DK2245145T3 - Fremstilling af aktive stærkt phosphorylerede humane lysosomale sulfataseenzymer og anvendelser deraf - Google Patents
Fremstilling af aktive stærkt phosphorylerede humane lysosomale sulfataseenzymer og anvendelser deraf Download PDFInfo
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- DK2245145T3 DK2245145T3 DK09702074.7T DK09702074T DK2245145T3 DK 2245145 T3 DK2245145 T3 DK 2245145T3 DK 09702074 T DK09702074 T DK 09702074T DK 2245145 T3 DK2245145 T3 DK 2245145T3
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Claims (15)
1. Rekombinant human N-acetylgalactosamin-6-sulfatase (GALNS)-enzymsammensætning, hvilken enzymsammensætning omfatter GALNS-enzymer, som omfatter en aminosyresekvens, der er mindst 95% identisk med aminosyrerne 27 til 522 ifølge SEQ ID NO: 4, og er anvendelig til behandling af en lysosomal ophobningssygdom, der er forårsaget af eller forbundet med en mangel i nævnte GALNS, hvor GALNS-enzymerne i sammensætningen: (a) har mindst 50% omdannelse af cysteinresten i position 53 til Ca-formylglycin (FGly); og (b) er N-bundet glycosyleret ved asparaginresterne i positionerne 178 og 397, og hvor mindst 50% af de oligomannosekæder, der er bundet til asparaginresten i position 178, er bis-phosphoryleret, eventuelt hvor GALNS-enzymet er et fusionsprotein, som omfatter et cellemålsøgningssignal, der er placeret i den N- eller C-terminale ende af GALNS-enzymet.
2. GALNS-enzymsammensætning ifølge krav 1, hvor den lysosomale ophobningssygdom er mukopolysakkaridose type IVa (MPS IVa) eller Morquio A-syndrom eller multipel sulfatase-mangel.
3. GALNS-enzymsammensætning ifølge et hvilket som helst af kravene 1 eller 2, hvor GALNS-enzymet består af et hovedbånd på 55-60 kDa, som er mindst 75% af de synlige proteiner eller mindst 85% af de synlige proteiner som bestemt ved Coomassie Blue- farvning ved udsættelse for SDS-PAGE under reducerende betingelser.
4. GALNS-enzymsammensætning ifølge et hvilket som helst af kravene 1 eller 2, hvor GALNS-enzymet består af et hovedbånd på 55-60 kDa, som er mindst ca. 90% af de synlige proteiner som bestemt ved Coomassie Blue-farvning ved udsættelse for SDS-PAGE under reducerende betingelser.
5. GALNS-enzymsammensætning ifølge et hvilket som helst af kravene 1-4, hvor GALNS-enzymet har mindst 70% omdannelse af cysteinresten i position 53 til Ca-formylglycin (FGly).
6. GALNS-enzymsammensætning ifølge et hvilket som helst af kravene 1-4, hvor GALNS-enzymet har mindst 90% omdannelse af cysteinresten i position 53 til Ca-formylglycin (FGly) .
7. Sammensætning ifølge krav 1 til anvendelse ved behandling af mukopolysakkaridose type IVa (MPS IVa) eller Morquio A-syndrom eller multipel sulfatase-mangel.
8. Anvendelse af en oprenset, rekombinant human N-acetylgalactosamin-6-sulfatase (GALNS)-enzymsammensætning ifølge et hvilket som helst af kravene 1-6 til fremstilling af et lægemiddel til behandling af mukopolysakkaridose type IVa (MPS IVa) eller Morquio A-syndrom eller multipel sulfatase-mangel.
9. Sammensætning til anvendelse ifølge krav 7 eller anvendelse ifølge krav 8, hvor GALNS-enzymet består af et hovedbånd på 55-60 kDa, som er mindst 75% af de synlige proteiner eller mindst 85% af de synlige proteiner som bestemt ved Coomassie Blue-farvning ved udsættelse for SDS-PAGE under reducerende betingelser.
10. Sammensætning til anvendelse ifølge krav 7 eller anvendelse ifølge krav 8, hvor GALNS-enzymet består af et hovedbånd på 55-60 kDa, som er mindst 90% af de synlige proteiner som bestemt ved Coomassie Blue-farvning ved udsættelse for SDS-PAGE under reducerende betingelser.
11. Sammensætning til anvendelse ifølge et hvilket som helst af kravene 7-10 eller anvendelse ifølge et hvilket som helst af kravene 8-10, hvor GALNS-enzymet har mindst 70% omdannelse af cysteinresten i position 53 til Ca-formylglycin (FGly).
12. Sammensætning til anvendelse ifølge et hvilket som helst af kravene 7-10 eller anvendelse ifølge et hvilket som helst af kravene 8-10, hvor GALNS-enzymet har mindst 90% omdannelse af cysteinresten i position 53 til Ca-formylglycin (FGly).
13. Sammensætning til anvendelse ifølge et hvilket som helst af kravene 7-12 eller anvendelse ifølge et hvilket som helst af kravene 8-12, hvor behandlingens virkning bestemmes ved at måle urinudskillelsen af keratansulfat (KS) hos individet, der har MPS IVa eller Morquio A-syndrom, hvor KS-niveauerne i urinen fra individet, der har MPS IVa eller Morquio A-syndrom, sammenlignes med KS-niveauerne i urinen fra normale individer og/eller fra et ubehandlet individ, der har MPS IVa eller Morquio A-syndrom, og/eller fra det samme individ inden behandling med GALNS-enzymet, eller hvor behandlingens virkning bestemmes ved hjælp af funktionsvurdering af individet ved at måle udholdenhed ved gangtest, gang op ad trapper eller lunge-/åndedrætsfunktion, eventuelt hvor der ved gangtesten måles den distance, der gås på 6 eller 12 minutter, eller hvor der ved gang op ad trapper måles det antal trin, der er gået opad pr. minut, eller hvor lunge-/åndedrætsfunktionen måles ved hjælp af hjertefunktion (ekkokardiogram) eller ved hjælp af lungefunktion (FVC, FEVI eller peakflow).
14. Sammensætning til anvendelse eller anvendelse ifølge krav 13, hvor der opnås mere end 25% reduktion i urin-KS efter behandling med GALNS-enzymet, eller hvor der opnås mere end 50% reduktion i urin-KS efter behandling med GALNS-enzymet.
15. GALNS-enzymsammensætning ifølge et hvilket som helst af kravene 1-6, sammensætning til anvendelse ifølge et hvilket som helst af kravene 7-14 eller anvendelse ifølge et hvilket som helst af kravene 8-14, hvor cellemålsøgningssignalet omfatter et knoglemålsøgningspeptid.
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