Esther Poelman1, Marianne Hoogeveen-Westerveld2, Marian A Kroos-de Haan2, Johanna M P van den Hout1, Kees J Bronsema3, Nico C van de Merbel3, Ans T van der Ploeg1, W W M Pim Pijnappel4. 1. Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Pediatrics, Division of Metabolic Diseases and Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands. 2. Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands. 3. Bioanalytical Laboratory, PRA Health Sciences, Early Development Services, Assen, The Netherlands; Analytical Biochemistry, Department of Pharmacy, University of Groningen, Groningen, The Netherlands. 4. Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Pediatrics, Division of Metabolic Diseases and Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands. Electronic address: w.pijnappel@erasmusmc.nl.
Abstract
OBJECTIVE: To evaluate whether immunomodulation at start of enzyme replacement therapy induces immune tolerance to recombinant human acid alpha-glucosidase (rhGAA) in patients with classic infantile Pompe disease. STUDY DESIGN: Three patients (1 cross reactive immunologic material negative, 2 cross reactive immunologic material positive) were treated with 4 weekly doses of rituximab, weekly methotrexate, and monthly intravenous immunoglobulin and enzyme replacement therapy at 40 mg/kg/week. Antibody titers were measured using enzyme-linked immunosorbent assay. Neutralizing effects on rhGAA activity and cellular uptake were determined and combined with pharmacokinetic analysis. Clinical efficacy was evaluated by (ventilator-free) survival, reduction in left ventricular mass index, and improvement of motor function. RESULTS: Immunomodulation induced B cell depletion that was accompanied by absence of antibody formation in all 3 patients. Upon cessation of rituximab treatment, all 3 patients showed B cell recovery, which was accompanied by formation of very high sustained antibody titers in 2 patients. Neutralizing effects on infused rhGAA were low to mild/moderate. All patients were alive at study end, learned to walk, and showed (near) normalization of left ventricular mass index. CONCLUSIONS: Immunomodulation as recommended in the literature prevented formation of rhGAA antibodies only during B cell depletion but failed to induce immune tolerance in 2 out of 3 patients.
OBJECTIVE: To evaluate whether immunomodulation at start of enzyme replacement therapy induces immune tolerance to recombinant human acid alpha-glucosidase (rhGAA) in patients with classic infantile Pompe disease. STUDY DESIGN: Three patients (1 cross reactive immunologic material negative, 2 cross reactive immunologic material positive) were treated with 4 weekly doses of rituximab, weekly methotrexate, and monthly intravenous immunoglobulin and enzyme replacement therapy at 40 mg/kg/week. Antibody titers were measured using enzyme-linked immunosorbent assay. Neutralizing effects on rhGAA activity and cellular uptake were determined and combined with pharmacokinetic analysis. Clinical efficacy was evaluated by (ventilator-free) survival, reduction in left ventricular mass index, and improvement of motor function. RESULTS: Immunomodulation induced B cell depletion that was accompanied by absence of antibody formation in all 3 patients. Upon cessation of rituximab treatment, all 3 patients showed B cell recovery, which was accompanied by formation of very high sustained antibody titers in 2 patients. Neutralizing effects on infused rhGAA were low to mild/moderate. All patients were alive at study end, learned to walk, and showed (near) normalization of left ventricular mass index. CONCLUSIONS: Immunomodulation as recommended in the literature prevented formation of rhGAA antibodies only during B cell depletion but failed to induce immune tolerance in 2 out of 3 patients.
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