Chemistry:Anti-interleukin-6

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Short description: Drugs to suppress IL-6 signalling

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. ↑ 1.0 1.1 1.2 "Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling". The Journal of Clinical Investigation 121 (9): 3375–83. 2011. doi:10.1172/JCI57158. PMID 21881215. 
  2. ↑ "Interleukin-6 and new strategies for the treatment of cancer, hyperproliferative diseases and paraneoplastic syndromes". Expert Opinion on Therapeutic Targets 9 (4): 737–52. 2005. doi:10.1517/14728222.9.4.737. PMID 16083340. 
  3. ↑ "Interleukin-6: a new therapeutic target". Arthritis Research & Therapy 8 (Suppl 2): S5. 2006. doi:10.1186/ar1969. 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. http://www.news-medical.net/news/2007/07/16/27599.aspx. 
  6. ↑ "Interleukin 6 as a therapeutic target in systemic-onset juvenile idiopathic arthritis". Current Opinion in Rheumatology 15 (5): 581–6. 2003. doi:10.1097/00002281-200309000-00010. PMID 12960484. 
  7. ↑ 7.0 7.1 7.2 7.3 "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. 2014. doi:10.1136/annrheumdis-2013-205002. PMID 24833786. 
  8. ↑ "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. 2013. doi:10.1136/annrheumdis-2012-202470. PMID 23144446. PMC 3595140. https://archive-ouverte.unige.ch/unige:73677/ATTACHMENT01. 
  9. ↑ http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125496s000lbl.pdf[full citation needed][yes|permanent dead link|dead link}}]
  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. http://www.medicalnewstoday.com/articles/131407.php. 
  13. ↑ "Article > UCB's RA drug does not overly impress in Phase II". Archived from the original on 2015-12-22. https://web.archive.org/web/20151222101614/http://www.pharmatimes.com/article/12-09-28/UCB_s_RA_drug_does_not_overly_impress_in_Phase_II.aspx. Retrieved 2015-07-26. [full citation needed]
  14. ↑ "The novel guanylhydrazone CPSI-2364 ameliorates ischemia reperfusion injury after experimental small bowel transplantation". Transplantation 95 (11): 1315–23. 2013. doi:10.1097/TP.0b013e31828e72fa. PMID 23598944. 
  15. ↑ "ArGEN-X Wins €1.5M IWT Grant to Progress Camelid-Derived Human Antibody Pipeline". 27 Sep 2010. http://www.genengnews.com/gen-news-highlights/argen-x-wins-1-5m-iwt-grant-to-progress-camelid-derived-human-antibody-pipeline/81243979/. 
  16. ↑ "RuiYi (Formerly Anaphore) and arGEN-X Announce Exclusive Worldwide License Agreement for ARGX-109, a Novel anti-IL-6 Antibody" (Press release).
  17. ↑ "Formatech to Donate Services to Formulate and Fill Femta Pharmaceuticals' FM101 Monoclonal Antibody under Its "Fillanthrop". 30 July 2010. http://www.fiercebiotech.com/press-releases/formatech-donate-services-formulate-and-fill-femta-pharmaceuticals-fm101-monoclonal-a. 
  18. ↑ "Regeneron, Sanofi Launch Clinical Trial of Kevzara as Coronavirus Treatment" (in en-US). 2020-03-16. https://www.genengnews.com/news/regeneron-sanofi-launch-clinical-trial-of-kevzara-as-coronavirus-treatment/. 
  19. ↑ "ChinaXiv.org 中国科学院科技论文预发布平台". http://www.chinaxiv.org/abs/202003.00026. 
  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" (in en). Acta Biomedica: Atenei Parmensis 93 (1): e2021473. doi:10.23750/abm.v93i1.12208. ISSN 2531-6745. PMID 35315395. PMC 8972884. https://mattioli1885journals.com/. 
  21. ↑ "EUSA Pharma initiates study of siltuximab to treat Covid-19 patients" (in en-GB). 2020-03-19. https://www.clinicaltrialsarena.com/news/eusa-pharma-siltuximab-study-covid-19/. 
  22. ↑ "Exercise-induced increase in serum interleukin-6 in humans is related to muscle damage". The Journal of Physiology 499 (3): 833–41. 1997. doi:10.1113/jphysiol.1997.sp021972. PMID 9130176. 
  23. ↑ 23.0 23.1 "Muscle as a secretory organ". Comprehensive Physiology 3 (3): 1337–62. 2013. doi:10.1002/cphy.c120033. ISBN 9780470650714. PMID 23897689. 
  24. ↑ "Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts". The Lancet Respiratory Medicine 4 (7): 574–84. 2016. doi:10.1016/S2213-2600(16)30048-0. PMID 27283230. 
  25. ↑ "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. 2008. doi:10.1073/pnas.0802865105. PMID 18490655. Bibcode: 2008PNAS..105.7534J. 



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