HRP20090324T1 - Moduliranje interakcije između hgf beta lanca i c-met - Google Patents

Moduliranje interakcije između hgf beta lanca i c-met Download PDF

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HRP20090324T1
HRP20090324T1 HR20090324T HRP20090324T HRP20090324T1 HR P20090324 T1 HRP20090324 T1 HR P20090324T1 HR 20090324 T HR20090324 T HR 20090324T HR P20090324 T HRP20090324 T HR P20090324T HR P20090324 T1 HRP20090324 T1 HR P20090324T1
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K. Kirchhofer Daniel
A. Lazarus Robert
Yao Xiaoyi
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Genentech
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Abstract

Postupak za pretraživanje ili za identifikaciju tvari koja selektivno veže lanac aktiviranog fatora rasta hepatocita (hepatocyte growth factor, HGF), naznačen time, da spomenuti postupak obuhvaća: usporedbu (i) vezanja tvari kandidata na aktivirani HGF lanac, s (ii) vezanjem tvari kandidata na usporedbeni HGF lanac, pri čemu spomenuti usporedbeni lanac u usporedbi s aktiviranim HGF lancem ima smanjeno vezanje na c-met, prema čemu se tvar kandidat, koja pokazuje veći afinitet vezanja na aktivirani HGF lanac nego na usporedbeni HGFlanac, bira kao tvar koja selektivno veže aktivirani HGF lanac. Patent sadrži još 37 patentnih zahtjeva.

Claims (38)

1. Postupak za pretraživanje ili za identifikaciju tvari koja selektivno veže β lanac aktiviranog fatora rasta hepatocita (hepatocyte growth factor, HGF), naznačen time, da spomenuti postupak obuhvaća: usporedbu (i) vezanja tvari kandidata na aktivirani HGF β lanac, s (ii) vezanjem tvari kandidata na usporedbeni HGF β lanac, pri čemu spomenuti usporedbeni β lanac u usporedbi s aktiviranim HGF β lancem ima smanjeno vezanje na c-met, prema čemu se tvar kandidat, koja pokazuje veći afinitet vezanja na aktivirani HGF β lanac nego na usporedbeni HGF β lanac, bira kao tvar koja selektivno veže aktivirani HGF β lanac.
2. Postupak prema zahtjevu 1, naznačen time, da se usporedbeni β lanac nalazi unutar jednolančanog HGF polipeptida.
3. Postupak prema zahtjevu 1, naznačen time, da je usporedbeni β lanac fuzioniran na svom N-kraju na dio C-terminalnog područja HGF β lanca, pri čemu položaj 494 (koji odgovara divljem tipu humanog HGF) C-terminalnog područja je amino kiselina različita od arginina.
4. Postupak prema zahtjevu 3, naznačen time, da amino kiselina na položaju 494 je glutaminska kiselina.
5. Postupak prema zahtjevu 3 ili 4, naznačen time, da dio C-terminalnog područja HGF-a obuhvaća aminokiselinsku sekvencu od ostatka 479 do 494 humanog HGF-a.
6. Postupak za pretraživanje tvari koja blokira c-met aktivaciju, naznačen time, da spomenuti postupak obuhvaća pretraživanje tvari koja veže c-met i koja blokira specifično vezanje HGF β lanca na c-met.
7. Postupak prema zahtjevu 6, naznačen time, da se tvar nadmeće s HGF β lancem za vezanje na c-met.
8. Upotreba tvari koja inhibira specifično vezanje HGF β lanca na c-met, naznačena time, da se koristi u pripravi lijeka za liječenje patoloških stanja povezanih s aktivacijom c-met u pojedincu, pri čemu tvar je: (a) peptid koji uključuje aminokiselinsku sekvencu koja ima najmanje 60%-tni sekvencni identitet sa sekvencom VDWVCFRDLGCDWEL; (b) antitijelo ili njegov fragment koji se specifično veže na spomenuti aktivirani HGF β lanac; ili (c) njihova kombinacija, pri čemu se tvar veže na aktivirani HGF β lanac i inhibira specifično vezanje spomenutog aktiviranog HGF β lanca na c-met, i pri čemu patološko stanje je rak, tumor, poremećaj proliferacije stanica, imunosni poremećaj ili poremećaj povezan s angiogenezom.
9. Tvar koja inhibira specifično vezanje HGF β lanca na c-met, naznačena time, da spomenuta tvar je: (a) peptid koji uključuje aminokiselinsku sekvencu koja ima najmanje 60%-tnu identičnost sekvence sa sekvencom VDWVCFRDLGCDWEL; (b) antitijelo ili njegov fragment koji se specifično veže na spomenuti aktivirani HGF β lanac; ili (c) njihova kombinacija, pri čemu se tvar veže na aktivirani HGF β lanac i inhibira specifično vezanje spomenutog aktiviranog HGF β lanca na c-met, za liječenje patološkog stanja povezanog s aktivacijom c-met u pojedincu, pri čemu patološko stanje je rak, tumor, poremećaj proliferacije stanica, imunosni poremećaj ili poremećaj povezan s angiogenezom.
10. Upotreba prema zahtjevu 8 ili tvar prema zahtjevu 9, naznačena time, da je identitet aminokiselinske sekvence najmanje 70%, 80%, 90%, 95% ili 98%.
11. Upotreba prema zahtjevu 8 ili tvar prema zahtjevu 9, naznačena time, da peptid uključuje aminokiselinsku sekvencu VDWVCFRDLGCDWEL ili aminokiselinsku sekvencu odabranu iz skupine prikazane u tablici 1 koju čine: V D W I C F R D I G C D W V V V D W I C L R D V G C D W V Q V D W V C F R D F G C D W V V V D W V C F R D F G C D W V L V D W V C F R D F G C D W V H V D W V C F R D F G C Y W E Q V D W V C F R D F G c W F E S V D W V C F R D H G C E Y V E V D W V C F R D I G C D W V L V D W V C F R E F G C D W V L V D W V C F R E I G C D W V L V D W V C F R G I G C D W V L V D W V C L R D I G C D W V P V D W V C F R D L G C D Y E H V D W V C F R D L G C D Y V L V D W V C F R E L G C D W V V V D W V C F R E L G C D W V F V D W V C F R D M G C Y Y E L V D W V C F R D M G C D W V L V D W V C F R D S G C Y Y A T V D W V C F R D T G C D W V L V D W V C F R D V G C D W V Q V D W V C F R D V G C D W V L V D W V C F R E V G C D W V L V D W V C F R D V G C D W V M V D W V C F R D Y G C D M V P V D W V C F R D V G C D W V Q V D W V C F R D Y G C E W V A V D W V C F R D V G C E W V V V N W V C F R D I G C D W V L V N W V C F R D L G C D W V A V N W V C F R D L G C D W V L V N W V C F R D L G C D W V P V N W V C F R D L G C D W V V V N W V C F R D Q G C D W V L V N W V C F R D V G C D W V L V N W V C F R E L G C D W V L V N W V C L R D V G C D W V L
12. Upotreba prema zahtjevu 8 ili tvar prema zahtjevu 9, naznačena time, da se peptid sastoji od aminokiselinske sekvence prikazane u zahtjevu 11.
13. Upotreba prema zahtjevu 8 ili tvar prema zahtjevu 9, naznačena time, da antitijelo je monoklono, jednolančano, kimerno, humanizirano ili humano antitijelo.
14. Upotreba ili tvar prema bilo kojem zahtjevu 8 do 13, naznačena time, da rak je rak dojke, kolorektalni rak, rak pluća, rak pankreasa ili glioblastom.
15. Upotreba ili tvar prema bilo kojem zahtjevu 8 do 14, naznačena time, da je tvar dobivena bilo kojim postupkom prema zahtjevima 1-5.
16. Postupak za pretraživanje HGF receptor antagonista koji blokira vezanje HGF na njegov receptor, naznačen time, da spomenuti postupak uključuje selekciju tvari koja se veže na najmanje jedan od ostataka 534, 578, 619, 673, 692, 693, 694, 695, 696, 699 i/ili 702 od HGF β lanca.
17. Postupak prema zahtjevu 16, naznačen time, da se tvar veže barem na ostatke 673 i 695.
18. Postupak prema zahtjevu 17, naznačen time, da se tvar također veže barem na jedan od ostataka 534, 578 i 692.
19. Molekula koja se veže na β lanac aktivirnog hepatocitnog faktora rasta i inhibira specifično vezanje spomenutog aktiviranog HGF β lanca na c-met, naznačena time, da spomenuta molekula je: (a) peptid koji uključuje aminokiselinsku sekvencu koja ima najmanje 60%-tnu identičnost sekvence sa sekvencom VDWVCFRDLGCDWEL; (b) antitijelo ili njegov fragment koji se specifično veže na spomenuti aktivirani HGF β lanac; ili (c) njihova kombinacija.
20. Molekula prema zahtjevu 19, naznačena time, da identitet aminokiselinske sekvence je najmanje 70%, 80%, 90%, 95% ili 98%.
21. Molekula prema zahtjevu 19, naznačena time, da peptid uključuje aminokiselinsku sekvence VDWVCFRDLGCDWEL ili aminokiselinsku sekvencu odabranu iz skupine prikazane u tablici 1 koju čine: V D W I C F R D I G C D W V V V D W I C L R D V G C D W V Q V D W V C F R D F G C D W V V V D W V C F R D F G C D W V L V D W V C F R D F G C D W V H V D W V C F R D F G C Y W E Q V D W V C F R D F G C W F E S V D W V C F R D H G C E Y V E V D W V C F R D I G C D W V L V D W V C F R E F G C D W V L V D W V C F R E I G C D W V L V D W V C F R G I G C D W V L V D W V C L R D I G C D W V P V D W V C F R D L G C D Y E H V D W V C F R D L G C D Y V L V D W V C F R E L G C D W V V V D W V C F R E L G C D W V F V D W V C F R D M G C Y Y E L V D W V C F R D M G C D W V L V D W V C F R D S G C Y Y A T V D W V C F R D T G C D W V L V D W V C F R D V G C D W V Q V D W V C F R D V G C D W V L V D W V C F R E V G C D W V L V D W V C F R D V G C D W V M V D W V C F R D Y G C D M V P V D W V C F R D V G C D W V Q V D W V C F R D Y G C E W V A V D W V C F R D V G C E W V V V N W V C F R D I G C D W V L V N W V C F R D L G C D W V A V N W V C F R D L G C D W V L V N W V C F R D L G C D W V P V N W V C F R D L G C D W V V V N W V C F R D Q G C D W V L V N W V C F R D V G C D W V L V N W V C F R E L G C D W V L V N W V C L R D V G C D W V L
22. Molekula prema zahtjevu 19, naznačena time, da se peptid sastoji od aminokiselinske sekvence prikazane u zahtjevu 21.
23. Molekula prema zahtjevu 19, naznačena time, da antitijelo je monoklono, jednolančano, kimerno, humanizirano ili humano antitijelo.
24. Molekula prema bilo kojem zahtjevu 19 do 23, naznačena time, da je afinitet vezanja molekule za aktivirani oblik lanca veći od afiniteta vezanja molekule za lanac u zimogenom obliku.
25. Molekula bilo kojem prema zahtjevu 19 do 24, naznačena time, da se ona veže na aktivnu stranu β lanca.
26. Molekula prema zahtjevu 25, naznačena time, da spomenuta aktivna strana uključuje barem jedan od ostataka 534, 578, 619, 673, 692, 693, 694, 695, 696, 699 i/ili 702 β lanca.
27. Molekula prema zahtjevu 25, naznačena time, da aktivirani β lanac ima konformaciju β lanca dobivenog cijepanjem jednolančanog HGF.
28. Molekula prema zahtjevu 27, naznačena time, da je spomenuto odcjepljenje na ili neposredno do ostataka 494 i 495 jednolančanog HGF.
29. Molekula prema zahtjevu 28, naznačena time, da se spomenuto cijepanje dešava između ostataka 494 i 495 jednolančanog HGF.
30. Molekule bilo kojem prema zahtjevu 19 do 24, naznačene time, da vezanje spomenute molekule na aktivirani β lanac inhibira aktivaciju c-met pomoću HGF.
31. Molekula bilo kojem prema zahtjevu 19 do 24, naznačena time, da vezanje spomenute molekule na aktivirani β lanac inhibira proliferaciju stanica induciranu s HGF.
32. Molekula bilo kojem prema zahtjevu 19 do 24, naznačena time, da vezanje spomenute molekule na aktivirani β lanac inhibira dimerizaciju c-met receptora.
33. Molekula bilo kojem prema zahtjevu 19-32, naznačena time, da je ona dobivena postupkom prema bilo kojem zahtjevu 1-5 i 16-18.
34. Molekula kao što je definirana prema kojem zahtjevu 19 do 33, naznačena time, da se ona upotrebljava u postupku liječenja patološkog stanja povezanog s aktivacijom c-met u pojedincu.
35. Molekula prema zahtjevu 34, naznačena time, da patološko stanje je rak, tumor, poremećaj proliferacije stanica, imunološki poremećaj ili poremećaj povezan s angiogenezom.
36. Molekule prema zahtjevu 35, naznačene time, da rak je rak dojke, kolorektalni rak, rak pluća, rak pankreasa ili glioblastom.
37. Sastav, naznačen time, da on sadrži molekulu kako je definirana prema bilo kojem zahtjevu 19 do 36 u kombinaciji s nosačem.
38. Sastav prema zahtjevu 37, naznačen time, da nosač je farmaceutski prihvatljiv nosač.
HR20090324T 2003-06-06 2009-06-02 Moduliranje interakcije između hgf beta lanca i c-met HRP20090324T1 (hr)

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