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Clinical Trial
. 2024 Apr 23:15:1336599.
doi: 10.3389/fimmu.2024.1336599. eCollection 2024.

Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy

Hui-An Chen  1   2   3 , Rai-Hseng Hsu  1   2   3 , Ching-Ya Fang  2 , Ankit K Desai  4 , Ni-Chung Lee  1   2   3 , Wuh-Liang Hwu  1   2   5 , Fuu-Jen Tsai  6 , Priya S Kishnani  4 , Yin-Hsiu Chien  1   2   3
Affiliations
Clinical Trial

Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy

Hui-An Chen et al. Front Immunol. .

Abstract

Introduction: Pompe disease, a lysosomal storage disorder, is characterized by acid α-glucosidase (GAA) deficiency and categorized into two main subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The primary treatment, enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), faces challenges due to immunogenic responses, including the production of anti-drug antibody (ADA), which can diminish therapeutic efficacy. This study aims to assess the effectiveness of immune tolerance induction (ITI) therapy in cross-reactive immunologic material (CRIM)-positive Pompe disease patients with established high ADA levels.

Method: In a single-center, open-label prospective study, we assessed ITI therapy's efficacy in Pompe disease patients, both IOPD and LOPD, with persistently elevated ADA titers (≥1:12,800) and clinical decline. The ITI regimen comprised bortezomib, rituximab, methotrexate, and intravenous immunoglobulin. Biochemical data, biomarkers, ADA titers, immune status, and respiratory and motor function were monitored over six months before and after ITI.

Results: This study enrolled eight patients (5 IOPD and 3 LOPD). After a 6-month ITI course, median ADA titers significantly decreased from 1:12,800 (range 1:12,800-1:51,200) to 1:1,600 (range 1:400-1:12,800), with sustained immune tolerance persisting up to 4.5 years in some cases. Serum CK levels were mostly stable or decreased, stable urinary glucose tetrasaccharide levels were maintained in four patients, and no notable deterioration in respiratory or ambulatory status was noted. Adverse events included two treatable infection episodes and transient symptoms like numbness and diarrhea.

Conclusion: ITI therapy effectively reduces ADA levels in CRIM-positive Pompe disease patients with established high ADA titers, underscoring the importance of ADA monitoring and timely ITI initiation. The findings advocate for personalized immunogenicity risk assessments to enhance clinical outcomes. In some cases, prolonged immune suppression may be necessary, highlighting the need for further studies to optimize ITI strategies for Pompe disease treatment. ClinicalTrials.gov NCT02525172; https://clinicaltrials.gov/study/NCT02525172.

Keywords: Pompe disease; alglucosidase alfa; anti-drug antibody; enzyme replacement therapy; immunomodulation therapy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Classification and ADA development in pompe disease patients ERT. ERT, enzyme replacement therapy; IOPD, infantile-onset Pompe disease; LOPD, late-onset Pompe disease; MTX, methotrexate; ADA, anti-drug antibodies; ITI, immune tolerance induction therapy. This flowchart depicts the categorization and distribution of Pompe patients under enzyme replacement therapy (ERT). The chart distinguishes between classic infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The patients are further categorized based on the initial ERT dosage, methotrexate (MTX) usage, and anti-drug antibody (ADA) titers. “NBS” refers to newborn screening, indicating patients diagnosed via neonatal screening protocols. “Clinical cases” show those diagnosed based on clinical symptoms. The multiplier in parentheses (e.g., 2x) signifies the fold increase in ERT dosage relative to the standard dose. A “Higher (2x)” dosage indicates that the patient received a higher dosage of 40 mg/kg every other week, while “Higher (4x)” indicates that the patient received a weekly dose of 40 mg/kg. The study enrolled eight patients who developed high ADA titers for further analysis.
Figure 2
Figure 2
Trajectory of anti-drug antibody following alglucosidase alfa treatment in pompe disease patients. This figure illustrates the progression of anti-drug antibodies (ADA) titers over time for each patient undergoing enzyme replacement therapy (ERT), with ERT dosages indicated above each graph. The grey area in each panel indicates the period during which immune tolerance induction (ITI) therapy was conducted. For Patient B1, the ERT dosage was increased from the conventional 20 mg/kg every other week (Q2W) to a weekly 20 mg/kg (QW) for five months in the fifth year of ERT, denoted by “†.” Patient B2 received several ERT dosage modifications during the study, denoted by*, with specific dosages detailed in Figure 3 . Patient B3 was initially administered a doubled dose of alglucosidase alfa at 40 mg/kg Q2W, which was later increased to a quadrupled dosage (40 mg/kg QW, indicated by Δ) before returning to the standard dosage after four months.
Figure 3
Figure 3
Biomarker fluctuations in relation to ERT dosage adjustments during ITI for subjects A2 and B2. This figure presents the relationship between serum CK, urinary glucose tetrasaccharide (Glc4), and anti-rhGAA antibody (ADA) titers against the backdrop of enzyme replacement therapy (ERT) dosage adjustments during the immune tolerance induction (ITI) period for subjects A2 (A) and B2 (B). Notable changes in ERT dosages are indicated above each graph, with the timeline post-ITI initiation plotted on the X-axis.
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References

    1. van der Ploeg AT, Reuser AJ. Pompe's disease. Lancet. (2008) 372:1342–53. doi: 10.1016/S0140-6736(08)61555-X - DOI - PubMed
    1. Kishnani PS, Hwu WL, Mandel H, Nicolino M, Yong F, Corzo D, et al. . A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J Pediatr. (2006) 148:671–6. doi: 10.1016/j.jpeds.2005.11.033 - DOI - PubMed
    1. Hagemans ML, Winkel LP, Van Doorn PA, Hop WJ, Loonen MC, Reuser AJ, et al. . Clinical manifestation and natural course of late-onset Pompe's disease in 54 Dutch patients. Brain. (2005) 128:671–7. doi: 10.1093/brain/awh384 - DOI - PubMed
    1. Kishnani PS, Corzo D, Nicolino M, Byrne B, Mandel H, Hwu WL, et al. . Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurol. (2007) 68:99–109. doi: 10.1212/01.wnl.0000251268.41188.04 - DOI - PubMed
    1. Diaz-Manera J, Kishnani PS, Kushlaf H, Ladha S, Mozaffar T, Straub V, et al. . Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial. Lancet Neurol. (2021) 20:1012–26. doi:10.1016/S1474-4422(21)00241-6 - DOI - PubMed

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The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study received funding from Sanofi. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.