Anti-CD40 agonist antibodies: preclinical and clinical experience

The cell-surface molecule CD40, a member of the tumor necrosis factor receptor superfamily, broadly regulates immune activation and mediates tumor apoptosis. CD40 is expressed by antigen-presenting cells (APC) and engagement of its natural ligand on T cells activates APC including dendritic cells and B cells. Agonistic CD40 antibodies have been shown to substitute for T cell help provided by CD4+ lymphocytes in murine models of T cell-mediated immunity. In tumor-bearing hosts, CD40 agonists trigger effective immune responses against tumor-associated antigens. In contrast, CD40 is also expressed on many tumor cells and its ligation in this setting mediates a direct cytotoxic effect. Engagement of CD40 on tumor cells results in apoptosis in vitro and impaired tumor growth in vivo. These observations have prompted efforts to use agonistic CD40 antibodies for the treatment of cancer patients and initial clinical results have been promising.