A mechanistic perspective, clinical applications, and phage-display-assisted discovery of TNFα inhibitors

TNFα participates in a variety of physiological processes, but at supra-physiological concentrations it has been implicated in the pathology of inflammatory and autoimmune diseases. Therefore, much attention has been devoted to the development of strategies that overcome the effects of aberrant TNFα concentration. Promising strategies include drugs that destabilize the active (trimeric) form of TNFα and antagonists of TNFα receptor type I. Underpinning these strategies is the successful application of phage-display technology to identify anti-TNFα peptides and antibodies. Here, we review the development of inhibitors of the TNFα-TNF receptor system, with particular focus on the phage-display-assisted identification of molecules that interfere with this system by acting as inhibitors of TNFα or by sequestering TNFα away from its receptor.