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DE14176593T1 - ADAM6 Mäuse - Google Patents

ADAM6 Mäuse Download PDF

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Publication number
DE14176593T1
DE14176593T1 DE14176593.3T DE14176593T DE14176593T1 DE 14176593 T1 DE14176593 T1 DE 14176593T1 DE 14176593 T DE14176593 T DE 14176593T DE 14176593 T1 DE14176593 T1 DE 14176593T1
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rodent
cell
sequence
antibody
antigen
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Sean Stevens
Andrew J. Murphy
Lynn Macdonald
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Regeneron Pharmaceuticals Inc
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Regeneron Pharmaceuticals Inc
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Publication of DE14176593T1 publication Critical patent/DE14176593T1/de
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Abstract

Ein Nagetier umfassend eine B-Zelle, die eine umgelagerte Immunglobulinsequenz umfasst, die mit einer Sequenz der konstanten Region einer Nagetier-Schwere-Kette funktionsfähig verknüpft ist, die umgelagerte Immunglobulinsequenz umfassend eine V-, D- und/oder J-Sequenz einer humanen schweren Kette, die B-Zelle umfassend in ihrem Genom eine integrierte Adam6-Sequenz oder Ortholog oder Homolog davon, wobei die integrierte Adam6-Sequenz
(a) in einem ersten Allel aber nicht in einem zweiten Allel vorhanden ist und auf demselben Chromosom ist wie die umgelagerte Immunglobulinsequenz; oder
(b) in einem ersten Allel und einem zweiten Allel vorhanden ist; oder
(c) in einem ersten Allel aber nicht in einem zweiten Allel vorhanden ist und auf einem unterschiedlichen Chromosom ist als die umgelagerte Immunglobulinsequenz.

Claims (16)

  1. Ein Nagetier umfassend eine B-Zelle, die eine umgelagerte Immunglobulinsequenz umfasst, die mit einer Sequenz der konstanten Region einer Nagetier-Schwere-Kette funktionsfähig verknüpft ist, die umgelagerte Immunglobulinsequenz umfassend eine V-, D- und/oder J-Sequenz einer humanen schweren Kette, die B-Zelle umfassend in ihrem Genom eine integrierte Adam6-Sequenz oder Ortholog oder Homolog davon, wobei die integrierte Adam6-Sequenz (a) in einem ersten Allel aber nicht in einem zweiten Allel vorhanden ist und auf demselben Chromosom ist wie die umgelagerte Immunglobulinsequenz; oder (b) in einem ersten Allel und einem zweiten Allel vorhanden ist; oder (c) in einem ersten Allel aber nicht in einem zweiten Allel vorhanden ist und auf einem unterschiedlichen Chromosom ist als die umgelagerte Immunglobulinsequenz.
  2. Das Nagetier von Anspruch 1, wobei die Adam6-Sequenz auf einem Transgen ist, das von einem heterologen Promoter getrieben wird, wobei vorzugsweise der heterologe Promoter ein nicht-Immunglobulin-Promoter ist.
  3. Das Nagetier von Anspruch 1 oder 2, wobei die Sequenz der konstanten Region einer Nagetier-Schwere-Kette eine Sequenz einer Nagetier-Schwere-Kette umfasst, ausgewählt aus der Gruppe, bestehend aus einer CH1, einem Gelenk, einer CH2, einer CH3 und einer Kombination davon.
  4. Das Nagetier von einem der Ansprüche 1–3, wobei eine Mehrheit der B-Zellen des Nagetiers jene integrierte Adam6-Sequenz oder Ortholog oder Homolog davon umfasst.
  5. Das Nagetier von einem der Ansprüche 1–4, wobei mindestens 90% der B-Zellen des Nagetiers in ihrem Genom jene integrierte Adam6-Sequenz oder Ortholog oder Homolog davon umfassen.
  6. Eine Nagetier-B-Zelle umfassend eine umgelagerte nicht-endogene Immunglobulin-variable-Gensequenz, die mit einem Nagetier-Immunglobulin-konstante-Region-Gen funktionsfähig verknüpft ist, wobei die B-Zelle eine integrierte Nukleinsäuresequenz umfasst, die für ein in einem männlichen Nagetier funktionellen Adam6-Protein oder Ortholog oder Homolog davon kodiert.
  7. Die B-Zelle von Anspruch 6, wobei jene integrierte Nukleinsäuresequenz auf einem Nukleinsäuremolekül ist, das an die umgelagerte nicht-endogene Immunglobulin-variable-Gensequenz angrenzt.
  8. Die B-Zelle von Anspruch 6, wobei jene integrierte Nukleinsäuresequenz auf einem Nukleinsäuremolekül ist, das von dem Nukleinsäuremolekül verschieden ist, das die umgelagerte nicht-endogene Immunglobulin-variable-Gensequenz umfasst.
  9. Eine Hybridomzelle die aus der B-Zelle nach einem der Ansprüche 6–8 erzeugt wird.
  10. Verwendung eines Nagetiers entsprechend einem der Ansprüche 1–5 zur Herstellung eines chimären Antikörpers, eines vollständig humanen Antikörpers, eines vollständig humanen Fab-Fragments und/oder eines vollständig humanen F(ab)2-Fragments.
  11. Ein Verfahren zur Herstellung eines Antikörpers, der spezifisch gegen ein Antigen ist, umfassen die Schritte von: a) Immunisieren eines Nagetiers entsprechend einem der Ansprüche 1–5 mit dem Antigen; b) Isolieren mindestens einer Zelle aus dem Nagetier, das den Antikörper herstellt, der spezifisch gegen das Antigen ist; und c) Kultivieren mindestens einer Zelle die den Antikörper aus Schritt b) herstellt und Erhalten jenes Antikörpers, wobei vorzugsweise das Kultivieren in Schritt c) mit mindestens einer Hybridomzelle durchgeführt wird, die von der mindestens einen in Schritt b) erhaltenen Zelle hergestellt wurde.
  12. Ein Verfahren zur Herstellung eines vollständig humanen Antikörpers, der spezifisch gegen ein Antigen ist, umfassen die Schritte von: a) Immunisieren eines Nagetiers entsprechend einem der Ansprüche 1–5 mit dem Antigen; b) Isolieren mindestens einer Zelle aus dem Nagetier, das den Antikörper herstellt, der spezifisch gegen das Antigen ist; c) Erzeugen mindestens einer Zelle, die den vollständig humanen Antikörper herstellt, der von dem Antikörper aus Schritt b) abgeleitet wurde und spezifisch gegen das Antigen ist; und d) Kultivieren mindestens einer Zelle die den Antikörper aus Schritt c) herstellt und Erhalten jenes Antikörpers.
  13. Ein Verfahren zur Herstellung eines vollständig humanen Antikörpers, der spezifisch gegen ein Antigen ist, umfassen die Schritte von: a) Expression in einer Säugetierzelle jenes vollständig humanen Antikörpers, für den ein oder mehr variable-Region-Sequenzen abgeleitet wurden durch: i) Immunisieren eines Nagetiers entsprechend einem der Ansprüche 1–5 mit dem Antigen; ii) Isolieren mindestens einer Zelle aus dem Nagetier, das den Antikörper herstellt, der spezifisch gegen das Antigen ist; iii) Bestimmen einer oder mehr variable-Region-Sequenzen des hergestellten Antikörpers; und b) Kultivieren der Säugetierzelle, so dass der vollständig humane Antikörper hergestellt wird; und c) Erhalten jenes vollständig humanen Antikörpers.
  14. Das Verfahren von einem der Ansprüche 11 und 12, wobei die mindestens eine in Schritt b) erhaltene Zelle ein Splenozyt oder eine B-Zelle ist.
  15. Das Verfahren nach einem der Ansprüche 11–13, wobei der Antikörper ein monoklonaler Antikörper ist.
  16. Das Verfahren nach einem der Ansprüche 11–14, wobei Immunisieren mit dem Antigen im Schritt a) mit einem Protein, DNA, einer Kombination von DNA und Protein, oder Zellen, die das Antigen exprimieren, durchgeführt wird.
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