B-cell receptor signaling inhibitors for treatment of autoimmune inflammatory diseases and B-cell malignancies

Int Rev Immunol. 2013 Aug;32(4):397-427. doi: 10.3109/08830185.2013.818140.

Abstract

B-cell receptor (BCR) signaling is essential for normal B-cell development, selection, survival, proliferation, and differentiation into antibody-secreting cells. Similarly, this pathway plays a key role in the pathogenesis of multiple B-cell malignancies. Genetic and pharmacological approaches have established an important role for the Spleen tyrosine kinase (Syk), Bruton's tyrosine kinase (Btk), and phosphatidylinositol 3-kinase isoform p110delta (PI3Kδ) in coupling the BCR and other BCRs to B-cell survival, migration, and activation. In the past few years, several small-molecule inhibitory drugs that target PI3Kδ, Btk, and Syk have been developed and shown to have efficacy in clinical trials for the treatment of several types of B-cell malignancies. Emerging preclinical data have also shown a critical role of BCR signaling in the activation and function of self-reactive B cells that contribute to autoimmune diseases. Because BCR signaling plays a major role in both B-cell-mediated autoimmune inflammation and B-cell malignancies, inhibition of this pathway may represent a promising new strategy for treating these diseases. This review summarizes recent achievements in the mechanism of action, pharmacological properties, and clinical activity and toxicity of these BCR signaling inhibitors, with a focus on their emerging role in treating lymphoid malignancies and autoimmune disorders.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antineoplastic Agents / therapeutic use*
  • Autoimmune Diseases / drug therapy*
  • Autoimmune Diseases / metabolism*
  • B-Lymphocytes / physiology
  • Humans
  • Leukemia, B-Cell / drug therapy*
  • Leukemia, B-Cell / metabolism*
  • Lymphoma, B-Cell / drug therapy*
  • Lymphoma, B-Cell / metabolism*
  • Receptors, Antigen, B-Cell / metabolism*
  • Signal Transduction / drug effects*

Substances

  • Antineoplastic Agents
  • Receptors, Antigen, B-Cell