DK2852610T3 - Produktion af fucosylerede glycoproteiner - Google Patents

Produktion af fucosylerede glycoproteiner Download PDF

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DK2852610T3
DK2852610T3 DK13725617.8T DK13725617T DK2852610T3 DK 2852610 T3 DK2852610 T3 DK 2852610T3 DK 13725617 T DK13725617 T DK 13725617T DK 2852610 T3 DK2852610 T3 DK 2852610T3
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seq
deletion
activity
filamentous fungal
polypeptide
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Jari Natunen
Ann Westerholm-Parvinen
Hanna Salo
Jussi Joensuu
Heli Viskari
Christopher Landowski
Anne Huuskonen
Anne Kanerva
Anna-Liisa Hänninen
Noora Salovuori
Merja Penttilä
Juhani Saarinen
Markku Saloheimo
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Glykos Finland Oy
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    • C07K14/43545—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from worms from nematodes from Caenorhabditis
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    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
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    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
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    • C12N9/0004—Oxidoreductases (1.)
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    • C12N9/10—Transferases (2.)
    • C12N9/1048—Glycosyltransferases (2.4)
    • C12N9/1051—Hexosyltransferases (2.4.1)
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    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
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Claims (14)

1. Filamentøs svampecelle til produktion af glycoproteiner med pattedyrlignende fucosylerede N-glycaner omfattende mindst en deletions- eller disruptionsmutation i et gen, der koder for en endogen protease, hvilken mutation reducerer sådan endogen proteaseaktivitet sammenlignet med en filamentøs modersvampecelle, der ikke har mutationen, endvidere omfattende et polynukleotid, der koder for et polypeptid, der har a1,6 fucosyltransferaseaktivitet, og et eller flere polynukleotider, der koder for et polypeptid, der har GDP-fucosesynteseaktivitet, hvor GDP-fucosesynteseaktivitet omfatter a. GMD-polynukleotid eller et funktionelt variantpolynukleotid, der koder for et polypeptid, der har GDP-mannose-dehydrataseaktivitet, og b. FX-polynukleotid eller et funktionelt variantpolynukleotid, der koder for et polypeptid, der har både GDP-keto-deoxy-mannose-epimerase- og GDP-keto-deoxy-galactose-reductaseaktivitet og eventuelt GDP-fucosetransporteraktivitet, og hvor den filamentøse svampecelle er Trichoderma-ceWe.
2. Filamentøs svampecelle ifølge krav 1, hvor polynukleotidet, der koder for polypeptidet, der har a1,6 fucosyltransferaseaktivitet, omfatter enten polynukleotidet fra SEQ ID NO:1 eller et funktionelt variantpolynukleotid, der koder for et polypeptid, der har mindst 50 %, mindst 60 %, mindst 70 %, mindst 90 % eller mindst 95 % identitet med SEQ ID NO:6, hvor polypeptidet har a1,6 fucosyltransferaseaktivitet.
3. Filamentøs svampecelle ifølge krav 1 eller 2, hvor det ene eller de flere polynukleotider, der koder for polypeptidet, der har GDP-fucosesynteseaktivitet omfatter a. C. elegans GMD-polynukleotid fra SEQ ID NO:2 eller et funktionelt variantpolynukleotid, der koder for et polypeptid, der har mindst 50 %, mindst 60 %, mindst 70 %, mindst 90 % eller mindst 95 % identitet med SEQ ID NO:7, hvor polypeptidet har GDP-mannose-dehydrataseaktivitet; og b. C. elegans FX-polynukleotid fra SEQ ID NO:3 eller et funktionelt variantpolynukleotid, der koder for et polypeptid, der har mindst 50 %, mindst 60 %, mindst 70 %, mindst 90 % eller mindst 95 % identitet med SEQ ID NO:8, hvor polypeptidet har både GDP-keto-deoxy-mannose-epimerase- og GDP-keto-deoxy-galactose-reductaseaktivitet; og, eventuelt, hvor polynukleotidet, der koder for GDP-fucosetransporter er C. elegans GFTr fra SEQ ID NO:4 eller et funktionelt variantpolynukleotid, der koder for et polypeptid, der har mindst 50 %, mindst 60 %, mindst 70 %, mindst 90 % eller mindst 95 % identitet med SEQ ID NO:9, hvor polypeptidet har GDP-fucosetransporteraktivitet.
4. Filamentøs svampecelle ifølge et hvilket som helst af de foregående krav, hvor polypeptidet, der har fucosyltransferaseaktivitet, endvidere omfatter en Golgi-målrettet sekvens til målretning af ekspression af polypeptidet i den filamentøse svampecelles Golgi-compartment, såsom en Golgi-målrettet sekvens omfattende den N-terminale del af polypeptidet fra SEQ ID NO: 10.
5. Filamentøs svampecelle ifølge et hvilket som helst af de foregående krav, hvor cellen har en mutation, der nedsætter ekspressionsniveauet af et ALG3-gen sammenlignet med ekspressionsniveauet i en modercelle, der ikke har en sådan mutation.
6. Filamentøs svampecelle ifølge et hvilket som helst af kravene 1-4, der endvidere omfatter et eller flere polynukleotider, der koder for et polypeptid udvalgt fra gruppen bestående af: i. a1,2 mannosidase, ii. N-acetylglucosaminyltransferase I katalytisk domæne, iii. α mannosidase II, iv. N-acetylglucosaminyltransferase II katalytisk domæne og, eventuelt, v. endvidere omfattende et polynukleotid, der koder for β1,4 galactosyltransferase.
7. Filamentøs svampecelle ifølge et hvilket som helst af de foregående krav, hvor et fucosyltransferase, et N-acetylglucosaminyltransferase I, et α mannosidase II, et N-acetylglucosaminyltransferase II og/eller et β1,4 galactosyltransferase omfatter Golgi-målrettet sekvens udvalgt fra gruppen af N-terminal del af GnTI, fortrinsvis human GnTI, N-terminal del af GnTII, fortrinsvis human GnTII og N-terminal del af Kre2, fortrinsvis T. reese/'Kre2.
8. Filamentøs svampecelle ifølge et hvilket som helst af de foregående krav, der endvidere omfatter et eller flere polynukleotider, der koder for et polypeptid udvalgt fra gruppen bestående af: i) glucosamin UDP-N-acetylglucosamin-2-epimerase/N- acetylmannosaminkinase, ii) N-acetylneuraminsyresynthase, iii) N-acetylneuraminsyrephosphatase, iv) cytidinmonophosphat-N-acetylneuraminsyresynthetase, v) CMP-sialinsyretransporter og vi) sialyltransferase.
9. Filamentøs svampecelle ifølge et hvilket som helst af de foregående krav, hvor mutationen reducerer proteaseaktiviteten af en endogen protease udvalgt fra gruppen bestående af Trichoderma reesei pep1 (SEQ ID NO:17), Trichoderma reesei pep2 (SEQ ID NO:18), Trichoderma reesei pep3 (SEQ ID NO:19), Trichoderma reesei pep4 (SEQ ID NO:20), Trichoderma reesei pep5 (SEQ ID NO:21), Trichoderma reesei pep7 (SEQ ID NO:23), Trichoderma reesei pep8 (SEQ ID NO:410), Trichoderma reesei pep11 (SEQ ID NO:411), Trichoderma reesei pep12 (SEQ ID NO:412), Trichoderma reesei tpp1 (SEQ ID NO:34), Trichoderma reesei tsp1 (SEQ ID NO:24), Trichoderma reesei slp1 (SEQ ID NO:25), Trichoderma reesei slp2 (SEQ ID NO:26), Trichoderma reesei slp3 (SEQ ID NO:27), Trichoderma reesei slp5 (SEQ ID NO:28), Trichoderma reesei slp6 (SEQ ID NO:29), Trichoderma reesei slp7 (SEQ ID NO:30), Trichoderma reesei slp8 (SEQ ID NO:31), Trichoderma reesei gap1 (SEQ ID NO:32) og Trichoderma reesei gap2 (SEQ ID NO:33).
10. Filamentøs svampecelle ifølge krav 9, hvor cellen omfatter mutationer, der reducerer eller eliminerer aktiviteten af de a. tre endogene proteaser pep1, tsp1 og slp1 hos Trichoderma reesei; b. tre endogene proteaser gap1, slp1 og pep1 hos Trichoderma reesei; c. tre endogene proteaser udvalgt fra gruppen bestående af pep1, pep2, pep3, pep4, pep5, pep8, pep11, pep12, tsp1, slp1, slp2, slp3, slp7, gap1 og gap2 hos Trichoderma reesei; d. tre til seks proteaser udvalgt fra gruppen bestående af pep1, pep2, pep3, pep4, pep5, tsp1, slp1, slp2, slp3, gap1 og gap2 hos Trichoderma reesei; eller e. syv til ti proteaser udvalgt fra gruppen bestående af pep1, pep2, pep3, pep4, pep5, pep7, pep8, tsp1, slp1, slp2, slp3, slp5, slp6, slp7, slp8, tpp1, gap1 og gap2 hos Trichoderma reesei.
11. Filamentøs svampecelle ifølge et hvilket som helst af de foregående krav, hvor cellen endvidere omfatter mutationer i et eller flere gener, der koder for glycosylhydrolaser, hvor mutationerne eliminerer eller reducerer aktiviteten af de tilsvarende hydrolaser, og hvor hydrolaserne er udvalgt fra gruppen bestående af xylanase, cellobiohydrolase og endoglucanase.
12. Fremgangsmåde til produktion af et glycoprotein eller antistof med fucosyleret N-glycan omfattende: a. tilvejebringelse af en filamentøs svampecelle ifølge et hvilket som helst af de foregående krav, hvilken celle endvidere omfatter et polynukleotid, der koder for et glycoprotein eller et antistof, og b. dyrkning af cellen for at producere glycoproteinet eller antistoffet med fucosyleret N-glycan.
13. Fremgangsmåde ifølge krav 12, hvor det fucosylerede N-glycan er udvalgt fra gruppen bestående af Man3GlcNAc2(Fuc), GlcNAcMan3GlcNAc2(Fuc), GlcNAc2Man3GlcNAc2(Fuc), Gali-2GlcNAc2Man3GlcNAc2(Fuc), Neu5Aci-2Gali-2GlcNAc2Man3GlcNAc2(Fuc), og eventuelt hvor mindst 5 mol%, mindst 10 mol% eller mindst 15 mol% af de samlede secernerede N-glycaner består af GlcNAc2Man3GlcNAc2(Fuc).
14. Fremgangsmåde ifølge et hvilket som helst af kravene 12 og 13, hvor polynukleotidet, der koder for et glycoprotein eller et antistof er et rekombinant polynukleotid, der koder for et heterologt glycoprotein eller heterologt antistof.
DK13725617.8T 2012-05-23 2013-05-23 Produktion af fucosylerede glycoproteiner DK2852610T3 (da)

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