Neutralizing anti-drug antibodies against alpha-galactosidase A (nADA)

Neutralizing anti-drug antibodies (nADAs) against alpha-galactosidase A are immunoglobulins formed by the immune system in response to enzyme replacement therapies (ERTs) such as agalsidase alfa and agalsidase beta, used in the treatment of Fabry disease (Lenders et al., 2018, J Am Soc Nephrol). These antibodies are most commonly observed in male patients with the "classic" phenotype who lack endogenous enzyme expression (CRIM-negative), making the therapeutic protein appear as a foreign antigen (Linthorst et al., 2004, Kidney Int). The nADAs function by binding to the recombinant enzyme, which can either sterically hinder the catalytic site or prevent the enzyme from binding to the mannose-6-phosphate receptors required for cellular uptake into the lysosomes (van der Veen et al., 2019, J Inherit Metab Dis). Consequently, the presence of high-titer nADAs is associated with increased levels of plasma globotriaosylsphingosine (lyso-Gb3) and a loss of clinical efficacy, leading to worsened renal and cardiac outcomes (Lenders et al., 2022, Journal of Medical Genetics). Therapeutic approaches to mitigate the impact of nADAs include immune tolerance induction (ITI) using immunosuppressive agents like methotrexate or rituximab, or the use of pharmacological chaperones like migalastat that may stabilize the enzyme (Parini et al., 2018, Molecular Genetics and Metabolism).

Other names

Anti-agalsidase antibodiesAnti-alpha-galactosidase A antibodiesNeutralizing antibodies to ERTAgalsidase-specific neutralizing antibodiesAnti-drug antibodies (ADA) to agalsidase

Neutralizing antibodies bind to the exogenous alpha-galactosidase A enzyme, inhibiting its catalytic activity or blocking its receptor-mediated endocytosis into lysosomes via the cation-independent mannose-6-phosphate receptor (CI-M6PR). Immunosuppressive drugs used in immune tolerance induction (ITI) protocols target the B-cells and plasma cells responsible for producing these antibodies to restore therapeutic efficacy.