Of the various biologic agents approved for RA, rituximab (Rituxan) and abatacept (Orencia) are the first to target B-cells. Rituximab is a monoclonal α-CD20 antibody that causes complete and prolonged depletion of peripheral B-cells, thereby impacting multiple mechanisms through which B-cells contribute to disease progression . Abatacept is a fusion protein of human cytotoxic T-lymphocyte-associated antigen (CTLA-4) and the Fc portion (the antibody fragment without antigen binding sites) of human immunoglobulin. Abatacept binds CD80/86 on B-cells, thereby blocking the costimulatory interaction with CD28 necessary for T-cell activation. Other biologic agents in clinical development that target B-cell function include belimumab (Benlysta) and atacicept. Belimumab is an antibody to B-lymphocyte stimulator (BLys) and has met the primary efficacy endpoints in two Phase III studies in SLE . Atacicept binds to BLys and APRIL (a proliferation-inducing ligand) both of which are ligands for TNF family receptors that promote B-cell maturation and proliferation . Atacicept is currently in Phase II trials for RA, MS, and SLE.
The influence of B-cells on disease pathology, and their successful targeting with biologic agents, has stimulated great interest in the discovery of small molecules that modulate B-cell function. Three kinases have emerged as the principal B-cell targets for small-molecule therapeutics: Bruton’s tyrosine kinase (Btk), spleen tyrosine kinase (Syk), and phosphoinositide-3 kinase (PI3K).