Can we design a better anti-cytokine therapy?

Abstract

Cytokine neutralization is successfully used for treatment of various autoimmune diseases and chronic inflammatory conditions. The complex biology of the two well-characterized proinflammatory cytokines TNF and IL-6 implicates unavoidable consequences when it comes to their global blockade. Because systemic cytokine ablation may result in unwanted side effects, efforts have been made to develop more specific cytokine inhibitors, which would spare the protective immunoregulatory functions of a given cytokine. In this article, we review current research and summarize new strategies for improved anti-TNF and anti-IL-6 biologics, which specifically target only selected parts of the signaling cascades mediated by these ligands.

Clinical Utility of Extracorporeal Cytokine Hemoadsorption Therapy: A Literature Review

“…IL-6 binds to the IL-6 receptor (IL-6R), which exists both in membrane-bound and soluble forms (sIL-6R). IL-6 binding involves both gp130 and sIL-6R, and the IL-6/sIL-6R/ gp130 complex mediates downstream signaling and activation of the JAK-STAT pathway [119]. Studies have demonstrated that the deleterious effects of IL-6 almost exclusively involve sIL-6R, whereas the membranebound form protects against infections and is involved in tissue regeneration [119,122].…”

“…Most of the proinflammatory actions of TNF are believed to be mediated by TNF receptor-1. The roles of the TNF receptor-2, while incompletely understood [119], may include the resolution of inflammation [124,125], tissue regeneration, neuroprotection [126], and suppression of cytotoxic T-cell populations that cause type 1 diabetes mellitus [127]. Removal of serum TNF may compromise signaling through this receptor, thus abrogating these physiologic functions.…”

“…IL-6 binding involves both gp130 and sIL-6R, and the IL-6/sIL-6R/ gp130 complex mediates downstream signaling and activation of the JAK-STAT pathway [119]. Studies have demonstrated that the deleterious effects of IL-6 almost exclusively involve sIL-6R, whereas the membranebound form protects against infections and is involved in tissue regeneration [119,122]. Treatment with exogenous IL-6 has also been shown to improve viral clearance in patients with human immunodeficiency virus [123].…”

“…They are absolutely necessary for the proper functioning of the localized and systemic host immune response. Re-DOI: 10.1159/000492379 moval of IL-6 and TNF-α may, for example, alter cell signaling and attenuate the innate immune response to PAMPs and DAMPs [119]. Both cytokines are evolutionarily conserved and are part of a bundle of "common responses" to infectious stimuli [3,[119][120][121].…”

Cytokines, reverse genetics and anti-cytokine therapy

“…4. Structural scheme of bi-specific antibodies, recognizing hTNF and mouse myeloid cell surface molecules (F4/80 and CD11b), as well as the control construct, binding hTNF, but not any of the surface molecules of murine macrophages Следующим шагом должна стать разработка прототипов лекарств, которые по тому же принципу могли бы взаимодействовать с маркерами миелоидных клеток человека [15]. К сожалению, наша фармацевтическая промышленность сконцентрирована на аналогах уже разработанных и одобренных зарубежных лекарств и пока не заинтересована в развитии проектов, которые неизбежно сопряжены с рисками.…”