Towards the next generation of anti-TNF drugs

Although pivotal to the immune system homeostasis, tumor necrosis factor (TNF) becomes deleterious when de-regulated. The currently marketed TNF blockers are highly efficacious in rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, uveitis and inflammatory bowel disease; reactivation of tuberculosis and exacerbation of pre-existing multiple sclerosis remain their most important safety issues. The endogenous protein progranulin binds TNF receptor-1 (TNFR1) and TNFR2, thus blocking their interactions with TNF. Domains of the extracellular region of TNFR, termed preligand-binding assembly domain (PLAD), mediate receptor-chain trimerization which is essential for signaling. Therapeutic administration of either progranulin or soluble versions of TNFR1 PLAD in mouse models of diseases in which TNF is relevant yielded beneficial results, opening the door to the next generation of non-antibody anti-TNF drugs for a variety of non-infectious inflammatory conditions. Whether these drugs may target TNF in a more refined way than the current blockers, perhaps being more efficacious without compromising the protective role of TNF in host defense and (auto)immunity, remains to be seen.