HRP20180291T1 - Postupci za sparivanje ciljajućeg peptida na rekombinantne lizosomalne enzime za poboljšano liječenje lizosomskih bolesti nakupljanja - Google Patents
Postupci za sparivanje ciljajućeg peptida na rekombinantne lizosomalne enzime za poboljšano liječenje lizosomskih bolesti nakupljanja Download PDFInfo
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- HRP20180291T1 HRP20180291T1 HRP20180291TT HRP20180291T HRP20180291T1 HR P20180291 T1 HRP20180291 T1 HR P20180291T1 HR P20180291T T HRP20180291T T HR P20180291TT HR P20180291 T HRP20180291 T HR P20180291T HR P20180291 T1 HRP20180291 T1 HR P20180291T1
- Authority
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- Croatia
- Prior art keywords
- recombinant human
- lysosomal enzyme
- human lysosomal
- modified
- peptide
- Prior art date
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- 102000004190 Enzymes Human genes 0.000 title claims 26
- 108090000790 Enzymes Proteins 0.000 title claims 26
- 230000002132 lysosomal effect Effects 0.000 title claims 26
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- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims 5
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- 101001045440 Homo sapiens Beta-hexosaminidase subunit alpha Proteins 0.000 claims 2
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- 201000004502 glycogen storage disease II Diseases 0.000 claims 2
- 125000001909 leucine group Chemical class [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 claims 2
- UYODNFCNVXOLKR-UHFFFAOYSA-N 1-(6-hydrazinylpyridine-3-carbonyl)oxy-2,5-dioxopyrrolidine-3-sulfonic acid;propan-2-one Chemical compound CC(C)=O.C1=NC(NN)=CC=C1C(=O)ON1C(=O)C(S(O)(=O)=O)CC1=O UYODNFCNVXOLKR-UHFFFAOYSA-N 0.000 claims 1
- RMBMWXHVTXYPQN-UHFFFAOYSA-N 1-[3-[(1-hydroxy-2,5-dioxopyrrolidin-3-yl)methyl]phenyl]pyrrole-2,5-dione Chemical group O=C1N(O)C(=O)CC1CC1=CC=CC(N2C(C=CC2=O)=O)=C1 RMBMWXHVTXYPQN-UHFFFAOYSA-N 0.000 claims 1
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- KXVZDWWIFXDBRJ-UHFFFAOYSA-N 3-[[3-(2,5-dioxopyrrol-1-yl)phenyl]methyl]-1-hydroxy-2,5-dioxopyrrolidine-3-sulfonic acid Chemical compound O=C1N(O)C(=O)CC1(S(O)(=O)=O)CC1=CC=CC(N2C(C=CC2=O)=O)=C1 KXVZDWWIFXDBRJ-UHFFFAOYSA-N 0.000 claims 1
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- 101710124976 Beta-hexosaminidase A Proteins 0.000 claims 1
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Classifications
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Claims (9)
1. Postupak za dobivanje ciljajućeg peptida konjugiranog na rekombinantni lizosomalni enzim, naznačen time da postupak sadrži:
(a)
i. modificiranje amino (N)-terminalnog kraja i jednog ili više lizinskih ostataka na rekombinantnom ljudskom lizosomalnom enzimu korištenjem prvog sredstva za umrežavanje što dovodi do rekombinantnog ljudskog lizosomalnog enzima modificiranog prvim sredstvom za umrežavanje;
ii. modificiranje prve aminokiseline od kratke proširujuće poveznice na amino (N)- terminalnom kraju na varijantu IGF-2 peptida korištenjem drugog sredstva za umrežavanje što dovodi do varijante IGF-2 peptida modificirane drugim sredstvom za umrežavanje; i
iii. konjugiranje prvog sredstva za umrežavanje-modificiranog rekombinantnog ljudskog lizosomalnog enzima na drugo sredstvo za umrežavanje-modificirane varijante IGF-2 peptida koja sadrži kratku proširujuću poveznicu; ili
(b) konjugiranje heterobifunkcionalnog sredstva za umrežavanje na varijantu IGF-2 peptida; i konjugiranje heterobifunkcionalnim sredstvom za umrežavanje modificirane varijante IGF-2 peptida na rekombinantni ljudski lizosomalni enzim pomoću reakcije s N-terminalnim krajem i jednog ili više lizinskih ostataka na rekombinantni ljudski lizosomalni enzim; ili
(c) konjugiranje heterobifunkcionalnog sredstva za umrežavanje na rekombinantni ljudski lizosomalni enzim pomoću reakcije s N-terminalnim krajem i jednog ili više lizinskih ostataka na rekombinantni ljudski lizosomalni enzim; i konjugiranje heterobifunkcionalnim sredstvom za umrežavanje modificiranog rekombinantnog ljudskog lizosomalnog enzima na varijantu IGF-2 peptida;
pri čemu je rekombinantni ljudski lizosomalni enzim odabran od rekombinantne ljudske α-glukozidaze (rhGAA), rekombinantne ljudske α-galaktozidaze A (GLA), rekombinantne ljudske kisele β-glukuronidaze (GUS), rekombinantne ljudske α-iduronidaze A (IduA), rekombinantne ljudske izuronidat 2-sulfataze (I2S), rekombinantne ljudske β-heksosaminidaze A (HeksA), rekombinantne ljudske β-heksosaminidaze B (HeksB), rekombinantne ljudske α-manozidaze A, rekombinantne ljudske β-glukocerebrozidaze (GlcCerase), rekombinantne ljudske kisele lipaze (LPA) ili bilo kojem njihove kombinacije; i
pri čemu je prvo sredstvo za umrežavanje odabrano od N- sukcinimidil 6-hidrazinonikotinat aceton (S-Hynic), sulfo-sukcinimidil 6-hidrazonikotinat aceton (sulfo-S-HyNic), C6-sukcinimidil 6-hidrazino-nicotinamid (C6-S-Hynic), sukcinimidil 4-hidrazidotereftalat hidroklorid (SHTH) sukcinimidil 4-hidrazinij nikotinat hidroklorid (SHNH) ili N-hidroksisukcinimid ester-(PEG)n-hidrazid, gdje n je 3-24 PEG jedinica; i drugo sredstvo za umrežavanje je odabrano od PEG4-pentafluorobenzen-4-formilbenzoata (PEG4-PFB), sukcinimidil 4-formilbenzoata (SFB) i C6-sukcinimidil 4-formilbenzoata (C6-SFB); ili
prvo sredstvo za umrežavanje je odabrano od N-hidroksisukcinimid ester fosfina (NHS-fosfin), sulfo-N-hidroksisukcinimid ester-fosfina (sulfo-NHS-fosfin), N- hidroksisukcinimid ester-tetraoksapentadekan acetilen (NHS-PEG4-acetilen) ili N- hidroksisukcinimid ester-(PEG)n acetilen, pri čemu n je 3-24 PEG jedinica, heterobifunkcionalna sredstva za umrežavanje koja se mogu cijepati kao što je NHS-PEG3-S-S-acetilen ili heterobifunkcionalna sredstva za umrežavanje koja sadrže ciklooktine kao što je difluorociklooktin (DIFO) i dibenzociklooktin (DIBO); i drugo sredstvo za umrežavanje je odabrano od N-hidroksisukcinimid ester-PEG4-azid (HS-PEG4-azid), N-hidroksisukcinimid ester azid (NHS-azid), N-hidroksisukcinimid ester-(PEG)n azid, pri čemu n je 3-24 PEG jedinica, ili NHS-PEG3-S-S-azid; ili
heterobifunkcionalno sredstvo za umrežavanje je odabrano od m-maleimidobenziol-N-hidroksisukcinimid ester (MBS), sulfo-m-maleimidobenziol-N-hidroksisukcinimid ester (sulfo-MBS) i sulfosukcinimidil-4-(N-maleimidometil)cikloheksan-1-karboksilat (SMCC); i
pri čemu varijanta IGF-2 peptida sadrži jednu ili više od sljedećih modifikacija u odnosu na prirodnu ljudsku IGF-2 sekvencu:
supstituciju arginina s glutaminskom kiselinom na položaju 6;
brisanje aminokiselina 1-4 i 6;
brisanje aminokiselina 1-4, 6 i 7;
brisanje aminokiselina 1-4 i 6 i supstituciju lizina s treoninom na položaju 7;
brisanje aminokiselina 1-4 i supstituciju glicina s glutaminskom kiselinom na položaju 6 i
supstituciju lizina s treoninom na položaju 7;
supstituciju leucina s tirozinom na položaju 27;
supstituciju leucina s valinom na položaju 43;
supstituciju arginina s lizinom na položaju 65;
i/ili varijanta IGF-2 peptida sadrži afinitetnu oznaku i/ili proširujuću regiju poveznice od barem 5 aminokiselina koje prethode IGF-2.
2. Postupak prema zahtjevu 1 naznačen time da varijanta IGF2 peptida sadrži aminokiselinsku sekvencu od SEQ ID NO: 2
3. Postupak prema zahtjevu 1 ili 2 naznačen time da kratka proširujuća poveznica sadrži 5 do 20 ostataka aminokiselina.
4. Postupak prema zahtjevu 1 ili zahtjevu 2, naznačen time da proširujuća poveznica sadrži SEQ ID NO: 3.
5. Postupak prema bilo kojem od zahtjeva 1-4 naznačen time da su dva lizinska ostatka modificirana na rekombinantnom ljudskom lizosomalnom enzimu.
6. Postupak prema bilo kojem od zahtjeva 1 do 5 naznačen time da je rekombinantni ljudski lizosomalni enzim dobiven pomoću kvasca, stanica kukaca, biljnih stanica, gljivica, transgenih životinja i in vitro translacijskih sustava.
7. Konjugat, koji sadrži jednu ili više varijanti IGF-2 peptida kemijski konjugiranih na rekombinantni ljudski lizosomalni enzim, naznačen time da se konjugat može dobiti postupkom prema bilo kojem od zahtjeva 1 do 5 i sadrži:
ljudski lizosomalni enzim modificiran na amino (N)-terminalnom kraju i jedan ili više lizinskih ostataka konjugacijom na poveznicu; i
varijantu IGF-2 peptida koja sadrži kratku proširujuću poveznicu na amino terminalnom kraju; pri čemu je prva aminokiselina kratke proširujuće poveznice konjugirana na poveznicu;
pri čemu je rekombinantni ljudski lizosomalni enzim kako je definirano u zahtjevu 1;
pri čemu je varijanta IGF-2 peptida kako je definirano u zahtjevu 1
pri čemu poveznica je proizvod reakcija prvog i drugog sredstva za umrežavanje kako je definirano u zahtjevu 1 ili sredstva za umrežavanje kako je definirano u zahtjevu 1.
8. Konjugat prema zahtjevu 7 naznačen time da je za uporabu za liječenje lizosomske bolesti nakupljanja koja je odabrana od Pompeove bolesti, Fabryjeve bolesti, i Gaucherove bolesti, MPS I, MPS II, MPS VII, Tay Sachs, Sandhoff, α-manozidoze, i Wohlmanove bolesti, pri čemu:
modificirani rekombinantni ljudski lizosomalni enzim je kisela α-glukozidaza za liječenje Pompeove bolesti; ili
modificirani rekombinantni ljudski lizosomalni enzim je kisela α-galaktozidaza A za liječenje Fabryeve bolesti; ili
modificirani rekombinantni ljudski lizosomalni enzim je kisela β-glukocerebrozidaza za liječenje Gaucherove bolesti; ili
modificirani rekombinantni ljudski lizosomalni enzim je kisela α-iduronidaza za liječenje mukopolisaharidoze I (MPS I); ili
modificirani rekombinantni ljudski lizosomalni enzim je kisela iduronidat 2-sulfataza (I2S) za liječenje mukopolisaharidoze II (MPS II); ili
modificirani rekombinantni ljudski lizosomalni enzim je kisela β-glukuronidaze za liječenje mukopolisaharidoze VII (MPS VII); ili
modificirani rekombinantni ljudski lizosomalni enzim je β-heksosaminidaza A za liječenje GM2 gangliozidoze (Tay-Sachs); ili
modificirani rekombinantni ljudski lizosomalni enzim je β-heksosaminidaza B za liječenje GM2 gangliozidoze (Sandhoff); ili
modificirani rekombinantni ljudski lizosomalni enzim je kisela lipaza za liječenje Wohlmanove bolesti; ili
modificirani rekombinantni ljudski lizosomalni enzim je kisela α-manozidaza za liječenje α-manozidoze.
9. Farmaceutski pripravak naznačen time da sadrži konjugat prema zahtjevu 7 i farmaceutski prihvatljiv nosač.
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| CN106414485A (zh) * | 2014-04-04 | 2017-02-15 | 韦斯塔隆公司 | 人工活化的毒性肽 |
| WO2016025519A1 (en) * | 2014-08-11 | 2016-02-18 | Shire Human Genetic Therapies, Inc. | Mannose-6-phosphate bearing peptides fused to lysosomal enzymes |
| EA038986B1 (ru) * | 2014-09-30 | 2021-11-18 | Амикус Терапьютикс, Инк. | Высокоактивная кислая альфа-глюкозидаза с повышенным содержанием углеводов |
| CN104356238B (zh) * | 2014-10-15 | 2018-01-09 | 大连理工大学 | 一种重组蛋白a亲和配基的定点固定化方法 |
| JP6700298B2 (ja) * | 2015-03-11 | 2020-05-27 | オーシーヴィー インテレクチュアル キャピタル リミテッド ライアビリティ カンパニー | 繊維材料でマフラーを充填する方法及びシステム |
| JP2018538008A (ja) | 2015-11-06 | 2018-12-27 | バイオマリン ファーマシューティカル インコーポレイテッド | リソソーム酵素の取り込みを中和する抗体または他の因子の検出のための細胞ベースアッセイ |
| HUE052155T2 (hu) * | 2015-12-08 | 2021-04-28 | Regeneron Pharma | Enzimek internalizálására szolgáló készítmények és módszerek |
| AU2018281280A1 (en) | 2017-06-07 | 2020-01-16 | Regeneron Pharmaceuticals, Inc. | Compositions and methods for internalizing enzymes |
| KR20200018483A (ko) | 2017-06-14 | 2020-02-19 | 비로메틱스 아게 | 호흡기 합포체 바이러스에 대한 방어를 위한 고리형 펩티드 |
| JP2021500857A (ja) | 2017-10-02 | 2021-01-14 | デナリ セラピューティクス インコーポレイテッドＤｅｎａｌｉ Ｔｈｅｒａｐｅｕｔｉｃｓ Ｉｎｃ． | 酵素補充療法用酵素を含む融合タンパク質 |
| US11492610B2 (en) | 2018-03-08 | 2022-11-08 | California Institute Of Technology | Sample multiplexing for single-cell RNA sequencing |
| AU2019261982A1 (en) | 2018-04-30 | 2020-10-15 | Amicus Therapeutics, Inc. | Gene therapy constructs and methods of use |
| BR112021006829A2 (pt) | 2018-10-10 | 2021-07-20 | Amicus Therapeutics, Inc. | composições de polipeptídeos estabilizados com ligações dissulfeto e métodos de uso |
| US20220023434A1 (en) | 2018-12-19 | 2022-01-27 | The Board Of Trustees Of The Leland Stanford Junior University | Bifunctional Molecules for Lysosomal Targeting and Related Compositions and Methods |
| CN113260377A (zh) | 2018-12-20 | 2021-08-13 | 维罗米蒂克斯股份公司 | 脂肽构建块和合成病毒样颗粒 |
| AU2020266552A1 (en) * | 2019-04-30 | 2021-11-11 | Amicus Therapeutics, Inc. | Compositions useful for treatment of Pompe disease |
| CN110373405B (zh) * | 2019-07-24 | 2023-12-15 | 杭州恩和生物科技有限公司 | 一种接枝聚合物的生物酶及其制备方法和固定方法 |
| JP2022552254A (ja) * | 2019-10-10 | 2022-12-15 | アミカス セラピューティックス インコーポレイテッド | バリアントｉｇｆ２構築体 |
| US20230355737A1 (en) | 2020-09-28 | 2023-11-09 | Dbv Technologies | Particle comprising an rsv-f protein for use in rsv vaccination |
| US20240024507A1 (en) | 2020-12-01 | 2024-01-25 | The Trustees Of The University Of Pennsylvania | Novel compositions with tissue-specific targeting motifs and compositions containing same |
| MX2023012513A (es) | 2021-04-23 | 2023-12-15 | Univ Pennsylvania | Nuevas composiciones con motivos selectivos para el cerebro y composiciones que las contienen. |
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| US20030072761A1 (en) * | 2001-10-16 | 2003-04-17 | Lebowitz Jonathan | Methods and compositions for targeting proteins across the blood brain barrier |
| US7355018B2 (en) | 2003-09-30 | 2008-04-08 | Regeneron Pharmaceuticals, Inc. | Modified IGF1 polypeptides with increased stability and potency |
| ES2830350T3 (es) | 2008-05-07 | 2021-06-03 | Biomarin Pharm Inc | Péptidos de dirección lisosómica y usos de los mismos |
| CN102448494B (zh) * | 2009-02-13 | 2016-02-03 | 免疫医疗公司 | 具有胞内可裂解的键的免疫共轭物 |
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| KR101955054B1 (ko) | 2019-03-07 |
| WO2012166653A2 (en) | 2012-12-06 |
| WO2012166653A3 (en) | 2014-05-01 |
| RS56913B1 (sr) | 2018-05-31 |
| EP2714752A4 (en) | 2015-08-26 |
| CA2836318C (en) | 2018-11-27 |
| KR20140033155A (ko) | 2014-03-17 |
| NO2820016T3 (hr) | 2017-12-30 |
| BR112013030432A2 (pt) | 2016-12-13 |
| US9545450B2 (en) | 2017-01-17 |
| JP2014518063A (ja) | 2014-07-28 |
| US20140302001A1 (en) | 2014-10-09 |
| CA2836318A1 (en) | 2012-12-06 |
| PT2714752T (pt) | 2018-02-26 |
| US10660972B2 (en) | 2020-05-26 |
| CN108586621A (zh) | 2018-09-28 |
| CN104160033B (zh) | 2018-06-01 |
| TR201802230T4 (tr) | 2018-03-21 |
| US20170319710A1 (en) | 2017-11-09 |
| KR20190022943A (ko) | 2019-03-06 |
| CN104160033A (zh) | 2014-11-19 |
| PL2714752T3 (pl) | 2018-04-30 |
| ES2660185T3 (es) | 2018-03-21 |
| EP2714752A2 (en) | 2014-04-09 |
| HUE038172T2 (hu) | 2018-09-28 |
| LT2714752T (lt) | 2018-03-12 |
| CY1120485T1 (el) | 2019-07-10 |
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| SI2714752T1 (en) | 2018-03-30 |
| EP2714752B1 (en) | 2017-11-22 |
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