JPWO2021116469A5 - - Google Patents

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JPWO2021116469A5
JPWO2021116469A5 JP2022535443A JP2022535443A JPWO2021116469A5 JP WO2021116469 A5 JPWO2021116469 A5 JP WO2021116469A5 JP 2022535443 A JP2022535443 A JP 2022535443A JP 2022535443 A JP2022535443 A JP 2022535443A JP WO2021116469 A5 JPWO2021116469 A5 JP WO2021116469A5
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Priority claimed from PCT/EP2020/085863 external-priority patent/WO2021116469A2/en
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ペプチド－ＭＨＣ（ｐＭＨＣ）特異的結合タンパク質を生産する方法であって、前記結合タンパク質が、標的ペプチド－ＭＨＣ複合体に対して結合特異性を有する設計された反復ドメインを含む、方法であって、前記方法が、
（ａ）設計された反復ドメインの集合体を提供するステップと、
（ｂ）組換え標的ペプチド－ＭＨＣ複合体を提供するステップと、
（ｃ）前記標的ペプチド－ＭＨＣ複合体への特異的結合のための前記設計された反復ドメインの集合体をスクリーニングして、前記標的ペプチド－ＭＨＣ複合体に対する結合特異性を有する少なくとも１つの設計された反復ドメインを得るステップと、を含む、方法。 1. A method of producing a peptide-MHC (pMHC)-specific binding protein, said binding protein comprising designed repeat domains having binding specificity for a target peptide-MHC complex, the method comprising: The method includes:
(a) providing a collection of designed repeat domains;
(b) providing a recombinant target peptide-MHC complex;
(c) screening said population of designed repeat domains for specific binding to said target peptide-MHC complex to identify at least one designed repeat domain having binding specificity for said target peptide-MHC complex; obtaining a repeated domain. 前記設計された反復ドメインが、設計されたアンキリン反復ドメインである、請求項１に記載の方法。 2. The method of claim 1, wherein the engineered repeat domain is an engineered ankyrin repeat domain. 前記集合体が、固定された位置とランダム化された位置とを含む設計された反復ドメインを含み、前記集合体の設計された反復ドメインが、前記ランダム化された位置のうちの少なくとも１つにおいて互いに異なる、請求項１又は２に記載の方法。 the ensemble includes a designed repeating domain including fixed locations and randomized locations, and the designed repeating domain of the ensemble includes at least one of the randomized locations. The method according to claim 1 or 2, which is different from each other. 前記設計されたリピートタンパク質の集合体が、リボソームディスプレイによって提供される、請求項１～３のいずれか一項に記載の方法。 4. A method according to any one of claims 1 to 3, wherein the designed population of repeat proteins is provided by ribosome display. 前記方法が更に、（ｉ）第２の組換えペプチド－ＭＨＣ複合体を提供するステップであって、前記第２のペプチド－ＭＨＣ複合体の前記ペプチドが、少なくとも１つのアミノ酸残基だけ前記標的ペプチドとは異なるアミノ酸配列を含む、提供するステップと、（ｉｉ）前記第２の組換えペプチド－ＭＨＣ複合体に対する結合特異性を有する負の選択設計反復ドメインによって前記集合体から除去するステップと、を含む、請求項１～４のいずれか一項に記載の方法。 The method further comprises the step of: (i) providing a second recombinant peptide-MHC complex, wherein the peptide of the second peptide-MHC complex is isolated from the target peptide by at least one amino acid residue. (ii) removing from said assembly by a negative selection engineered repeat domain having binding specificity for said second recombinant peptide-MHC complex. The method according to any one of claims 1 to 4, comprising: 標的ペプチド－ＭＨＣ複合体に対する結合特異性を有する前記反復ドメインが、ＰＢＳ中の前記標的ペプチド－ＭＨＣ複合体に、１０-7Ｍを下回る解離定数（ＫD）で結合する、請求項１～５のいずれか一項に記載の方法。 Claims 1-5, wherein said repeat domain with binding specificity for a target peptide-MHC complex binds said target peptide-MHC complex in PBS with a dissociation constant (K D ) below 10 −7 M. The method described in any one of the above. 標的ペプチド－ＭＨＣ複合体に対する結合特異性を有する前記反復ドメインの前記標的ペプチド－ＭＨＣ複合体への結合が、前記標的ペプチドの少なくとも１個、少なくとも２個、少なくとも３個、少なくとも４個、少なくとも５個、少なくとも６個、又は少なくとも７個のアミノ酸残基との前記反復ドメインの相互作用を含む、請求項１～６のいずれか一項に記載の方法。 The binding of the repeat domain having binding specificity for the target peptide-MHC complex to the target peptide-MHC complex is determined by binding to at least one, at least two, at least three, at least four, at least five of the target peptides. 7. A method according to any one of claims 1 to 6, comprising interaction of said repetitive domain with 1, at least 6, or at least 7 amino acid residues. 標的ペプチド－ＭＨＣ複合体に対する結合特異性を有する前記反復ドメインの、前記標的ペプチド－ＭＨＣ複合体への結合が、前記反復ドメインと前記ＭＨＣの少なくとも１つのアミノ酸残基との相互作用を含む、請求項１～７のいずれか一項に記載の方法。 The binding of the repeat domain having binding specificity for a target peptide-MHC complex to the target peptide-MHC complex comprises an interaction between the repeat domain and at least one amino acid residue of the MHC. The method according to any one of Items 1 to 7. 前記標的ペプチドが、細胞内タンパク質、好ましくは腫瘍細胞において発現する細胞内タンパク質に由来する、請求項１～８のいずれか一項に記載の方法。 A method according to any one of claims 1 to 8, wherein the target peptide is derived from an intracellular protein, preferably an intracellular protein expressed in tumor cells. 前記標的ペプチドが、ＮＹ－ＥＳＯ－１に由来し、好ましくは、前記標的ペプチドが、配列番号１９若しくは配列番号３４のアミノ酸配列を含むか、又はそれからなる、請求項１～９のいずれか一項に記載の方法。 Any one of claims 1 to 9, wherein the target peptide is derived from NY-ESO-1, preferably the target peptide comprises or consists of the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 34. The method described in. 前記標的ペプチドが、ＥＢＮＡ－１に由来し、好ましくは、前記標的ペプチドが、配列番号９２のアミノ酸配列を含むか、又はそれからなる、請求項１～９のいずれか一項に記載の方法。 A method according to any one of claims 1 to 9, wherein the target peptide is derived from EBNA-1, preferably the target peptide comprises or consists of the amino acid sequence of SEQ ID NO: 92. 前記標的ペプチドが、ＭＡＧＥ－Ａ３に由来し、好ましくは、前記標的ペプチドが、配列番号１５５のアミノ酸配列を含むか、又はそれからなる、請求項１～９のいずれか一項に記載の方法。 The method according to any one of claims 1 to 9, wherein the target peptide is derived from MAGE-A3, preferably the target peptide comprises or consists of the amino acid sequence of SEQ ID NO: 155. 前記標的ペプチドが、ＨＢｃＡｇに由来し、好ましくは、前記標的ペプチドが、配列番号２５５のアミノ酸配列を含むか、又はそれからなる、請求項１～９のいずれか一項に記載の方法。 The method according to any one of claims 1 to 9, wherein the target peptide is derived from HBcAg, preferably the target peptide comprises or consists of the amino acid sequence of SEQ ID NO: 255. 前記ＭＨＣが、ＭＨＣクラスＩである、請求項１～１３のいずれか一項に記載の方法。 The method according to any one of claims 1 to 13, wherein the MHC is MHC class I. 請求項１～１４のいずれか一項に記載の方法によって得ることができる設計された反復ドメインを含む、組換え結合タンパク質。 Recombinant binding protein comprising a designed repeat domain obtainable by the method according to any one of claims 1 to 14. 第１の設計された反復ドメインを含む組換え結合タンパク質であって、前記第１の反復ドメインが、第１の標的ペプチド－ＭＨＣ複合体に対する結合特異性を有し、好ましくは、前記第１の標的ペプチドが、（ｉ）腫瘍細胞において発現するタンパク質に由来するペプチド、（ｉｉ）感染因子、好ましくはウイルス感染因子のタンパク質に由来するペプチド、及び（ｉｉｉ）自己免疫障害と関係するタンパク質に由来するペプチドからなる群から選択される、組換え結合タンパク質。 A recombinant binding protein comprising a first designed repeat domain, said first repeat domain having binding specificity for a first target peptide-MHC complex, preferably said first repeat domain having binding specificity for a first target peptide-MHC complex. The target peptide is (i) a peptide derived from a protein expressed in tumor cells, (ii) a peptide derived from a protein of an infectious agent, preferably a viral infectious agent, and (iii) a protein associated with an autoimmune disorder. A recombinant binding protein selected from the group consisting of peptides. 前記第１の標的ペプチドが、細胞内タンパク質、好ましくは腫瘍細胞において発現する細胞内タンパク質に由来する、請求項１６に記載の結合タンパク質。 17. A binding protein according to claim 16, wherein the first target peptide is derived from an intracellular protein, preferably an intracellular protein expressed in tumor cells. 前記第１の反復ドメインが、ＰＢＳ中の前記第１の標的ペプチド－ＭＨＣ複合体に、１０-7Ｍを下回る解離定数（ＫD）で結合する、請求項１６又は１７に記載の結合タンパク質。 18. The binding protein of claim 16 or 17, wherein the first repeat domain binds the first target peptide-MHC complex in PBS with a dissociation constant (K D ) of less than 10 −7 M. 前記第１の標的ペプチド－ＭＨＣ複合体への前記第１の反復ドメインの結合が、前記第１の標的ペプチドの少なくとも１個、少なくとも２個、少なくとも３個、少なくとも４個、少なくとも５個、少なくとも６個、又は少なくとも７個のアミノ酸残基との前記第１の反復ドメインの相互作用を含む、請求項１６～１８のいずれか一項に記載の結合タンパク質。 The binding of the first repeat domain to the first target peptide-MHC complex is such that the binding of the first repeat domain to the first target peptide-MHC complex comprises at least one, at least two, at least three, at least four, at least five, at least one of the first target peptides. Binding protein according to any one of claims 16 to 18, comprising interactions of said first repeat domain with 6 or at least 7 amino acid residues. 前記第１の標的ペプチド－ＭＨＣ複合体への前記第１の反復ドメインの結合が、前記第１の反復ドメインと前記第１のＭＨＣの少なくとも１個のアミノ酸残基との相互作用を含む、請求項１６～１９のいずれか一項に記載の結合タンパク質。 3. Binding of the first repeat domain to the first target peptide-MHC complex comprises an interaction between the first repeat domain and at least one amino acid residue of the first MHC. The binding protein according to any one of items 16 to 19. 前記第１のＭＨＣが、ＭＨＣクラスＩである、請求項１６～２０のいずれか一項に記載の結合タンパク質。 A binding protein according to any one of claims 16 to 20, wherein the first MHC is MHC class I. 前記ＭＨＣクラスＩが、ＨＬＡ－Ａ*０２である、請求項２１に記載の結合タンパク質。 22. The binding protein of claim 21, wherein the MHC class I is HLA-A * 02. 前記第１の標的ペプチドが、ＮＹ－ＥＳＯ－１に由来する、請求項１６～２２のいずれか一項に記載の結合タンパク質。 Binding protein according to any one of claims 16 to 22, wherein the first target peptide is derived from NY-ESO-1. 前記第１の標的ペプチドが、配列番号１９若しくは配列番号３４のアミノ酸配列を有する、請求項１６～２３のいずれか一項に記載の結合タンパク質。 The binding protein according to any one of claims 16 to 23, wherein the first target peptide has an amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 34. 前記第１の反復ドメインが、設計されたアンキリン反復ドメインである、請求項１６～２４のいずれか一項に記載の結合タンパク質。 A binding protein according to any one of claims 16 to 24, wherein the first repeat domain is an engineered ankyrin repeat domain. 前記第１のアンキリン反復ドメインが、（１）配列番号：３７～７２及び（２）配列番号３７～７２のうちのいずれかにおける９個までのアミノ酸が別のアミノ酸によって置換されている配列からなる群から選択されるアミノ酸配列を含むアンキリン反復モジュールを含む、請求項２５に記載の結合タンパク質。 The first ankyrin repeat domain consists of a sequence in which up to 9 amino acids in any of (1) SEQ ID NOs: 37-72 and (2) SEQ ID NOs: 37-72 are substituted with another amino acid. 26. The binding protein of claim 25, comprising an ankyrin repeat module comprising an amino acid sequence selected from the group. 前記第１のアンキリン反復ドメインが、配列番号２０～３３のうちのいずれか１つと少なくとも８０％のアミノ酸配列同一性を有するアミノ酸配列を含み、配列番号２０～３３の位置１のＧ及び／又は位置２のＳが場合により失われており、かつ配列番号２０～３３の最後から２番目の位置のＡは、場合によりＬによって置換されており、及び／又は配列番号２０～３３の最後の位置のＡが、場合によりＮによって置換されている、請求項２５又は２６に記載の結合タンパク質。 said first ankyrin repeat domain comprises an amino acid sequence having at least 80% amino acid sequence identity with any one of SEQ ID NOs: 20-33; 2 is optionally missing, and the A in the penultimate position of SEQ ID NO: 20-33 is optionally replaced by L, and/or the A in the last position of SEQ ID NO: 20-33 is optionally missing. 27. A binding protein according to claim 25 or 26, wherein A is optionally replaced by N. 前記結合タンパク質が更に、第２の設計された反復ドメインを含み、前記第２の反復ドメインが、第２の標的ペプチド－ＭＨＣ複合体に対する結合特異性を有し、好ましくは前記第２の標的ペプチドが、（ｉ）腫瘍細胞において発現するタンパク質に由来するペプチド、（ｉｉ）感染因子、好ましくはウイルス感染因子のタンパク質に由来するペプチド、及び（ｉｉｉ）自己免疫障害と関係するタンパク質に由来するペプチドからなる群から選択される、請求項１５～２７のいずれか一項に記載の結合タンパク質。 The binding protein further comprises a second designed repeat domain, said second repeat domain having binding specificity for a second target peptide-MHC complex, preferably said second target peptide. from (i) peptides derived from proteins expressed in tumor cells, (ii) peptides derived from proteins of infectious agents, preferably viral infectious agents, and (iii) peptides derived from proteins associated with autoimmune disorders. A binding protein according to any one of claims 15 to 27, selected from the group consisting of: 前記第２の標的ペプチドが、細胞内タンパク質、好ましくは腫瘍細胞において発現する細胞内タンパク質に由来する、請求項２８に記載の結合タンパク質。 29. A binding protein according to claim 28, wherein the second target peptide is derived from an intracellular protein, preferably an intracellular protein expressed in tumor cells. 第２の標的ペプチド－ＭＨＣ複合体に対する結合特異性を有する前記第２の反復ドメインが、ＰＢＳ中の前記第２の標的ペプチド－ＭＨＣ複合体に、１０-7Ｍを下回る解離定数（ＫD）で結合する、請求項２８又は２９に記載の結合タンパク質。 said second repeat domain having binding specificity for a second target peptide-MHC complex binds said second target peptide-MHC complex in PBS with a dissociation constant (K D ) below 10 −7 M; 30. The binding protein according to claim 28 or 29, which binds with. 前記第２の標的ペプチド－ＭＨＣ複合体への前記第２の反復ドメインの結合が、前記第２の標的ペプチドの少なくとも１個、少なくとも２個、少なくとも３個、少なくとも４個、少なくとも５個、少なくとも６個、又は少なくとも７個のアミノ酸残基との前記第２の反復ドメインの相互作用を含む、請求項２８～３０のいずれか一項に記載の結合タンパク質。 The binding of the second repeat domain to the second target peptide-MHC complex is such that the binding of the second repeat domain to the second target peptide-MHC complex comprises at least one, at least two, at least three, at least four, at least five, at least one of the second target peptides. 31. A binding protein according to any one of claims 28 to 30, comprising interactions of said second repeat domain with 6 or at least 7 amino acid residues. 前記第２の標的ペプチド－ＭＨＣ複合体への前記第２の反復ドメインの結合が、前記第２の反復ドメインと前記第２のＭＨＣの少なくとも１個のアミノ酸残基との相互作用を含む、請求項２８～３１のいずれか一項に記載の結合タンパク質。 3. Binding of the second repeat domain to the second target peptide-MHC complex comprises an interaction between the second repeat domain and at least one amino acid residue of the second MHC. The binding protein according to any one of paragraphs 28 to 31. 前記第２のＭＨＣが、ＭＨＣクラスＩである、請求項２８～３２のいずれか一項に記載の結合タンパク質。 The binding protein according to any one of claims 28 to 32, wherein the second MHC is MHC class I. 前記第２の標的ペプチドが、前記第１の標的ペプチドと同じタンパク質に由来する、請求項２８～３３のいずれか一項に記載の結合タンパク質。 A binding protein according to any one of claims 28 to 33, wherein the second target peptide is derived from the same protein as the first target peptide. 前記第２の標的ペプチドが、前記第１の標的ペプチドと同じアミノ酸配列を有する、請求項２８～３４のいずれか一項に記載の結合タンパク質。 A binding protein according to any one of claims 28 to 34, wherein the second target peptide has the same amino acid sequence as the first target peptide. 前記第２の反復ドメインが、前記第１の反復ドメインと同じアミノ酸配列を有する、請求項２８～３５のいずれか一項に記載の結合タンパク質。 36. A binding protein according to any one of claims 28 to 35, wherein said second repeat domain has the same amino acid sequence as said first repeat domain. 前記第２の反復ドメインが、前記第１の反復ドメインと比較して、異なるアミノ酸配列を有する、請求項２８～３５のいずれか一項に記載の結合タンパク質。 A binding protein according to any one of claims 28 to 35, wherein the second repeat domain has a different amino acid sequence compared to the first repeat domain. 前記第２の標的ペプチドが、前記第１の標的ペプチドと比較して異なるアミノ酸配列を有する、請求項２８～３４のいずれか一項に記載の結合タンパク質。 A binding protein according to any one of claims 28 to 34, wherein the second target peptide has a different amino acid sequence compared to the first target peptide. 前記第２の標的ペプチドが、前記第１の標的ペプチドが由来するタンパク質とは異なるタンパク質に由来する、請求項２８～３３のいずれか一項に記載の結合タンパク質。 A binding protein according to any one of claims 28 to 33, wherein the second target peptide is derived from a different protein than the protein from which the first target peptide is derived. 前記第２のＭＨＣが、ＨＬＡ－Ａ*０２である、請求項２８～３９のいずれか一項に記載の結合タンパク質。 The binding protein according to any one of claims 28 to 39, wherein the second MHC is HLA-A * 02. 前記第２のＭＨＣが、ＨＬＡ－Ａ*０２ではない、請求項２８～３９のいずれか一項に記載の結合タンパク質。 Binding protein according to any one of claims 28 to 39, wherein the second MHC is not HLA-A * 02. 前記第２の反復ドメインが、設計されたアンキリン反復ドメインである、請求項２８～４１のいずれか一項に記載の結合タンパク質。 42. A binding protein according to any one of claims 28 to 41, wherein the second repeat domain is an engineered ankyrin repeat domain. 前記第２のアンキリン反復ドメインが、（１）配列番号：３７～７２及び（２）配列番号３７～７２のうちのいずれかにおける９個までのアミノ酸が別のアミノ酸によって置換されている配列からなる群から選択されるアミノ酸配列を含むアンキリン反復もジュールを含む、請求項４２に記載の結合タンパク質。 The second ankyrin repeat domain consists of a sequence in which up to 9 amino acids in any of (1) SEQ ID NOs: 37-72 and (2) SEQ ID NOs: 37-72 are substituted with another amino acid. 43. The binding protein of claim 42, wherein the ankyrin repeat comprising an amino acid sequence selected from the group also comprises Joule. 前記第２のアンキリン反復ドメインが、配列番号２０～３３のうちのいずれか１つと少なくとも８０％のアミノ酸配列同一性を有するアミノ酸配列を含み、配列番号２０～３３の位置１のＧ及び／又は位置２のＳが場合により失われており、かつ配列番号２０～３３の最後から２番目の位置のＡは、場合によりＬによって置換されており、及び／又は配列番号２０～３３の最後の位置のＡが、場合によりＮによって置換されている、請求項４２又は４３に記載の結合タンパク質。 said second ankyrin repeat domain comprises an amino acid sequence having at least 80% amino acid sequence identity with any one of SEQ ID NOs: 20-33; 2 is optionally missing, and the A in the penultimate position of SEQ ID NO: 20-33 is optionally replaced by L, and/or the A in the last position of SEQ ID NO: 20-33 is optionally missing. 44. A binding protein according to claim 42 or 43, wherein A is optionally replaced by N. 前記結合タンパク質が、配列番号１６～１８のうちのいずれか１つと少なくとも８０％のアミノ酸配列同一性を有するアミノ酸配列を含むポリペプチドを含む、請求項２８～３４、４０，及び４２～４４のいずれか一項に記載の結合タンパク質。 Any of claims 28-34, 40, and 42-44, wherein the binding protein comprises a polypeptide comprising an amino acid sequence having at least 80% amino acid sequence identity with any one of SEQ ID NOs: 16-18. The binding protein according to item 1. 前記結合タンパク質が更に、免疫細胞の表面上に発現するタンパク質に対する結合特異性を有する結合因子を含む、請求項１５～４５のいずれか一項に記載の結合タンパク質。 46. The binding protein according to any one of claims 15 to 45, wherein the binding protein further comprises a binding factor having binding specificity for a protein expressed on the surface of an immune cell. 前記免疫細胞がＴ細胞である、請求項４６に記載の結合タンパク質。 47. The binding protein of claim 46, wherein the immune cell is a T cell. 前記Ｔ細胞が、ＣＤ８＋細胞障害性Ｔ細胞である、請求項４７に記載の結合タンパク質。 48. The binding protein of claim 47, wherein the T cell is a CD8+ cytotoxic T cell. 前記免疫細胞の表面上に発現するタンパク質が、前記Ｔ細胞受容体複合体の一部であるタンパク質である、請求項４６又は４７に記載の結合タンパク質。 48. The binding protein of claim 46 or 47, wherein the protein expressed on the surface of the immune cell is a protein that is part of the T cell receptor complex. 前記Ｔ細胞受容体複合体の一部である前記タンパク質が、分化クラスター３（ＣＤ３）である、請求項４９に記載の結合タンパク質。 50. The binding protein of claim 49, wherein the protein that is part of the T cell receptor complex is cluster of differentiation 3 (CD3). 前記結合因子が、抗体、抗体模倣物、足場タンパク質、リピートタンパク質、又は設計された反復ドメインである、請求項４６～５０のいずれか一項に記載の結合タンパク質。 A binding protein according to any one of claims 46 to 50, wherein the binding agent is an antibody, an antibody mimetic, a scaffold protein, a repeat protein, or an engineered repeat domain. 前記結合因子が、設計されたアンキリン反復ドメインである、請求項４６～５１のいずれか一項に記載の結合タンパク質。 A binding protein according to any one of claims 46 to 51, wherein the binding agent is an engineered ankyrin repeat domain. 前記結合因子が、前記第１の反復ドメイン及び／又は、存在する場合、前記第２の反復ドメインにペプチドリンカーを用いて共有結合している、請求項４６～５２のいずれか一項に記載の結合タンパク質。 53. The binding agent according to any one of claims 46 to 52, wherein the binding agent is covalently linked to the first repeat domain and/or, if present, the second repeat domain using a peptide linker. binding protein. 前記ペプチドリンカーが、高プロリン－トレオニンペプチドリンカーである、請求項５３に記載の結合タンパク質。 54. The binding protein of claim 53, wherein the peptide linker is a high proline-threonine peptide linker. 前記ペプチドリンカーのアミノ酸配列が、１～１７個のアミノ酸の長さを有する、請求項５３又は５４に記載の結合タンパク質。 55. A binding protein according to claim 53 or 54, wherein the amino acid sequence of the peptide linker has a length of 1 to 17 amino acids. 前記結合タンパク質が、前記第１の標的ペプチド－ＭＨＣ複合体の認識を阻害することができ、かつ／又は前記結合タンパク質が前記第２の反復ドメインを含む場合、Ｔ細胞受容体による前記第２の標的ペプチド－ＭＨＣ複合体の認識を阻害することができる、請求項１５～５５のいずれか一項に記載の結合タンパク質。 When said binding protein is capable of inhibiting recognition of said first target peptide-MHC complex and/or comprises said second repeat domain, said second Binding protein according to any one of claims 15 to 55, capable of inhibiting recognition of a target peptide-MHC complex. 請求項１５～５６のいずれか一項に定義されるような、第１若しくは第２の標的ペプチド－ＭＨＣ複合体に対する結合特異性を有する前記設計された反復ドメイン、をコードする、又は請求項１５～５６のいずれか一項に記載の結合タンパク質をコードする、核酸。 said designed repeat domain with binding specificity for a first or second target peptide-MHC complex as defined in any one of claims 15 to 56, or claim 15 A nucleic acid encoding a binding protein according to any one of items 1 to 56. 請求項１５～５６のいずれか一項に記載の結合タンパク質又は請求項５７に記載の核酸と、医薬として許容され得る担体及び／又は希釈剤と、を含む、医薬組成物。 A pharmaceutical composition comprising a binding protein according to any one of claims 15 to 56 or a nucleic acid according to claim 57 and a pharmaceutically acceptable carrier and/or diluent. 哺乳動物、好ましくはヒトにおけるＴ細胞の腫瘍限局性活性化の方法に使用するための医薬であって、医薬は請求項１５～５５のいずれか一項に記載の結合タンパク質又は請求項５７に記載の核酸を含み、前記方法は、前記哺乳動物に、請求項１５～５５のいずれか一項に記載の結合タンパク質又は請求項５７に記載の核酸を投与するステップを含み、前記第１の標的ペプチド及び／又は、前記結合タンパク質が前記第２の反復ドメインを含む場合、前記第２の標的ペプチドが、腫瘍細胞において発現するタンパク質に由来する、医薬。 A medicament for use in a method for tumor-localized activation of T cells in a mammal, preferably a human, wherein the medicament comprises a binding protein according to any one of claims 15 to 55 or a binding protein according to claim 57. the first target peptide, the method comprising administering to the mammal a binding protein according to any one of claims 15 to 55 or a nucleic acid according to claim 57; and/or when said binding protein comprises said second repeat domain, said second target peptide is derived from a protein expressed in tumor cells. 前記第１の標的ペプチド及び／又は、前記結合タンパク質が前記第２の反復ドメインを含む場合、前記第２の標的ペプチドが、腫瘍細胞において発現するタンパク質に由来する、哺乳動物、好ましくはヒトにおけるＴ細胞の腫瘍限局性活性化の方法における使用のための、請求項１５～５５のいずれか一項に記載の結合タンパク質又は請求項５７に記載の核酸。 When said first target peptide and/or said binding protein comprises said second repeat domain, said second target peptide is derived from a protein expressed in tumor cells, and is derived from a protein expressed in tumor cells. A binding protein according to any one of claims 15 to 55 or a nucleic acid according to claim 57 for use in a method of tumor-localized activation of cells. 哺乳動物、好ましくはヒトにおけるＴ細胞の感染症限局性活性化の方法に使用するための医薬であって、医薬は請求項１５～５５のいずれか一項に記載の結合タンパク質又は請求項５７に記載の核酸を含み、前記方法は、前記哺乳動物に、請求項１５～５５のいずれか一項に記載の結合タンパク質又は請求項５７に記載の核酸を投与するステップを含み、前記第１の標的ペプチド及び／又は、前記結合タンパク質が前記第２の反復ドメインを含む場合、前記第２の標的ペプチドが、感染因子のタンパク質に由来する、医薬。 A medicament for use in a method for infection-localized activation of T cells in a mammal, preferably a human, the medicament comprising a binding protein according to any one of claims 15 to 55 or a binding protein according to claim 57. wherein the method comprises administering to the mammal a binding protein according to any one of claims 15 to 55 or a nucleic acid according to claim 57, wherein the first target When the peptide and/or the binding protein comprises the second repeat domain, the second target peptide is derived from a protein of an infectious agent. 前記第１の標的ペプチド及び／又は、前記結合タンパク質が前記第２の反復ドメインを含む場合、前記第２の標的ペプチドが、感染因子のタンパク質に由来する、哺乳動物、好ましくはヒトにおけるＴ細胞の感染症限局性活性化の方法における使用のための、請求項１５～５５のいずれか一項に記載の結合タンパク質又は請求項５７に記載の核酸。 When said first target peptide and/or said binding protein comprises said second repeat domain, said second target peptide is derived from a protein of an infectious agent, and is derived from a T cell in a mammal, preferably a human. A binding protein according to any one of claims 15 to 55 or a nucleic acid according to claim 57 for use in a method of infectious disease localized activation. 患者の医学的状態を処置するための医薬であって、治療有効量の請求項１５～５６のいずれか一項に記載の結合タンパク質、請求項５７に記載の核酸、又は請求項５８に記載の医薬組成物を含む、医薬。 59. A medicament for treating a medical condition in a patient, comprising a therapeutically effective amount of a binding protein according to any one of claims 15 to 56, a nucleic acid according to claim 57, or a nucleic acid according to claim 58. A medicament, including a pharmaceutical composition. 医学的状態を処置する方法における使用のための、請求項１５～５６のいずれか一項に記載の結合タンパク質、請求項５７に記載の核酸、又は請求項５８に記載の医薬組成物。 A binding protein according to any one of claims 15 to 56, a nucleic acid according to claim 57, or a pharmaceutical composition according to claim 58 for use in a method of treating a medical condition. 哺乳動物、好ましくはヒトにおける医学的状態を決定する方法であって、
（ｉ）前記哺乳動物から得られた細胞試料又は組織試料を請求項１５～５６のいずれか一項に記載の結合タンパク質と接触させるステップと、
（ｉｉ）前記細胞試料又は組織試料への前記結合タンパク質の特異的結合を検出するステップと、を含む、方法。 A method for determining a medical condition in a mammal, preferably a human, comprising:
(i) contacting a cell or tissue sample obtained from said mammal with a binding protein according to any one of claims 15 to 56;
(ii) detecting specific binding of the binding protein to the cell or tissue sample. 前記医学的状態が、癌、感染症、好ましくはウイルス感染症、又は自己免疫疾患である、請求項６３若しくは６５に記載の方法、又は請求項６４に記載の使用のための結合タンパク質。 66. A method according to claim 63 or 65, or a binding protein for use according to claim 64, wherein the medical condition is cancer, an infectious disease, preferably a viral infection, or an autoimmune disease. 前記医学的状態が癌である、請求項６３若しくは６５に記載の方法、又は請求項６４に記載の使用のための結合タンパク質。 66. A method according to claim 63 or 65, or a binding protein for use according to claim 64, wherein the medical condition is cancer. 前記医学的状態が、感染症、好ましくはウイルス感染症である、請求項６３若しくは６５に記載の方法、又は請求項６４に記載の使用のための結合タンパク質。 66. A method according to claim 63 or 65, or a binding protein for use according to claim 64, wherein the medical condition is an infectious disease, preferably a viral infection. 前記医学的状態が自己免疫疾患である、請求項６３若しくは６５に記載の方法、又は請求項６４に記載の使用のための結合タンパク質。 66. A method according to claim 63 or 65, or a binding protein for use according to claim 64, wherein the medical condition is an autoimmune disease. 腫瘍細胞の破壊のために、腫瘍に罹患している患者における腫瘍細胞を標的とする方法に使用するための医薬であって、前記医薬が、請求項１５～５６のいずれか一項に記載の結合タンパク質、請求項５７に記載の核酸、又は請求項５８に記載の医薬組成物を含み、前記方法が、前記患者に治療有効量の請求項１５～５６のいずれか一項に記載の結合タンパク質、請求項５７に記載の核酸、又は請求項５８に記載の医薬組成物を投与するステップを含み、前記第１の標的ペプチド及び／又は、前記結合タンパク質が前記第２の反復ドメインを含む場合、前記第２の標的ペプチドが、前記腫瘍細胞において発現するタンパク質、好ましくは前記腫瘍細胞において発現する細胞内タンパク質に由来する、医薬。 A medicament for use in a method of targeting tumor cells in a patient suffering from a tumor for the destruction of tumor cells, said medicament comprising: a binding protein, a nucleic acid according to claim 57, or a pharmaceutical composition according to claim 58; , a nucleic acid according to claim 57, or a pharmaceutical composition according to claim 58, when said first target peptide and/or said binding protein comprises said second repetitive domain, A medicament, wherein said second target peptide is derived from a protein expressed in said tumor cell, preferably an intracellular protein expressed in said tumor cell. 前記結合タンパク質が更に、腫瘍細胞を殺滅することができる毒性因子を含む、請求項７０に記載の医薬。 71. A medicament according to claim 70, wherein the binding protein further comprises a virulence factor capable of killing tumor cells. 前記第１の標的ペプチド及び／又は、前記結合タンパク質が前記第２の反復ドメインを含む場合、前記第２の標的ペプチドが、腫瘍細胞において発現するタンパク質、好ましくは腫瘍細胞において発現する細胞内タンパク質に由来する、腫瘍細胞の破壊のために、腫瘍に罹患している患者において腫瘍細胞を標的とする方法において使用するための、請求項１５～５６のいずれか一項に記載の結合タンパク質、請求項５７に記載の核酸、又は請求項５８に記載の医薬組成物。 When said first target peptide and/or said binding protein comprises said second repeat domain, said second target peptide binds to a protein expressed in a tumor cell, preferably an intracellular protein expressed in a tumor cell. 57. A binding protein according to any one of claims 15 to 56 for use in a method of targeting tumor cells in a patient suffering from a tumor for the destruction of tumor cells derived from the protein. 58. The nucleic acid according to claim 57, or the pharmaceutical composition according to claim 58. 前記結合タンパク質が更に、腫瘍細胞を殺滅することができる毒性因子を含む、請求項７２に記載の使用のための結合タンパク質、核酸、又は医薬組成物。 73. A binding protein, nucleic acid, or pharmaceutical composition for use according to claim 72, wherein the binding protein further comprises a virulence factor capable of killing tumor cells. 感染細胞の破壊のために、ウイルス感染症に罹患している患者における感染細胞を標的とする方法に使用するための医薬であって、前記医薬が、請求項１５～５６のいずれか一項に記載の結合タンパク質、請求項５７に記載の核酸、又は請求項５８に記載の医薬組成物を含み、前記方法が、前記患者に治療有効量の請求項１５～５６のいずれか一項に記載の結合タンパク質、請求項５７に記載の核酸、又は請求項５８に記載の医薬組成物を投与するステップを含む、方法であって、前記第１の標的ペプチド及び／又は、前記結合タンパク質が前記第２の反復ドメインを含む場合、前記第２の標的ペプチドが、前記感染細胞において発現するタンパク質、好ましくは前記感染細胞において発現するウイルス特異的タンパク質に由来する、医薬。 A medicament for use in a method of targeting infected cells in a patient suffering from a viral infection for the destruction of infected cells, said medicament according to any one of claims 15 to 56. a binding protein according to claim 57, or a pharmaceutical composition according to claim 58; 59. A method comprising administering a binding protein, a nucleic acid according to claim 57, or a pharmaceutical composition according to claim 58, wherein the first target peptide and/or the binding protein said second target peptide is derived from a protein expressed in said infected cell, preferably a virus-specific protein expressed in said infected cell. 前記結合タンパク質が更に、感染細胞を殺滅することができる毒性因子を含む、請求項７４に記載の医薬。 75. A medicament according to claim 74, wherein the binding protein further comprises a virulence factor capable of killing infected cells. 前記第１の標的ペプチド及び／又は、前記結合タンパク質が前記第２の反復ドメインを含む場合、前記第２の標的ペプチドが、感染細胞において発現するタンパク質、好ましくは前記感染細胞において発現するウイルス特異的タンパク質に由来する、前記感染細胞の破壊のために、ウイルス感染症に罹患している患者において前記感染細胞を標的とする方法において使用するための、請求項１５～５６のいずれか一項に記載の結合タンパク質、請求項５７に記載の核酸、又は請求項５８に記載の医薬組成物。 When said first target peptide and/or said binding protein comprises said second repeat domain, said second target peptide comprises a protein expressed in infected cells, preferably a virus-specific protein expressed in said infected cells. 57. A method according to any one of claims 15 to 56 for use in a method of targeting infected cells in a patient suffering from a viral infection for the destruction of infected cells derived from a protein. a binding protein according to claim 57, a nucleic acid according to claim 57, or a pharmaceutical composition according to claim 58. 前記結合タンパク質が更に、感染細胞を殺滅することができる毒性因子を含む、請求項７６に記載の使用のための結合タンパク質、核酸、又は医薬組成物。 77. A binding protein, nucleic acid, or pharmaceutical composition for use according to claim 76, wherein said binding protein further comprises a virulence factor capable of killing infected cells. 前記医学的状態又は腫瘍が、脂肪肉腫、神経芽腫、滑膜肉腫、黒色腫、及び卵巣癌からなる群から選択される、請求項６３、６６～６７、６９及び７０のいずれか一項に記載の方法、又は請求項６４、７２及び７３のいずれか一項に記載の結合タンパク質、核酸若しくは医薬組成物。 Any one of claims 63, 66-67, 69 and 70, wherein the medical condition or tumor is selected from the group consisting of liposarcoma, neuroblastoma, synovial sarcoma, melanoma, and ovarian cancer. 74. A method as described, or a binding protein, nucleic acid or pharmaceutical composition according to any one of claims 64, 72 and 73.
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