JPWO2020198665A5 - - Google Patents
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- JPWO2020198665A5 JPWO2020198665A5 JP2021558525A JP2021558525A JPWO2020198665A5 JP WO2020198665 A5 JPWO2020198665 A5 JP WO2020198665A5 JP 2021558525 A JP2021558525 A JP 2021558525A JP 2021558525 A JP2021558525 A JP 2021558525A JP WO2020198665 A5 JPWO2020198665 A5 JP WO2020198665A5
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（ａ）ＣＤＲ１が、
（ｉ）配列番号１１０８、１１２９、１０９３～１１０７、および１１０９～１１２８のいずれか１つのアミノ酸配列、
（ｉｉ）配列番号８７～１１５のいずれか１つのアミノ酸配列、
（ｉｉｉ）配列番号８５１～８６１のいずれか１つのアミノ酸配列、
（ｉｖ）（ｉ）～（ｉｉｉ）のアミノ酸配列のいずれか１つの中に１～５個のアミノ酸置換、欠失、または挿入を有するアミノ酸配列、
を含み、
（ｂ）ＣＤＲ２が、
（ｉ）配列番号１２８、１２６、１１６～１２５、１２７、および１２９～１４４のいずれか１つのアミノ酸配列、
（ｉｉ）配列番号８６２～８７６のいずれか１つのアミノ酸配列、
（ｉｉｉ）（ｉ）～（ｉｉ）のアミノ酸配列のいずれか１つの中に１～５個のアミノ酸置換、欠失、または挿入を有するアミノ酸配列、
を含み、かつ
（ｃ）ＣＤＲ３が、
（ｉ）配列番号１５９、１５７、１４５～１５６、１５８、１６０～１７５のいずれか１つのアミノ酸配列、
（ｉｉ）配列番号８７７～８７９のいずれか１つのアミノ酸配列、
（ｉｉｉ）（ｉ）～（ｉｉ）のアミノ酸配列のいずれか１つの中に１～５個のアミノ酸置換、欠失、または挿入を有するアミノ酸配列、
を含む、
線維芽細胞活性化タンパク質（ＦＡＰ）結合物質。 A fibroblast activation protein (FAP) binding agent comprising a targeting moiety, wherein the targeting moiety comprises three complementarity determining regions (CDR1, CDR2 and CDR3),
(a) CDR1 is
(i) the amino acid sequence of any one of SEQ ID NOS: 1108, 1129, 1093-1107, and 1109-1128;
(ii) the amino acid sequence of any one of SEQ ID NOS:87-115;
(iii) the amino acid sequence of any one of SEQ ID NOs:851-861;
(iv) an amino acid sequence having 1 to 5 amino acid substitutions, deletions or insertions in any one of the amino acid sequences of (i)-(iii);
including
(b) CDR2 is
(i) the amino acid sequence of any one of SEQ ID NOS : 128, 126 , 116-125, 127, and 129-144;
(ii) the amino acid sequence of any one of SEQ ID NOS:862-876;
(iii) an amino acid sequence having 1-5 amino acid substitutions, deletions or insertions in any one of the amino acid sequences of (i)-(ii);
and (c) CDR3 is
(i) the amino acid sequence of any one of SEQ ID NOS : 159, 157 , 145-156, 158, 160-175;
(ii) the amino acid sequence of any one of SEQ ID NOS:877-879;
(iii) an amino acid sequence having 1-5 amino acid substitutions, deletions or insertions in any one of the amino acid sequences of (i)-(ii);
including,
Fibroblast activation protein (FAP) binding agent.
任意選択で、前記ターゲティング部分が、任意選択でＶＨＨまたはヒト化ＶＨＨを含む単一ドメイン抗体であり、
任意選択で、前記ＦＡＰ結合物質が、
（ａ）配列番号１０８７、１０９２、１０８６、１０８８～１０９１のいずれか１つ、
（ｂ）配列番号２～４２のいずれか１つ、
（ｃ）配列番号４６～８６のいずれか１つ、
（ｄ）配列番号８３７～８５０のいずれか１つ、または
（ｅ）配列番号１０４５～１０８５のいずれか１つ、
と少なくとも９０％の配列類似性を有するアミノ酸配列を含む、
請求項１に記載のＦＡＰ結合物質。 The FAP-binding substance is a full-length antibody, a full-length antibody, a single domain antibody, an antibody composed only of recombinant heavy chains (VHH), a single chain antibody (scFv), an antibody composed only of shark heavy chains ( VNAR) , Fv , Fab, Fab', or F(ab ' ) 2 ;
optionally, said targeting moiety is a single domain antibody, optionally comprising a VHH or a humanized VHH;
Optionally, said FAP binding agent is
(a) any one of SEQ ID NOs: 1087, 1092, 1086, 1088-1091;
(b) any one of SEQ ID NOS: 2-42;
(c) any one of SEQ ID NOS: 46-86;
(d) any one of SEQ ID NOS:837-850, or
(e) any one of SEQ ID NOS: 1045-1085;
comprising an amino acid sequence having at least 90% sequence similarity with
2. The FAP binding agent of claim 1.
任意選択で、前記シグナル伝達物質が、野生型インターフェロン、野生型インターロイキン、野生型腫瘍壊死因子、またはその改変型の１種または複数から選択され、
任意選択で、前記シグナル伝達物質が、配列番号１７６または１７７と少なくとも９５％の同一性を有するアミノ酸配列を含む改変インターフェロンアルファ２（ＩＦＮα２）であり、かつ前記改変ヒトＩＦＮα２が、配列番号１７６または１７７のアミノ酸配列を有する野生型ＩＦＮα２に比べて改善された安全性を付与する１個または複数の変異を有し、
任意選択で、前記ＩＦＮα２が、
（ａ）配列番号１７６または配列番号１７７を基準にして位置１４４～１５４に１個または複数の変異、または
（ｂ）配列番号１７６または１７７を基準にして位置Ｒ１４９、Ｌ１５、Ａ１９、Ｒ２２、Ｒ２３、Ｌ２６、Ｆ２７、Ｌ３０、Ｋ３１、Ｄ３２、Ｒ３３、Ｈ３４、Ｄ３５、Ｑ４０、Ｈ５７、Ｅ５８、Ｑ６１、Ｆ６４、Ｎ６５、Ｔ６９、Ｌ８０、Ｙ８５、Ｙ８９、Ｔ１０６、Ｄ１１４、Ｌ１１７、Ｒ１２０、Ｒ１２５、Ｋ１３３、Ｋ１３４、Ｒ１４４、Ａ１４５、Ｍ１４８、Ｓ１５２、Ｌ１５３、およびＮ１５６に１個または複数の変異、
を有し、
任意選択で、前記変異が、
（ａ）配列番号１７６または１７７を基準にしてＲ１４９Ａ、Ｌ１５Ａ、Ａ１９Ｗ、Ｒ２２Ａ、Ｒ２３Ａ、Ｌ２６Ａ、Ｆ２７Ａ、Ｌ３０Ａ、Ｌ３０Ｖ、Ｋ３１Ａ、Ｄ３２Ａ、Ｒ３３Ｋ、Ｒ３３Ａ、Ｒ３３Ｑ、Ｈ３４Ａ、Ｄ３５Ａ、Ｑ４０Ａ、Ｈ５７Ｙ、Ｅ５８Ｎ、Ｑ６１Ｓ、Ｆ６４Ａ、Ｎ６５Ａ、Ｔ６９Ａ、Ｌ８０Ａ、Ｙ８５Ａ、Ｙ８９Ａ、Ｄ１１４Ｒ、Ｌ１１７Ａ、Ｒ１２０Ａ、Ｒ１２５Ａ、Ｋ１３３Ａ、Ｋ１３４Ａ、Ｒ１４４Ａ、Ａ１４５Ｇ、Ａ１４５Ｍ、Ｍ１４８Ａ、Ｓ１５２Ａ、Ｌ１５３Ａ、およびＮ１５６Ａである、または
（ｂ）配列番号１７６または１７７のアミノ酸配列を基準にしてＲ１４９Ａ、Ｒ３３Ａ、Ｔ１０６Ｘ ３ 、Ｒ１２０Ｅ、Ｒ１４４Ｘ １ 、Ａ１４５Ｘ ２ 、Ｍ１４８Ａ、およびＬ１５３Ａから選択される１個または複数の変異であって、Ｘ １ が、Ａ、Ｓ、Ｔ、Ｙ、Ｌ、およびＩから選択され、Ｘ ２ が、Ｇ、Ｈ、Ｙ、Ｋ、およびＤから選択され、およびＸ ３ が、ＡおよびＥから選択される変異である、
請求項１に記載のＦＡＰ結合物質。 said FAP binding agent further comprises one or more signaling agents , optionally said targeting moiety and said signaling agent are linked by one or more linkers;
optionally, said signaling agent is selected from one or more of wild-type interferon, wild-type interleukin, wild-type tumor necrosis factor, or modified forms thereof;
Optionally, said signaling agent is a modified interferon alpha 2 (IFNα2) comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 176 or 177, and said modified human IFNα2 comprises SEQ ID NO: 176 or 177 having one or more mutations that confer improved safety compared to wild-type IFNα2 having the amino acid sequence of
Optionally, said IFNα2 is
(a) one or more mutations at positions 144-154 relative to SEQ ID NO: 176 or SEQ ID NO: 177, or
(b) positions R149, L15, A19, R22, R23, L26, F27, L30, K31, D32, R33, H34, D35, Q40, H57, E58, Q61, F64, N65 relative to SEQ ID NO: 176 or 177 , T69, L80, Y85, Y89, T106, D114, L117, R120, R125, K133, K134, R144, A145, M148, S152, L153, and N156;
has
Optionally, said mutation is
(a) R149A, L15A, A19W, R22A, R23A, L26A, F27A, L30A, L30V, K31A, D32A, R33K, R33A, R33Q, H34A, D35A, Q40A, H57Y, E58N, based on SEQ ID NO: 176 or 177; is Q61S, F64A, N65A, T69A, L80A, Y85A, Y89A, D114R, L117A, R120A, R125A, K133A, K134A, R144A, A145G, A145M, M148A, S152A, L153A, and N156A, or
(b) one or more mutations selected from R149A, R33A, T106X3, R120E, R144X1, A145X2, M148A, and L153A, based on the amino acid sequence of SEQ ID NO: 176 or 177, wherein X1 is selected from A, S, T, Y, L, and I; X2 is selected from G, H, Y, K, and D; and X3 is selected from A and E. be,
2. The FAP binding agent of claim 1 .
前記シグナル伝達物質が、配列番号１７８と少なくとも９５％の同一性を有するアミノ酸配列を含む改変インターフェロンβ（ＩＦＮβ）であり、かつ前記改変ヒトＩＦＮβが、配列番号１７８のアミノ酸配列を有する野生型ＩＦＮβに比べて改善された安全性を付与する１個または複数の変異を有し、任意選択で、前記改変ヒトＩＦＮβが、配列番号１７８の位置Ｗ２２、Ｒ２７、Ｌ３２、Ｒ３５、Ｖ１４８、Ｌ１５１、Ｒ１５２、およびＹ１５５に１個または複数の変異を含み、任意選択で、前記改変ヒトＩＦＮβが、配列番号１７８を基準にしてＷ２２Ｇ、Ｒ２７Ｇ、Ｌ３２Ａ、Ｌ３２Ｇ、Ｒ３５Ａ、Ｒ３５Ｇ、Ｖ１４８Ｇ、Ｌ１５１Ｇ、Ｒ１５２Ａ、Ｒ１５２Ｇから選択される１個または複数の変異を含む、または
前記シグナル伝達物質が、配列番号１８２と少なくとも９５％の同一性を有するアミノ酸配列を含む改変腫瘍壊死因子α（ＴＮＦα）であり、かつ前記改変ＴＮＦαが、配列番号１８２のアミノ酸配列を有する野生型ＴＮＦαに比べて低減された受容体結合親和性を付与する１個または複数の変異を有し、任意選択で、前記改変ＴＮＦαが、配列番号１８２を基準にして位置８７、９７、１１５、２９、３１、３２、８４、８５、８６、８８、８９、１４５、１４６および１４７に１個または複数の変異を有し、任意選択で、前記変異が、配列番号１８２を基準にしてＹ８７Ｑ、Ｙ８７Ｌ、Ｙ８７Ａ、Ｙ８７Ｆ、Ｙ８７Ｈ、Ｉ９７Ａ、Ｉ９７Ｑ、Ｉ９７Ｓ、Ｙ１１５Ｇ、Ｙ１１５Ａ、Ｌ２９Ｓ、Ｒ３２Ｇ、Ｒ３２Ｗ、Ｎ３４Ｇ、Ｑ６７Ｇ、Ｈ７３Ｇ、Ｌ７５Ｇ、Ｌ７５Ａ、Ｌ７５Ｓ、Ｔ７７Ａ、Ｓ８６Ｇ、Ｓ８６Ｔ、Ｖ９１Ｇ、Ｖ９１Ａ、Ｔ１０５Ｇ、Ｐ１０６Ｇ、Ａ１０９Ｙ、Ｐ１１３Ｇ、Ｅ１２７Ｇ、Ｎ１３７Ｇ、Ｄ１４３Ｎ、Ａ１４５Ｇ、Ａ１４５Ｒ、Ａ１４５Ｔ、Ｅ１４６Ｄ、Ｅ１４６Ｋ、およびＳ１４７Ｄの１個または複数であり、任意選択で、位置Ｙ８７の変異が、Ｙ８７Ｑ、Ｙ８７Ｌ、Ｙ８７Ａ、およびＹ８７Ｆから選択される、および／または位置Ｉ９７の変異が、Ｉ９７Ａ、Ｉ９７Ｑ、およびＩ９７Ｓから選択される、および／または位置Ｙ１１５の変異が、Ｙ１１５ＡおよびＹ１１５Ｇから選択される、
請求項３に記載のＦＡＰ結合物質。 wherein the signaling agent is C86, L15, A19, R23, S25, L30, D32, R33, H34, Q40 , D115, L118, K121, R126, E133, K134, K135, R145, based on SEQ ID NO: 1042; A modified interferon alpha 1 ( IFNα1 ) having mutations in one or more amino acids at positions A146, M149, R150, S153, L154, and N157, wherein said mutations are optionally C86S relative to SEQ ID NO: 1042 , C86A, L15A, A19W, R23A, S25A, L30A, L30V, D32A, R33K, R33A, R33Q, H34A, Q40A, D115R , L118A, K121A, K121E, R126A, R126E, E133A, K134A, K135A, R14 Ｒ１４５Ｅ、Ｒ１４５Ｇ、Ｒ１４５Ｈ、Ｒ１４５Ｉ、Ｒ１４５Ｋ、Ｒ１４５Ｌ、Ｒ１４５Ｎ、Ｒ１４５Ｑ、Ｒ１４５Ｓ、Ｒ１４５Ｔ、Ｒ１４５Ｖ、Ｒ１４５Ｙ、Ａ１４６Ｄ、Ａ１４６Ｅ、Ａ１４６Ｇ、Ａ１４６Ｈ、Ａ１４６Ｉ、Ａ１４６Ｋ、Ａ１４６Ｌ、Ａ１４６Ｍ、Ａ１４６Ｎ、Ａ１４６Ｑ、Ａ１４６Ｒ、Ａ１４６Ｓ、Ａ１４６Ｔ、 selected from A146V, A146Y, M149A, M149V, R150A, S153A, L154A, and N157A, or
said signaling agent is a modified interferon beta (IFNβ) comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 178, and said modified human IFN beta is a wild-type IFN beta having the amino acid sequence of SEQ ID NO: 178 optionally, said modified human IFN beta has one or more mutations that confer improved safety compared to the one or more mutations at Y155, optionally wherein said modified human IFN beta is selected from W22G, R27G, L32A, L32G, R35A, R35G, V148G, L151G, R152A, R152G with reference to SEQ ID NO: 178 contains one or more mutations that
said signaling agent is a modified tumor necrosis factor alpha (TNFα) comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 182, and said modified TNFα has the amino acid sequence of SEQ ID NO: 182 wild-type TNFα optionally, said modified TNFα is at positions 87, 97, 115, 29, 31 relative to SEQ ID NO: 182 , 32, 84, 85, 86, 88, 89, 145, 146 and 147, optionally wherein said mutations are relative to SEQ ID NO: 182: Y87Q, Y87L, Y87A, Y87F, Y87H, I97A, I97Q, I97S, Y115G, Y115A, L29S, R32G, R32W, N34G, Q67G, H73G, L75G, L75A, L75S, T77A, S86G, S86T, V91G, V91A, T105G, P106G, P1109Y, one or more of E127G, N137G, D143N, A145G, A145R, A145T, E146D, E146K, and S147D, optionally the mutation at position Y87 is selected from Y87Q, Y87L, Y87A, and Y87F, and /or the mutation at position I97 is selected from I97A, I97Q, and I97S, and/or the mutation at position Y115 is selected from Y115A and Y115G,
4. A FAP binding agent according to claim 3 .
任意選択で、前記１個または複数の追加のターゲティング部分が、ＰＤ－１、ＰＤ－Ｌ１、ＰＤ－Ｌ２、ＣＴＬＡ４、ＯＸ４０Ｌ、ＯＸ４０、ＣＤ２０、ＸＣＲ１、Ｆｌｔ３、またはＣｌｅｃ９Ａを認識するまたは機能的に調節し、
任意選択で、前記ＦＡＰ結合物質が、腫瘍細胞にまたは腫瘍環境に細胞傷害性Ｔ細胞を動員し、
任意選択で、前記ＦＡＰ結合物質が、その活性を実質的に機能的に調節することなくＦＡＰを認識するまたは結合する、
請求項１～４のいずれか１項に記載のＦＡＰ結合物質。 said FAP binding agent comprises one or more additional targeting moieties, optionally said one or more additional targeting moieties recognize tumor antigens and/or antigens on immune cells or functionally modulating, optionally said immune cells are selected from T cells, B cells, dendritic cells, macrophages, neutrophils and NK cells;
Optionally, said one or more additional targeting moieties recognize or functionally regulate PD-1, PD-L1, PD-L2, CTLA4, OX40L, OX40, CD20, XCR1, Flt3, or Clec9A death,
optionally, said FAP binding agent recruits cytotoxic T cells to the tumor cell or to the tumor environment;
optionally, said FAP binding agent recognizes or binds FAP without substantially functionally modulating its activity;
The FAP-binding substance according to any one of claims 1-4 .
任意選択で、前記自己免疫疾患および／または神経変性疾患が、多発性硬化症であり、
任意選択で、前記ＦＡＰ結合物質が、患者において免疫抑制をもたらす、使用。 Use of a FAP-binding agent according to any one of claims 1 to 5 in the manufacture of a medicament for treating or preventing autoimmune and/or neurodegenerative diseases,
optionally, said autoimmune and/or neurodegenerative disease is multiple sclerosis;
Optionally, the use wherein said FAP-binding agent causes immunosuppression in the patient .
任意選択で、前記線維性疾患が、肝線維症、肺線維症、原発性硬化性胆管炎（ＰＳＣ）、慢性肝疾患、非アルコール性脂肪性肝疾患（ＮＡＦＬＤ）、非アルコール性脂肪性肝炎（ＮＡＳＨ）、Ｃ型肝炎感染症、アルコール性肝疾患、肝損傷、肝硬変、および骨髄異形成症候群から選択される、使用。 Use of a FAP-binding agent according to any one of claims 1-5 in the manufacture of a medicament for treating or preventing a fibrotic disease,
Optionally, said fibrotic disease is liver fibrosis, pulmonary fibrosis, primary sclerosing cholangitis (PSC), chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis ( NASH), hepatitis C infection, alcoholic liver disease, liver injury, cirrhosis, and myelodysplastic syndrome.
（ａ）ＣＤＲ１が、
（ｉ）配列番号１１０８、１１２９、１０９３～１１０７、および１１０９～１１２８のいずれか１つのアミノ酸配列、
（ｉｉ）配列番号８７～１１５のいずれか１つのアミノ酸配列、
（ｉｉｉ）配列番号８５１～８６１のいずれか１つのアミノ酸配列、
（ｉｖ）配列番号８８２、９１５、９２０、９２３、９２８、９３１、９３６、９３９、９４４、９４７、９５２、９５５、９６０、９６３、９６８、９７１、９７６、９７９、９８４、９８７、９９２、９９５、１０００、１００３、１００８、１０１１、１０１６、１０１９、１０２４、１０２７、１０３２、１０３５のいずれか１つのアミノ酸配列、または
（ｖ）（ｉ）～（ｉｖ）のアミノ酸配列のいずれか１つの中に１～５個のアミノ酸置換、欠失、または挿入を有するアミノ酸配列
を含み、
（ｂ）ＣＤＲ２が、
（ｉ）配列番号１２８、１２６、１１６～１２５、１２７、および１２９～１４４のいずれか１つのアミノ酸配列、
（ｉｉ）配列番号８６２～８７６のいずれか１つのアミノ酸配列、
（ｉｉｉ）配列番号８８３、９１６、９２１、９２４、９２９、９３２、９３７、９４０、９４５、９４８、９５３、９５６、９６１、９６４、９６９、９７２、９７７、９８０、９８５、９８８、９９３、９９６、１００１、１００４、１００９、１０１２、１０１７、１０２０、１０２５、１０２８、１０３３、１０３６のいずれか１つのアミノ酸配列、または
（ｉｖ）（ｉ）～（ｉｉｉ）のアミノ酸配列のいずれか１つの中に１～５個のアミノ酸置換、欠失、または挿入を有するアミノ酸配列、
を含み、および
（ｃ）ＣＤＲ３が、
（ｉ）配列番号１５９、１５７、１４５～１５６、１５８、１６０～１７５のいずれか１つのアミノ酸配列、
（ｉｉ）配列番号８７７～８７９のいずれか１つのアミノ酸配列、
（ｉｉｉ）配列番号８８４、９１７、９２２、９２５、９３０、９３３、９３８、９４１、９４６、９４９、９５４、９５７，９６２、９６５、９７０、９７３、９７８、９８１、９８６、９８９、９９４、９９７、１００２、１００５、１０１０、１０１３、１０１８、１０２１、１０２６、１０２９、１０３４、１０３７のいずれか１つのアミノ酸配列、または
（ｉｖ）（ｉ）～（ｉｉｉ）のアミノ酸配列のいずれか１つの中に１～５個のアミノ酸置換、欠失、または挿入を有するアミノ酸配列、
を含む、キメラタンパク質。 1. A chimeric protein comprising at least one targeting moiety that targets or binds fibroblast activation protein (FAP) and a wild-type or modified signaling entity, wherein said targeting moiety comprises three complementarity determining regions. (CDR1, CDR2, and CDR3),
(a) CDR1 is
(i) the amino acid sequence of any one of SEQ ID NOS: 1108, 1129, 1093-1107, and 1109-1128;
(ii) the amino acid sequence of any one of SEQ ID NOS:87-115;
(iii) the amino acid sequence of any one of SEQ ID NOs:851-861;
(iv) SEQ. , 1003, 1008, 1011, 1016, 1019, 1024, 1027, 1032, 1035, or (v) 1 to 5 in any one of the amino acid sequences of (i) to (iv) comprising amino acid sequences having 1 amino acid substitution, deletion, or insertion;
(b) CDR2 is
(i) the amino acid sequence of any one of SEQ ID NOS : 128, 126 , 116-125, 127, and 129-144;
(ii) the amino acid sequence of any one of SEQ ID NOS:862-876;
(iii) SEQ. , 1004, 1009, 1012, 1017, 1020, 1025, 1028, 1033, 1036, or (iv) 1-5 in any one of the amino acid sequences of (i)-(iii) amino acid sequences having amino acid substitutions, deletions, or insertions;
and (c) the CDR3 is
(i) the amino acid sequence of any one of SEQ ID NOS : 159, 157 , 145-156, 158, 160-175;
(ii) the amino acid sequence of any one of SEQ ID NOS:877-879;
(iii) SEQ. , 1005, 1010, 1013, 1018, 1021, 1026, 1029, 1034, 1037, or (iv) 1-5 in any one of the amino acid sequences of (i)-(iii) amino acid sequences having amino acid substitutions, deletions, or insertions;
A chimeric protein comprising
任意選択で、前記線維芽細胞が、癌、感染症、免疫異常、自己免疫疾患、線維性疾患、および心臓血管疾患から選択される疾患に関連し、
任意選択で、前記ターゲティング部分が、Ｆ２線維芽細胞を標的にする、
請求項１２に記載のキメラタンパク質。 said chimeric protein directly or indirectly alters said disease-associated fibroblast microenvironment and/or said chimeric protein directly or indirectly polarizes said disease-associated fibroblast,
optionally, said fibroblasts are associated with a disease selected from cancer, infectious diseases, immune disorders, autoimmune diseases, fibrotic diseases, and cardiovascular diseases;
optionally, said targeting moiety targets F2 fibroblasts;
13. A chimeric protein according to claim 12 .
任意選択で、前記ターゲティング部分が、任意選択でＶＨＨまたはヒト化ＶＨＨを含む、単一ドメイン抗体であり、
任意選択で、前記ターゲティング部分が、
（ａ）配列番号１０８７、１０９２、１０８６、１０８８～１０９１のいずれか１つ、
（ｂ）配列番号２～４２のいずれか１つ、
（ｃ）配列番号４６～８６のいずれか１つ、
（ｄ）配列番号８３７～８５０のいずれか１つ、
（ｅ）配列番号１０４５～１０８５のいずれか１つ、
（ｆ）配列番号８８０、９１８、９２６、９３４、９４２、９５０、９５８、９６６、９７４、９８２、９９０、９９８、１００６、１０１４、１０２２、１０３０のＶＨ鎖のいずれか１つ、または
（ｇ）配列番号８８１、９１９、９２７、９３５、９４３、９５１、９５９、９６７、９７５、９８３、９９１、９９９、１００７、１０１５、１０２３、１０３１のＶＬ鎖のいずれか１つ、
と少なくとも９０％の配列類似性を有するアミノ酸配列を含む、
請求項１２に記載のキメラタンパク質。 wherein said targeting moiety is a full length antibody, a single domain antibody, a recombinant heavy chain only antibody (VHH), a single chain antibody (scFv), a shark heavy chain only antibody (VNAR) , Fv , Fab, Fab' , or F(ab′) 2 ,
optionally, said targeting moiety is a single domain antibody, optionally comprising a VHH or a humanized VHH;
Optionally, said targeting moiety is
(a) any one of SEQ ID NOs: 1087, 1092, 1086, 1088-1091;
(b) any one of SEQ ID NOS: 2-42;
(c) any one of SEQ ID NOS: 46-86;
(d) any one of SEQ ID NOS:837-850;
(e) any one of SEQ ID NOS: 1045-1085;
(f) any one of the VH chains of SEQ ID NO: 880, 918, 926, 934, 942, 950, 958, 966, 974, 982, 990, 998, 1006, 1014, 1022, 1030, or
(g) any one of the VL chains of SEQ ID NO: 881, 919, 927, 935, 943, 951, 959, 967, 975, 983, 991, 999, 1007, 1015, 1023, 1031;
comprising an amino acid sequence having at least 90% sequence similarity with
13. A chimeric protein according to claim 12 .
任意選択で、前記シグナル伝達物質が、配列番号１７６または１７７と少なくとも９５％の同一性を有するアミノ酸配列を含む変異体インターフェロンアルファ２（ＩＦＮα２）であり、かつ前記変異体ヒトＩＦＮα２が、配列番号１７６または１７７のアミノ酸配列を有する野生型ＩＦＮα２に比べて改善された安全性を付与する１個または複数の変異を有し、
任意選択で、前記ＩＦＮα２が、
（ａ）配列番号１７６または配列番号１７７を基準にして位置１４４～１５４に１個または複数の変異、または
（ｂ）配列番号１７６または１７７を基準にして位置Ｒ１４９、Ｌ１５、Ａ１９、Ｒ２２、Ｒ２３、Ｌ２６、Ｆ２７、Ｌ３０、Ｋ３１、Ｄ３２、Ｒ３３、Ｈ３４、Ｄ３５、Ｑ４０、Ｈ５７、Ｅ５８、Ｑ６１、Ｆ６４、Ｎ６５、Ｔ６９、Ｌ８０、Ｙ８５、Ｙ８９、Ｔ１０６、Ｄ１１４、Ｌ１１７、Ｒ１２０、Ｒ１２５、Ｋ１３３、Ｋ１３４、Ｒ１４４、Ａ１４５、Ｍ１４８、Ｓ１５２、Ｌ１５３、およびＮ１５６での１個または複数の変異であって、任意選択で前記変異が、配列番号１７６または１７７を基準にしてＲ１４９Ａ、Ｌ１５Ａ、Ａ１９Ｗ、Ｒ２２Ａ、Ｒ２３Ａ、Ｌ２６Ａ、Ｆ２７Ａ、Ｌ３０Ａ、Ｌ３０Ｖ、Ｋ３１Ａ、Ｄ３２Ａ、Ｒ３３Ｋ、Ｒ３３Ａ、Ｒ３３Ｑ、Ｈ３４Ａ、Ｄ３５Ａ、Ｑ４０Ａ、Ｈ５７Ｙ、Ｅ５８Ｎ、Ｑ６１Ｓ、Ｆ６４Ａ、Ｎ６５Ａ、Ｔ６９Ａ、Ｌ８０Ａ、Ｙ８５Ａ、Ｙ８９Ａ、Ｄ１１４Ｒ、Ｌ１１７Ａ、Ｒ１２０Ａ、Ｒ１２５Ａ、Ｋ１３３Ａ、Ｋ１３４Ａ、Ｒ１４４Ａ、Ａ１４５Ｇ、Ａ１４５Ｍ、Ｍ１４８Ａ、Ｓ１５２Ａ、Ｌ１５３Ａ、およびＮ１５６Ａ、任意選択でＭ１４８Ａ、Ｒ１４９Ａ、またはＬ１５３Ａの１個または複数である、変異
を有する、
請求項１２に記載のキメラタンパク質。 Said signaling agent is selected from one or more of interferons, interleukins, and tumor necrosis factors, and modified forms thereof; optionally said targeting moiety and said signaling agent comprise one or more connected by a linker,
Optionally, said signaling agent is a mutant interferon alpha 2 (IFNα2) comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 176 or 177, and said mutant human IFNα2 is SEQ ID NO: 176 or having one or more mutations that confer improved safety compared to wild-type IFNα2 having a 177 amino acid sequence;
Optionally, said IFNα2 is
(a) one or more mutations at positions 144-154 relative to SEQ ID NO: 176 or SEQ ID NO: 177, or
(b) positions R149, L15, A19, R22, R23, L26, F27, L30, K31, D32, R33, H34, D35, Q40, H57, E58, Q61, F64, N65 relative to SEQ ID NO: 176 or 177 , T69, L80, Y85, Y89, T106, D114, L117, R120, R125, K133, K134, R144, A145, M148, S152, L153, and N156, and optionally the mutation is R149A, L15A, A19W, R22A, R23A, L26A, F27A, L30A, L30V, K31A, D32A, R33K, R33A, R33Q, H34A, D35A, Q40A, H57Y, E58N relative to SEQ ID NO: 176 or 177 , Q61S, F64A, N65A, T69A, L80A, Y85A, Y89A, D114R, L117A, R120A, R125A, K133A, K134A, R144A, A145G, A145M, M148A, S152A, L153A, and N156A, optionally M149A, or R1 A mutation that is one or more of L153A
having
13. A chimeric protein according to claim 12 .
任意選択で、前記シグナル伝達物質が、配列番号１７８と少なくとも９５％の同一性を有するアミノ酸配列を含む改変インターフェロンβ（ＩＦＮβ）であり、かつ前記改変ヒトＩＦＮβが、配列番号１７８のアミノ酸配列を有する野生型ＩＦＮβに比べて改善された安全性を付与する１個または複数の変異を有し、任意選択で、前記改変ヒトＩＦＮβが、配列番号１７８の位置Ｗ２２、Ｒ２７、Ｌ３２、Ｒ３５、Ｖ１４８、Ｌ１５１、Ｒ１５２、およびＹ１５５に１個または複数の変異を含み、任意選択で、前記改変ヒトＩＦＮβが、配列番号１７８を基準にしてＷ２２Ｇ、Ｒ２７Ｇ、Ｌ３２Ａ、Ｌ３２Ｇ、Ｒ３５Ａ、Ｒ３５Ｇ、Ｖ１４８Ｇ、Ｌ１５１Ｇ、Ｒ１５２Ａ、Ｒ１５２Ｇから選択される１個または複数の変異を含む、または
前記シグナル伝達物質が、配列番号１８２と少なくとも９５％の同一性を有するアミノ酸配列を含む改変腫瘍壊死因子α（ＴＮＦα）であり、かつ前記改変ＴＮＦαが、配列番号１８２のアミノ酸配列を有する野生型ＴＮＦαに比べて低減された受容体結合親和性を付与する１個または複数の変異を有し、任意選択で、前記改変ＴＮＦαが、配列番号１８２を基準にして位置８７、９７、１１５、２９、３１、３２、８４、８５、８６、８８、８９、１４５、１４６および１４７に１個または複数の変異を有し、任意選択で、前記変異が、配列番号１８２を基準にしてＹ８７Ｑ、Ｙ８７Ｌ、Ｙ８７Ａ、Ｙ８７Ｆ、Ｙ８７Ｈ、Ｉ９７Ａ、Ｉ９７Ｑ、Ｉ９７Ｓ、Ｙ１１５Ｇ、Ｙ１１５Ａ、Ｌ２９Ｓ、Ｒ３２Ｇ、Ｒ３２Ｗ、Ｎ３４Ｇ、Ｑ６７Ｇ、Ｈ７３Ｇ、Ｌ７５Ｇ、Ｌ７５Ａ、Ｌ７５Ｓ、Ｔ７７Ａ、Ｓ８６Ｇ、Ｓ８６Ｔ、Ｖ９１Ｇ、Ｖ９１Ａ、Ｔ１０５Ｇ、Ｐ１０６Ｇ、Ａ１０９Ｙ、Ｐ１１３Ｇ、Ｅ１２７Ｇ、Ｎ１３７Ｇ、Ｄ１４３Ｎ、Ａ１４５Ｇ、Ａ１４５Ｒ、Ａ１４５Ｔ、Ｅ１４６Ｄ、Ｅ１４６Ｋ、およびＳ１４７Ｄの１個または複数であり、任意選択で、位置Ｙ８７での変異が、Ｙ８７Ｑ、Ｙ８７Ｌ、Ｙ８７Ａ、およびＹ８７Ｆから選択される、および／または位置Ｉ９７での変異が、Ｉ９７Ａ、Ｉ９７Ｑ、およびＩ９７Ｓから選択される、および／または位置Ｙ１１５での変異が、Ｙ１１５ＡおよびＹ１１５Ｇから選択される、
請求項１２に記載のキメラタンパク質。 wherein the signaling substance is C86, L15, A19, R23, S25, L30, D32, R33, H34, Q40 , D115, L118, K121, R126, E133, K134, K135, R145 based on SEQ ID NO: 1042 , A146, M149, R150, S153, L154, and N157 , optionally wherein said mutations are relative to SEQ ID NO: 1042 . C86S, C86A, L15A, A19W, R23A, S25A, L30A, L30V, D32A, R33K, R33A, R33Q, H34A, Q40A, D115R, L118A, K121A, K121E, R126A, R126E, E133A, K134A, K145A, Ｒ１４５Ｄ、Ｒ１４５Ｅ、Ｒ１４５Ｇ、Ｒ１４５Ｈ、Ｒ１４５Ｉ、Ｒ１４５Ｋ、Ｒ１４５Ｌ、Ｒ１４５Ｎ、Ｒ１４５Ｑ、Ｒ１４５Ｓ、Ｒ１４５Ｔ、Ｒ１４５Ｖ、Ｒ１４５Ｙ、Ａ１４６Ｄ、Ａ１４６Ｅ、Ａ１４６Ｇ、Ａ１４６Ｈ、Ａ１４６Ｉ、Ａ１４６Ｋ、Ａ１４６Ｌ、Ａ１４６Ｍ、Ａ１４６Ｎ、Ａ１４６Ｑ、Ａ１４６Ｒ、Ａ１４６Ｓ、 selected from A146T, A146V, A146Y, M149A, M149V, R150A, S153A, L154A, and N157A, or
Optionally, said signaling agent is a modified interferon-beta (IFNβ) comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 178, and said modified human IFN-β has the amino acid sequence of SEQ ID NO: 178 having one or more mutations that confer improved safety compared to wild-type IFN beta, optionally said modified human IFN beta is at positions W22, R27, L32, R35, V148, L151 of SEQ ID NO: 178 , R152, and Y155, and optionally said modified human IFN beta is W22G, R27G, L32A, L32G, R35A, R35G, V148G, L151G, R152A, with reference to SEQ ID NO: 178; contains one or more mutations selected from R152G, or
said signaling agent is a modified tumor necrosis factor alpha (TNFα) comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 182, and said modified TNFα has the amino acid sequence of SEQ ID NO: 182 wild-type TNFα optionally, said modified TNFα is at positions 87, 97, 115, 29, 31 relative to SEQ ID NO: 182 , 32, 84, 85, 86, 88, 89, 145, 146 and 147, optionally wherein said mutations are relative to SEQ ID NO: 182: Y87Q, Y87L, Y87A, Y87F, Y87H, I97A, I97Q, I97S, Y115G, Y115A, L29S, R32G, R32W, N34G, Q67G, H73G, L75G, L75A, L75S, T77A, S86G, S86T, V91G, V91A, T105G, P106G, P1109Y, one or more of E127G, N137G, D143N, A145G, A145R, A145T, E146D, E146K, and S147D, optionally the mutation at position Y87 is selected from Y87Q, Y87L, Y87A, and Y87F; and/or the mutation at position I97 is selected from I97A, I97Q, and I97S, and/or the mutation at position Y115 is selected from Y115A and Y115G.
13. A chimeric protein according to claim 12 .
任意選択で、前記１個または複数の追加のターゲティング部分が、ＰＤ－１、ＰＤ－Ｌ１、ＰＤ－Ｌ２、ＣＴＬＡ４、ＯＸ４０Ｌ、ＯＸ４０、ＣＤ２０、ＸＣＲ１、Ｆｌｔ３、またはＣｌｅｃ９Ａを認識するまたは機能的に調節し、
任意選択で、前記キメラタンパク質が、腫瘍細胞にまたは腫瘍環境に細胞傷害性Ｔ細胞を動員し、
任意選択で、前記キメラタンパク質が、その活性を実質的に機能的に調節することなくＦＡＰを認識するまたは結合する、
請求項１２に記載のキメラタンパク質。 said chimeric protein comprises one or more additional targeting moieties, optionally said one or more additional targeting moieties recognize or functionally modulate a tumor antigen, and/or Said one or more additional targeting moieties recognize or functionally modulate an antigen on an immune cell, optionally wherein said immune cell is a T cell, a B cell, a dendritic cell, a macrophage, a selected from neutrophils, and NK cells,
Optionally, said one or more additional targeting moieties recognize or functionally regulate PD-1, PD-L1, PD-L2, CTLA4, OX40L, OX40, CD20, XCR1, Flt3, or Clec9A death,
optionally, said chimeric protein recruits cytotoxic T cells to the tumor cell or to the tumor environment;
optionally, said chimeric protein recognizes or binds FAP without substantially functionally modulating its activity;
13. A chimeric protein according to claim 12 .
任意選択で、前記自己免疫疾患および／または神経変性疾患が、多発性硬化症であり、任意選択で、前記キメラタンパク質が、患者において免疫抑制をもたらす、
使用。 Use of the chimeric protein according to any one of claims 12-17 in the manufacture of a medicament for treating or preventing autoimmune and/or neurodegenerative diseases,
optionally, said autoimmune and/or neurodegenerative disease is multiple sclerosis and optionally said chimeric protein results in immunosuppression in the patient.
use .
任意選択で、前記線維性疾患が、肝線維症、肺線維症、原発性硬化性胆管炎（ＰＳＣ）、慢性肝疾患、非アルコール性脂肪性肝疾患（ＮＡＦＬＤ）、非アルコール性脂肪性肝炎（ＮＡＳＨ）、Ｃ型肝炎感染症、アルコール性肝疾患、肝損傷、肝硬変、および骨髄異形成症候群から選択される、
使用。 Use of the chimeric protein according to any one of claims 12-17 in the manufacture of a medicament for treating or preventing a fibrotic disease,
Optionally, said fibrotic disease is liver fibrosis, pulmonary fibrosis, primary sclerosing cholangitis (PSC), chronic liver disease, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis ( NASH), hepatitis C infection, alcoholic liver disease, liver injury, cirrhosis, and myelodysplastic syndrome;
use .
Ｆｃドメインの１種または複数のエフェクター機能を低減または除去する、前記Ｆｃドメイン中のＦｃ鎖対形成を促進する、および／または前記Ｆｃドメイン中のヒンジ領域を安定化する１個または複数の変異を任意選択で有するＦｃドメイン、
および野生型または改変シグナル伝達物質、
を含むＦｃベースキメラタンパク質複合体であって、
前記ターゲティング部分が、３個の相補性決定領域（ＣＤＲ１、ＣＤＲ２、およびＣＤＲ３）を含み、
（ａ）ＣＤＲ１が、
（ｉ）配列番号１１０８、１１２９、１０９３～１１０７、および１１０９～１１２８のいずれか１つのアミノ酸配列、
（ｉｉ）配列番号８７～１１５のいずれか１つのアミノ酸配列、
（ｉｉｉ）配列番号８５１～８６１のいずれか１つのアミノ酸配列、
（ｉｖ）配列番号８８２、９１５、９２０、９２３、９２８、９３１、９３６、９３９、９４４、９４７、９５２、９５５、９６０、９６３、９６８、９７１、９７６、９７９、９８４、９８７、９９２、９９５、１０００、１００３、１００８、１０１１、１０１６、１０１９、１０２４、１０２７、１０３２、１０３５のいずれか１つのアミノ酸配列、または
（ｖ）（ｉ）～（ｉｖ）のアミノ酸配列のいずれか１つの中に１～５個のアミノ酸置換、欠失、または挿入を有するアミノ酸配列
を含み、
（ｂ）ＣＤＲ２が、
（ｉ）配列番号１２８、１２６、１１６～１２５、１２７、および１２９～１４４のいずれか１つのアミノ酸配列、
（ｉｉ）配列番号８６２～８７６のいずれか１つのアミノ酸配列、
（ｉｉｉ）配列番号８８３、９１６、９２１、９２４、９２９、９３２、９３７、９４０、９４５、９４８、９５３、９５６、９６１、９６４、９６９、９７２、９７７、９８０、９８５、９８８、９９３、９９６、１００１、１００４、１００９、１０１２、１０１７、１０２０、１０２５、１０２８、１０３３、１０３６のいずれか１つのアミノ酸配列、または
（ｉｖ）（ｉ）～（ｉｉｉ）のアミノ酸配列のいずれか１つの中に１～５個のアミノ酸置換、欠失、または挿入を有するアミノ酸配列、
を含み、および
（ｃ）ＣＤＲ３が、
（ｉ）配列番号１５９、１５７、１４５～１５６、１５８、１６０～１７５のいずれか１つのアミノ酸配列、
（ｉｉ）配列番号８７７～８７９のいずれか１つのアミノ酸配列、
（ｉｉｉ）配列番号８８４、９１７、９２２、９２５、９３０、９３３、９３８、９４１、９４６、９４９、９５４、９５７、９６２、９６５、９７０、９７３、９７８、９８１、９８６、９８９、９９４、９９７、１００２、１００５、１０１０、１０１３、１０１８、１０２１、１０２６、１０２９、１０３４、１０３７のいずれか１つのアミノ酸配列、または
（ｉｖ）（ｉ）～（ｉｉｉ）のアミノ酸配列のいずれか１つの中に１～５個のアミノ酸置換、欠失、または挿入を有するアミノ酸配列、
を含む、
Ｆｃベースキメラタンパク質複合体。 at least one targeting moiety that targets and binds fibroblast activation protein (FAP); and reducing or eliminating one or more effector functions of the Fc domain, promoting Fc chain pairing in said Fc domain. and/or an Fc domain optionally having one or more mutations that stabilize the hinge region in said Fc domain;
and a wild-type or modified signaling agent,
An Fc-based chimeric protein complex comprising
said targeting moiety comprises three complementarity determining regions (CDR1, CDR2, and CDR3);
(a) CDR1 is
(i) the amino acid sequence of any one of SEQ ID NOS: 1108, 1129, 1093-1107, and 1109-1128;
(ii) the amino acid sequence of any one of SEQ ID NOS:87-115;
(iii) the amino acid sequence of any one of SEQ ID NOs:851-861;
(iv) SEQ. , 1003, 1008, 1011, 1016, 1019, 1024, 1027, 1032, 1035, or (v) 1 to 5 in any one of the amino acid sequences of (i) to (iv) comprising amino acid sequences having 1 amino acid substitution, deletion, or insertion;
(b) CDR2 is
(i) the amino acid sequence of any one of SEQ ID NOS : 128, 126 , 116-125, 127, and 129-144;
(ii) the amino acid sequence of any one of SEQ ID NOS:862-876;
(iii) SEQ. , 1004, 1009, 1012, 1017, 1020, 1025, 1028, 1033, 1036, or (iv) 1-5 in any one of the amino acid sequences of (i)-(iii) amino acid sequences having amino acid substitutions, deletions, or insertions;
and (c) the CDR3 is
(i) the amino acid sequence of any one of SEQ ID NOS : 159, 157 , 145-156, 158, 160-175;
(ii) the amino acid sequence of any one of SEQ ID NOS:877-879;
(iii) SEQ. , 1005, 1010, 1013, 1018, 1021, 1026, 1029, 1034, 1037, or (iv) 1-5 in any one of the amino acid sequences of (i)-(iii) amino acid sequences having amino acid substitutions, deletions, or insertions;
including,
Fc-based chimeric protein complexes.
任意選択で、前記線維芽細胞が、癌、感染症、免疫異常、自己免疫疾患、線維性疾患、および心臓血管疾患から選択される疾患に関連し、
任意選択で、前記ターゲティング部分が、Ｆ２線維芽細胞を標的にする、
請求項２３に記載のＦｃベースキメラタンパク質複合体。 said complex directly or indirectly alters said disease-associated fibroblast microenvironment and/or said complex directly or indirectly polarizes disease-associated fibroblasts,
optionally, said fibroblasts are associated with a disease selected from cancer, infectious diseases, immune disorders, autoimmune diseases, fibrotic diseases, and cardiovascular diseases;
optionally, said targeting moiety targets F2 fibroblasts;
24. The Fc-based chimeric protein conjugate of claim 23 .
任意選択で、前記ターゲティング部分が、ＶＨＨまたはヒト化ＶＨＨを任意選択で含む単一ドメイン抗体であり、
任意選択で、前記ターゲティング部分が、
（ａ）配列番号１０８７、１０９２、１０８６、１０８８～１０９１のいずれか１つ、
（ｂ）配列番号２～４２のいずれか１つ、
（ｃ）配列番号４６～８６のいずれか１つ、
（ｄ）配列番号８３７～８５０のいずれか１つ、
（ｅ）配列番号１０４５～１０８５のいずれか１つ、
（ｇ）配列番号８８０、９１８、９２６、９３４、９４２、９５０、９５８、９６６、９７４、９８２、９９０、９９８、１００６、１０１４、１０２２、１０３０のＶＨ鎖のいずれか１つ、または
（ｈ）配列番号８８１、９１９、９２７、９３５、９４３、９５１、９５９、９６７、９７５、９８３、９９１、９９９、１００７、１０１５、１０２３、１０３１のＶＬ鎖のいずれか１つ、
と少なくとも９０％の配列類似性を有するアミノ酸配列を含み、
任意選択で、前記ターゲティング部分が、免疫細胞上の抗原または受容体を認識し結合する認識ドメインを含み、任意選択で、前記免疫細胞が、Ｔ細胞、Ｂ細胞、樹状細胞、マクロファージ、好中球、およびＮＫ細胞から選択される、
請求項２３に記載のＦｃベースキメラタンパク質複合体。 wherein said targeting moiety is a single domain antibody, recombinant heavy chain only antibody (VHH), single chain antibody (scFv), shark heavy chain only antibody (VNAR) , Fv , Fab, Fab', or F(ab) ') 2 , and
optionally, said targeting moiety is a single domain antibody optionally comprising a VHH or a humanized VHH;
Optionally, said targeting moiety is
(a) any one of SEQ ID NOs: 1087, 1092, 1086, 1088-1091;
(b) any one of SEQ ID NOS: 2-42;
(c) any one of SEQ ID NOS: 46-86;
(d) any one of SEQ ID NOS:837-850;
(e) any one of SEQ ID NOS: 1045-1085;
(g) any one of the VH chains of SEQ ID NO: 880, 918, 926, 934, 942, 950, 958, 966, 974, 982, 990, 998, 1006, 1014, 1022, 1030, or
(h) any one of the VL chains of SEQ ID NO: 881, 919, 927, 935, 943, 951, 959, 967, 975, 983, 991, 999, 1007, 1015, 1023, 1031;
comprising an amino acid sequence having at least 90% sequence similarity with
Optionally, said targeting moiety comprises a recognition domain that recognizes and binds to antigens or receptors on immune cells, optionally said immune cells are T cells, B cells, dendritic cells, macrophages, neutrophils. spheres, and NK cells;
24. The Fc-based chimeric protein conjugate of claim 23 .
任意選択で、前記シグナル伝達物質が、配列番号１７６または１７７と少なくとも９５％の同一性を有するアミノ酸配列を含む変異体インターフェロンアルファ２（ＩＦＮα２）であり、かつ前記変異体ヒトＩＦＮα２が、配列番号１７６または１７７のアミノ酸配列を有する野生型ＩＦＮα２に比べて改善された安全性を付与する１個または複数の変異を有し、
任意選択で、前記ＩＦＮα２が、
（ａ）配列番号１７６または配列番号１７７を基準にして位置１４４～１５４に１個または複数の変異、または
（ｂ）配列番号１７６または１７７を基準にして位置Ｒ１４９、Ｌ１５、Ａ１９、Ｒ２２、Ｒ２３、Ｌ２６、Ｆ２７、Ｌ３０、Ｋ３１、Ｄ３２、Ｒ３３、Ｈ３４、Ｄ３５、Ｑ４０、Ｈ５７、Ｅ５８、Ｑ６１、Ｆ６４、Ｎ６５、Ｔ６９、Ｌ８０、Ｙ８５、Ｙ８９、Ｄ１１４、Ｌ１１７、Ｒ１２０、Ｒ１２５、Ｋ１３３、Ｋ１３４、Ｒ１４４、Ａ１４５、Ｍ１４８、Ｓ１５２、Ｌ１５３、およびＮ１５６に１個または複数の変異
を有し、
任意選択で、前記変異が、配列番号１７６または１７７を基準にしてＲ１４９Ａ、Ｌ１５Ａ、Ａ１９Ｗ、Ｒ２２Ａ、Ｒ２３Ａ、Ｌ２６Ａ、Ｆ２７Ａ、Ｌ３０Ａ、Ｌ３０Ｖ、Ｋ３１Ａ、Ｄ３２Ａ、Ｒ３３Ｋ、Ｒ３３Ａ、Ｒ３３Ｑ、Ｈ３４Ａ、Ｄ３５Ａ、Ｑ４０Ａ、Ｈ５７Ｙ、Ｅ５８Ｎ、Ｑ６１Ｓ、Ｆ６４Ａ、Ｎ６５Ａ、Ｔ６９Ａ、Ｌ８０Ａ、Ｙ８５Ａ、Ｙ８９Ａ、Ｄ１１４Ｒ、Ｌ１１７Ａ、Ｒ１２０Ａ、Ｒ１２５Ａ、Ｋ１３３Ａ、Ｋ１３４Ａ、Ｒ１４４Ａ、Ａ１４５Ｇ、Ａ１４５Ｍ、Ｍ１４８Ａ、Ｓ１５２Ａ、Ｌ１５３Ａ、およびＮ１５６Ａ、任意選択でＭ１４８Ａ、Ｒ１４９Ａ、またはＬ１５３Ａの１個または複数である、
請求項２３に記載のＦｃベースキメラタンパク質複合体。 said signaling agent is selected from one or more of interferons, interleukins, and tumor necrosis factors, and modified forms thereof;
Optionally, said signaling agent is a mutant interferon alpha 2 (IFNα2) comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 176 or 177, and said mutant human IFNα2 is SEQ ID NO: 176 or having one or more mutations that confer improved safety compared to wild-type IFNα2 having a 177 amino acid sequence;
Optionally, said IFNα2 is
(a) one or more mutations at positions 144-154 relative to SEQ ID NO: 176 or SEQ ID NO: 177, or
(b) positions R149, L15, A19, R22, R23, L26, F27, L30, K31, D32, R33, H34, D35, Q40, H57, E58, Q61, F64, N65 relative to SEQ ID NO: 176 or 177 , T69, L80, Y85, Y89, D114, L117, R120, R125, K133, K134, R144, A145, M148, S152, L153, and N156
has
Optionally, said mutation is R149A, L15A, A19W, R22A, R23A, L26A, F27A, L30A, L30V, K31A, D32A, R33K, R33A, R33Q, H34A, D35A, Q40A relative to SEQ ID NO: 176 or 177 , H57Y, E58N, Q61S, F64A, N65A, T69A, L80A, Y85A, Y89A, D114R, L117A, R120A, R125A, K133A, K134A, R144A, A145G, A145M, M148A, S152A, L153A, and N156A, optionally 8A M14 , R149A, or L153A;
24. The Fc-based chimeric protein conjugate of claim 23 .
前記前記シグナル伝達物質が、配列番号１７８と少なくとも９５％の同一性を有するアミノ酸配列を含む変異体インターフェロンβ（ＩＦＮβ）であり、かつ前記変異体ヒトＩＦＮβが、配列番号１７８のアミノ酸配列を有する野生型ＩＦＮβに比べて改善された安全性を付与する１個または複数の変異を有し、任意選択で、前記改変ヒトＩＦＮβが、配列番号１７８の位置Ｗ２２、Ｒ２７、Ｌ３２、Ｒ３５、Ｖ１４８、Ｌ１５１、Ｒ１５２、およびＹ１５５に１個または複数の変異を含み、任意選択で、前記改変ヒトＩＦＮβが、配列番号１７８のＷ２２Ｇ、Ｒ２７Ｇ、Ｌ３２Ａ、Ｌ３２Ｇ、Ｒ３５Ａ、Ｒ３５Ｇ、Ｖ１４８Ｇ、Ｌ１５１Ｇ、Ｒ１５２Ａ、Ｒ１５２Ｇから選択される１個または複数の変異を含む、または
前記シグナル伝達物質が、配列番号１８２と少なくとも９５％の同一性を有するアミノ酸配列を含む改変腫瘍壊死因子α（ＴＮＦα）であり、かつ前記改変ＴＮＦαが、配列番号１８２のアミノ酸配列を有する野生型ＴＮＦαに比べて低減された受容体結合親和性を付与する１個または複数の変異を有し、任意選択で、前記改変ＴＮＦαが、配列番号１８２を基準にして位置８７、９７、１１５、２９、３１、３２、８４、８５、８６、８８、８９、１４５、１４６および１４７に１個または複数の変異を有し、任意選択で、前記変異が、配列番号１８２を基準にしてＹ８７Ｑ、Ｙ８７Ｌ、Ｙ８７Ａ、Ｙ８７Ｆ、Ｙ８７Ｈ、Ｉ９７Ａ、Ｉ９７Ｑ、Ｉ９７Ｓ、Ｙ１１５Ｇ、Ｙ１１５Ａ、Ｌ２９Ｓ、Ｒ３２Ｇ、Ｒ３２Ｗ、Ｎ３４Ｇ、Ｑ６７Ｇ、Ｈ７３Ｇ、Ｌ７５Ｇ、Ｌ７５Ａ、Ｌ７５Ｓ、Ｔ７７Ａ、Ｓ８６Ｇ、Ｓ８６Ｔ、Ｖ９１Ｇ、Ｖ９１Ａ、Ｔ１０５Ｇ、Ｐ１０６Ｇ、Ａ１０９Ｙ、Ｐ１１３Ｇ、Ｅ１２７Ｇ、Ｎ１３７Ｇ、Ｄ１４３Ｎ、Ａ１４５Ｇ、Ａ１４５Ｒ、Ａ１４５Ｔ、Ｅ１４６Ｄ、Ｅ１４６Ｋ、およびＳ１４７Ｄの１個または複数であり、任意選択で、位置Ｙ８７での変異が、Ｙ８７Ｑ、Ｙ８７Ｌ、Ｙ８７Ａ、およびＹ８７Ｆから選択される、および／または位置Ｉ９７での変異が、Ｉ９７Ａ、Ｉ９７Ｑ、およびＩ９７Ｓから選択される、および／または位置Ｙ１１５での変異が、Ｙ１１５ＡおよびＹ１１５Ｇから選択される、
請求項２３に記載のＦｃベースキメラタンパク質複合体。 wherein the modified interferon is C86, L15, A19, R23, S25, L30, D32, R33, H34, Q40 , D115, L118, K121, R126, E133, K134, K135, R145, based on SEQ ID NO: 1042; IFNα1 having mutations in one or more amino acids at positions A146, M149, R150, S153, L154 and N157 , optionally wherein said mutations are C86S, C86A, relative to SEQ ID NO: 1042 L15A, A19W, R23A, S25A, L30A, L30V, D32A, R33K, R33A, R33Q, H34A, Q40A, D115R, L118A, K121A, K121E, R126A, R126E, E133A, K134A, K135A, R145A, R145G, R145G, R145E, Ｒ１４５Ｈ、Ｒ１４５Ｉ、Ｒ１４５Ｋ、Ｒ１４５Ｌ、Ｒ１４５Ｎ、Ｒ１４５Ｑ、Ｒ１４５Ｓ、Ｒ１４５Ｔ、Ｒ１４５Ｖ、Ｒ１４５Ｙ、Ａ１４６Ｄ、Ａ１４６Ｅ、Ａ１４６Ｇ、Ａ１４６Ｈ、Ａ１４６Ｉ、Ａ１４６Ｋ、Ａ１４６Ｌ、Ａ１４６Ｍ、Ａ１４６Ｎ、Ａ１４６Ｑ、Ａ１４６Ｒ、Ａ１４６Ｓ、Ａ１４６Ｔ、Ａ１４６Ｖ、Ａ１４６Ｙ、 selected from M149A, M149V, R150A, S153A, L154A, and N157A, or
wherein said signaling agent is a mutant interferon beta (IFN beta) comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 178, and said mutant human IFN beta has the amino acid sequence of SEQ ID NO: 178. having one or more mutations that confer improved safety compared to type IFN beta, optionally said modified human IFN beta comprises positions W22, R27, L32, R35, V148, L151 of SEQ ID NO: 178; one or more mutations in R152, and Y155, and optionally said modified human IFN beta is selected from W22G, R27G, L32A, L32G, R35A, R35G, V148G, L151G, R152A, R152G of SEQ ID NO: 178 contains one or more mutations that
said signaling agent is a modified tumor necrosis factor alpha (TNFα) comprising an amino acid sequence having at least 95% identity to SEQ ID NO: 182, and said modified TNFα has the amino acid sequence of SEQ ID NO: 182 wild-type TNFα optionally, said modified TNFα is at positions 87, 97, 115, 29, 31 relative to SEQ ID NO: 182 , 32, 84, 85, 86, 88, 89, 145, 146 and 147, optionally wherein said mutations are relative to SEQ ID NO: 182: Y87Q, Y87L, Y87A, Y87F, Y87H, I97A, I97Q, I97S, Y115G, Y115A, L29S, R32G, R32W, N34G, Q67G, H73G, L75G, L75A, L75S, T77A, S86G, S86T, V91G, V91A, T105G, P106G, P1109Y, one or more of E127G, N137G, D143N, A145G, A145R, A145T, E146D, E146K, and S147D, optionally the mutation at position Y87 is selected from Y87Q, Y87L, Y87A, and Y87F; and/or the mutation at position I97 is selected from I97A, I97Q, and I97S, and/or the mutation at position Y115 is selected from Y115A and Y115G.
24. The Fc-based chimeric protein conjugate of claim 23 .
前記Ｆｃドメインが、ＩｇＧ、ＩｇＡ、ＩｇＤ、ＩｇＭ、またはＩｇＥ由来であり、任意選択で、前記ＩｇＧが、ＩｇＧ１、ＩｇＧ２、ＩｇＧ３、またはＩｇＧ４から選択される、
請求項２３に記載のＦｃベースキメラタンパク質複合体。 further comprising one or more linkers;
said Fc domain is derived from IgG, IgA, IgD, IgM or IgE, optionally said IgG is selected from IgG1, IgG2, IgG3 or IgG4;
24. The Fc-based chimeric protein conjugate of claim 23 .
前記Ｆｃドメインに対する前記１個または複数の変異が、前記Ｆｃドメイン中のＦｃ鎖間のイオン対形成をもたらす、および／または
前記Ｆｃドメインに対する前記１個または複数の変異が、前記Ｆｃドメイン中のノブインホール対形成をもたらす、および／または
前記Ｆｃドメインに対する前記１個または複数の変異が、前記Ｆｃドメインのエフェクター機能の低減または除去をもたらす、
請求項２３に記載のＦｃベースキメラタンパク質複合体。 said Fc chain pairing is facilitated by ion-pairing and/or knobby-hole pairing, and/or
said one or more mutations to said Fc domain result in ion-pairing between Fc chains in said Fc domain, and/or
said one or more mutations to said Fc domain result in knob-in-hole pairing in said Fc domain, and/or
said one or more mutations to said Fc domain result in a reduction or elimination of an effector function of said Fc domain;
24. The Fc-based chimeric protein conjugate of claim 23 .
任意選択で、前記１個または複数の追加のターゲティング部分が、ＰＤ－１、ＰＤ－Ｌ１、ＰＤ－Ｌ２、ＣＴＬＡ４、ＯＸ４０Ｌ、ＯＸ４０、ＣＤ２０、Ｆｌｔ３、ＸＣＲ１およびＣｌｅｃ９Ａを認識するかまたは機能的に調節する、
請求項２３に記載のＦｃベースキメラタンパク質複合体。 said conjugate comprises one or more additional targeting moieties, optionally said one or more additional targeting moieties recognize or functionally modulate a tumor antigen, and/or Said one or more additional targeting moieties recognize or functionally modulate an antigen on an immune cell, optionally said immune cell is a T cell, a B cell, a dendritic cell, a macrophage, a selected from neutrophils, and NK cells,
Optionally, said one or more additional targeting moieties recognize or functionally regulate PD-1, PD-L1, PD-L2, CTLA4, OX40L, OX40, CD20, Flt3, XCR1 and Clec9A do,
24. The Fc-based chimeric protein conjugate of claim 23 .
請求項２３に記載のＦｃベースキメラタンパク質複合 said complex recognizes or binds FAP without substantially functionally modulating its activity;
Fc-based chimeric protein conjugate according to claim 23
任意選択で、前記Ｆｃが、ヒトＩｇＧ１であり、かつＬ２３４、Ｌ２３５、Ｋ３２２、Ｄ２６５、Ｐ３２９およびＰ３３１（ＥＵナンバリングに準拠）の１個または複数を任意選択で含む、
請求項２３に記載のＦｃベースキメラタンパク質複合体。 5A -F, 6A-H, 7A-H, 8A-D, 9A-F, 10A-J, 11A-D, 12A-F, 13A-J, 14A-F , 15A-L, 16A-L, 17A-F, 18A-L, 19A-L, 20A-J, 21A-J , 22A-F, and 23A-F;
optionally, said Fc is human IgG1 and optionally comprises one or more of L234, L235, K322, D265, P329 and P331 (according to EU numbering);
24. The Fc-based chimeric protein conjugate of claim 23 .
Use of the Fc-based chimeric protein complex according to any one of claims 23-35 in the manufacture of a medicament for treating or preventing fibrotic diseases.
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| US201962825575P | 2019-03-28 | 2019-03-28 | |
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| PCT/US2020/025427 WO2020198665A1 (en) | 2019-03-28 | 2020-03-27 | Fibroblast activation protein binding agents and use thereof |
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| EP1806365A1 (en) * | 2006-01-05 | 2007-07-11 | Boehringer Ingelheim International GmbH | Antibody molecules specific for fibroblast activation protein and immunoconjugates containing them |
| EP2483316A1 (en) * | 2009-10-02 | 2012-08-08 | Ludwig Institute for Cancer Research Ltd. | Anti-fibroblast activation protein antibodies and methods and uses thereof |
| CA2973040A1 (en) * | 2015-01-09 | 2016-07-14 | Mabimmune Diagnostics Ag | Novel anti-fibroblast activation protein (fap) antibodies and uses derived thereof |
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