Anti-IL-6

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]

Anti-IL-6 Receptor antibodies: Treatment of Coronavirus-associated pulmonary pathology

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]

Luteolin reduces IL-6 production in some neurons.[25]

References
  1. Jones SA, Scheller J, Rose-John S (2011). "Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling". The Journal of Clinical Investigation. 121 (9): 3375–83. doi:10.1172/JCI57158. PMC 3163962. PMID 21881215.
  2. Barton BE (2005). "Interleukin-6 and new strategies for the treatment of cancer, hyperproliferative diseases and paraneoplastic syndromes". Expert Opinion on Therapeutic Targets. 9 (4): 737–52. doi:10.1517/14728222.9.4.737. PMID 16083340. S2CID 45421426.
  3. Smolen JS, Maini RN (2006). "Interleukin-6: a new therapeutic target". Arthritis Research & Therapy. 8 (Suppl 2): S5. doi:10.1186/ar1969. PMC 3226077. PMID 16899109.
  4. Stein and Sutherland (1998). "IL-6 as a drug discovery target". Drug Discovery Today. 3 (5): 202–213. doi:10.1016/S1359-6446(97)01164-1.
  5. "Interleukin-6 – new target in the battle against Ras-induced cancers". 2007.
  6. Yokota S (2003). "Interleukin 6 as a therapeutic target in systemic-onset juvenile idiopathic arthritis". Current Opinion in Rheumatology. 15 (5): 581–6. doi:10.1097/00002281-200309000-00010. PMID 12960484. S2CID 24296997.
  7. Tanaka Y, Martin Mola E (2014). "IL-6 targeting compared to TNF targeting in rheumatoid arthritis: studies of olokizumab, sarilumab and sirukumab". Annals of the Rheumatic Diseases. 73 (9): 1595–7. doi:10.1136/annrheumdis-2013-205002. PMID 24833786.
  8. Schoels MM, van der Heijde D, Breedveld FC, et al. (2013). "Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement". Ann. Rheum. Dis. 72 (4): 583–9. doi:10.1136/annrheumdis-2012-202470. PMC 3595140. PMID 23144446.
  9. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125496s000lbl.pdf%5B%5D%5B%5D
  10. Korneev, KV; Atretkhany, KN; Drutskaya, MS; Grivennikov, SI; Kuprash, DV; Nedospasov, SA (January 2017). "TLR-signaling and proinflammatory cytokines as drivers of tumorigenesis". Cytokine. 89: 127–135. doi:10.1016/j.cyto.2016.01.021. PMID 26854213.
  11. FDA Gives Nod to Sarilumab for Rheumatoid Arthritis. 2017
  12. "UCB Announces Start Of Phase I Study For Antibody Drug Candidate CDP6038". 2 Dec 2008.
  13. "Article > UCB's RA drug does not overly impress in Phase II". Archived from the original on 2015-12-22. Retrieved 2015-07-26.
  14. Websky Mv FJ, Ohsawa I, Praktiknjo M, Wehner S, Abu-Elmagd K, Kitamura K, Kalff JC, Schaefer N, Pech T (2013). "The novel guanylhydrazone CPSI-2364 ameliorates ischemia reperfusion injury after experimental small bowel transplantation". Transplantation. 95 (11): 1315–23. doi:10.1097/TP.0b013e31828e72fa. PMID 23598944. S2CID 45761175.
  15. "ArGEN-X Wins €1.5M IWT Grant to Progress Camelid-Derived Human Antibody Pipeline". 27 Sep 2010.
  16. "RuiYi (Formerly Anaphore) and arGEN-X Announce Exclusive Worldwide License Agreement for ARGX-109, a Novel anti-IL-6 Antibody".
  17. "Formatech to Donate Services to Formulate and Fill Femta Pharmaceuticals' FM101 Monoclonal Antibody under Its "Fillanthrop". 30 July 2010.
  18. "Regeneron, Sanofi Launch Clinical Trial of Kevzara as Coronavirus Treatment". GEN - Genetic Engineering and Biotechnology News. 2020-03-16. Retrieved 2020-04-11.
  19. "ChinaXiv.org 中国科学院科技论文预发布平台". www.chinaxiv.org. Retrieved 2020-04-11.
  20. Mutua, Victor; Henry, Brandon Michael; Csefalvay, Chris von; Cheruiyot, Isaac; Vikse, Jens; Lippi, Giuseppe; Bundi, Brian; Mong'are, Newnex (2022). "Tocilizumab in addition to standard of care in the management of COVID-19: a meta-analysis of RCTs". Acta Biomedica Atenei Parmensis. 93 (1): e2021473. doi:10.23750/abm.v93i1.12208. ISSN 2531-6745. PMC 8972884. PMID 35315395.
  21. "EUSA Pharma initiates study of siltuximab to treat Covid-19 patients". Clinical Trials Arena. 2020-03-19. Retrieved 2020-04-11.
  22. Bruunsgaard H, Galbo H, Halkjaer-Kristensen J, Johansen TL, MacLean DA, Pedersen BK (1997). "Exercise-induced increase in serum interleukin-6 in humans is related to muscle damage". The Journal of Physiology. 499 (3): 833–41. doi:10.1113/jphysiol.1997.sp021972. PMC 1159298. PMID 9130176.
  23. Pedersen BK (2013). "Muscle as a secretory organ". Comprehensive Physiology. 3 (3): 1337–62. doi:10.1002/cphy.c120033. ISBN 9780470650714. PMID 23897689.
  24. Peters MC, McGrath KW, Hawkins GA, Hastie AT, Levy BD, Israel E, Phillips BR, Mauger DT, Comhair SA, Erzurum SC, Johansson MW, Jarjour NN, Coverstone AM, Castro M, Holguin F, Wenzel SE, Woodruff PG, Bleecker ER, Fahy JV (2016). "Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts". The Lancet Respiratory Medicine. 4 (7): 574–84. doi:10.1016/S2213-2600(16)30048-0. PMC 5007068. PMID 27283230.
  25. Jang S, Kelley KW, Johnson RW (2008). "Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1". Proceedings of the National Academy of Sciences of the United States of America. 105 (21): 7534–9. Bibcode:2008PNAS..105.7534J. doi:10.1073/pnas.0802865105. PMC 2396685. PMID 18490655.
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