HRP20100271T1 - DOBIVANJE TNFR-Fc - Google Patents
DOBIVANJE TNFR-Fc Download PDFInfo
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- HRP20100271T1 HRP20100271T1 HR20100271T HRP20100271T HRP20100271T1 HR P20100271 T1 HRP20100271 T1 HR P20100271T1 HR 20100271 T HR20100271 T HR 20100271T HR P20100271 T HRP20100271 T HR P20100271T HR P20100271 T1 HRP20100271 T1 HR P20100271T1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
- C07K14/7151—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for tumor necrosis factor [TNF], for lymphotoxin [LT]
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/62—DNA sequences coding for fusion proteins
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- C12P21/00—Preparation of peptides or proteins
- C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
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- C12N2500/00—Specific components of cell culture medium
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- C12N2500/00—Specific components of cell culture medium
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Abstract
Postupak za proizvodnju Fc regije fuzijskog proteina imunoglobulina faktora nekroze tumora (TNFR-Fc) u staničnoj kulturi na veliko, što se sastoji od koraka: dobivanja stanične kulture, koja sadrži: stanice sisavaca, koje sadrže gen koji kodira TNFR-Fc gen koji se pokazuje u uvjetima stanične kulture; imedij, koji sadrži glutamin, a ima osobine medija koje se biraju iz grupe koju čine: (i) kumulativna količina aminokiselina po jedinici volumena veća od oko 70 mM, (ii) molski odnos kumulativnog glutamina prema kumulativnom asparaginu manji od oko 2, (iii) molski odnos kumulativnog glutamina prema kumulativnim ukupnim aminokiselinama manji od oko 0,2, (iv) molski odnos kumulativnih neorganskih iona prema kumulativnim ukupnim aminokiselinama između oko 0,4 i 1, (v) kombiniranu kumulativnu količinu glutamina i asparagina po jedinici volumena veću od oko 16 mM, i njihove kombinacije; održavanja spomenute kulture u inicijalnoj fazi rasta, pod prvim skupom uvjeta kulture, tijekom prvog vremenskog perioda, dovoljnog da se dozvoli spomenutim stanicama da se reproduciraju do gustoće vitalnih stanica unutar opsega od oko 20%-80% od maksimalno moguće gustoće vitalnih stanica, kada se spomenuta kultura održava pod prvim skupom uvjeta kulture; izmjene najmanje jednog uvjeta kulture, tako da se zatim primjenjuje drugi skup uvjeta kulture; održavanja spomenute kulture tijekom drugog vremenskog perioda pod ovim drugim skupom uvjeta, a u drugom periodu vremena se akumulira TNFR-Fc u staničnoj kulturi. Patent sadrži još 49 patentnih zahtjeva.
Claims (50)
1. Postupak za proizvodnju Fc regije fuzijskog proteina imunoglobulina faktora nekroze tumora (TNFR-Fc) u staničnoj kulturi na veliko, što se sastoji od koraka:
dobivanja stanične kulture, koja sadrži:
stanice sisavaca, koje sadrže gen koji kodira TNFR-Fc gen koji se pokazuje u uvjetima stanične kulture; i
medij, koji sadrži glutamin, a ima osobine medija koje se biraju iz grupe koju čine: (i) kumulativna količina aminokiselina po jedinici volumena veća od oko 70 mM, (ii) molski odnos kumulativnog glutamina prema kumulativnom asparaginu manji od oko 2, (iii) molski odnos kumulativnog glutamina prema kumulativnim ukupnim aminokiselinama manji od oko 0,2, (iv) molski odnos kumulativnih neorganskih iona prema kumulativnim ukupnim aminokiselinama između oko 0,4 i 1, (v) kombiniranu kumulativnu količinu glutamina i asparagina po jedinici volumena veću od oko 16 mM, i njihove kombinacije;
održavanja spomenute kulture u inicijalnoj fazi rasta, pod prvim skupom uvjeta kulture, tijekom prvog vremenskog perioda, dovoljnog da se dozvoli spomenutim stanicama da se reproduciraju do gustoće vitalnih stanica unutar opsega od oko 20%-80% od maksimalno moguće gustoće vitalnih stanica, kada se spomenuta kultura održava pod prvim skupom uvjeta kulture;
izmjene najmanje jednog uvjeta kulture, tako da se zatim primjenjuje drugi skup uvjeta kulture;
održavanja spomenute kulture tijekom drugog vremenskog perioda pod ovim drugim skupom uvjeta, a u drugom periodu vremena se akumulira TNFR-Fc u staničnoj kulturi.
2. Postupak prema Zahtjevu 1, gdje spomenuti medij sadrži molski odnos kumulativnog glutamina prema kumulativnom asparaginu koji je manji od oko 2; a
spomenuti medij ima dvije karakteristike medija, koje se biraju iz grupe koju čine: (i) medij sadrži količinu kumulativnih aminokiselina po jedinici volumena veću od oko 70 mM, (iii) molski odnos kumulativnog glutamina prema kumulativnim ukupnim aminokiselinama manji od oko 0,2, (iv) molski odnos kumulativnih neorganskih iona prema kumulativnim ukupnim aminokiselinama između oko 0,4 i 1, (v) kombiniranu kumulativnu količinu glutamina i asparagina po jedinici volumena veću od oko 16 mM, i njihove kombinacije.
3. Postupak prema Zahtjevu 1, gdje se spomenuti uvjet stanične kulture, u spomenutom koraku promjene najmanje jednog uvjeta kulture, bira iz grupe koju čine: (i) temperatura, (ii) pH, (iii) osmolaritet, (iv) sadržaj kemijskog induktanta, i njihove kombinacije.
4. Postupak prema Zahtjevu 1, gdje je inicijalna koncentracija glutamina u spomenutom mediju manja od ili jednaka 10 mM.
5. Postupak prema Zahtjevu 1, gdje je inicijalna koncentracija glutamina u spomenutom mediju manja od ili jednaka 4 mM.
6. Postupak prema Zahtjevu 1, gdje je ukupna kumulativna količina glutamina po jedinici volumena u spomenutom mediju manja ili jednaka 10 mM.
7. Postupak prema Zahtjevu 1, gdje je ukupna kumulativna količina glutamina po jedinici volumena u spomenutom mediju manja ili jednaka 4 mM.
8. Postupak prema Zahtjevu 1, gdje se glutamin osigurava samo u inicijalnom mediju, u polaznoj staničnoj kulturi.
9. Postupak prema Zahtjevu 1, gdje je inicijalna gustoća spomenutih stanica sisavaca najmanje 2×105 stanica/mL.
10. Postupak prema Zahtjevu 1, gdje je inicijalna gustoća spomenutih stanica sisavaca najmanje 2×106 stanica/mL.
11. Postupak prema Zahtjevu 1, gdje korak osiguravanja sadrži osiguravanje najmanje oko 1000 L kulture.
12. Postupak prema Zahtjevu 1, gdje korak osiguravanja sadrži osiguravanje najmanje oko 10.000 L kulture.
13. Postupak prema Zahtjevu 1, gdje spomenuti prvi skup uvjeta sadrži prvi opseg temperature, koji je približno od 30°C do 42°C.
14. Postupak prema Zahtjevu 1, gdje spomenuti prvi skup uvjeta sadrži prvi opseg temperature koji je približno 37°C.
15. Postupak prema Zahtjevu 1, gdje spomenuti prvi skup uvjeta sadrži drugi opseg temperature, koji je približno od 25°C do 41°C.
16. Postupak prema Zahtjevu 1, gdje spomenuti prvi skup uvjeta sadrži drugi opseg temperature, koji je približno od 29°C do 35°C.
17. Postupak prema Zahtjevu 1, gdje spomenuti prvi skup uvjeta sadrži drugi opseg temperature, koji je približno 31°C.
18. Postupak prema Zahtjevu 1, što sadrži još i drugi korak izmjene, poslije spomenute prve izmjene najmanje jednog od uvjeta kulture, a koji se sastoji od izmjene najmanje jednog od uvjeta kulture, tako da se u kulturi primjenjuje treći skup uvjeta.
19. Postupak prema Zahtjevu 18, gdje drugi korak izmjene sadrži izmjenu najmanje jednog od uvjeta kulture, koji se bira iz grupe koju čine: (i) temperatura, (ii) pH, (iii) osmolaritet, (iv) sadržaj kemijskog induktanta, i njihove kombinacije.
20. Postupak prema Zahtjevu 18, gdje spomenuti treći skup uvjeta sadrži treći opseg temperature, koji je približno od 27 do 37°C.
21. Postupak prema Zahtjevu 1, gdje spomenuti prvi vremenski period traje između 1 i 7 dana.
22. Postupak prema Zahtjevu 1, gdje spomenuti prvi vremenski period traje približno 4 dana.
23. Postupak prema Zahtjevu 1, gdje spomenuti prvi vremenski period i spomenuti drugi vremenski period traju najmanje 5 dana.
24. Postupak prema Zahtjevu 1, gdje u koraku održavanja spomenute kulture u drugom vremenskom periodu, sadržaj laktata opada, poslije dostizanja maksimalnog sadržaja laktata u kulturi.
25. Postupak prema Zahtjevu 1, gdje u koraku održavanja spomenute kulture u drugom periodu vremena, sadržaj amonija opada, poslije dostizanja maksimalnog sadržaja amonija u kulturi.
26. Postupak prema Zahtjevu 1, gdje je spomenuta količina dobivenog TNFR-Fc najmanje 1,5-put veća nego količina dobivenog TNFR-Fc pod inače identičnim uvjetima, u inače identičnom mediju, kojem nedostaju spomenute karakteristike medija.
27. Postupak prema Zahtjevu 1, gdje je spomenuta ukupna količina dobivenog TNFR-Fc najmanje 2-puta veća nego količina dobivenog TNFR-Fc pod inače identičnim uvjetima, u inače identičnom mediju, kojem nedostaju spomenute karakteristike medija.
28. Postupak prema Zahtjevu 1, gdje se spomenuta stanična kultura osigurava još i s komponentama suplemenata.
29. Postupak prema Zahtjevu 28, gdje se spomenute komponente suplemenata osiguravaju u više intervala.
30. Postupak prema Zahtjevu 28, gdje se spomenute komponente suplemenata biraju iz grupe koju čine hormoni i/ili drugi faktori rasta, određeni ioni (kao što su natrijev, kloridni, kalcijev, magnezijev i fosfatni), puferi, vitamini, nukleozidi ili nukleotidi, mikroelementi (neorganski spojevi obično prisutni u vrlo niskim konačnim koncentracijma), aminokiseline, lipidi, ili glukoza ili neki drugi izvor energije.
31. Postupak prema Zahtjevu 1, što se spomenutoj kulturi ne dodaju komponente suplemenata tijekom trajanja proizvodnje spomenutog TNFR-Fc.
32. Postupak prema Zahtjevu 1, što se u spomenutoj kulturi glutamin zamjenjuje glicilglutaminom.
33. Postupak prema Zahtjevu 1, što je spomenuta kumulativna ukupna količina histidina, izoleucina, leucina, metionina, fenilalanina, triptofana, tirozina i prolina po jedinici volumena u spomenutom mediju veća od približno 25 mM.
34. Postupak prema Zahtjevu 1, što je spomenuta kumulativna ukupna količina histidina, izoleucina, leucina, metionina, fenilalanina, triptofana, tirozina i prolina po jedinici volumena u spomenutom mediju veća od približno 35 mM.
35. Postupak prema Zahtjevu 1, gdje spomenuti medij ima karakteristike medija koje se biraju iz grupe koju čine:
(i) kumulativna ukupna količina histidina po jedinici volumena veća od približno 1,7 mM;
(ii) kumulativna ukupna količina izoleucina po jedinici volumena veća od približno 3,5 mM;
(iii) kumulativna ukupna količina leucina po jedinici volumena veća od približno 5,5 mM;
(iv) kumulativna ukupna količina metionina po jedinici volumena veća od približno 2,0 mM;
(v) kumulativna ukupna količina fenilalanina po jedinici volumena veća od približno 2,5 mM;
(vi) kumulativna ukupna količina prolina po jedinici volumena veća od približno 2,5 mM;
(vii) kumulativna ukupna količina triptofana po jedinici volumena veća od približno 1,0 mM;
(viii) kumulativna ukupna količina tirozina po jedinici volumena veća od približno 2,0 mM.
36. Postupak prema Zahtjevu 1, što je kumulativna ukupna količina serina po jedinici volumena u spomenutom mediju veća od približno 10 mM.
37. Postupak prema Zahtjevu 1, što je kumulativna ukupna količina asparagina po jedinici volumena u spomenutom mediju veća od približno 8 mM.
38. Postupak prema Zahtjevu 1, što je kumulativna ukupna količina asparagina po jedinici volumena u spomenutom mediju veća od približno 12 mM.
39. Postupak prema Zahtjevu 1, što je kumulativna ukupna količina fosfora po jedinici volumena u spomenutom mediju veća od približno 5 mM.
40. Postupak prema Zahtjevu 1, što je kumulativna ukupna količina glutamata po jedinici volumena u spomenutom mediju manja od približno 1 mM.
41. Postupak prema Zahtjevu 1, što je kumulativna ukupna količina kalcij pantotenata po jedinici volumena u spomenutom mediju veća od približno 20 mg/L.
42. Postupak prema Zahtjevu 1, što je kumulativna ukupna količina nikotinamida po jedinici volumena u spomenutom mediju veća od približno 25 mg/L.
43. Postupak prema Zahtjevu 1, što je kumulativna ukupna količina piridoksina i piridoksala po jedinici volumena u spomenutom mediju veća od približno 35 mg/L.
44. Postupak prema Zahtjevu 1, što je kumulativna ukupna količina riboflavina po jedinici volumena u spomenutom mediju veća od približno 2,0 mg/L.
45. Postupak prema Zahtjevu 1, što je kumulativna ukupna količina tiamin hidrohlorida po jedinici volumena u spomenutom mediju veća od približno 35 mg/L.
46. Postupak prema Zahtjevu 1, što se spomenuti medij sastoji od medija koji sadrži glutamin i ima karakteristike medija koje se biraju iz grupe koju čine:
(i) polazna koncentracija aminokiselina veća od oko 70 mM, (ii) molski odnos polaznog glutamina prema polaznom asparaginu manji od oko 2, (iii) molski odnos polaznog glutamina prema polaznim ukupnim aminokiselinama manji od oko 0,2, (iv) molski odnos polaznih neorganskih iona prema polaznim ukupnim aminokiselinama između oko 0,4 i 1, (v) polazna konacetracija kombiniranih glutamina i asparagina veća od oko 16 mM, i njihove kombinacije.
47. Postupak za proizvodnju TNFR-Fc na velikoj skali proizvodnje stanica iz kulture, što sadrži korake:
dobijanja stanične kulture, koja sadrži:
stanice sisavaca, koje sadrže gen koji kodira TNFR-Fc, gen koji se pokazuje u uvjetima stanične kulture; i
definirani medij, koji sadrži glutamin, a ima najmanje dvije osobine medija koje se biraju iz grupe koju čine: (i) polazna koncentracija aminokiselina veća od oko 70 mM, (ii) molski odnos glutamina prema asparaginu manji od oko 2, (iii) molski odnos glutamina prema ukupnim aminokiselinama manji od oko 0,2, (iv) molski odnos neorganskih iona prema ukupnim aminokiselinama između oko 0,4 i 1, (v) kombiniranu koncentraciju glutamina i asparagina veću od oko 16 mM;
održavanja spomenute kulture u inicijalnoj fazi rasta pod prvim skupom uvjeta kulture, tijekom prvog vremenskog perioda, dovoljno da se dozvoli spomenutim stanicama da se reproduciraju unutar opsega od oko 20%-80% od maksimalno moguće gustoće vitalnih stanica, ako se spomenuta kultura održava pod prvim skupom uvjeta kulture;
izmjene najmanje jednog uvjeta kulture, tako da se primjenjuje drugi skup uvjeta kulture;
održavanja spomenute kulture tijekom drugog vremenskog perioda pod ovim drugim skupom uvjeta, a u ovom drugom vremenskom periodu u staničnoj kulturi se akumulira TNFR-Fc.
48. Postupak prema Zahtjevu 47, što spomenuti medij ima karakteristike medija: i) polaznu koncentraciju aminokiselina veću od oko 70 mM, ii) molski odnos glutamina prema asparaginu manji od oko 2, iii) molski odnos glutamina prema ukupnim aminokiselinama manji od oko 0,2, iv) molski odnos neorganskih iona prema ukupnim aminokiselinama između oko 0,4 i 1, i v) kombiniranu koncentraciju glutamina i asparagina veću od oko 16 mM.
49. Postupak prema bilo kojem od Zahtjeva 1-2, ili 46-48, što je:
sadržaji laktata su niži od sadržaja koji su opaženi pod inače identičnim uvjetima u inače identičnom mediju, kojem nedostaju spomenute karakteristike;
sadržaji amonija su niži od sadržaja koji su opaženi pod inače identičnim uvjetima u inače identičnom mediju, kojem nedostaju spomenute karakteristike; i
ukupna količina proizvedenog TNFR-Fc je bar toliko velika kao što se opaža pod inače identičnim uvjetima u inače identičnom mediju, kojem nedostaju spomenute karakteristike.
50. Postupak prema Zahtjevima 1 do 47, što se proizvedeni TNFR-Fc izolira i/ili pročišćava za upotrebu ili za dobivanje farmaceutskih proizvoda.
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