Immunophenotype Associated with High Sustained Antibody Titers Against Enzyme Replacement Therapy in Infantile-onset Pompe Disease

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2024 Jan 22

PMID 38250073

Authors

Ankit K Desai

P Brian Smith

John S Yi

Amy S Rosenberg

Trevor D Burt

Priya S Kishnani

Affiliations

Soon will be listed here.

Abstract

Introduction: The efficacy of enzyme replacement therapy (ERT) with alglucosidase alfa for infantile-onset Pompe disease (IOPD) is limited in some patients due to the development of high and sustained antibody titers (HSAT; ≥12,800).

Methods: We carried out detailed immunophenotyping of IOPD patients (n=40), including analysis of circulating cell populations by flow cytometry and plasma cytokines by multiplex array, to determine whether patients with HSAT have unique immunological characteristics compared to those with low titers (LT; <12,800).

Results: Compared to patients with LT, patients who develop HSAT were skewed toward a type 2 immune profile, with an increased frequency of Th2 cells that was positively correlated with levels of Th2 (IL-4, IL-5, IL-13) and pro-inflammatory (IL-6, TNF-α, MIP-1α, MIP-1β) cytokines. B cells were increased in HSAT patients with a decreased fraction of unswitched memory B cells. Plasma GM-CSF concentrations were lower on average in HSAT patients, while CXCL11 was elevated. Finally, using principal components analysis, we derived an HSAT Signature Score that successfully stratified patients according to their antibody titers.

Discussion: The immune profiles revealed in this study not only identify potential biomarkers of patients that developed HSAT but also provide insights into the pathophysiology of HSAT that will ultimately lead to improved immunotherapy strategies.

Citing Articles

Advances in Pompe Disease Treatment: From Enzyme Replacement to Gene Therapy.

Colella P Mol Diagn Ther. 2024; 28(6):703-719.

PMID: 39134822 DOI: 10.1007/s40291-024-00733-x.

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

Chen H, Hsu R, Fang C, Desai A, Lee N, Hwu W Front Immunol. 2024; 15:1336599.

PMID: 38715621 PMC: 11074348. DOI: 10.3389/fimmu.2024.1336599.

An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation.

Desai A, Shrivastava G, Grant C, Wang R, Burt T, Kishnani P Front Immunol. 2024; 15:1360369.

PMID: 38524130 PMC: 10959098. DOI: 10.3389/fimmu.2024.1360369.

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