Anti-interleukin-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]

Contents

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]

Related Research Articles

<span class="mw-page-title-main">Rheumatoid arthritis</span> Type of autoimmune arthritis

Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involved, with the same joints typically involved on both sides of the body. The disease may also affect other parts of the body, including skin, eyes, lungs, heart, nerves and blood. This may result in a low red blood cell count, inflammation around the lungs, and inflammation around the heart. Fever and low energy may also be present. Often, symptoms come on gradually over weeks to months.

<span class="mw-page-title-main">C-reactive protein</span> Mammalian protein found in humans

C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T cells. Its physiological role is to bind to lysophosphatidylcholine expressed on the surface of dead or dying cells in order to activate the complement system via C1q.

In immunology, cytokine release syndrome (CRS) is a form of systemic inflammatory response syndrome (SIRS) that can be triggered by a variety of factors such as infections and certain drugs. It refers to cytokine storm syndromes (CSS) and occurs when large numbers of white blood cells are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. CRS is also an adverse effect of some monoclonal antibody medications, as well as adoptive T-cell therapies. When occurring as a result of a medication, it is also known as an infusion reaction.

<span class="mw-page-title-main">Interleukin 10</span> Anti-inflammatory cytokine

Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, interleukin 10 is encoded by the IL10 gene. IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins. Consequently, the functional receptor consists of four IL-10 receptor molecules. IL-10 binding induces STAT3 signalling via the phosphorylation of the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 by JAK1 and Tyk2 respectively.

<span class="mw-page-title-main">Interleukin 6</span> Cytokine protein

Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the IL6 gene.

<span class="mw-page-title-main">Anakinra</span> Pharmaceutical drug

Anakinra, sold under the brand name Kineret, is a biopharmaceutical medication used to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes, familial Mediterranean fever, and Still's disease. It is a recombinant and slightly modified version of the human interleukin 1 receptor antagonist protein. It is marketed by Swedish Orphan Biovitrum. Anakinra is administered by subcutaneous injection.

A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma, so TNF inhibitors may be used in their treatment. The important side effects of TNF inhibitors include lymphomas, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects.

<span class="mw-page-title-main">Biological therapy for inflammatory bowel disease</span>

Biological therapy, the use of medications called biopharmaceuticals or biologics that are tailored to specifically target an immune or genetic mediator of disease, plays a major role in the treatment of inflammatory bowel disease. Even for diseases of unknown cause, molecules that are involved in the disease process have been identified, and can be targeted for biological therapy. Many of these molecules, which are mainly cytokines, are directly involved in the immune system. Biological therapy has found a niche in the management of cancer, autoimmune diseases, and diseases of unknown cause that result in symptoms due to immune related mechanisms.

<span class="mw-page-title-main">Interleukin 15</span> Cytokine with structural similarity to Interleukin-2

Interleukin-15 (IL-15) is a protein that in humans is encoded by the IL15 gene. IL-15 is an inflammatory cytokine with structural similarity to Interleukin-2 (IL-2). Like IL-2, IL-15 binds to and signals through a complex composed of IL-2/IL-15 receptor beta chain (CD122) and the common gamma chain. IL-15 is secreted by mononuclear phagocytes following infection by virus(es). This cytokine induces the proliferation of natural killer cells, i.e. cells of the innate immune system whose principal role is to kill virally infected cells.

<span class="mw-page-title-main">Interleukin 20</span> Protein-coding gene in the species Homo sapiens

Interleukin 20 (IL20) is a protein that is in humans encoded by the IL20 gene which is located in close proximity to the IL-10 gene on the 1q32 chromosome. IL-20 is a part of an IL-20 subfamily which is a part of a larger IL-10 family.

Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, a severe form of arthritis in children, and COVID‑19. It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer. Tocilizumab was jointly developed by Osaka University and Chugai, and was licensed in 2003 by Hoffmann-La Roche.

Interleukin 35 (IL-35) is a recently discovered anti-inflammatory cytokine from the IL-12 family. Member of IL-12 family - IL-35 is produced by wide range of regulatory lymphocytes and plays a role in immune suppression. IL-35 can block the development of Th1 and Th17 cells by limiting early T cell proliferation.

Adult-onset Still's disease (AOSD) is a form of Still's disease, a rare systemic autoinflammatory disease characterized by the classic triad of fevers, joint pain, and a distinctive salmon-colored bumpy rash. The disease is considered a diagnosis of exclusion. Levels of the iron-binding protein ferritin may be extremely elevated with this disorder. AOSD may present in a similar manner to other inflammatory diseases and to autoimmune diseases, which must be ruled out before making the diagnosis.

<span class="mw-page-title-main">Interleukin-17A</span> Protein-coding gene in the species Homo sapiens

Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.

An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include interleukin-1 (IL-1), IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF) and play an important role in mediating the innate immune response. Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions.

Siltuximab is a chimeric monoclonal antibody. It binds to interleukin-6. Siltuximab has been investigated for the treatment of neoplastic diseases: metastatic renal cell cancer, prostate cancer, other types of cancer, and for Castleman's disease.

<span class="mw-page-title-main">Secukinumab</span> Monoclonal antibody against IL-17

Secukinumab, sold under the brand name Cosentyx among others, is a human IgG1κ monoclonal antibody used for the treatment of psoriasis, ankylosing spondylitis, and psoriatic arthritis. It binds to the protein interleukin (IL)-17A and is marketed by Novartis.

Sarilumab, sold under the brand name Kevzara, is a human monoclonal antibody medication against the interleukin-6 receptor. Regeneron Pharmaceuticals and Sanofi developed the drug for the treatment of rheumatoid arthritis (RA), for which it received US FDA approval on 22 May 2017 and European Medicines Agency approval on 23 June 2017.

Olokizumab is an immunomodulator. It binds to interleukin 6. Hence acting as an Anti-IL-6 therapeutic aimed at inflammatory disease e.g. rheumatoid arthritis (RA).

Lenzilumab is a humanized monoclonal antibody that targets colony stimulating factor 2 (CSF2)/granulocyte-macrophage colony stimulating factor (GM-CSF).

References

  1. 1 2 3 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. 1 2 3 4 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.[ full citation needed ]
  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" (Press release).
  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. 1 2 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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