NL2015603A - Common light chain mouse. - Google Patents
Common light chain mouse. Download PDFInfo
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- NL2015603A NL2015603A NL2015603A NL2015603A NL2015603A NL 2015603 A NL2015603 A NL 2015603A NL 2015603 A NL2015603 A NL 2015603A NL 2015603 A NL2015603 A NL 2015603A NL 2015603 A NL2015603 A NL 2015603A
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- human
- light chain
- mouse
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Claims (27)
1. Een gastheercel omvattende: (a) een eerste nucleïnezuur sequentie coderend voor een eerste humane immunoglobuline zware keten welke aan een eerste antigen bindt, waarbij de eerste humane immunoglobuline zware keten een sequentie omvat van een eerste variabele domein van de humane zware keten welke gecodeerd wordt door een nucleotide sequentie verkregen uit van een eerste muis welke geïmmuniseerd is met het eerste antigen; (b) een tweede nucleïnezuur sequentie coderend voor een tweede humane immunoglobuline zware keten welke aan een tweede antigen bindt, waarbij de tweede humane immunoglobuline zware keten een sequentie omvat van een tweede variabele domein van de humane zware keten welke gecodeerd wordt door een nucleotide sequentie verkregen uit een tweede muis welke geïmmuniseerd is met het tweede antigen; waarbij de eerste en de tweede muis beide tot expressie brengen (i) een variabel domein van de humane immunoglobuline lichte keten welke gecodeerd wordt door een enkel herrangschikt variabel gebied van de humane immunoglobuline lichte keten gen sequentie afkomstig van dezelfde herrangschikte humane Vk1-39/Jk sequentie welke aanwezig is in de kiembaan van de muis, waarbij de herrangschikte humane Vk1-39/Jk sequentie een humaan kiembaan Vk1-39 gen segment en een humaan kiembaan Jk gen segment omvat, welke herranschikte Vk1-39/Jk sequentie operabel gekoppeld is aan een constant gebied van de immunoglobuline lichte keten sequentie, en (ii) een meervoud van variabele domeinen van de humane immunoglobuline zware keten; en (c) een derde nucleïnezuur sequentie coderend voor een humane immunoglobuline lichte keten omvattende een enkel herrangschikt variabel gebied van de humane immunoglobuline lichte keten gen sequentie afkomstig van dezelfde herrangschikte humane Vk1-39/Jk sequentie; waarbij ten minste één van de eerste of de tweede variabele domeinen van het humane immunoglobuline afkomstig is van een herrangschikt humaan Vh/D/Jh gebied geselecteerd uit de groep bestaande uit de herrangschikkingen zoals beschreven in tabellen 29 en 30 hieronder:
waarbij de gastheercel de eerste, de tweede en de derde nucleïnezuur sequenties tot expressie brengt, daarbij een bispecifïek antigeen-bindend eiwit vormend welke het eerste en het tweede antigeen bindt.
2. De gastheercel volgens conclusie 1 waarbij de eerste muis en de tweede muis dezelfde muis of verschillende muizen zijn.
3. De gastheercel volgens conclusie 1 of 2, waarbij het humane kiembaan J segment Jk5 is.
4. De gastheercel volgens een der conclusies 1-3, waarbij de muis geen endogene κ immunoglobuline lichte keten variabel gen segment heeft welke in staat is te herrangschikken om zodoende een gen te vormen welke codeert voor een variabel domein van de immunoglobuline lichte keten.
5. De gastheercel volgens een der conclusies 1-4, waarbij het eerste en het tweede antigeen: twee verschillende antigenen zijn; of hetzelfde antigeen zijn en de eerste en de tweede humane immunoglobuline zware ketens twee verschillende epitopen van hetzelfde antigeen binden.
6. De gastheercel volgens een der conclusies 1-5, waarbij: de kiembaan van de eerste muis of tweede muis een humaan Vh gen segment omvat geselecteerd uit VH3-49, Vh3-66, Vh4-28, en/ofVH4-61.
7. De gastheercel volgens een der conclusies 1-6, waarbij: het variabele domein van de humane immunoglobuline zware keten van het eerste of de tweede zware keten afkomstig is van een humaan Vh gen segment geselecteerd uit Vh3-49, Vh3-66, Vh4-28 en/ofVH4-61.
8. De gastheercel volgens conclusie 5, waarbij de eerste en tweede antigenen hetzelfde antigeen zijn en de bindingsreactie van het bispecifïeke antigeen-bindend eiwit met het genoemde zelfde antigeen ten minste tweemaal zo hoog is dan de bindingsreactie van een monospecifïek antigeen-bindend eiwit welke alleen het eerste humane immunoglobuline zware keten omvat en/of een monospecifïek antigeen-bindend eiwit welke alleen het tweede humane immunoglobuline zware keten omvat.
9. De gastheercel volgens een der conclusies 1-8, waarbij de eerste of de tweede humane imrnunoglobuline zware keten van het bispecifieke antigeen-bindend eiwit, maar niet beide, een aminozuur modificatie omvat welke haar affiniteit voor Eiwit A reduceert.
10. De gastheercel volgens conclusie 9, waarbij de modificatie geselecteerd is uit 95R (EUR 435R), 96F (EUR 436F), of een combinatie hiervan.
11. De gastheercel volgens een der conclusies 1-10, waarbij in de eerste en tweede muis het constante gebied van de imrnunoglobuline lichte keten sequentie een humane, muis of rat sequentie is en/of de murine Ch is een muis of rat Ch.
12. Een bispecifiek antigeen-bindend eiwit welke tot expressie gebracht wordt door een gastheercel volgens een der conclusies 1-11.
13. Werkwijze voor het genereren van een gastheercel voor gebruik in het maken van een bispecifieke antilichamen omvattende de volgende stappen: (a) verkrijgen van een eerste nucleïnezuur sequentie coderend voor een eerste variabele gebied van de humane immuunglobuline zware keten afkomstig van een B cel van een eerste genetisch gemodificeerde muis welke geïmmuniseerd is met een eerste antigeen van belang welke een eerste epitoop omvat, welke eerste muis: (i) een kiembaan omvat welke homozygoot of heterozygoot is voor een enkel herrangschikt variabel gebied van de humane imrnunoglobuline lichte keten gen sequentie afkomstig van een herrangschikte humane Vk1-39/Jk sequentie, waarbij de herrangschikte humane Vk1-39/Jk sequentie een humane kiembaan Vk1-39 gen segment omvat en een humane kiembaan Jk segment, waarbij de herrangschikte humane Vk1-39/Jk sequentie operabel gekoppeld is aan een constant gebied van de imrnunoglobuline lichte keten sequentie; en (ii) een kiembaan omvat die niet herrangschikte humane Vh gen segmenten, humane D gen segmenten en humane Jh gen segmenten heeft, waarbij de niet herrangschikte humane Vh gen segmenten operabel gekoppeld zijn aan een murine Ch gebied; en (iii) een populatie van B cellen omvat waarbij elke B cel van deze populatie een variabel domein van de humane immunoglobuline lichte keten tot expressie brengt welke afkomstig is van de herrangschikte humane Vk1-39/Jk sequentie en waarbij de B cel populatie ten minste één B cel omvat welke een variabel domein van de humane immunoglobuline zware keten tot expressie brengt welke afkomstig is van een herrangschikt humaan Vh/D/Jh gebied. (b) verkrijgen van een tweede nucleïnezuur sequentie coderend voor een tweede variabele gebied van de humane immuunglobuline zware keten afkomstig van een B cel van een tweede genetisch gemodificeerde muis welke geïmmuniseerd is met een tweede antigeen van belang welke een tweede epitoop omvat, welke tweede muis: (i) een kiembaan omvat welke homozygoot of heterozygoot is voor hetzelfde enkele herrangschikte variabel gebied van de humane immunoglobuline lichte keten gen sequentie als in de eerste muis, welke afkomstig is van dezelfde herrangschikte humane Vk1-39/Jk sequentie als in de eerste muis, waarbij de herrangschikte humane Vk1-39/Jk sequentie het humane kiembaan Vk1-39 gen segment omvat en het humane kiembaan Jk segment, waarbij de herrangschikte humane Vk1-39/Jk sequentie operabel gekoppeld is aan een constant gebied van de immunoglobuline lichte keten sequentie; (ii) een kiembaan omvat die niet herrangschikte humane Vh gen segmenten, humane D gen segmenten en humane Jh gen segmenten heeft, waarbij de niet herrangschikte humane Vh gen segmenten operabel gekoppeld zijn aan een murine Ch gebied; en (iii) een populatie van B cellen omvat waarbij elke B cel van deze populatie een variabel domein van de humane immunoglobuline lichte keten tot expressie brengt welke afkomstig is uit de herrangschikte humane Vk1-39/Jk sequentie en waarbij de B cel populatie ten minste één B cel omvat welke een variabel domein van de humane immunoglobuline zware keten tot expressie brengt welke afkomstig is uit een herrangschikt humaan Vh/D/Jh gebied. (c) verkrijgen van een derde nucleïnezuur sequentie omvattende deze enkele herrangschikte variabele gebied van de humane immunoglobulin lichte keten gen sequentie afkomstig van een humane Vk1-39/Jk sequentie welke aanwezig is in de kiembaan van de eerste en de tweede muis; en (d) introduceren in een gastheercel van de eerste, tweede en derde nucleïnezuur sequenties en kweken van de gastheercel zodat de eerste, tweede en derde nucleïnezuur sequenties tot expressie komen, daarbij vormend een bispecifiek antigeen-bindend eiwit welke bindt aan het eerste en de tweede epitopen van het eerste en het tweede antigeen van belang, waarbij ten minste één van de eerste of de tweede domeinen van de humane immunoglobuline zware keten verkregen is door een herrangschikking geselecteerd uit de groep bestaande uit de herrangschikkingen zoals uiteengezet in Tabel 29 en Tabel 30 hieronder:
14. Werkwijze voor het vervaardigen van een bispecifïek antigeen-bindend eiwit omvattende: (a) tot expressie brengen van een eerste variabel domein van de humane immunoglobuline zware keten welke gecodeerd wordt door een eerste variabel gebied van de humane immunoglobuline zware keten afkomstig van een B cel van een eerste genetische gemanipuleerde muis welke geïmmuniseerd is met een eerste antigeen van belang welke een eerste epitoop omvat, welke eerste muis: (i) een kiembaan omvat welke homozygoot of heterozygoot is voor een enkel herrangschikt variabel gebied van de humane immunoglobuline lichte keten gen sequentie, welke is afkomstig van een herrangschikte humane Vk1-39/Jk sequentie, waarbij de herrangschikte humane Vk1-39/Jk sequentie een humane kiembaan Vk1-39 gen segment en een humane kiembaan Jk segment omvat, welke herrangschikte humane Vk1-39/Jk sequentie operabel gekoppeld is aan een constant gebied van de immunoglobuline lichte keten sequentie; (ii) een kiembaan omvat welke niet herrangschikte humane Vh gen segmenten, humane D gen segmenten en humane Jh gen segmenten heeft, welke niet herrangschikte humane Vh gen segmenten operabel gekoppeld zijn aan een murine Ch gebied; (iii) een populatie van B cellen omvat waarbij elke B cel in de populatie een variabel domein van de humane immunoglobuline lichte keten tot expressie brengt welke afkomstig is van de herrangschikte humane Vk1-39/Jk sequentie en waarbij de B cel populatie ten minste één B cel omvat welke een variabel domein van de humane immunoglobuline zware keten tot expressie brengt; (b) tot expressie brengen van een tweede variabele domein van de humane immunoglobuline zware keten welke gecodeerd wordt door een tweede variabel gebied van de humane immunoglobuline zware keten afkomstig van een B cel van een tweede genetische gemanipuleerde muis welke geïmmuniseerd is met een tweede antigeen van belang welke een tweede epitoop omvat, welke tweede muis: (i) een kiembaan omvat welke homozygoot of heterozygoot is voor een enkele herrangschikte variabel gebied van de humane immunoglobuline lichte keten gen sequentie welke afkomstig is van dezelfde herrangschikte humane Vk1-39/Jk sequentie als in de eerste muis, waarbij de herrangschikte humane Vk1-39/Jk sequentie het humane kiembaan Vk1-39 gen segment en het humane Jk segment omvat, welke herrangschikte humane Vk1-39/Jk sequentie operabel gekoppeld is aan een constant gebied van een immunoglobuline lichte keten sequentie; (ii) een kiembaan omvat welke niet herrangschikte humane Vh gen segmenten, humane D gen segmenten en humane Jh gen segmenten heeft, welke niet herrangschikte humane Vh gen segmenten operabel gekoppeld zijn aan een murine Ch gebied; (iii) een populatie van B cellen omvat waarbij elke B cel in de populatie een variabel domein van de immunoglobuline lichte keten tot expressie brengt welke afkomstig is van de herrangschikte humane Vk1-39/Jk sequentie en waarbij de B cel populatie ten minste één B cel omvat welke een variabel domein van de humane immunoglobuline zware keten tot expressie brengt; en (c) koppelen van de tot expressie gebrachte eerste humane immunoglobuline zware keten welke het variabele domein omvat welke gecodeerd wordt door de eerste variabele gebied van de humane immunoglobuline zware keten met een enkele humane lichte keten en met de tot expressie gebrachte tweede humane immunoglobuline zware keten welke ook gekoppeld wordt met de enkele humane immunoglobuline lichte keten, de tweede humane immunoglobuline zware keten omvattende een variabel domein gecodeerd door een tweede variabele gebied van de humane immunoglobuline zware keten, zodoende genererend een bispecifïek antigeen-bindend eiwit, waarbij ten minste één van de eerste of de tweede humane immunoglobuline zware ketens afkomstig is uit een herrangschikking gekozen uit de groep bestaande uit de herrangschikkingen zoals genoemd in Tabellen 29 en 30 hieronder:
15. De werkwijze volgens conclusie 13 of 14 waarbij de eerste muis en de tweede muis dezelfde muis of verschillende muizen zijn.
16. De werkwijze volgens een der conclusies 13-15, waarbij het humane kiembaan J segment Jk5 is.
17. De werkwijze volgens een der conclusies 13-16, waarbij dezelfde of verschillende muizen geen endogeen variabel gebied van de κ immunoglobuline lichte keten gen segment bevatten welke in staat is te herrangschikken om zodoende een gen te vormen welke codeert voor een variabel domein van de immunoglobuline lichte keten.
18. De werkwijze volgens een der conclusies 13-17, waarbij de eerste en de tweede antigenen: twee verschillende antigenen zijn; of hetzelfde antigeen zijn en de eerste en de tweede humane immunoglobuline zware ketens aan verschillende epitopen op hetzelfde antigeen binden.
19. De werkwijze volgens een der conclusies 13-18, waarbij: de kiembaan van de eerste muis of de tweede muis een humaan Vh gen segment heeft geselecteerd uit Vh3-49, Vh3-66, Vh4-28 en/of Vh4-61.
20. De werkwijze volgens een der conclusies 13-19, waarbij: het humane variabel domein van de immunoglobuline zware keten van het eerste of tweede zware keten is afkomstig van een humaan Vh gen segment geselecteerd uit Vh3-49, Vh3-66, Vh4-28 en/of Vh4-61.
21. De werkwijze volgens conclusie 18, waarbij de eerste en tweede antigenen hetzelfde antigeen zijn en de bindingsreactie van het bispecifieke antigeen-bindend eiwit met het zelfde antigeen ten minste tweemaal zo groot is als de bindingsreactie van een monospecifïek antigeen-bindend eiwit welke alleen de eerste humane immunoglobuline zware keten en/of een monospecifïek antigeen-bindend eiwit welke alleen de tweede humane immunoglobuline zware keten omvat.
22. De werkwijze volgens een der conclusies 13-21, waarbij het eerste of het tweede humane immunoglobuline zware keten van het bispecifieke antigeen-bindend eiwit, maar niet beide, een aminozuur modificatie heeft welke haar affiniteit voor Eiwit A reduceert.
23. De werkwijze volgens conclusie 22, waarbij de modificatie is geselecteerd uit 95R (EUR 435R), 96F (EUR 436F) of een combinatie hiervan.
24. De werkwijze volgens een der conclusies 13-23, waarbij in de eerste en de tweede muis het constante gebied van de immunoglobuline lichte keten sequentie een humane, muis of rat sequentie is, en/of het murine Ch is muis of rat Ch.
25. Een gastheercel vervaardigd volgens de methode van conclusie 13.
26. Een bispecifiek antigeen-bindend eiwit vervaardigd met de gastheercel volgens conclusie 25.
27. Een bispecifiek antigeen-bindend eiwit vervaardigd volgens de werkwijze volgens een der conclusies 14-24.
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| NL2014775A (en) | 2015-06-09 |
| NL2015603B1 (en) | 2016-09-23 |
| WO2014160179A4 (en) | 2014-11-20 |
| NL2012424A (en) | 2014-09-16 |
| RU2015143108A (ru) | 2017-04-20 |
| NL2013851C2 (en) | 2015-06-08 |
| AU2014244079A1 (en) | 2015-09-24 |
| MX2015012540A (es) | 2016-04-19 |
| JP2016519568A (ja) | 2016-07-07 |
| HK1218550A1 (zh) | 2017-02-24 |
| NL2013851A (en) | 2015-01-12 |
| EP2970437A1 (en) | 2016-01-20 |
| WO2014160179A1 (en) | 2014-10-02 |
| CN105189545A (zh) | 2015-12-23 |
| NL2014775B1 (en) | 2016-03-16 |
| KR20150126863A (ko) | 2015-11-13 |
| NL2012424C2 (en) | 2014-12-08 |
| CA2903696A1 (en) | 2014-10-02 |
| SG11201506294TA (en) | 2015-09-29 |
| IL240562A0 (en) | 2015-09-24 |
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