Enzyme therapy for Fabry disease: Neutralizing antibodies toward agalsidase alpha and beta.

Fabry disease is an X-linked inherited disorder that is caused by excessive lysosomal globotriaosylceramide (CTH) storage due to a deficiency in α-galactosidase A (α-Gal A). Two recombinant enzyme preparations have been approved as treatment modality. We studied emergence and properties of α-Gal A antibodies in treated patients.

During the first 6 to 12 months of intravenous administration of recombinant enzymes (rh-α-Gal A) formation of antibodies was studied in 18 adult Fabry patients (two females).

The female patients did not develop detectable amounts of antibodies following enzyme therapy. After 6 months of treatment with either agalsidase alpha or beta, 11/16 male patients showed high titers of immunoglobulin G (IgG) antibodies that cross-react in vitro similarly with both recombinant enzymes. The anti–rh-α-Gal A IgG neutralizes rh-α-Gal A activity in vitro for 65% to 95%. During infusion with rh-α-Gal A, circulating enzyme-antibody complexes are formed and these complexes are taken up by leukocytes in the peripheral blood. After 6 months of treatment all IgG-negative patients showed a significant (P < 0.01) reduction of urinary CTH (1890 ± 797 to 603 ± 291 nmol CTH/24hr urine), compared to IgG-positive patients (mean increase from 2535 ± 988 to 2723 ± 1212), suggesting a negative effect of circulating antibodies on renal tubular CTH clearance.

Emergence of antibodies with in vivo neutralizing capacities is frequently encountered in treated Fabry disease patients. Complete cross-reactivity of these antibodies suggests that it is unlikely that switching from one to the other recombinant protein prevents the immune response and related effects. Further studies on the clinical implications of α-Gal A antibodies are essential.