JPWO2019152979A5 - - Google Patents

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JPWO2019152979A5
JPWO2019152979A5 JP2020564042A JP2020564042A JPWO2019152979A5 JP WO2019152979 A5 JPWO2019152979 A5 JP WO2019152979A5 JP 2020564042 A JP2020564042 A JP 2020564042A JP 2020564042 A JP2020564042 A JP 2020564042A JP WO2019152979 A5 JPWO2019152979 A5 JP WO2019152979A5
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amino acid
chimeric protein
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Priority claimed from PCT/US2019/016629 external-priority patent/WO2019152979A1/en
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（ａ）少なくとも１つの、線維芽細胞活性化タンパク質（ＦＡＰ）結合物質であるターゲティング部分と、
（ｂ）１つ以上の変異を有する改変型ヒトインターフェロンアルファ２（ＩＦＮα２）シグナル伝達物質であって、前記１つ以上の変異が、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、改変型ヒトインターフェロンアルファ２（ＩＦＮα２）シグナル伝達物質と、
を含むキメラタンパク質であって、
前記ターゲティング部分が、疾患関連の線維芽細胞を標的とし、
前記キメラタンパク質が、前記疾患関連の線維芽細胞の機能、および／または前記疾患関連の線維芽細胞を含む疾患微小環境、を直接的または間接的に変化させる、
キメラタンパク質。 (A) At least one targeting moiety that is a fibroblast-activating protein (FAP) binding agent .
(B) A modified human interferon alpha 2 (IFNα2) signaling agent with one or more mutations, wherein the one or more mutations are compared to wild-type IFNα2 having the amino acid sequence of SEQ ID NO: 176 or 177. With a modified human interferon alpha 2 (IFNα2) signaling agent that confer improved safety ,
Is a chimeric protein containing
The targeting moiety targets disease-related fibroblasts and
The chimeric protein directly or indirectly alters the function of the disease-related fibroblasts and / or the disease microenvironment containing the disease-related fibroblasts.
Chimeric protein. 前記ＦＡＰ結合物質が、Ｆ２線維芽細胞を直接的または間接的に極性化する、請求項１に記載のキメラタンパク質。 The chimeric protein according to claim 1 , wherein the FAP binding substance directly or indirectly polarizes F2 fibroblasts. 前記ＦＡＰ結合物質が、細胞傷害性Ｔ細胞を腫瘍細胞に、または腫瘍微小環境に、動員する、請求項１に記載のキメラタンパク質。 The chimeric protein of claim 1 , wherein the FAP binding agent recruits cytotoxic T cells into tumor cells or into the tumor microenvironment. 前記ＦＡＰ結合物質は、実質的にＦＡＰの活性を機能的に調節することなくＦＡＰを認識または結合する、請求項１に記載のキメラタンパク質。 The chimeric protein according to claim 1 , wherein the FAP binding substance recognizes or binds to FAP without substantially regulating the activity of FAP. 前記ターゲティング部分が、完全長抗体、単一ドメイン抗体、組換え重鎖のみの抗体（ＶＨＨ）、単鎖抗体（ｓｃＦｖ）、サメ重鎖のみの抗体（ＶＮＡＲ）、マイクロタンパク質、ｄａｒｐｉｎ、アンチカリン、アドネクチン、Ｆｖ、Ｆａｂ、Ｆａｂ’、またはＦ（ａｂ’） The 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), a microprotein, darpin, anticarin, and the like. Adnectin, Fv, Fab, Fab', or F (ab') ２2 である、請求項１に記載のキメラタンパク質。The chimeric protein according to claim 1. 前記ＦＡＰ結合物質が、３つの相補性決定領域（ＣＤＲ１、ＣＤＲ２、およびＣＤＲ３）を含み、
（ａ）ＣＤＲ１が、配列番号９５のアミノ酸配列または配列番号８７～９４もしくは配列番号９６～１１５のいずれか１つを有するアミノ酸配列を含み、
（ｂ）ＣＤＲ２が、配列番号１２１のアミノ酸配列または配列番号１１６～１２０もしくは配列番号１２２～１４４のいずれか１つを有するアミノ酸配列を含み；および
（ｃ）ＣＤＲ３が、配列番号１５２のアミノ酸配列または配列番号１４５～１５１もしくは配列番号１５３～１７５のいずれか１つを有するアミノ酸配列を含む、
請求項１に記載のキメラタンパク質。 The FAP binding material comprises three complementarity determining regions (CDR1, CDR2, and CDR3).
( A ) CDR1 comprises an amino acid sequence having either the amino acid sequence of SEQ ID NO: 95 or any one of SEQ ID NOs: 87-94 or SEQ ID NOs: 96-115.
( B ) CDR2 comprises an amino acid sequence of SEQ ID NO: 121 or any one of SEQ ID NOs: 116-120 or SEQ ID NOs: 122-144; and ( c ) CDR3 of SEQ ID NO: 152. Includes an amino acid sequence or an amino acid sequence having any one of SEQ ID NOs: 145 to 151 or SEQ ID NOs: 153-175.
The chimeric protein according to claim 1 . 前記ターゲティング部分が、配列番号５８または配列番号２～４２、４６～５７もしくは５９～８６のいずれか１つと少なくとも９５％の配列類似性を有するアミノ酸配列を含む、請求項１に記載のキメラタンパク質。 The chimeric protein of claim 1, wherein the targeting moiety comprises an amino acid sequence having at least 95% sequence similarity to any one of SEQ ID NOs: 58 or SEQ ID NOs: 2-42, 46-57 or 59-86. 前記変異型ヒトＩＦＮα２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み、配列番号１７６または１７７を基準にして位置１４４～１５４に、または配列番号１７６または１７７を基準にして位置Ｌ１５、Ａ１９、Ｒ２２、Ｒ２３、Ｌ２６、Ｆ２７、Ｌ３０、Ｌ３０、Ｋ３１、Ｄ３２、Ｒ３３、Ｈ３４、Ｄ３５、Ｑ４０、Ｈ５７、Ｅ５８、Ｑ６１、Ｆ６４、Ｎ６５、Ｔ６９、Ｌ８０、Ｙ８５、Ｙ８９、Ｄ１１４、Ｌ１１７、Ｒ１２０、Ｒ１２５、Ｋ１３３、Ｋ１３４、Ｒ１４４、Ａ１４５、Ａ１４５、Ｍ１４８、Ｒ１４９、Ｓ１５２、Ｌ１５３、およびＮ１５６のうちの１つもしくは複数に、１つまたは複数の変異を有する、請求項１に記載のキメラタンパク質。 The mutant human IF Nα 2 comprises an amino acid sequence having at least 95% identity with SEQ ID NO: 176 or 177 , with positions 144-154 relative to SEQ ID NO: 176 or 177, or SEQ ID NO: 176 or 177. Positions L15, A19, R22, R23, L26, F27, L30, L30, K31, D32, R33, H34, D35, Q40, H57, E58, Q61, F64, N65, T69, L80, Y85, Y89, as a reference. 1 according to claim 1 , wherein one or more of D114, L117, R120, R125, K133, K134, R144, A145, A145, M148, R149, S152, L153, and N156 have one or more mutations . The chimeric protein described. 前記変異型ヒトＩＦＮα２が、位置Ｒ１４９、Ｍ１４８、またはＬ１５３に１つまたは複数の変異を有する、請求項８に記載のキメラタンパク質。 The chimeric protein of claim 8, wherein the mutant human IFNα2 has one or more mutations at positions R149, M148, or L153. 前記変異が、配列番号１７６または１７７を基準にして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、Ｒ１４９Ａ、Ｓ１５２Ａ、Ｌ１５３Ａ、およびＮ１５６Ａの１つまたは複数、場合によりＭ１４８Ａ、Ｒ１４９Ａ、またはＬ１５３Ａである、請求項８に記載のキメラタンパク質。 The mutation is based on SEQ ID NO: 176 or 177 as 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, R149A, S152A, L153A, and N156. , R149A, or L153A, according to claim 8. 前記ＦＡＰ結合物質は、腫瘍抗原、または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免疫細胞上の抗原、を認識するか機能的に調節する、１つ以上のさらなるターゲティング部分を含む、請求項１に記載のキメラタンパク質。 The FAP binding agent recognizes or functionally regulates tumor antigens or antigens on immune cells selected from T cells, B cells, dendritic cells, macrophages, neutrophils, and NK cells. The chimeric protein of claim 1, comprising one or more additional targeting moieties. 前記１つ以上のさらなるターゲティング部分は、ＰＤ－１、ＰＤ－Ｌ１、ＰＤ－Ｌ２、ＣＴＬＡ４、ＯＸ４０Ｌ、ＯＸ４０、ＣＤ２０、ＸＣＲ１、およびＣｌｅｃ９Ａを認識するか機能的に調節する、請求項１１に記載のキメラタンパク質。 11. Chimeric protein. 前記疾患関連の線維芽細胞は、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する、請求項１に記載のキメラタンパク質。 The chimeric protein according to claim 1, wherein the disease-related fibroblast is associated with a disease selected from cancer, infectious diseases, immune disorders, autoimmune diseases, fibrous diseases, and cardiovascular diseases. 請求項１に記載のキメラタンパク質またはその成分をコードする、組換え核酸。 A recombinant nucleic acid encoding the chimeric protein according to claim 1 or a component thereof . 請求項１４に記載の核酸を含む、宿主細胞。 A host cell comprising the nucleic acid of claim 14 . 癌、感染症、免疫異常、線維性疾患、および／または自己免疫疾患の治療または予防における使用のための組成物であって、請求項１～１３のいずれか１項に記載のキメラタンパク質を含む、組成物。 A composition for use in the treatment or prevention of cancer , infectious diseases, immune disorders, fibrous diseases, and / or autoimmune diseases, comprising the chimeric protein according to any one of claims 1 to 13 . , Composition . ３つの相補性決定領域（ＣＤＲ１、ＣＤＲ２、およびＣＤＲ３）を含むＦＡＰ結合物質であって、 A FAP binding agent containing three complementarity determining regions (CDR1, CDR2, and CDR3).
（ａ）ＣＤＲ１が、配列番号９５のアミノ酸配列または配列番号８７～９４もしくは配列番号９６～１１５のいずれか１つを有するアミノ酸配列を含み、 (A) CDR1 comprises an amino acid sequence having either the amino acid sequence of SEQ ID NO: 95 or any one of SEQ ID NOs: 87-94 or SEQ ID NOs: 96-115.
（ｂ）ＣＤＲ２が、配列番号１２１のアミノ酸配列または配列番号１１６～１２０もしくは配列番号１２２～１４４のいずれか１つを有するアミノ酸配列を含み；および (B) CDR2 comprises an amino acid sequence having either the amino acid sequence of SEQ ID NO: 121 or any one of SEQ ID NOs: 116-120 or SEQ ID NOs: 122-144; and
（ｃ）ＣＤＲ３が、配列番号１５２のアミノ酸配列または配列番号１４５～１５１もしくは配列番号１５３～１７５のいずれか１つを有するアミノ酸配列を含む、 (C) CDR3 comprises an amino acid sequence of SEQ ID NO: 152 or an amino acid sequence having any one of SEQ ID NOs: 145 to 151 or SEQ ID NOs: 153 to 175.
ＦＡＰ結合物質。FAP binding substance. 前記ターゲティング部分が、完全長抗体、単一ドメイン抗体、組換え重鎖のみの抗体（ＶＨＨ）、単鎖抗体（ｓｃＦｖ）、サメ重鎖のみの抗体（ＶＮＡＲ）、マイクロタンパク質、ｄａｒｐｉｎ、アンチカリン、アドネクチン、Ｆｖ、Ｆａｂ、Ｆａｂ’、またはＦ（ａｂ’） The 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), a microprotein, darpin, anticarin, and the like. Adnectin, Fv, Fab, Fab', or F (ab') ２2 である、請求項１７に記載のＦＡＰ結合物質。The FAP binding substance according to claim 17. 前記ターゲティング部分が、配列番号５８または配列番号２～４２、４６～５７もしくは５９～８６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１７に記載のＦＡＰ結合物質。 17. The FAP binding agent of claim 17, wherein the targeting moiety comprises an amino acid sequence having at least 90% sequence similarity to any one of SEQ ID NOs: 58 or SEQ ID NOs: 2-42, 46-57 or 59-86. .. 請求項１７に記載のＦＡＰ結合物質またはその成分をコードする、組換え核酸。 A recombinant nucleic acid encoding the FAP binding substance according to claim 17 or a component thereof. 請求項２０に記載の核酸を含む、宿主細胞。 A host cell comprising the nucleic acid of claim 20. 癌、感染症、免疫異常、線維性疾患、および／または自己免疫疾患の治療または予防における使用のための組成物であって、請求項１７～１９のいずれか１項に記載のＦＡＰ結合物質を含む、組成物。 The FAP binding agent according to any one of claims 17 to 19, which is a composition for use in the treatment or prevention of cancer, infectious diseases, immune disorders, fibrous diseases, and / or autoimmune diseases. Including, composition.
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