Gómez-Cerezo Jorge F, Fernández-Martín Julián, Barba-Romero Miguel Ángel, Sánchez-Martínez Rosario, Hermida-Ameijeiras Alvaro, Camprodon-Gómez Maria, Ortolano Saida, Lopez-Rodriguez Mónica A
European University of Madrid Biomedical Research Foundation, Infanta Sofia University Hospital and Henares University Hospital, Madrid, Spain.
Working Group on Rare Diseases of the Spanish Society of Internal Medicine (GTEM-SEMI), Madrid, Spain.
Orphanet J Rare Dis. 2025 May 26;20(1):253. doi: 10.1186/s13023-025-03705-4.
In patients with Fabry disease (FD), treatment with enzyme replacement therapy (ERT), may trigger the formation of anti-drug antibodies (ADAs). The consequences of this immune reaction range from the transient appearance of clinically insignificant ADAs to the generation of neutralizing antibodies that negate the clinical benefit of the biotherapeutic agent, lead to side effects (such as injection site reactions), and even cause severe, life-threatening symptoms. Many factors may influence the immunogenicity of these therapeutic proteins. Currently, there are three commercially available long-term ERT treatments in patients with FD: agalsidase alfa, agalsidase beta, and more recently, pegunigalsidase alfa. Neutralizing ADAs are present in approximately 40% of male FD patients treated with ERT based on agalsidase alfa or agalsidase beta and have shown in vitro cross-reactivity with both agalsidases. Their formation seems to be irreversible, meaning that most patients with positive neutralizing ADAs remain so for up to 10 years after starting treatment. Recent studies show that in some patients, pre-existing ADAs against agalsidase alfa and agalsidase beta have lower affinity and lower inhibitory effects against pegunigalsidase alfa. Additionally, in clinical trials involving naïve patients, neutralizing antibodies were mostly transient, although further studies are needed to confirm these findings in clinical practice. The formation of ADAs is often associated with a worse clinical prognosis and a faster progression of the disease. Given the rapid progression of FD, measuring ADAs titers is essential to provide personalised treatment for each patient. This is why international recommendations highlight the importance of monitoring the existence of ADAs, their neutralising activity, and globotriaosylsphingosine (lyso-Gb3) levels in patients receiving ERT. However, several unresolved issues remain, such as the importance of ADAs levels (particularly neutralising ADAs), the standardisation of assay methods, the interpretation of results, and the implications of these findings for therapeutic strategies. Overcoming the development of ADAs is critical to improving treatment outcomes in patients with FD, different strategies have been explored to address this challenge. The present work aims to review latest developments related to all aspects mentioned above, while also analyzing the potential role of therapeutic innovations.
在法布里病（FD）患者中，采用酶替代疗法（ERT）进行治疗可能会引发抗药抗体（ADA）的形成。这种免疫反应的后果范围广泛，从临床上无显著意义的ADA短暂出现，到产生中和抗体，后者会抵消生物治疗药物的临床益处，导致副作用（如注射部位反应），甚至引发严重的、危及生命的症状。许多因素可能影响这些治疗性蛋白质的免疫原性。目前，有三种可用于FD患者的长期ERT治疗药物：阿加糖酶α、阿加糖酶β，以及最近的聚乙二醇化阿加糖酶α。在接受基于阿加糖酶α或阿加糖酶β的ERT治疗的男性FD患者中，约40%存在中和ADA，并且已显示出在体外与这两种阿加糖酶具有交叉反应性。它们的形成似乎是不可逆的，这意味着大多数中和ADA呈阳性的患者在开始治疗后的长达10年时间里一直保持这种状态。最近的研究表明，在一些患者中，预先存在的针对阿加糖酶α和阿加糖酶β的ADA对聚乙二醇化阿加糖酶α的亲和力较低且抑制作用较弱。此外，在涉及初治患者的临床试验中，中和抗体大多是短暂的，不过还需要进一步研究以在临床实践中证实这些发现。ADA的形成通常与更差的临床预后和疾病更快进展相关。鉴于FD进展迅速，检测ADA滴度对于为每位患者提供个性化治疗至关重要。这就是为什么国际指南强调在接受ERT治疗的患者中监测ADA的存在、其中和活性以及球三糖基鞘氨醇（溶血型Gb3）水平的重要性。然而，仍有几个未解决的问题，例如ADA水平（特别是中和ADA）的重要性、检测方法的标准化、结果的解释以及这些发现对治疗策略的影响。克服ADA的产生对于改善FD患者的治疗结果至关重要，人们已经探索了不同策略来应对这一挑战。本研究旨在综述上述各方面的最新进展，同时分析治疗创新的潜在作用。
