Therapeutic interventions targeting CD40L (CD154) and CD40: the opportunities and challenges

CD40 was originally identified as a receptor on B-cells that delivers contact-dependent T helper signals to B-cells through interaction with CD40 ligand (CD40L, CD154). The pivotal role played by CD40-CD40L interaction is illustrated by the defects in B-lineage cell development and the altered structures of secondary lymphoid tissues in patients and engineered mice deficient in CD40 or CD40L. CD40 signaling also provides critical functions in stimulating antigen presentation, priming of helper and cytotoxic T-cells and a variety of inflammatory reactions. As such, dysregulations in the CD40-CD40L costimulation pathway are prominently featured in human diseases ranging from inflammatory conditions to systemic autoimmunity and tissue-specific autoimmune diseases. Moreover, studies in CD40-expressing cancers have provided convincing evidence that the CD40-CD40L pathway regulates survival of neoplastic cells as well as presentation of tumor-associated antigens to the immune system. Extensive research has been devoted to explore CD40 and CD40L as drug targets. A number of anti-CD40L and anti-CD40 antibodies with diverse biological effects are in clinical development for treatment of cancer and autoimmune diseases. This chapter reviews the role of CD40-CD40L costimulation in disease pathogenesis, the characteristics of therapeutic agents targeting this pathway and status of their clinical development.