HRP20131107T1 - Anti-notch1 nrr-protutijela i postupak njihove uporabe - Google Patents

Anti-notch1 nrr-protutijela i postupak njihove uporabe Download PDF

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HRP20131107T1
HRP20131107T1 HRP20131107AT HRP20131107T HRP20131107T1 HR P20131107 T1 HRP20131107 T1 HR P20131107T1 HR P20131107A T HRP20131107A T HR P20131107AT HR P20131107 T HRP20131107 T HR P20131107T HR P20131107 T1 HRP20131107 T1 HR P20131107T1
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notch1
nrr
antibody
hvr
sequence
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HRP20131107AT
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Christian W. Siebel
Yan Wu
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Genentech, Inc.
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Claims (25)

1. Izolirano anti-Notch1-protutijelo negativnog regulatorskog područja (NRR), naznačeno time, da spomenuto protutijelo, kada je vezano na spomenuti Notch1-NRR, smanjuje signalizaciju od Notch1, s time da Notch1-NRR je humani Notch1-NRR koji ima amino kiselinsku sekvencu prikazanu kao amino kiseline 1446 do 1735 od SEQ ID NO:56 ili je mišji Notch1-NRR koji ima amino kiselinsku sekvencu prikazanu kao amino kiseline 1446 do 1725 od SEQ ID NO:57.
2. Izolirano anti-Notch1-NRR-protutijelo prema zahtjevu 1, naznačeno time, da spomenuto protutijelo veže humani Notch1-NRR i mišji Notch1-NRR.
3. Izolirano anti-Notch1-NRR-protutijelo prema zahtjevu 1 ili 2, naznačeno time, da se spomenuto protutijelo veže na Notch1-NRR s Kd od 1 × 10-7 ili jačim.
4. Izolirano anti-Notch1-NRR-protutijelo prema zahtjevu 1 ili 2, naznačeno time, da spomenuto vezanje je s (i) Kd od 1 x 10-8 ili jačim ili (ii) Kd od 1 × 10-9 ili jačim.
5. Izolirano anti-Notch1-NRR-protutijelo prema bilo kojem zahtjevu od 1 do 4, naznačeno time, da obuhvaća: (a) barem jedan, dva, tri, četiri ili pet hipervarijabilnih područja (HVR) sekvenca odabranih iz skupine koju čine: (i) HVR-L1 koje sadrži sekvencu A1-A11, gdje A1-A11 je RASQDVSTAVA (SEQ ID NO:7) (ii) HVR-L2 koje sadrži sekvencu B1-B7, gdje B1-B7 je SASFLYS (SEQ ID NO:8) (iii) HVR-L3 koje sadrži sekvencu C1-C9, gdje C1-C9 je QQSYTTPPT (SEQ ID NO:9) (iv) HVR-H1 koje sadrži sekvencu D1-D10, gdje D1-D10 je GFTFSSYWIH (SEQ ID NO:1) (v) HVR-H2 koje sadrži sekvencu E1-E18, gdje E1-E18 je ARINPSNGSTNYADSVKG (SEQ ID NO:2) (vi) HVR-H3 koje sadrži sekvencu F1-F14, gdje F1-F14 je ARGSGFRWVMDY (SEQ ID NO:6) i (b) barem jednu varijantu HVR, gdje varijanta HVR sekvence sadrži supstituciju barem jednog ostatka sekvence prikazane u SEQ ID NO:1 do SEQ ID NO:12.
6. Protutijelo prema zahtjevu 5, naznačeno time, da HVR-L3 varijanta obuhvaća 1, 2, 3 ili 4 supstitucije u bilo kojoj kombinaciji od sljedećih pozicija: C3, C4, C5 i C8, gdje C3 je S ili F, C4 je Y ili F, C5 je T ili S i C8 je P ili A ili S; ili gdje HVR-H2 varijanta obuhvaća 1, 2, 3 ili 4 supstitucije u bilo kojoj kombinaciji od sljedećih pozicija: E6, E8, E10 i E11, gdje E6 je S ili P ili A, E8 je G ili R, E10 je T ili A ili N, a E11 je N ili H ili Q ili R.
7. Izolirano anti-Notch1-NRR-protutijelo prema bilo kojem zahtjevu od 1 do 4, naznačeno time, da protutijelo obuhvaća barem jednu, barem dvije, barem tri ili sve četiri od sljedećih: (i) HVR-H1 sekvenca koja sadrži sekvencu SEQ ID NO:1; (ii) HVR-H2 sekvenca koja sadrži sekvencu SEQ ID NO:2, 3, 4 ili 5; (iii) HVR-H3 sekvenca koja sadrži sekvencu SEQ ID NO:6; i (iv) HVR-L3 sekvenca koja sadrži sekvencu SEQ ID NO:10, 11 ili 12.
8. Protutijelo prema zahtjevu 7, naznačeno time, da protutijelo obuhvaća HVR-L1, HVR-L2, HVR-L3, HVR-H1, HVR-H2 i HVR-H3, gdje svaka po redu sadrži: (i) SEQ ID NO:7, 8, 9, 1, 2, 6; (ii) SEQ ID NO:7, 8, 10, 1, 3, 6; (iii) SEQ ID NO:7, 8, 11, 1, 4, 6; ili (iv) SEQ ID NO:7, 8, 12, 1, 5, 6.
9. Protutijelo, naznačeno time, da se (i) natječe s protutijelom prema zahtjevu 8 za vezanje na Notch1-NRR, ili (ii) veže na isti epitop na Notch1-NRR kao protutijelo prema zahtjevu 8.
10. Protutijelo prema bilo kojem zahtjevu od 5 do 8, naznačeno time, da protutijelo obuhvaća (i) okvirnu sekvencu, gdje barem dio od okvirne sekvence je humana konsenzualna okvirna sekvenca, (ii) humanu podgrupu κ konsenzualne okvirne sekvence ili (iii) humanu podgrupu III jakog lanca od konsenzualne okvirne sekvence.
11. Protutijelo prema zahtjevu 10 (iii), naznačeno time, da protutijelo obuhvaća supstituciju na jednoj ili više od pozicija 71, 73 ili 78, pri čemu, opcijski, supstitucija je jedan ili više od R71A, N73T ili N78A.
12. Polinukleotid, naznačen time, da kodira protutijelo prema bilo kojem od zahtjeva 1 do 11.
13. Vektor, naznačen time, da obuhvaća polinukleotid prema zahtjevu 12, pri čemu, opcijski, taj vektor je vektor ekspresije.
14. Stanica domaćina, naznačena time, da obuhvaća vektor prema zahtjevu 13, pri čemu, opcijski, ta stanica domaćina je prokariotska, eukariotska ili od sisavca.
15. Postupak izrade anti-Notch1-NRR-protutijela, naznačen time, da spomenuti postupak obuhvaća (a) ekspresiju vektora ekspresije prema zahtjevu 13 u prikladnoj stanici domaćina i (b) ponovno dobivanje protutijela.
16. Anti-Notch1-NRR-protutijelo prema bilo kojem zahtjevu od 1 do 11, naznačeno time, da se upotrebljava u postupku liječenja.
17. Anti-Notch1-NRR-protutijelo prema bilo kojem zahtjevu od 1 do 11, naznačeno time, da se upotrebljava u postupku liječenja pojedinca koji ima poremećaj povezan s povećanjem signalizacije Notch1, pri čemu postupak obuhvaća davanje djelotvorne količine spomenutog anti-Notch1-NRR-protutijela pojedincu, pri čemu taj poremećaj je (i) rak, tumor, i/ili poremećaj proliferacije stanice, (ii) neurodegenerativni poremećaj ili (iii) sadrži patološko stanje povezano s angiogenezom koja je intraokularna neovaskularna bolest.
18. Anti-Notch1-NRR-protutijelo za uporabu prema zahtjevu 17, naznačeno time, da poremećaj je rak, tumor, i/ili poremećaj proliferacije stanice odabran iz skupine koju čine kolorektalni rak, gastrointestinalni rak, rak pluća, rak dojke, rak jajnika, akutna limfoblastična leukemija T-stanica (T-ALL) i melanom.
19. Anti-Notch1-NRR-protutijelo za uporabu prema zahtjevu 18, naznačeno time, da poremećaj je adenokarcinom crijeva ili adenom, rak pluća ne-malih stanica, rak jajnika ili karcinom dojke.
20. Anti-Notch1-NRR-protutijelo za uporabu prema bilo kojem zahtjevu od 17 do 19, naznačeno time, da postupak nadalje obuhvaća davanje pojedincu djelotvorne količine drugog lijeka, pri čemu anti-Notch1-NRR-protutijelo je prvi lijek.
21. Anti-Notch1-NRR-protutijelo za uporabu prema zahtjevu 20, naznačeno time, da drugi lijek je (i) neko drugo protutijelo, kemoterapeutsko sredstvo, cititoksično sredstvo, anti-angiogensko sredstvo, imunosupresivno sredstvo, prolijek, citokin, antagonist citokina, citotoksična radioterapija, kortikosteroid, anti-emetik, cjepivo protiv raka, analgetik ili sredstvo inhibicije rasta, ili (ii) tamoksifen, letrozol, eksemestan, anastrozol, irinotekan, cetuksimab, fulvestrant, vinorelbin, erlotinib, bevacizumab, vinkristin, imatinib, sorafenib, lapatinib ili trastuzumab.
22. Anti-Notch1-NRR-protutijelo za uporabu prema zahtjevu 20 ili 21, naznačeno time, da se drugi lijek daje prije ili neposredno nakon davanja anti-Notch1-NRR-protutijela, ili istovremeno s anti-Notch1-NRR-protutijelom.
23. Anti-Notch1-NRR-protutijelo za uporabu prema bilo kojem zahtjevu od 17 do 22, naznačeno time, da navedeni pojedinac je čovjek.
24. Anti-Notch1-NRR-protutijelo za uporabu prema zahtjevu 17, naznačeno time, da je poremećaj povezan s aktiviranjem mutacije u Notch1-amino kiselinskoj sekvenci.
25. Sastav, naznačen time, da obuhvaća anti-Notch1-NRR-protutijelo prema bilo kojem zahtjevu od 1 do 11 i farmaceutski nosač.
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