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DK2822577T3 - Rekombinante faktor viii-proteiner - Google Patents

Rekombinante faktor viii-proteiner Download PDF

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Publication number
DK2822577T3
DK2822577T3 DK13749382.1T DK13749382T DK2822577T3 DK 2822577 T3 DK2822577 T3 DK 2822577T3 DK 13749382 T DK13749382 T DK 13749382T DK 2822577 T3 DK2822577 T3 DK 2822577T3
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amino acid
seq
fviii
protein
recombinant
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DK13749382.1T
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John Kulman
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Bioverativ Therapeutics Inc
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    • C07K14/745—Blood coagulation or fibrinolysis factors
    • C07K14/755—Factors VIII, e.g. factor VIII C (AHF), factor VIII Ag (VWF)
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Claims (15)

1. Rekombinant faktor VIII- (FVIII) protein, der omfatter: et første polypeptid, der omfatter formel I: (A1) - a1 - (A2) - a2 - [B]; og et andet polypeptid, der omfatter formel II: a3 - (A3) - (C1); hvor det første polypeptid og det andet polypeptid er kondenseret eller eksisterer som en heterodimer; hvor a) A1 er et A1-domæne af FVIII; b) A2 er et A2-domæne af FVIII; c) [B] er et B-domæne af FVIII, et fragment deraf, eller er deleteret; d) A3 er et A3-domæne af FVIII; e) C1 er et C1-domæne af FVIII; og f) a1, a2 og a3 er sure spacer-områder; hvor A1-domænet omfatter et permissivt loop-1 (A1-1) område og et permissivt loop-2- (A1-2) område, hvori en heterolog del kan indsættes uden eliminering af det rekombinante proteins prokoagulerende aktivitet; hvor A2-domænet omfatter et permissivt loop-1 (A2-1) område og et permissivt loop-2 (A2-2) område, hvori en heterolog del kan indsættes uden eliminering af det rekombinante proteins prokoagulerende aktivitet; hvor A3-domænet omfatter et permissivt loop-1 (A3-1) område og et permissivt loop-2 (A3-2) område, hvori en heterolog del kan indsættes uden eliminering af det rekombinante proteins prokoagulerende aktivitet; hvor mindst ét af områderne A1 -1, A1 -2, A2-1, A2-2, A3-1, A3-2 eller a3 omfatter en heterolog del, og hvor det rekombinante FVIIl-protein har prokoagulerende aktivitet.
2. Rekombinant FVIIl-protein ifølge krav 1, hvor den heterologe del ikke er en del afen XTEN.
3. Rekombinant FVII l-protein ifølge krav 1 eller 2, hvor (a) A1-1-området svarer til et område i nativt maturt humant FVIII fra ca. aminosyre 15 til ca. aminosyre 45 eller fra ca. aminosyre 18 til ca. aminosyre 41 ifølge SEQ ID NO: 1, (b) AI-2-området svarer til et område i nativt maturt humant FVIII fra ca. aminosyre 201 til ca. aminosyre 232 eller fra ca. aminosyre 218 til ca. aminosyre 229 ifølge SEQ ID NO: 1, (c) A2-1-området svarer til et område i nativt maturt humant FVIII fra ca. aminosyre 395 til ca. aminosyre 421 eller fra ca. aminosyre 397 til ca. aminosyre 418 ifølge SEQ ID NO: 1, (d) A2-2-området svarer til et område i nativt maturt humant FVIII fra ca. aminosyre 577 til ca. aminosyre 635 eller fra ca. aminosyre 595 til ca. aminosyre 607 ifølge SEQ ID NO: 1, (e) A3-1-området svarer til et område i nativt maturt humant FVIII fra ca. aminosyre 1705 til ca. aminosyre 1732 eller fra ca. aminosyre 1711 til ca. aminosyre 1725 ifølge SEQ ID NO: 1, og (f) A3-2-området svarer til et område i nativt maturt humant FVIII fra ca. aminosyre 1884 til ca. aminosyre 1917 eller fra ca. aminosyre 1899 til ca. aminosyre 1911 ifølge SEQ ID NO: 1.
4. Rekombinant FVIIl-protein ifølge krav 1, hvor den heterologe del er indsat umiddelbart på nedstrømssiden af en aminosyre, der svarer til en aminosyre i maturt nativt humant FVIII valgt fra gruppen bestående af: aminosyre 18 ifølge SEQ ID NO: 1, aminosyre 22 ifølge SEQ ID NO: 1, aminosyre 26 ifølge SEQ ID NO: 1, aminosyre 40 ifølge SEQ ID NO: 1, aminosyre 188 ifølge SEQ ID NO: 1, aminosyre 216 ifølge SEQ ID NO: 1, aminosyre 220 ifølge SEQ ID NO: 1, aminosyre 221 ifølge SEQ ID NO: 1, aminosyre 224 ifølge SEQ ID NO: 1, aminosyre 333 ifølge SEQ ID NO: 1, aminosyre 336 ifølge SEQ ID NO: 1, aminosyre 339 ifølge SEQ ID NO: 1, aminosyre 399 ifølge SEQ ID NO: 1, aminosyre 403 ifølge SEQ ID NO: 1, aminosyre 409 ifølge SEQ ID NO: 1, aminosyre 416 ifølge SEQ ID NO: 1, aminosyre 442 ifølge SEQ ID NO: 1, aminosyre 490 ifølge SEQ ID NO: 1, aminosyre 599 ifølge SEQ ID NO: 1, aminosyre 603 ifølge SEQ ID NO: 1, aminosyre 1711 ifølge SEQ ID NO: 1, aminosyre 1720 ifølge SEQ ID NO: 1, aminosyre 1725 ifølge SEQ ID NO: 1, aminosyre 1796 ifølge SEQ ID NO: 1, aminosyre 1802 ifølge SEQ ID NO: 1, aminosyre 1900 ifølge SEQ ID NO: 1, aminosyre 1905 ifølge SEQ ID NO: 1, aminosyre 1910 ifølge SEQ ID NO: 1 og en hvilken som helst kombination deraf.
5. Rekombinant FVIIl-protein ifølge et hvilket som helst af krav 1 til 4, hvor en supplerende heterolog del indsættes i a3 umiddelbart på nedstrømssiden af en aminosyre, der svarer til aminosyre 1656 ifølge SEQ ID NO: 1.
6. Rekombinant FVIIl-protein ifølge et hvilket som helst af krav 1 til 5, der endvidere omfatter mindst to, tre, fire, fem, seks, syv, otte eller ni supplerende heterologe dele.
7. Rekombinant FVII l-protein ifølge et hvilket som helst af krav 1 til 6, hvor mindst én heterolog del omfatter et element, der øger proteinets in v/Vo-halveringstid, hvor elementet er valgt fra: (a) albumin; (b) albuminbindende polypeptid; (c) Fc; (d) PAS; (e) C-terminal-peptidet (CTP) af β-underenheden af humant chorion-gonadotropin; (f) polyethylenglycol (PEG); (g) hydroxyethylstivelse (HES); (h) albumin-bindende små molekyler; (i) en clearance-receptor, eller et fragment deraf, hvor clearance-receptoren blokerer binding af det rekombinante FVIII-protein til FVIII-clearance-receptorer; (j) et lavdensitets-lipoprotein-receptor-relateret protein 1 (LRP1) eller et FVIII-bindingsfragment deraf; og (k) en hvilken som helst kombination af (a)-(h).
8. Rekombinant FVI I l-protein ifølge et hvilket som helst af krav 1 til 7, hvor den mindst ene heterologe del omfatter et peptid eller polypeptid, der muliggør visualisering eller lokalisering af det rekombinante FVIII-protein in vitro, in vivo, ex vivo, eller en hvilken som helst kombination deraf; hvor peptidet eller polypeptidet, der muliggør visualisering eller lokalisering, er valgt fra: (a) et biotinacceptorpeptid, (b) et liponsyreacceptorpeptid, (c) et fluorescerende protein, (d) GFP, (e) RFP, (f) YFP, (g) egfp, (h) EYFP, (i) et cystein-holdigt peptid til ligering af et biarsenisk farvestof eller til konjugering af metastabelt technetium, (j) 4',5'-bis(1,3,2-dithioarsolan-2-yl)fluorescein (FIAsH), (k) et peptid til konjugering af europium-clathrater til fluorescensresonans-energioverførsels- (FRET) baserede proksimitets-assays og (l) en hvilken som helst kombination deraf.
9. Isoleret nukleinsyre, der omfatter en sekvens, der koder for rekombinant FVIII-protein ifølge et hvilket som helst af krav 1 til 8.
10. Ekspressionsvektor, der omfatter nukleinsyren ifølge krav 9.
11. Ekspressionsvektor ifølge krav 10, hvor vektoren er valgt fra: (a) et plasmid, (b) et phagemid, (c) et virus, (d) en retrovirusvektor, (e) en adenovirusvektor, (f) en adenoassocieret virusvektor, (g) en SV40-type virusvektor, (h) en polyomavirusvektor, (i) en Epstein-Barr-virusvektor, (j) en papillomavirusvektor, (k) en herpesvirusvektor, (l) en vacciniavirusvektor, (m) en poliovirusvektor, (n) en Moloney-murin leukæmivirusvektor, (o) en Harvey-murin sarkomvirusvektor, (p) en murin mammatumorvirusvektor, (q) en Rous sarkomvirusvektor og (r) et hvilket som helst derivat deraf.
12. Værtscelle, der omfatter den isolerede nukleinsyre ifølge krav 9 eller ekspressionsvektoren ifølge krav 10 eller 11.
13. Sammensætning, der omfatter rekombinant FVI I l-protein ifølge et hvilket som helst af krav 1 til 8, den isolerede nukleinsyre ifølge krav 9, ekspressionsvektoren ifølge krav 10 eller 11 eller værtscellen ifølge krav 12 og en farmaceutisk acceptabel excipiens.
14. Rekombinant FVI Il-protein ifølge et hvilket som helst af krav 1 til 8, isoleret nukleinsyre ifølge krav 10, ekspressionsvektor ifølge krav 10 eller 11, værtscelle ifølge krav 12, eller sammensætning ifølge krav 13 til anvendelse i behandling, forebyggelse, håndtering, bedring, diagnose eller billeddannelse afen koaguleringssygdom eller tilstand hos en patient med behov derfor, hvor koaguleringssygdommen eller tilstanden er hæmofili.
15. Fremgangsmåde til fremstilling af et rekombinant FVI Il-protein, der omfatter dyrkning af værtscellen ifølge krav 12 under egnede forhold, hvor det rekombinante FVII l-protein udtrykkes.
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