CD40 is a tumor necrosis factor receptor superfamily member expressed broadly on antigen-presenting cells (APC) such as dendritic cells, B cells, and monocytes as well as many non-immune cells and a range of cancers. Agonistic CD40 mAb have been shown to activate APC and promote anti-cancer T cell responses and to foster cytotoxic myeloid cells with the potential to control cancer in the absence of T-cell immunity. Thus, agonistic CD40 mAb are fundamentally different from mAb which block negative immune checkpoint such as anti-CTLA-4 or anti-PD-1. Initial clinical trials of agonistic CD40 mAb have shown highly promising results in the absence of disabling toxicity, both in single-agent studies and in combination with chemotherapy; however, numerous questions remain regarding dose, schedule, route of administration, and formulation. Recent findings regarding the role played by the IgG isotype and the Fc gamma receptor (FcγR) in mAb crosslinking, together with insights into mechanisms of action, particularly with regards to the role of myeloid cells, are predicted to help design next-generation CD40 agonistic reagents with greater efficacy.
Vonderheide RH, Glennie MJ. Agonistic CD40 antibodies and cancer therapy. Clinical cancer research?: an official journal of the American Association for Cancer Research. 2013;19(5):1035-1043.