DK2825036T3 - Histidinmanipulerede letkædeantistoffer og genetisk modificerede gnavere til generering heraf - Google Patents

Histidinmanipulerede letkædeantistoffer og genetisk modificerede gnavere til generering heraf Download PDF

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DK2825036T3
DK2825036T3 DK13713652.9T DK13713652T DK2825036T3 DK 2825036 T3 DK2825036 T3 DK 2825036T3 DK 13713652 T DK13713652 T DK 13713652T DK 2825036 T3 DK2825036 T3 DK 2825036T3
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light chain
human
histidine
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gene sequence
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John Mcwhirter
Lynn Macdonald
Andrew J Murphy
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Regeneron Pharma
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Claims (20)

1. Genetisk modificeret gnaver, der i sin kimbane ved et endogent immunoglobulin-letkædelocus omfatter et immunoglobulin-letkædelocus, der omfatter en enkelt omarrangeret human immunoglobulin-letkæde-variabel-gensekvens afledt af en omarrangeret Vk1-39/Jk- eller VK3-20/JK-sekvens, hvor den enkelte omarrangerede humane immunoglobulin-letkæde-region-gensekvens er operativt bundet til en immunoglobulin-letkæde-konstant-region-gensekvens, og hvor (i) den enkelte omarrangerede humane immunoglobulin-letkæde-region-gensekvens omfatter VK1-39/Ji<-gensekvensen, der omfatter en udskiftning af mindst én ikke-histidinkodon med en histidinkodon designet til at udtrykke et histidin (a) ved en position udvalgt fra 105,106,108,111 og en kombination deraf; (b) ved positionerne 105,106,108 og 111 eller (c) ved positionerne 106,108 og 111; eller (ii) den enkelte omarrangerede humane immunoglobulin-letkæde-region-gensekvens omfatter Vk3-20/Jk omfattende en udskiftning af mindst én ikke-histidinkodon med en histidinkodon designet til at udtrykke et histidin (a) ved en position udvalgt fra 105,106,107,109 og en kombination deraf; (b) ved positionerne 105,106,107 og 109 eller (c) ved positionerne 105,106 og 109; hvor positionerne er i henhold til IMGT-nummerering.
2. Gnaver ifølge krav 1, hvor: immunoglobulin-letkæde-konstant-region-gensekvensen er en gnaver-immunoglobulin-letkæde-konstant-region-gensekvens, såsom en endogen gnaver-immunoglobulin-letkæde-konstant-region-gensekvens.
3. Gnaver ifølge et hvilket som helst af de foregående krav, hvor: gnaveren endvidere i sin kimbane omfatter en ikke-omarrangeret immunoglobulin-tungkæde-variabel-region-gensekvens, der omfatter humane Vh-, Dh- og JH-segmenter operativt bundet til en immunoglobulin-tungkæde-konstant-region-gensekvens, eventuelt hvor immunoglobulin-tungkæde-konstant-region-gensekvensen er en gnaver-immunoglobulin-tungkæde-konstant-region- gensekvens, såsom en endogen gnaver-immunoglobulin-konstant-region- gensekvens, eventuelt ved et endogent gnaver-immunoglobulin-tungkædelocus.
4. Gnaver ifølge et hvilket som helst af de foregående krav, hvor gnaveren mangler en funktionel ikke-omarrangeret immunoglobulin-letkæde-variabel-region.
5. Gnaver ifølge et hvilket som helst af de foregående krav, hvor den enkelte omarrangerede humane immunoglobulin-letkæde-region-gensekvens er afledt af en omarrangeret Vk1-39/Jk5- eller Vk3-20/Jk1-gensekvens.
6. Gnaver ifølge et hvilket som helst af de foregående krav, hvor gnaveren omfatter en population af antigenspecifikke antistoffer, der sammenlignet med en population af antigenspecifikke antistoffer genereret hos gnavere, som ikke omfatter en substitueret histidinkodon i en immunoglobulin-letkæde-variabel-region, er beriget med antigenspecifikke antistoffer, der udviser et fald i dissociativ halveringstid (ti/2) ved et surt pH sammenlignet med neutralt pH på mindst ca. 2-fold, mindst ca. 3-fold, mindst ca. 4-fold, mindst ca. 5-fold, mindst ca. 10-fold, mindst ca. 15-fold, mindst ca. 20-fold, mindst ca. 25-fold, mindst ca. 30-fold eller eventuelt ca. 30-fold eller mere.
7. Gnaver ifølge et hvilket som helst af de foregående krav, hvor gnaveren udtrykker et antistof, der omfatter et humant immunoglobulin-letkæde-variabelt-domæne med en substitution af mindst én ikke-histidinrest med et histidin ved en aminosyreposition kodet for af den mindst ene kodon, der er substitueret i immunoglobulin-letkæde-variabel-region-gensekvensen.
8. Gnaver ifølge et hvilket som helst af de foregående krav, hvor gnaveren er en rotte.
9. Gnaver ifølge et hvilket som helst af kravene 1 -7, hvor gnaveren er en mus.
10. Gnaver ifølge et hvilket som helst af kravene 8-9, hvor immunoglobulin-letkæde-konstant-region-gensekvensen er udvalgt fra en rotte- eller en muse- immunoglobulin-letkæde-konstant-region-gensekvens, eventuelt ved henholdsvis et endogent rotte-letkædelocus eller et endogent muse-letkædelocus; og hvor gnaveren eventuelt endvidere i sin kimbane omfatter en ikke-omarrangeret immunoglobulin-tungkæde-variabel-region-sekvens, der omfatter humane Vh-, Dh- og JH-segmenter operativt bundet til en immunoglobulin-tungkæde-konstant-region-gensekvens udvalgt fra en rotte- eller en muse-tungkæde-konstant-region-gensekvens; eventuelt henholdsvis ved et endogent rotte-tungkædelocus eller ved et endogent muse-immunoglobulin-tungkædelocus.
11. Gnaver ifølge krav 10, hvor gnaveren udtrykker en population af antigenspecifikke antistoffer som reaktion på et antigen af interesse, hvor samtlige antistoffer fra populationen omfatter: variable immunoglobulin-letkædedomæner afledt af den samme enkelte omarrangerede humane tungkæde-variabel-region-gensekvens, der omfatter en substitution af mindst én ikke-histidinkodon med en histidinkodon, og immunoglobulin-tungkæder, der omfatter humane tungkæde-variable-domæner afledt af et repertoire af humane tungkæde-V-, D- og J-segmenter.
12. Fremgangsmåde til frembringelse af gnaveren ifølge et hvilket som helst af de foregående krav, hvor fremgangsmåde omfatter udskiftning af samtlige funktionelle immunoglobulin-letkæde-variabel-region-gensekvenser ved et endogent immunoglobulin-letkædelocus hos gnaveren med den enkelte omarrangerede humane immunoglobulin-letkæde-region-gensekvens, hvor den enkelte omarrangerede humane immunoglobulin-letkæde-region-gensekvens er operativt bundet til en immunoglobulin-letkæde-konstant-region-gensekvens, såsom en endogen gnaver-letkæde-konstant-region-gensekvens ved det endogene gnaver-immunoglobulin-letkædelocus.
13. Fremgangsmåde til generering af et antistof, der har pH-afhængig binding til et antigen af interesse, hvilken fremgangsmåde omfatter: immunisering af en gnaver ifølge et hvilket som helst af kravene 1 til 11, eller en gnaver frembragt ved hjælp af fremgangsmåden ifølge krav 12 med et antigen af interesse; og opnåelse af en B-celle, der udtrykker et antistof, der binder til antigenet af interesse med en ønsket affinitet ved et neutralt pH, mens der udvises reduceret binding til antigenet af interesse ved et surt pH, og eventuelt (a) anvendelse af B-cellen til at frembringe et hybridom eller (b) isolering af DNA, der koder for antistoffet, fra B-cellen eller hybridomet og udskiftning af DNA’et i ekspressionsvektorer og transfektion af vektorerne ind i en værtscelle.
14. Fremgangsmåde ifølge krav 13, hvor antistoffet udviser en dissociativ halveringstid (ti/2) ved surt pH og 37 °C på ca. 2 minutter eller mindre.
15. Fremgangsmåde ifølge krav 13 eller 14, hvor fremgangsmåden er til frembringelse af et bispecifikt antistof, der har pH-afhængig binding til et eller flere antigener.
16. Fremgangsmåde ifølge krav 15, hvor fremgangsmåden omfatter: (a) identificering af en B-celle, der koder for et første tungkæde-variabelt-domæne, der binder en første epitop af interesse og udtrykker et antistof, der udviser pH-afhængig antigenbinding, og isolering af en første nukleinsyre, der koder for den variable tungkæderegion; og (b) identificering af en B-celle, der koder for et andet tungkæde-variabel-region-domæne, der binder en anden epitop af interesse og udtrykker et antistof, der udviser pH-afhængig antigenbinding, og isolering af en anden nukleinsyre, der koder for den anden tungkæde-variable-region; (c) udvælgelse af en tredje nukleinsyresekvens afledt af den enkelte omarrangerede humane immunoglobulin-letkæde-variabel-region-sekvens; og (d) ekspression af den første, anden og tredje nukleinsyresekvens, der udtrykker den første, anden og tredje nukleinsyresekvens for at danne det bispecifikke antistof.
17. Gnavercelle isoleret fra en gnaver ifølge et hvilket som helst af kravene 1 til 11, eller isoleret fra en gnaver frembragt ved fremgangsmåden ifølge krav 12, hvor cellen omfatter en enkelt omarrangeret human immunoglobulin-letkæde-variabel-gensekvens, der er operativt bundet til en immunoglobulin-letkæde-konstant-region-gensekvens og er afledt af en omarrangeret Vk1-39/Jk- eller Vk3-20/JK-sekvens, og hvor (i) den enkelte omarrangerede humane immunoglobulin-letkæde-region-gensekvens omfatter VKl-39/J«-gensekvensen, der omfatter en udskiftning af mindst én ikke-histidinkodon med en histidinkodon designet til at udtrykke et histidin (a) ved en position udvalgt fra 105, 106, 108, 111 og en kombination deraf (b) ved positionerne 105, 106, 108 og 111 eller (c) ved positionerne 106, 108 og 111; eller (ii) den enkelte omarrangerede humane immunoglobulin-letkæde-region-gensekvens omfatter Vk3-20/Jk omfattende en udskiftning af mindst én ikke-histidinkodon med en histidinkodon designet til at udtrykke et histidin (a) ved en position udvalgt fra 105,106,107, 109 og en kombination deraf; (b) ved positionerne 105, 106, 107, og 109, eller (c) ved positionerne 105, 106, og 109; hvor positionerne er i henhold til IMGT-nummerering.
18. Gnavercelle ifølge krav 17 hvor cellen er en B-celle.
19. Hybridom frembragt fra en B-celle isoleret fra gnaveren ifølge et hvilket som helst af kravene 1 til 11, eller en gnaver frembragt ved hjælp af fremgangsmåden ifølge krav 12, hvor hybridomet omfatter et immunoglobulin-letkædelocus, der omfatter en enkelt omarrangeret human immunoglobulin-letkæde-variabel-region-gensekvens, der er operativt bundet til en immunoglobulin-letkæde-konstant-region-gensekvens og er afledt af en omarrangeret Vk1-39/Jk-eller VK3-20/JK-sekvens, og hvor (i) den enkelte omarrangerede humane immunoglobulin-letkæde-region-gensekvens omfatter VKl-39/J«-gensekvensen, der omfatter en udskiftning af mindst én ikke-histidinkodon med en histidinkodon designet til at udtrykke et histidin (a) ved en position udvalgt fra 105, 106, 108, 111 og en kombination deraf (b) ved positionerne 105, 106, 108 og 111 eller (c) ved positionerne 106, 108 og 111; eller (ii) den enkelte omarrangerede humane immunoglobulin-letkæde-region-gensekvens omfatter Vk3-20/Jk omfattende en udskiftning af mindst én ikke-histidinkodon med en histidinkodon designet til at udtrykke et histidin (a) ved en position udvalgt fra 105,106,107,109 og en kombination deraf; (b) ved positionerne 105, 106, 107 og 109 eller (c) ved positionerne 105, 106 og 109; hvor positionerne er i henhold til IMGT-nummerering.
20. Gnavercelle, der omfatter et immunoglobulin-letkædelocus, der omfatter ved et endogent immunoglobulin-letkædelocus en enkelt omarrangeret human immunoglobulin-letkæde-variabel-gensekvens operativt bundet til en immunoglobulin-letkæde-konstant-region-sekvens og afledt af en omarrangeret Vk1-39/Jk- eller VK3-20/J«-sekvens, og hvor (i) den enkelte omarrangerede humane immunoglobulin-letkæde-region-gensekvens omfatter VKl-39/J«-gensekvensen, der omfatter en udskiftning af mindst én ikke-histidinkodon med en histidinkodon designet til at udtrykke et histidin (a) ved en position udvalgt fra 105, 106, 108, 111 og en kombination deraf (b) ved positionerne 105, 106, 108 og 111 eller (c) ved positionerne 106, 108 og 111; eller (ii) den enkelte omarrangerede humane immunoglobulin-letkæde-region-gensekvens omfatter Vk3-20/Jk omfattende en udskiftning af mindst én ikke-histidinkodon med en histidinkodon designet til at udtrykke et histidin (a) ved en position udvalgt fra 105,106,107, 109 og en kombination deraf; (b) ved positionerne 105, 106, 107 og 109, eller (c) ved positionerne 105, 106 og 109; hvor positionerne er i henhold til IMGT-nummerering.
DK13713652.9T 2012-03-16 2013-03-15 Histidinmanipulerede letkædeantistoffer og genetisk modificerede gnavere til generering heraf DK2825036T3 (da)

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