Blocking LINGO-1 Does Not Affect Inflammatory Markers in the Cerebrospinal Fluid of Individuals with Multiple Sclerosis (P1.186)

OBJECTIVE: To evaluate whether blocking LINGO-1 in individuals with MS is accompanied by changes in intrathecal inflammatory signals. BACKGROUND: LINGO-1 (leucine-rich repeats and immunoglobulin [Ig] domain-containing neurite outgrowth inhibitor receptor-interacting protein-1) is a component of CNS signaling complexes that suppress remyelination. Preclinical studies in the rodent experimental autoimmune encephalomyelitis model of MS show that blocking LINGO-1 improves remyelination in spinal cord axons with no concomitant effect on inflammation. BIIB033, a fully humanized monoclonal antibody, has been developed and tested in a phase I trial and affords the first view of the impact of LINGO-1 blockade in humans. METHODS: Twenty participants with RRMS (n=15) and SPMS (n=5) enrolled in the Phase 1, multiple, ascending-dose study of BIIB033 were randomized to receive 30, 60 and 100 mg/kg or placebo on days 0 and 14. Lumbar punctures were performed before dosing and repeated 2 weeks after the final dose of BIIB033. RNA was isolated from pelleted CSF cells and transcripts were analyzed by global microarray (Affymetrix) and quantitative polymerase chain reaction (qPCR). For qPCR, a custom panel was developed to evaluate transcripts representative of specific cell types and soluble proteins of the immune system, including Immunoglobulin isotypes, cytokines and chemokines. RESULTS: We did not observe any consistent changes in mRNA transcripts in the CSF cell pellet indicative of immune cell types or soluble effectors in response to BIIB033 administration. CONCLUSIONS: After treatment with BIIB033, a monoclonal antibody to LINGO-1, there were no significant changes in inflammatory markers in the CSF of study participants with RRMS and SPMS. This is similar to what has been observed in preclinical models of MS with LINGO-1 blockade. Study Supported by: Biogen Idec Disclosure: Dr. Ranger has received personal compensation for activities with Biogen Idec. Dr. Ranger holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Ranger was involved as an investigator. Dr. Ray has received personal compensation for activities with Biogen Idec. Dr. Ray holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Ray was involved as an investigator. Dr. Szak has received personal compensation for activities with Biogen Idec as an employee. Dr. Szak holds stock and/or stock options in Biogen Idec stock, which sponsored research in which Dr. Szak was involved as an investigator. Dr. Dearth has received personal compensation for activities with Biogen Idec as an employee. Dr. Dearth holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Dearth was involved as an investigator. Dr. Allaire has received personal compensation for activities with Biogen Idec as an employee. Dr. Allaire holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Allaire was involved as an investigator. Dr Allaire holds stock and/or stock options in Biogen Idec. Dr. Cadavid has received personal compensation for activities with Biogen Idec. Dr. Cadavid holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Cadavid was involved as an investigator. Dr. Cadavid hodls stock and/or stock options in Biogen Idec.