The Effect of Anti-drug Antibodies on the Bioavailability of Alglucosidase Alfa in Classic Infantile Pompe Disease

Background: The impact of anti‑drug antibodies (ADAs) on the bioavailability of recombinant human acid α-glucosidase (rhGAA) in classic infantile Pompe disease remains incompletely understood. Objective: The aim of this study was to investigate the effects of ADAs on the bioavailability of rhGAA in classic infantile Pompe disease. Methods: We analyzed 15 pharmacokinetic (PK) curves from 13 patients receiving rhGAA. High titers were defined as ≥ 1:31250. Alpha-glucosidase activity in plasma was measured using protein A beads to precipitate ADA-bound rhGAA, and sepharose as control. Neutralizing effects were assessed in fibroblasts and culture medium after incubation with patient sera and a fixed amount of rhGAA. Peak activity (Cmax) and area under the curve (AUC) were calculated by non-compartmental analysis. Results: rhGAA bioavailability was affected in six of nine high-titer patients (n = 1, 1:31,250; n = 5, ≥ 1:156,250). AUC was reduced by 11–52% in the protein A assay compared with sepharose (n = 5). Fibroblast uptake studies demonstrated neutralizing effects with intracellular enzyme activity reduced to 47–71% (n = 5). No ADA effect was detectable in three patients. At the group level, high-ADA patients showed significantly lower Cmax in both assays and a lower AUC in the protein A assay compared with non-high-ADA patients. Slower infusion schemes, as management for infusion-associated reactions, correlated inversely with Cmax (R = − 0.64), but not AUC. Immunomodulation eliminated the effects of ADAs, as shown in two patients. Conclusions: High ADAs have heterogenous effects on rhGAA bioavailability. Titers ≥1:156,250, mostly, had a measurable effect, capturing up to > 50% of infused rhGAA. A high titer, per se, did not imply neutralizing effects. Where available, functional assays, including PK curves and uptake studies, may contribute to characterize ADA effects.