Anti-IL-6

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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]

Several agents are in clinical trials: sarilumab,[11] olokizumab (CDP6038)[12][13] elsilimomab, BMS-945429(ALD518), sirukumab (CNTO 136), 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] FM101[17]

Exercise induced IL-6 may be beneficial[edit]

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.[18] 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.[19] 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.[19]

Food and diet[edit]

It has been reported that lunasin, a soy peptide, reduces inflammation by reducing interleukin 6 and may help in leukemia[vague].[20]

IL6 and asthma[edit]

Obesity is a known risk factor in the development of severe asthma, and work has suggested that IL6 plays a role in regulating disease severity in obese asthma.[21]

Luteolin reduces IL-6 production in some neurons.[22]

References[edit]

  1. ^ a b c 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 3163962Freely accessible. 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. 
  3. ^ Smolen JS, Maini RN (2006). "Interleukin-6: a new therapeutic target". Arthritis Research & Therapy. 8 (Suppl 2): S5. doi:10.1186/ar1969. PMC 3226077Freely accessible. 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. 
  7. ^ a b c d 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 3595140Freely accessible. PMID 23144446. 
  9. ^ http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125496s000lbl.pdf[full citation needed]
  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. ^ http://www.clinicaltrials.gov/ct2/results?term=sarilumab[full citation needed]
  12. ^ "UCB Announces Start Of Phase I Study For Antibody Drug Candidate CDP6038". 2 Dec 2008. 
  13. ^ "Archived copy". Archived from the original on 2015-12-22. Retrieved 2015-07-26. [full citation needed]
  14. ^ Websky Mv FJ, Ohsawa I, Praktiknjo M, Wehner S, Abu-Elmagd K, Kitamura K, Kalff JC, Schaefer N, Pech T. "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. 
  15. ^ "ArGEN-X Wins €1.5M IWT Grant to Progress Camelid-Derived Human Antibody Pipeline". 27 Sep 2010. 
  16. ^ http://www.prnewswire.com/news-releases/ruiyi-formerly-anaphore-and-argen-x-announce-exclusive-worldwide-license-agreement-for-argx-109-a-novel-anti-il-6-antibody-172634271.html[full citation needed]
  17. ^ "Formatech to Donate Services to Formulate and Fill Femta Pharmaceuticals' FM101 Monoclonal Antibody under Its "Fillanthrop". 30 July 2010. 
  18. ^ 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 1159298Freely accessible. PMID 9130176. 
  19. ^ a b Pedersen BK (2013). "Muscle as a secretory organ". Comprehensive Physiology. 3 (3): 1337–62. doi:10.1002/cphy.c120033. ISBN 9780470650714. PMID 23897689. 
  20. ^ http://www.foodconsumer.org/newsite/Nutrition/Supplements/soy_protein_helps_fight_cancer_and_inflammation_021220090906.html[full citation needed]
  21. ^ 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 5007068Freely accessible. PMID 27283230. 
  22. ^ 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 2396685Freely accessible. PMID 18490655.