B Cell Receptor Recognition of Glatiramer Acetate is Required for Efficacy through Antigen Presentation and Cytokine Production

Abstract

Multiple Sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS) leading to neuronal demyelination, lack of remyelination, and axonal loss. If left untreated, patients inevitably suffer from severe cognitive, psychological and physical disabilities.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. Even amongst the emergence of new therapeutic options for patients with MS, the myelin basic protein mimetic, Copaxone (glatiramer acetate, GA), remains the most commonly prescribed drug in the United States. As specific B cell depletion appears to be the most effective therapy for MS patients, the goal of this study was to further elucidate the mechanism of action of GA on B lymphocytes. Our studies show that GA directly interacts with human and murine B cell receptors (BCR) inducing the activation of B lymphocytes and BCR recognition of GA is required for efficacy in an animal model of MS. GA loaded B lymphocytes resulted in IL-2 production from CD4 + T cells suggesting B lymphocytes serve as an antigen presentation source for GA. In fifty-percent of the MS patients tested, GA stimulation reduced baseline levels of the pro-inflammatory cytokines IL-6 and TNFα in purified B lymphocytes, while other cytokines were not consistently altered. Taken together, this data suggests that the mechanism of action of GA on B lymphocytes includes the presentation of GA to T lymphocytes in the context of an anti-inflammatory cytokine milieu. The results from this study 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.

Functional effects of the antigen glatiramer acetate are complex and tightly associated with its composition

“…This model system has demonstrated utility as a means to model GA's interaction with lymphocytes (Bakshi et al, 2013;Towfic et al, 2014); and similar studies in a human monocyte cell line have been used to study GA's impact on APCs (Kolitz et al, 2015). Together, these studies represent all three key elements required for GA's activation of "the immunological triad"including lymphocytes, immunogenic epitopes, and APCs (Jackson et al, 2014;Sellebjerg et al, 2013), while also accounting for some of the factors that further modulate therapeutic response in vivo. Utilizing learnings from previous studies of GA in these cell types, a reciprocal-control experimental design was applied in order to further elucidate GA's MoA and to assess the degree to which these mechanisms are sensitive to differences in composition and manufacturing of the therapeutic antigen.…”

“…GA also induces type-II monocytes, which direct differentiation of Th2 and protective Tregs (Kim et al, 2004;Weber et al, 2007), an effect that is independent of antigen specificity; thus cross-reactivity of T cells with myelin antigen is not required for therapeutic benefit (Weber et al, 2007). In addition, GA promotes production of neurotrophic factors such as BDNF by T cells (Arnon and Aharoni, 2004), and induces B-cell activation, which appears necessary for GA response in animal models (Jackson et al, 2014). Data from GAtreated MS patients indicate that GA also modulates CD8 + T cell activity (Karandikar et al, 2002).…”