HRP20171644T1 - Polipeptidi hormona rasta kao i postupci za njihovu proizvodnju i uporabu - Google Patents

Polipeptidi hormona rasta kao i postupci za njihovu proizvodnju i uporabu Download PDF

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HRP20171644T1
HRP20171644T1 HRP20171644TT HRP20171644T HRP20171644T1 HR P20171644 T1 HRP20171644 T1 HR P20171644T1 HR P20171644T T HRP20171644T T HR P20171644TT HR P20171644 T HRP20171644 T HR P20171644T HR P20171644 T1 HRP20171644 T1 HR P20171644T1
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fusion protein
xten
amino acid
hgh
acid sequence
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HRP20171644TT
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Volker Schellenberger
Joshua Silverman
Willem P. Stemmer
Chia-Wei Wang
Nathan Geething
Jeffrey L. Cleland
Benjamin Spink
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Amunix Operating Inc.
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Priority claimed from PCT/US2010/023106 external-priority patent/WO2010091122A1/en
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Publication of HRP20171644T1 publication Critical patent/HRP20171644T1/hr

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    • C—CHEMISTRY; METALLURGY
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • C07K2319/00—Fusion polypeptide
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Claims (19)

1. Fuzijski protein koji obuhvaća sekvencu hormona rasta (GH) odabranu od ljudskog hormona rasta koji je prikazan u Tablici 1 i jedne njegove varijante sekvence koja je najmanje 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% ili 99% identična aminokiselinskoj sekvenci od ljudskog hormona rasta, kao što je prikazano u Tablici 1, pri čemu je navedeni GH povezan na produljeni rekombinantni polipeptid (XTEN) s najmanje 200 aminokiselinskih ostataka, pri čemu je XTEN naznačen time, da: (a) XTEN-sekvenca obuhvaća najmanje 200 međusobno dodirnih aminokiselina koje pokazuju najmanje 90% identiteta sekvence s usporednom duljinom aminokiselinske sekvence odabrane iz skupine koju čine AE912, AE288, AD576, AE576, AE624, AD836, AE864, AF864, AG864, AM875, AM923 i AM1318, kao što je prikazano u Tablici 3; (b) XTEN-sekvenci nedostaje predviđeni epitop T-stanice, pomoću analize putem TEPITOP-algoritma, dok se predviđanje TEPITOP-algoritmom za epitope unutar XTEN-sekvence, temelji na vrijednosti od -6 ili više; (c) on ima vrijednost podsekvence koja iznosi manje od 10; i (d) suma ostataka glicina (G), alanina (A), serina (S), treonina (T), glutamata (E) i prolina (P), sačinjava više od 90% ukupne količine aminokiselinskih ostataka od XTEN-a.
2. Fuzijski protein prema zahtjevu 1, naznačen time, da nadalje obuhvaća drugi XTEN, pri čemu drugi XTEN obuhvaća aminokiselinsku sekvencu koja pokazuje najmanje 90% identiteta sekvence od aminokiselinske sekvence odabrane iz skupine koju čine: (a) GTSESAATPESGPGTSTEPSEGSAPGTSTEPSEGSAP; (b) GTSTEPSEGSAPGSPAGSPTSTEEGTSTEPSEGSAP; (c) AE144 kao što je prikazano u Tablici 3; i (d) AE288 kao što je prikazano u Tablici 3, te pritom fuzijski protein preuzima konfiguraciju višestrukog XTEN, koja je prikazana u Tablici 5.
3. Fuzijski protein prema zahtjevu 1 ili zahtjevu 2, naznačen time, da se fuzijski protein veže na receptor/e hormona rasta sa smanjenim afinitetom vezanja u usporedbi s onim od odgovarajućeg GH kojemu nedostaje XTEN, pri čemu je afinitet vezanja opcijski smanjen za najmanje oko 10 puta.
4. Fuzijski protein prema zahtjevu 1, naznačen time, da obuhvaća aminokiselinsku sekvencu koja ima najmanje 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% ili 99% identiteta sekvence od aminokiselinske sekvence odabrane iz skupine koju čine AE912-hGH, AE288-hGH, AD576-hGH, AE576-hGH, AE624-hGH, AD836-hGH, AE864-hGH, AF864-hGH, AG864-hGH, AM875-hGH, AM923-hGH i AM1318-hGH, kao što je prikazano u Tablici 35, pri čemu fuzijski protein opcijski obuhvaća sljedeće: (i) aminokiselinsku sekvencu koja ima najmanje 90% identiteta sekvence od aminokiselinske sekvence odabrane od AE912-hGH-AE144 i AE912-hGH-AE288, koje su prikazane u Tablici 36; ili (ii) aminokiselinsku sekvencu odabranu od AE912-hGH-AE144 i AE912-hGH-AE288, koje su prikazane u Tablici 36; ili (iii) aminokiselinsku sekvencu koja ima najmanje 99% identiteta sekvence od aminokiselinske sekvence od AE912-hGH-AE144 koja je prikazana u Tablici 36.
5. Fuzijski protein prema zahtjevu 4, naznačen time, da obuhvaća aminokiselinsku sekvencu koja ima najmanje 90% identiteta od aminokiselinske sekvence od AE912-hGH-AE144 ili AE912-hGH-AE288, koje su prikazane u Tablici 36.
6. Fuzijski protein prema zahtjevu 5, naznačen time, da obuhvaća aminokiselinsku sekvencu koja ima najmanje 99% identiteta od aminokiselinske sekvence od AE912-hGH-AE144 ili AE912-hGH-AE288, koje su prikazane u Tablici 36.
7. Fuzijski protein, naznačen time, da obuhvaća aminokiselinsku sekvencu koja ima najmanje 90% identiteta od sekvence ljudskog hormona rasta koja je prikazana u Tablici 1, koja je povezana na sekvencu produljenog rekombinantnog polipeptida (XTEN-sekvencu), koja ima najmanje 90% identiteta sekvence od AE912, kao što je prikazano u Tablici 3.
8. Fuzijski protein prema zahtjevu 7, naznačen time, da obuhvaća drugi XTEN koji obuhvaća aminokiselinsku sekvencu koja ima najmanje 90% identiteta od aminokiselinske sekvence od: [image]
9. Fuzijski protein prema zahtjevu 1, naznačen time, da je konfiguriran u skladu s formulom I: (XTEN)x-GH-(XTEN)y (I) u kojoj za svako pojavljivanje, neovisno vrijedi: (a) x je ili 0 ili 1; i (b) y je ili 0 ili 1, kada su x+y ≥ 1.
10. Fuzijski protein prema bilo kojem od prethodnih zahtjeva, naznačen time, da on prilikom primjene na pojedincu, ima dulji terminalni poluživot nego odgovarajući GH kojemu nedostaje XTEN, kada se primjenjuje na pojedincu u usporedivoj molarnoj dozi.
11. Fuzijski protein prema bilo kojem od zahtjeva 1 do 9, naznačen time, da: (i) kada se primjenjuje jedna manja molarna količina fuzijskog proteina na pojedincu, nego od odgovarajućeg GH kojemu nedostaje XTEN, tada fuzijski protein postiže usporedivu površinu ispod krivulje (AUC) u usporedbi s odgovarajućim GH kojemu nedostaje XTEN; (ii) kada se primjenjuje jedna manja molarna količina fuzijskog proteina na pojedincu, nego od odgovarajućeg GH kojemu nedostaje XTEN, tada fuzijski protein postiže usporediv terapeutski učinak kao odgovarajući GH kojemu nedostaje XTEN; (iii) kada se fuzijski protein primjenjuje na pojedincu smanjenom učestalošću u usporedbi s odgovarajućim GH kojemu nedostaje XTEN, a koji se primjenjuje na pojedincu korištenjem neke druge ekvivalentne molarne količine, tada fuzijski protein postiže usporedivu površinu ispod krivulje (AUC) u usporedbi s odgovarajućim GH kojemu nedostaje XTEN; (iv) kada se fuzijski protein primjenjuje na pojedincu smanjenom učestalošću u usporedbi s odgovarajućim GH kojemu nedostaje XTEN, a koji se primjenjuje na pojedincu korištenjem neke druge ekvivalentne molarne količine, tada fuzijski protein postiže usporedivi terapeutski učinak kao odgovarajući GH kojemu nedostaje XTEN.
12. Fuzijski protein prema zahtjevu 1, naznačen time, da nadalje obuhvaća drugi XTEN, pri čemu drugi XTEN obuhvaća aminokiselinsku sekvencu koja ima najmanje 90% identiteta od aminokiselinske sekvence od: [image]
13. Fuzijski protein, naznačen time, da obuhvaća aminokiselinsku sekvencu koja ima najmanje 99% identiteta sekvence od sekvence AE912-hGH-AE144, kako je prikazano u Tablici 36.
14. Farmaceutski sastav, naznačen time, da obuhvaća fuzijski protein prema bilo kojem od prethodnih zahtjeva, i farmaceutski prikladan nosač.
15. Farmaceutski sastav prema zahtjevu 14, naznačen time, da primjena navedenog sastava na pojedincu, postiže povećanje koncentracije IGF-1 u usporedbi s koncentracijom IGF-1 prije doziranja.
16. Postupak proizvodnje fuzijskog proteina koji obuhvaća ljudski hormon rasta (GH) fuzioniran na jedan ili više produljenih rekombinantnih polipeptida (XTEN), naznačen time, da postupak obuhvaća sljedeće: (a) pripremanje stanice domaćina koja obuhvaća molekulu rekombinantnog polinukleotida koji kodira fuzijski protein prema bilo kojem od zahtjeva 1 do 13; (b) kultiviranje stanice domaćina pod uvjetima koji dopuštaju ekspresiju fuzijskog proteina; i (c) obnavljanje fuzijskog proteina.
17. Postupak prema zahtjevu 16, naznačen time, da: (i) stanica domaćina je prokariotska stanica; ili (ii) fuzijski protein se obnavlja iz citoplazme stanice domaćina uglavnom u topivom obliku.
18. Fuzijski protein prema bilo kojem od zahtjeva 1 do 13, naznačen time, da se on upotrebljava u postupku liječenja stanja kod pojedinca koja se odnose na hormon rasta, pri čemu postupak obuhvaća primjenu terapeutski djelotvorne količine fuzijskog proteina na pojedincu.
19. Fuzijski protein za uporabu prema zahtjevu 18, naznačen time, da: (i) je stanje koje se odnosi na hormon rasta, odabrano od sljedećih: deficijencija hormona rasta, Turnerov sindrom, Prader-Willi-sindrom, kronični zastoj bubrega, retardacija intrauterinskog rasta, idiopatski nizak stas, stanje slabosti koje se odnosi na AIDS, pretilost, multipla skleroza, fibromialgija, Crohnova bolest, ulcerozni kolitis, mišićna distrofija, smanjenje mišićne mase, niska gustoća kostiju; ili (ii) primjena dvije ili više uzastopnih doza fuzijskog proteina koji se primjenjuje na pojedincu koristeći terapeutski djelotvoran dozni režim, rezultira u produljenju perioda između uzastopnih vrijednosti razine fuzijskog proteina u krvi od najviše vrijednosti Cmax i/ili najniže vrijednosti Cmin, u usporedbi s odgovarajućim GH kojemu nedostaje XTEN i koji se primjenjuje korištenjem jednog terapeutski djelotvornog doznog režima ustanovljenog za GH; ili (iii) se na pojedincu primjenjuje jedna manja molarna količina fuzijskog proteina u usporedbi s odgovarajućim GH kojemu nedostaje XTEN i koji se primjenjuje na pojedincu pod nekim drugim ekvivalentnim doznim režimom, te da fuzijski protein postiže usporedivi terapeutski učinak kao odgovarajući GH kojemu nedostaje XTEN; ili (iv) se fuzijski protein primjenjuje smanjenom učestalošću na pojedincu, u usporedbi s odgovarajućim GH kojemu nedostaje XTEN i koji se primjenjuje na pojedincu uporabom neke druge ekvivalentne molarne doze, te da fuzijski protein postiže usporedivi terapeutski učinak kao odgovarajući GH kojemu nedostaje XTEN; ili (v) je terapeutski učinak mjerni parametar koji se odabire od koncentracije IGF-1, koncentracije IGFBP3, brzine rasta, oslabljene tjelesne mase, ukupne tjelesne masnoće, masnoće trupa, reakcije na izlaganje inzulinu, brzine podjele hondrocita, broja hondrocita, gustoće kostiju, rasta kostiju, te povećanja širine epifizne ploče.
HRP20171644TT 2009-06-08 2017-10-27 Polipeptidi hormona rasta kao i postupci za njihovu proizvodnju i uporabu HRP20171644T1 (hr)

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US18511209P 2009-06-08 2009-06-08
US23683609P 2009-08-25 2009-08-25
US28095509P 2009-11-10 2009-11-10
PCT/US2010/023106 WO2010091122A1 (en) 2009-02-03 2010-02-03 Extended recombinant polypeptides and compositions comprising same
US12/699,761 US8673860B2 (en) 2009-02-03 2010-02-03 Extended recombinant polypeptides and compositions comprising same
EP10786725.1A EP2440241B1 (en) 2009-06-08 2010-06-08 Growth hormone polypeptides and methods of making and using same
PCT/US2010/037849 WO2010144502A2 (en) 2009-06-08 2010-06-08 Growth hormone polypeptides and methods of making and using same

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