Abstract
Immunogenicity of recombinant human acid-alpha glucosidase (rhGAA) in enzyme replacement therapy (ERT) is a safety and efficacy concern in the management of late-onset Pompe disease (LOPD). However, long-term effects of ERT on humoral and cellular responses to rhGAA are still poorly understood. To better understand the impact of immunogenicity of rhGAA on the efficacy of ERT, clinical data and blood samples from LOPD patients undergoing ERT for >4 years (n = 28) or untreated (n = 10) were collected and analyzed. In treated LOPD patients, anti-rhGAA antibodies peaked within the first 1000 days of ERT, while long-term exposure to rhGAA resulted in clearance of antibodies with residual production of non-neutralizing IgG. Analysis of T cell responses to rhGAA showed detectable T cell reactivity only after in vitro restimulation. Upregulation of several cytokines and chemokines was detectable in both treated and untreated LOPD subjects, while IL2 secretion was detectable only in subjects who received ERT. These results indicate that long-term ERT in LOPD patients results in a decrease in antibody titers and residual production of non-inhibitory IgGs. Immune responses to GAA following long-term ERT do not seem to affect efficacy of ERT and are consistent with an immunomodulatory effect possibly mediated by regulatory T cells.
Highlights
One important common side effect of enzyme replacement therapy (ERT) for Pompe disease is the induction of antibody responses against the infused protein, a phenomenon frequent in infantile patients who are cross-reactive immunological material (CRIM)-negative[4,12], that is associated with lack of efficacy and poor prognosis[13,14]
Statistical analysis of data, performed by comparison of titers measured during the first days of ERT (108 measurements) with those collected between and 1,000 days (82 measurements), between 1,001 and 1,500 days (64 measurements), and between 1,500 and 2,000 days of ERT (46 measurements), confirmed that the changes in antibody titers were significant (Fig. 1B). These results indicate that long-term ERT in late onset Pompe disease (LOPD) subjects is associated with a decrease of anti-recombinant human GAA (rhGAA) antibodies
Several factors contribute to shape the immune responses to an antigen, including the genetic background of the host[4,35], the immunogenicity of the therapeutic protein[36], polymorphisms in genes regulating immune responses[37], and presence of contaminants in the drug substance that can exert an adjuvant effect on immune responses[36]
Summary
One important common side effect of ERT for Pompe disease is the induction of antibody responses against the infused protein, a phenomenon frequent in infantile patients who are cross-reactive immunological material (CRIM)-negative[4,12], that is associated with lack of efficacy and poor prognosis[13,14]. Despite being CRIM positive, anti-rhGAA antibodies in response to ERT are found in LOPD patients, their role is unclear when it comes to the clinical response to enzyme supplementation[15]. In addition to neutralizing antibody responses, life-threatening allergic reactions associated with the production of immunoglobulin (Ig) E specific to the enzyme have been reported to occur following the infusion of rhGAA16. We characterized the immune responses to rhGAA in a large cohort of LOPD subjects either receiving long-term ERT or untreated. IgG subclass characterization shows production of non-inhibitory antibodies with no evident effect on enzyme activity or uptake, while rhGAA-specific T cell activation profile is consistent with immune modulation, possibly mediated by regulatory T cells
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