Immunogenicity in Fabry Disease: Current Issues, Coping Strategies, and Future Directions

Area of Science:

• Genetics and rare diseases
• Immunology
• Pharmacology

Background:

• Fabry disease (FD) is an X-linked lysosomal storage disorder caused by GLA gene mutations, leading to α-galactosidase A deficiency.
• Enzyme replacement therapy (ERT) using agalsidase-α or agalsidase-β is standard, but antidrug antibodies (ADAs) can impede efficacy and safety.
• ADA formation poses challenges to long-term FD management, impacting clinical outcomes and therapeutic adherence.

Purpose of the Study:

• To review the impact of immunogenicity, specifically ADAs, on ERT in Fabry disease.
• To analyze current strategies for managing ADA-related issues in FD patients.
• To compare the immunogenic profiles of agalsidase-α and agalsidase-β.

Main Methods:

• Literature review of recent studies on FD immunogenicity and ERT.
• Analysis of ADA formation, persistence, and clinical impact.
• Comparative assessment of agalsidase-α and agalsidase-β based on production, pharmacokinetics, pharmacodynamics, and immunogenicity.

Main Results:

• ADAs can increase drug clearance, form immune complexes, cause inflammation, and trigger infusion reactions, complicating FD.
• Agalsidase-α exhibits a more favorable tolerability profile with a lower incidence of ADAs compared to agalsidase-β.
• Despite overlapping efficacy, differences in production lead to distinct immunological implications for both ERT agents.

Conclusions:

• Personalized FD treatment requires selecting the appropriate ERT based on individual patient immunologic risk.
• Monitoring ADAs in naive patients and correlating serological data with clinical patterns is crucial for optimal management.
• Addressing immunogenicity is key to improving ERT effectiveness and patient outcomes in Fabry disease.