WO2021060425A1 - 全身性強皮症治療用医薬組成物 - Google Patents
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
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- C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
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Definitions
- the present invention relates to a pharmaceutical composition for the treatment of systemic scleroderma, which comprises an IL-17 pathway inhibitor as an active ingredient.
- the present invention relates to a method of treating systemic scleroderma using an IL-17 pathway inhibitor.
- Systemic scleroderma is a chronic disease characterized by hardening of the skin and internal organs.
- Systemic scleroderma includes "diffuse skin scleroderma systemic scleroderma” (dcSSc) in which skin sclerosis extends to the proximal limbs (upper arm, thigh) or trunk except for the face, and skin sclerosis is distal to the extremities (dcSSc). It is classified into two types, “localized scleroderma systemic scleroderma” (lcSSc), which is localized to the forearm and lower leg) and face.
- dcSSc diffuse skin scleroderma systemic scleroderma
- lcSSc localized scleroderma systemic scleroderma
- Systemic scleroderma is a progressive disease for which the pathogenic mechanism is unknown, there is no established treatment for skin sclerosis, and long-term treatment is required. Therefore, the main treatment is generally symptomatic treatment or the use of drugs that suppress the progression of the disease. Furthermore, since the lesion site (organ) differs depending on the degree of disease progression of each patient, the treatment method is also selected according to the symptom of each patient.
- Typical treatments for each organ include small doses of corticosteroids (for skin sclerosis), cyclophosphamide (for pulmonary fibrosis), proton pump inhibitors (for reflux esophagitis), Prostacycline derivatives (for vascular lesions), angiotensin converting enzyme inhibitors (for scleroderma renal sclerosis), endoserin receptor antagonists (for pulmonary hypertension) and the like.
- corticosteroids for skin sclerosis
- cyclophosphamide for pulmonary fibrosis
- proton pump inhibitors for reflux esophagitis
- Prostacycline derivatives for vascular lesions
- angiotensin converting enzyme inhibitors for scleroderma renal sclerosis
- endoserin receptor antagonists for pulmonary hypertension
- Non-Patent Documents 1-4 In a bleomycin-induced mouse systemic scleroderma model, a correlation between an increase in Th17 cell number and IL-17A concentration and skin and lung inflammation and hardening has been confirmed (Non-Patent Documents 5 and 6). It is known that the expression levels of IL-17RA mRNA and protein are increased in the lesioned skin of patients with systemic scleroderma. (Non-Patent Document 7)
- Brodalumab is an IgG2 monoclonal antibody that binds to human IL-17RA and blocks the biological activity of IL-17A, IL-17F, IL-17A / F heterodimer, and IL-17E (IL-25).
- Patent Document 8-10 Approved in Japan as a treatment for psoriasis vulgaris, psoriatic arthritis, pustular psoriasis and erythroderma psoriasis for which existing treatments are inadequate.
- a main object of the present invention is to provide a novel technique useful for the treatment of systemic scleroderma which may be accompanied by progressive skin sclerosis.
- the present invention provides the following [1]-[45].
- [1] A pharmaceutical composition for treating systemic scleroderma, which contains an IL-17 pathway inhibitor as an active ingredient.
- [2] A pharmaceutical composition for treating systemic scleroderma with progressive skin sclerosis, which contains an IL-17 pathway inhibitor as an active ingredient.
- [3] The pharmaceutical composition of [1] or [2], wherein the IL-17 pathway inhibitor is one or more selected from IL-17RA antagonists and IL-23R antagonists.
- [4] The pharmaceutical composition according to any one of [1]-[3], wherein the IL-17 pathway inhibitor is an antibody or an antibody fragment.
- the antibody is an anti-IL-17RA antibody, an anti-IL-17A antibody, an anti-IL-17A / F antibody, an anti-IL-23p40 subunit antibody and / or an anti-IL-23p19 subunit antibody, particularly bladarmab.
- [7] The pharmaceutical composition according to any one of [1]-[6], wherein the systemic scleroderma is diffuse skin sclerosing systemic scleroderma (dcSSc).
- dcSSc diffuse skin sclerosing systemic scleroderma
- [8] The pharmaceutical composition of [1]-[7] for lowering a patient's skin score (mRSS) by 3 or more from before treatment by 12 weeks after the start of administration.
- mRSS skin score
- the single dose of the IL-17 pathway inhibitor is 210 mg, which is subcutaneously administered on the first day, one week, and two weeks later, and thereafter, subcutaneously administered once every two weeks.
- the second therapeutic agent is an adrenocortical steroid, an antifibrotic drug, an immunosuppressant, a proton pump inhibitor, a prostacycline derivative, an angiotensin converting enzyme inhibitor, an endoserine receptor antagonist and a type 2 cannabinoid receptor.
- the pharmaceutical composition of [14] which is at least one selected from the group consisting of antagonists.
- the systemic scleroderma is diffuse skin sclerosing systemic scleroderma (dcSSc).
- the IL-17 pathway inhibitor is brodalumab, the single dose of which is 210 mg, which is subcutaneously administered on the first day, one week, two weeks later, and then subcutaneously once every two weeks. Composition.
- the IL-17 pathway inhibitor of [20] which is any one or more antibody or fragment thereof selected from the group consisting of ixekizumab, netakimab, bimekizumab, ustekinumab, chilldrakizumab, risankizumab, mirikizumab, brazikumab and guselkumab.
- Brodalumab an IL-17 pathway inhibitor of [21].
- the IL-17 pathway inhibitor according to any one of [17]-[22], wherein the systemic scleroderma is diffuse skin sclerosing systemic scleroderma (dcSSc).
- IL-17 pathway inhibitors for the production of pharmaceutical compositions for the treatment of systemic scleroderma.
- the antibody is an anti-IL-17RA antibody, an anti-IL-17A antibody, an anti-IL-17A / F antibody, an anti-IL-23p40 subunit antibody and / or an anti-IL-23p19 subunit antibody, particularly bladarmab.
- [30] Use of any of [24]-[29], wherein the systemic scleroderma is diffuse skin sclerosing systemic scleroderma (dcSSc).
- a method for treating systemic scleroderma which comprises a procedure for administering a pharmaceutical composition containing an IL-17 pathway inhibitor as an active ingredient to a subject.
- a method for treating systemic scleroderma with progressive skin sclerosis which comprises a procedure for administering to a subject a pharmaceutical composition containing an IL-17 pathway inhibitor as an active ingredient.
- the therapeutic method of [31] or [32], wherein the IL-17 pathway inhibitor is one or more selected from IL-17RA antagonists and IL-23R antagonists.
- the antibody is an anti-IL-17RA antibody, an anti-IL-17A antibody, an anti-IL-17A / F antibody, an anti-IL-23p40 subunit antibody and / or an anti-IL-23p19 subunit antibody or a fragment thereof.
- the treatment method of [34] which is one or more selected from the group consisting of brodalmab, sekkinumab, ixekizumab, netakimab, bimekizumab, ustekinumab, chilldrakizumab, risankizumab, mirikizumab, brazicumab and guselkumab.
- the therapeutic method of [35] wherein the antibody is brodalumab.
- [40] The treatment method according to any one of [31] to [39], wherein the skin score (mRSS) in the subject is reduced by 7 or more from that before the treatment by 52 weeks after the start of administration.
- the single dose of the IL-17 pathway inhibitor is 210 mg, which is subcutaneously administered on the first day, one week, and two weeks later, and thereafter, subcutaneously administered once every two weeks.
- the second therapeutic agent is a corticosteroid, an antifibrotic drug, an immunosuppressant, a proton pump inhibitor, a prostacyclin derivative, an angiotensin converting enzyme inhibitor, an endoserine receptor antagonist and a type 2 cannabinoid receptor.
- the treatment method of [44] which is at least one selected from the group consisting of antagonists.
- the present invention provides a novel technique effective for the treatment of systemic scleroderma which may be accompanied by progressive skin sclerosis.
- mRSS modified Rodnan total skin thickness score
- the vertical axis represents mRSS (the start of treatment is 0).
- the horizontal axis shows the period (weeks) from the first dose of brodalumab.
- the vertical axis represents mRSS (the start of treatment is 0).
- the horizontal axis shows the period (weeks) from the first dose of brodalumab.
- the present invention relates to a pharmaceutical composition for treating a patient with systemic scleroderma, which contains an IL-17 pathway inhibitor as an active ingredient and may be accompanied by progressive skin sclerosis.
- the present invention also includes a method for treating a patient with systemic scleroderma, which comprises a procedure for administering an IL-17 pathway inhibitor to a patient with systemic scleroderma who may be accompanied by progressive skin sclerosis. ..
- Systemic scleroderma is a chronic disease characterized by hardening of the skin and internal organs.
- Systemic scleroderma is "diffuse skin scleroderma systemic scleroderma (dcSSc)” in which skin sclerosis extends to the proximal limbs (upper arm, thigh) or trunk except for the face, and skin sclerosis is distal to the extremities (dcSSc). It is classified into two types, “localized skin sclerosing systemic scleroderma (lcSSc)", which is localized to the forearm and lower leg) and face.
- dcSSc skin sclerosing systemic scleroderma
- the systemic scleroderma targeted by the pharmaceutical composition or treatment method of the present invention is not limited to either diffuse scleroderma systemic scleroderma or localized scleroderma systemic scleroderma. , Diffuse skin sclerosing systemic scleroderma is preferred.
- Patients with systemic scleroderma who are the target of the pharmaceutical composition or therapeutic method of the present invention include patients with organ lesions in the lung, gastrointestinal tract, kidney or heart or joint flexion contracture in addition to the symptoms of skin sclerosis. It may be.
- the severity of skin sclerosis in systemic scleroderma can be evaluated by known methods.
- the modified Rodnan total skin thickness score (mRSS) can be evaluated by the following method described in the guidelines of the Japanese Dermatological Association.
- the body is divided into 17 parts (fingers, backs of hands, forearms, upper arms, face, precordium, abdomen, thighs, lower legs, backs of both feet), and the degree of skin hardening is 0 to 3 for each part.
- pinch the skin with both thumbs and the thickness of the skin Observe the mobility with the lower floor.
- the severity of sclerosis in Japan is 0 (normal: 0), 1-9 (mild: 1), 10-19 (moderate: 2), 20-29 (severe: 3), 30 or more (normal: 0), 1-9 (mild: 1), 10-19 (moderate: 2), 20-29 (severe: 3), 30 or more, according to the total mRSS in Japan. It is classified into very seven: 4) (Journal of the Japanese Society of Dermatology, 126 (10), 1831-1896, 2016).
- the measurement method of mRSS is JR face, 1993; 20 (11): p 1892-1896 and JR face. , 1995; 22: p1281-1285.
- the severity of skin hardening that is the subject of the pharmaceutical composition or therapeutic method of the present invention is not particularly limited, but mRSS is preferably 10 or more, more preferably 20 or more, and most preferably 20 or more and less than 30. That is, the severity of skin hardening is preferably moderate or higher, more preferably severe or higher, and most preferably moderate to severe.
- the target of the pharmaceutical composition or the treatment method of the present invention may be a patient with systemic scleroderma whose effect is insufficient with the existing treatment.
- the target of the pharmaceutical composition or the therapeutic method of the present invention may be a patient with systemic scleroderma having skin sclerosis whose effect is insufficient by the existing treatment.
- the subject of the pharmaceutical composition or therapeutic method of the present invention may be a patient with systemic scleroderma having moderate to severe skin sclerosis.
- the subject of the pharmaceutical composition or therapeutic method of the present invention may be a patient with systemic scleroderma having skin sclerosis in the early stage of onset. The early stage of onset refers to within 6 years after the onset.
- the subject of the pharmaceutical composition or therapeutic method of the present invention may be a patient with systemic scleroderma having reversible skin sclerosis.
- Reversible skin hardening refers to a condition in which the condition of the skin shows edema and hardening and does not lead to atrophy.
- the improvement of skin hardening may be confirmed by a known method.
- improvement of skin hardening can be confirmed by measuring mRSS over time after administration of the pharmaceutical composition of the present invention and confirming a decrease in mRSS as compared with before treatment.
- mRSS is 1, 2, 3, 4, 5, 6, 7, 8, 9, after a certain period of time from the administration of the pharmaceutical composition or the start of the treatment method, as compared with before the treatment. Or it means that it has decreased by 10 or more.
- mRSS is 2 or more by 8 weeks, 3 or more by 12 weeks, 3 or more by 16 weeks, 4 or more by 20 weeks, 5 by 24 weeks from the start of the administration or treatment method of the pharmaceutical composition of the present invention. As mentioned above, it can be reduced by 6 or more by 40 weeks and 7 or more by 52 weeks.
- the pharmaceutical composition and therapeutic method of the present invention improve or treat at least one symptom selected from the symptom of organ lesions or joint flexion contracture in the lung, gastrointestinal tract, kidney or heart, in addition to the symptom of skin sclerosis. Can be done.
- the pharmaceutical composition and therapeutic method of the present invention can improve or treat various symptoms based on systemic or local fibrosis.
- the improvement of each symptom can be evaluated by a known method. For example, improvement in lung function due to fibrosis in the lung can be evaluated by scoring lung function with a spirometer. Improvement of the symptoms of reflux esophagitis in the gastrointestinal tract can be evaluated by scoring patient symptoms using an F-scale questionnaire.
- the term “administration” means a single dose or multiple doses (hereinafter, also referred to as “continuous infusion”).
- the single dose of the IL-17 pathway inhibitor used in the present invention is not particularly limited, and it may be used at a dose that can be clinically applied with reference to the package insert of each inhibitor.
- the single dose is preferably 70 mg or more, more preferably 140 mg or more, and most preferably 210 mg.
- the dose may be appropriately increased or decreased during continuous infusion of the therapeutic agent.
- the single dose is typically 70 mg, 140 mg, 210 mg, or 280 mg.
- the administration interval of the pharmaceutical composition is not particularly limited, but for example, it is administered on the 1st day (hereinafter, also referred to as the 0th week), the 1st week and the 2nd week, and thereafter once or 4 times every 2 weeks. Administer once a week.
- the dosing interval may be appropriately extended or shortened. It is desirable that the administration interval is 1st day, 1st week, 2nd week, and thereafter once every 2 weeks.
- the dose and interval of administration are particularly preferably 210 mg per dose, and the dose is administered once every two weeks on the first day, one week, two weeks, and thereafter.
- the administration period of the pharmaceutical composition is not particularly limited, but may be, for example, 8, 10, 12, 16, 20, 24, 36, 48 or 52 weeks after the start of administration, or may be administered longer than 52 weeks.
- the administration period is preferably longer than 52 weeks.
- a drug holiday may be included during the administration period.
- the IL-17 pathway inhibitor in the present invention inhibits the interaction between IL-17RA and IL-17RA ligands (IL-17A, IL-17F, IL-17A / F, IL-17E, etc.) and is physiological. Includes a wide range of substances that can block active signals.
- an antagonist that inhibits the interaction between IL-17RA and IL-17RA ligand and blocks the physiological activity signal is referred to as "IL-17RA antagonist”.
- IL-23 is known to induce Th17 cells that produce IL-17RA ligands and is located upstream of the IL-17 pathway (Nature Reviews Drug Discovery 2015, volume 14, p11-12).
- the IL-17 pathway inhibitor of the present invention also includes a substance that can inhibit the interaction between IL-23 and IL-23R and block the bioactive signal.
- an agent that inhibits the interaction between IL-23 and IL-23R and blocks the physiological activity signal is referred to as an "IL-23R antagonist".
- the IL-17RA antagonist is, for example, an antagonist having an activity of inhibiting the binding of IL-17RA and the IL-17RA ligand, an antagonist having an activity of inhibiting the activation of IL-17RA initiated by the binding of the IL-17RA ligand, and the like.
- it may be an antagonist having an activity of inhibiting the association between IL-17RA and a receptor forming a heterodimer.
- the IL-23R antagonist may be, for example, an antagonist having an activity of inhibiting the binding between IL-23R and IL-23, and an antagonist having an activity of inhibiting the association of p19 and p40, which are subunits of IL-23. ..
- the IL-17RA antagonist and the IL-23R antagonist can be, for example, a small molecule, an antibody or fragment of the antibody, siRNA, an antisense oligonucleotide.
- the IL-17RA antagonist and the IL-23R antagonist are preferably antibodies or antibody fragments.
- an IL-17RA antagonist examples include anti-IL-17RA antibody, anti-IL-17A antibody, anti-IL-17F antibody, anti-IL-17A / F antibody, anti-IL-17E antibody and fragments thereof. ..
- IL-17RA antagonists include dihydroorotoic acid dehydrogenase inhibitors.
- Dihydroorotoic acid dehydrogenase inhibitors include bidfludimus.
- an IL-23R antagonist examples include an anti-IL-23p40 subunit antibody and an anti-IL-23p19 subunit antibody.
- anti-IL-23p40 subunit antibody examples include ustekizumab.
- anti-IL-23p19 subunit antibodies include tidrakizumab, risankizumab, millikizumab, brazicumab and guselkumab.
- the IL-17 pathway inhibitor is preferably an IL-17RA antagonist and an IL-23R antagonist, more preferably an IL-17RA antagonist.
- the IL-17RA antagonist is preferably brodalumab, which is an anti-IL-17RA antibody, netakimab, secukinumab or ixekizumab, which is an anti-IL-17A antibody, bimekizumab, which is an anti-IL-17A / F antibody, and most preferably brodalumab.
- the pharmaceutical composition or therapeutic method of the present invention can be used in combination with a second therapeutic agent or a second therapeutic method.
- the second therapeutic agent is, for example, an adrenocortical steroid, an antifibrotic drug, an immunosuppressant, a proton pump inhibitor, an angiotensin converting enzyme inhibitor, an endothelin receptor antagonist prostacyclin derivative or a type 2 cannabinoid receptor antagonist.
- corticosteroids include bredonizolone.
- Antifibrotic agents include, for example, pirfenidone and nintedanib.
- Immunosuppressants include, for example, cyclophosphamide, mycophenolate mofetil, cyclosporine, tacrolimus, azathioprine, mizoribine and methotrexate.
- Proton pump inhibitors include, for example, omeprazole, lansoprazole, rabeprazole and esomeprazole.
- Examples of angiotensin converting enzyme inhibitors include captopril, enalapril, alacepril, imidapril and temocapril.
- Endothelin receptor antagonists include, for example, bosentan, ambrisentan and macitentan.
- Prostacyclin derivatives include, for example, iloprost, beraprost, treprostinil, epoprostenol or clinprost.
- Examples of type 2 cannabinoid receptor antagonists include renavasam.
- the second treatment method includes, for example, high-dose intravenous immunoglobulin therapy (IVIG) or phototherapy.
- IVIG immunoglobulin therapy
- two or more kinds of IL-17 pathway inhibitors may be used in combination.
- the pharmaceutical composition or therapeutic method of the present invention also includes an embodiment in which it is used in combination with a second therapeutic agent.
- the antibody used in the present invention may be either a monoclonal antibody or a polyclonal antibody, and is preferably a monoclonal antibody that binds to a single epitope.
- the antibody may be a monoclonal antibody produced from a hybridoma, or a genetically modified antibody produced by a gene recombination technique.
- recombinant antibodies include mouse antibodies, rat antibodies, human chimeric antibodies (hereinafter simply referred to as "chimeric antibodies"), and humanized antibodies (also referred to as human complementarity determining regions (CDR) transplanted antibodies. ), And human antibodies. Chimeric antibodies, humanized antibodies, or human antibodies are preferably used to reduce immunogenicity in humans.
- examples of the monoclonal antibody used in the present invention include an antibody selected from the following (A) to (F) and the antibody fragment thereof.
- the CDR1, CDR2, and CDR3 of the heavy chain variable region (denoted as VH) of the antibody contain the amino acid sequences represented by SEQ ID NOs: 1, 2, and 3, respectively, and the light chain variable region of the antibody (denoted as VH).
- VL Monoclonal antibodies in which CDR1, CDR2, and CDR3 (denoted as VL) contain the amino acid sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively;
- B A monoclonal antibody in which the VH of the antibody contains the amino acid sequence shown by SEQ ID NO: 7 and the VL of the antibody contains the amino acid sequence shown by SEQ ID NO: 8.
- C A monoclonal antibody in which the heavy chain (H chain) of the antibody contains the amino acid sequence shown by SEQ ID NO: 9 and the L chain of the antibody contains the amino acid sequence shown by SEQ ID NO: 10.
- the antibody VHs CDR1, CDR2, and CDR3 contain the amino acid sequences represented by SEQ ID NOs: 1, 2, and 3, respectively, and the antibody VL CDR1, CDR2, and CDR3 are respectively sequenced.
- an antibody is an anti-human IL-17RA human monoclonal antibodies AM H 14 / AM L 14 (Patent Document 1) and recombinant anti-human IL-17RA human antibody Burodarumabu.
- the "monoclonal antibody” refers to an antibody secreted by a single cloned antibody-producing cell, which recognizes only one epitope (antibody determinant) and has an amino acid sequence (primary structure) constituting the monoclonal antibody. ) Is uniform.
- An “epitope” is a single amino acid sequence recognized for binding by a monoclonal antibody; a three-dimensional structure consisting of an amino acid sequence; a sugar chain, a glycolipid, a polysaccharide, an amino group, a carboxyl group, a phosphoric acid, a sulfuric acid, etc.
- An amino acid sequence to which a modified residue is bound and a three-dimensional structure consisting of an amino acid sequence to which the modified residue is bound.
- the "three-dimensional structure” is a three-dimensional structure possessed by a naturally occurring protein, and refers to a three-dimensional structure composed of a protein expressed in the cell or on the cell membrane.
- the antibody molecule is also referred to as immunoglobulin (hereinafter referred to as Ig).
- Human antibodies are classified into IgA1, IgA2, IgD, IgE, IgG1, IgG2, IgG3, IgG4, and IgM isotypes, depending on the differences between their molecular structures.
- IgG1, IgG2, IgG3, and IgG4, which have relatively high amino acid sequence homology, are also collectively referred to as IgG.
- the IgG class is preferable, and IgG selected from IgG1, IgG2, IgG4 and Fc variants in which one or more amino acid residue substitutions are added to the Fc region of the isotype antibody. Class is more preferred.
- the antibody molecule is composed of polypeptides called heavy chain (H chain) and light chain (L chain).
- the H chain is composed of VH and H chain constant regions (also referred to as CH) from the N-terminal side
- the L chain is composed of VL and L chain constant regions (also referred to as CL) from the N-terminal side, respectively.
- Chromatin antibody refers to an antibody composed of VH and VL of antibodies derived from animals other than humans and CH and CL of human antibodies.
- the type of animal from which the variable region is derived is not particularly limited as long as it is an animal that can be used for producing hybridomas such as mice, rats, hamsters, and rabbits.
- Humanized antibody is an antibody (humanized CDR transplanted antibody) obtained by transplanting VH and VL CDRs derived from non-human animal antibodies to appropriate positions of VH and VL of human antibodies.
- Human antibody means an antibody that can naturally exist in the human body or an antibody consisting of an amino acid sequence encoded by a human gene. Human antibodies also include antibodies obtained from human antibody phage libraries or human antibody-producing transgenic animals produced based on genetically engineered, cell-engineering, and developmental engineering techniques.
- the type of antibody fragment is not particularly limited, and examples thereof include peptides containing Fab, Fab', F (ab') 2 , scFv, diabodies, dsFv, and CDRs.
- the pharmaceutical composition of the present invention may contain only an IL-17 pathway inhibitor as an active ingredient, but is usually mixed with one or more pharmacologically acceptable carriers and prepared. It is preferable to provide it as a pharmaceutical preparation produced by any method well known in the technical field of science.
- a specific example of a pharmaceutical preparation contains 140 mg / mL of recombinant anti-human IL-17RA human antibody bladrumab as an active ingredient, and 10 mmol / L of L-glutamic acid as an additive, and 3% (w / v) of L-.
- the pharmaceutical formulation contains 140 mg / mL of recombinant anti-human IL-17RA human antibody brodalumab, and further, as an additive, 30 mmol / L L-glutamic acid, 2.4% (w / v) L-proline, Also included is a pharmaceutical formulation with a pH of 4.8, which comprises 0.01% (w / v) of polysorbate 20.
- the pharmaceutical formulation can be produced, for example, by the method described in WO 2011/08A120.
- the route of administration of the IL-17 pathway inhibitor in the pharmaceutical composition or therapeutic method of the present invention is preferably the most effective route for treatment.
- Specific examples of the administration route include oral administration or parenteral administration such as intraoral, intraairway, rectal, subcutaneous, intramuscular or intravenous administration, and subcutaneous or intravenous administration is preferable, and subcutaneous administration is more preferable.
- Examples of administration forms include sprays, capsules, tablets, powders, granules, syrups, emulsions, suppositories, injections, ointments, tapes and the like, and injections are preferable.
- the device for administering the therapeutic agent of the present invention can be appropriately selected during treatment.
- the administration device include, but are not limited to, prefilled syringes and automatic syringes.
- Brodalumab was prepared according to a conventional method as a recombinant human antibody derived from CHO cells having the antibody variable region amino acid sequence described in Patent Document 1.
- Table 3 presents information on the subjects who participated in the clinical trial. As shown in the table, 7 out of 8 patients with systemic scleroderma with moderate to severe skin sclerosis had severe (mRSS 20-29) skin sclerosis.
- the mRSS at 12 weeks after the start of administration was 3 or more from the baseline (mRSS at the start of treatment). It has decreased.
- mRSS decreased by 5 or more from the baseline
- mRSS decreased by 7 or more from the baseline.
- Treatment with bladrumab has been shown to result in a marked reduction in skin score as early as 12, 24 or 52 weeks after the start of treatment in patients with systemic scleroderma with moderate to severe skin sclerosis. It was.
- corticosteroids diexamethasone intravenous pulse therapy
- corticosteroids diexamethasone intravenous pulse therapy
- it will take some time (Rhcumatol lnt, 1994, 14, 91-94).
- the decrease of mRSS from the baseline 12 months after the start of treatment was only 3.6 (N Engl J Med, 2006, 354, 2655-66).
- SEQ ID NO: 1 Brodalumab_HCDR1 amino acid
- SEQ ID NO: 2 Brodalumab_HCDR2 amino acid
- SEQ ID NO: 3 Brodalmab_HCDR3 amino acid
- SEQ ID NO: 4 Brodalumab_LCDR1 amino acid
- SEQ ID NO: 5 Brodalmab_LCDR2 amino acid
- SEQ ID NO: 6 Brodalumab _LCDR3 amino acid sequence
- SEQ ID NO: 8 Brodalmab_VL amino acid sequence
- SEQ ID NO: 9 Brodalumab_H chain amino acid sequence
- SEQ ID NO: 10 Brodalmab_L chain amino acid sequence
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Abstract
Description
[1] IL-17経路阻害剤を有効成分として含有する、全身性強皮症治療用の医薬組成物。
[2] IL-17経路阻害剤を有効成分として含有する、進行性の皮膚硬化を伴う全身性強皮症治療用の医薬組成物。
[3] IL-17経路阻害剤が、IL-17RAアンタゴニストおよびIL-23Rアンタゴニストより選ばれるいずれか1以上である、[1]または[2]の医薬組成物。
[4] IL-17経路阻害剤が、抗体または抗体断片である、[1]―[3]のいずれかの医薬組成物。
[5] 前記抗体が、抗IL-17RA抗体、抗IL-17A抗体、抗IL-17A/F抗体、抗IL-23p40サブユニット抗体および/または抗IL-23p19サブユニット抗体であり、特にブロダルマブ、セクキヌマブ、イキセキズマブ、ネタキマブ、ビメキズマブ、ウステキヌマブ、チルドラキズマブ、リサンキズマブ、ミリキズマブ、ブラジクマブおよびグセルクマブからなる群より選ばれるいずれか1以上である、[4]の医薬組成物。
[6] 前記抗体が、ブロダルマブである、[5]の医薬組成物。
[7] 前記全身性強皮症が、びまん皮膚硬化型全身性強皮症(dcSSc)である、[1]-[6]のいずれかの医薬組成物。
[8] 患者のスキンスコア(mRSS)を、投与開始後12週までに治療前より3以上低下させるための、[1]-[7]の医薬組成物。
[9] 患者のスキンスコア(mRSS)を、投与開始後24週までに治療前より5以上低下させるための、[1]-[8]のいずれかの医薬組成物。
[10] 患者のスキンスコア(mRSS)を、投与開始後52週までに治療前より7以上低下させるための、[1]-[9]のいずれかの医薬組成物。
[11] 治療前のスキンスコア(mRSS)が20以上30未満である患者に用いるための、[1]-[10]のいずれかの医薬組成物。
[12] 前記IL-17経路阻害剤の1回投与用量が、70mg、140mg、210mg、または280mgである、[1]-[11]のいずれかの医薬組成物。
[13] 前記IL-17経路阻害剤の1回投与量が210mgであり、1日目、1週後、2週後に皮下投与され、以降、2週間に1回皮下投与される、[1]-[12]のいずれの医薬組成物。
[14] IL-17経路阻害剤以外の第2の治療剤と組み合わせて用いるための、[1]-[13]のいずれかの医薬組成物。
[15] 前記第2の治療剤が、副腎皮質ステロイド、抗線維化薬、免疫抑制剤、プロトンポンプ阻害剤、プロスタサイクリン誘導体、アンジオテンシン変換酵素阻害剤、エンドセリン受容体拮抗剤および2型カンナビノイド受容体拮抗剤からなる群から選ばれる少なくとも1以上である、[14]の医薬組成物。
[16]IL-17経路阻害剤を有効成分として含有する、全身性強皮症治療用の医薬組成物であり、
前記全身性強皮症が、びまん皮膚硬化型全身性強皮症(dcSSc)であり、
前記IL-17経路阻害剤がブロダルマブであり、その1回投与量が210mgであり、1日目、1週後、2週後に皮下投与され、以降、2週間に1回皮下投与される、医薬組成物。
[18] 進行性の皮膚硬化を伴う全身性強皮症の治療に用いるための、IL-17経路阻害剤。
[19] IL-17RAアンタゴニストおよびIL-23Rアンタゴニストより選ばれるいずれか1以上である、[17]または[18]のIL-17経路阻害剤。
[20] 抗体または抗体断片である、[17]-[19]のいずれかのIL-17経路阻害剤。
[21] 抗IL-17RA抗体、抗IL-17A抗体、抗IL-17A/F、抗IL-23p40サブユニット抗体および/または抗IL-23p19サブユニット抗体またはそれらの断片であり、特にブロダルマブ、セクキヌマブ、イキセキズマブ、ネタキマブ、ビメキズマブ、ウステキヌマブ、チルドラキズマブ、リサンキズマブ、ミリキズマブ、ブラジクマブおよびグセルクマブからなる群より選ばれるいずれか1以上の抗体またはその断片である、[20]のIL-17経路阻害剤。
[22] ブロダルマブである、[21]のIL-17経路阻害剤。
[23] 前記全身性強皮症が、びまん皮膚硬化型全身性強皮症(dcSSc)である、[17]-[22]のいずれかのIL-17経路阻害剤。
[25] 進行性の皮膚硬化を伴う全身性強皮症治療用の医薬組成物の製造のための、IL-17経路阻害剤の使用。
[26] IL-17経路阻害剤が、IL-17RAアンタゴニストおよびIL-23Rアンタゴニストより選ばれるいずれか1以上である、[24]または[25]の使用。
[27] IL-17経路阻害剤が、抗体または抗体断片である、[24]-[26]のいずれかの使用。
[28] 前記抗体が、抗IL-17RA抗体、抗IL-17A抗体、抗IL-17A/F抗体、抗IL-23p40サブユニット抗体および/または抗IL-23p19サブユニット抗体であり、特にブロダルマブ、セクキヌマブ、イキセキズマブ、ネタキマブ、ビメキズマブ、ウステキヌマブ、チルドラキズマブ、リサンキズマブ、ミリキズマブ、ブラジクマブおよびグセルクマブからなる群より選ばれるいずれか1以上である、[27]の使用。
[29] 前記抗体が、ブロダルマブである、[28]の使用。
[30] 前記全身性強皮症が、びまん皮膚硬化型全身性強皮症(dcSSc)である、[24]-[29]のいずれかの使用。
[32] 対象にIL-17経路阻害剤を有効成分として含有する医薬組成物を投与する手順を含む、進行性の皮膚硬化を伴う全身性強皮症の治療方法。
[33] IL-17経路阻害剤が、IL-17RAアンタゴニストおよびIL-23Rアンタゴニストより選ばれるいずれか1以上である、[31]または[32]の治療方法。
[34] IL-17経路阻害剤が、抗体または抗体断片である、[31]-[33]のいずれかの治療方法。
[35] 前記抗体が、抗IL-17RA抗体、抗IL-17A抗体、抗IL-17A/F抗体、抗IL-23p40サブユニット抗体および/または抗IL-23p19サブユニット抗体またはそれらの断片であり、特にブロダルマブ、セクキヌマブ、イキセキズマブ、ネタキマブ、ビメキズマブ、ウステキヌマブ、チルドラキズマブ、リサンキズマブ、ミリキズマブ、ブラジクマブおよびグセルクマブからなる群より選ばれるいずれか1以上である、[34]の治療方法。
[36] 前記抗体が、ブロダルマブである、[35]の治療方法。
[37] 前記全身性強皮症が、びまん皮膚硬化型全身性強皮症(dcSSc)である、[31]-[36]のいずれかの治療方法。
[38] 前記対象におけるスキンスコア(mRSS)が、投与開始後12週までに治療前より3以上低下する、[31]-[37]の治療方法。
[39] 前記対象におけるスキンスコア(mRSS)が、投与開始後24週までに治療前より5以上低下する、[31]-[38]のいずれかの治療方法。
[40] 前記対象におけるスキンスコア(mRSS)が、投与開始後52週までに治療前より7以上低下する、[31]-[39]のいずれかの治療方法。
[41] 前記対象の治療前のスキンスコア(mRSS)が20以上30未満である、[31]-[40]のいずれかの治療方法。
[42] 前記IL-17経路阻害剤の1回投与用量が、70mg、140mg、210mg、または280mgである、[31]-[41]のいずれかの治療方法。
[43] 前記IL-17経路阻害剤の1回投与量が210mgであり、1日目、1週後、2週後に皮下投与され、以降、2週間に1回皮下投与される、[31]-[42]のいずれかの治療方法。
[44] IL-17経路阻害剤以外の第2の治療剤を投与する手順をさらに含む、[31]-[43]のいずれかの治療方法。
[45] 前記第2の治療剤が、副腎皮質ステロイド、抗線維化薬、免疫抑制剤、プロトンポンプ阻害剤、プロスタサイクリン誘導体、アンジオテンシン変換酵素阻害剤、エンドセリン受容体拮抗剤および2型カンナビノイド受容体拮抗剤からなる群から選ばれる少なくとも1以上である、[44]の治療方法。
身体を17の部位(両手指、両手背、両前腕、両上腕、顔、前胸部、腹部、両大腿、両下腿、両足背)に分け、皮膚の硬化程度を各部位について0から3までの4段階で評価し(0=正常、1=軽度、2=中等度、3=高度、総計0から51までのスキンスコアとする。評価する際は、皮膚を両拇指ではさみ、皮膚の厚さと下床との可動性を観察する。皮膚が下床との可動性をまったく欠く場合を3、明瞭な皮膚硬化はないがやや厚ぼったく感じられるものを1とし、その中間を2と判定する。皮膚硬化の重症度は、日本ではmRSSの総計により、0(normal:0)、1~9(mild:1)、10~19(moderate:2)、20~29(severe:3)、30以上(very severe:4)に分類される(日本皮膚科学会雑誌、126(10)、1831-1896、2016)。mRSSの測定法はJ Rheumatol,1993;20(11):p 1892-1896とJ Rheumatol,1995;22:p1281-1285にも開示がある。
本発明の医薬組成物又は治療方法の対象は、既存治療で効果不十分な、皮膚硬化を有する全身性強皮症の患者であっても良い。
本発明の医薬組成物又は治療方法の対象は、中等症から重症の皮膚硬化を有する全身性強皮症の患者であっても良い。
本発明の医薬組成物又は治療方法の対象は、発症初期の皮膚硬化を有する全身性強皮症の患者であっても良い。発症初期とは、発症後6年以内を指す。
本発明の医薬組成物又は治療方法の対象は、可逆性の皮膚硬化を有する全身性強皮症の患者であっても良い。可逆性の皮膚硬化とは、皮膚の状態が浮腫および硬化を示し、萎縮に至っていない状態を指す。
投与量及び投与間隔は、特に好ましくは、1回投与量を210mgとし、1日目、1週後、2週後、以降は2週間に1回投与とされる。
IL-23は、IL-17RAリガンドを産生するTh17細胞を誘導することが知られており、IL-17経路の上流に位置する(Nature Reviews Drug Discovery 2015,volume14,p11-12)。よって、本発明のIL-17経路阻害剤には、IL-23とIL-23Rとの相互作用を阻害し、生理活性シグナルを遮断し得る物質も含まれる。以下、IL-23とIL-23Rとの相互作用を阻害し、生理活性シグナルを遮断するものを「IL-23Rアンタゴニスト」と称する。
IL-17RAアンタゴニストは、例えば、IL-17RAとIL-17RAリガンドとの結合を阻害する活性を有するアンタゴニスト、IL-17RAリガンドの結合により開始されるIL-17RA活性化を阻害する活性を有するアンタゴニスト、またはIL-17RAとヘテロダイマーを形成する受容体との間の会合を阻害する活性を有するアンタゴニストであってよい。
IL-23Rアンタゴニストは、例えば、IL-23RとIL-23との結合を阻害する活性を有するアンタゴニスト、IL-23のサブユニットであるp19とp40の会合を阻害する活性を有するアンタゴニストであって良い。
第2の治療剤は、例えば、副腎皮質ステロイド、抗線維化薬、免疫抑制剤、プロトンポンプ阻害剤、アンジオテンシン変換酵素阻害剤、エンドセリン受容体拮抗剤プロスタサイクリン誘導体又は2型カンナビノイド受容体拮抗剤である。
副腎皮質ステロイドとしては、例えば、ブレドニゾロンが挙げられる。
抗線維化薬としては、例えば、ピルフェニドンおよびニンテダニブが挙げられる。
免疫抑制剤としては、例えば、シクロホスファミド、ミコフェノール酸モフェチル、シクロスポリン、タクロリムス、アザチオプリン、ミゾリビンおよびメトトレキサートが挙げられる。
プロトンポンプ阻害剤としては、例えば、オメプラゾール、ランソプラゾール、ラベプラゾールおよびエソメプラゾールが挙げられる。
アンジオテンシン変換酵素阻害剤としては、例えば、カプトプリル、エナラプリル、アラセプリル、イミダプリルおよびテモカプリルが挙げられる。
エンドセリン受容体拮抗剤としては、例えば、ボセンタン、アンブリセンタンおよびマシテンタンが挙げられる。
プロスタサイクリン誘導体としては、例えば、イロプロスト、ベラプロスト、トレプロスチニル、エポプロステノール又はクリンプロストが挙げられる。
2型カンナビノイド受容体拮抗剤としては、例えばレナバサムが挙げられる。
第2の治療方法としては、例えば、免疫グロブリン大量静注療法(IVIG)または光線療法が挙げられる。
本発明の医薬組成物又は治療方法では、IL-17経路阻害剤は、2種類以上が組み合わせて用いられてもよい。
本発明の医薬組成物及び治療方法において、IL-17経路阻害剤と第2の治療剤を用いる場合、患者に対して同時又は別時に投与することができる。従って、本発明の医薬組成物又は治療方法には、第2の治療剤と併用する態様も含まれる。
(A)抗体の重鎖可変領域(VHと表記する)のCDR1、CDR2、およびCDR3が、それぞれ配列番号1、2、および3で示されるアミノ酸配列を含み、かつ、抗体の軽鎖可変領域(VLと表記する)のCDR1、CDR2、およびCDR3が、それぞれ配列番号4、5、および6で示されるアミノ酸配列を含むモノクローナル抗体;
(B)抗体のVHが配列番号7で示されるアミノ酸配列を含み、かつ、抗体のVLが配列番号8で示されるアミノ酸配列を含むモノクローナル抗体;
(C)抗体の重鎖(H鎖)が配列番号9で示されるアミノ酸配列を含み、かつ抗体のL鎖が配列番号10で示されるアミノ酸配列を含むモノクローナル抗体;
(D)前記(A)~(C)から選ばれるいずれか1の抗体と競合して、IL-17RAに結合する抗体;
(E)前記(A)~(C)から選ばれるいずれか1の抗体が結合するIL-17RAに存在するエピトープに結合する抗体;及び
(F)前記(A)~(C)から選ばれるいずれか1の抗体が有するアミノ酸配列と90%以上の配列同一性を有し、且つ、該抗体と同等の結合特異性並びに結合活性を有する抗体。
本発明に用いられる抗体クラスとしては、IgGクラスが好ましく、IgG1、IgG2、IgG4及び当該アイソタイプ抗体のFc領域に1つ又は2つ以上のアミノ酸残基置換が加えられたFc改変体から選ばれるIgGクラスがより好ましい。
(1)試験概要
組換え抗ヒトIL-17RAヒト抗体ブロダルマブの、中等度~重度の皮膚硬化を有する全身性強皮症患者を対象とした第I相臨床試験(以下、単に「臨床試験」とも称する)の概要を表1に提示する。臨床試験の被験者として、表2に示した条件を満たす全身性強皮症患者を選択し、ブロダルマブを投与した際の安全性および有効性等を評価した。各被験者には、210mgのブロダルマブを1日目、1週目、および2週目、そして以降は50週目まで2週間に1回皮下投与した。
臨床試験に参加した被験者について、皮膚硬化の程度を示すスキンスコア(mRSS)をブロダルマブの初回投与から経時的に測定した。得られた結果を図1及び図2に示す。mRSSは、全身17か所の皮膚を医師が両拇指でつまむことにより、それぞれの部位について皮膚硬化の程度を0~3の4段階で評価(0=正常、1=軽度、2=中等度、3=高度、総計は0~51)された。mRSSによる皮膚の重症度は、総計が0=normal、1~9=mild、10~19=moderate、20~29=severe、30以上=very severeと分類された。
一方、ブロダルマブによる治療では、重度の皮膚硬化を有する7名の患者を含む、中等度~重度の皮膚硬化を有する全身性強皮症患者のすべてにおいて、治療開始後12週、24週あるいは52週でmRSSの顕著な低下を達成できた。この結果は、ブロダルマブが、中等度~重度の皮膚硬化を伴う全身性強皮症に適用されて、従来の薬剤に比してきわめて早期の段階で治療効果を奏し得るものであることを示す。
配列番号2:ブロダルマブ_HCDR2のアミノ酸配列
配列番号3:ブロダルマブ_HCDR3のアミノ酸配列
配列番号4:ブロダルマブ_LCDR1のアミノ酸配列
配列番号5:ブロダルマブ_LCDR2のアミノ酸配列
配列番号6:ブロダルマブ_LCDR3のアミノ酸配列
配列番号7:ブロダルマブ_VHのアミノ酸配列
配列番号8:ブロダルマブ_VLのアミノ酸配列
配列番号9:ブロダルマブ_H鎖のアミノ酸配列
配列番号10:ブロダルマブ_L鎖のアミノ酸配列
Claims (14)
- IL-17経路阻害剤を有効成分として含有する、全身性強皮症治療用の医薬組成物。
- IL-17経路阻害剤が、IL-17RAアンタゴニストおよびIL-23Rアンタゴニストより選ばれるいずれか1以上である、請求項1に記載の医薬組成物。
- IL-17経路阻害剤が、抗体または抗体断片である、請求項1または2に記載の医薬組成物。
- 前記抗体が、ブロダルマブ、セクキヌマブ、イキセキズマブ、ネタキマブ、ビメキズマブ、ウステキヌマブ、チルドラキズマブ、リサンキズマブ、ミリキズマブ、ブラジクマブおよびグセルクマブからなる群より選ばれるいずれか1以上である、請求項3に記載の医薬組成物。
- 前記抗体が、ブロダルマブである、請求項4に記載の医薬組成物。
- 前記全身性強皮症が、びまん皮膚硬化型全身性強皮症(dcSSc)である、請求項1から5のいずれか1項に記載の医薬組成物。
- 患者のスキンスコア(mRSS)を、投与開始後12週までに治療前より3以上低下させるための、請求項1から6のいずれか1項に記載の医薬組成物。
- 患者のスキンスコア(mRSS)を、投与開始後24週までに治療前より5以上低下させるための、請求項1から7のいずれか1項に記載の医薬組成物。
- 患者のスキンスコア(mRSS)を、投与開始後52週までに治療前より7以上低下させるための、請求項1から8のいずれか1項に記載の医薬組成物。
- 治療前のスキンスコア(mRSS)が20以上30未満である患者に用いるための、請求項1から9のいずれか1項に記載の医薬組成物。
- 前記IL-17経路阻害剤の1回投与用量が、70mg、140mg、210mg、または280mgである、請求項1から10のいずれか1項に記載の医薬組成物。
- 前記IL-17経路阻害剤の1回投与量が210mgであり、1日目、1週後、2週後に皮下投与され、以降、2週間に1回皮下投与される、請求項1から11のいずれか1項に記載の医薬組成物。
- IL-17経路阻害剤以外の第2の治療剤と組み合わせて用いるための、請求項1から12のいずれか1項に記載の医薬組成物。
- 前記第2の治療剤が、副腎皮質ステロイド、抗線維化薬、免疫抑制剤、プロトンポンプ阻害剤、プロスタサイクリン誘導体、アンジオテンシン変換酵素阻害剤、エンドセリン受容体拮抗剤および2型カンナビノイド受容体拮抗剤からなる群から選ばれる少なくとも1以上である、請求項13に記載の医薬組成物。
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JP2021549013A JP7093940B2 (ja) | 2019-09-25 | 2020-09-25 | 全身性強皮症治療用医薬組成物 |
KR1020227013178A KR20220070244A (ko) | 2019-09-25 | 2020-09-25 | 전신성 강피증 치료용 의약 조성물 |
CN202080066358.8A CN114423455A (zh) | 2019-09-25 | 2020-09-25 | 用于治疗系统性硬化症的药物组合物 |
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Non-Patent Citations (6)
Title |
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HUANG, S ET AL.: "Effects of IL -17A on fibrosis of skin and lung in a mouse model of systemic sclerosis", CHINESE JOURNAL OF MICROBIOLOGY AND IMMUNOLOGY, vol. 37, no. 2, 2017, pages 105 - 111 * |
ICHIHARA, A ET AL.: "Treatment of psoriasis with ustekinumab improved skin tightening in systemic sclerosis", CLIN EXP RHEUMATOL, vol. 35, no. 4 Suppl 6, 12 October 2017 (2017-10-12), pages S208 - S210 * |
LIU, M ET AL.: "Interleukin-17A promotes functional activation of systemic sclerosis patient-derived dermal vascular smooth muscle cells by extracellular-regulated protein kinases signalling pathway", ARTHRITIS RES THER, vol. 16, no. 6, 2014, XP021213399, DOI: 10.1186/s13075-014-0512-2 * |
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TW202126330A (zh) | 2021-07-16 |
KR20220070244A (ko) | 2022-05-30 |
JPWO2021060425A1 (ja) | 2021-04-01 |
JP7093940B2 (ja) | 2022-07-01 |
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