HRP20201837T1 - Antitijelo koje veže erbb-2 i erbb-3 - Google Patents

Antitijelo koje veže erbb-2 i erbb-3 Download PDF

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HRP20201837T1
HRP20201837T1 HRP20201837TT HRP20201837T HRP20201837T1 HR P20201837 T1 HRP20201837 T1 HR P20201837T1 HR P20201837T T HRP20201837T T HR P20201837TT HR P20201837 T HRP20201837 T HR P20201837T HR P20201837 T1 HRP20201837 T1 HR P20201837T1
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erbb
antibody
heavy chain
variable region
chain variable
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HRP20201837TT
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Cecilia Anna Wilhelmina Geuijen
Cornelis Adriaan De Kruif
Mark Throsby
Ton Logtenberg
Alexander Berthold Hendrik Bakker
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Merus N.V.
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Claims (38)

1. Bispecifično antitijelo pune dužine koje sadrži prvo antigen-vezujuće mjesto koje veže domenu I ErbB-2 i drugo antigen-vezujuće mjesto koje veže domenu III ErbB-3, naznačeno time što antitijelo može smanjiti ligandom induciranu receptorsku funkciju ErbB-3 na ErbB-2 i ErbB-3 pozitivnoj stanici.
2. Bispecifično antitijelo u skladu sa patentnim zahtjevom 1, naznačeno time što antitijelo može smanjiti ligandom inducirani rast ErbB-2 i ErbB-3 pozitivne stanice.
3. Bispecifično antitijelo u skladu sa patentnim zahtjevom 2, naznačeno time što antitijelo može smanjiti ligandom inducirani rast ErbB-2 i ErbB-3 pozitivne stanice, pri čemu navedena stanica ima najmanje 100.000 ErbB-2 receptora na staničnoj površini po stanici.
4. Bispecifično antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-3, naznačeno time što je navedena stanica MCF-7 stanica, SKBR-3 stanica, NCI-N87 stanica, BxPC-3 stanica, BT-474 stanica ili JIMT-1 stanica.
5. Bispecifično antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-4, naznačeno time što drugo antigen-vezujuće mjesto ometa vezanje ErbB-3 liganda za ErbB-3.
6. Bispecifično antitijelo pune dužine koje sadrži prvo antigen-vezujuće mjesto koje veže ErbB-2 i drugo antigen-vezujuće mjesto koje veže ErbB-3, naznačeno time što navedeno prvo antigen-vezujuće mjesto veže domenu I ErbB-2 i navedeno drugo antigen-vezujuće mjesto veže domenu III ErbB-3.
7. Bispecifično antitijelo pune dužine koje sadrži prvo antigen-vezujuće mjesto koje veže domenu I ErbB-2 i drugo antigen-vezujuće mjesto koje veže domenu III ErbB-3, naznačeno time što je afinitet (KD) navedenog drugog antigen-vezujućeg mjesta za ErbB-3 pozitivnu stanicu jednak sa, ili viši od, afiniteta navedenog prvog antigen-vezujućeg mjesta za ErbB-2 pozitivnu stanicu.
8. Bispecifično antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-7, naznačeno time što antitijelo može smanjiti ligandom induciranu receptorsku funkciju ErbB-3 na ErbB-2 i ErbB-3 pozitivnoj stanici.
9. Bispecifično antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-8, naznačeno time što antitijelo može smanjiti ligandom inducirani rast ErbB-2 i ErbB-3 pozitivne stanice.
10. Bispecifično antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-9, naznačeno time što je afinitet (KD) navedenog drugog antigen-vezujućeg mjesta za ErbB-3 pozitivnu stanicu niži od ili jednak 2,0 nM, poželjno niži od ili jednak 1,39 nM, poželjnije niži od ili jednak 0,99 nM.
11. Bispecifično antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-10, naznačeno time što je afinitet (KD) navedenog prvog antigen-vezujućeg mjesta za ErbB-2 pozitivnu stanicu niži od ili jednak 5,0 nM, poželjno niži od ili jednak 4,5 nM, poželjno niži od ili jednak 4,0 nM.
12. Bispecifično antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-11, naznačeno time što je afinitet (KD) navedenog bispecifičnog antitijela za BT-474 stanice niži od ili jednak 5,0 nM, poželjno niži od ili jednak 4,0 nM, poželjnije niži od ili jednak 3,2 nM, i/ili pri čemu je afinitet navedenog bispecifičnog antitijela za SK-BR-3 stanice niži od ili jednak 5,0 nM, poželjno niži od ili jednak 3,0 nM, poželjnije niži od ili jednak 2,0 nM.
13. Antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-12, naznačeno time što je navedena ErbB-3 pozitivna stanica i/ili navedena ErbB-2 pozitivna stanica BT-474 stanica ili SK-BR-3 stanica.
14. Antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-13, naznačeno time što sadrži antigen-vezujuće mjesto koje veže najmanje jednu amino-kiselinu domene I ErbB-2 odabranu iz grupe koja se sastoji od T144, T164, R166, P172, G179, S180 i R181, i amino-kiselinske ostatke izložene na površini koji su locirani unutar oko 5 amino-kiselinskih pozicija od T144, T164, R166, P172, G179, S180 ili R181.
15. Antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-14, naznačeno time što sadrži antigen-vezujuće mjesto koje veže najmanje jednu amino-kiselinu domene III ErbB-3 odabranu iz grupe koja se sastoji od R426 i amino-kiselinskih ostataka izloženih na površini koji su locirani unutar 11,2 Å od R426 u nativnom ErbB-3 proteinu.
16. Antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-15, naznačeno time što navedeno antitijelo sadrži najmanje CDR3 sekvencu varijabilne regije teškog lanca specifičnog za ErbB-2 odabranog iz grupe koja se sastoji od MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031, i MF3003 kao što je prikazano na slici 16A ili slici 16E.
17. Antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-16, naznačeno time što navedeno antitijelo sadrži najmanje CDR3 sekvencu varijabilne regije teškog lanca specifičnog za ErbB-2 MF3958 kao što je prikazano na slici 16A.
18. Antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-17, naznačeno time što navedeno antitijelo sadrži najmanje CDR3 sekvencu varijabilne regije teškog lanca specifičnog za ErbB-3 odabranog iz grupe koja se sastoji od MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 i MF6074 kao što je prikazano na slici 16B ili slici 16E ili slici 37.
19. Antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-18, naznačeno time što navedeno antitijelo sadrži najmanje CDR3 sekvencu varijabilne regije teškog lanca specifičnog za ErbB-3 MF3178 kao što je prikazano na slici 16B.
20. Antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-19, naznačeno time što navedeno antitijelo sadrži najmanje CDR1, CDR2 i CDR3 sekvence varijabilne regije teškog lanca specifičnog za ErbB-2 odabranog iz grupe koja se sastoji od MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031, i MF3003 kao što je prikazano na slici 16A ili slici 16E, ili pri čemu navedeno antitijelo sadrži CDR sekvence koje se razlikuju u najviše 3 amino-kiseline, poželjno u najviše 2 amino-kiseline, poželjno u najviše 1 amino-kiselini od CDR1, CDR2 i CDR3 sekvenci MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031 ili MF3003.
21. Antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-20, naznačeno time što navedeno antitijelo sadrži najmanje CDR1, CDR2 i CDR3 sekvence varijabilne regije teškog lanca specifičnog za ErbB-2 MF3958 kao što je prikazano na slici 16A, ili pri čemu navedeno antitijelo sadrži CDR sekvence koje se razlikuju u najviše 3 amino-kiseline, poželjno u najviše 2 amino-kiseline, poželjno u najviše 1 amino-kiselini od CDR1, CDR2 i CDR3 sekvenci MF3958.
22. Antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-21, naznačeno time što navedeno antitijelo sadrži najmanje CDR1, CDR2 i CDR3 sekvence varijabilne regije teškog lanca specifičnog za ErbB-3 odabranog iz grupe koja se sastoji od MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 i MF6074 kao što je prikazano na slici 16B ili slici 16E ili slici 37, ili pri čemu navedeno antitijelo sadrži CDR sekvence koje se razlikuju u najviše 3 amino-kiseline, poželjno u najviše 2 amino-kiseline, poželjno u najviše 1 amino-kiselini od CDR1, CDR2 i CDR3 sekvenci MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 ili MF6074.
23. Antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-22, naznačeno time što navedeno antitijelo sadrži najmanje CDR1, CDR2 i CDR3 sekvence varijabilne regije teškog lanca specifičnog za ErbB-3 MF3178 kao što je prikazano na slici 16B, ili pri čemu navedeno antitijelo sadrži CDR sekvence koje se razlikuju u najviše 3 amino-kiseline, poželjno u najviše 2 amino-kiseline, poželjno u najviše 1 amino-kiselini od CDR1, CDR2 i CDR3 sekvenci MF3178.
24. Antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-23, naznačeno time što navedeno antitijelo sadrži sekvencu varijabilne regije teškog lanca specifičnog za ErbB-2 odabranu iz grupe koja se sastoji od sekvenci varijabilne regije teškog lanca MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031, i MF3003 kao što je prikazano na slici 16A ili slici 16E, ili pri čemu navedeno antitijelo sadrži sekvencu varijabilne regije teškog lanca koja se razlikuje u najviše 15 amino-kiselina od sekvenci varijabilne regije teškog lanca MF2973, MF3004, MF3958, MF2971, MF3025, MF2916, MF3991, MF3031 ili MF3003.
25. Antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-24, naznačeno time što navedeno antitijelo sadrži sekvencu varijabilne regije teškog lanca specifičnog za ErbB-2 odabranu iz grupe koja se sastoji od sekvenci varijabilne regije teškog lanca MF3958 kao što je prikazano na slici 16A, ili pri čemu navedeno antitijelo sadrži sekvencu varijabilne regije teškog lanca koja se razlikuje u najviše 15 amino-kiselina od sekvenci varijabilne regije teškog lanca MF3958.
26. Antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-25, naznačeno time što navedeno antitijelo sadrži sekvencu varijabilne regije teškog lanca specifičnog za ErbB-3 odabranu iz grupe koja se sastoji od sekvenci varijabilne regije teškog lanca MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 i MF6074 kao što je prikazano na slici 16B ili slici 16E ili slici 37, ili pri čemu navedeno antitijelo sadrži sekvencu varijabilne regije teškog lanca koja se razlikuje u najviše 15 amino-kiselina od sekvenci varijabilne regije teškog lanca MF3178; MF3176; MF3163; MF6055; MF6056; MF6057; MF6058; MF6059; MF6060; MF6061; MF6062; MF6063; MF6064; MF6065; MF6066; MF6067; MF6068; MF6069; MF6070; MF6071; MF6072; MF6073 ili MF6074.
27. Antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-26, naznačeno time što navedeno antitijelo sadrži sekvencu varijabilne regije teškog lanca specifičnog za ErbB-3 odabranu iz grupe koja se sastoji od sekvenci varijabilne regije teškog lanca MF3178 kao što je prikazano na slici 16B, ili pri čemu navedeno antitijelo sadrži sekvencu varijabilne regije teškog lanca koja se razlikuje u najviše 15 amino-kiselina od sekvenci varijabilne regije teškog lanca MF3178.
28. Bispecifično antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-27, koje je afukozilirano kako bi se pojačala ADCC.
29. Bispecifično antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-28, naznačeno time što sadrži dva različita teška lanca imunoglobulina sa kompatibilnim domenama heterodimerizacije.
30. Bispecifično antitijelo u skladu sa patentnim zahtjevom 29, naznačeno time što su navedene kompatibilne domene heterodimerizacije kompatibilne CH3 domene heterodimerizacije teškog lanca imunoglobulina.
31. Bispecifično antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-30, naznačeno time što oba kraka sadrže zajednički laki lanac.
32. Bispecifično antitijelo u skladu sa patentnim zahtjevom 31, naznačeno time što je navedeni zajednički laki lanac laki lanac germinativne linije, poželjno preuređeni kapa laki lanac ljudske germinativne linije koji sadrži segment IgVKl-39 gena, najpoželjnije preuređeni kapa laki lanac ljudske germinativne linije IgVK1-39*01/IGJK1*01.
33. Farmaceutski pripravak koji sadrži bispecifično antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-32.
34. Antitijelo u skladu sa bilo kojim od patentnih zahtjeva 1-32, za uporabu u liječenju subjekta koji ima ili je u opasnosti da ima ErbB-2, ErbB-3 ili ErbB-2/ErbB-3 pozitivan tumor.
35. Bispecifično antitijelo pune dužine koje sadrži prvo antigen-vezujuće mjesto koje veže domenu I ErbB-2 i drugo antigen-vezujuće mjesto koje veže domenu III ErbB-3 za uporabu u liječenju ErbB-2, ErbB-3 ili ErbB-2/ErbB-3 pozitivnog tumora, naznačeno time što navedeno liječenje sadrži primjenu navedenog bispecifičnog antitijela i najmanje jednog spoja odabranog iz grupe koja se sastoji od inhibitora komponente PI3Kinaznog puta, inhibitora komponente MAPK puta, lijeka koji ometa mikrotubule i HDAC inhibitora, poželjno primjenu navedenog bispecifičnog antitijela i najmanje jednog spoja odabranog iz grupe koja se sastoji od inhibitora tirozin kinaze, inhibitora PI3Ka, inhibitora Akt, inhibitora mTOR, inhibitora Src, vorinostata i paklitaksela, subjektu koji ima ErbB-2, ErbB-3 ili ErbB-2/ErbB-3 pozitivan tumor.
36. Bispecifično antitijelo pune dužine koje sadrži prvo antigen-vezujuće mjesto koje veže domenu I ErbB-2 i drugo antigen-vezujuće mjesto koje veže domenu III ErbB-3 za uporabu u liječenju ili prevenciji nastanka metastaze ErbB-2, ErbB-3 ili ErbB-2/ErbB-3 pozitivne tumorske stanice, naznačeno time što navedene ErbB-2, ErbB-3 ili ErbB-2/ErbB-3 pozitivne tumorske stanice imaju nivo ekspresije heregulina koji je najmanje 60%, poželjno najmanje 70%, poželjnije najmanje 80%, poželjnije najmanje 85%, poželjnije najmanje 90% ili 95% nivoa ekspresije heregulina BXPC3 ili MCF7 stanica.
37. Antitijelo za uporabu u skladu sa bilo kojim od patentnih zahtjeva 34-36, naznačeno time što navedeni subjekt ima ErbB-2 ili ErbB-2/ErbB-3 pozitivan tumor koji ima manje od 1.000.000 ErbB-2 receptora na staničnoj površini po stanici.
38. In vitro uporaba antitijela u skladu sa bilo kojim od patentnih zahtjeva 1-32 za suzbijanje, poželjno inhibiciju, fosforilaciju Akt, ERK i/ili S6 ribosomskog proteina.
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