B Cell Receptor Recognition Of Glatiramer Acetate Is Required For Efficacy In Experimental Autoimmune Encephalomyelitis And Results In Differential Cytokine Production In MS Patients (P1.210)

Objective: To further elucidate the mechanism of action of Copaxone on B lymphocytes to lay a strong foundation for combination therapy and prediction of optimal responders. Background: Multiple Sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) leading to neuronal demyelination, lack of remyelination, and axonal loss. Although not yet approved, B cell depletion achieved with anti-CD20 monoclonal antibodies is the most effective therapy to-date in MS patients. As this therapeutic depletes immune cells potentially important in pathogen immunity, an immense need remains for highly efficacious therapeutics maintaining a favorable safety profile. Copaxone (Glatiramer Acetate-GA) is one of the safest therapies for MS patients, thus further characterization of its effects on B lymphocytes is warranted. Results and methods: Our studies show that GA binds to human and murine B cell receptors resulting in activation and cytokine production. This interaction is required for efficacy, as B cells from GA treated wild-type but not BCR-HEL tg donors transferred the treatment effect of GA into experimental autoimmune encephalomyelitis recipients. The mechanism of BCR dependent GA induced efficacy occurs through antigen presentation, cytokine production and indirect effects on CD11c+ cells. GA stimulation reduced baseline levels of the pro-inflammatory cytokines IL-6 and TNFα in purified B lymphocytes from treatment naive MS patients, while other cytokines were not consistently altered. Conclusions: This data, in combination with previous reports showing an alteration in the cytokine profiles of GA specific B cells, suggest that the mechanism of action of GA on B lymphocytes includes the presentation of GA to T lymphocytes, cytokine production, and interactions with other immune cells. Taken together, these data provide a strong foundation for future exploration of optimal Copaxone responders or synergistic combination therapies with an improved risk: benefit ratio compared to currently approved therapeutics for MS. This research was supported by a grant from Teva Pharmaceutical Industries, Ltd. Disclosure: Dr. Jackson has received research support from Teva Neuroscience. Dr. Selva has nothing to disclose. Dr. Niedzielko has nothing to disclose. Dr. Vollmer has received personal compensation for activities with Cleveland Clinic, Novartis, Mandell Center for Multiple Sclerosis, Teva Neuroscience, Questcor Pharmaceuticals, Biogen Idec, Xenoport, University of Florida PeerView, and Krog & Partners. Dr. Vollmer has received research support from Biogen Idec, Teva Neuroscience, Genzyme Corp., Ono Pharmaceuticals, Elan Pharmaceuticals, Novartis, Avanir Pharmaceuticals, and Janssen Pharmaceutica.