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Description
[本発明１００１]
対象における加齢性疾患または炎症性疾患を治療する方法であって、前記対象に、
（ｉ）ＮＫ細胞活性化物質および／またはＮＫ細胞および／またはモノクローナル抗体の治療有効量と、
（ｉｉ）Ｔｒｅｇ細胞活性化物質および／またはＴｒｅｇ細胞および／またはモノクローナル抗体および／または終末糖化産物（ＡＧＥ）阻害剤の治療有効量と
を投与することを含む、前記方法。
[本発明１００２]
前記加齢性疾患が炎症老化関連である、本発明１００１の方法。
[本発明１００３]
（ｉ）が（ｉｉ）と実質的に同時に前記対象に投与される、本発明１００１または１００２の方法。
[本発明１００４]
（ｉｉ）が前記対象に投与される前に、（ｉ）が前記対象に投与される、本発明１００１または１００２の方法。
[本発明１００５]
（ｉ）が前記対象に投与される前に、（ｉｉ）が前記対象に投与される、本発明１００１または１００２の方法。
[本発明１００６]
前記対象にＮＫ細胞の治療有効量を投与することを含む、本発明１００１～１００５のいずれかの方法。
[本発明１００７]
前記ＮＫ細胞が、末梢血から単離された、臍帯血から単離された、またはｉＰＳＣから単離されて分化した、自己、ハプロタイプ一致、または同種異系ＮＫ細胞である、本発明１００６の方法。
[本発明１００８]
前記対象から前記ＮＫ細胞を単離することと、
前記ＮＫ細胞の増殖を誘導または増加させるのに十分な条件下で、前記単離されたＮＫ細胞を液体培養培地中で培養することと
をさらに含み、
前記単離するステップおよび前記培養するステップの後に、前記ＮＫ細胞が前記対象に投与される、
本発明１００７の方法。
[本発明１００９]
前記液体培養培地が多鎖キメラポリペプチドを含む、本発明１００８の方法。
[本発明１０１０]
前記ＮＫ細胞がキメラ抗原受容体を含む、本発明１００６～１００９のいずれかの方法。
[本発明１０１１]
前記キメラ抗原受容体が組織因子またはＣＤ２６に特異的に結合する細胞外ドメインを含む、本発明１０１０の方法。
[本発明１０１２]
前記対象にＮＫ細胞活性化物質および／またはモノクローナル抗体の治療有効量を投与することを含む、本発明１００１～１００５のいずれかの方法。
[本発明１０１３]
前記ＮＫ細胞活性化物質が１つ以上の多鎖キメラポリペプチドである、本発明１０１２の方法。
[本発明１０１４]
前記モノクローナル抗体が抗組織因子抗体および／または抗ＣＤ２６抗体のうちの１つ以上である、本発明１０１２の方法。
[本発明１０１５]
前記ＮＫ細胞活性化物質が１つ以上の多鎖キメラポリペプチドを含み、前記モノクローナル抗体が抗組織因子抗体および／または抗ＣＤ２６抗体のうちの１つ以上を含む、本発明１０１２の方法。
[本発明１０１６]
前記対象にＴｒｅｇ細胞の治療有効量を投与することを含む、本発明１００１～１０１５のいずれかの方法。
[本発明１０１７]
前記Ｔｒｅｇ細胞が、末梢血または臍帯血から単離された、自己Ｔｒｅｇ細胞、ハプロタイプ一致Ｔｒｅｇ細胞、または同種異系Ｔｒｅｇ細胞である、本発明１０１６の方法。
[本発明１０１８]
前記対象から前記Ｔｒｅｇ細胞を単離することと、
前記Ｔｒｅｇ細胞の増殖を誘導または増加させるのに十分な条件下で、前記単離されたＴｒｅｇ細胞を液体培養培地中で培養することと
をさらに含み、
前記単離するステップおよび前記培養するステップの後に、前記Ｔｒｅｇ細胞が前記対象に投与される、
本発明１０１７の方法。
[本発明１０１９]
前記対象から前記Ｔｒｅｇ細胞を単離する前記ステップが、前記対象からＴｒｅｇ細胞を含む試料を得ることと、ＣＤ３９に結合することができる抗体またはリガンドを使用して前記試料から前記Ｔｒｅｇ細胞を単離することとを含む、本発明１０１８の方法。
[本発明１０２０]
前記試料から前記Ｔｒｅｇ細胞を単離する前記ステップが、
ＣＤ３９を発現するＴｒｅｇ細胞へのリガンドの前記抗体の結合を可能にする条件下で、前記試料を、ＣＤ３９に結合することができる前記抗体またはリガンドと混合することと、
前記抗体またはリガンドに結合した前記Ｔｒｅｇ細胞を前記試料中の他の成分から分離し、それにより、前記Ｔｒｅｇ細胞を単離することと
を含む、本発明１０１９の方法。
[本発明１０２１]
前記抗体が、マウス、ヒト化、もしくはヒト抗体であるか、もしくはそれらの抗原結合断片である、および／または
前記抗体もしくは前記リガンドが、ビオチン、アビジン、ストレプトアビジン、もしくは蛍光色素のうちの少なくとも１つで標識されているか、もしくは粒子、ビーズ、樹脂、もしくは固体支持体に結合している、
本発明１０１９または１０２０の方法。
[本発明１０２２]
前記分離が、フローサイトメトリー、蛍光標識細胞分取（ＦＡＣＳ）、遠心分離、またはカラム、プレート、粒子、もしくはビーズベースの方法の使用を含む、本発明１０２０の方法。
[本発明１０２３]
前記Ｔ ｒｅｇ 細胞が、新鮮または凍結された末梢血、臍帯血、末梢血単核細胞、リンパ球、ＣＤ４ ＋ Ｔ細胞、またはＴ ｒｅｇ 細胞を含む試料から単離された、自己Ｔ ｒｅｇ 細胞、ハプロタイプ一致Ｔ ｒｅｇ 細胞、または同種異系Ｔ ｒｅｇ 細胞である、本発明１０１８～１０２２のいずれかの方法。
[本発明１０２４]
前記Ｔ ｒｅｇ 細胞がＣＤ４ ＋ ＣＤ２５ ＋ Ｆｏｘｐ３ ＋ 細胞である、本発明１０１８～１０２３のいずれかの方法。
[本発明１０２５]
前記Ｔ ｒｅｇ 細胞がＣＤ４ ＋ ＣＤ２５ ＋ ＣＤ１２７ ｄｉｍ－ 細胞である、本発明１０１８～１０２３のいずれかの方法。
[本発明１０２６]
前記Ｔ ｒｅｇ 細胞がインビトロおよびインビボで免疫抑制性である、本発明１０１８～１０２５のいずれかの方法。
[本発明１０２７]
前記液体培養培地が１つ以上の単鎖キメラポリペプチドを含む、本発明１０１８～１０２６のいずれかの方法。
[本発明１０２８]
前記Ｔｒｅｇ細胞がキメラ抗原受容体を含む、本発明１０１６～１０２７のいずれかの方法。
[本発明１０２９]
前記キメラ抗原受容体が組織因子またはＣＤ３６に特異的に結合する細胞外ドメインを含む、本発明１０２８の方法。
[本発明１０３０]
前記対象にＴｒｅｇ細胞活性化物質および／またはモノクローナル抗体および／またはＡＧＥ阻害剤の治療有効量を投与することを含む、本発明１００１～１０１５のいずれかの方法。
[本発明１０３１]
前記Ｔｒｅｇ細胞活性化物質が１つ以上の単鎖キメラポリペプチドである、本発明１０３０の方法。
[本発明１０３２]
前記モノクローナル抗体が抗組織因子抗体および／または抗ＣＤ３６抗体の一方または両方である、本発明１０３０の方法。
[本発明１０３３]
前記ＡＧＥ阻害剤が可溶性ＲＡＧＥトラップである、本発明１０３０の方法。
[本発明１０３４]
前記Ｔｒｅｇ細胞活性化物質が１つ以上の単鎖キメラポリペプチドを含み、前記モノクローナル抗体が抗組織因子抗体および／または抗ＣＤ３６抗体のうちの１つ以上を含み、前記ＡＧＥ阻害剤が１つ以上の可溶性ＲＡＧＥトラップを含む、本発明１０３０の方法。
[本発明１０３５]
前記多鎖キメラポリペプチドが、
（ａ）第１のキメラポリペプチドであって、
（ｉ）第１の標的結合ドメイン、
（ｉｉ）可溶性組織因子ドメイン、および
（ｉｉｉ）一対の親和性ドメインの第１のドメイン
を含む、前記第１のキメラポリペプチドと、
（ｂ）第２のキメラポリペプチドであって、
（ｉ）一対の親和性ドメインの第２のドメイン、および
（ｉｉ）第２の標的結合ドメイン
を含む、前記第２のキメラポリペプチドと
を含み、
前記第１のキメラポリペプチドおよび前記第２のキメラポリペプチドが、前記一対の親和性ドメインの前記第１のドメインと前記第２のドメインとの結合を介して会合する、
本発明１００９、１０１３、または１０１５の方法。
[本発明１０３６]
前記単鎖キメラポリペプチドが、
（ｉ）第１の標的結合ドメイン、
（ｉｉ）可溶性組織因子ドメイン、および
（ｉｉｉ）第２の標的結合ドメイン
を含む、本発明１０２７、１０３１、または１０３４の方法。
[本発明１０３７]
前記加齢性障害が、アルツハイマー病、動脈瘤、嚢胞性線維症、膵炎における線維症、緑内障、高血圧症、特発性肺線維症、炎症性腸疾患、椎間板変性、黄斑変性、骨関節炎、２型真性糖尿病、脂肪萎縮、リポジストロフィー、アテローム性動脈硬化症、白内障、ＣＯＰＤ、特発性肺線維症、腎移植不全、肝線維症、骨量喪失、心筋梗塞、サルコペニア、創傷治癒、脱毛症、心筋細胞肥大、骨関節炎、パーキンソン病、加齢性肺組織弾性喪失、黄斑変性、悪液質、糸球体硬化症、肝硬変、ＮＡＦＬＤ、骨粗しょう症、筋萎縮性側索硬化症、ハンチントン病、脊髄小脳失調症、多発性硬化症、神経変性、脳卒中、がん、認知症、血管疾患、感染感受性、慢性炎症、および腎機能障害からなる群から選択される、本発明１００１～１０３７のいずれかの方法。
[本発明１０３８]
前記炎症性疾患が、リウマチ性関節炎、炎症性腸疾患、エリテマトーデス、ループス腎炎、糖尿病性腎症、ＣＮＳ損傷、アルツハイマー病、パーキンソン病、筋萎縮性側索硬化症、クローン病、多発性硬化症、ギラン・バレー症候群、乾癬、グレーブス病、潰瘍性大腸炎、および非アルコール性脂肪性肝炎からなる群から選択される、本発明１００１～１０３７のいずれかの方法。
本発明の他の特徴および利点は、以下の発明を実施するための形態および図、ならびに特許請求の範囲から明らかになるであろう。
[Present invention 1001]
A method of treating an age-related disease or an inflammatory disease in a subject, the method comprising:
(i) a therapeutically effective amount of NK cell activator and/or NK cell and/or monoclonal antibody;
(ii) a therapeutically effective amount of a Treg cell activator and/or a Treg cell and/or monoclonal antibody and/or an advanced glycation end product (AGE) inhibitor;
The method comprising administering.
[Present invention 1002]
The method of the present invention 1001, wherein the age-related disease is inflammation-aging related.
[Present invention 1003]
The method of invention 1001 or 1002, wherein (i) is administered to said subject substantially simultaneously with (ii).
[Present invention 1004]
The method of invention 1001 or 1002, wherein (i) is administered to said subject before (ii) is administered to said subject.
[Present invention 1005]
The method of invention 1001 or 1002, wherein (ii) is administered to said subject before (i) is administered to said subject.
[Present invention 1006]
The method of any of the inventions 1001-1005, comprising administering to said subject a therapeutically effective amount of NK cells.
[Present invention 1007]
The method of the invention 1006, wherein the NK cells are autologous, haploidentical, or allogeneic NK cells isolated from peripheral blood, isolated from umbilical cord blood, or isolated from iPSCs and differentiated. .
[Present invention 1008]
isolating the NK cells from the subject;
culturing the isolated NK cells in a liquid culture medium under conditions sufficient to induce or increase proliferation of the NK cells;
further including;
After the isolating step and the culturing step, the NK cells are administered to the subject;
Method of the invention 1007.
[Present invention 1009]
1008. The method of invention 1008, wherein said liquid culture medium comprises a multi-chain chimeric polypeptide.
[Present invention 1010]
The method of any of inventions 1006-1009, wherein said NK cell comprises a chimeric antigen receptor.
[Present invention 1011]
1010. The method of the invention 1010, wherein said chimeric antigen receptor comprises an extracellular domain that specifically binds tissue factor or CD26.
[Present invention 1012]
The method according to any of the inventions 1001 to 1005, comprising administering to the subject a therapeutically effective amount of an NK cell activator and/or a monoclonal antibody.
[Present invention 1013]
1012. The method of the invention 1012, wherein the NK cell activator is one or more multi-chain chimeric polypeptides.
[Present invention 1014]
1012. The method of the invention 1012, wherein said monoclonal antibody is one or more of an anti-tissue factor antibody and/or an anti-CD26 antibody.
[Present invention 1015]
1013. The method of the invention 1012, wherein the NK cell activator comprises one or more multi-chain chimeric polypeptides and the monoclonal antibody comprises one or more of an anti-tissue factor antibody and/or an anti-CD26 antibody.
[Present invention 1016]
The method of any of the inventions 1001-1015, comprising administering to said subject a therapeutically effective amount of Treg cells.
[Present invention 1017]
1016. The method of the invention 1016, wherein the Treg cells are autologous Treg cells, haploidentical Treg cells, or allogeneic Treg cells isolated from peripheral blood or umbilical cord blood.
[This invention 1018]
isolating the Treg cells from the subject;
culturing the isolated Treg cells in a liquid culture medium under conditions sufficient to induce or increase proliferation of the Treg cells;
further including;
After the isolating and culturing steps, the Treg cells are administered to the subject;
The method of the invention 1017.
[This invention 1019]
The step of isolating the Treg cells from the subject comprises obtaining a sample containing Treg cells from the subject and isolating the Treg cells from the sample using an antibody or a ligand capable of binding to CD39. The method of the invention 1018, comprising:
[This invention 1020]
The step of isolating the Treg cells from the sample comprises:
mixing the sample with the antibody or ligand capable of binding CD39 under conditions that allow the binding of the antibody of the ligand to Treg cells expressing CD39;
separating the Treg cells bound to the antibody or ligand from other components in the sample, thereby isolating the Treg cells;
The method of the invention 1019, comprising:
[Present invention 1021]
the antibody is a murine, humanized, or human antibody, or an antigen-binding fragment thereof; and/or
said antibody or said ligand is labeled with at least one of biotin, avidin, streptavidin, or a fluorescent dye, or is bound to a particle, bead, resin, or solid support;
The method of the invention 1019 or 1020.
[Present invention 1022]
The method of the invention 1020, wherein said separation comprises flow cytometry, fluorescence-activated cell sorting (FACS), centrifugation, or the use of column, plate, particle, or bead-based methods.
[Present invention 1023]
autologous T reg cells, haplotypes, wherein said T reg cells are isolated from a sample comprising fresh or frozen peripheral blood, umbilical cord blood, peripheral blood mononuclear cells, lymphocytes, CD4 + T cells, or T reg cells; The method of any of the invention 1018-1022, wherein the matched T reg cells or allogeneic T reg cells.
[Present invention 1024]
The method of any of the inventions 1018-1023, wherein the T reg cells are CD4 + CD25 + Foxp3 + cells.
[Present invention 1025]
The method of any of the inventions 1018-1023, wherein the T reg cells are CD4 + CD25 + CD127 dim- cells.
[Present invention 1026]
The method of any of the inventions 1018-1025, wherein said T reg cells are immunosuppressive in vitro and in vivo.
[Invention 1027]
The method of any of the inventions 1018-1026, wherein said liquid culture medium comprises one or more single chain chimeric polypeptides.
[Invention 1028]
The method of any of the inventions 1016-1027, wherein said Treg cell comprises a chimeric antigen receptor.
[Invention 1029]
1028. The method of the invention 1028, wherein said chimeric antigen receptor comprises an extracellular domain that specifically binds tissue factor or CD36.
[This invention 1030]
The method of any of the inventions 1001-1015, comprising administering to said subject a therapeutically effective amount of a Treg cell activator and/or a monoclonal antibody and/or an AGE inhibitor.
[Present invention 1031]
1030. The method of the invention 1030, wherein said Treg cell activator is one or more single chain chimeric polypeptides.
[Present invention 1032]
The method of the invention 1030, wherein the monoclonal antibody is one or both of an anti-tissue factor antibody and/or an anti-CD36 antibody.
[Present invention 1033]
1030. The method of the invention 1030, wherein said AGE inhibitor is a soluble RAGE trap.
[Present invention 1034]
the Treg cell activator comprises one or more single chain chimeric polypeptides, the monoclonal antibody comprises one or more of an anti-tissue factor antibody and/or an anti-CD36 antibody, and the AGE inhibitor comprises one or more 1030. The method of the invention 1030, comprising a soluble RAGE trap.
[Present invention 1035]
The multi-chain chimeric polypeptide is
(a) a first chimeric polypeptide,
(i) a first target binding domain;
(ii) a soluble tissue factor domain, and
(iii) the first domain of a pair of affinity domains;
the first chimeric polypeptide comprising;
(b) a second chimeric polypeptide,
(i) a second domain of the pair of affinity domains, and
(ii) second target binding domain
said second chimeric polypeptide comprising
including;
the first chimeric polypeptide and the second chimeric polypeptide associate through binding between the first domain and the second domain of the pair of affinity domains;
The method of invention 1009, 1013, or 1015.
[Present invention 1036]
The single chain chimeric polypeptide is
(i) a first target binding domain;
(ii) a soluble tissue factor domain, and
(iii) second target binding domain
The method of invention 1027, 1031, or 1034, comprising:
[Present invention 1037]
The age-related disorders include Alzheimer's disease, aneurysm, cystic fibrosis, fibrosis in pancreatitis, glaucoma, hypertension, idiopathic pulmonary fibrosis, inflammatory bowel disease, intervertebral disc degeneration, macular degeneration, osteoarthritis, type 2 Diabetes mellitus, lipoatrophy, lipodystrophy, atherosclerosis, cataract, COPD, idiopathic pulmonary fibrosis, renal transplant failure, liver fibrosis, bone loss, myocardial infarction, sarcopenia, wound healing, alopecia, cardiac myocytes Hypertrophy, osteoarthritis, Parkinson's disease, age-related loss of lung tissue elasticity, macular degeneration, cachexia, glomerulosclerosis, cirrhosis, NAFLD, osteoporosis, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia The method of any one of the invention 1001-1037, wherein the method is selected from the group consisting of: disease, multiple sclerosis, neurodegeneration, stroke, cancer, dementia, vascular disease, infection susceptibility, chronic inflammation, and renal dysfunction.
[Present invention 1038]
The inflammatory disease is rheumatoid arthritis, inflammatory bowel disease, lupus erythematosus, lupus nephritis, diabetic nephropathy, CNS injury, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Crohn's disease, multiple sclerosis, The method of any of the inventions 1001-1037, selected from the group consisting of Guillain-Barre syndrome, psoriasis, Graves' disease, ulcerative colitis, and non-alcoholic steatohepatitis.
Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims.
Claims (32)
（ｉ）ＮＫ細胞活性化物質および／またはＮＫ細胞および／またはモノクローナル抗体の治療有効量と、
（ｉｉ）Ｔｒｅｇ細胞活性化物質および／またはＴｒｅｇ細胞および／またはモノクローナル抗体および／または終末糖化産物（ＡＧＥ）阻害剤の治療有効量と
を含む、前記医薬。 A medicament for treating an age-related disease or an inflammatory disease in a subject, the medicament comprising :
( i) a therapeutically effective amount of NK cell activator and/or NK cell and/or monoclonal antibody;
(ii) a therapeutically effective amount of a Treg cell activator and/or a Treg cell and/or monoclonal antibody and/or an advanced glycation end product (AGE) inhibitor ;
The above-mentioned medicament .
前記対象から前記ＮＫ細胞を単離することと、
前記ＮＫ細胞の増殖を誘導または増加させるのに十分な条件下で、前記単離されたＮＫ細胞を液体培養培地中で培養することと
を含むステップによって得られる、請求項７に記載の医薬。 The NK cell is
isolating the NK cells from the subject;
culturing the isolated NK cells in a liquid culture medium under conditions sufficient to induce or increase proliferation of the NK cells;
The medicament according to claim 7, obtained by the step comprising :
前記対象から前記Ｔｒｅｇ細胞を単離することと、
前記Ｔｒｅｇ細胞の増殖を誘導または増加させるのに十分な条件下で、前記単離されたＴｒｅｇ細胞を液体培養培地中で培養することと
を含むステップによって得られる、請求項１７に記載の医薬。 The Treg cells are
isolating the Treg cells from the subject;
culturing the isolated Treg cells in a liquid culture medium under conditions sufficient to induce or increase proliferation of the Treg cells;
The medicament according to claim 17, obtained by the step comprising :
（ａ）第１のキメラポリペプチドであって、
（ｉ）第１の標的結合ドメイン、
（ｉｉ）可溶性組織因子ドメイン、および
（ｉｉｉ）一対の親和性ドメインの第１のドメイン
を含む、前記第１のキメラポリペプチドと、
（ｂ）第２のキメラポリペプチドであって、
（ｉ）一対の親和性ドメインの第２のドメイン、および
（ｉｉ）第２の標的結合ドメイン
を含む、前記第２のキメラポリペプチドと
を含み、
前記第１のキメラポリペプチドおよび前記第２のキメラポリペプチドが、前記一対の親和性ドメインの前記第１のドメインと前記第２のドメインとの結合を介して会合する、
請求項９、１３、または１５に記載の医薬。 The multi-chain chimeric polypeptide is
(a) a first chimeric polypeptide,
(i) a first target binding domain;
(ii) a soluble tissue factor domain, and (iii) a first domain of a pair of affinity domains;
(b) a second chimeric polypeptide,
(i) a second domain of a pair of affinity domains; and (ii) a second chimeric polypeptide comprising:
the first chimeric polypeptide and the second chimeric polypeptide associate through binding between the first domain and the second domain of the pair of affinity domains;
The medicament according to claim 9, 13, or 15.
（ｉ）第１の標的結合ドメイン、
（ｉｉ）可溶性組織因子ドメイン、および
（ｉｉｉ）第２の標的結合ドメイン
を含む、請求項２３、２７、または３０に記載の医薬。 The single chain chimeric polypeptide is
(i) a first target binding domain;
31. The medicament of claim 23 , 27 , or 30 , comprising (ii) a soluble tissue factor domain, and (iii) a second target binding domain.
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