Fingolimod – ein neuer Immunmodulator

Zusammenfassung

Fingolimod (FTY720) ist ein Derivat des natürlichen Wirkstoffs Myriocin mit struktureller Ähnlichkeit zu Sphingosin, einem ubiquitär vorkommenden Sphingolipid. Fingolimod stellt einen neuen Immunmodulator dar, der hemmend in den Austritt von T- und B-Lymphozyten aus sekundären Lymphorganen eingreift, was zu einer Lymphopenie führt. Eine Phase-II-Studie mit MS-Patienten zeigte eine signifikante Verringerung der jährlichen Schubrate, die sich auch in einer Reduktion von Läsionen im MRT widerspiegelte bei akzeptabler Nebenwirkungsrate. Des Weiteren hat Fingolimod gegenüber der Therapie mit Interferon beta, Glatiramerazetat und Natalizumab den Vorteil, oral verfügbar zu sein. Vor einer sicheren Beurteilung der Substanz müssen die Ergebnisse zurzeit laufender größerer klinischer Studien abgewartet werden.

Summary

Fingolimod is a derivative of the naturally occurring immunosuppressive substance myriocin, with structural similarity to sphingosine, a ubiquitous sphingolipid. It acts as an immunomodulator interfering with the egress of T and B lymphocytes from secondary lymph organs, which results in lymphopenia. A phase II study in patients with multiple scerosis showed a significant reduction in annual relapse rate and lesions in magnetic resonance imaging with an acceptable rate of side effects. An advantage of fingolimod compared to interferon beta, glatirameracetate and natalizumab is its oral availability. Definitive assessment of the compound has to await the results of trials currently being performed.

Schlüsselwörter

Immunmodulation - Multiple Sklerose - Sphingosin-1-Phosphat-Rezeptor-Agonist

Keywords

immunomodulation - multiple sclerosis - sphingosine-1-phosphate receptor agonist

Literatur

• 1 Allende M L, Dreier J L, Mandala S, Proia R L. Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration.  J Biol Chem. 2004;  279 15396-15401
• 2 Brinkmann V, Davis M D, Heise C E. et al . The immune modulator FTY720 targets sphingosine 1-phosphate receptors.  J Biol Chem. 2002;  277 21453-21457
• 3 Budde K, Schmouder R L, Brunkhorst R. et al . First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients.  J Am Soc Nephrol. 2002;  13 1073-1083
• 4 Chiba K, Yanagawa Y, Masubuchi Y. et al . FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing.  J Immunol. 1998;  160 5037-5044
• 5 Graler M H, Goetzl E J. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors.  FASEB J. 2004;  18 551-553
• 6 Halin C, Scimone M L, Bonasio R. et al . The S1P-analog FTY720 differentially modulates T-cell homing via HEV: T-cell-expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer patches.  Blood. 2005;  106 1314-1322
• 7 Harada J, Foley M, Moskowitz M A, Waeber C. Sphingosine-1-phosphate induces proliferation and morphological changes of neural progenitor cells.  J Neurochem. 2004;  88 1026-1039
• 8 Hemmer B, Nessler S, Zhou D, Kieseier B, Hartung H P. Immunopathogenesis and immunotherapy of multiple sclerosis.  Nat Clin Pract Neurol. 2006;  2 201-211
• 9 Hla T, Lee M J, Ancellin N, Paik J H, Kluk M J. Lysophospholipids – receptor revelations.  Science. 2001;  294 1875-1878
• 10 Honig S M, Fu S, Mao X. et al . FTY720 stimulates multidrug transporter- and cysteinyl leukotriene-dependent T cell chemotaxis to lymph nodes.  J Clin Invest. 2003;  111 627-637
• 11 Jaillard C, Harrison S, Stankoff B. et al . Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival.  J Neurosci. 2005;  25 1459-1469
• 12 Kappos L, Antel J, Comi G. et al . Oral fingolimod (FTY720) for relapsing multiple sclerosis.  N Engl J Med. 2006;  355 1124-1140
• 13 Kovarik J M, Hartmann S, Bartlett M. et al . Oral-intravenous crossover study of fingolimod pharmacokinetics, lymphocyte responses and cardiac effects.  Biopharm Drug Dispos. 2007;  28 97-104
• 14 Kovarik J M, Schmouder R, Barilla D. et al . Multiple-dose FTY720: tolerability, pharmacokinetics, and lymphocyte responses in healthy subjects.  J Clin Pharmacol. 2004;  44 532-537
• 15 Koyrakh L, Roman M I, Brinkmann V, Wickman K. The heart rate decrease caused by acute FTY720 administration is mediated by the G protein-gated potassium channel I.  Am J Transplant. 2005;  5 529-536
• 16 Matloubian M, Lo C G, Cinamon G. et al . Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.  Nature. 2004;  427 355-360
• 17 Means C K, Brown J H. Sphingosine-1-phosphate receptor signalling in the heart.  Cardiovasc Res. 2009;  82 193-200
• 18 Mizugishi K, Yamashita T, Olivera A. et al . Essential role for sphingosine kinases in neural and vascular development.  Mol Cell Biol. 2005;  25 11113-11121
• 19 Park S I, Felipe C R, Machado P G. et al . Pharmacokinetic/pharmacodynamic relationships of FTY720 in kidney transplant recipients.  Braz J Med Biol Res. 2005;  38 683-694
• 20 Pinschewer D D, Ochsenbein A F, Odermatt B. et al . FTY720 immunosuppression impairs effector T cell peripheral homing without affecting induction, expansion, and memory.  J Immunol. 2000;  164 5761-5770
• 21 Rausch M, Hiestand P, Foster C A. et al . Predictability of FTY720 efficacy in experimental autoimmune encephalomyelitis by in vivo macrophage tracking: clinical implications for ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging.  J Magn Reson Imaging. 2004;  20 16-24
• 22 Rosen H, Goetzl E J. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network.  Nat Rev Immunol. 2005;  5 560-570
• 23 Salvadori M, Budde K, Charpentier B. et al . FTY720 versus MMF with cyclosporine in de novo renal transplantation: a 1-year, randomized controlled trial in Europe and Australasia.  Am J Transplant. 2006;  6 2912-2921
• 24 Sanchez T, Estrada-Hernandez T, Paik J H. et al . Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability.  J Biol Chem. 2003;  278 47281-47290
• 25 Sawicka E, Dubois G, Jarai G. et al . The sphingosine 1-phosphate receptor agonist FTY720 differentially affects the sequestration of CD4+/CD25+ T-regulatory cells and enhances their functional activity.  J Immunol. 2005;  175 7973-7980
• 26 Schluns K S, Lefrancois L. Cytokine control of memory T-cell development and survival.  Nat Rev Immunol. 2003;  3 269-279
• 27 Schmouder R, Serra D, Wang Y. et al . FTY720: placebo-controlled study of the effect on cardiac rate and rhythm in healthy subjects.  J Clin Pharmacol. 2006;  46 895-904
• 28 Singer I I, Tian M, Wickham L A. et al . Sphingosine-1-phosphate agonists increase macrophage homing, lymphocyte contacts, and endothelial junctional complex formation in murine lymph nodes.  J Immunol. 2005;  175 7151-7161
• 29 Tedesco-Silva H, Mourad G, Kahan B D. et al . FTY720, a novel immunomodulator: efficacy and safety results from the first phase 2A study in de novo renal transplantation.  Transplantation. 2005;  79 1553-1560
• 30 Tedesco-Silva H, Pescovitz M D, Cibrik D. et al . Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation.  Transplantation. 2006;  82 1689-1697
• 31 Webb M, Tham C S, Lin F F. et al . Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice.  J Neuroimmunol. 2004;  153 108-121
• 32 Yopp A C, Ochando J C, Mao M. et al . Sphingosine 1-phosphate receptors regulate chemokine-driven transendothelial migration of lymph node but not splenic T cells.  J Immunol. 2005;  175 2913-2924
• 33 Zemann B, Kinzel B, Muller M. et al . Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720.  Blood. 2006;  107 1454-1458
• 34 Zimmerlin A GPC. Role of CYP4F in the metabolic clearance of FTY720 – prediction of low drug to drug interaction potential.  TRANSPLANTATION. 2000;  69 S191