JPWO2020146221A5 - - Google Patents

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JPWO2020146221A5
JPWO2020146221A5 JP2021538982A JP2021538982A JPWO2020146221A5 JP WO2020146221 A5 JPWO2020146221 A5 JP WO2020146221A5 JP 2021538982 A JP2021538982 A JP 2021538982A JP 2021538982 A JP2021538982 A JP 2021538982A JP WO2020146221 A5 JPWO2020146221 A5 JP WO2020146221A5
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binding domain
antigen binding
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cancer
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Priority claimed from PCT/US2020/012296 external-priority patent/WO2020146221A1/en
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修飾ＩＬ－２を含むポリペプチドであって、前記修飾ＩＬ－２は、Ｐ６５、Ｄ８４及びＨ１６のアミノ酸位置に置換を含み、アミノ酸位置は配列番号１におけるアミノ酸位置に対応する、ポリペプチド。 A polypeptide comprising a modified IL-2, said modified IL-2 comprising substitutions at amino acid positions P65, D8 4 and H1 6, wherein the amino acid positions correspond to those in SEQ ID NO: 1 Polypeptide. 前記修飾ＩＬ－２は、修飾ヒトＩＬ－２である、請求項１に記載のポリペプチド。 2. The polypeptide of claim 1, wherein said modified IL-2 is modified human IL-2. アミノ酸位置Ｐ６５における置換は、Ｐ６５Ｒ、Ｐ６５Ｅ、Ｐ６５Ｋ、Ｐ６５Ｈ、Ｐ６５Ｙ、Ｐ６５Ｑ、Ｐ６５Ｄ、及びＰ６５Ｎから選択される、請求項１又は２に記載のポリペプチド。 3. The polypeptide of claim 1 or 2, wherein the substitution at amino acid position P65 is selected from P65R, P65E, P65K, P65H, P65Y, P65Q, P65D and P65N. アミノ酸位置Ｈ１６における置換は、Ｈ１６Ａ、Ｈ１６Ｇ、Ｈ１６Ｓ、Ｈ１６Ｔ、Ｈ１６Ｖ、及びＨ１６Ｐから選択される、請求項１～３のいずれかに記載のポリペプチド。 A polypeptide according to any preceding claim, wherein the substitution at amino acid position H16 is selected from H16A, H16G, H16S, H16T, H16V and H16P. アミノ酸位置Ｄ８４における置換は、Ｄ８４Ｓ、Ｄ８４Ｇ、Ｄ８４Ａ、Ｄ８４Ｔ、Ｄ８４Ｖ、及びＤ８４Ｐから選択される、請求項１～４のいずれかに記載のポリペプチド。 5. The polypeptide of any of claims 1-4, wherein the substitution at amino acid position D84 is selected from D84S, D84G, D84A, D84T, D84V and D84P. 前記修飾ＩＬ－２は、アミノ酸位置Ｍ２３に置換を含み、任意に、前記置換は、Ｍ２３Ａ、Ｍ２３Ｇ、Ｍ２３Ｓ、Ｍ２３Ｔ、Ｍ２３Ｖ、及びＭ２３Ｐから選択される、請求項１～５のいずれかに記載のポリペプチド。 6. A modified IL-2 according to any preceding claim, wherein said modified IL-2 comprises a substitution at amino acid position M23, optionally said substitution is selected from M23A, M23G, M23S, M23T, M23V and M23P. of polypeptides. 前記修飾ＩＬ－２は、アミノ酸位置Ｅ９５に置換を含み、任意に前記置換は、Ｅ９５Ｑ、Ｅ９５Ｇ、Ｅ９５Ｓ、Ｅ９５Ｔ、Ｅ９５Ｖ、Ｅ９５Ｐ、Ｅ９５Ｈ、及びＥ９５Ｎから選択される、請求項１～６のいずれかに記載のポリペプチド。 7. Any of claims 1-6, wherein said modified IL-2 comprises a substitution at amino acid position E95, optionally said substitution is selected from E95Q, E95G, E95S, E95T, E95V, E95P, E95H and E95N. the polypeptide of claim 1. 前記修飾ＩＬ－２は、アミノ酸位置Ｆ４２に置換を含み、任意に前記置換は、Ｆ４２Ｋ、Ｆ４２Ａ、Ｆ４２Ｒ、Ｆ４２Ｇ、Ｆ４２Ｓ、及びＦ４２Ｔから選択される、請求項１～７のいずれかに記載のポリペプチド。 8. The modified IL-2 of any of claims 1-7, wherein said modified IL-2 comprises a substitution at amino acid position F42, optionally said substitution is selected from F42K, F42A, F42R, F42G, F42S and F42T. Polypeptide. 前記修飾ＩＬ－２は、Ｙ４５及びＬ７２から選択される少なくとも１つのアミノ酸位置に少なくとも１つの置換を含み、任意に前記修飾ＩＬ－２は、Ｙ４５Ａ及びＬ７２Ｇから選択される少なくとも１つの置換を含む、請求項１～８のいずれかに記載のポリペプチド。 Said modified IL-2 comprises at least one substitution at at least one amino acid position selected from Y45 and L72 , optionally said modified IL-2 comprises at least one substitution selected from Y45A and L72G. , a polypeptide according to any one of claims 1-8. 前記修飾ＩＬ－２は、Ｐ６５Ｒ、Ｈ１６Ａ及びＤ８４Ｓ；Ｐ６５Ｒ、Ｈ１６Ａ、Ｄ８４Ｓ及びＭ２３Ａ；Ｐ６５Ｒ、Ｈ１６Ａ、Ｄ８４Ｓ及びＥ９５Ｑ；又は、Ｐ６５Ｒ、Ｈ１６Ａ、Ｄ８４Ｓ、Ｍ２３Ａ及びＥ９５Ｑ；の置換を含む、請求項１～９のいずれかに記載のポリペプチド。 P65R, H16A, D84S and M23A; P65R, H16A, D84S and E95Q; or P65R, H16A, D84S, M23A and E95Q; 10. The polypeptide according to any one of 9. 前記修飾ＩＬ－２は、Ｔ３及びＣ１２５から選択される少なくとも１つのアミノ酸位置に少なくとも１つの置換を含み、任意に前記修飾ＩＬ－２は、Ｔ３Ａ及びＣ１２５Ａから選択される少なくとも１つの置換を含む、請求項１～１０のいずれかに記載のポリペプチド。 Said modified IL-2 comprises at least one substitution at at least one amino acid position selected from T3 and C125 , optionally said modified IL-2 comprises at least one substitution selected from T3A and C125A. , a polypeptide according to any one of claims 1-10. 前記修飾ＩＬ－２は、Ｈ１６Ａ－Ｆ４２Ｋ、Ｄ８４Ｓ－Ｆ４２Ｋ、Ｅ１５Ｓ－Ｆ４２Ｋ、Ｍ２３Ａ－Ｆ４２Ｋ、Ｅ９５Ｑ－Ｆ４２Ｋ、Ｐ６５Ｒ－Ｈ１６Ａ、Ｐ６５Ｒ－Ｄ８４Ｓ、Ｐ６５Ｒ－Ｅ１５Ｓ、Ｐ６５Ｒ－Ｍ２３Ａ、Ｐ６５Ｒ－Ｅ９５Ｑ、Ｔ３Ａ－Ｃ１２５Ｓ、Ｔ３Ａ－Ｐ６５Ｒ－Ｃ１２５Ｓ、Ｔ３Ａ－Ｈ１６Ａ－Ｃ１２５Ｓ、Ｔ３Ａ－Ｄ８４Ｓ－Ｃ１２５Ｓ、Ｔ３Ａ－Ｈ１６Ａ－Ｐ６５Ｒ－Ｃ１２５Ｓ、Ｔ３Ａ－Ｐ６５Ｒ－Ｄ８４Ｓ－Ｃ１２５Ｓ、Ｔ３Ａ－Ｈ１６Ａ－Ｐ６５Ｒ－Ｄ８４Ｓ－Ｃ１２５Ｓ、Ｔ３Ａ－Ｈ１６Ａ－Ｍ２３Ａ－Ｐ６５Ｒ－Ｄ８４Ｓ－Ｃ１２５Ｓ、Ｔ３Ａ－Ｈ１６Ａ－Ｐ６５Ｒ－Ｄ８４Ｓ－Ｅ９５Ｑ－Ｃ１２５Ｓ、及びＴ３Ａ－Ｈ１６Ａ－Ｍ２３Ａ－Ｐ６５Ｒ－Ｄ８４Ｓ－Ｅ９５Ｑ－Ｃ１２５Ｓから選択される一連の置換を含む、請求項１～１１のいずれか一項に記載のポリペプチド。 Said modified IL-2 is H16A-F42K, D84S-F42K, E15S-F42K, M23A-F42K, E95Q-F42K, P65R-H16A, P65R-D84S, P65R-E15S, P65R-M23A, P65R-E95Q, T3A-C125S , T3A-P65R-C125S, T3A-H16A-C125S, T3A-D84S-C125S, T3A-H16A-P65R-C125S, T3A-P65R-D84S-C125S, T3A-H16A-P65R-D84S-C125S, T3A-H16A-M23A -P65R-D84S-C125S, T3A-H16A-P65R-D84S-E95Q-C125S, and T3A-H16A-M23A-P65R- D84S -E95Q-C125S. or the polypeptide according to claim 1. 前記修飾ＩＬ－２は、前記一連の置換を含み、任意の付加的な置換を含まない、請求項１２に記載のポリペプチド。 13. The polypeptide of claim 12 , wherein said modified IL-2 comprises said series of substitutions and does not contain any additional substitutions. 前記修飾ＩＬ－２は、配列番号８４と少なくとも９０％、９１％、９２％、９３％、９４％、９５％、９６％、９７％、９８％、又は９９％同一のアミノ酸配列を含むか、配列番号３～配列番号９、配列番号１１～配列番号２１、及び配列番号２３～配列番号３１から選択されるアミノ酸配列と少なくとも９０％、９１％、９２％、９３％、９４％、９５％、９６％、９７％、９８％、９９％、又は１００％同一のアミノ酸配列を含む、請求項１～１３のいずれか一項に記載のポリペプチド。 said modified IL-2 comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:84 ; and at least 90%, 91%, 92%, 93%, 94%, 95%, 14. A polypeptide according to any one of claims 1 to 13, comprising 96%, 97%, 98%, 99% or 100% identical amino acid sequences. 前記ポリペプチドは、Ｆｃ領域を含み、任意に前記修飾ＩＬ－２は、前記Ｆｃ領域のＮ末端又はＣ末端に融合している、請求項１～１４のいずれかに記載のポリペプチド。 15. The polypeptide of any of claims 1-14, wherein said polypeptide comprises an Fc region, and optionally said modified IL-2 is fused to the N-terminus or C-terminus of said Fc region. 前記Ｆｃ領域は、Ｋａｂａｔアミノ酸位置Ｔ３６６に置換を含むか、前記Ｆｃ領域は、Ｔ３６６、Ｌ３６８、及びＹ４０７から選択される少なくとも１つのＫａｂａｔアミノ酸位置に少なくとも１つの置換を含み、任意に前記Ｆｃ領域は、Ｔ３６６Ｗ置換を含むか、又は、前記Ｆｃ領域は、Ｔ３６６Ｓ、Ｌ３６８Ａ、及びＹ４０７Ｖ変異を含む、請求項１５に記載のポリペプチド。 said Fc region comprises a substitution at Kabat amino acid position T366, or said Fc region comprises at least one substitution at at least one Kabat amino acid position selected from T366, L368, and Y407; , the T366W substitution, or wherein the Fc region comprises the T366S, L368A, and Y407V mutations. 前記Ｆｃ領域は、Ｓ３５４及びＹ３４９から選択されるＫａｂａｔ位置に置換を含み、任意にＳ３５４Ｃ又はＹ３４９Ｃ置換を含む、請求項１５又は１６に記載のポリペプチド。 17. The polypeptide of claim 15 or 16, wherein said Fc region comprises substitutions at Kabat positions selected from S354 and Y349, optionally comprising S354C or Y349C substitutions. 前記Ｆｃ領域は、Ｋａｂａｔアミノ酸位置Ｈ４３５に置換を含み、任意にＨ４３５Ｒ及びＨ４３５Ｋから選択される置換を含む、請求項１５～１７のいずれかに記載のポリペプチド。 18. The polypeptide of any of claims 15-17, wherein said Fc region comprises a substitution at Kabat amino acid position H435, optionally a substitution selected from H435R and H435K. 前記Ｆｃ領域は、Ｍ２５２及びＭ４２８から選択される１つのＫａｂａｔアミノ酸位置に少なくとも１つの置換を含み、任意にＭ２５２Ｙ及びＭ４２８Ｖ置換を含む、請求項１５～１８のいずれかに記載のポリペプチド。 19. The polypeptide of any of claims 15-18, wherein said Fc region comprises at least one substitution at one Kabat amino acid position selected from M252 and M428, and optionally M252Y and M428V substitutions . 前記Ｆｃ領域は、Ｋａｂａｔアミノ酸Ｅ２３３、Ｌ２３４、及びＬ２３５の欠失を含むか、前記Ｆｃ領域は、Ｌ２３４、Ｌ２３５、及びＰ３２９から選択される少なくとも１つのアミノ酸位置に少なくとも１つの置換を含み、任意に前記Ｆｃ領域は、Ｌ２３４Ａ、Ｌ２３５Ａ、及びＰ３２９Ｇ置換を含む、請求項１５～１９のいずれかに記載のポリペプチド。 said Fc region comprises a deletion of Kabat amino acids E233, L234 and L235; or said Fc region comprises at least one substitution at at least one amino acid position selected from L234, L235 and P329; 20. The polypeptide of any of claims 15-19, wherein said Fc region comprises L234A, L235A and P329G substitutions. 前記Ｆｃ領域は、配列番号４７～配列番号８３から選択されるアミノ酸配列と少なくとも９０％、９１％、９２％、９３％、９４％、９５％、９６％、９７％、９８％、９９％、又は１００％同一のアミノ酸配列を含む、請求項１５～２０のいずれか一項に記載のポリペプチド。 The Fc region comprises at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, an amino acid sequence selected from SEQ ID NO: 47-SEQ ID NO: 83, or comprising 100% identical amino acid sequences. 前記Ｆｃ領域は、重鎖定常領域の一部であり、任意に前記重鎖定常領域は、ＩｇＧ１、ＩｇＧ２、ＩｇＧ３、又はＩｇＧ４定常領域である、請求項１５～２０のいずかに記載のポリペプチド。 21. The polypolysaccharide of any of claims 15-20, wherein said Fc region is part of a heavy chain constant region, optionally said heavy chain constant region is an IgGl, IgG2, IgG3, or IgG4 constant region. peptide. 前記修飾ＩＬ－２は、１個～２０個のアミノ酸を含むリンカーによって前記Ｆｃ領域又は重鎖定常領域のＣ末端に融合しており、任意に前記リンカーは、グリシンアミノ酸、又は、グリシン及びセリンアミノ酸を含む、請求項１５～２２に記載のポリペプチド。 Said modified IL-2 is fused to the C-terminus of said Fc region or heavy chain constant region by a linker comprising from 1 to 20 amino acids , optionally said linker comprising glycine amino acids, or glycine and serine amino acids. The polypeptide according to claims 15-22, comprising 前記ポリペプチドは、配列番号８６、配列番号８７、配列番号１０２、配列番号１０３、又は配列番号１０４のアミノ酸配列を含む、請求項１５、１６、２０、及び２３のいずれか一項に記載のポリペプチド。 24. The polypeptide of any one of claims 15, 16, 20, and 23 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:102, SEQ ID NO:103, or SEQ ID NO:104. peptide. 前記ポリペプチドは、少なくとも１つの抗原結合ドメインを含むか、或いは、前記ポリペプチドは、２つ、３つ、又は４つの抗原結合ドメインを含む、請求項１～２４のいずれかに記載のポリペプチド。 25. The polypeptide of any of claims 1-24, wherein said polypeptide comprises at least one antigen binding domain, alternatively said polypeptide comprises 2, 3 or 4 antigen binding domains. . 少なくとも１つの抗原結合ドメインは、Ｔ細胞抗原又はナチュラルキラー細胞抗原に特異的に結合する、請求項２５に記載のポリペプチド。 26. The polypeptide of claim 25 , wherein at least one antigen binding domain specifically binds to a T cell antigen or natural killer cell antigen. 少なくとも１つの抗原結合ドメインは、ＣＤ４＋Ｔ細胞抗原又はＣＤ８＋Ｔ細胞抗原に特異的に結合し、任意に、活性化ＣＤ４ ＋ Ｔ細胞又は活性化ＣＤ８ ＋ Ｔ細胞上の抗原に特異的に結合する、請求項２５又は２６に記載のポリペプチド。 The at least one antigen-binding domain specifically binds to a CD4 + T cell antigen or a CD8 + T cell antigen , optionally to an antigen on activated CD4 + T cells or activated CD8 + T cells. 27. The polypeptide of claim 25 or 26, wherein 少なくとも１つの抗原結合ドメインは、ＰＤ－１、ＣＴＬＡ－４、ＬＡＧ３、ＴＩＭ３、４－１ＢＢ、ＯＸ４０、ＧＩＴＲ、ＣＤ８ａ、ＣＤ８ｂ、ＣＤ４、ＮＫｐ３０、ＮＫＧ２Ａ、ＴＩＧＩＴ、ＴＧＦβＲ１、ＴＧＦβＲ２、Ｆａｓ、ＮＫＧ２Ｄ、ＮＫｐ４６、ＰＤ－Ｌ１、ＣＤ１０７ａ、ＩＣＯＳ、ＴＮＦＲ２、又はＣＤ１６ａに特異的に結合する、請求項２５～２７のいずれか一項に記載のポリペプチド。 at least one antigen binding domain is PD-1, CTLA-4, LAG3, TIM3, 4-1BB, OX40, GITR, CD8a, CD8b, CD4, NKp30, NKG2A, TIGIT, TGFβR1, TGFβR2, Fas, NKG2D, NKp46, 28. The polypeptide of any one of claims 25-27 , which specifically binds to PD-Ll, CD107a, ICOS, TNFR2, or CD16a. 少なくとも１つ又は各々の抗原結合ドメインは、ヒト又はヒト化抗原結合ドメインである、請求項２５～２８のいずれか一項に記載のポリペプチド。 29. The polypeptide of any one of claims 25-28 , wherein at least one or each antigen binding domain is a human or humanized antigen binding domain. 少なくとも１つ又は各々の抗原結合ドメインは、ＶＨＨドメインを含む、請求項２５～２９のいずれか一項に記載のポリペプチド。 30. The polypeptide of any one of claims 25-29 , wherein at least one or each antigen binding domain comprises a VHH domain. 少なくとも１つの抗原結合ドメインは、ＶＨドメイン及びＶＬドメインを含み、任意に、ペンブロリズマブ、ニボルマブ、ＡＭＰ－５１４、ＴＳＲ－０４２、ＳＴＩ－Ａ１１１０、イピリムマブ、トレメリムマブ、ウレルマブ、ウトミルマブ、アテゾリズマブ、及びデュルバルマブから選択される抗体のＶＨドメイン及びＶＬドメインを含む、請求項２５～２９のいずれかに記載のポリペプチド。 The at least one antigen-binding domain comprises a VH domain and a VL domain , optionally selected from pembrolizumab, nivolumab, AMP-514, TSR-042, STI-A1110, ipilimumab, tremelimumab, urelumab, utomilumab, atezolizumab, and durvalumab 30. A polypeptide according to any of claims 25-29, comprising the VH and VL domains of an antibody produced by a 前記少なくとも１つの抗原結合ドメインは、一本鎖Ｆｖ（ｓｃＦｖ）を含む、請求項３１に記載のポリペプチド。 32. The polypeptide of claim 31, wherein said at least one antigen binding domain comprises a single chain Fv (scFv). 前記ポリペプチドは、重鎖定常領域を含み、前記ＶＨドメインは、前記重鎖定常領域に融合し、前記ＶＬドメインは、前記ＶＨドメインと結合し、任意に前記ＶＬドメインは、軽鎖定常領域に融合し、任意に前記軽鎖定常領域は、カッパ及びラムダから選択される、請求項３１に記載のポリペプチド。 Said polypeptide comprises a heavy chain constant region, said VH domain fused to said heavy chain constant region, said VL domain bound to said VH domain, optionally said VL domain to a light chain constant region. 32. The polypeptide of claim 31, fused and optionally said light chain constant region is selected from kappa and lambda. 前記抗原結合ドメインは、それぞれ同じであり、及び／又は、前記抗原結合ドメインは、それぞれ同じ抗原に特異的に結合する、請求項２５～３３のいずれか一項に記載のポリペプチド。 34. The polypeptide of any one of claims 25-33, wherein the antigen binding domains are each the same and/or the antigen binding domains each specifically bind the same antigen. 少なくとも１つの抗原結合ドメインは、ＰＤ－１に特異的に結合し、少なくとも１つの他の抗原結合ドメインは、ＰＤ－１以外のＴ細胞抗原又はナチュラルキラー細胞抗原に特異的に結合する、請求項２５～３４のいずれか一項に記載のポリペプチド。 wherein at least one antigen binding domain specifically binds to PD-1 and at least one other antigen binding domain specifically binds to a T cell antigen other than PD-1 or a natural killer cell antigen; 35. The polypeptide according to any one of 25-34 . 前記ポリペプチドは、生理学的条件下でホモ二量体を形成する、請求項１５～３５のいずれか一項に記載のポリペプチド。 A polypeptide according to any one of claims 15 to 35 , wherein said polypeptide forms homodimers under physiological conditions. 前記修飾ＩＬ－２は、ＩＬ－２Ｒに対するヒト野生型ＩＬ－２の親和性より少なくとも２倍、３倍、４倍、５倍、６倍、７倍、８倍、９倍、少なくとも１０倍、少なくとも２０倍、少なくとも３０倍、少なくとも５０倍、又は少なくとも１００倍低い親和性でヒトＩＬ－２Ｒに結合する、請求項１～３６のいずれか一項に記載のポリペプチド。 said modified IL-2 has at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, at least 10-fold the affinity of human wild-type IL-2 for IL-2R; 37. The polypeptide of any one of claims 1-36 , which binds human IL-2R with at least 20-fold, at least 30-fold, at least 50-fold, or at least 100-fold lower affinity. 第１のポリペプチドと第２のポリペプチドとを含む複合体であって、前記第１のポリペプチドは、請求項１～３７のいずれか一項に記載のポリペプチドである、複合体。 A complex comprising a first polypeptide and a second polypeptide, wherein said first polypeptide is the polypeptide of any one of claims 1-37 . 前記第１のポリペプチドは、第１のＦｃ領域を含み、前記第２のポリペプチドは、第２のＦｃ領域を含み、任意に各Ｆｃ領域は、ヒトＩｇＧ１、ＩｇＧ２、ＩｇＧ３、及びＩｇＧ４から選択されるアイソタイプである、請求項３８に記載の複合体。 Said first polypeptide comprises a first Fc region and said second polypeptide comprises a second Fc region , optionally each Fc region from human IgG1, IgG2, IgG3 and IgG4. 39. The conjugate of claim 38, which is of a selected isotype. 各Ｆｃ領域は、アミノ酸Ｅ２３３、Ｌ２３４、及びＬ２３５の欠失を含み、及び／又は、各Ｆｃ領域は、Ｈ４３５Ｒ又はＨ４３５Ｋ変異を含み、及び／又は、各Ｆｃ領域は、変異Ｍ２５２Ｙ及びＭ４２８Ｌ又は変異Ｍ２５２Ｙ及びＭ４２８Ｖを含み、及び／又は、前記第１のＦｃ領域又は前記第２のＦｃ領域は、Ｔ３６６Ｗ変異を含み、他方のＦｃ領域は、変異Ｔ３６６Ｓ、Ｌ３６８Ａ、及びＹ４０７Ｖを含み、及び／又は、前記第１のＦｃ領域又は前記第２のＦｃ領域は、Ｓ３５４Ｃ変異を含む、請求項３８又は３９に記載の複合体。 Each Fc region comprises deletions of amino acids E233, L234 and L235 and/or each Fc region comprises H435R or H435K mutations and/or each Fc region comprises mutations M252Y and M428L or M252Y and M428V, and/or said first Fc region or said second Fc region comprises the T366W mutation and the other Fc region comprises the mutations T366S, L368A and Y407V, and/or 40. The conjugate of claim 38 or 39, wherein said first Fc region or said second Fc region comprises the S354C mutation. 各Ｆｃ領域は、独立して配列番号４７～配列番号８３から選択されるアミノ酸配列と少なくとも９０％、９１％、９２％、９３％、９４％、９５％、９６％、９７％、９８％、９９％、又は１００％同一のアミノ酸配列を含む、請求項３８～４０のいずれか一項に記載の複合体。 each Fc region independently comprises an amino acid sequence selected from A conjugate according to any one of claims 38 to 40 comprising 99% or 100% identical amino acid sequences. 前記第２のポリペプチドは、修飾ＩＬ２を含まない、請求項３８～４１のいずれか一項に記載の複合体。 The conjugate of any one of claims 38-41 , wherein said second polypeptide does not comprise modified IL2. 前記第１のポリペプチドは、第１の抗原結合ドメイン、Ｆｃ領域、及び修飾ＩＬ－２を含み、前記第１の抗原結合ドメインは、前記Ｆｃ領域のＮ末端に融合し、前記修飾ＩＬ－２は、前記Ｆｃ領域のＣ末端に融合し、前記第２のポリペプチドは、第２の抗原結合ドメイン及びＦｃ領域を含む、請求項３８～４２のいずれかに記載の複合体。 The first polypeptide comprises a first antigen-binding domain, an Fc region, and a modified IL-2 , wherein the first antigen-binding domain is fused to the N-terminus of the Fc region, and the modified IL-2 2 is fused to the C-terminus of said Fc region, said second polypeptide comprising a second antigen binding domain and an Fc region. ａ）前記第１の抗原結合ドメイン及び前記第２の抗原結合ドメインは、どちらもＰＤ－１に結合し、
ｂ）前記第１の抗原結合ドメインは、ＰＤ－１に結合し、かつ前記第２の抗原結合ドメインは、ＬＡＧ３に結合し、
ｃ）前記第１の抗原結合ドメインは、ＰＤ－１に結合し、かつ前記第２の抗原結合ドメインは、ＣＴＬＡ－４に結合し、
ｄ）前記第１の抗原結合ドメインは、ＰＤ－１に結合し、かつ前記第２の抗原結合ドメインは、４－１ＢＢに結合し、
ｅ）前記第１の抗原結合ドメインは、ＰＤ－１に結合し、かつ前記第２の抗原結合ドメインは、ＯＸ４０に結合し、
ｆ）前記第１の抗原結合ドメインは、ＰＤ－１に結合し、かつ前記第２の抗原結合ドメインは、ＧＩＴＲに結合し、
ｇ）前記第１の抗原結合ドメインは、ＰＤ－１に結合し、かつ前記第２の抗原結合ドメインは、ＣＤ８ａに結合し、
ｈ）前記第１の抗原結合ドメインは、ＰＤ－１に結合し、かつ前記第２の抗原結合ドメインは、ＣＤ８ｂに結合し、
ｉ）前記第１の抗原結合ドメインは、ＰＤ－１に結合し、かつ前記第２の抗原結合ドメインは、ＣＤ４に結合し、
ｊ）前記第１の抗原結合ドメインは、ＰＤ－１に結合し、かつ前記第２の抗原結合ドメインは、ＮＫｐ３０に結合し、
ｋ）前記第１の抗原結合ドメインは、ＰＤ－１に結合し、かつ前記第２の抗原結合ドメインは、ＮＫＧ２Ａに結合し、
ｌ）前記第１の抗原結合ドメインは、ＰＤ－１に結合し、かつ前記第２の抗原結合ドメインは、ＴＩＧＩＴに結合し、
ｍ）前記第１の抗原結合ドメインは、ＰＤ－１に結合し、かつ前記第２の抗原結合ドメインは、ＮＫＧ２Ｄに結合し、
ｎ）前記第１の抗原結合ドメインは、ＰＤ－１に結合し、かつ前記第２の抗原結合ドメインは、ＴＧＦＢＲ２に結合し、
ｏ）前記第１の抗原結合ドメインは、ＰＤ－１に結合し、かつ前記第２の抗原結合ドメインは、Ｆａｓに結合し、
ｐ）前記第１の抗原結合ドメインは、ＰＤ－１に結合し、かつ前記第２の抗原結合ドメインは、ＣＤ１０７ａに結合し、
ｑ）前記第１の抗原結合ドメインは、ＰＤ－１に結合し、かつ前記第２の抗原結合ドメインは、ＮＫｐ４６に結合し、
ｒ）前記第１の抗原結合ドメインは、ＣＤ８ａに結合し、かつ前記第２の抗原結合ドメインは、ＴＧＦＲβＲ２に結合し、
ｓ）前記第１の抗原結合ドメインは、ＣＤ８ａに結合し、かつ前記第２の抗原結合ドメインは、Ｆａｓに結合し、
ｔ）前記第１の抗原結合ドメインは、ＮＫＧ２Ｄに結合し、かつ前記第２の抗原結合ドメインは、ＴＧＦＲβＲ２に結合し、
ｕ）前記第１の抗原結合ドメインは、ＮＫＧ２Ｄに結合し、かつ前記第２の抗原結合ドメインは、Ｆａｓに結合し、
ｖ）前記第１の抗原結合ドメインは、ＮＫＧ２Ａに結合し、かつ前記第２の抗原結合ドメインは、ＴＧＦＲβＲ２に結合し、
ｗ）前記第１の抗原結合ドメインは、ＮＫＧ２Ａに結合し、かつ前記第２の抗原結合ドメインは、Ｆａｓに結合し、
ｘ）前記第１の抗原結合ドメインは、ＮＫｐ４６に結合し、かつ前記第２の抗原結合ドメインは、ＴＧＦＲβＲ２に結合し、
ｙ）前記第１の抗原結合ドメインは、ＮＫｐ４６に結合し、かつ前記第２の抗原結合ドメインは、Ｆａｓに結合し、
ｚ）前記第１の抗原結合ドメインは、ＣＴＬＡ－４に結合し、かつ前記第２の抗原結合ドメインは、ＬＡＧ３に結合し、
ａａ）前記第１の抗原結合ドメインは、ＣＴＬＡ－４に結合し、かつ前記第２の抗原結合ドメインは、Ｔｉｍ３に結合し、
ｂｂ）前記第１の抗原結合ドメインは、ＣＴＬＡ－４に結合し、かつ前記第２の抗原結合ドメインは、ＯＸ４０に結合し、
ｃｃ）前記第１の抗原結合ドメインは、ＣＴＬＡ－４に結合し、かつ前記第２の抗原結合ドメインは、ＧＩＴＲに結合し、
ｄｄ）前記第１の抗原結合ドメインは、ＣＴＬＡ－４に結合し、かつ前記第２の抗原結合ドメインは、ＣＤ１０７ａに結合し、
ｅｅ）前記第１の抗原結合ドメインは、ＣＴＬＡ－４に結合し、かつ前記第２の抗原結合ドメインは、ＮＫｐ４６に結合し、又は、
ｆｆ）前記第１の抗原結合ドメインは、ＩＣＯＳに結合し、かつ前記第２の抗原結合ドメインは、ＴＮＦＲ２に結合する、請求項４３に記載の複合体。 a) said first antigen-binding domain and said second antigen-binding domain both bind to PD-1;
b) said first antigen binding domain binds PD-1 and said second antigen binding domain binds LAG3;
c) said first antigen binding domain binds PD-1 and said second antigen binding domain binds CTLA-4;
d) said first antigen binding domain binds PD-1 and said second antigen binding domain binds 4-1BB;
e) said first antigen binding domain binds PD-1 and said second antigen binding domain binds OX40;
f) said first antigen binding domain binds to PD-1 and said second antigen binding domain binds to GITR;
g) said first antigen binding domain binds PD-1 and said second antigen binding domain binds CD8a;
h) said first antigen binding domain binds PD-1 and said second antigen binding domain binds CD8b;
i) said first antigen binding domain binds PD-1 and said second antigen binding domain binds CD4;
j) said first antigen binding domain binds PD-1 and said second antigen binding domain binds NKp30;
k) said first antigen binding domain binds to PD-1 and said second antigen binding domain binds to NKG2A;
l) said first antigen binding domain binds PD-1 and said second antigen binding domain binds TIGIT;
m) said first antigen binding domain binds to PD-1 and said second antigen binding domain binds to NKG2D;
n) said first antigen binding domain binds PD-1 and said second antigen binding domain binds TGFBR2;
o) said first antigen binding domain binds PD-1 and said second antigen binding domain binds Fas;
p) said first antigen binding domain binds PD-1 and said second antigen binding domain binds CD107a;
q) said first antigen binding domain binds to PD-1 and said second antigen binding domain binds to NKp46;
r) said first antigen binding domain binds CD8a and said second antigen binding domain binds TGFRβR2;
s) said first antigen binding domain binds CD8a and said second antigen binding domain binds Fas;
t) said first antigen binding domain binds to NKG2D and said second antigen binding domain binds to TGFRβR2;
u) said first antigen binding domain binds NKG2D and said second antigen binding domain binds Fas;
v) said first antigen binding domain binds to NKG2A and said second antigen binding domain binds to TGFRβR2;
w) said first antigen binding domain binds to NKG2A and said second antigen binding domain binds to Fas;
x) said first antigen binding domain binds NKp46 and said second antigen binding domain binds TGFRβR2;
y) said first antigen binding domain binds NKp46 and said second antigen binding domain binds Fas;
z) said first antigen binding domain binds CTLA-4 and said second antigen binding domain binds LAG3;
aa) said first antigen binding domain binds CTLA-4 and said second antigen binding domain binds Tim3;
bb) said first antigen binding domain binds CTLA-4 and said second antigen binding domain binds OX40;
cc) said first antigen binding domain binds CTLA-4 and said second antigen binding domain binds GITR;
dd) said first antigen binding domain binds CTLA-4 and said second antigen binding domain binds CD107a;
ee) said first antigen binding domain binds CTLA-4 and said second antigen binding domain binds NKp46, or
44. The conjugate of claim 43 , wherein ff) said first antigen binding domain binds ICOS and said second antigen binding domain binds TNFR2. 請求項１～３７のいずれか一項に記載のポリペプチド又は請求項３８～４４のいずれか一項に記載の複合体と、薬学的に許容可能な担体とを含む医薬組成物。 A pharmaceutical composition comprising a polypeptide according to any one of claims 1-37 or a conjugate according to any one of claims 38-44 and a pharmaceutically acceptable carrier. 請求項１～３７のいずれか一項に記載のポリペプチド又は請求項３８～４４のいずれか一項に記載の複合体をコードする単離された核酸。 An isolated nucleic acid encoding a polypeptide according to any one of claims 1-37 or a complex according to any one of claims 38-44 . 請求項４６に記載の核酸を含む発現ベクター。 47. An expression vector comprising the nucleic acid of claim 46 . 請求項４６に記載の核酸又は請求項４７に記載の発現ベクターを含む単離された宿主細胞。 48. An isolated host cell comprising the nucleic acid of claim 46 or the expression vector of claim 47 . 請求項１～３７のいずれか一項に記載のポリペプチド又は請求項３８～４４のいずれか一項に記載の複合体を発現する単離された宿主細胞。 An isolated host cell expressing a polypeptide according to any one of claims 1-37 or a conjugate according to any one of claims 38-44 . 請求項１～３７のいずれか一項に記載のポリペプチド又は請求項３８～４４のいずれか一項に記載の複合体を生産する方法であって、前記ポリペプチド又は複合体の発現に適した条件下で請求項４８又は４９に記載の宿主細胞をインキュベートすること、及び任意に前記ポリペプチド又は複合体を単離することを更に含む方法。 A method for producing a polypeptide according to any one of claims 1 to 37 or a conjugate according to any one of claims 38 to 44 , comprising: 50. A method further comprising incubating the host cell of claim 48 or 49 under conditions and optionally isolating said polypeptide or complex. ＣＤ４＋Ｔ細胞及び／又はＣＤ８＋Ｔ細胞の増殖を増加させる方法であって、Ｔ細胞を請求項１～３７のいずれか一項に記載のポリペプチド又は請求項３８～４４のいずれか一項に記載の複合体と接触させることを含み、前記ＣＤ４ ＋ Ｔ細胞及び／又はＣＤ８ ＋ Ｔ細胞は、ｉｎ ｖｉｔｒｏ又はｉｎ ｖｉｖｏで存在する、方法。 A method of increasing the proliferation of CD4 + T cells and/or CD8 + T cells, wherein the T cells are treated with a polypeptide according to any one of claims 1-37 or any one of claims 38-44 . 12. A method comprising contacting with a complex according to 1 , wherein said CD4 + T cells and/or CD8 + T cells are present in vitro or in vivo. ＮＫ細胞増殖を増加させる方法であって、ＮＫ細胞を請求項１～３７のいずれか一項に記載のポリペプチド又は請求項３８～４４のいずれか一項に記載の複合体と接触させることを含む、方法。 A method of increasing NK cell proliferation comprising contacting NK cells with the polypeptide of any one of claims 1-37 or the complex of any one of claims 38-44 . including, method. 癌を治療するための請求項４５に記載の医薬組成物。 46. A pharmaceutical composition according to claim 45 for treating cancer . 前記癌は、基底細胞癌、胆道癌、膀胱癌、骨癌、脳及び中枢神経系癌、乳癌、腹膜癌、子宮頸癌、絨毛癌、結腸直腸癌、結合組織癌、消化器系癌、子宮内膜癌、食道癌、眼癌、頭頸部癌、胃癌、胃腸癌、膠芽腫、肝癌、肝細胞癌、上皮内新生物、腎臓癌又は腎癌、喉頭癌、肝臓癌、肺癌、小細胞肺癌、非小細胞肺癌、肺腺癌、肺扁平上皮癌、黒色腫、骨髄腫、神経芽細胞腫、口腔癌、卵巣癌、膵臓癌、前立腺癌、網膜芽細胞腫、横紋筋肉腫、直腸癌、呼吸器系癌、唾液腺癌、肉腫、皮膚癌、扁平上皮癌、胃部癌、精巣癌、甲状腺癌、子宮又は子宮内膜癌、泌尿器系癌、外陰癌、リンパ腫、ホジキンリンパ腫、非ホジキンリンパ腫、Ｂ細胞リンパ腫、低悪性度／濾胞性非ホジキンリンパ腫（ＮＨＬ）、小リンパ球（ＳＬ）ＮＨＬ、中悪性度／濾胞性ＮＨＬ、中悪性度びまん性ＮＨＬ、高悪性度免疫芽球性ＮＨＬ、高悪性度リンパ芽球性ＮＨＬ、高悪性度小型非分割細胞ＮＨＬ、巨大病変ＮＨＬ、マントル細胞リンパ腫、ＡＩＤＳ関連リンパ腫、ワルデンストレームマクログロブリン血症、慢性リンパ球性白血病（ＣＬＬ）、急性リンパ芽球性白血病（ＡＬＬ）、有毛細胞白血病、並びに慢性骨髄芽球性白血病から選択される、請求項５３に記載の医薬組成物。 Said cancers include basal cell carcinoma, biliary tract cancer, bladder cancer, bone cancer, brain and central nervous system cancer, breast cancer, peritoneal cancer, cervical cancer, choriocarcinoma, colorectal cancer, connective tissue cancer, gastrointestinal cancer, uterus. Endometrial cancer, esophageal cancer, eye cancer, head and neck cancer, gastric cancer, gastrointestinal cancer, glioblastoma, liver cancer, hepatocellular carcinoma, intraepithelial neoplasm, renal cancer or renal cancer, laryngeal cancer, liver cancer, lung cancer, small cell Lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, melanoma, myeloma, neuroblastoma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma, rectum Cancer, respiratory system cancer, salivary gland cancer, sarcoma, skin cancer, squamous cell carcinoma, gastric cancer, testicular cancer, thyroid cancer, uterine or endometrial cancer, urinary system cancer, vulvar cancer, lymphoma, Hodgkin's lymphoma, non-Hodgkin's Lymphoma, B-cell lymphoma, low-grade/follicular non-Hodgkin lymphoma (NHL), small lymphocytic (SL) NHL, intermediate-grade/follicular NHL, intermediate-grade diffuse NHL, high-grade immunoblastic NHL , high-grade lymphoblastic NHL, high-grade small undivided cell NHL, bulky NHL, mantle cell lymphoma, AIDS-related lymphoma, Waldenström macroglobulinemia, chronic lymphocytic leukemia (CLL), acute 54. The pharmaceutical composition of claim 53, selected from lymphoblastic leukemia (ALL), hairy cell leukemia, and chronic myeloblastic leukemia. 追加の療法剤を含み、任意に前記追加の療法剤は、抗癌剤である、請求項５３又は５４に記載の医薬組成物。 55. The pharmaceutical composition of claim 53 or 54, comprising an additional therapeutic agent, optionally said additional therapeutic agent is an anti-cancer agent. 前記抗癌剤は、化学療法剤、抗癌生物製剤、放射線療法薬、ＣＡＲ－Ｔ療法薬、及び腫瘍溶解性ウイルスから選択され、任意に、前記抗癌生物製剤は抗体又はサイトカインである、請求項５５に記載の医薬組成物。 55. Said anti-cancer agent is selected from chemotherapeutic agents, anti-cancer biologics, radiotherapeutic agents, CAR-T therapeutic agents, and oncolytic viruses, optionally said anti-cancer biologics are antibodies or cytokines. The pharmaceutical composition according to . 前記追加の療法剤は、ＰＤ－１及び／又はＰＤ－Ｌ１を阻害するか、又は、ＶＩＳＴＡ、ｇｐＮＭＢ、Ｂ７Ｈ３、Ｂ７Ｈ４、ＨＨＬＡ２、ＣＴＬＡ４、又はＴＩＧＩＴを阻害する抗癌生物製剤である、請求項５５又は５６に記載の医薬組成物。 Claim 55, wherein said additional therapeutic agent is an anticancer biologic that inhibits PD-1 and/or PD-L1, or inhibits VISTA, gpNMB, B7H3, B7H4, HHLA2, CTLA4, or TIGIT. or the pharmaceutical composition according to 56 . 腫瘍切除及び／又は放射線療法と組み合わせられる、請求項５３～５７のいずれか一項に記載の医薬組成物。 Pharmaceutical composition according to any one of claims 53 to 57, in combination with tumor resection and/or radiotherapy.
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