Structure of the CD40-CD154 Complex with antagonist PG102 revealed by Cryo-EM

Abstract

CD40, one of the tumor necrosis factor superfamily receptors (TNFSFR), plays an important role in adaptive immune responses by promoting communication between immune cells and regulating their activity. It is essential for B cell activation and differentiation, T cell-mediated immunity, and macrophage and dendritic cell activation. Therefore, antibodies targeting CD40 are being studied to treat autoimmune diseases. mAb PG 102 plays a role in regulating immune responses by regulating CD40 signaling, key pathway of B cell activation and inflammation. PG 102 differs from the approach of existing CD40 antibodies in that it interferes with cell signaling without disrupting interaction between CD40 and its ligand, CD 154 (CD40L). Although the functionality of the PG 102 antibody has been proven in cell studies, its interacting region with CD40 is yet to be known. This study attempted to reveal the stmcture of the CD40 and PG102 complex using cryo-electron microscopy and to reveal the interaction between two molecules. Understanding the molecular basis of CD40 and PG 102 will reveal key structural features and functional mechanisms, which will aid in the design of more potent and selective CD40 antibodies with promising therapeutic potential.