Clinical targeting of the TNF and TNFR superfamilies

Abstract

Inhibitors of tumour necrosis factor (TNF) are among the most successful protein-based drugs (biologics) and have proven to be clinically efficacious at reducing inflammation associated with several autoimmune diseases. As a result, attention is focusing on the therapeutic potential of additional members of the TNF superfamily of structurally related cytokines. Many of these TNF-related cytokines or their cognate receptors are now in preclinical or clinical development as possible targets for modulating inflammatory diseases and cancer as well as other indications. This Review focuses on the biologics that are currently in clinical trials for immune-related diseases and other syndromes, discusses the successes and failures to date as well as the expanding therapeutic potential of modulating the activity of this superfamily of molecules.

Figure 1. Pro-inflammatory and death-inducing activity of TNFSF members

aTumour necrosis factor superfamily (TNFSF) molecules have canonical TNF homology domains and are active primarily as non-covalently associated homotrimers. TNF receptor superfamily (TNFRSF) molecules contain variable numbers of cysteine-rich domains in their ligand-binding extracellular regions (ectodomains). Soluble or membrane-expressed TNFSF molecules (sTNFSF and mTNFSF, respectively) can promote survival or inflammatory signalling by organizing TNFRSF monomers (for example, TNFR2, CD40, OX40, B cell activating factor receptor (BAFFR) and receptor activator of NF-κB ligand (RANK)) into trimeric or oligomeric configurations, allowing the recruitment of adaptor molecules called TNFR-associated factors (TRAFs) that activate serine/threonine kinase-dependent pathways. b | TNFSF molecules can promote apoptotic cell death by organizing TNFRSF monomers containing death domains (for example, TNFR1, FAS and TNF-related apoptosis-inducing ligand receptor (TRAILR)) into trimeric or oligomeric configurations that recruit adaptor molecules containing death effector domains (such as TNFR-associated death domain protein (TRADD) and FAS-associated death domain protein (FADD)), leading to the activation of cysteine/aspartate proteases (caspases). BAX, BCL-2-associated X protein; BID, BH3-interacting domain death agonist; IκBα, inhibitor of κB; IKKα, IκB kinase α; MAPK, mitogen-activated protein kinase; NIK, NF-κB-inducing kinase; p50, NF-κB subunit p50; p100, NF-κB precursor protein p100; RELA, transcription factor p65.

Figure 2. TNFSF targets and therapeutics in autoimmunity and inflammation

This simplified diagram highlights a few of the possible interactions between cells in the immune system (antigen-presenting cells (APCs), B cells and T cells) and tissue cells (such as epithelial cells, endothelial cells, fibroblasts, stromal cells, osteoclasts and neurons). These cells can be controlled by interactions between tumour necrosis factor superfamily (TNFSF) and TNF receptor superfamily (TNFRSF) molecules, which result in stimulatory or pro-inflammatory activity that is characteristic of autoimmune and inflammatory diseases. Several biologics that disrupt TNFSF interactions and that have been or are currently in clinical trials (TABLE 1) are listed. APRIL, a proliferation-inducing ligand; BAFF, B cell activating factor; BAFFR, BAFF receptor; BCMA, B cell maturation antigen; DR3, death domain receptor 3; GITR, glucocorticoid-induced TNFR-related protein; LTα, lymphotoxin-α; LTβ, lymphotoxin-β; LTβR, LTβ receptor; NGF, nerve growth factor; NGFR, NGF receptor; RANK, receptor activator of NF-κB; RANKL, RANK ligand; TACI, transmembrane activator and CAML interactor; TNF, tumour necrosis factor; TNFR1, TNF receptor 1; TWEAK, TNF-related weak inducer of apoptosis.

Figure 3. TNFRSF targets and therapeutics in cancer

This simplified diagram depicts tumour necrosis factor receptor superfamily (TNFRSF) molecules and ligands that are: being targeted on cells of the immune system (antigen-presenting cells (APCs), T cells and natural killer (NK) cells) to boost immune activity against a tumour cell; or being targeted on tumour cells to either directly promote apoptotic cell death or focus natural or artificial (drug- or toxin-induced) cytotoxic mechanisms towards a tumour cell. Several biologics that have been or are currently in clinical trials (TABLE 1) are listed. APRIL, a proliferation-inducing ligand; BAFF, B cell activating factor; BAFFR, BAFF receptor; FASL, FAS ligand; FN14, FGF-inducible 14; GITR, glucocorticoid-induced TNFR-related protein; TRAIL, TNF-related apoptosis-inducing ligand; TRAILR, TRAIL receptor.