title: Agonistic CD40 antibodies and cancer therapy.
abstract: Recent success in cancer immunotherapy has reinvigorated the hypothesis that the immune system can control many if not most cancers, in some cases producing durable responses in a way not seen with many small-molecule drugs. Agonistic CD40 monoclonal antibodies (mAb) offer a new therapeutic option which has the potential to generate anticancer immunity by various mechanisms. CD40 is a TNF receptor superfamily member expressed broadly on antigen-presenting cells (APC) such as dendritic cells, B cells, and monocytes as well as many nonimmune cells and a range of tumors. Agonistic CD40 mAb have been shown to activate APC and promote antitumor 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 about dose, schedule, route of administration, and formulation. Recent findings about the role played by the IgG isotype and the Fc gamma receptor (FcγR) in mAb cross-linking, together with insights into mechanisms of action, particularly with regard to the role of myeloid cells, are predicted to help design next-generation CD40 agonistic reagents with greater efficacy. Here, we will review the preclinical and clinical data and discuss the major issues facing the field.
authors: Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. rhv@exchange.upenn.edu
authors: Robert H
authors: RH
authors: Vonderheide
authors: Martin J
authors: MJ
authors: Glennie
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000819:agonists* / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens