Anti-IL-6 mAb(Vaccinex, Inc.)

Interleukin (IL)-6 is a major pro-inflammatory cytokine and central regulator of innate and adaptive immune responses. Clinical trials testing antibodies against IL-6 or its receptors have demonstrated its involvement in the pathogenesis of several autoimmune and inflammatory disorders and in the systemic inflammation and anemia associated to kidney failure and also in kidney allograft rejection. Additionally, the anti-IL-6 receptor antibody tocilizumab and the anti-IL-6 antibody clazakizumab have been studied for the treatment of naïve as well as resistant antibody-mediated kidney allograft rejection with mixed results in observational studies and early clinical development. Following promising results with a clazakizumab in a phase 2 placebo-controlled trial, a large phase 3 trial (IMAGINE) was terminated in 2024 for futility at interim analysis. Investigator-initiated clinical development continues in a smaller phase 3 trial testing tocilizumab (INTERCEPT). In this viewpoint article, we evaluate the pathophysiology of IL-6 in antibody-mediated kidney allograft rejection along with the current status of the clinical development of IL-6 targeting therapies for antibody-mediated kidney allograft rejection episodes within the wider frame of IL-6 targeting therapies in kidney failure that are considered the major causes of graft loss in kidney transplantation.

Interleukin‐6 (IL‐6), a pleiotropic cytokine, plays a pivotal role in the pathophysiology of various diseases including diabetes, atherosclerosis, Alzheimer's disease, multiple myeloma, rheumatoid arthritis, and prostate cancer. The signaling pathways associated with IL‐6 offer promising targets for therapeutic interventions in inflammatory diseases and IL‐6‐dependent tumors. Although certain anti‐IL‐6 monoclonal antibodies are currently employed clinically, their usage is hampered by drawbacks such as high cost and potential immunogenicity, limiting their application. Thus, the imperative arises to develop novel small non‐peptide molecules acting as IL‐6 inhibitors. Various natural products derived from diverse sources have been investigated for their potential to inhibit IL‐6 activity. Nevertheless, these natural products remain inadequately explored in terms of their structure‐activity relationships. In response, our review aims to provide syntheses and structure activity perspective of natural IL‐6 inhibitors. The comprehensive amalgamation of information presented in this review holds the potential to serve as a foundation for forthcoming research endeavors by medicinal chemists, facilitating the design of innovative IL‐6 inhibitors to address the complexities of inflammatory diseases.