Tan Luu

Introduction. A new promising immunotherapy treatment utilizing Chimeric Antigen Receptors (CAR) on genetically modified host T cells has a major auto immune side effect known as Cytokine Release Syndrome (CRS), a non-antigen specific toxicity that occurs as a result of high-level immune reaction that clinically manifests when large numbers of lymphocytes and release inflammatory cytokines¹. Interleukin-6 (IL-6) has been identified as the key player within CRS and can be reversed using Tocilizumab, an anti-IL-6 receptor antibody¹. Originally thought to have been released by the CAR T-cells, studies show that Antigen Presenting Cells (APCs) are the primary source of IL-6¹. Increasing studies are undergoing to understand the mechanism of IL-6 in causation to Cytokine Release Syndrome originating. Methods. Studies using mice and a IL-6 receptor (IL-6R) antibodies 25F10 and 2B10. 25F10 inhibits trans-signaling specifically whereas 2B10 inhibits binding of IL-6 to IL6R. Epitope mapping of 25F10 and binding experiments using Surface Plasmon Resonance were used to confirm mechanisms of IL-6². A human anti-trans-signaling drug NI-1201 based on 25F10 was also compared to tocilizumab via a signaling assay. Result. Epitope mapping demonstrated that the CIS and trans-signaling pathways uses different signaling pathways. Trans signaling forms a hexamer signaling complex that binds to gp130 on cells that do not express IL-6R which then leads to a series of inflammatory responses including increased transcription of inflammatory proteins via JAK/STAT pathway³. Conclusion. Selectively targeting the pro-inflammatory properties of Il-6, mediated by IL-6 trans-signaling is regarded as critical for successful intervention of disease. It is now known that the pleiotropic effect of IL-6 on various cells derives from the broad range of gp130 expression observed in a majority of cells within the body due to their immediate and transient expression in response to environmental stress factors such as infections and tissue injuries³. It is shown that the complex of soluble IL-6R (sIL-6R) strongly sensitizes target cells and a leading cause to several inflammatory diseases⁴. However, activities of IL-6 can be regenerative and protective during infection and inflammation by supporting the innate immune response⁵.

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