Protein-based drugs with their unequivocal specificity achieved the long sought milestone of selectively disrupting cytokine pathways to alleviate ongoing inflammation. Tumor necrosis factor (TNF), a member of the superfamily of cytokines involved in regulating immune and inflammatory processes, provides an exemplary model of protein therapeutics. Antibody and receptor-based inhibitors of TNF modify inflammation leading to dramatic improvement in patients with certain autoimmune diseases. Collectively, the structure, specificity and valence of these protein-based drugs provide direct evidence that the essential mechanism of action is antagonism of the ligand-receptor interaction. Accumulating clinical knowledge regarding TNF inhibitors also provide insights into the mechanisms involved in different autoimmune diseases. Experience in the development of an arsenal of biologics directed at TNF has additionally contributed to knowledge toward overcoming the challenges of protein drugs, which include production, delivery, antigenicity and pharmacodynamics. Dramatic clinical outcomes with TNF inhibitors are driving investigation and development of biologics toward other members of the TNF superfamily to selectively alter functional properties of the immune system.
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