DK2331136T3 - Frizzled-bindende midler og anvendelser deraf - Google Patents

Frizzled-bindende midler og anvendelser deraf Download PDF

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DK2331136T3
DK2331136T3 DK09817004.6T DK09817004T DK2331136T3 DK 2331136 T3 DK2331136 T3 DK 2331136T3 DK 09817004 T DK09817004 T DK 09817004T DK 2331136 T3 DK2331136 T3 DK 2331136T3
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seq
antibody
fzd
certain embodiments
human
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Satyajit Sujit Kumar Mitra
Austin L Gurney
Aaron Ken Sato
Fumiko Takada Axelrod
Timothy Charles Hoey
Sanjeev H Satyal
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Oncomed Pharm Inc
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Claims (21)

1. Monoklonalt antistof, der binder specifikt til en human frizzled-receptor udvalgt fra gruppen bestående af FZD8, FZD5, FZD1, FZD2 og FZD7 og hæmmer Wnt-binding til den humane frizzled-receptor, hvor antistoffet: (a) binder til sekvensen (K/Q)(F/Y)GF(Q/A) (SEQ ID NO: 69) og/eller sekvensen Q(DE/ED)AGLEVHQF(Y/W)PL (SEQ ID NO: 24) inden for den humane frizzled-receptor; (b) konkurrerer om specifik binding til human FZD8, FZD5, FZD1, FZD2 eller FZD7 i en kompetitiv bindingsassay med et antistof, der omfatter en tungkæ-de-variabel region omfattende SEQ ID NO: 10 og en letkæde-variabel region omfattende SEQ ID NO:14 eller SEQ ID NO:12; og/eller (c) omfatter en tungkæde-CDFH omfattende GFTFSHYTLS (SEQ ID NO: 1); en tungkæde-CDR2 omfattende VISGDGSYTYYADSVKG (SEQ ID NO: 2); og en tungkæde-CDR3 omfattende NFIKYVFAN (SEQ ID NO: 3); og en let-kæde-CDR1 omfattende SGDNIGSFYVH (SEQ ID NO: 7); en letkæde-CDR2 omfattende DKSNRPSG (SEQ ID NO: 8); og en letkæde-CDR3 omfattende QSYANTLSL (SEQ ID NO: 9).
2. Monoklonalt antistof ifølge krav 1, som binder specifikt til mere end en frizzled-receptor udvalgt fra gruppen bestående af FZD8, FZD5, FZD1, FZD2 og FZD7.
3. Monoklonalt antistof ifølge krav 2, hvor de humane frizzled-receptorer, hvortil antistoffet binder, omfatter FZD8 og FZD5.
4. Monoklonalt antistof ifølge krav 3, som specifikt binder til FZD8, FZD5, FZD1, FZD2 og FZD7.
5. Monoklonalt antistof ifølge et hvilket som helst af de foregående krav, hvor antistoffet er en antagonist af den/de humane frizzled-receptor(er).
6. Monoklonalt antistof ifølge et hvilket som helst af de foregående krav, som binder specifikt til human FZD8, hvor antistoffet: (a) binder til sekvensen QYGFA (SEQ ID NO:66); og/eller (b) binder til sekvensen QDEAGLEVHQFWPL (SEQ ID NO:67).
7. Monoklonalt antistof ifølge krav 6, som binder specifikt til human FZD8, hvor antistoffet: (a) binder til sekvensen QYGFA (SEQ ID NO:66) inden for FZD8; og/eller (b) binder til sekvensen GLEVHQ (SEQ ID NO: 25) inden for FZD8.
8. Monoklonalt antistof ifølge et hvilket som helst af de foregående krav, som er et antistoffragment.
9. Monoklonalt antistof ifølge et hvilket som helst af de foregående krav, hvor antistoffet omfatter: (a) en tungkæde-CDFM omfattende GFTFSHYTLS (SEQ ID NO:1); en tung-kæde-CDR2 omfattende VISGDGSYTYYADSVKG (SEQ ID NO:2); en tung-kæde-CDR3 omfattende NFIKYVFAN (SEQ ID NO:3); og (b) en letkæde-CDR1 omfattende SGDNIGSFYVH (SEQ ID NO:7) eller SGDKLGKKYAS (SEQ ID NO:4); en letkæde-CDR2 omfattende DKSNRPSG (SEQ ID NO:8) eller EKDNRPSG (SEQ ID NO:5); og en letkæde-CDR3 omfattende QSYANTLSL (SEQ ID NO:9) eller SSFAGNSLE (SEQ ID NO:6).
10. Monoklonalt antistof ifølge krav 9, hvor antistoffet omfatter: (a) en tungkæde-CDR1 omfattende GFTFSHYTLS (SEQ ID NO:1); en tung-kæde-CDR2 omfattende VISGDGSYTYYADSVKG (SEQ ID NO:2); en tung-kæde-CDR3 omfattende NFIKYVFAN (SEQ ID NO:3); og (b) en letkæde-CDR1 omfattende SGDNIGSFYVH (SEQ ID NO:7) eller SGDKLGKKYAS (SEQ ID NO:4); en letkæde-CDR2 omfattende DKSNRPSG (SEQ ID NO:8) og en letkæde-CDR3 omfattende QSYANTLSL (SEQ ID NO:9).
11. Monoklonalt antistof ifølge et hvilket som helst af de foregående krav, hvor antistoffet omfatter: (a) et polypeptid med mindst ca. 80 % sekvensidentitet med SEQ ID NO: 10; og/eller (b) et polypeptid med mindst ca. 80 % sekvensidentitet med SEQ ID NO: 14 eller SEQ ID NO: 12.
12. Monoklonalt antistof ifølge krav 1 til 3, hvor antistoffet specifikt binder human FZD5 og/eller FZD8 og omfatter: (a) en tungkæde-CDFM omfattende GFTFSSYYIT (SEQ ID NO:77); en tung-kæde-CDR2 omfattende TISYSSSNTYYADSVKG (SEQ ID NO:78); og en tungkæde-CDR3 omfattende SIVFDY (SEQ ID NO:79); og (b) en letkæde-CDR1 omfattende SGDALGNRYVY (SEQ ID NO: 80); en let-kæde-CDR2 omfattende SG (SEQ ID NO:81); og en letkæde-CDR3 omfattende GSWDTRPYPKY (SEQ ID NO:82).
13. Monoklonalt antistof ifølge et hvilket som helst af kravene 1 til 3 eller krav 12, hvor antistoffet specifikt binder FZD8 og/eller FZD5 og omfatter: (a) et polypeptid med mindst ca. 80 % identitet med SEQ ID NO:85; og/eller (b) et polypeptid med mindst ca. 80 % identitet med SEQ ID NO: 86.
14. Monoklonalt antistof ifølge krav 1 til 3, 12 eller 13, hvor antistoffet konkurrerer om specifik binding til human FZD8 og/eller FZD5 i en kompetitiv bin-dingsassay med et antistof omfattende en tungkæde-variabel region omfattende SEQ ID NO: 85 og en letkæde-variabel region omfattende SEQ ID NO: 86.
15. Farmaceutisk sammensætning omfattende et monoklonalt antistof og en farmaceutisk acceptabel vehikel, hvor antistoffet inhiberer wnt-binding til en human frizzled-receptor, og (i) antistoffet omfatter: (a) en tungkæde-CDR1 omfattende GFTFSFIYTLS (SEQ ID NO:1); en tung-kæde-CDR2 omfattende VISGDGSYTYYADSVKG (SEQ ID NO:2); og en tungkæde-CDR3 omfattende NFIKYVFAN (SEQ ID NO:3); og (b) en letkæde-CDR1 omfattende SGDNIGSFYVH (SEQ ID NO:7); en letkæ-de-CDR2 omfattende DKSNRPSG (SEQ ID NO:8); og en letkæde-CDR3 omfattende QSYANTLSL (SEQ ID NO:9), eller (ii) antistoffet kodes af sekvensen af et plasmid, der er deponeret hos ATCC som accessionsnummer PTA-9541.
16. Monoklonalt antistof ifølge krav 1 til 11 eller farmaceutisk sammensætning ifølge krav 15, hvor antistoffet omfatter en tungkæde-variabel region omfattende SEQ ID NO: 10; og en letkæde-variabel region omfattende SEQ ID NO: 14.
17. Monoklonalt antistof eller farmaceutisk sammensætning ifølge et hvilket som helst af de foregående krav, til anvendelse i en fremgangsmåde til behandling af menneske- eller dyrekroppen.
18. Monoklonalt antistof eller farmaceutisk sammensætning ifølge et hvilket som helst af kravene 1 til 16, til anvendelse i en fremgangsmåde til: (i) inhibering af tumorvækst hos et individ, (ii) behandling af cancer hos et individ, (iii) behandling af en lidelse hos et individ, hvor lidelsen er kendetegnet ved et forhøjet niveau af stamceller og/eller progenitorceller, (iv) behandling af en sygdom hos et individ, hvor sygdommen er forbundet med aktivering af Wnt-signalering, (v) induktion af celler i en tumor hos et individ til differentiering eller (vi) reduktion af tumorigeniciteten af en tumor, der omfatter cancerstamceller hos et individ; idet fremgangsmåden omfatter indgivelse af en terapeutisk virksom mængde af antistoffet eller den farmaceutiske sammensætning til individet.
19. Monoklonalt antistof eller farmaceutisk sammensætning ifølge et hvilket som helst af kravene 1 til 16, til anvendelse i en fremgangsmåde ifølge krav 18, hvor fremgangsmåden yderligere omfatter indgivelse af et andet terapeutisk middel.
20. Monoklonalt antistof eller farmaceutisk sammensætning ifølge et hvilket som helst af kravene 1 til 16, til anvendelse i en fremgangsmåde ifølge krav 19, hvor fremgangsmåden omfatter behandling af cancer hos et individ, og hvor det andet terapeutiske middel er et kemoterapeutisk middel.
21. Monoklonalt antistof eller farmaceutisk sammensætning ifølge et hvilket som helst af kravene 1 til 16, til anvendelse i en fremgangsmåde ifølge krav 20, hvor fremgangsmåden omfatter behandling af brystcancer hos et individ ved indgivelse af paclitaxel og en terapeutisk virksom mængde af antistoffet eller den farmaceutiske sammensætning til individet.
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