Natalizumab for Multiple Sclerosis: A Case in Point for the Impact of Translational Neuroimmunology This information is current as Afsaneh Shirani and Olaf Stüve of September 26, 2021. J Immunol 2017; 198:1381-1386; ; doi: 10.4049/jimmunol.1601358 http://www.jimmunol.org/content/198/4/1381 Downloaded from References This article cites 58 articles, 6 of which you can access for free at: http://www.jimmunol.org/content/198/4/1381.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 26, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Th eJournal of Translating Immunology Immunology Natalizumab for Multiple Sclerosis: A Case in Point for the Impact of Translational Neuroimmunology Afsaneh Shirani and Olaf Stuve€ Advances in translational neuroimmunology over the last flammation (4). Therefore, inhibition of leukocyte trafficking two decades have revolutionized the treatment of relaps- across the inflamed blood–brain barrier should provide an ef- ing forms of multiple sclerosis. A pathological hallmark fective anti-inflammatory therapy for MS (5). Natalizumab is a of multiple sclerosis is the presence of leukocytes in the a mAb that blocks the 4-integrin–mediated leukocyte– areas of disease activity in the CNS. Natalizumab inhibits endothelial interaction, resulting in inhibition of trafficking the trafficking of lymphocytes from the blood into the of lymphocytes from the blood into the CNS (6). Natalizu- brain and spinal cord by blocking the adhesion molecule mab was approved by the U.S. Food and Drug Administra- a tion (FDA) for the treatment of RRMS only 12 y after the Downloaded from 4-integrin. Representing the enormous success of a molecular targeted approach, natalizumab was the first discovery of its target molecule in 1992 and 7 y after the mAb approved for the treatment of relapsing–remitting beginning of its first clinical trial, a time line that is rather fast multiple sclerosis. However, only a few months after for development of new drugs (7). This was based on con- vincing clinical and radiological benefits in phase III trials (6). its approval, natalizumab was withdrawn from the mar- However, a few months after its FDA approval, natalizumab ket because of an unanticipated life threatening adverse was taken off the market because of a life-threatening com- http://www.jimmunol.org/ effect: progressive multifocal leukoencephalopathy. plication: progressive multifocal leukoencephalopathy (PML). Natalizumab was later reintroduced with required ad- Natalizumab was later reinstated with required adherence to a herence to a strict monitoring program. In this article, strict monitoring program. we review the bench-to-bedside journey of natalizumab, Although the bench-to-bedside journey of natalizumab along with the lessons learned from postmarketing stud- highlights the value of a molecular targeted approach in de- ies. The Journal of Immunology, 2017, 198: 1381– veloping new therapeutics for MS, natalizumab-associated 1386. PML emphasizes the importance of continued long-term post- marketing safety surveillance, sometimes warranting a bedside- by guest on September 26, 2021 he last two decades have witnessed a revolution in the to-bench switch. In this article, we review the translational treatment landscape for relapsing forms of multiple journey of natalizumab along with the lessons learned from T sclerosis (MS), with the introduction of mAb-based postmarketing studies. therapies and novel oral agents. This has been possible through Mechanism of action translational neuroimmunology approaches in MS research and Leukocyte trafficking across the blood–brain barrier involves the advent of modern tools in neuroimmunology, neurobiology, overlapping sequential steps, including tethering and rolling, and neuroimaging (1). The discovery and bench-to-bedside chemoattraction, cell adhesion, and proteolytic degradation of journey of natalizumab, as the first therapeutic mAb approved biological membranes (5). Rolling on endothelial cell walls for the treatment of relapsing forms of MS, is a case in point. allows leukocytes to identify the proper array of chemoattractants MS is a chronic inflammatory, autoimmune, demyelinating, and integrin ligands (5). Natalizumab (Tysabri; Biogen Idec, and neurodegenerative disease of the white and gray matter Cambridge, MA) is a humanized rIgG4 mAb that blocks ∼ a within the CNS. Affecting 2.5 million individuals world- the 4-integrin–mediated leukocyte–endothelial interaction, wide, MS is the most common cause of neurologic disability resulting in inhibition of trafficking of lymphocytes from the in young adults (2). Approximately 85% of patients pre- blood into the CNS (6). Natalizumab binds to a4-integrin sent with relapsing–remitting MS (RRMS) at diagnosis, which on lymphocytes, as well as on myeloid cells, thereby inhibiting is characterized by alternating episodes of neurologic disability their migration into the CNS tissue (8). (relapses) followed by complete or partial recovery from symp- The discovery of the target molecule for natalizumab dates toms (3). A major pathologic hallmark of MS is chronic in- back to 1992 (9); however, the interaction between endothelium Department of Neurology and Neurotherapeutics, University of Texas Southwestern Abbreviations used in this article: AFFIRM, Natalizumab Safety and Efficacy in Relapsing- Medical Center, Dallas, TX 75390; and Neurology Section, VA North Texas Health Remitting Multiple Sclerosis; EAE, experimental autoimmune encephalomyelitis; EDSS, Care System, Medical Service, Dallas VA Medical Center, Dallas, TX 75216 expanded disability status scale; FDA, U.S. Food and Drug Administration; GA, glatiramer acetate; IRIS, immune reconstitution inflammatory syndrome; JCV, John Cunningham ORCID: 0000-0002-8866-6426 (A.S.). virus; MRI, magnetic resonance imaging; MS, multiple sclerosis; PML, progressive multi- Received for publication August 5, 2016. Accepted for publication December 6, 2016. focal leukoencephalopathy; RRMS, relapsing–remitting MS; SENTINEL, Safety and Ef- ficacy of Natalizumab in Combination with IFN-b1a in Patients with Relapsing-Remitting Address correspondence and reprint requests to Dr. Olaf Stuve,€ Neurology Section, VA Multiple Sclerosis; VLA-4, very late activating Ag 4. North Texas Health Care System, Medical Service, 4500 South Lancaster Road, Dallas, TX 75216. E-mail address: [email protected] Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1601358 1382 TRANSLATING IMMUNOLOGY: NATALIZUMAB IN MULTIPLE SCLEROSIS and lymphocytes has been intriguing scientists since the two doses of monthly natalizumab (3 and 6 mg/kg) versus mid-1960s, when it was first demonstrated in rats that lymphocytes placebo for 6 mo, followed by a 6-mo observation in patients enter lymph nodes through specialized postcapillary blood vessels with relapsing MS, showed that both of the tested doses called high endothelial venules (10). Several studies focused on resulted in fewer inflammatory brain lesions and fewer re- mapping of molecules involved in the process of lymphocyte lapses over a 6-mo period (20). Later, a phase II randomized migration highlighted the role of integrins and selectins, partic- double-blind placebo-controlled trial, Glatiramer Acetate and ularly the cellular adhesion molecules, including ICAM and Natalizumab Combination Evaluation, compared the safety VCAM (11–13). The integrin very late activating Ag 4 (VLA-4; and tolerability of combination therapy with natalizumab plus a 4b1-integrin) was identified as a receptor for VCAM-1, and the glatiramer acetate (GA) versus GA only (21). Both groups had VCAM-1/VLA-4 ligand–receptor pair was suggested to play a a similar incidence of infection and infusion reactions, and major role in the recruitment of mononuclear leukocytes to no hypersensitivity reactions were reported. Therefore, it was inflammatory sites in vivo (14). In the early 1990s, scientists concluded that the combination of natalizumab and GA at Stanford University and Athena Neurosciences collaborated seemed safe and well tolerated during a 6-mo treatment in an attempt to further identify the adhesion receptors in- period (21). volved in lymphocyte homing to inflamed brain endothelium, using the animal model of MS, experimental autoimmune Pivotal phase III trials encephalomyelitis (EAE) (9). Using an in vitro adhesion assay The FDA approval of natalizumab was based on two pivotal phase on frozen sections of EAE CNS tissue, they showed that III trials in patients with relapsing forms of MS: the Natalizumab Downloaded from leukocytes selectively bind to the lumen of the vessels, a Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis