Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Natalizumab: Perspectives from the Bench to Bedside Afsaneh Shirani1 and Olaf Stüve1,2 1Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas 75390 2Neurology Section, VA North Texas Health Care System, Medical Service Dallas, VA Medical Center, Dallas, Texas 75216 Correspondence: [email protected] Probably no other disease-modifying drug for multiple sclerosis has a more fascinating story than natalizumab from both the bench to bedside perspective and the postmarketing experi- ence standpoint. Natalizumab is a monoclonal antibody that inhibits the trafficking of lympho- cytes from the blood into the central nervous system by blocking the adhesion molecule α4-integrin. Natalizumab was approved as a disease-modifying drug for relapsing remitting multiple sclerosis only 12 years after the discovery of its target molecule—atimeline that is rather fast for drug development. However, a few months after its U.S. Food and Drug Administration approval, natalizumab was withdrawn from the market because of an unanticipated complication—progressive multifocal leukoencephalopathy. It was later rein- stated with required adherence to a strict monitoring program and incorporation of mitigation strategies. he development of therapeutic monoclonal aspects related to natalizumab use in clinical Tantibodies shows the importance of a target- practice. centered approach to modify the course of mul- tiple sclerosis (MS) (Buttmann and Rieckmann DISCOVERY AND MECHANISM OF ACTION 2008). Natalizumab is the first monoclonal an- www.perspectivesinmedicine.org tibody approved for the treatment of relapsing Natalizumab (Tysabri, Biogen Idec, Cambridge, MS after convincingly showing clinically and MA) is a humanized recombinant immuno- radiologically significant effects in phase III tri- globulin (Ig)G4 monoclonal antibody that als (Stüve and Bennett 2007). In this review, we blocks the α4-integrin-mediated leukocyte–en- highlight the evolution of natalizumab from dothelial interaction, resulting in inhibition of bench to bedside, summarize findings from piv- trafficking of lymphocytes from the blood into otal clinical trials of natalizumab, and discuss the central nervous system (CNS) (Stüve and the relevant adverse effects, particularly multi- Bennett 2007). The discovery of the target mol- focal leukoencephalopthy, lessons learned from ecule for natalizumab dates back to 1992 (Yed- risk mitigation strategies, as well as several other nock et al. 1992); however, the interaction be- Editors: Howard L. Weiner and Vijay K. Kuchroo Additional Perspectives on Multiple Sclerosis available at www.perspectivesinmedicine.org Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a029066 Cite this article as Cold Spring Harb Perspect Med 2018;8:a029066 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press A. Shirani and O. Stüve tween endothelium and lymphocytes has been first phase I safety and pharmacokinetic study studied since the mid-1960s when it was first of a humanized α4-integrin antibody, natalizu- shown in rats that lymphocytes enter lymph mab (Antegren, Athena Neurosciences, South nodes through specialized blood vessels called San Francisco, CA) (Sheremata et al. 1999). high endothelial venules (Gowans and Knight 1964). Later, in the 1980s and early 1990s, several EARLY CLINICAL STUDIES studies focused on the mapping of molecules involved in the process of lymphocyte migration, A phase I, randomized, placebo-controlled, five- highlighting the role of integrins and selectins, level dose-escalation trial of a single IV dose of particularly the cellular adhesion molecules, in- natalizumab (with doses ranging from 0.03 to cluding intracellular adhesion molecule (ICAM) 3.0 mg/kg), showed that all tested doses were and vascular cell adhesion molecule (VCAM) safe and well tolerated, and justified further tri- (Osborn et al. 1989; Springer 1994; Butcher als (Sheremata et al. 1999). An open-label safety and Picker 1996). The integrin very-late-activat- and drug interaction study of natalizumab in ing antigen 4 (α4β1-integrin; VLA-4) was iden- combination with interferon (IFN)-β-1a in 38 tified as a receptor for VCAM-1, and the VCAM- patients with MS provided safety and tolerability 1/VLA-4 ligand–receptor pair was suggested to data to support efficacy trials of combination play a major role in the recruitment of mononu- therapy (Vollmer et al. 2004). A phase II, ran- clear leukocytes to inflammatory sites in vivo domized, double-blind, placebo-controlled trial (Elices et al. 1990). In an attempt to further iden- of natalizumab in 72 patients with active relaps- tify the adhesion receptors involved in lympho- ing MS showed a significant reduction in the cyte homing to inflamed brain endothelium, sci- number of new active lesions on magnetic reso- entists at Stanford University and Athena nance imaging (MRI) over the first 12 weeks of Neurosciences collaborated on investigating the study, but no significant difference in the this question in the animal model of MS, exper- second 12 weeks of the study (Tubridy et al. imental autoimmune encephalomyelitis (EAE) 1999). Another phase II trial aimed at assessing (Yednock et al. 1992). Using an in vitro adhesion the effect of a single dose of IV natalizumab (vs. assay on frozen sections of EAE, they showed placebo) soon after the onset of relapses in 180 that lymphocytes and monocytes selectively patients with MS (O’Connor et al. 2004). This bind to the lumen of the vessels, consistent study showed that natalizumab did not hasten with an endothelial interaction. They found clinical recovery after relapse; however, a signifi- that this binding was blocked by antibodies cant decrease in the volume of enhancing lesion against the α4-integrin molecule and not by an- volume was noted at 1 and 3 weeks after treat- www.perspectivesinmedicine.org tibodies against numerous alternative adhesion ment (O’Connor et al. 2004). Another impor- receptors (Yednock et al. 1992). This finding was tant phase II trial assessed the efficacy of two followed by an in vivo experiment in which ad- doses of monthly natalizumab (3 mg/kg and 6 ministration of antibodies to α4-integrin to EAE mg/kg) versus placebo for 6 months, followed by rats ameliorated the paralysis and prevented the a 6-month observation (Miller et al. 2003). The accumulation of leukocytes in the CNS as evi- study showed that both of the tested doses of denced by immunohistochemical studies of natalizumab led to fewer inflammatory brain brains from EAE rats. This was the first study lesions and fewer relapses over a 6-month period providing direct evidence to suggest that thera- in patients with relapsing MS (Miller et al. 2003). pies based on interfering with α4β1-integrin fl may be useful in treating in ammatory disease PIVOTAL CLINICAL TRIALS of the CNS such as MS (Yednocket al. 1992). The expression of adhesion molecules VLA-4 and The two pivotal phase III trials of natalizumab in VCAM-1 was later shown in an MS autopsy patients with relapsing forms of MS include AF- brain using immunohistochemical analysis FIRM (Natalizumab Safety and Efficacy in Re- (Verbeek et al. 1995). These studies led to the lapsing Remitting Multiple Sclerosis) and SEN- 2 Cite this article as Cold Spring Harb Perspect Med 2018;8:a029066 Downloaded from http://perspectivesinmedicine.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Natalizumab from Bench to Bedside TINEL (Safety and Efficacy of Natalizumab in combination with natalizumab 300 mg (589 pa- Combination with IFN-β-1a in Patients with tients) or placebo (582 patients) intravenously Relapsing Remitting Multiple Sclerosis) studies every 4 weeks for up to 116 weeks (Rudick et al. (Polman et al. 2006; Rudick et al. 2006). In the 2006). Similar to the AFFIRM study, inclusion AFFIRM study, the efficacy and safety of natali- criteria included patients ages 18 to 50 years, zumab as a monotherapy in relapsing remitting diagnosis of relapsing remitting MS, a baseline MS patients was investigated, whereas the SEN- EDSS score of ≤5, at least one relapse within the TINEL study was designed to evaluate the effi- 12 months before the study, and MRI lesions cacy and safety of natalizumab in combination consistent with MS. Primary and secondary with intramuscular IFN-β-1a (Avonex). end points were also defined identical to the In the AFFIRM study, a total of 942 patients AFFIRM study. The similar inclusion criteria were randomly assigned in a 2:1 ratio to receive and end-point definition allowed clinically use- intravenous natalizumab 300 mg (627 patients) ful conclusions to be drawn from these two stud- or placebo (315 patients) every 4 weeks for up to ies. Combination therapy with natalizumab was 116 weeks (Polman et al. 2006). The inclusion associated with 55% relative reduction in annu- criteria required patients ages 18 to 50 years, lized relapse rate (0.34% compared with 0.75% diagnosis of relapsing remitting MS, a base- with IFN-β-1a), 83% reduction in the number of line-Expanded Disability Status Scale (EDSS) new or enlarging T2 lesions at 2 years, 89% re- score of ≤5, at least one relapse within the 12 duction in the number of the gadolinium-en- months before the study, and MRI lesions con- hancing lesions, and 24% reduction in relative sistent with MS. The primary end points were risk of sustained disability progression at 2 years the rate of clinical relapses at 1 year, and rate of (Rudick et al. 2006). sustained disability progression as measured by Later, in a phase II, randomized, double- EDSS at 2 years. Secondary end points at 1 year blind, placebo-controlled trial called Glatiramer included the number of new or enlarging T2- Acetate and Natalizumab Combination Evalua- hyperintense lesions, the number of gadolini- tion (GLANCE), safety and tolerability of com- um-enhancing lesions, and the proportion of bination therapy with natalizumab added to gla- relapse-free patients.