Enzyme therapy in Gaucher disease type 1: Effect of neutralizing antibodies to acid β-glucosidase

Abstract

Gaucher disease type 1, a non-neuronopathic lysosomal storage disease, is caused by mutations at the acid β-glucosidase locus. Periodic infusions of macrophage-targeted acid β-glucosidase reverse hepatosplenomegaly, hematologic, and bony findings in many patients. Two patients receiving enzyme therapy developed neutralizing antibodies to acid β-glucosidase that were associated with a lack of improvement or progressive disease. After initial improvement, case 1 had no additional response to 2 years of high- dose (50 U/kg every 2 weeks) enzyme therapy. Similarly, case 2 initially showed a favorable response to enzyme therapy that plateaued after 1 year of treatment. Both patients developed minor allergic reactions and antibodies to acid β-glucosidase within the first 6 months of treatment. Enzyme therapy was discontinued in case 1, with resultant disease progression end need for splenectomy. An immunosuppression/tolerization protocol was initiated in case 2 because of disease progression and stable neutralizing antibody titers. The IgG neutralizing antibodies rapidly and completely inactivated the wild- type, but not the N370S, acid β-glucosidase in vitro. Antibodies to human serum albumin and chorionic gonadotropin also developed. The finding of neutralizing antibodies to acid β-glucosidase during enzyme therapy for Gaucher disease has significant implications for monitoring the therapeutic responses and for potential alternative future therapies for Gaucher disease.