T.P.21: Assessing immunogenicity of rhGAA in adult Pompe disease subjects

Abstract

Pompe disease (PD) is an inherited metabolic myopathy caused by a deficiency of the lysosomal enzyme acid <i>α</i>-glucosidase (GAA). Enzyme replacement therapy (ERT) has improved the outcome of PD, unfortunately the immune responses against GAA are not uncommon and in some cases prevent therapeutic efficacy. The aim of this study was to investigate the mechanisms of the immune responses against recombinant human GAA (rhGAA) in adult patients undergoing ERT. About one-third of all subjects screened (<i>n</i>=35) showed significant levels of anti-rhGAA binding antibodies, mainly IgG4. After dendritic cell maturation in the presence of rhGAA a positive IFN-gamma ELISpot signal was detectable in some of the subject's peripheral blood mononuclear cells, indicating GAA-specific T cell reactivity. Interestingly we were able to detect a <i>γ</i>response in PD subject previously untreated with rhGAA, thus naive to the antigen. The in vitro re-stimulation with rhGAA resulted in upregulation of proinflammatory cytokines and chemokines (IL-8, IL-12p70, MIP1<i>β</i>, TNF-<i>α</i> and MCP-1) in PD subjects but not in healthy donors who, conversely, secreted higher levels of IL-10. Similarly, markers of immune activation such as IL-1<i>β</i>, IFN-, GM-CSF, TNF-<i>α</i>, IL-6, and IL-4 were readily detectable in sera isolated from PD subjects undergoing ERT. While additional studies are needed to better define the subsets of B and T cells involved in immune responses to GAA, these study provide a comprehensive overview of activation of immunity in response to ERT in Pompe patients and may provide tools and strategies to monitor and manage immunogenicity of biotherapeutics.