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

Fabry disease (FD) is an X-linked systemic lysosomal storage disease caused by mutations in the galactosidase-α (GLA) gene, which encodes the α-galactosidase A (α-AGAL) enzyme. FD can lead to serious complications, including early death, if left untreated. For over 20 years, enzyme replacement therapy (ERT) based on the use of agalsidase-α and agalsidase-β has been the standard treatment for FD, alongside new molecules that have enriched the therapeutic armamentarium and others that are being tested to expand it further. Unfortunately, ERT can be associated with the formation of inhibiting antidrug antibodies (ADAs), which impact ERT clinical efficacy and have consequences affecting safety and therapeutic adherence. A group of FD specialists discussed the problem of immunogenicity in FD, analyzing the most recent literature and the strategies that are currently being used to address it. Once formed, fluctuating levels of ADAs persist and have an impact on the clinical picture and prognosis of the disease that is still the subject of lively scientific debate. The critical nature of ADAs is demonstrated by their ability to bind to the enzyme, increasing drug clearance while forming immune complexes that can build up in the tissues causing chronic inflammation that aggravates the progression of the disease and affects the onset of acute reactions after the infusion, impacting therapeutic adherence. Although similar in their therapeutic mechanism, agalsidase-α and agalsidase-β differ in their production process, with resulting differences from a pharmacokinetic and pharmacodynamic point of view and diverse immunological implications: despite showing rather overlapping efficacy outcomes, agalsidase-α demonstrates a better tolerability profile, with a lower frequency of ADAs, than agalsidase-β. Given the extreme variability of the clinical picture, it is crucial for optimal FD management that the most appropriate molecule is chosen by taking into account the unique immunological risk profile of each single patient, and particular attention should be paid to naïve subjects by periodic measurement of ADAs during therapy and cross-referencing data to correlate serological and clinical patterns.