2. Academic Validation
  3. Modeling the clinical phenotype of BTK inhibition in the mature murine immune system

Modeling the clinical phenotype of BTK inhibition in the mature murine immune system

  • J Immunol. 2014 Jul 1;193(1):185-97. doi: 10.4049/jimmunol.1302570.
Micah J Benson 1,  Varenka Rodriguez 2,  David von Schack 3,  Sean Keegan 2,  Tim A Cook 2,  Jason Edmonds 2,  Stephen Benoit 2,  Nilufer Seth 2,  Sarah Du 3,  Dean Messing 4,  Cheryl L Nickerson-Nutter 2,  Kyri Dunussi-Joannopoulos 2,  Andrew L Rankin 2,  Melanie Ruzek 2,  Mark E Schnute 5,  John Douhan 3rd 2
Affiliations

Affiliations

  • 1 Biotherapeutics Immunoscience, Pfizer Inc., Cambridge, MA 02140; Micah.Benson@Pfizer.com.
  • 2 Biotherapeutics Immunoscience, Pfizer Inc., Cambridge, MA 02140;
  • 3 Biotherapeutics Clinical Research and Development, Pfizer Inc., Cambridge, MA 02140;
  • 4 Biotherapeutics Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., Cambridge, MA 02140; and.
  • 5 Biotherapeutics Medicinal Chemistry, Pfizer Inc., Cambridge, MA 02140.
PMID: 24899507 DOI: 10.4049/jimmunol.1302570
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.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-164002
    BTK Inhibitor
    Btk