JPWO2020223550A5 - - Google Patents

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JPWO2020223550A5
JPWO2020223550A5 JP2021564784A JP2021564784A JPWO2020223550A5 JP WO2020223550 A5 JPWO2020223550 A5 JP WO2020223550A5 JP 2021564784 A JP2021564784 A JP 2021564784A JP 2021564784 A JP2021564784 A JP 2021564784A JP WO2020223550 A5 JPWO2020223550 A5 JP WO2020223550A5
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JP2022531325A (en
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Priority claimed from US16/827,302 external-priority patent/US11013764B2/en
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Priority claimed from PCT/US2020/030837 external-priority patent/WO2020223550A1/en
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キメラ融合タンパク質（ＣＦＰ）をコードする組換え核酸を含む組成物であって、ＣＦＰが、
（ａ）（ｉ）膜貫通ドメイン、および
（ｉｉ）少なくとも２つの細胞内シグナル伝達ドメインを含む細胞内ドメイン
を含む、食作用または係留受容体（ＰＲ）サブユニット、ならびに
（ｂ）標的細胞の抗原に特異的な抗原結合ドメインを含む細胞外ドメイン
を含み、前記膜貫通ドメインおよび前記細胞外ドメインが作動可能に連結されており；前記抗原がＣＤ１９またはＣＤ２２抗原ではなく；前記ＣＦＰが前記標的細胞の抗原に結合すると、前記ＣＦＰを発現する細胞の殺作用または食作用活性が、前記ＣＦＰを発現しない細胞と比較して少なくとも２０％増加し；殺作用または食作用活性がフローサイトメトリーによって測定される、組成物。 A composition comprising a recombinant nucleic acid encoding a chimeric fusion protein (CFP), wherein the CFP comprises
(a) a phagocytic or tethered receptor (PR) subunit comprising (i) a transmembrane domain, and (ii) an intracellular domain comprising at least two intracellular signaling domains, and (b) an antigen of a target cell wherein said transmembrane domain and said extracellular domain are operably linked; said antigen is not a CD19 or CD22 antigen; Upon antigen binding, the killing or phagocytic activity of cells expressing said CFP is increased by at least 20% compared to cells not expressing said CFP; killing or phagocytic activity is measured by flow cytometry ,Composition. 前記少なくとも２つの細胞内シグナル伝達ドメインの少なくとも１つが食作用または係留受容体に由来するか、または前記少なくとも２つの細胞内シグナル伝達ドメインが食作用活性化ドメインを含み、前記少なくとも２つの細胞内シグナル伝達ドメインの少なくとも１つが表２に列挙した受容体からなる群から選択される受容体に由来し、且つ前記少なくとも２つの細胞内シグナル伝達ドメインがＭｅｇｆ１０、ＭｅｒＴｋ、ＦｃＲ、またはＢａｉ１から選択される食作用受容体以外の受容体に由来する、請求項１に記載の組成物。 at least one of said at least two intracellular signaling domains is derived from a phagocytic or tethered receptor, or said at least two intracellular signaling domains comprise a phagocytosis activation domain, and said at least two cells at least one of the intracellular signaling domains is from a receptor selected from the group consisting of the receptors listed in Table 2, and said at least two intracellular signaling domains are selected from Megf10, MerTk, FcR, or Bai1 2. The composition of claim 1 , derived from a receptor other than the phagocytic receptor . 前記少なくとも２つの細胞内シグナル伝達ドメインが、炎症促進性シグナル伝達ドメインである細胞内シグナル伝達ドメインを含む、請求項１または２に記載の組成物。 3. The composition of claim 1 or 2 , wherein said at least two intracellular signaling domains comprise an intracellular signaling domain that is a pro -inflammatory signaling domain. 前記少なくとも２つの細胞内シグナル伝達ドメインの少なくとも１つが、レクチン、デクチン１、ＣＤ２０６、スカベンジャー受容体Ａ１（ＳＲＡ１）、ＭＡＲＣＯ、ＣＤ３６、ＣＤ１６３、ＭＳＲ１、ＳＣＡＲＡ３、ＣＯＬＥＣ１２、ＳＣＡＲＡ５、ＳＣＡＲＢ１、ＳＣＡＲＢ２、ＣＤ６８、ＯＬＲ１、ＳＣＡＲＦ１、ＳＣＡＲＦ２、ＣＸＣＬ１６、ＳＴＡＢ１、ＳＴＡＢ２、ＳＲＣＲＢ４Ｄ、ＳＳＣ５Ｄ、ＣＤ２０５、ＣＤ２０７、ＣＤ２０９、ＲＡＧＥ、ＣＤ１４、ＣＤ６４、Ｆ４／８０、ＣＣＲ２、ＣＸ３ＣＲ１、ＣＳＦ１Ｒ、Ｔｉｅ２、ＨｕＣＲＩｇ（Ｌ）、ＣＤ６４、ＣＤ３２ａ、ＣＤ１６ａ、ＣＤ８９、Ｆｃ－アルファ受容体Ｉ、ＣＲ１、ＣＤ３５、ＣＤ３ζ、ＣＲ３、ＣＲ４、Ｔｉｍ－１、Ｔｉｍ－４、ＴＮＦＲ１、ＭＤＡ５、ＣＤ４０、およびＣＤ１６９からなる群から選択されるタンパク質に由来する、請求項３に記載の組成物。 at least one of said at least two intracellular signaling domains is lectin, dectin 1, CD206, scavenger receptor A1 (SRA1), MARCO, CD36, CD163, MSR1, SCARA3, COLEC12, SCARA5, SCARB1, SCARB2, CD68, OLR1, SCARF1, SCARF2, CXCL16, STAB1, STAB2, SRCRB4D, SSC5D, CD205, CD207, CD209, RAGE, CD14, CD64, F4/80, CCR2, CX3CR1, CSF1R, Tie2, HuCRIg(L), CD64, CD32a, CD16a , CD89, Fc-alpha receptor I, CR1, CD35, CD3ζ, CR3, CR4, Tim-1, Tim-4, TNFR1, MDA5, CD40, and CD169. 3. The composition according to 3 . 前記少なくとも２つの細胞内シグナル伝達ドメインがＰＩ３Ｋ動員ドメインを含む、請求項３に記載の組成物。 4. The composition of claim 3 , wherein said at least two intracellular signaling domains comprise a PI3K recruitment domain. 前記少なくとも２つの細胞内シグナル伝達ドメインがＦｃＲγ細胞内ドメインを含む、請求項１～５のいずれか一項に記載の組成物。 The composition of any one of claims 1-5 , wherein said at least two intracellular signaling domains comprise an FcRγ intracellular domain. 前記少なくとも２つの細胞内シグナル伝達ドメインの少なくとも１つが、以下から選択される細胞内シグナル伝達ドメインを含む、請求項６に記載の組成物：7. The composition of claim 6, wherein at least one of said at least two intracellular signaling domains comprises an intracellular signaling domain selected from:
ＰＩ３Ｋ動員ドメイン；PI3K recruitment domain;
ＣＤ４０受容体細胞内シグナル伝達ドメイン；CD40 receptor intracellular signaling domain;
ＴＦＮＲ１受容体細胞内シグナル伝達ドメイン；TFNR1 receptor intracellular signaling domain;
ＭＤＡ５シグナル伝達ドメイン、ＴＬＲ３細胞内ドメイン；MDA5 signaling domain, TLR3 intracellular domain;
ＴＬＲ４細胞内ドメイン；ＴＬＲ７細胞内ドメイン；TLR4 intracellular domain; TLR7 intracellular domain;
ＴＬＲ９細胞内ドメイン；ＴＲＩＦ細胞内ドメイン；TLR9 intracellular domain; TRIF intracellular domain;
ＲＩＧ－１細胞内ドメイン；ＭＹＤ８８細胞内ドメイン；RIG-1 intracellular domain; MYD88 intracellular domain;
ＭＡＬ細胞内ドメイン；ＩＲＡＫ１細胞内ドメイン；MAL intracellular domain; IRAK1 intracellular domain;
ＩＦＮ受容体細胞内ドメイン；IFN receptor intracellular domain;
ＮＬＲＰファミリーメンバー由来細胞内ドメイン；an intracellular domain derived from an NLRP family member;
ＮＬＲＰ１－１４細胞内ドメイン；NLRP1-14 intracellular domain;
ＮＯＤ１細胞内ドメイン；NOD1 intracellular domain;
ＮＯＤ２細胞内ドメイン；NOD2 intracellular domain;
パイリン細胞内ドメイン；pyrin intracellular domain;
ＡＩＭ２細胞内ドメイン；AIM2 intracellular domain;
ＮＬＲＣ４細胞内ドメイン；NLRC4 intracellular domain;
ＦＣＧＲ３Ａ細胞内ドメイン；FCGR3A intracellular domain;
ＦＣＥＲＩＧ細胞内ドメイン；FCERIG intracellular domain;
Ｔａｎｋ１結合キナーゼ（ＴＮＫ）細胞内ドメイン；Tank1-binding kinase (TNK) intracellular domain;
カスパーゼドメイン；caspase domain;
プロカスパーゼ結合ドメインおよびこれらの任意の組合せ。Pro-caspase binding domains and any combination thereof. 前記少なくとも２つの細胞内ドメインが、ＣＤ３ゼータＴＣＲサブユニット、ＣＤ３イプシロンＴＣＲサブユニット、ＣＤ３ガンマＴＣＲサブユニット、ＣＤ３デルタＴＣＲサブユニット、ＴＣＲゼータ鎖、Ｆｃイプシロン受容体１鎖、Ｆｃイプシロン受容体２鎖、Ｆｃガンマ受容体１鎖、Ｆｃガンマ受容体２ａ鎖、Ｆｃガンマ受容体２ｂ１鎖、Ｆｃガンマ受容体２ｂ２鎖、Ｆｃガンマ受容体３ａ鎖、Ｆｃガンマ受容体３ｂ鎖、Ｆｃベータ受容体１鎖、ＴＹＲＯＢＰ（ＤＡＰ１２）、ＣＤ５、ＣＤ１６ａ、ＣＤ１６ｂ、ＣＤ２２、ＣＤ２３、ＣＤ３２、ＣＤ６４、ＣＤ７９ａ、ＣＤ７９ｂ、ＣＤ８９、ＣＤ２７８、ＣＤ６６ｄ、これらの機能的断片、およびこれらに対して少なくとも１つから２０以下の改変を有するこれらのアミノ酸配列の群から選択される少なくとも１つのＩＴＡＭドメインをさらに含む、請求項１～３のいずれか一項に記載の組成物。 said at least two intracellular domains are CD3 zeta TCR subunit, CD3 epsilon TCR subunit, CD3 gamma TCR subunit, CD3 delta TCR subunit, TCR zeta chain, Fc epsilon receptor 1 chain, Fc epsilon receptor 2 chain , Fc gamma receptor 1 chain, Fc gamma receptor 2a chain, Fc gamma receptor 2b1 chain, Fc gamma receptor 2b2 chain, Fc gamma receptor 3a chain, Fc gamma receptor 3b chain, Fc beta receptor 1 chain, TYROBP (DAP12), CD5, CD16a, CD16b, CD22, CD23, CD32, CD64, CD79a, CD79b, CD89, CD278, CD66d, functional fragments thereof, and having at least 1 to no more than 20 modifications thereto A composition according to any one of claims 1 to 3 , further comprising at least one ITAM domain selected from the group of these amino acid sequences. 前記ＣＦＰがＣＤ４７阻害ドメインを含む細胞内ドメインを含む、請求項１に記載の組成物。 2. The composition of claim 1, wherein said CFP comprises an intracellular domain comprising a CD47 inhibitory domain. 請求項１～２のいずれか１項に記載の組成物であって、前記キメラ融合タンパク質が前記膜貫通ドメインおよび前記細胞外抗原結合ドメインに作動可能に連結された細胞外ドメインを含み、該細胞外ドメインが受容体の細胞外ドメイン、ヒンジ、スペーサーまたはリンカーをさらに含み、3. The composition of any one of claims 1-2, wherein said chimeric fusion protein comprises an extracellular domain operably linked to said transmembrane domain and said extracellular antigen binding domain, wherein said cell the ectodomain further comprises a receptor extracellular domain, hinge, spacer or linker;
任意に、前記細胞外ドメインはＦｃＲ－アルファ、ＦｃＲβ、ＦｃＲε（ＦＣＥＲ１Ａ）細胞外ドメインまたはＦｃＲγ細胞外ドメインからの配列を含み、前記ＦｃｇＲはＦＤＧＲ１Ａ、ＦＣＧＲ２Ａ、ＦＣＧＲ２Ｂ、ＦＣＧＲ２Ｃ、ＦＣＧＲ３Ａ、ＦＣＧＲ３Ｂであり；任意に、ＦＣＡＲ細胞外ドメインであるか、または任意に、ＩｇＡ、ＩｇＤ、ＩｇＥ、ＩｇＧ、ＩｇＭ、ＦｃＲγＩ、ＦｃＲγＩＩＡ、ＦｃＲγＩＩＢ、ＦｃＲγＩＩＣ、ＦｃＲγＩＩＩＡ、ＦｃＲγＩＩＩＢ、ＦｃＲｎ、ＴＲＩＭ２１、ＦｃＲＬ５細胞外ドメインであり；任意に、前記細胞外ドメインはＣＤ８アルファのヒンジドメインを含む、組成物。optionally, said extracellular domain comprises a sequence from FcR-alpha, FcRβ, FcRε (FCER1A) extracellular domain or FcRγ extracellular domain, said FcgR is FDGR1A, FCGR2A, FCGR2B, FCGR2C, FCGR3A, FCGR3B; is an FCAR extracellular domain, or optionally an IgA, IgD, IgE, IgG, IgM, FcRγI, FcRγIIA, FcRγIIB, FcRγIIC, FcRγIIIA, FcRγIIIB, FcRn, TRIM21, FcRL5 extracellular domain; The composition, wherein said extracellular domain comprises the hinge domain of CD8alpha. 前記細胞外抗原結合ドメインが抗体ドメインを含み、該抗体ドメインが、機能的抗体断片、一本鎖可変断片（ｓｃＦｖ）、Ｆａｂ、単一ドメイン抗体（ｓｄＡｂ）、ナノボディ、Ｖsaid extracellular antigen binding domain comprises an antibody domain, said antibody domain being functional antibody fragment, single chain variable fragment (scFv), Fab, single domain antibody (sdAb), nanobody, V ＨH. ドメイン、Ｖdomain, V ＬL. ドメイン、ＶＮＡＲドメイン、Ｖdomain, VNAR domain, V ＨＨHH ドメイン、二重特異性抗体、ディアボディ、またはこれらの機能的断片もしくは組合せを含む、請求項１に記載の組成物。2. The composition of claim 1, comprising domains, bispecific antibodies, diabodies, or functional fragments or combinations thereof. 前記標的細胞ががん細胞であり、前記抗原ががん抗原である、請求項１～１１のいずれか一項に記載の組成物であって、The composition according to any one of claims 1 to 11, wherein the target cell is a cancer cell and the antigen is a cancer antigen,
該抗原が、チミジンキナーゼ（ＴＫ１）、ヒポキサンチン－グアニン ホスホリボシルトランスフェラーゼ（ＨＰＲＴ）、受容体チロシンキナーゼ様オーファン受容体１（ＲＯＲ１）、ムチン－１、ムチン－１６（ＭＵＣ１６）、ＭＵＣ１、上皮増殖因子受容体ｖＩＩＩ（ＥＧＦＲｖＩＩＩ）、メソテリン、ヒト上皮増殖因子受容体２（ＨＥＲ２）、メソテリン、ＥＢＮＡ－１、ＬＥＭＤ１、ホスファチジルセリン、がん胎児性抗原（ＣＥＡ）、Ｂ細胞成熟抗原（ＢＣＭＡ）、グリピカン３（ＧＰＣ３）、卵胞刺激ホルモン受容体、線維芽細胞活性化タンパク質（ＦＡＰ）、エリスロポエチン産生肝細胞癌Ａ２（ＥｐｈＡ２）、ＥｐｈＢ２、ナチュラルキラー群２Ｄ（ＮＫＧ２Ｄ）リガンド、ジシアロガングリオシド２（ＧＤ２）、ＣＤ２、ＣＤ３、ＣＤ４、ＣＤ５、ＣＤ７、ＣＤ８、ＣＤ１９、ＣＤ２０、ＣＤ２２、ＣＤ２４、ＣＤ３０、ＣＤ３３、ＣＤ３８、ＣＤ４４ｖ６、ＣＤ４５、ＣＤ５６ＣＤ７９ｂ、ＣＤ９７、ＣＤ１１７、ＣＤ１２３、ＣＤ１３３、ＣＤ１３８、ＣＤ１７１、ＣＤ１７９ａ、ＣＤ２１３Ａ２、ＣＤ２４８、ＣＤ２７６、ＰＳＣＡ、ＣＳ－１、ＣＬＥＣＬ１、ＧＤ３、ＰＳＭＡ、ＦＬＴ３、ＴＡＧ７２、ＥＰＣＡＭ、ＩＬ－１、インテグリン受容体、ＰＲＳＳ２１、ＶＥＧＦＲ２、ＰＤＧＦＲ－β、ＳＳＥＡ－４、ＥＧＦＲ、ＮＣＡＭ、プロスターゼ、ＰＡＰ、ＥＬＦ２Ｍ、ＧＭ３、ＴＥＭ７Ｒ、ＣＬＤＮ６、ＴＳＨＲ、ＧＰＲＣ５Ｄ、ＡＬＫ、ＩＧＬＬ１、皮膚リンパ球関連抗原（ＣＬＡ）およびこれらの組合せからなる群から選択される、組成物。The antigen is thymidine kinase (TK1), hypoxanthine-guanine phosphoribosyltransferase (HPRT), receptor tyrosine kinase-like orphan receptor 1 (ROR1), mucin-1, mucin-16 (MUC16), MUC1, epithelial proliferation factor receptor vIII (EGFRvIII), mesothelin, human epidermal growth factor receptor 2 (HER2), mesothelin, EBNA-1, LEMD1, phosphatidylserine, carcinoembryonic antigen (CEA), B-cell maturation antigen (BCMA), glypican 3 (GPC3), follicle-stimulating hormone receptor, fibroblast-activating protein (FAP), erythropoietin-producing hepatocellular carcinoma A2 (EphA2), EphB2, natural killer group 2D (NKG2D) ligand, disialoganglioside 2 (GD2), CD2, CD3, CD4, CD5, CD7, CD8, CD19, CD20, CD22, CD24, CD30, CD33, CD38, CD44v6, CD45, CD56CD79b, CD97, CD117, CD123, CD133, CD138, CD171, CD179a, CD213A2, CD248, CD276, PSCA, CS-1, CLECL1, GD3, PSMA, FLT3, TAG72, EPCAM, IL-1, integrin receptor, PRSS21, VEGFR2, PDGFR-β, SSEA-4, EGFR, NCAM, prostase, PAP, ELF2M, A composition selected from the group consisting of GM3, TEM7R, CLDN6, TSHR, GPRC5D, ALK, IGLL1, cutaneous lymphocyte-associated antigen (CLA) and combinations thereof. 前記抗原が卵巣がん抗原またはＴリンパ腫抗原である、請求項１２に記載の組成物。13. The composition of claim 12, wherein said antigen is an ovarian cancer antigen or a T lymphoma antigen. 前記抗原がＣＤ５抗原である、請求項１３に記載の組成物。14. The composition of claim 13, wherein said antigen is the CD5 antigen. 前記抗原がＨＥＲ２抗原である、請求項１３に記載の組成物。14. The composition of claim 13, wherein said antigen is the HER2 antigen. 前記ＣＦＰが細胞で発現される場合、前記ＣＦＰが前記細胞の細胞膜に機能的に組み込まれる、請求項１～１５のいずれか一項に記載の組成物。16. The composition of any one of claims 1-15, wherein when said CFP is expressed in a cell, said CFP is functionally integrated into the cell membrane of said cell. 前記ＣＦＰが膜貫通ドメインを含み、前記膜貫通ドメインおよび前記細胞外抗原結合ドメインはリンカーによって作動可能に連結されている、請求項１に記載の組成物。2. The composition of claim 1, wherein said CFP comprises a transmembrane domain, and said transmembrane domain and said extracellular antigen binding domain are operably linked by a linker. 前記膜貫通ドメインが、ＣＤ８膜貫通ドメイン、ＦｃＲα鎖細胞内ドメインを伴うＦｃＲα鎖膜貫通ドメイン、ＦｃＲβ鎖細胞内ドメインを伴うＦｃＲβ鎖膜貫通ドメイン、ＴＲＥＭ細胞内ドメインを伴うＴＲＥＭ膜貫通ドメインであり、ここでＴＲＥＭはＴＲＥＭ１、ＴＲＥＭ２またはＴＲＥＭ３であり、said transmembrane domain is a CD8 transmembrane domain, an FcRα chain transmembrane domain with an FcRα chain intracellular domain, an FcRβ chain transmembrane domain with an FcRβ chain intracellular domain, a TREM transmembrane domain with a TREM intracellular domain; where TREM is TREM1, TREM2 or TREM3;
前記組換え核酸はＤＡＰ１２動員ドメインをコードし、前記膜貫通ドメインはＤＡＰ１２とオリゴマー化する膜貫通ドメインを含む、請求項１７に記載の組成物。18. The composition of claim 17, wherein said recombinant nucleic acid encodes a DAP12 recruitment domain, said transmembrane domain comprising a transmembrane domain that oligomerizes with DAP12. 前記ＦｃＲα鎖または前記ＦｃＲβ鎖を含む膜貫通ドメインが、細胞で発現される場合、該細胞の内在性ＦｃＲγと複合体を形成する、請求項１８に記載の組成物。19. The composition of claim 18, wherein the transmembrane domain comprising said FcR[alpha] chain or said FcR[beta] chain forms a complex with endogenous FcR[gamma] of said cell when expressed in said cell. 前記ＣＦＰを発現する細胞が、前記ＣＦＰを発現しない細胞と比較して、前記抗原を発現する標的細胞の食作用の少なくとも１．２倍、１．３倍、１．４倍、１．５倍、１．６倍、１．７倍、１．８倍、１．９倍、２倍、３倍、４倍、５倍、６倍、７倍、８倍、９倍、１０倍、２０倍、３０倍、４０倍、または５０倍の増加を示し、食作用がフローサイトメトリーによって測定される、請求項１に記載の組成物。at least 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold the phagocytosis of target cells expressing said antigen compared to cells not expressing said CFP , 1.6x, 1.7x, 1.8x, 1.9x, 2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x, 10x, 20x , 30-fold, 40-fold, or 50-fold increase and phagocytosis is measured by flow cytometry. 前記抗原を発現する標的細胞ががん細胞である、請求項２０に記載の組成物。21. The composition of claim 20, wherein the antigen-expressing target cells are cancer cells. 前記ＣＦＰを発現する細胞が、前記ＣＦＰを発現しない細胞と比較して、サイトカインの産生の増加を示し、前記サイトカインが、ＩＬ－１、ＩＬ３、ＩＬ－６、ＩＬ－１２、ＩＬ－１３、ＩＬ－２３、ＴＮＦ、ＣＣＬ２、ＣＸＣＬ９、ＣＸＣＬ１０、ＣＸＣＬ１１、ＩＬ－１８、ＩＬ－２３、ＩＬ－２７、ＣＳＦ、ＭＣＳＦ、ＧＭＣＳＦ、ＩＬ１７、ＩＰ－１０、ＲＡＮＴＥＳ、インターフェロンからなる群から選択される、請求項２１に記載の組成物。Cells expressing said CFP exhibit increased production of cytokines compared to cells not expressing said CFP, said cytokines being IL-1, IL3, IL-6, IL-12, IL-13, IL -23, TNF, CCL2, CXCL9, CXCL10, CXCL11, IL-18, IL-23, IL-27, CSF, MCSF, GMCSF, IL17, IP-10, RANTES, interferon. 21. The composition according to 21. 請求項２１に記載の組成物であって、前記ＣＦＰを発現する細胞が：22. The composition of claim 21, wherein the CFP-expressing cells are:
前記ＣＦＰを発現しない細胞と比較して、エフェクター活性の増加を示す；exhibiting increased effector activity compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、交差提示の増加を示す；exhibiting increased cross-presentation compared to cells not expressing said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＭＨＣクラスＩＩタンパク質の発現の増加を示す；exhibiting increased expression of MHC class II proteins compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＣＤ８０の発現の増加を示す；exhibiting increased expression of CD80 compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＣＤ８６の発現の増加を示す；exhibiting increased expression of CD86 compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＭＨＣクラスＩタンパク質の発現の増加を示す；exhibiting increased expression of MHC class I proteins compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＴＲＡＩＬ／ＴＮＦファミリー細胞死受容体の発現の増加を示す；exhibiting increased expression of a TRAIL/TNF family cell death receptor compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、Ｂ７－Ｈ２の発現の増加を示す；exhibiting increased expression of B7-H2 compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＬＩＧＨＴの発現の増加を示す；showing increased expression of LIGHT compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＨＶＥＭの発現の増加を示す；exhibiting increased expression of HVEM compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＣＤ４０の発現の増加を示す；exhibiting increased expression of CD40 compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＴＬ１Ａの発現の増加を示す；exhibiting increased expression of TL1A compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、４１ＢＢＬの発現の増加を示す；showing increased expression of 41BBL compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＯＸ４０Ｌの発現の増加を示す；showing increased expression of OX40L compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＧＩＴＲＬ細胞死受容体の発現の増加を示す；exhibiting increased expression of the GITRL death receptor compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＣＤ３０Ｌの発現の増加を示す；exhibiting increased expression of CD30L compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＴＩＭ４の発現の増加を示す；showing increased expression of TIM4 compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＴＩＭ１リガンドの発現の増加を示す；exhibiting increased expression of TIM1 ligand compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＳＬＡＭの発現の増加を示す；exhibiting increased expression of SLAM compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＣＤ４８の発現の増加を示す；exhibiting increased expression of CD48 compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＣＤ５８の発現の増加を示す；exhibiting increased expression of CD58 compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＣＤ１５５の発現の増加を示す；exhibiting increased expression of CD155 compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＣＤ１１２の発現の増加を示す；exhibiting increased expression of CD112 compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＰＤＬ１の発現の増加を示す；exhibiting increased expression of PDL1 compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、Ｂ７－ＤＣの発現の増加を示す；showing increased expression of B7-DC compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、呼吸性バーストの増加を示す；exhibiting increased respiratory burst compared to cells not expressing said CFP;
前記ＣＦＰを発現しない細胞と比較して、ＲＯＳ産生の増加を示す；exhibiting increased ROS production compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、ｉＮＯＳ産生の増加を示す；exhibiting increased iNOS production compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、細胞外小胞産生の増加を示す；exhibiting increased extracellular vesicle production compared to cells that do not express said CFP;
前記ＣＦＰを発現しない細胞と比較して、前記抗原を発現する標的細胞によるトロゴサイトーシスの増加を示す；またはexhibiting increased trogocytosis by target cells expressing said antigen compared to cells not expressing said CFP; or
前記ＣＦＰを発現しない細胞と比較して、食作用のＣＤ４７媒介性阻害に対する抵抗性の増加を示す、組成物。A composition that exhibits increased resistance to CD47-mediated inhibition of phagocytosis compared to cells that do not express said CFP. 前記細胞内ドメインが、Ｒａｃ阻害ドメイン、Ｃｄｃ４２阻害ドメイン、ＧＴＰａｓｅ阻害ドメイン、Ｆ－アクチン解離活性化ドメイン、ＡＲＨＧＡＰ１２活性化ドメイン、ＡＲＨＧＡＰ２５活性化ドメインまたはＳＨ３ＢＰ１活性化ドメインを含むか、あるいは前記ＣＦＰが全長の細胞内シグナル伝達ドメインを含まない、請求項１に記載の組成物。said intracellular domain comprises a Rac inhibitory domain, a Cdc42 inhibitory domain, a GTPase inhibitory domain, an F-actin dissociation activation domain, an ARHGAP12 activation domain, an ARHGAP25 activation domain or an SH3BP1 activation domain; 2. The composition of claim 1, which does not contain an intracellular signaling domain. 食作用または係留受容体（ＰＲ）融合タンパク質（ＣＦＰ）をコードする組換え核酸を含む組成物であって、Ｎ末端からＣ末端に向かって：A composition comprising a recombinant nucleic acid encoding a phagocytic or tethered receptor (PR) fusion protein (CFP), comprising, from N-terminus to C-terminus:
（ａ）標的細胞のＣＤ５抗原に特異的な抗原結合ドメインを含む細胞外ドメイン；(a) an extracellular domain comprising an antigen-binding domain specific for the CD5 antigen of a target cell;
（ｂ）ＣＤ８ヒンジとＣＤ８膜貫通ドメイン、および(b) the CD8 hinge and CD8 transmembrane domain, and
（ｃ）ＦＣＥＲ１Ｇ細胞内シグナル伝達ドメインとＰＩ３Ｋ動員ドメインとを含む細胞内ドメイン(c) an intracellular domain comprising the FCER1G intracellular signaling domain and the PI3K recruitment domain;
を含む、組成物。A composition comprising: 前記ＣＦＰがシグナルペプチドをさらに含み、任意に、前記シグナルペプチドがＧＭＣＳＦシグナルペプチドである、請求項１に記載の組成物。2. The composition of claim 1, wherein said CFP further comprises a signal peptide, optionally said signal peptide is the GMCSF signal peptide. 前記ＣＦＰが、配列番号１、配列番号２、配列番号４、配列番号７、配列番号１７、配列番号２７または配列番号２９と少なくとも９０％同一であるアミノ酸配列を含む１つまたはそれ以上のドメインを含む、請求項１に記載の組成物。said CFP comprises one or more domains comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 4, SEQ ID NO: 7, SEQ ID NO: 17, SEQ ID NO: 27 or SEQ ID NO: 29; 2. The composition of claim 1, comprising: 前記ＣＦＰが、配列番号１４のアミノ酸配列または配列番号１４と少なくとも９０％同一である配列を含む、請求項１に記載の組成物。2. The composition of claim 1, wherein said CFP comprises the amino acid sequence of SEQ ID NO:14 or a sequence that is at least 90% identical to SEQ ID NO:14. 請求項１～２８のいずれか一項に記載の組成物を含む、がんの治療に用いるための医薬組成物であって、前記組換え核酸がＲＮＡであり、医薬組成物が脂質ナノ粒子をさらに含む、医薬組成物。29. A pharmaceutical composition for use in treating cancer comprising the composition of any one of claims 1-28, wherein the recombinant nucleic acid is RNA and the pharmaceutical composition comprises lipid nanoparticles. Further comprising a pharmaceutical composition. 請求項１～２８のいずれか一項に記載の組成物を含む細胞を含む、請求項２９に記載の医薬組成物であって、前記細胞は骨髄性細胞、未成熟骨髄性細胞、非極性化または未分化骨髄性細胞、ＣＤ１４＋／ＣＤ１６30. The pharmaceutical composition of claim 29, comprising cells comprising the composition of any one of claims 1-28, said cells being myeloid cells, immature myeloid cells, non-polarized or undifferentiated myeloid cells, CD14+/CD16 ｌｏｗlow 細胞、ＣＤ１４＋／ＣＤ１６cells, CD14+/CD16 －- 細胞、ＣＤ１４cells, CD14 －- ／ＣＤ１６/CD16 ＋+ 細胞であり、前記細胞は食細胞であるか、または前記細胞は幹細胞由来細胞、マクロファージ、樹状細胞、リンパ球、肥満細胞、単球、好中球、ミクログリア、好酸球、好塩基球、骨髄性前駆細胞、モザイク表現型細胞または星状細胞；自家細胞、同種異系細胞であるか、または前記細胞はＭ１マクロファージ細胞もしくはＭ２マクロファージ細胞である、医薬組成物。is a cell, said cell is a phagocyte, or said cell is stem cell-derived cell, macrophage, dendritic cell, lymphocyte, mast cell, monocyte, neutrophil, microglia, eosinophil, basophil, A pharmaceutical composition, wherein myeloid progenitor cells, mosaic phenotype cells or astrocytes; autologous cells, allogeneic cells, or said cells are M1 macrophage cells or M2 macrophage cells.
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