DK3202898T3 - Terapeutiske nuclease-sammensætninger og fremgangsmåder - Google Patents
Terapeutiske nuclease-sammensætninger og fremgangsmåder Download PDFInfo
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- DK3202898T3 DK3202898T3 DK16198956.1T DK16198956T DK3202898T3 DK 3202898 T3 DK3202898 T3 DK 3202898T3 DK 16198956 T DK16198956 T DK 16198956T DK 3202898 T3 DK3202898 T3 DK 3202898T3
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- hybrid nuclease
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Claims (15)
1. Polypeptid, der omfatter en RNase, en DNase, og et variant Fc-domæne, hvori RNasen er operativt koblet, eventuelt med en linker, til det variante Fc-domæne, og hvori DNasen er operativt koblet, eventuelt med en linker, til det variante Fc-domæne, hvilket variante Fc-domæne er et variant humant IgGl-Fc-domæne, der indeholder en aminosyresubstitution, som formindsker binding, sammenlignet med vildtypen, til en Fcy-receptor eller et komplementprotein, eller begge, hvilket polypeptid omfatter en reduceret effektorfunktion, der eventuelt er valgt fra gruppen bestående af opsonisering, fagocytose, komplementafhængig cytotoksicitet, og antistofafhængig, cellulær cytotoksicitet.
2. Polypeptidet ifølge krav 1, hvor (a) RNasen er en human RNase, såsom en human pankreatisk RNase 1; og/eller (b) DNasen er udvalgt fra gruppen der består af Type-1 human DNase, en human DNase 1L3, eller human TREX1; og/eller (c) Fc-domænet omfatter et hængseldomæne, et CH2-domæne og et CH3-domæne; og/eller (d) en ledersekvens, såsom det humane VK3LP-peptid, der er koblet til N-terminalen af Rnasen eller til N-terminalen af DNasen.
3. Polypeptid ifølge krav 1 eller krav 2, hvor (a) Fc-domænet omfatter et modificeret hængseldomæne, der omfatter mindst en substitution, hvilket modificerede hængseldomæne eventuelt omfatter en mutation i en eller flere af de tre hængselcysteiner, såsom SCC eller SSS; og/eller (b) hvor Fc-domænet omfatter et modificeret CH2-domæne, der omfatter mindst én substitution, hvilken substitution eventuelt er valgt fra gruppen bestående af P238S, P331S, N297S eller en kombination deraf.
4. Polypeptidet ifølge krav 1 eller krav 2, hvor (a) RNasen omfatter en aminosyresekvens, der er mindst 90 % identisk med aminosyresekvensen anført i SEQ ID NO: 149 eventuelt uden dens ledersekvens, eller den omfatter 100 eller flere sammenhængende aminosyrer fra SEQ ID NO: 149; og/eller (b) hvor DNasen omfatter en human DNase, eventuelt DNase 1, der evenuelt omfatter en aminosyresekvens som angivet i SEQ ID NO: 139, SEQ ID NO: 143 eller SEQ ID NO: 142, eller omfatter en aminosyresekvens med mindst 90 % indentite med amniosyresekvensen som angivet i SEQ ID NO: 139, SEQ ID NO: 143 ellerr SEQ ID NO: 142; og/eller (c) Fc-domænet omfatter en aminosyresekvens, der er mindst 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, eller 98 % identisk med aminosyresekvensen anført i SEQ ID NO: 145, der eventuelt omfatter et modificeret hængseldomæne, som omfattende mindst en substitution, hvilket modificerede hængseldomæne eventuelt omfatter en mutation i en eller flere af de tre cysteiner, såsom SCC eller SSS; og/eller eventuelt omfatter en eller flere Fc-mutationer, der er valgt fra P238S, P331S, K322S, og N297S.
5. Polypeptidet ifølge krav 1, hvor; polypeptidet omfatter en aminosyresekvens, der er mindst 90 %, 91 %, 92 %, 93 %, 94 %, 95 %, 96 %, 97 %, eller 98 % identisk med aminosyresekvensen, som er anført i SEQ ID NO: 153, der eventuelt er uden dens ledersekvens; hvor Fc-domænet eventuelt omfatter et modificeret hængseldomæne, der omfatter mindst en substitution, hvilket modificerede hængseldomæne eventuelt omfatter en mutation i en eller flere af de tre hængselcysteiner, såsom SCC eller SSS; og/eller et modificeret CH2-domæne, der omfatter mindst én substitution, som er valgt fra gruppen bestående af P238S, P331S, N297S eller kombination deraf.
6. Polypeptid ifølge ethvert foregående krav, hvor RNasen er operativt koblet til Fc-domænet via et linkerdomæne, hvilket linkerdomæne eventuelt er en polypeptidlinker, såsom en gly-ser-linker; og/eller hvor RNasen er operativt koblet til N-terminalen af Fc-domænet, eventuelt med en linker; og/eller hvor RNasen er operativt koblet til C-terminalen af Fc-domænet, eventuelt med en linker; og/eller hvor polypeptidet omfatter en human VK3LP-peptidledersekvens, der er koblet til N-terminalen af RNasen.
7. Polypeptidet ifølge et hvilket som helst af de foregående krav, hvor DNasen er operativt koblet til Fc-domænet via et andet linkerdomæne, hvor det andet linkerdomæne et linkerpolypeptid, såsom et NLG-peptid; og/eller hvor DNasen er operativt koblet til N-terminalen af Fc- domænet, eventuelt med en linker; og/eller hvor Dnasen er operativt koblet til C-terminalen af Fc- domænet, eventuely med en linker; og/eller hvor polypeptid omfatter en human VK3LP-peptidledersekvens, der er koblet tikl N-termainalen af DNasen.
8. Sammensætning, der omfatter polypeptidet ifølge ethvert af de foregående krav og en farmaceutisk acceptabel bærer.
9. Nucleinsyremolekyle, der koder for polypeptidet ifølge et hvilket som helst af kravene 1 til 7.
10. Rekombinant ekspressionsvektor, der omfatter et nucleinsyremolekyle ifølge krav 9.
11. Værtscelle, der er transformeret med den rekombinante ekspressionsvektor ifølge krav 10.
12. Fremgangsmåde til fremstilling af polypeptidet ifølge ethvert af kravene 1 til 7, hvilken fremgangsmåde omfatter at tilvejebringe en værtscelle, der omfatter en nucleinsyresekvens, som koder for polypeptidet; og at opretholde værtscellen under betingelser, ved hvilke polypeptidet udtrykkes.
13. Polypeptid ifølge et hvilket som helst af kravene 1 til 7 til anvendelse i en fremgangsmåde til behandling eller forebyggelse af en tilstand, der er forbundet med en unormal immunreaktion; hvilken tilstand eventuelt er en autoimmun sygdom, eventuelt systemisk lupus erythematosus (SLE), eller eventuelt er valgt fra gruppen bestående af insulinafhængig diabetes mellitus, multipel sklerose, eksperimentel autoimmun encephalomyelitis, rheumatoid arthritis, eksperimentel autoimmun arthritis, myasthenia gravis, thyroiditis, en eksperimentel form for uveoretinitis, Hashimotos thyroiditis, primær myxødem, thyrotoksikose, perniciøs anæmi, autoimmun atrofisk gastritis, Addisons sygdom, præmatur menopause, mandlig infertilitet, juvenil diabetes, Goodpastures syndrom, pemphigus vulgaris, pemfigoid, sympatisk oftalmi, fakogen uveitis, autoimmun hæmolytisk anæmi, idiopatisk leukopeni, primær biliær cirrhosis, aktiv kronisk hepatitis Hbs-ve, kryptogen cirrhose, ulcerøs colitis, Sjøgrens syndrom, scleroderma, Wegeners granulomatose, polymyositis, dermatomyositis, discord LE, systemisk lupus erythematosus (SLE), og bindevævssygdom.
14. Dimert polypeptid, der omfatter et polypeptid ifølge et hvilket som helst af kravene 1-7, eventuelt en homodimer.
15. Sammensætning, der omfatter det dimere polypeptid ifølge krav 14 og en farmaceutisk acceptabel excipiens.
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