SI2714752T1 - Postopki za spajanje tarčnih peptidov za rekombinantne lizosomalne encime za izboljšana zdravljenja bolezni lizosomskega shranjevanja - Google Patents
Postopki za spajanje tarčnih peptidov za rekombinantne lizosomalne encime za izboljšana zdravljenja bolezni lizosomskega shranjevanja Download PDFInfo
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- SI2714752T1 SI2714752T1 SI201231229T SI201231229T SI2714752T1 SI 2714752 T1 SI2714752 T1 SI 2714752T1 SI 201231229 T SI201231229 T SI 201231229T SI 201231229 T SI201231229 T SI 201231229T SI 2714752 T1 SI2714752 T1 SI 2714752T1
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- Slovenia
- Prior art keywords
- recombinant human
- lysosomal enzyme
- modified
- human lysosomal
- crosslinking agent
- Prior art date
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- 102000004190 Enzymes Human genes 0.000 title claims abstract 30
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- 230000002132 lysosomal effect Effects 0.000 title claims abstract 30
- 238000000034 method Methods 0.000 title claims abstract 13
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- FPKVOQKZMBDBKP-UHFFFAOYSA-N 1-[4-[(2,5-dioxopyrrol-1-yl)methyl]cyclohexanecarbonyl]oxy-2,5-dioxopyrrolidine-3-sulfonic acid Chemical compound O=C1C(S(=O)(=O)O)CC(=O)N1OC(=O)C1CCC(CN2C(C=CC2=O)=O)CC1 FPKVOQKZMBDBKP-UHFFFAOYSA-N 0.000 claims 2
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- 125000000637 arginyl group Chemical class N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims 2
- 125000002534 ethynyl group Chemical group [H]C#C* 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
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- GVJXGCIPWAVXJP-UHFFFAOYSA-N 2,5-dioxo-1-oxoniopyrrolidine-3-sulfonate Chemical compound ON1C(=O)CC(S(O)(=O)=O)C1=O GVJXGCIPWAVXJP-UHFFFAOYSA-N 0.000 claims 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims 1
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- Enzymes And Modification Thereof (AREA)
Claims (9)
- Postopki za spajanje tarčnih peptidov na rekombinantne lizosomalne encime za izboljšana zdravljenja bolezni lizosomskega shranjevanja1. Postopek izdelave tarčnega peptida, konjugiranega na lizosomalni encim, kjer postopek obsega: (a) i. modificiran) e amino (N)-terminusa in enega ali več ostankov lizina na rekombinantnem humanem lizosomalnem encimu z uporabo prvega premreževalnega sredstva, da dobimo humani lizosomalni encim modificiran s prvim premreževalnim sredstvom; ii. modificiranje prve amino kisline s kratkim podaljsevalnim linkerjem na (N)-terminus na varianti peptida IGF-2 z uporabo drugega premreževalnega sredstva, da dobimo varianto peptida IGF-2 modificirano z drugim premreževalnim sredstvom; in iii. konjugiranje rekombinantnega humanega lizosomalnega encima modificiranega s prvim premreževalnim sredstvom na varianto peptida IGF-2, ki vsebuje kratek podalj sevalni linker, modificirano z drugim premreževalnim sredstvom; ali (b) konjugiranje heterobifunkcionalnega premreževalnega sredstva na varianto peptida IGF-2 in konjugiranje variante peptida IGF-2 modificirane s heterobifunkcionalnim premreževalnim sredstvom na rekombinantni humani lizosomalni encim z reakcijo z N-terminus in enim ali več ostankom lizina na rekombinantni humani lizosomalni encim; ali (c) konjugiranje heterobifunkcionalnega premreževalnega sredstva na rekombinantni humani lizosomalni encim z reakcijo z N-terminus in enim ali več ostankom lizina na rekombinantni humani lizosomalni encim; in konjugiranje rekombinantnega humanega lizosomalnega encima modificiranega s heterobifunkcionalnim premreževalnim sredstvom na varianto peptida IGF-2; kjer je rekombinantni humani lizosomalni encim izbran izmed rekombinantne humane α-glukozidaze (rhGAA), rekombinantne humane α-galaktozidaze A (GLA), rekombinantne humane kisle β-glukuronidaze (GUS), rekombinantne humane α-iduronidaze A (IduA), rekombinantne humane izuronidat 2-sulfataze (I2S), rekombinanme humane β-heksozaminidaze A (HexA), rekombinantne humane β-heksozaminidaze B (HexB), rekombinantne humane α-manozidaze A, rekombinantne humane β-glukocerebrozidaze (GlcCerase), rekombinantne humane kisle lipaze (LPA) ali katerekoli njihove kombinacije; in kjer je prvo premreževalno sredstvo izbrano iz skupine, ki vsebuje N-sukcinimidil 6-hidrazinonikotinat aceton (S-Hynic), sulfo-sukcinimidil 6-hidrazonikotinat aceton (sulfo-S-HyNic), C6-sukcinimidil 6-hidrazino-nikotinamid (C6-S-Hynic), sukcinimidil 4-hidrazidotereftalat hidroklorid (SHTH) sukcinimidil 4- hidrazinijev nikotinat hidroklorid (SHNH) ali N-hidroksisukcinimid ester-(PEG)„-hidrazid, kjer je n od 3 do 24 enot PEG; in je drugo premreževalno sredstvo izbrano iz skupine, ki vsebuje PEG4-pentafluorobenzen-4-formilbenzoat (PEG4-PFB), sukcinimidil 4-formilbenzoat (SFB) in C6-sukcinimidil 4-formilbenzoat (C6-SFB); ali je prvo premreževalno sredstvo izbrano iz skupine, ki vsebuje N-hidroksisukcinimid ester fosfin (NHS-fosfin), sulfo-N-hidroksisukcinimid ester-fosfin (sulfo-NHS-fosfin), N- hidroksisukcinimid ester-tetraoksapentadekan acetilen (NHS-PEG4-acetilen) ali N- hidroksisukcinimid ester-(PEG)n acetilen, kjer je n od 3 do 24 enot PEG, cepljive heterobifunkcionalne premreževalce, kot je NHS-PEG3-S-S-acetilen ali heterobifunkcionalne premreževalce, ki vsebujejo ciklooktine kot je difluorociklooktin (DIFO) in dibenzociklooktin (DIBO); in je drugo premreževalno sredstvo izbrano iz skupine, ki vsebuje N-hidroksi sukcinimid ester-PEG4-azid (HS-PEG4-azid), N-hidroksisukcinimind ester azid (NHS-azid), N-hidroksisukcinimid ester-(PEG)„ azid, kjer je n od 3 do 24 enot PEG ali NHS-PEG3-S-S-azid; ali je heterobifunkcionalni premreževalec izbran iz skupine, ki vsebuje m-maleimidobenziol-N-hidroksisukcinimid ester (MBS), sulfo-m-maleimidobenziol-N-hidroksisukcinimid ester (sulfo-MBS) in sulfosukcinimidil-4-(N-maleimidometil)cikloheksan-l-karboksilat (SMCC); in kjer varianta peptida IGF-2 vsebuje eno ali več izmed naslednjih modifikacij, glede na naravno zaporedje humane IGF-2: substitucijo arginina z glutaminsko kislini na položaju 6; izbris amino kislin 1-4 in 6; izbris amino kislin 1-4, 6 in 7; izbris amino kislin 1-4 in 6 in substitucijo lizina s treoninom na položaju 7; izbris amino kislin 1-4 in substitucijo glicina z glutaminsko kislini na položaju 6 in substitucijo lizina s treoninom na položaju 7; substitucijo levcina s tirozinom na položaju 27; substitucijo levcina z valinom na položaju 43; substitucijo arginin z lizinom na položaju 65; in/ali ima varianta peptida IGF-2 afinitetno oznako in/ali področje podaljSevalnega linkeija z vsaj 5 amino kislinami pred IGF-2.
- 2. Postopek po zahtevku 1, kjer variant peptida IGF2 vsebuje zaporedje amino kislin SEQ ID NO: 2
- 3. Postopek po zahtevku 1 ali 2, kjer kratki podaljševalni linker vsebuje od 5 do 20 amino kislinskih ostankov.
- 4. Postopek po zahtevku 1 ali zahtevku 2, kjer podaljševalni linker vsebuje zaporedje SEQ ID NO: 3.
- 5. Postopek po kateremkoli zahtevku od 1 do 4, kjer sta dva ostanka lizina modificirana na rekombinantne humane lizosomalnem encimu.
- 6. Postopek po kateremkoli zahtevku od 1 do 5, kjer je rekombinantni humani lizosomalni encim izdelan z uporabo kvasa, celic insektov, celic rastlin, gliv, transgenih živali in translacij skih sistemov in vitro.
- 7. Konjugat, ki vsebuje eno ali več variant peptidov IGF-2 peptides, kemično konjugiranih na rekombinantni humani lizosomalni encim, kjer konjugat lahko pridobimo po postopku po kateremkoli zahtevku od 1 do 5 in obsega: humani lizosomalni encim modificiran na amino (N)-terminusu in enega ali več ostankov lizina, s konjugiranjem na linker; in varianto peptida IGF-2, ki vsebuje kratki podaljševalni linker na amino terminusu; kjer je prva amino kislina kratkega podaljsevalnega linkerja konjugirana na linker; kjer je rekombinantni humani lizosomalni encim kot je opisan v zahtevku 1; kjer je varianta peptida IGF-2, kot je opisana v zahtevku 1 kjer je linker produkt reakcij prvega in drugega premreževalnega sredstva, kot je opisano v zahtevku 1 ali heterobifunkcionalnega premreževalca, kot je opisano v zahtevku 1.
- 8. Konjugat po zahtevku 7, za uporabo v zdravljenju bolezni lizosomskega shranjevanja izbrane iz skupine, ki vsebuje Pompejevo bolezen, Fabryevo bolezen in Gaucherjevo bolezen, MPS I, MPS II, MPS VII, Tay Sachsovo bolezen, Sandhoffovo bolezen, α-manozidozo in Wohlmanovo bolezen, kjer: je modificirani rekombinantni humani lizosomalni encim kisla α-glukozidaza za zdravljenje Pompejeve bolezni; ali modificirani rekombinantni humani lizosomalni encim je kisla a-galaktozidaza A z zdravljenje Fabryeve bolezni; ali modificirani rekombinantni humani lizosomalni encim is kisla β-glukocerebrozidaza za zdravljenje Gaucherjeve bolezni; ali modificirani rekombinantni humani lizosomalni encim je kisla α-iduronidaza za zdravljenje mukopolisaharidoze I (MPS I); ali modificirani rekombinantni humani lizosomalni encim je kisla iduronidat 2-sulfataza (I2S) za zdravljenje mukopolisaharidoze II (MPS II); ali modificirani rekombinantni humani lizosomalni encim je kisla β-glukuronidaza za zdravljenje mukopolisaharidoze VII (MPS VII); ali modificirani rekombinantni humani lizosomalni encim je β-heksozaminidaza A za zdravljenje GM2 gangliozidoze (Tay-Sachs); ali modificirani rekombinantni humani lizosomalni encim β-heksozaminidaza B za zdravljenje GM2 gangliozidoze (Sandhoff); ali modificirani rekombinantni humani lizosomalni encim je kisla lipaza za zdravljenje Wohlmanove bolezni; ali modificirani rekombinantni humani lizosomalni encim je kisla α-manozidaza za zdravljenje a-manozidoze.
- 9. Farmacevtski sestavek, ki vsebuje konjugat po zahtevku 7 in farmacevtsko sprejemljiv nosilec.
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| KR102444555B1 (ko) * | 2014-04-04 | 2022-09-21 | 베스타론 코포레이션 | 인위적으로 활성화된 펩타이드 |
| EA201790178A1 (ru) * | 2014-08-11 | 2017-07-31 | Шир Хьюман Дженетик Терапис, Инк. | Пептиды, несущие маннозо-6-фосфат, слитые с лизосомальным ферментом |
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| WO2016145244A1 (en) * | 2015-03-11 | 2016-09-15 | Ocv Intellectual Capital, Llc | Methods and systems for filling mufflers with fibrous material |
| US11262348B2 (en) | 2015-11-06 | 2022-03-01 | Biomarin Pharmaceutical Inc. | Cell-based assays for detection of antibodies or other factors that neutralize uptake of lysosomal enzymes |
| DK3386534T3 (da) * | 2015-12-08 | 2020-11-30 | Regeneron Pharma | Sammensætninger og fremgangsmåder til internalisering af enzymer |
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| AU2018285412B2 (en) | 2017-06-14 | 2022-06-23 | Universität Zürich | Cyclic peptides for protection against respiratory syncytial virus |
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| US11492610B2 (en) | 2018-03-08 | 2022-11-08 | California Institute Of Technology | Sample multiplexing for single-cell RNA sequencing |
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| BR112021006829A2 (pt) | 2018-10-10 | 2021-07-20 | Amicus Therapeutics, Inc. | composições de polipeptídeos estabilizados com ligações dissulfeto e métodos de uso |
| CN113301925A (zh) | 2018-12-19 | 2021-08-24 | 小利兰·斯坦福大学理事会 | 用于溶酶体靶向的双官能分子以及相关的组合物和方法 |
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| 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 |
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| US20230355737A1 (en) | 2020-09-28 | 2023-11-09 | Dbv Technologies | Particle comprising an rsv-f protein for use in rsv vaccination |
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| CA2836318C (en) | 2018-11-27 |
| CN108586621A (zh) | 2018-09-28 |
| CA2836318A1 (en) | 2012-12-06 |
| TR201802230T4 (tr) | 2018-03-21 |
| EP2714752A2 (en) | 2014-04-09 |
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| WO2012166653A2 (en) | 2012-12-06 |
| JP2017225444A (ja) | 2017-12-28 |
| NO2820016T3 (sl) | 2017-12-30 |
| JP2014518063A (ja) | 2014-07-28 |
| RS56913B1 (sr) | 2018-05-31 |
| HUE038172T2 (hu) | 2018-09-28 |
| US20170319710A1 (en) | 2017-11-09 |
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