HRP20211748T1 - Postupci i sastavi za sekreciju heterolognih polipeptida - Google Patents

Postupci i sastavi za sekreciju heterolognih polipeptida Download PDF

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HRP20211748T1
HRP20211748T1 HRP20211748TT HRP20211748T HRP20211748T1 HR P20211748 T1 HRP20211748 T1 HR P20211748T1 HR P20211748T T HRP20211748T T HR P20211748TT HR P20211748 T HRP20211748 T HR P20211748T HR P20211748 T1 HRP20211748 T1 HR P20211748T1
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signal peptide
antibody
variant
host cell
polynucleotide
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HRP20211748TT
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Dorothea Reilly
Yizhou ZHOU
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F. Hoffmann - La Roche Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C12N15/625—DNA sequences coding for fusion proteins containing a sequence coding for a signal sequence
    • C—CHEMISTRY; METALLURGY
    • 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
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C—CHEMISTRY; METALLURGY
    • 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
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/70—Vectors or expression systems specially adapted for E. coli
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
    • C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
    • C—CHEMISTRY; METALLURGY
    • 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
    • C12N2800/00—Nucleic acids vectors

Claims (23)

1. Postupak za povećanje sekrecije teškog lanca protutijela i/ili lakog lanca protutijela iz stanice domaćina E. coli, naznačen time, da obuhvaća uzgoj stanice domaćina E. coli koja sadrži polinukleotid koji sadrži (1) prvi polinukleotid koji kodira prvi signalni peptid operabilno povezan s polinukleotidom koji kodira teški lanac protutijela, pri čemu je prosječna hidrofobnost signalnog peptida veća od oko 0,5; i (2) drugi polinukleotid koji kodira drugi signalni peptid koji je operabilno povezan s polinukleotidom koji kodira laki lanac protutijela, pri čemu je prosječna hidrofobnost drugog signalnog peptida veća od oko 0,5, pri čemu se, nakon ekspresije protutijela u stanici domaćina, teški i laki lanci nabiru i grupiraju tako da tvore biološki aktivno protutijelo, pri čemu su prvi i drugi signalni peptid varijanta signalnog peptida DsbA, pri čemu varijanta signalnog peptida DsbA sadrži a) mutaciju na ostatku L11 i/ili S18Y slijeda SEQ ID NO: 3, pri čemu varijanta signalnog peptida DsbA ima veću prosječnu hidrofobnost od signalnog peptida DsbA divljeg tipa slijeda SEQ ID NO: 3, koji ima prosječnu hidrofobnost 0,50; ili b) mutaciju na ostatku L11 i/ili S18Y, pri čemu mutacija na ostatku L11 je L11I i pri čemu varijanta signalnog peptida DsbA ima veću prosječnu hidrofobnost od signalnog peptida DsbA divljeg tipa slijeda SEQ ID NO: 3, koji ima prosječnu hidrofobnost 0,50; ili c) slijed SEQ ID NO: 13 ili 15.
2. Postupak prema patentnom zahtjevu 1, naznačen time, da a) polinukleotid u stanici domaćinu nadalje sadrži promotor; ili b) polinukleotid u stanici domaćinu nadalje sadrži promotor, pri čemu je promotor prokariotski promotor odabran iz skupine koju čine phoA, tac, lpp, lac-lpp, lac, ara i T7 promotor.
3. Postupak prema bilo kojem od patentnih zahtjeva od 1 do 2, naznačen time, da je stanica domaćin E. coli soja deficijentnog a) u endogenim proteaznim aktivnostima, ili b) u endogenim proteaznim aktivnostima, pri čemu genotipu E. coli nedostaju geni degP i prc, a nosi mutirani gen spr.
4. Postupak prema bilo kojem od patentnih zahtjeva od 1 do 3, naznačen time, da stanica domaćin nadalje sadrži polinukleotid koji kodira najmanje jedan prokariotski polipeptid odabran iz skupine koju čine a) DsbA, DsbC, DsbG i FkpA, ili b) DsbA, DsbC, DsbG i FkpA, pri čemu polinukleotid kodira i DsbA i DsbC.
5. Postupak prema bilo kojem od patentnih zahtjeva od 1 do 4, naznačen time, da je protutijelo a) monoklonsko protutijelo; ili b) monoklonsko protutijelo, pri čemu je monoklonsko protutijelo kimerno protutijelo, protutijelo s afinitetnom maturacijom, bispecifično, humanizirano ili humano protutijelo.
6. Varijantni signalni peptid DsbA koji sadrži mutaciju na ostatku L11 i/ili S18Y slijeda SEQ ID NO: 3, pri čemu varijanta ima a) veću prosječnu hidrofobnost od signalnog peptida DsbA slijeda SEQ ID NO: 3, koji ima prosječnu hidrofobnost 0,50; ili b) veću prosječnu hidrofobnost od signalnog peptida DsbA slijeda SEQ ID NO: 3, koji ima prosječnu hidrofobnost 0,50, i pri čemu mutacija na ostatku L11 je L11I.
7. Varijantni signalni peptid STII koji sadrži mutaciju u ostatku S11 slijeda SEQ ID NO: 1, pri čemu varijantni signalni peptid STII ima a) veću prosječnu hidrofobnost od signalnog peptida STII slijeda SEQ ID NO: 1, koji ima prosječnu hidrofobnost 0,40; b) veću prosječnu hidrofobnost od signalnog peptida STII slijeda SEQ ID NO: 1, koji ima prosječnu hidrofobnost 0,40, i pri čemu je mutacija S11 A, S11I ili S11L.
8. Varijantni signalni peptid koji se sastoji od slijeda SEQ ID NO: 8, 11, 13, 15, 31 ili 33.
9. Varijantni signalni peptid prema bilo kojem od patentnih zahtjeva od 6 do 7, spojen s a) heterolognim proteinom, ili b) heterolognim proteinom, pri čemu je heterologni polipeptid i) teški lanac protutijela; ili ii) laki lanac protutijela; ili iii) laki i teški lanac protutijela; ili iv) multimerni polipeptid; ili v) imunoadhezin.
10. Polinukleotidni slijed koji kodira varijantni signalni peptid prema bilo kojem od patentnih zahtjeva od 6 do 7.
11. Polinukleotidni slijed prema patentnom zahtjevu 10 operabilno povezan s polinukleotidom koji kodira heterologni polipeptid, pri čemu se nakon ekspresije heterolognog polipeptida u stanici domaćina heterologni polipeptid nabire i grupira tako da tvori a) biološki aktivan heterologni polipeptid; ili b) biološki aktivan heterologni polipeptid, pri čemu je stanica domaćin i) prokariotska stanica domaćin; ili ii) E. coli.
12. Polinukleotid koji kodira protutijelo, pri čemu navedeni polinukleotid sadrži (1) polinukleotid koji kodira prvi signalni peptid operabilno povezan s polinukleotidom koji kodira teški lanac protutijela i (2) polinukleotid koji kodira drugi signalni peptid koji je operabilno povezan s polinukleotidom koji kodira laki lanac protutijela, pri čemu se nakon ekspresije protutijela u stanici domaćina teški i laki lanci nabiru i grupiraju tako da tvore biološki aktivno protutijelo, pri čemu a) prvi i/ili drugi signalni peptid je varijantni signalni peptid prema patentnom zahtjevu 6 ili 7, ili naznačen time, da se prvi i/ili drugi signalni peptid sastoji od ili sadrži slijed SEQ ID NO: 8, 11, 13, 15, 31 ili 33; ili b) prvi i/ili drugi signalni peptid je varijantni signalni peptid prema patentnom zahtjevu 6 ili 7, ili naznačen time, da se prvi i/ili drugi signalni peptid sastoji od ili sadrži slijed SEQ ID NO: 8, 11, 13, 15, 31 ili 33, pri čemu polinukleotid koji kodira protutijelo nadalje sadrži (3) polinukleotid koji kodira treći signalni peptid operabilno povezan s polinukleotidom koji kodira Fc polipeptid, pri čemu je treći signalni peptid i) varijantni signalni peptid DsbA slijeda SEQ ID NO: 3, pri čemu varijanta sadrži H regiju prosječne hidrofobnosti veće od 0,5; ili ii) varijantni signalni peptid DsbA koji sadrži mutaciju na ostatku L11 i/ili S18 slijeda SEQ ID NO: 3, pri čemu varijanta ima veću prosječnu hidrofobnost od signalnog peptida DsbA slijeda SEQ ID NO: 3, koji ima prosječnu hidrofobnost 0,50; ili iii) varijantni signalni peptid DsbA koji sadrži mutaciju na ostatku L11 i/ili S18 slijeda SEQ ID NO: 3, pri čemu varijanta ima veću prosječnu hidrofobnost od signalnog peptida DsbA slijeda SEQ ID NO: 3, koji ima prosječnu hidrofobnost 0,50, pri čemu je mutacija L11I i/ili S18Y; ili iv) varijantni signalni peptid STII koji sadrži mutaciju u ostatku S11 slijeda SEQ ID NO: 1, pri čemu varijanta signalnog peptida STII ima veću prosječnu hidrofobnost od signalnog peptida STII slijeda SEQ ID NO: 1, koji ima prosječnu hidrofobnost 0,40; ili v) varijantni signalni peptid STII koji sadrži mutaciju u ostatku S11 slijeda SEQ ID NO: 1, pri čemu varijantni signalni peptid STII ima veću prosječnu hidrofobnost od signalnog peptida STII slijeda SEQ ID NO: 1, koji ima prosječnu hidrofobnost 0,40, pri čemu je mutacija S11A, Sill ili S11L; ili vi) se sastoji ili sadrži slijed SEQ ID NO: 8, 11, 13, 15, 31 ili 33.
13. Polinukleotid prema bilo kojem od patentnih zahtjeva od 11 do 12, koji nadalje sadrži promotor operabilno povezan s a) heterolognim polipeptidom; ili b) heterolognim polipeptidom, pri čemu je promotor prokariotski promotor odabran iz skupine koju čine phoA, tac, lpp, lac-lpp, lac, ara, trp i T7 promotor.
14. Polinukleotid prema bilo kojem od patentnih zahtjeva od 11 do 13, koji nadalje sadrži (a) prvi promotor, pri čemu je prvi promotor operabilno povezan s lakim lancem i (b) drugi promotor, pri čemu je drugi promotor operabilno povezan s a) teškim lancem; ili b) teškim lancem, pri čemu su prvi i drugi promotor oba phoA promotori.
15. Polinukleotid prema patentnom zahtjevu 14, koji nadalje sadrži (c) treći promotor, naznačen time, da je treći promotor operabilno povezan s a) Fc polipeptidom, ili b) Fc polipeptidom, pri čemu je treći promotor phoA promotor.
16. Polinukleotid prema bilo kojem od patentnih zahtjeva od 12 do 15, naznačen time, da je protutijelo a) monoklonsko protutijelo; ili b) monoklonsko protutijelo, pri čemu je protutijelo kimerno protutijelo, bispecifično protutijelo, humanizirano protutijelo, fragment protutijela ili humano protutijelo; ili c) fragment protutijela, naznačen time, da je fragment protutijela jednokrako protutijelo.
17. Vektor, naznačen time, da sadrži a) polinukleotid prema bilo kojem od patentnih zahtjeva od 11 do 16; ili b) polinukleotid prema bilo kojem od patentnih zahtjeva od 11 do 16, naznačen time, da je vektor ekspresijski vektor.
18. Stanica domaćin kojasadrži a) polinukleotid prema patentnim zahtjevima od 10 do 16; ili b) polinukleotid prema patentnim zahtjevima od 10 do 16, naznačena time, da je stanica domaćin i) prokariotska stanica; ili ii) E. coli, pri čemu, opcionalno, genotipu E. coli nedostaju geni degP i prc, a nosi mutirani gen spr; ili iii) E. coli soja deficijentnog u i) endogenim proteaznim aktivnostima; ili ii) endogenim proteaznim aktivnostima, pri čemu genotipu E. coli nedostaju geni degP i prc, a nosi mutirani gen spr.
19. Stanica domaćin prema patentnom zahtjevu 18, naznačena time, da stanica domaćin a) nadalje sadrži polinukleotid koji kodira i) prokariotski protein šaperon; ili ii) prokariotski protein šaperon, pri čemu je prokariotski protein šaperon DsbA i/ili DsbC; i/ili b) pri čemu stanica domaćin prekomjerno eksprimira prokariotski protein šaperon.
20. Postupak za dobivanje heterolognog polipeptida (kao što je teški lanac i/ili laki lanac protutijela), naznačen time, da obuhvaća uzgoj stanice domaćina prema bilo kojem od patentnih zahtjeva od 18 do 19, na način da se eksprimira nukleinska kiselina, pri čemu se, nakon ekspresije navedenog polinukleotida u stanici domaćinu, heterologni polipeptid nabire tako da tvori biološki aktivan heterologni polipeptid.
21. Postupak prema patentnom zahtjevu 20, naznačen time, da postupak nadalje obuhvaća a) dobivanje heterolognog polipeptida iz i) uzgoja stanice domaćina; ili ii) uzgoja stanice domaćina, pri čemu je heterologni polipeptid dobiven iz medija uzgoja stanice domaćina; i/ili b) kombiniranje dobivenog heterolognog polipeptida s farmaceutski prihvatljivim nosačem, pomoćnom tvari ili nosačem za pripravu farmaceutskog pripravka koji sadrži heterologni polipeptid.
22. Postupak za sekreciju heterolognog polipeptida (kao što je teški lanac i/ili laki lanac protutijela), naznačen time, da obuhvaća uzgoj stanice domaćina prema bilo kojem od patentnih zahtjeva od 18 do 19, na način da se eksprimira nukleinska kiselina i luči heterologni polipeptid.
23. Postupak za translokaciju heterolognog polipeptida (kao što je teški lanac i/ili laki lanac protutijela) iz stanice, pri čemu navedeni postupak obuhvaća uzgoj stanice domaćina prema bilo kojem od patentnih zahtjeva od 18 do 19, na način da se eksprimira nukleinska kiselina i translocira heterologni polipeptid.
HRP20211748TT 2014-03-14 2015-03-16 Postupci i sastavi za sekreciju heterolognih polipeptida HRP20211748T1 (hr)

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US201461953629P 2014-03-14 2014-03-14
US201562107981P 2015-01-26 2015-01-26
US201562108476P 2015-01-27 2015-01-27
EP15716209.0A EP3116999B1 (en) 2014-03-14 2015-03-16 Methods and compositions for secretion of heterologous polypeptides
PCT/US2015/020783 WO2015139046A1 (en) 2014-03-14 2015-03-16 Methods and compositions for secretion of heterologous polypeptides

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