DK2473522T3 - Smoothened-mutant og fremgangsmåder til anvendelse af samme - Google Patents

Smoothened-mutant og fremgangsmåder til anvendelse af samme Download PDF

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DK2473522T3
DK2473522T3 DK10751758.3T DK10751758T DK2473522T3 DK 2473522 T3 DK2473522 T3 DK 2473522T3 DK 10751758 T DK10751758 T DK 10751758T DK 2473522 T3 DK2473522 T3 DK 2473522T3
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antibody
amino acid
smo
antibodies
nucleic acid
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DK10751758.3T
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Sauvage Frederic J De
Gerrit J P Dijkgraaf
Thomas Januario
Robert L Yauch
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Genentech Inc
Curis Inc
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/72—Assays involving receptors, cell surface antigens or cell surface determinants for hormones
    • G01N2333/726—G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/10—Screening for compounds of potential therapeutic value involving cells

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Claims (25)

1. Isoleret nukleinsyremolekyle, der koder for et mutant-SMO-protein, som omfatter en aminosyresekvens, der er mindst 95 % identisk med SEQ ID NO: 1. hvor aminosyresekvensen omfatter en aminosyre, som ikke er asparagin-syre, ved aminosyren svarende til aminosyre 473 med SEQ ID NO:2.
2. Isoleret nukleinsyresekvens ifølge krav 1, hvor mutant-SMO-proteinet omfatter aminosyresekvensen med SEQ ID NO: 2, hvor aminosyresekvensen omfatter en histidin, glycin, phenylalanin, tyrosin, leucin, isoleucin, prolin, se-rinthreonin, methionin, glutamin eller asparagin ved aminosyren svarende til aminosyre 473 med SEQ ID NO:2.
3. Isoleret nukleinsyresekvens ifølge krav 1, omfattende en parental nukleinsyresekvens med SEQ ID NO: 3, hvor sekvensen indeholder en mutation, der ændrer sekvensen, der koder for aminosyren svarende til aminosyre 473 med SEQ ID NO:2, til kodning af en anden aminosyre.
4. Nukleinsyresonde, der er i stand til specifikt at hybridisere til en nukleinsyre, der koder for et muteret SMO-protein eller et fragment deraf, hvilket muterede SMO-protein eller fragment deraf omfatter en mutation i sekvensen, der koder for aminosyren svarende til aminosyre 473 med SEQ ID NO:2, hvor nukleinsyresonden differentieret binder nukleinsyresonden, der koder for det muterede SMO-protein eller fragmentet over en nukleinsyre, der koder et vildtype SMO-protein eller fragment.
5. Sonde ifølge krav 4, hvor sonden er komplementær til nukleinsyren, der koder for det muterede SMO-protein eller fragmentet deraf.
6. Sonde ifølge krav 4 med en længde på ca. 10 til ca. 50 nukleotider.
7. Sonde ifølge krav 4, yderligere omfattende et detekterbart mærke.
8. Isoleret mutant-SMO-protein, omfattende en aminosyresekvens, der er mindst 95 % identisk med SEQ ID NO: 2,hvor aminosyresekvensen omfatter en aminosyre, som ikke er asparaginsyre, ved aminosyren svarende til ami- nosyre 473 med SEQ ID NO:2.
9. Isoleret mutant-SMO-protein ifølge krav 8, omfattende aminosyresekven-sen med SEQ ID NO: 2,hvor aminosyresekvensen omfatter en aminosyre, som ikke er asparaginsyre, ved aminosyren svarende til aminosyre 473 med SEQ ID NO:2.
10. Isoleret mutant-SMO-protein ifølge krav 8 eller 9, hvor aminosyresekvensen omfatter en histidin, glycin, phenylalanin, tyrosin, leucin, isoleucin, prolin, serinthreonin, methionin, glutamin eller asparagin ved aminosyren svarende til aminosyre 473 med SEQ ID NO:2.
11. Antistof, der specifikt binder til mutant-SMO-proteinet ifølge krav 8 eller 9, hvor antistoffet ikke binder et vildtype SMO-protein med en asparaginsyre ved position 473.
12. Antistof ifølge krav 11, hvor antistoffet er et monoklonalt antistof, et kimært antistof, et humaniseret antistof, et enkeltkædet antistof eller et antigen-bindende fragment deraf.
13. Antistof ifølge krav 11, hvor antistoffet er konjugeret til et cytotoksisk middel.
14. Antistof ifølge krav 11, hvor antistoffet inhiberer SMO-protein-aktivitet.
15. Fremgangsmåde til påvisning af et muteret SMO-gen i en prøve, hvor det muterede SMO-gen koder for et muteret SMO-protein eller et fragment deraf, hvor det muterede SMO-protein eller fragmentet deraf omfatter en mutation ved aminosyrepositionen svarende til aminosyreposition 473 med SEQ ID NO:2, hvor fremgangsmåden omfatter at amplificere fra prøven en nukleinsyre, som har en længde på mindst 20 nukleotider og koder for mutationen ved aminosyrepositionen svarende til aminosyreposition 473 med SEQ ID NO:2, og at sammenligne den elektroforetiske mobilitet af den amplificerede nukleinsyre med den elektroforetiske mobilitet af det tilsvarende vildtype SMO-gene eller fragment deraf.
16. Fremgangsmåde ifølge krav 15, hvor den elektroforetiske mobilitet bestemmes på polyacrylamidgel.
17. Fremgangsmåde til identificering af mindst en SMO-mutation i en prøve, omfattende at bringe en nukleinsyre fra prøven i kontakt med en nukleinsyresonde, der er i stand til specifikt at hybridisere til en nukleinsyre, der koder for et muteret SMO-protein eller et fragment deraf, hvor nukleinsyren omfatter en mutation, der ændrer sekvensen, der koder for aminosyre 473, til en aminosyre, der ikke er asparaginsyre, og at påvise hybridiseringen.
18. Fremgangsmåde ifølge krav 17, hvor sonden er detekterbart mærket.
19. Fremgangsmåde ifølge krav 17, hvor sonden er en antisense-oligomer.
20. Fremgangsmåde ifølge krav 17, hvor SMO-genet eller et fragment deraf i nukleinsyreprøven amplificeres og bringes i kontakt med prøven.
21. Fremgangsmåde til identificering af en tumor hos et menneskeligt individ, som er resistent over for behandling med GDC-0449, omfattende at bestemme tilstedeværelsen af et muteret SMO-gen eller muteret SMO-protein i en prøve af tumoren, hvor mutationen er lokaliseret i det SMO-gen, der koder for aminosyre 473, hvor tilstedeværelsen af det muterede SMO-gen eller muterede SMO-protein indikerer, at tumoren er resistent over for behandling med et GDC-0449.
22. Fremgangsmåde ifølge krav 21, hvor tilstedeværelsen eller fraværet af mutationen udføres ved at undersøge en nukleinsyreprøve eller en proteinprøve.
23. Fremgangsmåde til screening for forbindelser, der inhiberer signalering af et mutant-SMO-protein, som indeholder en mutation ved aminosyre 473, omfattende at bringe mutant-SMO-proteinet i kontakt med en testforbindelse og at påvise bindingen af forbindelsen til mutant-SMO-proteinet, hvorved bindingen af testforbindelsen til mutant-SMO-protein indikerer, at testforbindelsen er en inhibitor af mutant-SMO-protein.
24. Fremgangsmåde til screening for forbindelser, der inhiberer signalering af et mutant-SMO-protein, som indeholder en mutation ved aminosyre 473, omfattende at bringe en celle, der eksprimerer mutant-SMO-proteinet, i kontakt med en testforbindelse og at påvise aktivitet af Gli i cellen, hvorved tilstedeværelsen af Gli-aktivitet indikerer, at testforbindelsen ikke er en inhibitor af mutant-SMO-protein.
25. Forbindelse til anvendelse i en fremgangsmåde til behandling af cancer, hvor forbindelsen specifikt binder til et mutant-SMO-protein med en mutation, der resulterer i en aminosyre ved position 473, som ikke er asparaginsyre, hvor forbindelse er enten: (i) et antistof, der specifikt binder et mutant-SMO med en aminosyre, som ikke er asparaginsyre ved position 473; eller (ii) en forbindelse med formel I, II og/eller III:
Formel I Formel II Formel III
DK10751758.3T 2009-09-02 2010-09-02 Smoothened-mutant og fremgangsmåder til anvendelse af samme DK2473522T3 (da)

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ES2694857T3 (es) 2014-02-04 2018-12-27 Genentech, Inc. Smoothened mutante y métodos de uso de la misma
WO2016126972A1 (en) * 2015-02-04 2016-08-11 Genentech, Inc. Mutant smoothened and methods of using the same
CA2987067A1 (en) 2015-06-05 2016-12-08 Dana-Farber Cancer Institute, Inc. Compounds and methods for treating cancer
AU2017213826A1 (en) 2016-02-04 2018-08-23 Curis, Inc. Mutant smoothened and methods of using the same

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