The Role of Monoclonal Antibodies in Neurological Disorders Valerie Gendron, MD, and Syed A. Rizvi, MD MO N O C LO N AL A nt IBODY T REA T ME 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 Alemtuzumab natalizumab, or beta-1a plus placebo by Alemtuzumab is a humanized mono- MUL T IPLE SC LEROSIS intravenous infusion every four weeks. clonal antibody directed against CD52, a In multiple sclerosis, autoreactive T Combination therapy with natalizumab cell surface antigen 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 monoclonal antibody for encephalopathy (PML), both of whom subcutaneous interferon 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 integrin, 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 Daclizumab 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 NOVEMBER 2011 surface antigen, which is identical to were randomized to receive placebo or PERIPHERAL NEUROPA T HIES the interleukin-2 receptor, located on rituximab 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- Ocrelizumab, 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 NEUROMYELI T IS OP 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 B cell 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.