ENOrphanet Journal of Rare Diseases | Impact of Anti-Drug Antibodies on the Efficacy and Safety of Enzyme Replacement Therapy in Fabry Disease
日期: August 28, 2026
分类: Frontiers
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This study systematically evaluates the clinical significance of anti-drug antibodies (ADA) in patients with Fabry disease, providing critical evidence for designing more precise treatment strategies and immunogenicity monitoring protocols for Fabry disease.
Literature Overview
The article titled 'Evaluating the relationship between antidrug antibodies and efficacy and safety outcomes in patients with Fabry disease receiving enzyme replacement therapy: a systematic literature review,' published in Orphanet Journal of Rare Diseases, systematically investigates the association between anti-drug antibody (ADA) status and treatment outcomes in terms of efficacy and safety among Fabry disease patients undergoing enzyme replacement therapy (ERT). By conducting a systematic literature review (SLR), the study integrates existing evidence to clarify the impact of ADA on disease-related biomarkers, renal function, cardiovascular outcomes, and infusion-related reactions, while also highlighting limitations in current evidence and suggesting directions for future research.Background Knowledge
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to deficient α-galactosidase A (α-Gal A) enzyme activity. This deficiency results in the accumulation of globotriaosylceramide (Gb3) and its deacylated form, lyso-Gb3, across multiple organ systems, ultimately causing severe complications such as renal failure, heart failure, and stroke. The current standard of care is enzyme replacement therapy (ERT), including agalsidase alfa, agalsidase beta, and the newer pegunigalsidase alfa. However, ERT may induce the development of anti-drug antibodies (ADA), particularly neutralizing antibodies (NAbs), which can inhibit enzyme activity or accelerate drug clearance, thereby affecting both efficacy and safety. Although some studies suggest associations between ADA and elevated biomarkers or infusion reactions, causality remains unclear, partly due to inconsistent ADA detection methods, variable follow-up durations, and patient heterogeneity at baseline. Additionally, male patients, especially those with the classical phenotype, are more prone to develop ADA, particularly in association with nonsense or frameshift mutations. This study aims to systematically synthesize existing clinical data to evaluate the real-world impact of ADA status on long-term treatment outcomes, addressing the statistical limitations of individual studies and providing a framework for future prospective research.
Research Methods and Core Experiments
The research team followed PRISMA guidelines to systematically search MEDLINE, Embase, Cochrane Library, and clinical trial registries for clinical studies published up to March 4, 2025, that reported on ADA status in relation to ERT efficacy and safety outcomes. Eligible studies included randomized controlled trials, single-arm studies, observational studies, case series, and registry analyses, provided that data were stratified by ADA status. A total of 24 studies were included in the analysis, covering disease-related biomarkers (e.g., lyso-Gb3, Gb3), renal function (eGFR), cardiovascular outcomes, and adverse events (AEs) or infusion-related reactions (IRRs). Due to significant heterogeneity across studies (e.g., ERT type, ADA detection methods, follow-up duration), meta-analysis was not feasible, and thus a descriptive and narrative synthesis approach was adopted. ADA status was defined in various ways, including IgG antibodies (ERT-IgG), neutralizing activity (ERTi), or combinations thereof, with some studies distinguishing between baseline ADA positivity and treatment-emergent ADA. Data analysis focused on statistically significant associations (p ≤ 0.05) between ADA positivity and clinical outcomes.Key Findings and Insights
Research Implications and Outlook
The study underscores the potential negative regulatory role of ADA in Fabry disease treatment, particularly in biomarker control and infusion tolerance. From a research perspective, future studies should adopt standardized ADA detection methods, differentiate between neutralizing and non-neutralizing antibodies, and perform multivariate analyses incorporating patient genotype, phenotype, and baseline disease severity. From a drug development standpoint, next-generation ERTs (e.g., pegunigalsidase alfa) should be designed to minimize immunogenicity risks. In clinical monitoring, regular ADA testing may help identify high-risk patients, enabling personalized infusion regimens or combined immunomodulatory strategies. Furthermore, animal models (e.g., GLA knockout mouse) could be used to simulate ADA formation and validate its impact on organ pathology.
Conclusion
This systematic literature review reveals that the presence of anti-drug antibodies (ADA) may reduce the efficacy of enzyme replacement therapy in patients with Fabry disease and increase the risk of infusion-related reactions. Despite heterogeneity in the existing evidence, most studies consistently show that ADA positivity is associated with elevated levels of biomarkers such as lyso-Gb3 and increased rates of IRRs. This suggests that clinical practice should enhance ADA monitoring, especially in male patients with the classical phenotype. Future prospective, multicenter studies are needed to standardize ADA detection methods and further investigate ADA subtypes (e.g., IgG4 vs. IgG1), dynamic titer changes, and their associations with hard endpoints such as end-stage renal disease and cardiovascular events. From a translational medicine perspective, this study lays the foundation for optimizing individualized treatment strategies—by identifying patients at high immunogenic risk early, preventive measures (e.g., immune adsorption or combined immunosuppression) can be implemented to improve long-term outcomes. Moreover, emerging strategies such as gene therapy or mRNA-based therapies may circumvent the ADA issue and represent promising future directions. In summary, ADA is not merely a pharmacodynamic interfering factor but should be recognized as an actionable node in Fabry disease management, and its monitoring is expected to become an integral part of future care systems.
