Clinical targeting of the TNF and TNFR superfamilies

Abstract

Inhibitors of tumour necrosis factor (TNF) are among the most successful protein-based drugs for reducing inflammation associated with several autoimmune diseases. Five distinct antibody- or receptor-based drugs directed at blocking TNF are approved for treating rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, psoriasis, ankylosing spondylitis, Crohn's disease and ulcerative colitis. TNF belongs to a superfamily of molecules comprising 19 structurally related proteins (ligands) that bind to one or more molecules in a family of 29 structurally similar receptors. Members of this superfamily initiate a broad range of physiological functions and provide key communication to regulate the development and activity of the immune, nervous, bone and ectodermal systems in mammals. Biologics targeting many of the proteins related to TNF or their cognate receptors are now in preclinical or clinical development. Therapeutic approaches include generating blocking and/or neutralizing reagents to prevent the TNFSF–TNFRSF interactions in order to reduce pathology in autoimmune and inflammatory diseases or other indications; developing agonist reagents to enhance signalling through a TNFRSF member to augment immune responses against tumours; and producing immunotoxins or death-inducing reagents that bind to TNFSF or TNFRSF members for the direct killing of tumours. Studies so far have led to the successful development of three drugs in addition to the TNF inhibitors: targeting CD30 to kill certain cancers, blocking receptor activator of NF-κB ligand (RANKL) to reduce osteoporosis, and inhibiting B cell activating factor (BAFF) to suppress symptoms of systemic lupus erythematosus. This article reviews the current range of biologics targeting all of the molecules in the TNF and TNF receptor superfamily that have been or are in clinical trials for autoimmune and inflammatory diseases, cancer and several other indications, focusing on the challenges in their development as well as emerging therapeutic targets.