DK2486941T3 - Humane antistoffer, der binder cxcr4, og anvendelser deraf - Google Patents

Humane antistoffer, der binder cxcr4, og anvendelser deraf Download PDF

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DK2486941T3
DK2486941T3 DK12155398.6T DK12155398T DK2486941T3 DK 2486941 T3 DK2486941 T3 DK 2486941T3 DK 12155398 T DK12155398 T DK 12155398T DK 2486941 T3 DK2486941 T3 DK 2486941T3
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sequence
cxcr4
antibody
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Michelle Kuhne
Peter Brams
Dawn M Tanamachi
Alan Korman
Josephine M Cardarelli
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Squibb & Sons Llc
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    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Claims (26)

  1. HUMANE ANTISTOFFER, DER BINDER CXCR4, OG ANVENDELSER DERAF PATENTKRAV
    1. Monoklonalt antistof eller en antigenbindende del deraf, der specifikt binder til human CXCR4 udtrykt på en celleoverflade og omfatter et variabelt tungkædeområde, der omfatter aminosyrer med en sekvens, der er mindst 90 % identisk med sekvensen ifølge SEQ ID NO: 49 kodet for af et humant Vh 3-48 kimbane-immunglobulingen og et variabelt letkædeområde, der omfatter aminosyrer med en sekvens, der er mindst 90 % identisk med sekvensen ifølge SEQ ID NO: 50 kodet for af et humant VK LI5 kimbane-immunglobulingen, hvor det monoklonale antistof eller antigenbindende del deraf inducerer apoptose i celler, der udtrykker human CXCR4, og hæmmer vækst og/eller inducerer apoptose af CXCR4+ tumorceller in vivo.
  2. 2. Monoklonalt antistof eller antigenbindende del deraf ifølge krav 1, der omfatter: (a) et variabelt tungkædeområde CDR1, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 1 eller én konservativ aminosyresubstitution deraf; et variabelt tungkædeområde CDR2, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 5 eller én konservativ aminosyresubstitution deraf; et variabelt tungkædeområde CDR3, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 9; et variabelt letkædeområde CDR1, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 13 eller én konservativ aminosyresubstitution deraf; et variabelt letkædeområde CDR2, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 17 eller én konservativ aminosyresubstitution deraf; og et variabelt letkædeområde CDR3, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 21 eller én konservativ aminosyresubstitution deraf; (b) et variabelt tungkædeområde CDR1, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 2 eller én konservativ aminosyresubstitution deraf; et variabelt tungkædeområde CDR2, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 6 eller én konservativ aminosyresubstitution deraf; et variabelt tungkædeområde CDR3, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 10; et variabelt letkædeområde CDR1, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 14 eller én konservativ aminosyresubstitution deraf; et variabelt letkædeområde CDR2, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 18 eller én konservativ aminosyresubstitution deraf; og et variabelt letkædeområde CDR3, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 22 eller én konservativ aminosyresubstitution deraf; (c) et variabelt tungkædeområde CDR1, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 3 eller én konservativ aminosyresubstitution deraf; et variabelt tungkædeområde CDR2, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 7 eller én konservativ aminosyresubstitution deraf; et variabelt tungkædeområde CDR3, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 11; et variabelt letkædeområde CDR1, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 15 eller én konservativ aminosyresubstitution deraf; et variabelt letkædeområde CDR2, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 19 eller én konservativ aminosyresubstitution deraf; og et variabelt letkædeområde CDR3, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 23 eller én konservativ aminosyresubstitution deraf; eller (d) et variabelt tungkædeområde CDR1, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 4 eller én konservativ aminosyresubstitution deraf; et variabelt tungkædeområde CDR2, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 8 eller én konservativ aminosyresubstitution deraf; et variabelt tungkædeområde CDR3, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 12; et variabelt letkædeområde CDR1, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 16 eller én konservativ aminosyresubstitution deraf; et variabelt letkædeområde CDR2, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 20 eller én konservativ aminosyresubstitution deraf; og et variabelt letkædeområde CDR3, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 24 eller én konservativ aminosyresubstitution deraf.
  3. 3. Monoklonalt antistof eller antigenbindende del deraf ifølge krav 2, der omfatter: (a) et variabelt tungkædeområde, der omfatter aminosyrer med en sekvens, der er mindst 80 % homolog med sekvensen ifølge SEQ ID NO: 25 eller 41, og et variabelt letkædeområde, der omfatter aminosyrer med cn sekvens, der er mindst 80 % homolog med sekvensen ifølge SEQ ID NO: 29 eller 45; (b) et variabelt tungkædeområde, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 26 eller 42 eller en sekvens, der er mindst 80 % homolog dermed, og et variabelt letkædeområde, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 30 eller 46 eller en sekvens, der er mindst 80 % homolog dermed; (c) et variabelt tungkædeområde, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 27 eller 43 eller en sekvens, der er mindst 80 % homolog dermed, og et variabelt letkædeområde, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 31 eller 47 eller en sekvens, der er mindst 80 % homolog dermed; eller (d) et variabelt tungkædeområde, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 28 eller 44 eller en sekvens, der er mindst 80 % homolog dermed, og et variabelt letkædeområde, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 32 eller 48 eller en sekvens, der er mindst 80 % homolog dermed.
  4. 4. Monoklonalt antistof eller antigenbindende del deraf ifølge krav 2, der omfatter: (a) et variabelt tungkædeområde, der består af aminosyrer med sekvensen ifølge SEQ ID NO: 26 og et variabelt letkædeområde, der består af aminosyrer med sekvensen ifølge SEQ ID NO: 30; (b) et variabelt tungkædeområde, der består af aminosyrer med sekvensen ifølge SEQ ID NO: 27 og et variabelt letkædeområde, der består af aminosyrer med sekvensen ifølge SEQ ID NO: 31; eller (c) et variabelt tungkædeområde, der består af aminosyrer med sekvensen ifølge SEQ ID NO: 28 og et variabelt letkædeområde, der består af aminosyrer med sekvensen ifølge SEQ ID NO: 32.
  5. 5. Monoklonalt antistof eller antigenbindende del deraf ifølge et hvilket som helst af kravene 1-4, der (a) hæmmer binding af SDF-1 til human CXCR4; (b) hæmmer SDF -1 -induceret calciumstrøm i celler, der udtrykker human CXCR4; (c) hæmmer SDF -1 -induceret migration af celler, der udtrykker human CXCR4; og/eller (d) hæmmer dannelse af kapillærrør via humane navleveneendotelceller; (e) hæmmer metastaser af CXCR4+ tumorceller; (f) forlænger overlevelsestid for et CXCR4+ tumorbærende individ; (g) er af en IgG 1 - eller IgG4-isotype eller en antigenbindende del deraf; og/eller (h) er et kimært, humaniseret eller humant antistof eller en antigenbindende del deraf.
  6. 6. Monoklonalt antistof eller antigenbindende del deraf ifølge et hvilket som helst af kravene 1 -5, der (a) binder til human CXCR4 udtrykt på en celleoverflade med en KD på 1 x 10'8 M eller mindre; (b) binder til human CXCR4 udtrykt på en celleoverflade med en KD på 5 x 10'9 M eller mindre; (c) hæmmer binding af SDF-1 til human CXCR4 med en EC50 på 50 nM eller mindre; (d) hæmmer SDF-1-induceret calciumstrøm i celler, der udtrykker human CXCR4, med en EC50 på 3 nM eller mindre; og/eller (e) hæmmer SDF-1-induceret migration af celler, der udtrykker human CXCR4, med en EC50 på 50 nM eller mindre.
  7. 7. Monoklonalt antistof ifølge et hvilket som helst af kravene 1 -6, hvor det monoklonale antistof er et fuldlængde-antistof.
  8. 8. Monoklonalt antistof antigenbindende del ifølge et hvilket som helst af kravene 1-6, hvor den antigenbindende del er et bivalent F(ab')2-fragment.
  9. 9. Immunkonjugat, der omfatter det monoklonale antistof eller antigenbindende del deraf ifølge et hvilket som helst af kravene 1-8, og som er bundet til et terapeutisk middel, såsom et cytotoksin eller en radioaktiv isotop.
  10. 10. Bispecifikt molekyle, der omfatter det monoklonale antistof eller den antigenbindende del deraf ifølge et hvilket som helst af kravene 1-8, og som er bundet til en anden funktionsdel med en anden bindingsspecificitet end det monoklonale antistof eller den antigenbindende del deraf.
  11. 11. Sammensætning, der omfatter: (a) det monoklonale antistof eller den antigenbindende del deraf ifølge et hvilket som helst af kravene 1-8; (b) immunkonjugatet ifølge krav 9; eller (c) det bispecifikke molekyle ifølge krav 10; og en farmaceutisk acceptabel bærer.
  12. 12. Isoleret nukleinsyre, der koder for det monoklonale antistof eller den antigenbindende del deraf ifølge et hvilket som helst af kravene 1-8, eller en ekspressionsvektor, der omfatter nukleinsyren.
  13. 13. Værtscelle, der omfatter ekspressionsvektoren ifølge krav 12.
  14. 14. Fremgangsmåde til fremstilling af et anti-CXCR4-antistof eller en antigenbindende del deraf, der omfatter ekspression af antistoffet eller en antigenbindende del deraf i værtscellen ifølge krav 13 og isolering af antistoffet eller en antigenbindende del deraf fra værtscellen.
  15. 15. Fremgangsmåde in vitro til modulering af CXCR4-aktivitet i en celle, der udtrykker CXCR4-receptoren, hvilken fremgangsmåde omfatter etablering af kontakt mellem cellen og det monoklonale antistof eller den antigenbindende del deraf ifølge et hvilket som helst af kravene 1-8, således at CXCR4-aktivilet i cellen moduleres.
  16. 16. Fremgangsmåde ifølge krav 15, hvor (a) cellen er en tumorcelle, der udtrykker CXCR4 og fremgangsmåden resulterer i hæmning af vækst af tumorcellen; eller (b) cellen er en T-celle, der udtrykker CXCR4 og fremgangsmåden resulterer i hæmning af indtrængning af HIV i cellen.
  17. 17. Monoklonalt antistof eller antigenbindende del deraf ifølge et hvilket som helst af kravene 1-8 til anvendelse i en terapeutisk fremgangsmåde til: (a) modulering af CXCR4-aktivitet i en celle fra et individ; (b) hæmning af vækst eller metastase af en tumorcelle hos et individ, eventuelt hvor tumorcellen er valgt fra en celle af en B-celleleukæmi, et lymfom, en akut lymfoblastisk leukæmi, en akut myeloid leukæmi, et småcellet lungekarcinom, en ikke-småcellet lungecancer, en brystcancer, en ovariecancer, en prostatacancer, en pankreascancer, en thyroideacancer, et nasopharyngealt karcinom, et melanom, et nyrecellekarcinom, et neuroblastom, et glioblastom, et rhabdomyosarkom, en colorektalcancer, en nyrecancer, et osteosarkom og en metastatisk lungecancer; (c) hæmning af indtrængning af HIV i cn T-ccllc hos et individ, hvor HIV’ct anvender CXCR4 som coreceptor for indtrængning i T-cellen; (d) hæmning af inflammation hos et individ, der er ramt af en inflammatorisk forstyrrelse; (e) hæmning af angiogenese hos et individ; eller (f) stimulering af mobilisering af CD34+ stamceller fra knoglemarv til perifert blod hos et individ, eventuelt hvor fremgangsmåden endvidere omfatter indsamling af CD34+ stamcellerne fra det perifere blod.
  18. 18. Monoklonalt antistof eller antigenbindende del deraf ifølge et hvilket som helst af kravene 1-8 til anvendelse, i kombination med et andet terapeutisk middel, i en fremgangsmåde til behandling af cancer hos et individ.
  19. 19. Monoklonalt antistof eller antigenbindende del deraf til anvendelse ifølge krav 18, hvor det andet terapeutiske middel er et antistof, der binder til CTLA-4, PD-1 eller PD-L1.
  20. 20. Monoklonalt antistof eller antigenbindende del deraf til anvendelse ifølge krav 18, hvor canceren er en pankreascancer eller et småcellet lungekarcinom.
  21. 21. Monoklonalt antistof eller antigenbindende del deraf til anvendelse ifølge krav 18, hvor det andet terapeutiske middel er et antistof, der binder til PD-1.
  22. 22. Monoklonalt antistof eller antigenbindende del deraf, der specifikt binder til human CXCR4 udtrykt på en celleoverflade til anvendelse, i kombination med et andet terapeutisk middel, i en fremgangsmåde til behandling af cancer hos et individ, hvor det monoklonale antistof eller den antigenbindende del deraf omfatter en tungekæde-CDRl, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 1; en tungekæde-CDR2, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 5; en tungekæde-CDR3, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 9; en letkæde-CDRl, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 13; en letkæde-CDR2, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 17; og en letkæde-CDR3, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 21.
  23. 23. Monoklonalt antistof eller antigenbindende del deraf til anvendelse ifølge krav 22, hvor det monoklonale antistof eller den antigenbindende del deraf omfatter et variabelt tungkædeområde, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 25 og et variabelt letkædeområde, der omfatter aminosyrer med sekvensen ifølge SEQ ID NO: 29.
  24. 24. Monoklonalt antistof eller antigenbindende del deraf til anvendelse ifølge krav 22 eller krav 23, hvor det andet terapeutiske middel er et antistof, der binder til CTLA-4, PD-1 eller PD-L1.
  25. 25. Monoklonalt antistof eller antigenbindende del deraf til anvendelse ifølge krav 22 eller krav 23, hvor canceren er en pankreascancer eller et småcellet lungekarcinom.
  26. 26. Monoklonalt antistof eller antigenbindende del deraf til anvendelse ifølge krav 22 eller krav 23, hvor det andet terapeutiske middel er et antistof, der binder til PD-1.
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