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Olamkicept

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Olamkicept, also known as soluble gp130Fc or sgp130Fc (other designations are FE 999301, FE301, TJ301) is an immunosuppressive drug candidate, which selectively blocks activities of the cytokine Interleukin-6, which are mediated by the soluble Interleukin-6 [1]. Interleukin-6 is a cytokine, which plays a dominant role in the regulation of the immune response and also in autoimmunity. Furthermore, Interleukin-6 has been demonstrated to be involved in the regulation of metabolism and body [2]. Interleukin-6 also has many activities on neural [3]. It was invented by the German biochemist Stefan Rose-John and it was further developed by the biotech company Conaris, which gave an exclusive world-wide license to the Swiss-based biopharmaceutical company [4]. In December 2016, Ferring and the biotech company I-MAB signed a licensing agreement granting I-MAB exclusive rights in Asia to Olamkicept for the treatment of autoimmune disease [5].

Mechanism of action

On cells, Interleukin-6 binds to an Interleukin-6 receptor, which, however, is not signaling [6]. The complex of Interleukin-6 and the Interleukin-6 receptor binds to a second receptor protein, gp130, which thereupon dimerizes and initiates intracellular [7]. The gp130 receptor is present on all cells of the human body, whereas the Interleukin-6 receptor is only expressed by some cells such as hepatocytes and some [7] leukocytes. Since Interleukin-6 exhibits only measurable affinity to the Interleukin-6 receptor but not to gp130, only cells which express the Interleukin-6 receptor can respond to Interleukin-6. It was found that the Interleukin-6 receptor can be cleaved from the cell membrane by the protease ADAM17 generating a soluble [8] receptor. Interestingly, the soluble Interleukin-6 receptor can still bind Interleukin-6 and the complex of Interleukin-6 and Interleukin-6 receptor can bind to gp130 even on cells, which do not express the membrane-bound Interleukin-6 receptor. This mode of signaling has named Interleukin-6 trans-signaling [9]. The protein Olamkicept consists of the extracellular portion of gp130 fused (and thereby dimerized) to the constant portion of a human IgG1 antibody. Like membrane bound gp130, the protein Olamkicept does not bind Interleukin-6 alone but only the complex of Interleukin-6 and soluble Interleukin-6 receptor. Therefore, Olamkicept only inhibits Interleukin-6 trans-signaling but not Interleukin-6 signaling via the membrane-bound Interleukin-6 receptor [10]. It has been shown that Interleukin-6 activities via the membrane-bound Interleukin-6 receptor are regenerative and protect from bacterial infections whereas Interleukin-6 activities via the soluble Interleukin-6 receptor are considered pro-inflammatory [11]. Therefore, Olamkicept only blocks the pro-inflammatory activities of the cytokine Interleukin-6.

Research

In many animal disease models of human pathologies it was tested whether the specific blockade of Interleukin-6 trans-signaling by the Olamkicept protein was superior to a global blockade with an Interleukin-6 or an Interleukin-6 receptor neutralizing antibody [12]. It turned out that the specific blockade of Interleukin-6 trans-signaling was superior to global Interleukin-6 blockade in models of e.g. sepsis [13], of acute lung injury after severe acute pancreatitis [14] and of abdominal aortic aneurysm [15]. Furthermore, it was shown that Interleukin-6 trans-signaling plays a dominant role in colon cancer [16] and lung cancer [17].

Medical use

The Olamkicept protein underwent phase I clinical studies in 2013/14 and is currently in phase II clinical trials in patients with active inflammatory bowel disease in Germany [18] and in China, Taiwan, South Korea and Australia [19].

References

  1. ^ Jones, S. A.; Scheller, J.; Rose-John, S. (2011). "Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. - PubMed - NCBI". The Journal of Clinical Investigation. 121 (9): 3375–83. doi:10.1172/JCI57158. PMC 3163962. PMID 21881215.
  2. ^ Febbraio, M. A.; Rose-John, S.; Pedersen, B. K. (April 20, 2010). "Is interleukin-6 receptor blockade the Holy Grail for inflammatory diseases?". Clinical Pharmacology and Therapeutics. 87 (4): 396–398. doi:10.1038/clpt.2010.1. PMID 20305672.
  3. ^ Rothaug, M.; Becker-Pauly, C.; Rose-John, S. (2016). "The role of interleukin-6 signaling in nervous tissue. - PubMed - NCBI". Biochimica et Biophysica Acta. 1863 (6 Pt A): 1218–27. doi:10.1016/j.bbamcr.2016.03.018. PMID 27016501.
  4. ^ "Ferring" (PDF).
  5. ^ "Ferring and IMAB sign licensing agreement granting IMAB exclusive rights in Asia to olamkicept for the treatment of autoimmune disease". December 19, 2016.
  6. ^ Yamasaki, K.; Taga, T.; Hirata, Y.; Yawata, H.; Kawanishi, Y.; Seed, B.; Taniguchi, T.; Hirano, T.; Kishimoto, T. (1988). "Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. - PubMed - NCBI". Science. 241 (4867): 825–8. doi:10.1126/science.3136546. PMID 3136546.
  7. ^ a b Taga, T.; Kishimoto, T. (April 20, 1997). "Gp130 and the interleukin-6 family of cytokines". Annual Review of Immunology. 15: 797–819. doi:10.1146/annurev.immunol.15.1.797. PMID 9143707.
  8. ^ Müllberg, J.; Schooltink, H.; Stoyan, T.; Günther, M.; Graeve, L.; Buse, G.; Mackiewicz, A.; Heinrich, P. C.; Rose-John, S. (February 20, 1993). "The soluble interleukin-6 receptor is generated by shedding". European Journal of Immunology. 23 (2): 473–480. doi:10.1002/eji.1830230226. PMID 8436181.
  9. ^ Rose-John, S.; Heinrich, P. C. (1994). "Soluble receptors for cytokines and growth factors: generation and biological function. - PubMed - NCBI". The Biochemical Journal. 300 ( Pt 2): 281–90. doi:10.1042/bj3000281. PMC 1138158. PMID 8002928.
  10. ^ Jostock, T.; Müllberg, J.; Ozbek, S.; Atreya, R.; Blinn, G.; Voltz, N.; Fischer, M.; Neurath, M. F.; Rose-John, S. (January 20, 2001). "Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses". European Journal of Biochemistry. 268 (1): 160–167. doi:10.1046/j.1432-1327.2001.01867.x. PMID 11121117.
  11. ^ Scheller, Jürgen; Chalaris, Athena; Schmidt-Arras, Dirk; Rose-John, Stefan (May 20, 2011). "The pro- and anti-inflammatory properties of the cytokine interleukin-6". Biochimica et Biophysica Acta. 1813 (5): 878–888. doi:10.1016/j.bbamcr.2011.01.034. PMID 21296109.
  12. ^ Garbers, Christoph; Heink, Sylvia; Korn, Thomas; Rose-John, Stefan (June 20, 2018). "Interleukin-6: designing specific therapeutics for a complex cytokine". Nature Reviews. Drug Discovery. 17 (6): 395–412. doi:10.1038/nrd.2018.45. PMID 29725131.
  13. ^ Barkhausen, Tanja; Tschernig, Thomas; Rosenstiel, Philip; van Griensven, Martijn; Vonberg, Ralf-Peter; Dorsch, Martina; Mueller-Heine, Annika; Chalaris, Athena; Scheller, Jürgen; Rose-John, Stefan; Seegert, Dirk; Krettek, Christian; Waetzig, Georg H. (June 20, 2011). "Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model". Critical Care Medicine. 39 (6): 1407–1413. doi:10.1097/CCM.0b013e318211ff56. PMID 21336117 – via PubMed.
  14. ^ Zhang, Hong; Neuhöfer, Patrick; Song, Liang; Rabe, Björn; Lesina, Marina; Kurkowski, Magdalena U.; Treiber, Matthias; Wartmann, Thomas; Regnér, Sara; Thorlacius, Henrik; Saur, Dieter; Weirich, Gregor; Yoshimura, Akihiko; Halangk, Walter; Mizgerd, Joseph P.; Schmid, Roland M.; Rose-John, Stefan; Algül, Hana (March 20, 2013). "IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality". The Journal of Clinical Investigation. 123 (3): 1019–1031. doi:10.1172/JCI64931. PMC 3582130. PMID 23426178.
  15. ^ Paige, Ellie; Clément, Marc; Lareyre, Fabien; Sweeting, Michael; Raffort, Juliette; Grenier, Céline; Finigan, Alison; Harrison, James; Peters, James E.; Sun, Benjamin B.; Butterworth, Adam S.; Harrison, Seamus C.; Bown, Matthew J.; Lindholt, Jes S.; Badger, Stephen A.; Kullo, Iftikhar J.; Powell, Janet; Norman, Paul E.; Scott, D. Julian A.; Bailey, Marc A.; Rose-John, Stefan; Danesh, John; Freitag, Daniel F.; Paul, Dirk S.; Mallat, Ziad (February 20, 2019). "Interleukin-6 Receptor Signaling and Abdominal Aortic Aneurysm Growth Rates". Circulation. Genomic and Precision Medicine. 12 (2): e002413. doi:10.1161/CIRCGEN.118.002413. PMC 6383754. PMID 30657332.
  16. ^ Schmidt, Stefanie; Schumacher, Neele; Schwarz, Jeanette; Tangermann, Simone; Kenner, Lukas; Schlederer, Michaela; Sibilia, Maria; Linder, Markus; Altendorf-Hofmann, Annelore; Knösel, Thomas; Gruber, Elisabeth S.; Oberhuber, Georg; Bolik, Julia; Rehman, Ateequr; Sinha, Anupam; Lokau, Juliane; Arnold, Philipp; Cabron, Anne-Sophie; Zunke, Friederike; Becker-Pauly, Christoph; Preaudet, Adele; Nguyen, Paul; Huynh, Jennifer; Afshar-Sterle, Shoukat; Chand, Ashwini L.; Westermann, Jürgen; Dempsey, Peter J.; Garbers, Christoph; Schmidt-Arras, Dirk; Rosenstiel, Philip; Putoczki, Tracy; Ernst, Matthias; Rose-John, Stefan (April 2, 2018). "ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling". The Journal of Experimental Medicine. 215 (4): 1205–1225. doi:10.1084/jem.20171696. PMC 5881468. PMID 29472497.
  17. ^ Brooks, Gavin D.; McLeod, Louise; Alhayyani, Sultan; Miller, Alistair; Russell, Prudence A.; Ferlin, Walter; Rose-John, Stefan; Ruwanpura, Saleela; Jenkins, Brendan J. (February 15, 2016). "IL6 Trans-signaling Promotes KRAS-Driven Lung Carcinogenesis". Cancer Research. 76 (4): 866–876. doi:10.1158/0008-5472.CAN-15-2388. PMID 26744530.
  18. ^ "DRKS - Deutsches Register Klinischer Studien (German Clinical Trials Register)". www.drks.de.
  19. ^ [1]
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