Glatiramer Acetate Complements Anti-CD20-Mediated B-Cell Depletion in Treatment of CNS Autoimmune Disease (P04.124)

Abstract

Objective: To investigate whether glatiramer acetate (GA) may complement immunomodulatory properties of anti-CD20 in the multiple sclerosis (MS) model experimental autoimmune encephalomyelitis (EAE). Background Recent MS trials demonstrated that therapeutic B-cell depletion reduces formation of central nervous system inflammatory lesions, which may relate to an impaired activation of encephalitogenic T-cells. Experimental evidence indicates however that B-cell depletion is also associated with an enhanced pro-inflammatory differentiation of myeloid APC, indicating that anti-CD20 collaterally depletes subset(s) of B-cells with regulatory properties. We hypothesized that GA treatment, which immunomodulates myeloid APC, may reverse loss of B-cell APC regulation and complement anti-CD20 in treatment of CNS autoimmune disease. Design/Methods: We tested the combination of anti-CD20 and GA in two models; in MOG protein-induced EAE, in which activated B-cells contribute to disease development and in MOG p35-55-induced EAE, a model which does not involve B-cells. Female C57Bl/6 mice were injected weekly with 0.2mg of murine anti-CD20 or isotype starting 3 weeks prior to immunization. Upon EAE onset, mice were randomized to receive 150µg GA/d or PBS alone; representative mice were evaluated for cytokine production (TNF, IL-10) of CD11b + APC. Results: In EAE induced by MOG p35-55, anti-CD20 exacerbated disease severity, which was associated with a pronounced pro-inflammatory cytokine profile of myeloid APC (more TNF, less IL-10). Additive GA treatment reversed EAE exacerbation and restored APC cytokine production to the levels of non-B-cell-depleted mice. In MOG protein-induced EAE, anti-CD20 treatment abrogated development of myelin-specific T-cells and ameliorated disease severity despite a similar pro-inflammatory differentiation of myeloid APC. GA treatment again reversed pro-inflammatory APC differentiation, which, in this model, was associated with synergistic clinical benefit of GA and anti-CD20. Conclusions: Collectively, our findings suggest that GA-treatment counterbalances concomitant loss of B-cell regulation upon pan-B-cell depletion. Additive GA-treatment may be useful to enhance both safety and effectiveness of anti-CD20 in treatment of MS. Disclosure: Dr. Hertzenberg has nothing to disclose. Dr. Lehmann-Horn has nothing to disclose. Dr. LaLive has nothing to disclose. Dr. Bernard has nothing to disclose. Dr. Zamvil has received personal compensation for activities with Biogen Idec, Teva Neuroscience and EMD Serono-Pfizer. Dr. Zamvil has received research support from the National Institutes of Health, National Multiple Sclerosis Society, the Maisin Foundation, the Guthy Jackson Charitable Foundation, Teva Neuroscience, and Boehringer Ingelheim Pharmaceuticals, Inc. Dr. Hemmer has received personal compensation for activities with Hoffmann la Roche, Merck Serono, Biogen Idec, Novartis, Micromet and Bayer Pharmaceuticals Corporation as scientific advisor and speaker. Dr. Hemmer has received research support from Novartis, Bayer Pharmaceuticals Corporation, Biogen Idec, Merck Serono and Teva Neuroscience. Dr. Weber has received personal compensation for activities with Hoffmann-LaRoche, Genentech, Inc., Novartis, Bayer Pharmaceuticals Corporation, Merck Serono, Biogen Idec and Teva Neuroscience as a speaker and/or participant on an advisory board. Dr. Weber has received research support from Teva Neuroscience.