Chapter Two. Protein Therapeutics Targeted at the TNF Superfamily
ABSTRACT 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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ABSTRACT: Homotrimeric TNF superfamily ligands signal by inducing trimers of their cognate receptors. As a biologically active heterotrimer, Lymphotoxin(LT)α1β2 is unique in the TNF superfamily. How the three unique potential receptor-binding interfaces in LTα1β2 trigger signaling via LTβ Receptor (LTβR) resulting in lymphoid organogenesis and propagation of inflammatory signals is poorly understood. Here we show that LTα1β2 possesses two binding sites for LTβR with distinct affinities and that dimerization of LTβR by LTα1β2 is necessary and sufficient for signal transduction. The crystal structure of a complex formed by LTα1β2, LTβR, and the fab fragment of an antibody that blocks LTβR activation reveals the lower affinity receptor-binding site. Mutations targeting each potential receptor-binding site in an engineered single-chain variant of LTα1β2 reveal the high-affinity site. NF-κB reporter assays further validate that disruption of receptor interactions at either site is sufficient to prevent signaling via LTβR.Proceedings of the National Academy of Sciences 11/2013; 110(49). DOI:10.1073/pnas.1310838110 · 9.81 Impact Factor
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ABSTRACT: The journey from the discoveries of lymphotoxin (LT) and tumor necrosis factor (TNF) to the present day age of cytokine inhibitors as therapeutics has been an exciting one with many participants and highs and lows; the saga is compared to that in “The Wizard of Oz”. This communication summarizes the contributions of key players in the discovery of the cytokines and their receptors, the changes in nomenclature, and the discovery of the LT family’s crucial role in secondary and tertiary lymphoid organs. The remarkable advances in therapeutics are detailed as are remaining problems. Finally, special tribute is paid to two pioneers in the field who have recently passed away: Byron H. Waksman and Lloyd Old.Cytokine & growth factor reviews 04/2014; 25(2). DOI:10.1016/j.cytogfr.2014.02.001 · 6.54 Impact Factor