Anti-interleukin-6 agents are a class of therapeutics. Interleukin 6 is a cytokine relevant to many inflammatory diseases and many cancers.[1] Hence, anti-IL6 agents have been sought.[2][3][4][5][6] In rheumatoid arthritis they can help patients unresponsive to TNF inhibitors.[7]
The first approved medication in this class, tocilizumab (Actemra), is an antibody directed against the IL6-receptor.[8] The second, siltuximab (Sylvant), is directed against IL-6 itself.[1][9] Siltuximab is approved for treatment of human immunodeficiency virus-negative and HHV-8-negative patients with multicentric Castleman's disease. Siltuximab was also tested in the phase I/II study for therapy of patients with metastatic castration-associated prostate cancer in combination with docetaxel and in renal cell carcinoma; phase II trials in ovarian cancer resulted in 39% of patients showed disease stabilization via IL-6-regulated downregulation of CCL2, CXCL12 and VEGF.
Tocilizumab was first used in large-cell lung carcinoma. In phase I/II trial of tocilizumab in ovarian cancer EGFR pathway upregulation was observed and after inhibition of this pathway by gefitinib tumor growth was decreased both in vitro and in vivo.[10]
Sarilumab was approved by US FDA in 2017 for rheumatoid arthritis.[11]
Several agents are in clinical trials: olokizumab (CDP6038)[12][13] elsilimomab, clazakizumab (BMS-945429, ALD518), sirukumab (CNTO 136), levilimab (BCD-089), and CPSI-2364 an apparent macrophage-specific inhibitor of the p38 mitogen-activated protein kinase pathway.[14] ALX-0061.[7]: Table1
e.g. for rheumatoid arthritis : clazakizumab, olokizumab, sarilumab and sirukumab have all reported encouraging phase 2 results.[7] Sirukumab is in multiple phase 3 trials.[7]: Table1
Agents in pre-clinical development include ARGX-109,[15][16] FE301,[1]and FM101.[17]
During the COVID-19 pandemic, antagonistic antibodies against the IL-6 receptors were tested in clinical trials to assess their use in treating or preventing severe pneumonia in critically ill COVID-19 patients. Such antibodies include tocilizumab and sarilumab.[18][19][20] Antibodies against IL-6 itself, such as siltuximab, were also investigated.[21]Also: Levilimab.
Exercise induced IL-6
New research has found IL-6 to be an anti-inflammatory cytokine with multiple beneficial effects when released by contracting muscle as a myokine. IL-6 had previously been classified as a proinflammatory cytokine. Therefore, it was first thought that the exercise-induced IL-6 response was related to muscle damage.[22] However, it has become evident that eccentric exercises are not associated with a larger increase in plasma IL-6 than exercise involving concentric “nondamaging” muscle contractions. This finding demonstrates that muscle damage is not required to provoke an increase in plasma IL-6 during exercise. In fact, eccentric exercise may result in a delayed peak and a much slower decrease of plasma IL-6 during recovery.[23] Anti-IL-6 therapies should therefore take into consideration the (beneficial) anti-inflammatory effects of myokines generally, including the now-established multiple benefits of muscle-derived Interleukin 6.[23]
IL6 and asthma
Obesity is a known risk factor in the development of severe asthma, and work has suggested that IL-6 plays a role in regulating disease severity in obesity-related asthma.[24]