DK2185192T3 - Lentivirale genoverførselsvektorer og deres medicinske anvendelser - Google Patents
Lentivirale genoverførselsvektorer og deres medicinske anvendelser Download PDFInfo
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Claims (41)
1. Kombination af forbindelser til anvendelse til terapeutisk eller profylaktisk behandling af en infektion med et immundefektvirus, hvor forbindelserne administreres sekventielt til en mammaliavært til fremkaldelse af et beskyttende specifikt cellulært immunrespons mod infektionen, som mindst omfatter: (i) lentivirale vektorpartikler, der er pseudotypet med et første bestemt glycosyleret (G) protein fra et vesikulært stomatitisvirus (VSV); (ii) lentivirale vektorpartikler, der er pseudotypet med et andet bestemt VSV-G-protein, der er forskelligt fra det første bestemte VSV-G-protein; hvor den lentivirale vektorpartikel ifølge (i) og (ii) i dens genom omfatter et rekombinant polynukleotid, der koder for et eller adskillige polypeptider, der mindst omfatter ét antigen, der er afledt af et GAG-antigen fra immundefektvirusset og; hvor det første og andet VSV-G-protein er henholdsvis VSV-G fra Indiana-stammen og VSV-G fra New Jerseystammen, og eventuelt: (iii) lentivirale vektorpartikler, der er pseudotypet med et tredje bestemt VSV-G-protein, hvor det tredje VSV-G-protein ikke seroneutraliserer med det første og andet VSV-G-protein.
2. Kombination af forbindelser til anvendelse ifølge krav 1, hvor det rekombinante polynukleotid i genomet i vektorpartiklen ikke koder for et biologisk aktivt POL-polyprotein.
3. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 eller 2, hvor det første og andet og, hvis det er til stede, det tredje VSV-G-protein stammer fra vira med forskellige serotyper og især er valgt blandt VSV-G-proteiner, der udtrykkes af plasmiderne, der er deponeret ved CNCM som pThV-VSV.G (IND-CO) CNCM i-3842 eller som en alternativ version af pThV-VSV.G (IND-CO), CNCM i-4056, pThV-VSV.G (NJ-CO) CNCM i-3843 eller som en alternativ version pThV-VSV.G (NJ-CO) CNCM I-4058 eller pThV-VSV.G (COCAL-CO) CNCM i-4055, pThV-VSV.G (ISFA-CO) CNCM i-4057 og pThV-VSV.G (SVCV-CO) CNCM i-4059.
4. Kombination af forbindelser til anvendelse ifølge krav 1 eller 2, hvor mindst ét af det første og andet VSV-G-protein er rekombinant, og det/de rekombinant(e) VSV-G-protein(er) omfatter eksportdeterminanten YTDIE af VSV-G fra en Indiana-serotypestamme, og hvor det tredje VSV-G-protein, hvis det er til stede, er rekombinant, og det rekombinante VSV-G-protein omfatter eksportdeterminanten YTDIE af VSV-G fra en Indiana-serotypestamme.
5. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 3, hvor en eller adskillige lentivirale vektorer er pseudotypet med VSV-G-protein(er), der er muteret, især ved substitution, tilføjelse eller deletion af en eller adskillige aminosyrerester i forhold til en eller flere bestemte native reference-VSV-G-proteiner eller er modificeret til forøgelse af dets glycosylering eller til forøgelse af dets ekspressionskapacitet eller dets optagelseskapacitet af de lentivirale partikler.
6. Kombination af forbindelser til anvendelse ifølge krav 5, hvor mutationen af VSV-G-proteinet påvirker en eller adskillige aminosyrerester af det transmembrane domæne af VSV-G.
7. Kombination af forbindelser ifølge et hvilket som helst af kravene 1 til 6, hvor det første og andet VSV-G-protein er forskellige og kodes af et nukleinsyremolekyle, der er indbefattet i plasmid pThV-VSV-G (IND-co), der er deponeret under nummer I-3842, eller en variant deraf, der er deponeret under nummer I-4056, eller i plasmid pThV-VSV-G (NJ-co), der er deponeret under nummer I-3843, eller en variant deraf, der er deponeret under nummer I-4058.
8. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 7, hvor det første eller andet VSV-G-protein kodes af nukleinsyremolekylet, der omfatter sekvensen i figur 6 eller 7, eller hvor det første og andet kappeprotein er forskellige og har en aminosyresekvens valgt blandt de, der er vist i figur 6 eller 7.
9. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 7, hvor det tredje eller det/de yderligere VSV-G-protein(er) er valgt blandt proteinet/proteinerne, der kodes af et nukleinsyremolekyle eller har en aminosyresekvens, der er vist i figur 6 til 13 eller 14 til 18.
10. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 9, hvor den pseudotypede lentivirale vektor er en human lentivi rusbaseret vektor.
11. Kombination af forbindelser til anvendelse ifølge krav 10, hvor den pseudotypede lentivirale vektor er en HIV-baseret vektor.
12. Kombination af forbindelser til anvendelse ifølge krav 6 eller 7, hvor de pseudotypede lentivirale vektorpartikler er replikations-inkompetente lentivirale vektorer.
13. Kombination af forbindelser til anvendelse ifølge krav 7 eller 8, hvor de pseudotypede lentivirale vektorpartikler er integrerings-inkompetente lentivirale vektorer.
14. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 13, hvor det lentivirale vektorgenom omfatter en funktionel lentiviral DNA-flap af HIV-1.
15. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 10 til 14, hvor: - 3’-LTR-sekvensen af det lentivirale vektorgenom mindst mangler aktivatoren (enhanceren) for U3-regionen, især hvor 3'-LTR mangler U3-regionen eller har en deletion af en del af U3-regionen; og/eller - U3-regionen af LTR-5' er erstattet af ikke-lentiviral U3 eller af en promotor, der er egnet til at drive tat-uafhængig primær transkription.
16. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 10, hvor det lentivirale vektorgenom omfatter følgende sekvenser: 1. en 5'-LTR, eventuelt hvor den tat-afhængige U3-sekvens, der driver transkriptionen af genomet, er erstattet af en promotorsekvens; 2. et psi (qj)-indkapslingssignal; 3. en RRE (Rev-responsivt element)-sekvens; 4. en DNA-flapsekvens, der er indsat opstrøms for antigenet og fortrinsvis placeret i en omtrent central position i vektorgenomet; hvor antigenet er under kontrol af en promotor, især en cytomegalovirus (CMV)-promotor; 5. eventuelt en WPRE (skovmurmeldyr (Woodchuck)-hepatitis B-virus-post-responsivt element)-sekvens; og 6. en 3'-LTR-region, der mangler U3-regionen.
17. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 13, hvor den lentivirale genomvektor i de lentivirale vektorpartikler er afledt af plasmid pTRIPAU3.CMV-GFP, der er deponeret ved CNCM under nummer i-2330 den 11. oktober 1999, eller af pTRIPAU3.CMV-SIV-GAGco-WPRE, der er deponeret ved CNCM under nummer 1-3841 den 10. oktober 2007, eller af pTRIPAU3.CMV-SIV-GAG-WPRE, der er deponeret ved CNCM under nummer i-3840 den 10. oktober 2007, ved substitution af GFP eller af den SIV-GAG-kodende sekvens med et HIV-GAG-afledt antigen.
18. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 17, hvor polynukleotidet koder for et antigen afledt af et GAG-antigen fra Hl V-1.
19. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 17, hvor polynukleotidet koder for et antigen afledt af GAG fra et immundefektvirus og har aminosyresekvensen for de naturlige GAG-antigener blandt GAG-polyproteinet eller matrixproteinet eller capsidproteinet eller nukleocapsidproteinet eller er et fragment af et sådant polyprotein eller af et sådant matrix-, capsid eller nukleocapsidproteinet eller er et GAG-antigen, der er modificeret i forhold til det naturlige GAG-antigen, især ved mutation, herunder ved deletion, substitution eller tilføjelse af en eller adskillige aminosyrerester i aminosyresekvensen, eller er modificeret ved posttranslationelle modifikationer, hvor det modificerede GAG-antigen er valgt, så det enten er biologisk funktionelt eller biologisk ikke-funktionelt.
20. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 17, hvor det rekombinante polynukleotid koder for et biologisk ikke-funktionelt polypeptid, der er afledt af et GAG-antigen fra HIV eller fra SIV eller fra FIV, hvor polypeptidet ikke åbner mulighed for dannelsen af GAG-pseudopartikler eller GAG-POL-pseudopartikler fra celler, der er transduceret med de lentivirale vektorer.
21. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 20, hvor det GAG-afledte antigen er et GAGAmyr-protein, der er fri for myristylering.
22. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 18, hvor det GAG-afledte antigen har aminosyresekvensen i figur 21,26 eller 38.
23. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 19, hvor polynukleotidet, der koder for GAG-polyproteinet eller et polypeptid, der er afledt deraf, udtrykkes af en kodonoptimeret nukleotidsekvens til muliggørelse af forbedret translation i mammaliaceller, især i humane celler, i forhold til nukleotidsekvensen for det native gen.
24. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 20, hvor det rekombinante polynukleotid yderligere koder for et polypeptid valgt blandt polypeptider afledt af et NEF-antigen, et TAT-antigen, et REV-antigen fra et immundefektvirus, et POL-antigen fra et immundefektvirus eller en kombination deraf.
25. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 20, hvor det rekombinante polynukleotid koder for et fusionsprotein, der omfatter det GAG-afledte antigen med sekvensen i figur 21, det POL-afledte antigen, der omfatter eller har aminosyresekvensen i figur 21, og det NEF-afledte antigen, der omfatter eller har aminosyresekvensen, der fremgår af figur 21, hvor fusionsproteinet har en af følgende strukturer: 5'-GAG-POL-NEF-3' eller 5'-POL-NEF-GAG-3' eller 5'-POL-GAG-NEF-3' eller 5'-NEF-GAG-POL-3' eller 5'-NEF-POL-GAG-3' eller 5'-GAG-NEF-POL-3'.
26. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 25, hvor de lentivirale vektorer (i) og/eller (ii) er formuleret i en sammensætning, der er fri for et adjuvans for immunresponset.
27. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 26, som yderligere omfatter et immunmodulerende middel.
28. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 27, hvor de lentivirale vektorer er formuleret i sammensætninger, der er egnet til injektion til en vært.
29. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 27, hvor de lentivirale vektorer er formuleret i sammensætninger, der er egnet til subkutan injektion.
30. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 29 til anvendelse i et administrationsprogram, der omfatter priming af immunresponset og efterfølgende boosting af immunresponset i en mammaliavært, hvor den (i) lentivirale vektor, der er pseudotypet med det første VSV-G-protein, administreres adskilt i tid fra den (ii) lentivirale vektor, der er pseudotypet med det andet VSV-G-protein, og hvis de er til stede, de (iii) lentivirale vektorer, der er pseudotypet med det tredje VSV-G-protein, hvor hver af de lentivirale vektorer (i) og (ii) og, hvis de er til stede, (iii) administreres enten til priming eller til boosting af immunresponset.
31. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 5 til 30, hvor den lentivirale vektor, der er pseudotypet med VSV-G-proteinet fra Indiana-stammen, anvendes til priming, og den lentivirale vektor, der er pseudotypet med VSV-G-proteinet fra New Jersey-stammen, anvendes til boosting, eller hvor den lentivirale vektor, der er pseudotypet med VSV-G-proteinet fra New jersey-stammen, anvendes til priming, og den lentivirale vektor, der er pseudotypet med VSV-G-proteinet fra Indiana-stammen, anvendes til boosting.
32. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 26 til terapeutisk behandling af humane værter, der er inficeret med et humant immundefektvirus (HIV).
33. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 26 til terapeutisk behandling af humane værter, der er inficeret med HIV-1 eller HIV-2.
34. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 31 til profylaktisk behandling af humane værter mod infektion af et humant immundefektvirus.
35. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 30 til profylaktisk behandling af humane værter mod infektion af HIV-1 eller HIV-2.
36. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 35 til anvendelse i et terapeutisk program, der også omfatter administration af et eller flere antiretrovirale kemiske lægemidler, der forhindrer retrovirusreplikation.
37. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 35 til anvendelse i et terapeutisk program, der også omfatter administration af et eller flere anti retrovi rale kemiske lægemidler, der forhindrer retrovirusreplikation, valgt blandt inhibitor(er) af retroviral reverse transkriptase (RT) og inhibitor(er) af retroviral protease.
38. Kombination af forbindelser til anvendelse ifølge krav 37, hvor en eller adskillige inhibitorer af retroviral reverse transkriptase og en eller adskillige inhibitorer af retroviral protease anvendes til administration.
39. Kombination af forbindelser til anvendelse ifølge krav 37 eller 38 til anvendelse samtidig med anti retrovi rale lægemidler.
40. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 33 til 36, hvor administrationen af forbindelserne varer ved, efter at administrationen af det eller de anti retrovi rale lægemidler er standset, eller hvor administrationen af anti retrovi rale lægemidler afbrydes adskillige gange i et bestemt tidsrum under administration af forbindelserne.
41. Kombination af forbindelser til anvendelse ifølge et hvilket som helst af kravene 1 til 39 i et administrationsprogram, der omfatter priming af immunresponset og efterfølgende boosting af immunresponset hos en mammaliavært, - til kontrol af viræmien efter eksponering for eller efter infektion med retrovirus, særligt et HIV, og især til begrænsning eller reducering af virusbelastningen hos værten; og/eller - til induktion af beskyttende cellulær immunitet mod retrovi russet, især HIV, hos en vært; og/eller - til beskyttelse mod virusreplikation efter eksponering for eller efter infektion med HIV-retrovirusset; og/eller - til beskyttelse mod udtømning af det centrale hukommelses-CD4+-T-cellerespons, især i den akutte fase af infektion med retrovi russet, især HIV; og/eller - til bevarelse af det centrale hukommelses-CD4+-T-cellerespons, især i den kroniske fase af infektion med retrovi russet, især HIV; og/eller - til tidligere og/eller højere tilbagevenden af det na'ive og centrale hukommelses-CD8+-T-cellerespons under primær infektion med retrovi russet, især HIV; og/eller - til forebyggelse mod viral undvigelse fra immunpres til derved muliggørelse af langtidskontrol af infektionen med retrovi russet, især HIV.
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| EP07291251.2A EP2047861B1 (en) | 2007-10-12 | 2007-10-12 | Lentiviral gene transfer vectors suitable for iterative administration and their medicinal applications |
| EP08156405 | 2008-05-16 | ||
| PCT/IB2008/002930 WO2009019612A2 (en) | 2007-08-03 | 2008-08-01 | Lentiviral gene transfer vectors and their medicinal applications |
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