title: Modeling the clinical phenotype of BTK inhibition in the mature murine immune system.
abstract: Inhibitors of Bruton's tyrosine kinase (BTK) possess much promise for the treatment of oncologic and autoimmune indications. However, our current knowledge of the role of BTK in immune competence has been gathered in the context of genetic inactivation of btk in both mice and man. Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice. We implicate BTK in tonic BCR signaling, demonstrate dependence of the T3 B cell subset and IgM surface expression on BTK activity, and find that B1 cells survive and function independently of BTK. Although BTK inhibition does not impact humoral memory survival, Ag-driven clonal expansion of memory B cells and Ab-secreting cell generation are inhibited. These data define the role of BTK in the mature immune system and mechanistically predict the clinical phenotype of chronic BTK inhibition.
authors.affiliation: Biotherapeutics Immunoscience, Pfizer Inc., Cambridge, MA 02140; Micah.Benson@Pfizer.com.
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Benson
authors.affiliation: Biotherapeutics Immunoscience, Pfizer Inc., Cambridge, MA 02140;
authors.forename: Varenka
authors.initials: V
authors.lastname: Rodriguez
authors.affiliation: Biotherapeutics Clinical Research and Development, Pfizer Inc., Cambridge, MA 02140;
authors.forename: David
authors.initials: D
authors.lastname: von Schack
authors.affiliation: Biotherapeutics Immunoscience, Pfizer Inc., Cambridge, MA 02140;
authors.forename: Sean
authors.initials: S
authors.lastname: Keegan
authors.affiliation: Biotherapeutics Immunoscience, Pfizer Inc., Cambridge, MA 02140;
authors.forename: Tim A
authors.initials: TA
authors.lastname: Cook
authors.affiliation: Biotherapeutics Immunoscience, Pfizer Inc., Cambridge, MA 02140;
authors.forename: Jason
authors.initials: J
authors.lastname: Edmonds
authors.affiliation: Biotherapeutics Immunoscience, Pfizer Inc., Cambridge, MA 02140;
authors.forename: Stephen
authors.initials: S
authors.lastname: Benoit
authors.affiliation: Biotherapeutics Immunoscience, Pfizer Inc., Cambridge, MA 02140;
authors.forename: Nilufer
authors.initials: N
authors.lastname: Seth
authors.affiliation: Biotherapeutics Clinical Research and Development, Pfizer Inc., Cambridge, MA 02140;
authors.forename: Sarah
authors.initials: S
authors.lastname: Du
authors.affiliation: Biotherapeutics Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Cambridge, MA 02140; and.
authors.forename: Dean
authors.initials: D
authors.lastname: Messing
authors.affiliation: Biotherapeutics Immunoscience, Pfizer Inc., Cambridge, MA 02140;
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Nickerson-Nutter
authors.affiliation: Biotherapeutics Immunoscience, Pfizer Inc., Cambridge, MA 02140;
authors.forename: Kyri
authors.initials: K
authors.lastname: Dunussi-Joannopoulos
authors.affiliation: Biotherapeutics Immunoscience, Pfizer Inc., Cambridge, MA 02140;
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Rankin
authors.affiliation: Biotherapeutics Immunoscience, Pfizer Inc., Cambridge, MA 02140;
authors.forename: Melanie
authors.initials: M
authors.lastname: Ruzek
authors.affiliation: Biotherapeutics Medicinal Chemistry, Pfizer Inc., Cambridge, MA 02140.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Schnute
authors.affiliation: Biotherapeutics Immunoscience, Pfizer Inc., Cambridge, MA 02140;
authors.forename: John
authors.initials: J
authors.lastname: Douhan
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral / Q000502:physiology*; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory / Q000502:physiology*; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D018448:Models, Immunological; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
chemical_list: D007075:Immunoglobulin M; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse