Therapeutic challenges in two adolescent male patients with Fabry disease and high antibody titres

Mhanni, Aizeddin A.; Auray‐Blais, Christiane; Boutin, Michel; Johnston, Alie; LeMoine, Kaye; Patterson, Jill; Aerts, Johannes M. F. G.; West, Michael; Rockman‐Greenberg, Cheryl

doi:10.1016/j.ymgmr.2020.100618

Cited by 4 publications

(3 citation statements)

References 37 publications

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“…It is well known that classic Fabry patients, especially those who harbor nonsense mutations, frequently develop antibodies against recombinant α-Gal A proteins, and the formation of neutralizing antibodies adversely affects the efficacy of ERT (26)(27)(28)(29). Recently, Mhanni et al reported that two Fabry men developed very high antibody titers during ERT (30). The levels of plasma and urine Lyso-Gb3 and its analogs, and urine Gb3 levels remained extremely high.…”

Section: Discussionmentioning

confidence: 99%

Profiles of Globotriaosylsphingosine Analogs and Globotriaosylceramide Isoforms Accumulated in Body Fluids from Various Phenotypic Fabry Patients

Shiga,

Tsukimura,

Kubota

et al. 2024

Intern. Med.

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Objectives Fabry disease is characterized by the systemic accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3), which are widely used as biomarkers of the disease. However, few reports have described the relationship of Lyso-Gb3 analogs and Gb3 isoforms with the disease. The present study determined the profiles of Lyso-Gb3 analogs and Gb3 isoforms accumulated in body fluids from various phenotypic Fabry patients to elucidate the basis of the disease. Methods Plasma Lyso-Gb3 and related analogs were measured in 15 classic Fabry men, 6 later-onset Fabry men, 11 Fabry women, and 36 controls, while urinary Gb3 isoforms were measured in 5 classic Fabry men, 5 later-onset Fabry men, 17 Fabry women, and 11 controls, using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Furthermore, these values were monitored for a classic Fabry man, in whom neutralizing anti-drug antibodies had developed following enzyme replacement therapy (ERT). ResultsThe levels of plasma Lyso-Gb3 analogs/urinary Gb3 isoforms were higher in Fabry patients than in controls, especially in classic Fabry men. However, minor differences in the ratio of each Lyso-Gb3 analog and Gb3 isoform with respect to the total Lyso-Gb3 analogs and Gb3 isoforms, respectively, were observed among individual classic Fabry men. Their time courses were well associated with the development and attenuation of anti-drug antibodies in a patient with classic Fabry disease during ERT. Conclusion Quantification of Lyso-Gb3 analogs and Gb3 isoforms provides us with more detailed information about the substrates that accumulated in the body fluids of Fabry patients than does quantification of Lyso-Gb3 and Gb3 alone, so this approach may be useful for elucidating the basis of Fabry disease.

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Section: Discussionmentioning

confidence: 99%

Profiles of Globotriaosylsphingosine Analogs and Globotriaosylceramide Isoforms Accumulated in Body Fluids from Various Phenotypic Fabry Patients

Shiga,

Tsukimura,

Kubota

et al. 2024

Intern. Med.

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show abstract

“…To better differentiate the impact, the study populations being compared should have a comparable disease burden before therapy initiation and comparable types of mutations. However, recent case studies confirmed the deleterious effects of ADAs by showing massive Gb3 accumulation in various tissues in an affected male patient even after 6 years of ERT [52] and increasing lyso-Gb3 levels and lack of improvement in symptoms such as abdominal pain and acroparesthesias in two men after 3 years of ERT with high antibody titers [53].…”

Section: Clinical Impact Of Neutralizing Anti-drug Antibodies (Adas)mentioning

confidence: 98%

Mechanisms of Neutralizing Anti-drug Antibody Formation and Clinical Relevance on Therapeutic Efficacy of Enzyme Replacement Therapies in Fabry Disease

Lenders

Brand

2021

Drugs

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“…Mhanni et al [ 13 ] and Hongo et al [ 14 ] reported lack of ERT efficacy due to HSAT in Fabry patients who had markedly increased levels of globotriaosylsphingosine (Lyso-Gb3), which is a specific biomarker commonly used to monitor ERT response even under ERT. It was also suggested that HSAT in IOPD at or below 1:6250 likely did not hold clinical significance.…”

Section: The Mechanism Of the Immune Response To Enzyme Replacement T...mentioning

confidence: 99%

Advances in Immune Tolerance Induction in Enzyme Replacement Therapy

İnci,

Ezgü,

Tümer

2024

Pediatr Drugs

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Inborn errors of metabolism (IEMs) are a group of genetic diseases that occur due to the either deficiency of an enzyme involved in a metabolic/biochemical pathway or other disturbances in the metabolic pathway including transport protein or activator protein deficiencies, cofactor deficiencies, organelle biogenesis, maturation or trafficking problems. These disorders are collectively significant due to their substantial impact on both the well-being and survival of affected individuals. In the quest for effective treatments, enzyme replacement therapy (ERT) has emerged as a viable strategy for patients with many of the lysosomal storage disorders (LSD) and enzyme substitution therapy in the rare form of the other inborn errors of metabolism including phenylketonuria and hypophosphatasia. However, a major challenge associated with enzyme infusion in patients with these disorders, mainly LSD, is the development of high antibody titres. Strategies focusing on immunomodulation have shown promise in inducing immune tolerance to ERT, leading to improved overall survival rates. The implementation of immunomodulation concurrent with ERT administration has also resulted in a decreased occurrence of IgG antibody development compared with cases treated solely with ERT. By incorporating the knowledge gained from current approaches and analysing the outcomes of immune tolerance induction (ITI) modalities from clinical and preclinical trials have demonstrated significant improvement in the efficacy of ERT. In this comprehensive review, the progress in ITI modalities is assessed, drawing insights from both clinical and preclinical trials. The focus is on evaluating the advancements in ITI within the context of IEM, specifically addressing LSDs managed through ERT.

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Therapeutic challenges in two adolescent male patients with Fabry disease and high antibody titres

Cited by 4 publications

References 37 publications

Profiles of Globotriaosylsphingosine Analogs and Globotriaosylceramide Isoforms Accumulated in Body Fluids from Various Phenotypic Fabry Patients

Profiles of Globotriaosylsphingosine Analogs and Globotriaosylceramide Isoforms Accumulated in Body Fluids from Various Phenotypic Fabry Patients

Mechanisms of Neutralizing Anti-drug Antibody Formation and Clinical Relevance on Therapeutic Efficacy of Enzyme Replacement Therapies in Fabry Disease

Advances in Immune Tolerance Induction in Enzyme Replacement Therapy

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