Immune tolerance after long-term enzyme-replacement therapy among patients who have mucopolysaccharidosis I

Background Enzyme-replacement therapy has been assessed as a treatment for patients who have mucopolysaccharidosis I (alpha-L-iduronidase deficiency). We aimed to investigate the humoral immune response to recombinant human alpha-L-iduronidase among these patients. Methods We characterised the antibody titres and specific linear sequence epitope reactivity of serum antibodies to alpha-L-iduronidase for ten patients with mucopolysaccharidosis 1, at the start of treatment and after 6, 12, 26, 52, and 104 weeks. We compared the values for patients' samples with those for samples from normal human controls. Findings Before enzyme-replacement therapy, all patients had low serum antibody titres to recombinant human alpha-L-iduronidase that were within the control range. Five of the ten patients produced higher-than-normal titres of antibody to the replacement protein during the treatment course (serum antibody titres 130 000-500 000 and high-affinity epitope reactivity). However, by week 26, antibody reactivity was reduced, and by week 104 all patients had low antibody titres and only low-affinity epitope reactivity. Patients who had mucopolysaccharidosis I with antibody titres within the normal range at 6-12 weeks did not subsequently develop immune responses. Interpretation After 2 years of treatment, patients who initially had an immune reaction developed immune tolerance to alpha-L-iduronidase. This finding has positive implications for long-term enzyme-replacement therapy in patients who have mucopolysaccharidosis I.