DK2219672T3 - Anti-vegf-antistofsammensætninger og fremgangsmåder - Google Patents

Anti-vegf-antistofsammensætninger og fremgangsmåder Download PDF

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DK2219672T3
DK2219672T3 DK08846743.6T DK08846743T DK2219672T3 DK 2219672 T3 DK2219672 T3 DK 2219672T3 DK 08846743 T DK08846743 T DK 08846743T DK 2219672 T3 DK2219672 T3 DK 2219672T3
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antibody
vegf
amino acid
antibodies
tumor
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Anita Kavlie
Kyle Schlunegger
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Peregrine Pharmaceuticals Inc
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Claims (31)

1
1. Isoleret antistof, der bindes til VEGF og som omfatter mindst én variabel 5 tungkæderegion, der omfatter tre CDR og mindst én variabel letkæderegion, der omfatter tre CDR, hvor den variable letkæderegion omfatter: (a) en variabel let (VL) CDR1, der har aminosyresekvensen SEQ ID NO: 8 eller en sekvens i alt væsentligt homolog dertil, (b) en VL CDR2, der har aminosyresekvensen SEQ ID NO: 9 eller en sekvens i alt 10 væsentligt homolog dertil, og (c) en VL CDR3, der har aminosyresekvensen SEQ ID NO: 10 eller en sekvens i alt væsentligt homolog dertil; og hvor den variable tungkæderegion omfatter: (d) en variabel tung (VH) CDR1, der har aminosyresekvensen SEQ ID NO: 5 eller 15 en sekvens i alt væsentligt homolog dertil, (e) en VH CDR2, der har aminosyresekvensen SEQ ID NO: 6 eller en sekvens i alt væsentligt homolog dertil, og (f) en VH CDR3, der har aminosyresekvensen SEQ ID NO: 7 eller en sekvens i alt væsentligt homolog dertil, 2 0 hvor den i alt væsentligt homologe sekvens er en sekvens, der indeholder 1,2 eller 3 aminosyresubstitutioner sammenlignet med den givne CDR-sekvens; og hvor det isolerede antistof, der har den i alt væsentlige homologe sekvens, (i) bindes mindst til humant VEGF og muse VEGF, (ii) signifikant hæmmer VEGF-binding til VEGF-receptor VEGFR2 (KDR/Flk-1) uden 2 5 væsentligt at hæmme VEGF-binding til VEGF-receptor VEGFR1 (Flt-1), og (iii) bevarer evne til specifikt at bindes til den samme epitop af VEGF som genkendt af et antistof, der omfatter en variabel let (VL) CDR1, der har aminosyresekvensen SEQ ID NO: 8, en VL CDR2, der har aminosyresekvensen SEQ ID NO: 9, en VL CDR3, der har aminosyresekvensen SEQ ID NO: 10, en variabel tung (VH) CDR1, 3 0 der har aminosyresekvensen SEQ ID NO: 5, en VH CDR2, der har aminosyresekvensen SEQ ID NO: 6, og en VH CDR3, der har aminosyresekvensen SEQ ID NO: 7.
2. Antistof ifølge krav 1, hvor antistoffet omfatter en variabel let (VL) CDR1, der har 35 aminosyresekvensen SEQ ID NO: 8, en VL CDR2, der har aminosyresekvensen SEQ ID NO: 9, en VL CDR3, der har aminosyresekvensen SEQ ID NO: 10, en variabel tung (VH) CDR1, der har aminosyresekvensen SEQ ID NO: 5, en VH CDR2, der har aminosyresekvensen SEQ ID NO: 6, og en VH CDR3, der har aminosyresekvensen SEQ ID NO: 7.
3. Antistof ifølge krav 1 eller krav 2, hvor den variable letkæderegion har 5 aminosyresekvensen SEQ ID NO: 4, eller en sekvens, der er mindst 80 % sekvensidentisk dermed, og/eller hvor den variable tungkæderegion har aminosyresekvensen SEQ ID NO: 3, eller en sekvens, der er mindst 80 % sekvensidentisk dermed.
4. Antistof ifølge krav 3, hvor den variable letkæderegion har aminosyresekvensen SEQ ID NO: 4 og den variable tungkæderegion har aminosyresekvensen SEQ ID NO: 3.
5. Antistof ifølge et hvilket som helst af kravene 1 til 3, hvor antistoffet omfatter 15 aminosyresekvensen SEQ ID NO: 21, eller en sekvens, der er mindst 80 % sekvensidentisk dermed.
6. Antistof ifølge et hvilket som helst af kravene 1 til 5, hvor antistoffet er et fuldt humant antistof. 20
7. Antistof ifølge et hvilket som helst af kravene 1 til 6, hvor antistoffet er et helt antistof, der omfatter en konstant antistofregion, fortrinsvis er antistoffet et IgG-antistof, mere fortrinsvis omfatter antistoffet en tungkæde, der har aminosyresekvensen SEQ ID NO: 24, eller en sekvens, der er mindst 80 % sekvensidentisk dermed og en 2 5 letkæde, der har aminosyresekvensen SEQ ID NO: 25, eller en sekvens, der er mindst 80 % sekvensidentisk dermed.
8. Antistof ifølge krav 7, hvor antistoffet omfatter en tungkæde, der har aminosyresekvensen SEQ ID NO: 24, og en letkæde, der har aminosyresekvensen 30 SEQ ID NO: 25.
9. Antistof ifølge et hvilket som helst af kravene 1 til 6, hvor antistoffet er et antigenbindingsfragment af et antistof, fortrinsvis er antigenbindingsfragmentet af antistoffet en Fab, Fab', F(ab')2, scFv, Fv, dsFv, ds-scFv, Fd, DAB, TandAb-dimer, 35 lineært antistof, Minibody, Diabody eller bispecifikt antistoffragment.
10. Antistof ifølge et hvilket som helst af kravene 1 til 9, hvor antistoffet er forbundet med mindst et første diagnostisk eller terapeutisk middel, fortrinsvis er antistoffet forbundet med mindst et første radioterapeutisk middel, kemoterapeutisk middel, /I Π nnti^nniAnant οαλα+λολιπγΙι iAaranrla '-ln+i+i ιΚι ilinlαίrvnirJrJr\l anticellulært eller cytotoksisk middel, steroid, cytokin, chemokin eller koagulant, eller eventuelt er antistoffet forbundet med: (a) en arsen rad i oisotop; (b) taxol, docetaxel, paclitaxel, cisplatin, gemcitabin, en combretastatin, doxorubicin 5 eller adriamycin; (c) et ricin-, gelonin-, abrin-, diphtheri-, pseudomonas- eller pertussistoksin; (d) en V-type ATPaseinhibitor; (e) IL-2, IL-12, TNF-α, et interferon eller LEC eller (f) trunkeret vævsfaktor. 10
11. Antistof ifølge et hvilket som helst af de foregående krav, hvor antistoffet har en bindingsaffinitet for VEGF, der svarer til en Kd på mindre end 10 nM, når antistoffet er i IgG-format.
12. Immunkonjugat, der omfatter antistoffet ifølge et hvilket som helst af kravene 1 til 11 forbundet med mindst et første terapeutisk eller diagnostisk middel.
13. Sammensætning, der omfatter mindst et første antistof ifølge et hvilket som helst af kravene 1 til 11 eller et immunkonjugat deraf, fortrinsvis hvor sammensætningen er 2 0 en farmaceutisk acceptabel sammensætning, og eventuelt hvor sammensætningen eller den farmaceutisk acceptable sammensætning endvidere omfatter mindst et andet terapeutisk middel.
14. Sammensætning ifølge krav 13, hvor mindst et andet terapeutisk middel er et 2 5 kemoterapeutisk middel.
15. Sammensætning ifølge krav 14, hvor mindst et andet terapeutisk middel er udvalgt fra gruppen bestående af pyrimidinanaloger, platinkoordinationskomplekser og camptotheciner. 30
16. Sammensætning ifølge krav 15, hvor mindst et andet terapeutisk middel er 5-fluorouracil, oxaliplatin, cisplatin eller irinotecan.
17. Nukleinsyremolekyle, der omfatter en nukleotidsekvensregion, der koder for 35 antistoffet ifølge et hvilket som helst af kravene 1 til 11, hvor fortrinsvis (i) nukleotidsekvensregionen koder for et antistof, der har aminosyresekvensen SEQ ID NO: 21, eller en sekvens, der er mindst 80 % sekvensidentisk dermed, hvor nukleotidsekvensregionen fortrinsvis har nukleotidsekvensen SEQ ID NO: 20; eller (ii) nukleotidsekvensregionen koder for et antistof, der omfatter en tungkæde, der Ά Π hor CCH ΙΓϊ ΜΠ· 0/1 ollor an aal/\/ana rlar ar minrlat ΟΠ 0/ sekvensidentisk dermed, og en letkæde, der har aminosyresekvensen SEQ ID NO: 25, eller en sekvens, der er mindst 80 % sekvensidentisk dermed, hvor fortrinsvis nukleotidsekvensregionen, der koder for SEQ ID NO: 24, har nukleotidsekvensen SEQ ID NO: 22, og hvor nukleotidsekvensregionen, der koder for SEQ ID NO: 25, 5 har nukleotidsekvensen SEQ ID NO: 23.
18. Ekspressionsvektor, der omfatter nukleinsyremolekyet ifølge krav 17.
19. Værtscelle eller virus, der omfatter nukleinsyremolekylet ifølge krav 17 eller 10 ekspressionsvektoren ifølge krav 18.
20. Kit, der omfatter i mindst en første beholder: (a) antistof ifølge et hvilket som helst af kravene 1 til 11; (b) immunkonjugat ifølge krav 12; 15 (c) sammensætning ifølge et hvilket som helst af kravene 13-16; (d) nukleinsyremolekylet ifølge krav 17; (e) ekspressionsvektoren ifølge krav 18 eller (f) værtscelle eller virus ifølge krav 19. 2 0 21. Fremgangsmåde til fremstilling af et antistof ifølge et hvilket som helst af kravene 1- 11, der omfatter: (a) dyrkning af en værtscelle, der omfatter ekspressionsvektoren ifølge krav 18 underforhold, hvor det kodede antistof kan udtrykkes; og (b) opnåelse af det udtrykte antistof fra værtscellen. 25
22. Fremgangsmåde til binding af VEGF, der omfatter etablering af kontakt mellem en sammensætning, der omfatter VEGF, og antistof ifølge et hvilket som helst af kravene 1 til 11, eller et immunkonjugat deraf. 3 0 23. Fremgangsmåde til detektering af VEGF, der omfatter etablering af kontakt mellem en sammensætning mistænkt for at indeholde VEGF og antistof ifølge et hvilket som helst af kravene 1 til 11, elleret immunkonjugat deraf, underforhold, hvor dannelsen af VEGF/antistofkomplekser og detektering af de således dannede komplekser kan tillades. 35
24. Fremgangsmåde in vitro til diagnosticering af en angiogen sygdom eller en lymfangiogen sygdom hos et dyr, der omfatter: (a) etablering af kontakt mellem en testprøve fra dyret og antistoffet ifølge et hvilket som helst af kravene 1 til 11, eller et immunkonjugat deraf, under forhold, hvor Λ Π of X/Cf^C/ontictAfl/Amrlfil/car Unn ♦illn/^ae·· (b) detektering af VEGF/antistofkomplekser således dannet, og derved bestemmelse af mængden af VEGF i testprøven; og (c) sammenligning af mængden af VEGF i testprøven med mængden af VEGF i en tilsvarende kontrolprøve, hvor en øget mængde af VEGF i testprøven i forhold til 5 mængden af VEGF i kontrolprøven er tegn på en angiogen sygdom eller en lymfangiogen sygdom.
25. Fremgangsmåde ifølge krav 24, hvor den angiogene sygdom eller lymfangiogene sygdom er cancer, neurovaskulær øjensygdom, makulær degeneration, 10 aldersbetinget makulær degeneration, arthritis, rheumatoid arthritis, aterosklerose, diabetisk retinopati, thyroid hyperplasi, Graves’ sygdom, hæmangiom, neovaskulært glaukom eller psoriasis.
26. Antistof ifølge et hvilket som helst af kravene 1 til 11, eller et immunkonjugat deraf, 15 til anvendelse til terapi eller diagnosticering in vivo.
27. Antistof eller immunkonjugat ifølge krav 26 til anvendelse til terapi eller diagnosticering in vivo ifølge krav 26, hvor terapien er af en angiogen sygdom ved hæmning af angiogenese eller af en lymfangiogen sygdom ved hæmning af 2 0 lymfangiogenese, og hvor diagnosticeringen in vivo er af en angiogen eller lymfangiogen sygdom.
28. Antistof eller immunkonjugat ifølge krav 26 eller krav 27 til anvendelse til terapi eller diagnosticering in vivo ifølge krav 26 eller krav 27, hvor terapien eller 2 5 diagnosticeringen in vivo er af en sygdom udvalgt fra gruppen bestående af cancer, neurovaskulær øjensygdom, makulær degeneration, aldersbetinget makulær degeneration, arthritis, rheumatoid arthritis, aterosklerose, diabetisk retinopati, thyroid hyperplasi, Graves’ sygdom, hæmangiom, neovaskulært glaukom og psoriasis. 30
29. Antistof eller immunkonjugat ifølge et hvilket som helst af kravene 26 til 28 til anvendelse til terapi ifølge et hvilket som helst af kravene 26 til 28, der endvidere omfatter anvendelse af et andet terapeutisk middel.
30. Antistof eller immunkonjugat ifølge krav 29 til anvendelse til terapi ifølge krav 29, hvor det andet terapeutiske middel er et kemoterapeutisk middel.
31. Antistof eller immunkonjugat ifølge krav 30 til anvendelse til terapi ifølge krav 30, hvor det andet terapeutiske middel er udvalgt fra gruppen bestående af /ΙΠ λλ^^ΙλλλίηΛ^
32. Antistof eller immunkonjugat ifølge krav 31 til anvendelse til terapi ifølge krav 31, hvor det andet terapeutiske middel er 5-fluoruracil, oxaliplatin, cisplatin eller irinotecan. 5
33. Antistof eller immunkonjugat ifølge et hvilket som helst af kravene 26 til 32 til anvendelse til terapi eller diagnosticering in vivo ifølge et hvilket som helst af kravene 26 til 32, hvor terapien eller diagnosticeringen er udført på et menneskeligt individ.
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