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

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. The aim of this study was to investigate the effects of ADAs on the bioavailability of rhGAA in classic infantile Pompe disease. 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 ( C max ) and area under the curve (AUC) were calculated by non-compartmental analysis. 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 C max 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 C max ( R = − 0.64), but not AUC. Immunomodulation eliminated the effects of ADAs, as shown in two patients. 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.