fragment thereof may be administered subcutaneously at 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 to 250 mg, 120 mg, 150 mg, 180 mg or 240 mg to a subject with ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis or ankylosing spondylitis.

[0258] In one embodiment of the present invention, the anti-TNFα antibody or binding fragment thereof may be administered subcutaneously in an amount of 90 to 180 mg when the subject weighs less than 80 kg, and in an amount of 190 to 270 mg when the subject weighs 80 kg or more.

[0259] In one embodiment of the present invention, the anti-TNFα antibody or antigen-binding fragment thereof may be administered subcutaneously in a dose of 60 to 120 mg when the subject weighs 40 kg or more and / or is 20 years or less, 19 years or less, 18 years or less, 17 years or less, 2 to 18 years, 2 to 17 years, or 6 to 17 years or a pediatric-adolescent patient, and in a dose of 40 to 60 mg when the subject weighs 40 kg or less and / or is 20 years or less, 19 years or less, 18 years or less, 17 years or less, 2 to 18 years, 2 to 17 years, or 6 to 17 years or a pediatric-adolescent patient.

[0260] In one embodiment of the present invention, the anti-TNFα antibody or binding fragment thereof may be administered subcutaneously at a dose of 40 to 120 mg to a subject aged 20 years or younger, 19 years or younger, 18 years or younger, 17 years or younger, 2 to 18 years, 2 to 17 years, or 6 to 17 years. In one embodiment of the present invention, if the subject's condition does not improve or the therapeutic response is lost, the dose of the anti-TNFα antibody or binding fragment thereof may be increased. More specifically, the administered dose may be increased 1.1 to 3 times, 1.1 to 2.5 times, 1.1 to 2.1 times, 1.5 to 2.1 times, 1.7 to 2.1 times, or 2 times.

[0261] In one embodiment of the present invention, if the condition does not improve or the therapeutic response is lost in a subject who is 20 years of age or younger, 19 years of age or younger, 18 years of age or younger, 17 years of age or younger, 2 to 18 years of age, 2 to 17 years of age, or 6 to 17 years of age or a child or adolescent, the dosage may be increased by 1.5 to 2 times. In addition, if the subject weighs 40 kg or more, the dosage of the anti-TNFα antibody or binding fragment thereof may be increased from 60 mg to 120 mg, and if the subject weighs 40 kg or less, the dosage of the anti-TNFα antibody or binding fragment thereof may be increased from 40 mg to 60 mg.

[0262] The criteria for determining that treatment response has been lost in Crohn's disease may be an increase of 70 points or more in the CDAI score alone, resulting in a total CDAI score of 220 or more. Additionally, the criteria for determining that treatment response has been lost in pediatric and adolescent Crohn's disease patients aged 20 years or younger, 19 years or younger, 18 years or younger, 17 years or younger, 2 to 18 years, 2 to 17 years, or 6 to 17 years may be a PCDAI score of 30 or higher, with an increase of 15 points or more compared to the PCDAI after 5 administrations of an anti-TNFα antibody or its binding fragment.

[0263] In ulcerative colitis, the criteria for determining that a treatment response has been lost may be if the subject satisfies the following conditions a) and at least one of b) or c):

[0264] a) If the Bleeding subscore increases by 1 or more points from the lowest score where the actual value is greater than 1 point; and

[0265] b) If the partial Mayo score increases by 2 or more points from the lowest score with an actual value of 4 or more points; or

[0266] c) If the endoscopic subscore increases by 1 or more point from the lowest score where the actual value is greater than 1 point.

[0267] Additionally, the criteria for determining that treatment response has been lost in children and adolescents with ulcerative colitis aged 20 years or younger, 19 years or younger, 18 years or younger, 17 years or younger, 2 to 18 years, 2 to 17 years, or 6 to 17 years are a total score of 5 or more based on the modified Mayo score measured after 5 administrations of anti-TNFα antibody or binding fragment thereof and an endoscopic score of 2 or more.

[0268] In one embodiment of the present invention, if the subject's condition does not improve and the dose of the anti-TNFα antibody or binding fragment thereof is increased to 240 mg, it may be preferable not to increase the dose further. If a subject who was previously administered 240 mg is administered a dose that is increased beyond that, liver damage due to high drug concentrations may occur.

[0269] In one embodiment of the present invention, the increasing dosage of the anti-TNFα antibody or binding fragment thereof may be performed after 5 weeks, 10 weeks, 15 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 32 weeks, or 35 weeks. More preferably, the dosage may be increased after 30 weeks. If the dosage is increased before that, there may not be enough time to confirm the efficacy of the existing dosage, and if the dosage is increased after that, there may be a side effect of worsening the condition of the subject.

[0270] In one embodiment of the present invention, the anti-TNFα antibody or binding fragment thereof may be administered subcutaneously at intervals of 1 to 8 weeks. Specifically, the anti-TNFα antibody or binding fragment thereof 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.

[0271] In another embodiment of the present invention, the anti-TNFα antibody or binding fragment thereof may be administered subcutaneously at intervals of two to four weeks, preferably at intervals of two weeks.

[0272] In one embodiment of the present invention, after subcutaneous administration to a subject, the lowest blood concentration (C) of the anti-TNFα antibody or antigen-binding fragment thereof trough; Minimum concentration immediately before the next application) may be maintained at 0.01 μg / ml or more. More specifically, it may be a method of administration in which the minimum 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.

[0273] In one embodiment of the present invention, in the case of a subject having rheumatoid arthritis disease, after subcutaneous administration to the subject, the lowest blood concentration (C) of the anti-TNFα antibody or antigen-binding fragment thereof trough ) may be an administration method in which the lowest blood concentration (C) of the anti-TNFα antibody or antigen-binding fragment thereof for a subject with rheumatoid arthritis is maintained at 0.01 μg / ml or more, 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 more. Preferably, the lowest blood concentration (C) of the anti-TNFα antibody or antigen-binding fragment thereof for a subject with rheumatoid arthritis trough ) can be 1 μg / ml.

[0274] In one embodiment of the present invention, for a subject having at least one disease 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 lowest blood concentration (C) of the anti-TNFα antibody or antigen-binding fragment thereof trough ) may be an administration method in which the concentration 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.

[0275] Preferably, the lowest blood concentration (C) of an anti-TNFα antibody or antigen-binding fragment thereof for an IBD subject trough ) can be 5 μg / ml.

[0276] Pre-medication

[0277] Prior to the step of subcutaneous administration of the anti-TNFα antibody or binding fragment thereof, a step of intravenous administration of the anti-TNFα antibody or antigen-binding fragment thereof may be included.

[0278] In one embodiment of the present invention, prior to the subcutaneous administration step, the step of intravenously administering the anti-TNFα antibody or antigen-binding fragment thereof may be performed at least once, twice, or three times.

[0279] In one embodiment of the present invention, a) in the case of a subject having rheumatoid arthritis, the anti-TNFα antibody or antigen-binding fragment thereof may be administered intravenously twice before subcutaneous administration, and b) in the case of a subject having at least one disease selected from the group consisting of ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis, the anti-TNFα antibody or antigen-binding fragment thereof may be administered intravenously twice or three times before subcutaneous administration.

[0280] In one embodiment of the present invention, the subject may be a subject who received two intravenous administrations of the anti-TNFα antibody or antigen-binding fragment thereof at weeks 0 and 2, or a subject who received three intravenous administrations at weeks 0, 2, and 6, prior to subcutaneous administration.

[0281] In one embodiment of the present invention, a) for a subject having rheumatoid arthritis, the anti-TNFα antibody or antigen-binding fragment thereof may be administered intravenously twice at week 0 and week 2 before subcutaneous administration, and b) for a subject having at least one disease selected from the group consisting of ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis, the anti-TNFα antibody or antigen-binding fragment thereof may be administered intravenously twice at week 0 and week 2 before subcutaneous administration; or three times at week 0, week 2, and week 6.

[0282] In one embodiment of the present invention, prior to the subcutaneous administration step, a step may be included in which an anti-TNFα antibody or antigen-binding fragment thereof is intravenously administered at a dose of 1 to 10 mg / kg. Specifically, a step in which 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / kg is intravenously administered may be included.

[0283] In another embodiment of the present invention, prior to the subcutaneous administration step, a step of intravenously administering 2 to 8 mg / kg of an anti-TNFα antibody or antigen-binding fragment thereof may be included. In another embodiment of the present invention, prior to the subcutaneous administration step, a step of intravenously administering 3 to 5 mg / kg of an anti-TNFα antibody or antigen-binding fragment thereof may be included.

[0284] In one embodiment of the present invention, a) a subject having rheumatoid arthritis disease may be intravenously administered 3 mg / kg per dose of an anti-TNFα antibody or an antigen-binding fragment thereof, and b) a subject having at least one disease selected from the group consisting of ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis may be intravenously administered 5 mg / kg per dose of an anti-TNFα antibody or an antigen-binding fragment thereof.

[0285] In one embodiment of the present invention, prior to the subcutaneous administration step, a step of intravenously administering an anti-TNFα antibody or an antigen-binding fragment thereof may be included, and the time interval between the final intravenous administration and the first subcutaneous administration may be 1 to 8 weeks. Specifically, a step of administering at intervals of 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 weeks may be included.

[0286] In another embodiment of the present invention, prior to the subcutaneous administration step, a step of intravenously administering an anti-TNFα antibody or an antigen-binding fragment thereof may be included, and the time interval between the last intravenous administration and the first subcutaneous administration may be 2 to 8 weeks, 2 to 4 weeks, 4 weeks, preferably 2 weeks.

[0287] In another embodiment of the present invention, the timing of the first subcutaneous administration was set to minimize the possibility of ADAs that may occur due to low blood infliximab concentrations by making the pre-dose concentration level as close as possible to the steady-state blood concentration during the subcutaneous administration period. The optimal interval between the final intravenous administration and the first subcutaneous administration considering the above conditions was determined through simulations based on the developed population PK model. The simulation results showed that the mean blood concentration at week 10, 2 to 4 weeks after the final intravenous administration, more preferably 4 weeks later, was most similar to the expected steady-state pre-dose concentration level during the maintenance period of subcutaneous administration, and also showed low blood concentration fluctuations. Therefore, setting the first subcutaneous administration at week 10 is expected to most quickly reach the expected steady-state mean pre-dose concentration level during the trial period.

[0288] If the first subcutaneous administration is administered less than 2 weeks after the last intravenous administration, blood concentrations may be higher than the expected pre-dose concentration at steady state during the maintenance period of subcutaneous administration. If the first subcutaneous administration is administered more than 6 weeks after the last intravenous administration, blood concentrations may be lower than the expected pre-dose concentration at steady state during the maintenance period of subcutaneous administration. The expected average pre-dose concentration at steady state during the study may be reached relatively later than if the subcutaneous administration is administered at 4 weeks (10 weeks).

[0289] In another embodiment of the present invention, the subject may be a subject who received two intravenous administrations of the anti-TNFα antibody or antigen-binding fragment thereof at weeks 0 and 2, or a subject who received three intravenous administrations at weeks 0, 2, and 6, prior to subcutaneous administration.

[0290] Combination administration

[0291] Other biologic agents or chemotherapeutic agents may be administered together with the anti-TNFα antibody or antigen-binding fragment thereof of the present invention. Administration may be concurrent with, prior to, or subsequent to administration of the anti-TNFα antibody or antigen-binding fragment thereof.

[0292] In one embodiment of the present invention, the co-administered biologic agent may include etanercept, infliximab, adalimumab, sertolizumab pegol, golimumab, or a combination thereof.

[0293] In one embodiment of the present invention, the co-administered chemotherapeutic agent may include a disease-modifying antirheumatic drug (DMARD), a steroid, or an immunosuppressant.

[0294] In one embodiment of the present invention, the disease-modifying antirheumatic drug (DMARD) administered in combination may include methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, or a combination thereof.

[0295] In one embodiment of the present invention, the co-administered steroid may include a corticosteroid, a glucocorticoid, cortisol, a mineralocorticoid, aldosterone, or a combination thereof.

[0296] In one embodiment of the present invention, the co-administered immunosuppressant may include azathioprine, 6-mercaptor leuprolide, cyclosporin A, tacrolimus, mycophenoric acid, bredynine, mTOR inhibitor, antilymphocyte antibody, or a combination thereof.

[0297] In one embodiment of the present invention, an antihistamine, hydrocortisone, paracetamol and / or a non-sedating antihistamine may be co-administered with the anti-TNFα antibody or antigen-binding fragment thereof.

[0298] -product

[0299] The present invention also provides a product comprising a composition containing an anti-TNFα antibody or a binding fragment thereof; and a container containing the composition in a sealed state.

[0300] The composition containing the anti-TNFα antibody or binding fragment thereof is as described above.

[0301] In one embodiment of the present invention, the product may be a kit comprising a composition containing the anti-TNFα antibody or binding fragment thereof.

[0302] In one embodiment of the present invention, the product may further include instructions for using, storing, or both a composition containing the anti-TNFα antibody or binding fragment thereof. The instructions for use may include treatment of a disease in which TNFα activity is detrimental, and may include the route of administration, dosage, and timing of administration.

[0303] In one embodiment of the present invention, the container may be formed from a material such as, but not limited to, glass, polymer (plastic), metal, etc. In one embodiment of the present invention, the container is, but not limited to, a sterile container, bottle, vial, cartridge, syringe (pre-filled syringe, autoinjector), or tube. In one embodiment of the present invention, the container may be a glass or polymer vial, or a glass or polymer pre-filled syringe.

[0304] Specific product forms such as the vials, cartridges, pre-filled syringes, and auto-injectors, and methods for filling the stable liquid pharmaceutical preparation into the vials, cartridges, pre-filled syringes, and auto-injectors, etc., can be easily obtained or practiced by those skilled in the art to which the present invention pertains. For example, U.S. Patent Nos. 4,861,335 and 6,331,174 disclose specific product forms and filling methods for pre-filled syringes. For example, U.S. Patent Nos. 5,085,642 and 5,681,291 disclose specific product forms and assembly methods for auto-injectors. Commercially available products such as the vials, cartridges, pre-filled syringes, and auto-injectors can be used as they are, or products that are separately custom-made can be used in consideration of the physical properties, administration site, dosage, etc. of the composition containing the anti-TNFα antibody or binding fragment thereof.

[0305] In one embodiment of the present invention, the interior of the container may not be coated with silicone oil. If coated with silicone oil, stability may be reduced. The container may be a single-dose or multi-dose container.

[0306] In one embodiment of the present invention, the product may include other tools necessary from a commercial and user standpoint, such as needles, syringes, and the like.

[0307] Hereinafter, the present invention will be described in detail by way of examples. The following examples are intended only to illustrate the present invention, and the scope of the present invention is not limited by the following examples.

[0308] Example 1. Evaluation of the efficacy and safety of subcutaneous injection of infliximab as maintenance therapy in children and adolescents with Crohn's disease (CD).

[0309] Example 1-1. Clinical Protocol

[0310] This trial is a randomized, double-blind, multicenter, phase 3 trial designed to evaluate the efficacy, PK, PD, and safety of infliximab SC.

[0311] This trial consists of three study periods, including a screening period, a treatment period (induction phase, maintenance phase, and extension phase), and an end-of-trial visit.

[0312] Screening period: Screening is performed between days -42 and 0 (up to 6 weeks) prior to the first dose of IV infliximab administered during the induction phase.

[0313] Patients must meet all of the following criteria to be enrolled in this clinical trial.

[0314] * Patients who are male or female between the ages of 6 and 17

[0315] * Patients with moderately to severely active CD with a Pediatric Crohn's Disease Activity Index (PCDAI) score of 30 or more

[0316] * Patients with ileo-colonic Crohn's disease who have an endoscopic activity score (Simplified Endoscopic Activity Score for Crohn's Disease) of 6 or more, or patients with ileo-colonic Crohn's disease who have a score of 4 or more and an ulcer score in at least one segment.

[0317] * Patients diagnosed with Crohn's disease through radiology, biopsy, or endoscopic examination at any time before the first dose of the trial drug

[0318] * Those who have received appropriate treatment with primary nutritional therapy and / or corticosteroids and / or immunosuppressants for active Crohn's disease but have not responded, are intolerant to them, or have medical contraindications to them.

[0319] Meanwhile, patients cannot be enrolled in clinical trials if they meet any of the following criteria:

[0320] * Patients who have previously used two or more biological agents, or two or more Janus kinase (JAK) inhibitors, or two or more JAK inhibitors and biological agents

[0321] * Patients who have used TNF-α inhibitors or biological agents for less than 5 half-lives prior to the first administration of clinical drugs (day 0)

[0322] * Patients who did not respond to or were intolerant to TNF-α inhibitors previously used for the treatment of Crohn's disease

[0323] * Patients who have previously received infliximab for the treatment of Crohn's disease or other diseases

[0324] * Patients with allergy to infliximab or other murine and / or human protein excipients or hypersensitivity to immunoglobulin products

[0325] * Patients diagnosed with very early onset inflammatory bowel disease (VED) with evidence or clinical features of an underlying genetic defect that affects immune function or disrupts epithelial barrier function (monogenic inflammatory bowel disease)

[0326] Composition and method of administration of the test drug to be administered subcutaneously: The test drug to be administered to the patient is a composition containing infliximab, sorbitol, polysorbate, acetic acid, and water for injection. The test drug is a formulation commercially available in Europe as Remsima SC, in the form of a pre-filled syringe containing 120 mg of infliximab, sorbitol, polysorbate, acetic acid, and water for injection. When the administration dose is 40 mg or 60 mg, a portion of the test drug contained in the pre-filled syringe can be aliquoted into a sterile vial and then administered subcutaneously to the patient using a subcutaneous injection syringe.

[0327] Treatment period:

[0328] * Public induction phase (administered at weeks 0, 2, and 6)

[0329] * Double-blind maintenance phase (administration from week 10 to week 54)

[0330] * Double-blind extension phase (administration from week 56 to week 102)

[0331] In the open-label induction phase, only patients who met all inclusion criteria and none of the exclusion criteria as of Day 0 (Week 0) were enrolled in the clinical trial. All enrolled patients received induction treatment at visits on Weeks 0, 2, and 6, in which infliximab was administered IV (5 mg / kg) over 2 hours. Patients who received three full doses of infliximab via IV infusion and achieved a PCDAI score of 30 or less at Week 10 were classified as responders and were randomly assigned to receive either high-dose or low-dose infliximab via the SC route before Day 70 (Week 10) if the safety profile was satisfactory, as determined by the investigator.

[0332] Randomization to dose assignment is stratified by the following criteria:

[0333] * Weight at 10 weeks (less than 40 kg or more than 40 kg)

[0334] * Experience with use of biological agents and / or JAK inhibitors (use or non-use)

[0335] * Achieved clinical remission at week 10 (achieved or not achieved remission based on PCDAI score)

[0336] The double-blind maintenance phase consists of additional high- or low-dose SC infliximab administration, with the final dose administered at week 54.

[0337] * High-dose test group 1)

[0338] · Infliximab 120 mg administered SC every 2 weeks from week 10 to week 54 (patient body weight ≥40 kg)

[0339] · Infliximab 60 mg administered SC every 2 weeks from weeks 10 to 54 (patients weighing <40 kg)

[0340] * Low-dose test group 2)

[0341] · Infliximab 60 mg administered SC every 2 weeks from week 10 to week 54 (patient body weight ≥40 kg)

[0342] · Infliximab 40 mg administered SC every 2 weeks from weeks 10 to 54 (patients weighing <40 kg)

[0343] In the double-blind extension phase, patients who complete the maintenance phase by week 54 and, in the opinion of the investigator, would benefit from continued treatment will receive the same dose as in the maintenance phase, with the extension phase beginning at week 56 and lasting until week 102.

[0344] If a patient in the low-dose group initially responded to the drug but subsequently lost that response, a dose escalation to a higher dose was permitted starting at week 22. Loss of response was defined as a PCDAI score of 30 or higher and a 15-point increase from week 10.

[0345] In the double-blind extension phase only, if the patient's body weight increases from <40 kg to ≥40 kg, a dose increase from infliximab 40 mg or 60 mg to infliximab 60 mg or 120 mg is permitted.

[0346] Patients may receive premedication 30 to 60 minutes prior to IV infliximab administration, including but not limited to antihistamines, hydrocortisone, paracetamol, and / or non-sedating antihistamines, at the investigator's discretion during the trial. Patients may also receive premedication at the investigator's discretion for SC infliximab administration.

[0347] End-of-Study Visit: A final visit to complete the study will be conducted 4 weeks after the last dose. For patients who discontinue study treatment early before switching to high- or low-dose SC infliximab at Week 10, the end-of-study visit will be conducted 8 weeks after the last IV infliximab dose.

[0348] Example 1-2. Population PK Analysis Results and PK-PD Modeling for Pediatric and Adolescent CD Patients

[0349] Population PK analyses and PK-PD modeling for pediatric and adolescent CD patients were based on data from intravenous infliximab in healthy adults, adults with ankylosing spondylitis, adults with rheumatoid arthritis, and adults with Crohn's disease, and data from subcutaneous infliximab in healthy adults, adults with rheumatoid arthritis, adults with Crohn's disease, and adults with ulcerative colitis (see Clinicaltrials.gov identifiers NCT01220518, NCT01217086, NCT02096861, NCT03147248, NCT02883452, NCT04205643, and NCT03945019).

[0350] Population PK-PD modeling in pediatric and adolescent patients with CD was performed on hypothetical patients with a body weight range representative of pediatric patients aged 2 to <18 years, stratified into 10-kg weight groups. Maintenance doses of 40, 60, 80, 100, and 120 mg SC Q2W (from Week 10) were explored in the hypothetical pediatric and adolescent patient population and compared with exposures achieved with a maintenance dose regimen of 120 mg SC Q2W (from Week 10) in the adult patient population.

[0351] The simulated CDAI results showed no difference in the administered dose and body weight, and the infliximab administration dose was selected based on the PK simulation results.

[0352] The PK-PD model constructed based on the above data can be used to simulate the results of subcutaneous administration to pediatric and adolescent patients with indications for infliximab (e.g., rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, or ankylosing spondylitis).

[0353] The final population PK model was implemented as a two-compartment model with a depot compartment with linear elimination from the central compartment where infliximab infusion occurs and a first-order absorption rate into the central compartment. The covariate relationship between disease duration and baseline CDAI score was incorporated into the model. PK-PD modeling validation was performed using prediction-corrected visual predictive checks (pcVPC).

[0354] Example 1-3. Simulation results for determining the dosage for pediatric and adolescent CD patients.

[0355] The simulation results of PK parameters according to body weight strata showed that the 120 mg, 60 mg, and 40 mg doses were within the PK equivalence margin of 80% to 125%, respectively (see Tables 1 to 3). In addition, the simulated PK profiles in the low-dose and high-dose groups are presented in Fig. 1. Additional PK simulations were performed because higher drug exposure was observed in the pediatric and adolescent population weighing 10-20 kg (60 mg infliximab Q2W maintenance dose) and the pediatric and adolescent population weighing 40-60 kg (120 mg infliximab Q2W maintenance dose) compared to the adult population (120 mg Q2W maintenance dose). Accordingly, when compared with drug exposure according to the maintenance dose of 240 mg infliximab Q2W in the adult patient populations of NCT02883452, NCT04205643, and NCT03945019, administration of 60 mg or 120 mg every 2 weeks (high dose group) to children and adolescents resulted in AUC and C max It was shown that lower drug exposure occurred in the 240 mg infliximab Q2W maintenance dose. Since no safety issues were observed in the clinical trial results of the adult patient population administered the 240 mg infliximab Q2W maintenance dose, the dosage mentioned in Example 1-1 is expected to be an appropriate dosage in terms of safety.

[0356] Based on this, the dosing regimen for pediatric and adolescent CD patients to achieve maximum efficacy while minimizing drug exposure is as follows.

[0357] * High capacity group

[0358] · Infliximab 120 mg administered subcutaneously every 2 weeks from week 10 to week 54 (patient body weight ≥ 40 kg)

[0359] · Infliximab 60 mg administered subcutaneously every 2 weeks from weeks 10 to 54 (patients weighing < 40 kg)

[0360] * Low-dose group

[0361] · Infliximab 60 mg administered subcutaneously every 2 weeks from week 10 to week 54 (patient body weight ≥ 40 kg)

[0362] · Infliximab 40 mg administered subcutaneously every 2 weeks from weeks 10 to 54 (patients weighing < 40 kg)

[0363] Simulated C of the selected dosing regimen trough,w30Geometric mean ratio and 90% confidence interval of the dosing regimen. Trial population. Geometric mean ratio. 90% confidence interval. High-dose group. Patients weighing 40 kg or more. Fliximab 120 mg SC every 2 weeks. 80 - 90 kg. 0.87 (0.83, 0.91). 70 - 80 kg. 0.96 (0.92, 1.00). 60 - 70 kg. 1.08 (1.03, 1.12). 50 - 60 kg. 1.23 (1.18, 1.28). 40 - 50 kg. 1.44 (1.38, 1.51). Patients weighing less than 40 kg. Fliximab 60 mg SC every 2 weeks. 30 - 40 kg. 0.88 (0.85, 0.92). 20 - 30 kg. 1.16 (1.11, 1.21). 10 - 20 kg 1.75 (1.68, 1.83) Low-dose group Patients weighing 40 kg or more Fliximab 60 mg SC every 2 weeks 80 - 90 kg 0.44 (0.42, 0.45) 70 - 80 kg 0.48 (0.46, 0.50) 60 - 70 kg 0.54 (0.52, 0.56) 50 - 60 kg 0.62 (0.59, 0.64) 40 - 50 kg 0.72 (0.69, 0.75) Patients weighing less than 40 kg Fliximab 40 mg SC every 2 weeks 30 - 40 kg 0.59 (0.57, 0.62) 20 - 30 kg 0.77 (0.74, 0.81) 10 - 20 kg 1.17 (1.12, 1.22)*The simulated adult dosing regimen was infliximab IV 5 mg / kg administered over 2 hours at weeks 0, 2, and 6, followed by infliximab 120 mg subcutaneously administered at 2-week intervals starting at week 10. The simulated pediatric-adolescent dosing regimen was infliximab IV 5 mg / kg administered over 2 hours at weeks 0, 2, and 6, followed by infliximab 40 mg, 60 mg, 80 mg, 100 mg, or 120 mg subcutaneously administered at 2-week intervals starting at week 10.

[0364] Simulated C of the selected dosing regimen max,w28Geometric mean ratio and 90% confidence interval of the dosing regimen. Trial population. Geometric mean ratio. 90% confidence interval. High-dose group. Patients weighing 40 kg or more. Fliximab 120 mg SC every 2 weeks. 80 - 90 kg. 0.88 (0.85, 0.90). 70 - 80 kg. 0.96 (0.94, 0.99). 60 - 70 kg. 1.07 (1.04, 1.10). 50 - 60 kg. 1.21 (1.18, 1.24). 40 - 50 kg. 1.40 (1.37, 1.44). Patients weighing less than 40 kg. Fliximab 60 mg SC every 2 weeks. 30 - 40 kg. 0.85 (0.82, 0.87). 20 - 30 kg. 1.09 (1.06, 1.12). 10 - 20 kg 1.60 (1.56, 1.65) Low-dose group Patients weighing 40 kg or more Fliximab 60 mg SC every 2 weeks 80 - 90 kg 0.44 (0.43, 0.45) 70 - 80 kg 0.48 (0.47, 0.50) 60 - 70 kg 0.54 (0.52, 0.55) 50 - 60 kg 0.61 (0.59, 0.62) 40 - 50 kg 0.70 (0.68, 0.72) Patients weighing less than 40 kg Fliximab 40 mg SC every 2 weeks 30 - 40 kg 0.57 (0.55, 0.58) 20 - 30 kg 0.73 (0.71, 0.75) 10 - 20 kg 1.07 (1.04, 1.10)*The simulated adult dosing regimen is infliximab IV 5 mg / kg administered over 2 hours at weeks 0, 2, and 6, followed by infliximab 120 mg subcutaneously administered every 2 weeks at 2-week intervals starting from week 10. The simulated pediatric-adolescent dosing regimen is infliximab IV 5 mg / kg administered over 2 hours at weeks 0, 2, and 6, followed by infliximab SC 40 mg, 60 mg, 80 mg, 100 mg, or 120 mg subcutaneously administered every 2 weeks starting from week 10.

[0365] Simulated AUC of the selected dosing regimen w28-30Geometric mean ratio and 90% confidence interval of the dosing regimen. Trial population. Geometric mean ratio. 90% confidence interval. High-dose group. Patients weighing 40 kg or more. Fliximab 120 mg SC every 2 weeks. 80 - 90 kg. 0.87 (0.85, 0.90). 70 - 80 kg. 0.96 (0.93, 0.99). 60 - 70 kg. 1.07 (1.04, 1.11). 50 - 60 kg. 1.22 (1.18, 1.26). 40 - 50 kg. 1.42 (1.37, 1.46). Patients weighing less than 40 kg. Fliximab 60 mg SC every 2 weeks. 30 - 40 kg. 0.86 (0.83, 0.89). 20 - 30 kg. 1.11 (1.08, 1.15). 10 - 20 kg 1.65 (1.60, 1.70) Low-dose group Patients weighing 40 kg or more Fliximab 60 mg SC every 2 weeks 80 - 90 kg 0.44 (0.42, 0.45) 70 - 80 kg 0.48 (0.47, 0.50) 60 - 70 kg 0.54 (0.52, 0.55) 50 - 60 kg 0.61 (0.59, 0.63) 40 - 50 kg 0.71 (0.69, 0.73) Patients weighing less than 40 kg Fliximab 40 mg SC every 2 weeks 30 - 40 kg 0.57 (0.56, 0.59) 20 - 30 kg 0.74 (0.72, 0.77) 10 - 20 kg 1.10 (1.07, 1.14)*The simulated pediatric-adolescent dosing regimen included administering 5 mg / kg of infliximab IV over 2 hours at weeks 0, 2, and 6, followed by subcutaneous administration of 40 mg, 60 mg, 80 mg, 100 mg, or 120 mg of infliximab at 2-week intervals starting from week 10.

[0366] Example 2. Evaluation of the efficacy and safety of subcutaneous injection of infliximab as maintenance therapy in patients with ulcerative colitis (UC) in children and adolescents.

[0367] Example 2-1. Clinical Protocol

[0368] This trial is a randomized, double-blind, multicenter, phase 3 trial designed to evaluate the efficacy, PK, PD, and safety of infliximab SC.

[0369] This trial consists of three study periods, including a screening period, a treatment period (induction phase, maintenance phase, and extension phase), and an end-of-trial visit.

[0370] Screening period: Screening is performed between days -42 and 0 (up to 6 weeks) prior to the first dose of IV infliximab administered during the induction phase.

[0371] Patients must meet all of the following criteria to be enrolled in this clinical trial.

[0372] * Patients who are male or female between the ages of 6 and 17

[0373] * Patients with moderately to severely active ulcerative colitis (UC) with a modified Mayo score of 5 to 9

[0374] * If ulcerative colitis has been diagnosed through endoscopy, radiography, or histological examination (the histopathology report supporting the diagnosis must be available in original document before the first administration of clinical drug (day 0))

[0375] * Those who have received treatment for active ulcerative colitis but have not responded to, are intolerant to, or have medical contraindications to common treatment drugs such as corticosteroids and / or 6-mercaptopurine or azathioprine.

[0376] Meanwhile, patients cannot be enrolled in clinical trials if they meet any of the following criteria:

[0377] * Patients who have previously used two or more biological agents, two or more JAK inhibitors, or two or more combinations of both JAK inhibitors and biological agents

[0378] * Patients who have used TNF-α inhibitors or biological agents for less than 5 half-lives prior to the first administration of clinical drugs (day 0)

[0379] * Patients who have previously been administered TNF-α inhibitors for the treatment of UC but did not respond or were intolerant

[0380] * Patients who have previously received infliximab for the treatment of UC or other diseases

[0381] * Patients with allergy to infliximab or other murine and / or human protein excipients or hypersensitivity to immunoglobulin products

[0382] * Patients diagnosed with very early onset inflammatory bowel disease (VED) with evidence or clinical features of an underlying genetic defect that affects immune function or disrupts epithelial barrier function (monogenic inflammatory bowel disease)

[0383] Composition and method of administration of the test drug to be administered subcutaneously: The test drug to be administered to the patient is a composition containing infliximab, sorbitol, polysorbate, acetic acid, and water for injection. The test drug is in the form of a pre-filled syringe containing 120 mg of infliximab, sorbitol, polysorbate, acetic acid, and water for injection, and is a formulation commercially available in Europe as Remsima SC. When the administration dose is 40 mg or 60 mg, a portion of the test drug contained in the pre-filled syringe can be transferred to a sterile vial and then administered subcutaneously to the patient using a syringe for subcutaneous administration.

[0384] Treatment period:

[0385] * Public induction phase (administered at weeks 0, 2, and 6)

[0386] * Double-blind maintenance phase (administration from week 10 to week 54)

[0387] * Double-blind extension phase (administration from week 56 to week 102)

[0388] In the open-label induction phase, only patients who meet all inclusion criteria and none of the exclusion criteria as of Day 0 (Week 0) will be enrolled in the trial. All enrolled patients will receive induction therapy with IV infliximab (5 mg / kg) over 2 hours at visits on Weeks 0, 2, and 6. Among patients who received three full doses of infliximab via IV infusion and were classified as responders based on the Mayo score at Week 10, only those patients who, in the investigator's judgment, had no safety concerns will be randomly assigned to receive either high-dose or low-dose infliximab via the SC route before dosing on Day 70 (Week 10).

[0389] Randomization to dose assignment is stratified by the following criteria:

[0390] * Body weight at week 10 (< 40 kg or ≥ 40 kg)

[0391] * Experience with use of biological agents and / or JAK inhibitors (use or non-use)

[0392] * Achieved clinical remission at week 10 (achieved or not achieved remission by modified Mayo score)

[0393] The double-blind maintenance phase consists of additional high- or low-dose SC infliximab administration, with the final dose administered at week 54.

[0394] * High-dose test group 1)

[0395] · Infliximab 120 mg administered SC every 2 weeks from week 10 to week 54 (patient body weight ≥40 kg)

[0396] · Infliximab 60 mg administered SC every 2 weeks from weeks 10 to 54 (patients weighing <40 kg)

[0397] * Low-dose test group 2)

[0398] · Infliximab 60 mg administered SC every 2 weeks from week 10 to week 54 (patient body weight ≥40 kg)

[0399] · Infliximab 40 mg administered SC every 2 weeks from weeks 10 to 54 (patients weighing <40 kg)

[0400] In the double-blind extension phase, patients who completed the maintenance phase by Week 54 and who, in the opinion of the investigator, would benefit from continued treatment will receive the same dose as in the maintenance phase, with the extension phase beginning at Week 56 and continuing through Week 102.

[0401] If a patient in the low-dose group initially responded to the drug but subsequently lost that response, a dose escalation to a higher dose was permitted starting at week 22. Loss of response was defined as one of the following: a modified Mayo score increase of 2 points or more and 30% or more compared to week 10, a total score of 5 points or more, and an endoscopic score of 2 points or more.

[0402] In the double-blind extension phase only, if the patient's body weight increases from <40 kg to ≥40 kg, a dose increase from infliximab 40 mg or 60 mg to infliximab 60 mg or 120 mg is permitted.

[0403] Patients may receive premedication 30 to 60 minutes prior to starting IV infliximab, including but not limited to antihistamines, hydrocortisone, paracetamol, and / or non-sedating antihistamines, at the investigator's discretion during the trial. Patients may also receive premedication at the investigator's discretion for subcutaneous injections.

[0404] End-of-Study Visit: A final visit to complete the study will be conducted 4 weeks after the last dose. For patients who discontinue study treatment early before switching to high- or low-dose SC infliximab at Week 10, the end-of-study visit will be conducted 8 weeks after the last IV infliximab dose.

[0405] Example 2-2. Population PK Analysis Results and PK-PD Modeling for Pediatric and Adolescent UC Patients

[0406] Population PK analyses and PK-PD modeling were based on data from intravenous infliximab in healthy adults, adults with ankylosing spondylitis, adults with rheumatoid arthritis, and adults with Crohn's disease, and data from subcutaneous infliximab in healthy adults, adults with rheumatoid arthritis, adults with Crohn's disease, and adults with ulcerative colitis (Clinicaltrials.gov identifiers NCT01220518, NCT01217086, NCT02096861, NCT03147248, NCT02883452, NCT04205643, NCT03945019).

[0407] To perform population PK analysis and PK-PD modeling for pediatric and adolescent UC patients, we stratified hypothetical patients with a body weight range representing pediatric and adolescent patients aged 2 to <18 years into 10 kg weight groups. In the hypothetical pediatric and adolescent patient population, maintenance doses of 40, 60, 80, 100, and 120 mg SC Q2W (from week 10) were explored and compared with the exposure achieved with the maintenance dose regimen of 120 mg SC Q2W (from week 10) in the adult patient population.

[0408] Since the simulated partial Mayo and modified Mayo scores did not show differences in dose and body weight, the infliximab dose used in the clinical trial of Example 2-1 was selected based on the PK simulation results.

[0409] The PK-PD model constructed based on the above data can be used to simulate the outcomes of subcutaneous administration of infliximab to pediatric patients with indications for infliximab (e.g., rheumatoid arthritis, ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, or ankylosing spondylitis).

[0410] In addition to safety analyses for each indication (CD, RA, and AS), the Mayo score was included in the population PK and PK-PD modeling analysis for patients with UC. The final PK model was a two-compartment model with a linear elimination from the central compartment, where infliximab infusion occurred, and a depot compartment with a first-order absorption rate into the central compartment. The covariate relationship between disease duration and baseline Mayo score was incorporated into the model.

[0411] Example 2-3. Simulation results for determining dosage for pediatric and adolescent UC patients.

[0412] The simulation results of PK parameters according to weight class were within the PK equivalence margin of 80% to 125% at the 120 mg, 60 mg, and 40 mg doses (see Tables 1 to 3).

[0413] Additionally, simulated PK profiles in the low-dose and high-dose groups are presented in Figure 1. Additional PK simulations were performed because the pediatric and adolescent populations weighing 10-20 kg (60 mg Q2W maintenance dose) and the pediatric and adolescent populations weighing 40-60 kg (120 mg Q2W maintenance dose) were expected to have higher drug exposure compared to the 120 mg Q2W maintenance dose administered to the adult population.

[0414] In clinical trials NCT02883452, NCT04205643, and NCT03945019, when infliximab was administered subcutaneously at a maintenance dose of 240 mg Q2W to adult patients, AUC and C were significantly lower in children and adolescents when infliximab was administered subcutaneously at 60 mg or 120 mg Q2W. max It was shown that lower drug exposure was observed in the adult clinical trial results. Since no safety issues were observed when administering the 240 mg Q2W maintenance dose, the dosage suggested in Example 2-1 is expected to be appropriate in terms of safety.

[0415] Based on the simulation results, the subcutaneous administration regimen for pediatric and adolescent UC patients that provides maximum efficacy while minimizing drug exposure is as follows.

[0416] * High capacity group

[0417] · Infliximab 120 mg administered SC every 2 weeks from week 10 to week 54 (patient body weight ≥ 40 kg)

[0418] · Infliximab 60 mg administered SC every 2 weeks from week 10 to week 54 (patient body weight < 40 kg)

[0419] * Low-dose group

[0420] · Infliximab 60 mg administered SC every 2 weeks from week 10 to week 54 (patient body weight ≥ 40 kg)

[0421] · Infliximab 40 mg administered SC every 2 weeks from week 10 to week 54 (patient body weight < 40 kg)

[0422] Example 3. Stability of the composition

[0423] In order to confirm whether the composition administered subcutaneously in Examples 1 and 2 above has stability even if it contains a high concentration of infliximab, a formulation having the composition shown in Table 4 below was prepared, and the stability was measured after 0 weeks, 4 weeks, 8 weeks, and 12 weeks at temperatures of 5°C and 25°C.

[0424] Composition: Antibody surfactant, sugar alcohol buffer, 220 mg / ml infliximab, 0.05% w / v polysorbate 80, 3.8% w / v sorbitol, 90 mM acetate

[0425] Even after 12 weeks, there was little change in color and turbidity, and even if a high concentration of antibody was included, there was almost no change in color and turbidity, so it was confirmed that the formulation with the composition of Table 4 had excellent stability (Fig. 2). In addition, when the antigen binding ability of infliximab was measured by ELISA, the change was not significant, and when the immunoglobulin G content, heavy chain, and light chain contents were measured by CE-SDS, the change range was not significant after 12 months, indicating that the formulation with the composition of Table 4 had excellent stability (Fig. 3). Furthermore, when the number of peaks and particles not visible to the naked eye of the formulation with the composition of Table 4 was measured by an MFI analyzer or an HIAC particle counter after 12 months, it was confirmed that the formulation had high stability (see Figs. 4 and 5).

Claims

1. A method for treating a TNFα-related disease, comprising administering to a subject a pharmaceutical composition comprising an anti-TNFα antibody or an antigen-binding fragment thereof, wherein the method comprises subcutaneously administering to the subject a dose of 40 to 300 mg of the anti-TNFα antibody or an antigen-binding fragment thereof at intervals of 1 to 8 weeks.

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. A method according to paragraph 1 or 2, wherein the subject is a person aged 20 years or younger, 19 years or younger, 18 years or younger, 17 years or younger, 2 to 18 years, 2 to 17 years, or 6 to 17 years.

4. A method according to any one of claims 1 to 3, wherein a dose of 40 to 120 mg of an anti-TNFα antibody or an antigen-binding fragment thereof is administered to the subject.

5. A method according to any one of claims 1 to 4, wherein when the subject's condition does not improve or the therapeutic response is lost, the dose of the anti-TNFα antibody or antigen-binding fragment thereof is increased and administered.

6. A method according to any one of claims 1 to 5, wherein the anti-TNFα antibody or antigen-binding fragment thereof is administered to the subject in a dose of 40 mg, 60 mg, or 120 mg.

7. In any one of paragraphs 1 to 6, A method comprising administering to a subject an anti-TNFα antibody or an antigen-binding fragment thereof at intervals of 1, 2, 3, 4, 5, 6, 7 or 8 weeks.

8. In any one of paragraphs 1 to 7, A method of administering an anti-TNFα antibody or an antigen-binding fragment thereof to a subject at two-week intervals.

9. In any one of paragraphs 1 to 8, If the subject's body weight is 40 kg or more, 60 to 120 mg of anti-TNFα antibody or antigen-binding fragment thereof is administered. A method of administering 40 to 60 mg of an anti-TNFα antibody or an antigen-binding fragment thereof when the subject's body weight is 40 kg or less.

10. In any one of paragraphs 1 to 9, A method in which, if the subject's body weight is 40 kg or more, 120 mg of anti-TNFα antibody or antigen-binding fragment thereof is administered subcutaneously 5 times, and then 60 mg of anti-TNFα antibody or antigen-binding fragment thereof is administered from the 6th administration.

11. In any one of paragraphs 1 to 9, A method in which, if the subject's body weight is 40 kg or less, 60 mg of anti-TNFα antibody or antigen-binding fragment thereof is administered subcutaneously 5 times, and then 40 mg of anti-TNFα antibody or antigen-binding fragment thereof is administered from the 6th administration.

12. A method according to any one of claims 1 to 11, wherein the anti-TNFα antibody or antigen-binding fragment thereof is administered in combination with at least one selected from the group consisting of disease-modifying antirheumatic drugs (DMARDs), steroids, and immunosuppressants.

13. In paragraph 12, the disease-modifying antirheumatic drug (DMARD) is selected from the group consisting of Methotrexate, Leflunomide, Sulfasalazine, and Hydroxychloroquine. The above steroid is selected from the group consisting of corticosteroids, glucocorticoids, cortisol, mineralocorticoids and aldosterone, A method wherein the immunosuppressant is selected from the group consisting of azathioprine, 6-mercaptopurine, cyclosporin A, tacrolimus, mycophenoric acid, bredynine, mTOR inhibitors, and antilymphocyte antibodies.

14. A method according to any one of claims 1 to 13, wherein the subject is a subject who has received intravenous administration of an anti-TNFα antibody or an antigen-binding fragment thereof at least once before subcutaneous administration.

15. A method according to claim 14, wherein the subject is a subject who has received intravenous administration of an anti-TNFα antibody or an antigen-binding fragment thereof two or three times before subcutaneous administration.

16. In paragraph 14, a) For subjects with rheumatoid arthritis disease, anti-TNFα antibody or antigen-binding fragment thereof is administered intravenously twice before subcutaneous administration, b) A method for treating a subject having at least one disease selected from the group consisting of ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis, wherein the subject has received two or three intravenous administrations of an anti-TNFα antibody or an antigen-binding fragment thereof prior to subcutaneous administration.

17. In paragraph 14, before subcutaneous administration, Subjects who received two intravenous administrations of anti-TNFα antibody or antigen-binding fragment thereof at weeks 0 and 2, or Method: Subjects received intravenous administration three times in weeks 0, 2, and 6.

18. A method according to claim 14, wherein the subject is a subject who has been intravenously administered an anti-TNFα antibody or an antigen-binding fragment thereof at a dose of 1 to 10 mg / kg per dose.

19. A method according to claim 18, wherein the subject is a subject who has been intravenously administered an anti-TNFα antibody or an antigen-binding fragment thereof at a dose of 3 to 5 mg / kg per dose.

20. In paragraph 14, a) For subjects with rheumatoid arthritis disease, intravenous administration of anti-TNFα antibody or antigen-binding fragment thereof at a dose of 3 mg / kg per dose; b) A method in which a subject having at least one disease selected from the group consisting of ulcerative colitis, Crohn's disease, plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis is intravenously administered an anti-TNFα antibody or an antigen-binding fragment thereof at a dose of 5 mg / kg per dose.

21. A method according to claim 14, wherein the first subcutaneous administration is performed 2 to 8 weeks after the last intravenous administration.

22. A method according to claim 21, wherein the first subcutaneous administration is performed 4 weeks after the last intravenous administration.

23. In any one of paragraphs 1 to 22, after subcutaneous administration to a subject, the lowest blood concentration (C) of the anti-TNFα antibody or antigen-binding fragment thereof trough ) is maintained at 0.01 μg / ml or higher.

24. In paragraph 23, a) In subjects with rheumatoid arthritis disease, the lowest blood concentration (C) of anti-TNFα antibody or its antigen-binding fragment after subcutaneous administration trough ) is maintained at 1 μg / ml or more, b) In the case of 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 lowest blood concentration (C) of anti-TNFα antibody or antigen-binding fragment thereof after subcutaneous administration trough ) is maintained at 5 μg / ml or more.

25. In any one of paragraphs 1 to 24, After subcutaneous administration, the subject has one or more of the following characteristics: a) a decrease in DAS28 (Disease Activity Score in 28 joints) of at least 2.0; or b) CDAI (Crohn's disease activity index) decreases by at least 70.

26. In any one of paragraphs 1 to 25, Prior to subcutaneous administration, the subject has one or more of the following characteristics: a) Subjects with an inadequate response to disease-modifying antirheumatic drugs (DMARDs), including methotrexate; b) Subjects who have not previously been treated with methotrexate or other DMARDs; c) Subjects with severe inflammatory symptoms and elevated serum markers associated with inflammation who do not respond adequately to conventional treatment; or d) Patients who have not responded adequately to systemic therapy, including methotrexate, cyclosporine, or psoralen ultraviolet A therapy (PUVA), are intolerant to such therapy, or are contraindicated in such therapy.

27. In any one of paragraphs 1 to 26, Prior to subcutaneous administration, the subject has one or more of the following characteristics: a) Those who do not respond adequately to treatment with corticosteroids, 6-mercaptopurine, azathioprine or immunosuppressants, are intolerant to such treatment or are contraindicated to such treatment; or b) Subjects who do not respond to conventional treatment, including antibiotics, excretion, or immunosuppressive therapy.

28. In any one of paragraphs 1 to 27, the anti-TNFα antibody or antigen-binding fragment thereof, A light chain variable region comprising a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 domain comprising the amino acid sequence represented by YAS, and a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 2; and A method comprising a heavy chain variable region comprising a CDR1 domain comprising an amino acid sequence of SEQ ID NO: 3, a CDR2 domain comprising an amino acid sequence of SEQ ID NO: 4, and a CDR3 domain comprising an amino acid sequence of SEQ ID NO:

5.

29. A method according to any one of claims 1 to 28, wherein the anti-TNFα antibody is infliximab.

30. A method according to any one of claims 1 to 29, wherein the pharmaceutical composition comprising an anti-TNFα antibody or an antigen-binding fragment thereof comprises (A) 90 to 220 mg / ml or 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 90 mM or 1 to 50 mM of a buffer comprising acetate.

31. A method according to any one of claims 1 to 30, wherein the pharmaceutical composition comprising an anti-TNFα antibody or an antigen-binding fragment thereof is filled in a sterile container, a pre-filled syringe, or an auto-injector.

32. A pharmaceutical composition for treating a TNFα-related disease, comprising an anti-TNFα antibody or an antigen-binding fragment thereof, wherein the anti-TNFα antibody or an antigen-binding fragment thereof is administered subcutaneously at a dose of 40 to 300 mg at intervals of 1 to 8 weeks. 33.(a) a pharmaceutical composition comprising an anti-TNFα antibody or an antigen-binding fragment thereof; and (b) A kit comprising instructions directing subcutaneous administration of an anti-TNFα antibody or antigen-binding fragment thereof at a dose of 40 to 300 mg at intervals of 1 to 8 weeks for the treatment of a subject with a TNFα-related disease.

34. Use of an anti-TNFα antibody or an antigen-binding fragment thereof for the manufacture of a medicament for treating a TNFα-related disease by administering to a subject, wherein a dose of 40 to 300 mg of the anti-TNFα antibody or an antigen-binding fragment thereof is administered subcutaneously at intervals of 1 to 8 weeks.

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