The Role of Monoclonal in Neurological Disorders Valerie Gendron, MD, and Syed A. Rizvi, MD  Mo n o c l o n a l a nt i b o d y t r e a t m e nt is enlarging hyperintense T2 MRI lesions in Safety for Rest of World (TYGRIS- standard therapy for multiple sclerosis by 83% over two years, and reduce the ROW), a safety observational cohort and is under investigation for neuromy- rate of clinical relapse by 68% at one program designed to obtain long-term elitis optica, peripheral neuropathies, and year.6 The second study, SENTINEL, safety data in MS patients treated outside inflammatory myopathies. This review randomized 1171 patients having at least of the US.3,4,5 will highlight the uses of monoclonal one relapse in 12 months while on beta- antibodies in these diseases. 1a therapy, to receive either beta-1a plus , or beta-1a plus placebo by Alemtuzumab is a humanized mono- Mu l t i p l e Sc l e r o s i s intravenous infusion every four weeks. clonal directed against CD52, a In multiple sclerosis, autoreactive T Combination therapy with natalizumab cell surface located on T cells, B cells cross the blood-brain barrier under was found to reduce the risk of sustained cells, monocytes, macrophages, and eo- the influence of proinflammatory cy- disability progression by 24%, reduce the sinophils. Its mechanism of action is still tokines and cellular adhesion molecules, rate of clinical relapse by 54% at one year unknown, but its end result is profound resulting in an attack on myelin, with and by 55% at two years, and reduce the lymphopenia. Early studies of alemtu- resulting inflammation, degeneration number of new or enlarging hyperintense zumab showed significantly reduced and demyelination.1 Given the multi- T2 lesions by 83% at two years.7 annual relapse rate in both relapsing- tude of interactions involved in the im- Based on promising data at one remitting and secondary progressive MS. munopathogenesis of multiple sclerosis, year outcome measures, and a generally Despite this, the secondary progressive several immunological pathways may be tolerable side effect profile, natalizumab group showed sustained disability, while targeted with highly specific and selective was approved in November 2004, prior the relapsing-remitting group showed antibodies. to completion of the phase three stud- a reduction in disability. 8 This was fol- ies. Three months later, in February lowed by a phase 2 study, including 334 Natalizumab 2005, two patients were found to have patients with early relapsing-remitting At present time, the only FDA developed progressive multifocal leuko- multiple sclerosis randomized to either approved for encephalopathy (PML), both of whom subcutaneous beta-1a three the treatment of multiple sclerosis is had received combination therapy with times per week or annual intravenous natalizumab, a humanized monoclonal beta-1a in the SENTINEL trial. Natali- alemtuzumab at either 12mg or 24mg antibody directed against the α4 sub- zumab was voluntarily withdrawn from over 36 months. Alemtuzumab was unit of the α4β1 , also known the market. In June 2006, it was placed found to significantly reduce the rate of as very late antigen-4 (VLA4), which back on the market, with the caveat that disability, the annual relapse rate, and the is expressed on the surface of activated it be used as monotherapy in patients with lesion burden on MRI when compared lymphocytes. Vascular cell adhesion mol- relapsing forms of MS.3,4,5 to interferon beta 1a. Patients receiving ecule (VCAM), expressed on the luminal Natalizumab is currently being used alemtuzumab were found to have signifi- surface of vascular endothelium, acts as as a second line agent in the treatment cantly higher rates of autoimmune disor- the receptor for VLA4. Their interaction of relapsing and remitting (RRMS) or ders, most commonly hyperthyroidism ultimately results in lymphocyte adhesion secondary progressive (SPMS) with and immune thrombocytopenic purpura. to vascular endothelium and lymphocyte relapses with excellent tolerability and 9 There are currently two phase three tri- translocation across the endothelium. By encouraging results. The risk of PML als underway, CARE-MS I, comparing its action on VLA4, natalizumab blocks remains and seems to increase with alemtuzumab to interferon beta-1a in this interaction, in effect inhibiting lym- duration of therapy. At the time of treatment naïve patients, and CARE-MS phocyte migration across the blood brain writing this manuscript more than 90 II, comparing alemtuzumab to interferon barrier.2,3,4,5 cases of PML have been reported, with a beta-1a in patients who have received Early studies on natalizumab had mortality of about 20%, out of a total of an adequate trial of disease modifying shown positive results, which led to two approximately 83,000 patients exposed therapy, but continue to have relapses. phase III multicenter randomized con- to natalizumab (press release). There All patients receiving alemtuzumab in trol studies. The first study, AFFIRM, are ongoing studies of the safety of na- these studies are also followed in an ex- randomized 942 patients to receive either talizumab continues, through both the tension study designed to evaluate safety natalizumab or placebo by intravenous Tysabri Outreach Unified Commitment and efficacy.10 infusion every four weeks. Natalizumab to Health (TOUCH) program, requir- was found to reduce the risk of sustained ing enrollment before receiving the drug progression of disability by 42% over two in the United States, and through the Daclizumab is a humanized mono- years, reduce the accumulation of new or Tysabri Global Observational Program clonal antibody, directed against CD25 333 Volume 94 No. 11 No v e m b e r 2011 surface antigen, which is identical to were randomized to receive placebo or Pe r i p h e r a l Ne u r o p a t h i e s the -2 receptor, located on every 24 weeks for a total Rituximab has also been tried in a activated T cells. Interleukin-2 induces of 96 weeks. There were no significant number of peripheral neuropathies. In secretion of proinflammatory cytokines differences between rituximab and multifocal motor neuropathy (MMN), and stimulates proliferation of lympho- placebo in terms of time to confirmed a rare, symmetric, demyelinating, purely cytes. Daclizumab acts as an antagonist at disease progression, although in a sub- motor neuropathy, approximately 30- the interleukin-2 receptor. Results from group analysis, there was a significant 50% of patients have been found to have preliminary open label trials showed sig- difference in a subset of patients who anti-GM1 antibodies in serum, suggesting nificantly decreased numbers of contrast were younger and had an inflammatory a role for humoral immunity. IVIG is enhancing lesions on MRI, decreased component to their disease process.16 first line therapy; however some patients exacerbation rates, and decreased Ex- , a humanized MCA against have a decreased efficacy over time and panded Disability Status Scale (EDSS) CD20 is being studied in MS in phase therefore require very frequent infusions. scores. Decreased EDSS scores were III trials. Rituximab has been looked at in small also observed in five of 14 patients with case reports in this group of patients, secondary progressive multiple sclerosis, with conflicting results. One case report an important finding, as there is cur- Early studies on showed yearly rituximab resulted in reduc- rently no therapeutic option for this natalizumab had tion of IVIG dosage from every seven days group of patients.3,4,5,11 A phase II study to every 12 days over a five year period,19 of nine patients with multiple sclerosis shown positive but another showed that in two patients on interferon therapy, with continued results, which with MMN, one had a decrease in total relapses and contrast enhancing lesions, IVIG dosage while the other required showed significant reduction in contrast led to two phase an increase, and there was no significant enhancing lesions, number of relapses, III multicenter change in any of the secondary clinical EDSS scores, timed ambulation scores, endpoints including strength or sensory and neurologic rating scale.12 A larger, randomized control improvement, or change in rankin disabil- phase II study, CHOICE, included 230 studies. ity scores.20 In this same study, one patient patients already on interferon beta, ran- with sensory ataxic neuropathy related to domized to combination therapy with Sjogren’s syndrome was also treated with daclizumab subcutaneously injected at a Ne u r o m y e l i t i s o p t i c a rituximab and showed a 63% reduction dose of either 2mg/kg every two weeks, Neuromyelitis optica (Devic’s dis- in IVIG dose at one year. Two patients or 1mg/kg every four weeks versus com- ease) is an inflammatory demyelinating with chronic inflammatory demyelinating bination therapy with placebo. There disease that attacks the spinal cord and polyneuropathy showed no reduction in was a statistically significant decrease optic nerves. It is associated with more dose of IVIG needed to maintain remis- in the mean number of new or enhanc- rapid disability than typical multiple sion, however in other case reports its ing lesions in the high dose daclizumab sclerosis. A specific antibody against use has appeared more encouraging. 20,21 group. 13 Phase III trials are currently aquaporin-4 channels in the CNS has Anti-myelin associated glycoprotein underway, evaluating daclizumab vs. been found to be highly specific for this (anti-MAG) neuropathy, a chronic sen- interferon beta-1a as well as safety and disease. There is a prominence of IgG sorimotor demyelinating polyneuropathy efficacy studies.10 and complement in neuromyelitis optica unresponsive to conventional treatments (NMO) lesions, suggesting involve- including steroids, plasma exchange, or Rituximab ment in pathophysiology. Rituximab has IVIG is another entity in which rituximab Rituximab is a chimeric monoclo- therefore been considered a treatment has been tried. A double-blind placebo nal antibody against CD-20 antibodies option. One open label study of eight controlled trial randomizing 13 anti- expressed on B cells. It causes B cell patients with worsening NMO treated MAG patients to rituximab, and 13 to lysis though its effects on complement with rituximab showed that six of the placebo, showed that four of 13 patients activation, antibody-dependent cellular eight patients remained attack free dur- treated with rituximab showed improve- cytotoxicity, and apoptosis. A phase II, ing an average time period of 12 months, ment in leg disability scores whereas zero double blind, trial involving 104 pa- and the EDSS score improved from a of 13 placebo patients showed improve- tients with relapsing remitting multiple pretreatment score of 7.5 to a score of ment. In addition, there was a significant sclerosis assigned to either rituximab or 5.5 at follow-up.17 Another retrospec- reduction in time to ten-meter walk in placebo showed that patients receiving tive analysis looked at 25 patients, 23 of the rituximab group.22 rituximab had significantly fewer total whom had previously relapsed on other and new gadolinium enhancing lesions therapies, found that median annualized My a s t h e n i a Gr a v i s on MRI, and fewer relapses when stud- post-treatment relapse rate went from 1.7 Myasthenia Gravis, an autoim- ied up to 48 weeks.15 Rituximab has also to zero at 19 month follow-up, and me- mune disorder affecting neuromuscular been looked at in patients with primary dian EDSS scores decreased from seven junction transmission is associated with progressive multiple sclerosis in the to five after treatment.18 antibodies to nicotinic acetylcholine OLYMPUS trial, in which 439 patients receptor (AchR) in about 80% of cases, 334 Medicine & Health/Rhode Island and to muscle-specific receptor tyrosine Testing (QMT) testing, a measure 7. Rudick R, Stuart W, Calabresi P, Confavreux kinase (MuSK) in about 10% of cases. In of strength in kilograms to measure C, Galetta S, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Eng patients difficult to control by conven- maximum voluntary isometric muscle J Med. 2006;354(9):911-923. tional therapy rituximab has been tried contractions. In addition, when using the 8. Coles A, Cox A, Le Page E, Jones J, Trip S, et and described in case reports. One such MRC scale, a validated ten-point scale al. The window of therapeutic opportunity in study looked at three AchR antibody to record strength, after six months of multiple sclerosis:Evidence from monoclonal antibody therapy. J Neuro. 2006;253:98- patients and three MuSK antibody pa- treatment there was a reversal of disease 108. tients and showed clinical improvement decline, with an average strength gain of 9. Coles A, Alastair D, Compston S, Selmaj K, as well as a significant difference in 11.4%. On patient self report, five of the Lake S, et al. Alemtuzumab vs. interferon beta- 23 1a in early multiple sclerosis. N Eng J Med. antibody titers. A controlled trial has 11 patients noticed an improvement in 2008;359(17):1786-1801. 25 yet to be performed, but a further open their daily activities. An active ongoing 10. www.clinicaltrials.gov label pilot study looking at rituximab in study is underway looking at , 11. Rose J, Watt H, White A, Carlson N. Treatment refractory myasthenia gravis is currently which blocks TNF-alpha, in a double- of multiple sclerosis with an anti-interleukin-2 receptor monoclonal antibody. Ann Neuro. underway. blind, randomized, placebo-controlled 2004;56:864-867. trial to evaluate whether it can delay 12. Rose J, Burns J, Bjorklund J, Klein J, Watt H, In f l a m m a t o r y My o p a t h i e s disease progression. et al. Daclizumab phase II trial in relapsing The inflammatory myopathies, and remitting multiple sclerosis: MRI and clinical results. Neurology. 2007;69:785- dermatomyositis, polymyositis, and Co nc l u s i o n 790. inclusion body myositis, are also felt to The potential role of MCA in the 13. Wynn D, Kaufman M, Montalban X, Vollmer have an association with autoantibodies. treatment of neurological disorders with T, Simon J, et al. Daclizumab in active relapsing First-line treatment is immunosuppres- an inflammatory autoimmune compo- multiple sclerosis (CHOICE study): a phase 2, randomised, double-blind, placebo-controlled, sive therapies, beginning with corti- nent is become increasingly apparent. add-on trial with interferon beta. The Lancet costeroids, with up to 70% of patients Natalizumab is currently the only MCA Neuurology. 2010;9(4):381-390. having an incomplete response. Further approved for the treatment of RRMS, 14. Segal B, Constantinescu C, Raychaudhuri treatment with mycophenolate mofetil, but several others are in late stage tri- A, Kim L, Fidelus-Gort R, et al. Repeated subcutaneous injections of IL12/23 p40 neu- , cyclosporine and IVIG als. While the efficacy of monoclonal tralising antibody, , in patients produces a variable response. This has antibodies in the treatment of RRMS with relapsing-remitting multiple sclerosis: a led to attempts to find further treatment seems to be better than the standard phase II, double-blind, placebo-controlled, randomised, dose-ranging study. The Lancet options. Rituximab has been looked at in disease modifying agents ( Neurology. 2008;7(9):796-804. small open label studies. One such study and Glatiramer Acetete), there is a sig- 15. Hauser S, Waubant E, Arnold D, Vollmer T, involved six patients with dermatomyo- nificant concern regarding long term side Antel J, et al. B cell depletion with rituximab sitis and showed clinical improvement effects. Ongoing and future trials will in relapsing-remitting multiple sclerosis. N Eng J Med. 2008;358(7):676-688. in muscle strength, rash, alopecia, and further clarify the role of MCA in the 16. O’Connor H, Freedman M, Calabresi P, Antel forced vital capacity measurements, treatment of MS and other neurological J, Simon J, et al. Rituximab in patients with correlating with time of B cell deple- disorders. primary progressive multiple sclerosis: results of tion by rituximab.24 Similar results have a randomized double-blind placebo-controlled multicenter trial. Ann Neuro. 2009;66(4):460- been found in small open-label clinical Re f e r e nc e s 471. trials involving polymyositis.21 A phase- 1. Goodin DS, Cohen BA, O’Connor P, Kappos 17. Cree B, Lamb S, Morgan K, Chen A, Waubant L, Stevens JC. Assessment: The use of natali- E, et al. An open label study on the effects of II, placebo controlled trial looking at zumab (Tysabri) for the treatment of multiple rituximab in the treatment of refractory rituximab in neuromyelitis optica. Neurology. sclerosis (an evidence-based review): report of 2005;64:1270-1272 adult and juvenile dermatomyositis and the Therapeutics and Technology Assessment 18. Jacob A, Weinshenker B, Violich I, McLin- adult polymyositis is currently under- subcommittee of the American Academy of skey N, Krupp L, et al. Treatment of neuro- Neurology. Neurology. 2008;71:766-773. myelitis optica with rituximab. Arch Neuro. way. Inclusion body myositis remains 2. Novak J, Lovett-Racke A, Racke M. Monoclonal the most difficult of the inflammatory 2008;65(11):1443-1448. antibody therapies and Neurologic Disorders. 19. Ruegg S, Fuhr P, Steck A. Rituximab stabilizes myopathies to treat. Again, small pilot Archives of Neurology. 2008;65(9):1162-1165. multifocal motor neuropathy increasingly less studies have looked at various monoclo- 3. Linker R, Kieseier B. Innovative monoclo- responsive to IVIg. Neurology. 2004;63:2178- nal antibody therapies in multiple sclerosis. nal antibodies as potential therapeutic 2179 Therapeutic Advances in Neurological Disorders. 20. Gorson, Natarajan N, Ropper A, Weinstein options. One study of 13 patients with 2008;1(1):33-42. R. Rituximab treatment in patients with inclusion body myositis treated with 4. Cree B. Emerging Monoclonal Antibody IVIg-dependent immune polyneuropathy: alemtuzumab for four days showed a Therapies for Multiple Sclerosis. The Neurolo- A prospective pilot trial. Muscle and Nerve gist. 2006;12:171-178. mean decline in total strength over a 12- 2007;35:66-69. 5. Helliwell C, Coles A. Monoclonal antibodies in 21. Kosmidis M, Dalakas M. Practical consider- month period after treatment of 14.9%. multiple sclerosis treatment: current and future ations on the use of rituximab in autoimmune In the first six months after treatment, steps. Therapeutic Advances in Neurological neurological disorders. Therap Adv Neuro. the decline was only 1.9%, correspond- Disorders. 2009;2(4):195-203. 2010;3(2):93-105. 6. Polman C, O’Connor P, Havrdova E, Hutchin- ing to a 13% differential gain, with four 22. Dalakas M, Rakocevic G, Salajegheh M, Dam- son M, Kappos L, et al. A randomized, brosia J, Hahn A, et al. Placebo-controlled trial patients showing mean strength gain of placebo-controlled trial of natalizumab for of rituximab in IgM anti-myelin-associated gly- 10% when using Quantitative Muscle relapsing multiple sclerosis. N Eng J Med. coprotein antibody demyelinating neuropathy. 2006;354(9):899-910. Ann Neuro. 2009;65(3):286-293. 335 Volume 94 No. 11 No v e m b e r 2011 23. Illa I, Diaz-Manera J, Rojas-Garcia R, Pradas J, Disclosure of Financial Interest Valerie Gendron, MD, is a resident in Rey A, et al. Sustained response to rituximab in Valerie Gendron, MD, and/or spous- Neurology at Rhode Island Hospital. anti-AchR and anti-MuSKpositive myasthenia gravis patients. J Neuroimmun. 2008;201-202- es/significant other have no financial Syed Rizvi, MD, is an Associate Profes- :90-94. interests to disclose. sor of Neurology and Director of the Rhode 24. Levine T. Rituximab in the treatment of Syed A. Rizvi, MD, discloses the Island Hospital Multiple Sclerosis Center. dermatomyositis. Arthritis and Rheumatism. following Consultant/Speakers Bureau/ 2005;52(2):601-607. 25. Dalakas M, Rakocevic G, Schmidt J, Salajegheh Grant Research Support: Teva, Biogen, Co r r e s p o n d e nc e M, McElroy B, et al. Effect of alemtuzamab Serono, , Acorda. Valerie Gendron, MD (CAMPATH-1H) in patients with inclusion- e-mail: [email protected] body myositis. Brain. 2009;132(6):1536- 1544.

336 Medicine & Health/Rhode Island