Agonistic CD40 antibodies and cancer therapy

Clin Cancer Res. 2013 Mar 1;19(5):1035-43. doi: 10.1158/1078-0432.CCR-12-2064.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use*
  • CD40 Antigens / agonists*
  • CD40 Antigens / immunology
  • Humans
  • Immunotherapy*
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / therapy*
  • T-Lymphocytes, Cytotoxic*

Substances

  • Antibodies, Monoclonal
  • CD40 Antigens