JP7403455B2 - 新規な構造を有する治療学的酵素融合タンパク質及びその用途 - Google Patents
新規な構造を有する治療学的酵素融合タンパク質及びその用途 Download PDFInfo
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Description
L及びL’はリンカーであって、それぞれ独立して同一または異なる種類のリンカーであり;
Fは、免疫グロブリンFc領域であり;
|は、共有結合であり;
:は、共有または非共有結合である。
L及びL’はリンカーであって、それぞれ独立して同一または異なる種類のリンカーであり;
Fは、免疫グロブリンFc領域であり;
|は、共有結合であり;
:は、共有または非共有結合である。
一つの具体例による組成物であって、上記リソソーム蓄積症は、ムコ多糖症(mucopolysaccharidosis, MPS)、グリコーゲン蓄積病(Glycogen storage disease)、スフィンゴリピドーシス(sphingolipidosis)、ニーマン・ピック病(Niemann-Pick disease)、ファブリー病(Fabry' s disease)、ゴーシェ病(Gaucher disease)、ハンター症候群(Hunter syndrome)、及びマロトー・ラミー症候群(Maroteaux-Lamy syndrome)からなる群から選択されることを特徴とする。
一つの具体例による酵素融合タンパク質を製造する方法であって、上記形質転換体を培養して培養物を得る段階、及び前記培養物から酵素融合タンパク質を回収する段階を含むことを特徴とする。
アスパラギンN アスパラギン酸D
システインC グルタミン酸E
グルタミンQ グリシンG
ヒスチジンH イソロイシンI
メチオニンM フェニルアラニンF
プロリンP セリンS
スレオニンT トリプトファンW
チロシンY バリンV
L及びL’はリンカーであって、それぞれ独立して同一または異なる種類のリンカーであり;
Fは、免疫グロブリンFc領域であり;
|は、共有結合であり;
:は、共有または非共有結合である。
本発明者らは、逆平行(anti-parallel)二量体の治療学的酵素を含む酵素融合タンパク質を生産するために、天然型α-ガラクトシダーゼ(alpha-galactosidase)とリンカー(配列番号10)、Fc免疫グロブリン領域(配列番号7)を遺伝子レベルで融合して発現ベクターに合成した。
《実施例2-1:α-ガラクトシダーゼ-Fc融合タンパク質の製造》
上記実施例で製造したα-ガラクトシダーゼ-Fc発現ベクター(pX0GC-alpha galactosidase-Fc)をCHO-S細胞株に形質導入し、α-ガラクトシダーゼ-Fc融合タンパク質を大量生産し得る細胞株を作製した。
α-ガラクトシダーゼ-Fcのin vitro酵素活性を確認するために、前記生産されたα-ガラクトシダーゼ-Fc融合タンパク質を酵素基質として知られているpNP-Gal(p-nitrophenyl-aD-galactopyranoside)と37℃で30分間の温度平衡をなすようにした。その後、基質溶液とα-ガラクトシダーゼ-Fcを37℃で30分間反応させ、その吸光度を測定することにより、α-ガラクトシダーゼ-Fcのin vitro酵素活性を測定した。
一方、前記実施例で製造されたα-ガラクトシダーゼ-Fc融合タンパク質をFc領域が結合していないアガルシダーゼβ(Agalsidase beta)とin vitro酵素活性を比較しようとした。
α-ガラクトシダーゼは、マンノース-6-リン酸受容体(M6PR, mannose-6-phosphate receptor)を通じて細胞に吸収された後、作用することが知られている。そこで、本発明者らはα-ガラクトシダーゼ-Fcの融合タンパク質が示す細胞吸収活性を次のように確認した。
各群別に採血時点当り3匹のICRマウス(mouse)にアガルシダーゼβ(対照群)と、上記実施例で製造したα-ガラクトシダーゼ-Fc融合タンパク質(試験群)の血液内安定性及び薬物動態係数を比較した。
本発明のまた別の態様は、以下のとおりであってもよい。
〔1〕下記化学式(1)で示される、酵素融合タンパク質:
・・・・(1)
ここで、X及びX’は治療学的酵素であって、それぞれ独立して同一または異なる種類の酵素であり、
L及びL’はリンカーであって、それぞれ独立して同一または異なる種類のリンカーであり;
Fは、免疫グロブリンFc領域であり;
|は、共有結合であり;
:は、共有または非共有結合である。
〔2〕前記治療学的酵素は、非共有結合を通じて二量体を形成するものである、前記〔1〕に記載の酵素融合タンパク質。
〔3〕前記治療学的酵素は、互いに逆平行(anti-parallel)で二量体を形成したものである、前記〔1〕に記載の酵素融合タンパク質。
〔4〕前記酵素融合タンパク質は、Fc領域が融合されていない治療学的酵素に比べて安定性が増加し、リソソーム受容体に対する結合力が減少したものである、前記〔1〕に記載の酵素融合タンパク質。
〔5〕前記酵素は、β-グルコシダーゼ(beta-glucosidase)、α-ガラクトシダーゼ(alpha-galactosidase)、β-ガラクトシダーゼ(beta-galactosidase)、イズロニダーゼ(iduronidase)、イズロン酸-2-スルファターゼ(iduronate-2-sulfatase)、ガラクトース-6-スルファターゼ(Galactose-6-sulfatase)、酸性αグルコシダーゼ(acid alpha-glucosidase)、酸性セラミダーゼ(acid ceramidase)、酸性スフィンゴミエリナーゼ(acid sphingomyelinsase)、ガラクトセレブロシダーゼ(galactocerebrosidsase)、アリルスルファターゼ(arylsulfatase)A,B、β-ヘキソサミニダーゼ(beta-hexosaminidase)A,B、ヘパリン-N-スルファターゼ(heparin N-sulfatase)、α-D-マンノシダーゼ(alpha-D-mannosidase)、β-グルクロニダーゼ(beta-glucuronidase)、N-アセチルガラクトサミン-6-スルファターゼ(N-acetylgalactosamine-6-sulfatase)、リソソーム酸性リパーゼ(lysosomal acid lipase)、α-N-アセチルグルコサミニダーゼ(alpha-N-acetyl-glucosaminidase)、グルコセレブロシダーゼ(glucocerebrosidase)、ブチリルコリンエステラーゼ(butyrylcholinesterase)、キチナーゼ(Chitinase)、グルタミン酸デカルボキシラーゼ(glutamate decarboxylase)、イミグルセラーゼ(imiglucerase)、リパーゼ(lipase)、ウリカーゼ(Uricase)、血小板活性因子アセチルヒドロラーゼ(Platelet-Activating Factor Acetylhydrolase)、中性エンドペプチダーゼ(neutral endopeptidase)、ミエロペルオキシダーゼ(myeloperoxidase)からなる群から選択される、前記〔1〕に記載の酵素融合タンパク質。
〔6〕前記酵素は、α-ガラクトシダーゼ(alpha-galactosidase)Aまたはβ-ガラクトシダーゼ(beta-galactosidase)である、前記〔5〕に記載の酵素融合タンパク質。
〔7〕前記免疫グロブリンFc領域は、天然型免疫グロブリンFc領域において少なくとも1つ以上のアミノ酸に置換(substitution)、追加(addition)、除去(deletion)、修飾(modification)、及びこれらの組み合わせからなる群から選択された変形が起きたものである、前記〔1〕に記載の酵素融合タンパク質。
〔8〕前記免疫グロブリンFc領域は、配列番号8のアミノ酸配列を有する免疫グロブリンFc領域の2番目のアミノ酸がプロリンで置換されたり;71番目のアミノ酸がグルタミンで置換されたり;または2番目のアミノ酸はプロリンで、71番目のアミノ酸はグルタミンで置換されたものである、前記〔7〕に記載の酵素融合タンパク質。
〔9〕前記免疫グロブリンFc領域は、鎖交換が起こらないものである、前記〔8〕に記載の酵素融合タンパク質。
〔10〕前記免疫グロブリンFc領域は、(a)CH1ドメイン、CH2ドメイン、CH3ドメイン及びCH4ドメイン;(b)CH1ドメイン及びCH2ドメイン;(c)CH1ドメイン及びCH3ドメイン;(d)CH2ドメイン及びCH3ドメイン;及び(e)CH1ドメイン、CH2ドメイン、CH3ドメイン及びCH4ドメイン中の1つまたは2つ以上のドメインと免疫グロブリンヒンジ領域またはヒンジ領域の一部との組み合わせで構成された群から選択されるものである、前記〔1〕に記載の酵素融合タンパク質。
〔11〕前記免疫グロブリンFc領域は、単量体(monomer)の形態である、前記〔1〕に記載の酵素融合タンパク質。
〔12〕前記免疫グロブリンFc領域は、ヒンジ領域、CH2ドメイン及びCH3ドメインからなるものである、前記〔1〕に記載の酵素融合タンパク質。
〔13〕前記免疫グロブリンFc領域は、ジスルフィド結合を形成することができる部位が除去されたり、天然型FcからN末端の一部のアミノ酸が除去されたり、天然型FcのN末端にメチオニン残基が付加されたり、補体結合部位が除去されたり、またはADCC(antibody dependent cell mediated cytotoxicity)部位が除去されたものである、前記〔1〕に記載の酵素融合タンパク質。
〔14〕前記免疫グロブリンFc領域は、非糖鎖化されたものである、前記〔1〕に記載の酵素融合タンパク質。
〔15〕前記免疫グロブリンFc領域は、IgG、IgA、IgD、IgE、またはIgMに由来した免疫グロブリンFc断片である、前記〔1〕に記載の酵素融合タンパク質。
〔16〕前記免疫グロブリンFc領域は、IgG、IgA、IgD、IgE、IgMからなる群から選択される免疫グロブリンに由来する異なる起源を有するドメインのハイブリッドである、前記〔1〕に記載の酵素融合タンパク質。
〔17〕前記免疫グロブリンFc領域は、IgG4 Fc領域である、前記〔16〕に記載の酵素融合タンパク質。
〔18〕前記免疫グロブリンIgG4 Fc領域のヒンジ領域がIgG1ヒンジ領域で置換された、前記〔17〕に記載の酵素融合タンパク質。
〔19〕前記酵素融合タンパク質は、配列番号6からなるアミノ酸配列を含むものである、前記〔1〕に記載の酵素融合タンパク質。
〔20〕前記〔1〕~〔19〕のいずれか一項に記載の酵素融合タンパク質を含むリソソーム蓄積症(lysosomal storage disorder, LSD)の予防または治療用薬学的組成物。
〔21〕前記リソソーム蓄積症は、ムコ多糖症(mucopolysaccharidosis, MPS)、グリコーゲン蓄積病(Glycogen storage disease)、スフィンゴリピドーシス(sphingolipidosis)、ニーマン・ピック病(Niemann-Pick disease)、ファブリー病(Fabry' s disease)、ゴーシェ病(Gaucher disease)、ハンター症候群(Hunter syndrome)、及びマロトー・ラミー症候群(Maroteaux-Lamy syndrome)からなる群から選択されるものである、前記〔20〕に記載のリソソーム蓄積症の予防または治療用薬学的組成物。
〔22〕前記組成物は、酵素のリソソーム受容体に対する結合力を減少させるものである、前記〔19〕に記載のリソソーム蓄積症の予防または治療用薬学的組成物。
〔23〕前記〔1〕~〔19〕のいずれか一項に記載の酵素融合タンパク質をコードするポリヌクレオチド。
〔24〕前記〔21〕に記載のポリヌクレオチドを含む発現ベクター。
〔25〕前記〔22〕に記載の発現ベクターが導入された形質転換体。
〔26〕(a)前記〔25〕に記載の形質転換体を培養して培養物を得る段階;及び
(b)前記培養物から酵素融合タンパク質を回収する段階を含む、酵素融合タンパク質を製造する方法。
Claims (21)
- 前記治療学的酵素は、非共有結合を通じて二量体を形成するものである、請求項1に記載の酵素融合タンパク質。
- 前記治療学的酵素は、互いに逆平行(anti-parallel)で二量体を形成したものである、請求項1に記載の酵素融合タンパク質。
- 前記酵素融合タンパク質は、免疫グロブリンFc領域が融合されていない治療学的酵素に比べて安定性が増加し、リソソーム受容体に対する結合力が減少したものである、請求項1に記載の酵素融合タンパク質。
- 前記酵素は、β-グルコシダーゼ(beta-glucosidase)、α-ガラクトシダーゼ(alpha-galactosidase)、β-ガラクトシダーゼ(beta-galactosidase)、イズロニダーゼ(iduronidase)、イズロン酸-2-スルファターゼ(iduronate-2-sulfatase)、ガラクトース-6-スルファターゼ(Galactose-6-sulfatase)、酸性αグルコシダーゼ(acid alpha-glucosidase)、酸性セラミダーゼ(acid ceramidase)、酸性スフィンゴミエリナーゼ(acid sphingomyelinsase)、ガラクトセレブロシダーゼ(galactocerebrosidsase)、アリールスルファターゼ(arylsulfatase)A,B、β-ヘキソサミニダーゼ(beta-hexosaminidase)A,B、ヘパリン-N-スルファターゼ(heparin N-sulfatase)、α-D-マンノシダーゼ(alpha-D-mannosidase)、β-グルクロニダーゼ(beta-glucuronidase)、N-アセチルガラクトサミン-6-スルファターゼ(N-acetylgalactosamine-6-sulfatase)、リソソーム酸性リパーゼ(lysosomal acid lipase)、α-N-アセチルグルコサミニダーゼ(alpha-N-acetyl-glucosaminidase)、グルコセレブロシダーゼ(glucocerebrosidase)、ブチリルコリンエステラーゼ(butyrylcholinesterase)、キチナーゼ(Chitinase)、グルタミン酸デカルボキシラーゼ(glutamate decarboxylase)、イミグルセラーゼ(imiglucerase)、リパーゼ(lipase)、ウリカーゼ(Uricase)、血小板活性因子アセチルヒドロラーゼ(Platelet-Activating Factor Acetylhydrolase)、中性エンドペプチダーゼ(neutral endopeptidase)、ミエロペルオキシダーゼ(myeloperoxidase)からなる群から選択される、請求項1に記載の酵素融合タンパク質。
- 前記酵素は、α-ガラクトシダーゼ(alpha-galactosidase)Aまたはβ-ガラクトシダーゼ(beta-galactosidase)である、請求項5に記載の酵素融合タンパク質。
- 前記免疫グロブリンFc領域は、天然型免疫グロブリンFc領域において少なくとも1つ以上のアミノ酸に置換(substitution)、追加(addition)、除去(deletion)、修飾(modification)、及びこれらの組み合わせからなる群から選択された変形がさらに起きたものである、請求項1に記載の酵素融合タンパク質。
- 前記免疫グロブリンFc領域は、鎖交換が起こらないものである、請求項1に記載の酵素融合タンパク質。
- 前記免疫グロブリンFc領域は、(b)CH1ドメイン及びCH2ドメイン;(c)CH1ドメイン及びCH3ドメイン;(d)CH2ドメイン及びCH3ドメイン;及び(e)CH1ドメイン、CH2ドメイン及びCH3ドメイン中の1つまたは2つ以上のドメインと免疫グロブリンヒンジ領域またはヒンジ領域の一部との組み合わせで構成された群から選択されるものである、請求項1に記載の酵素融合タンパク質。
- 前記免疫グロブリンFc領域は、単量体(monomer)の形態である、請求項1に記載の酵素融合タンパク質。
- 前記免疫グロブリンFc領域は、ヒンジ領域、CH2ドメイン及びCH3ドメインからなるものである、請求項1に記載の酵素融合タンパク質。
- 前記免疫グロブリンFc領域は、(a)ジスルフィド結合を形成することができる部位が除去されたり、(b)天然型FcからN末端の一部のアミノ酸が除去されたり、(c)天然型FcのN末端にメチオニン残基が付加されたり、(d)補体結合部位が除去されたり、または(e)ADCC(antibody dependent cell mediated cytotoxicity)部位が除去されたものである、請求項1に記載の酵素融合タンパク質。
- 前記免疫グロブリンFc領域は、非糖鎖化されたものである、請求項1に記載の酵素融合タンパク質。
- 前記酵素融合タンパク質は、配列番号6からなるアミノ酸配列を含むものである、請求項1に記載の酵素融合タンパク質。
- 請求項1~14のいずれか一項に記載の酵素融合タンパク質を含むリソソーム蓄積症(lysosomal storage disorder, LSD)の予防または治療用薬学的組成物。
- 前記リソソーム蓄積症は、ムコ多糖症(mucopolysaccharidosis, MPS)、グリコーゲン蓄積病(Glycogen storage disease)、スフィンゴリピドーシス(sphingolipidosis)、ニーマン・ピック病(Niemann-Pick disease)、ファブリー病(Fabry' s disease)、ゴーシェ病(Gaucher disease)、ハンター症候群(Hunter syndrome)、及びマロトー・ラミー症候群(Maroteaux-Lamy syndrome)からなる群から選択されるものである、請求項15に記載のリソソーム蓄積症の予防または治療用薬学的組成物。
- 前記組成物は、酵素のリソソーム受容体に対する結合力を減少させるものである、請求項15に記載のリソソーム蓄積症の予防または治療用薬学的組成物。
- 請求項1~14のいずれか一項に記載の酵素融合タンパク質をコードするポリヌクレオチド。
- 請求項18に記載のポリヌクレオチドを含む発現ベクター。
- 請求項19に記載の発現ベクターが導入された形質転換体。
- (a)請求項20に記載の形質転換体を培養して培養物を得る段階;及び
(b)前記培養物から酵素融合タンパク質を回収する段階を含む、酵素融合タンパク質を製造する方法。
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JP7403455B2 (ja) * | 2017-12-22 | 2023-12-22 | ハンミ ファーマシューティカル カンパニー リミテッド | 新規な構造を有する治療学的酵素融合タンパク質及びその用途 |
KR20220044560A (ko) * | 2019-08-07 | 2022-04-08 | 아미쿠스 세라퓨틱스, 인코포레이티드 | Gla 유전자에 돌연변이를 갖는 환자에서 파브리 질병을 치료하는 방법 |
CN116916947A (zh) | 2020-10-14 | 2023-10-20 | 戴纳立制药公司 | 包含磺基葡糖胺磺基水解酶的融合蛋白和其方法 |
CN116419760A (zh) * | 2020-11-13 | 2023-07-11 | 韩美药品株式会社 | 治疗酶融合蛋白在预防和治疗由法布里病引起或伴有法布里病的肾病中的用途 |
MX2023005579A (es) * | 2020-11-13 | 2023-05-29 | Hanmi Pharmaceutical Co Ltd | Uso de una proteina de fusion enzimatica terapeutica en la prevencion y el tratamiento de la neuropatia provocada por o acompa?ada de la enfermedad de fabry. |
KR20230134823A (ko) * | 2022-03-15 | 2023-09-22 | 주식회사 녹십자 | α-갈락토시다제 A의 융합단백질을 포함하는 동결 건조 제제 |
KR20230134822A (ko) * | 2022-03-15 | 2023-09-22 | 주식회사 녹십자 | α-갈락토시다제 A의 융합단백질을 포함하는 액상 제제 |
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JP2021507705A (ja) | 2021-02-25 |
CN111511910B (zh) | 2024-11-08 |
IL275248A (en) | 2020-07-30 |
US20210009984A1 (en) | 2021-01-14 |
PH12020550927A1 (en) | 2021-05-10 |
KR102712547B1 (ko) | 2024-10-04 |
NZ765453A (en) | 2024-03-22 |
AR113430A1 (es) | 2020-04-29 |
KR102588611B1 (ko) | 2023-10-16 |
TW201934753A (zh) | 2019-09-01 |
BR112020012346A2 (pt) | 2020-11-24 |
KR20230143985A (ko) | 2023-10-13 |
EA202091239A1 (ru) | 2020-09-09 |
EP3708661A1 (en) | 2020-09-16 |
AU2018388331A1 (en) | 2020-07-02 |
CA3086474A1 (en) | 2019-06-27 |
EP3708661A4 (en) | 2021-12-01 |
SG11202005510SA (en) | 2020-07-29 |
WO2019125059A1 (ko) | 2019-06-27 |
KR20190076909A (ko) | 2019-07-02 |
CN111511910A (zh) | 2020-08-07 |
MX2020006635A (es) | 2020-12-10 |
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