CD40 x FAP (bispecific)

Class

CD40 agonist / FAP antagonist bispecific antibody

Pathway

TNFRSF/CD40 costimulation combined with fibroblast activation protein-alpha stromal targeting

CD40 is a receptor in the tumor necrosis factor receptor superfamily found on dendritic cells, B cells, and macrophages—cells that present antigens and orchestrate immune responses. Engaging CD40 with its natural ligand, or with an agonist antibody, activates these antigen-presenting cells, upregulates costimulatory molecules, and strengthens the priming of T cells that can recognize and attack tumors. This makes CD40 agonism an attractive strategy in oncology, but activating it throughout the body tends to cause systemic inflammatory toxicity, since CD40-bearing immune cells are distributed widely. Fibroblast activation protein (FAP) offers a solution: it is expressed at high density on cancer-associated fibroblasts within the tumor stroma but is largely absent from healthy tissue. A bispecific molecule that binds both CD40 and FAP is designed to anchor itself to the tumor microenvironment through the FAP arm, then use that local tethering to cluster and activate CD40 receptors on nearby immune cells only where the antibody is retained. The combination aims to concentrate immune activation within tumors and their supporting stroma while limiting the diffuse receptor engagement that drives systemic side effects, a design relevant to cancers characterized by dense fibrotic or fibroblast-rich stroma.