HRP20160494T1 - Antigen-vezujući proteini za proproteinsku konvertazu subtilizin keksin tipa 9 (pcsk9) - Google Patents

Antigen-vezujući proteini za proproteinsku konvertazu subtilizin keksin tipa 9 (pcsk9) Download PDF

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HRP20160494T1
HRP20160494T1 HRP20160494TT HRP20160494T HRP20160494T1 HR P20160494 T1 HRP20160494 T1 HR P20160494T1 HR P20160494T T HRP20160494T T HR P20160494TT HR P20160494 T HRP20160494 T HR P20160494T HR P20160494 T1 HRP20160494 T1 HR P20160494T1
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Croatia
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chain variable
variable domain
sequence
identity
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HRP20160494TT
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Simon Mark Jackson
Nigel Pelham Clinton Walker
Derek Evan Piper
Bei Shan
Wenyan Shen
Joyce Chi Yee Chan
Chadwick Terence King
Randal Robert Ketchem
Christopher Mehlin
Teresa Arazas Carabeo
Qiong CAO
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Amgen Inc.
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Application filed by Amgen Inc. filed Critical Amgen Inc.
Publication of HRP20160494T1 publication Critical patent/HRP20160494T1/hr
Publication of HRP20160494T4 publication Critical patent/HRP20160494T4/hr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
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    • C12N15/1137—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against enzymes
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Claims (23)

1. Monoklonsko protutijelo ili njegov fragment koji se veže za ljudski PCSK9 i neutralizira ga tako da je suvišak navedenog protutijela ili njegovog fragmenta sposoban umanjiti količinu PCSK9 vezanog za LDLR u in vitro kompetetivnom veznom određivanju, pri čemu se navedeno monoklonsko protutijelo ili njegov fragment natječu za vezanje za PCSK9 s (a) protutijelom koje sadrži varijabilnu regiju teškog lanca aminokiselinskog slijeda iz SEQ ID NO: 49; i varijabilnu regiju lakog lanca aminokiselinskog slijeda iz SEQ ID NO: 23; ili (b) protutijelom koje sadrži varijabilnu regiju teškog lanca aminokiselinskog slijeda iz SEQ ID NO: 67; i varijabilnu regiju lakog lanca aminokiselinskog slijeda iz SEQ ID NO: 12.
2. Protein koji veže antigen, pri čemu (A) se navedeni protein koji veže antigen specifično veže za ljudski PCSK9 i neutralizira ga tako da je suvišak navedenog proteina koji veže antigen sposoban umanjiti količinu PCSK9 vezanog za LDLR u in vitro kompetetivnom veznom određivanju, navedeni protein koji veže antigen sadrži bilo: (i) (a) kombinaciju varijabilne domene lakog lanca i varijabilne domene teškog lanca odabrane između grupe kombinacija koje sa sastoje od: varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 9 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 71; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 10 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 72; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 12 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 67; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 16 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 52; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 17 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 51; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 20 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 54; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 21 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 55; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 22 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 56; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 23 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 49; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 24 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 57; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 26 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 50; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 30 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 64; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 31 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 62; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 33 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 65; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 35 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 79; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 36 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 80; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 37 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 76; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 38 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 77; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 39 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 78; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 40 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 83; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 461 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 459; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 465 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 463; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 473 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 471; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 477 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 475; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 485 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 483; (ii) (a) CDRH1 sadrži SEQ ID NO: 308, CDRH2 sadrži SEQ ID NO: 175 i CDRH3 sadrži SEQ ID NO: 180; ili (b) CDRH1 sadrži SEQ ID NO: 368, CDRH2 sadrži SEQ ID NO: 175 i CDRH3 sadrži SEQ ID NO: 180; i CDRL1 sadrži SEQ ID NO: 158, CDRL2 sadrži SEQ ID NO: 162 i CDRL3 sadrži SEQ ID NO: 395; (iii) CDRH1 sadrži SEQ ID NO: 368, CDRH2 sadrži SEQ ID NO: 174 i CDRH3 sadrži SEQ ID NO: 180, a CDRL1 sadrži SEQ ID NO: 158, CDRL2 sadrži SEQ ID NO: 162 i CDRL3 sadrži SEQ ID NO: 164; ili (iv) CDRH1 sadrži GFTFSSYWMS, CDRH2 sadrži SIKQDGSEKYYVDSVKG i CDRH3 sadrži DLVLMVYDIDYYYYGMDV, a CDRL1 sadrži RSSQSLLHSNGYNYLD, CDRL2 sadrži LGSNRAS i CDRL3 sadrži MOALOTPLT; ili (B) Navedeni protein koji veže antigen sadrži (a) varijabilnu domenu lakog lanca koja sadrži aminokiselinski slijed SEQ ID NO: 23 i varijabilnu domenu teškog lanca koja sadrži aminokiselinski slijed SEQ ID NO: 49; ili (b) varijabilnu domenu lakog lanca koja sadrži aminokiselinski slijed SEQ ID NO: 23, pri čemu je prvi ostatak glutaminska kiselina umjesto glutamina, i varijabilnu domenu teškog lanca koja sadrži aminokiselinski slijed SEQ ID NO: 49, pri čemu je prvi ostatak glutaminska kiselina umjesto glutamina.
3. Protein koji veže antigen iz patentnog zahtjeva 2(A)(i) sadrži kombinaciju varijabilne domene lakog lanca i varijabilne domene teškog lanca, pri čemu su varijabilna domena lakog lanca i varijabilna domena teškog lanca odabrane iz grupe kombinacija koja se sastoji od: varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 10 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 72; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 12 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 67; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 17 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 51; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 23 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 49; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 35 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 79; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 461 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 459; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 465 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 463; varijabilne domene lakog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 485 i varijabilne domene teškog lanca koja ima slijed s najmanje 90% podudaranja sa SEQ ID NO: 483; pri čemu se protein koji veže antigen specifično veže za PCSK9.
4. Protein koji veže antigen iz patentnog zahtjeva 3, pri čemu su varijabilna domena lakog lanca i varijabilna domena teškog lanca odabrane iz grupe kombinacija koja se sastoji od: varijabilne domene lakog lanca koja ima slijed naveden u SEQ ID NO: 10 i varijabilne domene teškog lanca koja ima slijed naveden u SEQ ID NO: 72; varijabilne domene lakog lanca koja ima slijed naveden u SEQ ID NO: 12 i varijabilne domene teškog lanca koja ima slijed naveden u SEQ ID NO: 67; varijabilne domene lakog lanca koja ima slijed naveden u SEQ ID NO: 17 i varijabilne domene teškog lanca koja ima slijed naveden u SEQ ID NO: 51; varijabilne domene lakog lanca koja ima slijed naveden u SEQ ID NO: 23 i varijabilne domene teškog lanca koja ima slijed naveden u SEQ ID NO: 49; varijabilne domene lakog lanca koja ima slijed naveden u SEQ ID NO: 35 i varijabilne domene teškog lanca koja ima slijed naveden u SEQ ID NO: 79; varijabilne domene lakog lanca koja ima slijed naveden u SEQ ID NO: 461 i varijabilne domene teškog lanca koja ima slijed naveden u SEQ ID NO: 459; varijabilne domene lakog lanca koja ima slijed naveden u SEQ ID NO: 465 i varijabilne domene teškog lanca koja ima slijed naveden u SEQ ID NO: 463; varijabilne domene lakog lanca koja ima slijed naveden u SEQ ID NO: 485 i varijabilne domene teškog lanca koja ima slijed naveden u SEQ ID NO: 483; pri čemu se protein koji veže antigen specifično veže za PCSK9.
5. Protein koji veže antigen iz patentnog zahtjeva 2(A)(ii) sadrži: (a) varijabilnu domenu lakog lanca koja sadrži aminokiselinski slijed SEQ ID NO: 23 i varijabilnu domenu teškog lanca koja sadrži aminokiselinski slijed SEQ ID NO: 49; ili (b) varijabilnu domenu lakog lanca koja sadrži aminokiselinski slijed SEQ ID NO: 23, pri čemu je prvi ostatak glutaminska kiselina umjesto glutamina, i varijabilnu domenu teškog lanca koja sadrži aminokiselinski slijed SEQ ID NO: 49, pri čemu je prvi ostatak glutaminska kiselina umjesto glutamina.
6. Protein koji veže antigen iz patentnog zahtjeva 2(B)(b) ili 5(b), nadalje obuhvaća glicinski ostatak na C-terminalnom kraju navedene varijabilne domene lakog lanca.
7. Protein koji veže antigen iz patentnog zahtjeva 2(A)(iii) obuhvaća varijabilnu domenu lakog lanca koja sadrži aminokiselinski slijed SEQ ID NO: 17 i varijabilnu domenu teškog lanca koja sadrži aminokiselinski slijed SEQ ID NO: 51.
8. Protein koji veže antigen iz patentnog zahtjeva 2(A)(iv) obuhvaća varijabilnu domenu lakog lanca koja sadrži aminokiselinski slijed SEQ ID NO: 461 i varijabilnu domenu teškog lanca koja sadrži aminokiselinski slijed SEQ ID NO: 459.
9. Protein koji veže antigen iz bilo kojeg od patentnih zahtjeva 2 do 8, nadalje obuhvaća: (a) konstantni slijed lakog lanca sa SEQ ID NO: 156; (b) konstantni slijed lakog lanca sa SEQ ID NO: 157; (c) konstantni slijed teškog lanca sa SEQ ID NO: 154; (d) konstantni slijed teškog lanca sa SEQ ID NO: 155; (e) Konstantni slijed lakog lanca sa SEQ ID NO: 156 i konstantni slijed teškog lanca sa SEQ ID NO: 154; (f) konstantni slijed lakog lanca sa SEQ ID NO: 157 i konstantni slijed teškog lanca sa SEQ ID NO: 154; (g) konstantni slijed lakog lanca sa SEQ ID NO: 156 i konstantni slijed teškog lanca sa SEQ ID NO: 155; (h) konstantni slijed lakog lanca sa SEQ ID NO: 157 i konstantni slijed teškog lanca sa SEQ ID NO: 155.
10. Protutijelo ili njegov fragment ili protein koji veže antigen iz bilo kojeg od prethodnih patentnih zahtjeva, pri čemu protutijelo ili njegov fragment ili protein koji veže antigen ima najmanje jednu od sljedećih karakteristika: (a) veže se za PCSK9 varijantu koja ima D374Y točkastu mutaciju; (b) odabrano je iz grupe koja se sastoji od ljudskog protutijela, humaniziranog protutijela, kimernog protutijela, monoklonskog protutijela, multispecifičnog protutijela, rekombinantnog protutijela, antigen-vezujućeg fragmenta protutijela, jednolančanog protutijela, dijatijela, Fab fragmenta, F(ab)2 fragmenta, IgG1 protutijela, IgG2 protutijela, IgG3 protutijela, IgG4 protutijela; (c) veže se za PCSK9 s Kd koja je manja od 1 nM, manja od 100 pM, manja od 10 pM ili je manja od 5 pM; ili (d) može blokirati vezanje D374Y PCSK9 za LDLR s IC50 manjom od 200 pM.
11. Protutijelo ili njegov fragment ili protein koji veže antigen iz bilo kojeg od prethodnih patentnih zahtjeva koje, kada je vezano za PCSK9: (a) veže se za PCSK9 s istom Kd kao referentno protutijelo; (b) inhibira vezanje PCSK9 za LDLR s istom IC50 kao navedeno referentno protutijelo; ili (c) natječe se za vezanje navedenog referentnog protutijela za PCSK9, pri čemu navedeno referentno protutijelo sadrži kombinaciju sljedova varijabilne domene lakog lanca i teškog lanca odabranu iz grupe koja se sastoji od varijabilne domene lakog lanca koja ima slijed naveden u SEQ ID NO: 10 i varijabilne domene teškog lanca koja ima slijed naveden u SEQ ID NO: 72; varijabilne domene lakog lanca koja ima slijed naveden u SEQ ID NO: 12 i varijabilne domene teškog lanca koja ima slijed naveden u SEQ ID NO: 67; varijabilne domene lakog lanca koja ima slijed naveden u SEQ ID NO: 17 i varijabilne domene teškog lanca koja ima slijed naveden u SEQ ID NO: 51; varijabilne domene lakog lanca koja ima slijed naveden u SEQ ID NO: 23 i varijabilne domene teškog lanca koja ima slijed naveden u SEQ ID NO: 49; varijabilne domene lakog lanca koja ima slijed naveden u SEQ ID NO: 35 i varijabilne domene teškog lanca koja ima slijed naveden u SEQ ID NO: 79; varijabilne domene lakog lanca koja ima slijed naveden u SEQ ID NO: 461 i varijabilne domene teškog lanca koja ima slijed naveden u SEQ ID NO: 459; varijabilne domene lakog lanca koja ima slijed naveden u SEQ ID NO: 465 i varijabilne domene teškog lanca koja ima slijed naveden u SEQ ID NO: 463; varijabilne domene lakog lanca koja ima slijed naveden u SEQ ID NO: 485 i varijabilne domene teškog lanca koja ima slijed naveden u SEQ ID NO: 483.
12. Nukleinska kiselina koja kodira protutijelo ili njegov fragment ili protein koji veže antigen iz bilo kojeg od prethodnih patentnih zahtjeva.
13. Rekombinantni ekspresijski vektor koji sadrži molekulu nukleinske kiseline iz patentnog zahtjeva 12.
14. Stanica domaćin koja sadrži vektor iz patentnog zahtjeva 13.
15. Hibridoma sposobna za stvaranje protutijela iz patentnog zahtjeva 10 ili 11.
16. Metoda za izradu protutijela ili njegovog fragmenta ili proteina koji veže antigen iz bilo kojeg od patentnih zahtjeva 1-11, obuhvaća korak priprave navedenog protutijela ili njegovog fragmenta ili proteina koji veže antigen iz stanice domaćina koja izlučuje navedeno protutijelo ili njegov fragment ili navedeni protein koji veže antigen.
17. Protutijelo ili njegov fragment ili protein koji veže antigen nastao ekspresijom rekombinantne
18. Metoda iz patentnog zahtjeva 16 ili protutijelo ili njegov fragment ili protein koji veže antigen iz patentnog zahtjeva 17, pri čemu je stanica domaćin odabrana iz grupe koja se sastoji od stanica ovarija kineskog hrčka (CHO), HeLa stanica, stanica bubrega mladunčeta hrčka (BHK), stanica bubrega majmuna (COS), stanica hepatocelularnog karcinoma čovjeka i epitelnih bubrežnih 293 stanica čovjeka.
19. Farmaceutski sastav obuhvaća najmanje jedno protutijelo ili njegov fragment ili najmanje jedan protein koji veže antigen u skladu s bilo kojim od patentnih zahtjeva 1 do 11, 17 ili 18 i farmaceutski prihvatljivi ekscipijens.
20. Farmaceutski sastav iz patentnog zahtjeva 19, pri čemu se farmaceutski sastav primjenjuje prije, zajedno s, ili nakon primjene barem jednog terapijskog agensa, pri čemu je opcionalno drugi terapijski agens statin.
21. Komplet za liječenje poremećaja povezanih s kolesterolom obuhvaća sastav iz patentnih zahtjeva 19 ili 20.
22. Protutijelo ili njegov fragment ili protein koji veže antigen iz s bilo kojeg od patentnih zahtjeva 1 do 11, 17 ili 18 za uporabu u liječenju ili prevenciji stanja povezanih s povišenim koncentracijama kolesterola u serumu subjekta.
23. Protutijelo ili njegov fragment ili protein koji veže antigen za uporabu u skladu s patentnim zahtjevom 22, pri čemu je stanje odabrano između hiperkolesterolemije, kardiovaskularne bolesti, metaboličkog sindroma, dijabetesa, moždanog udara i dislipidemije.
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