Abstract
PurposeTo evaluate whether immunomodulation can eliminate high sustained antibody levels, and thereby improve clinical outcome in classic infantile Pompe patients receiving enzyme replacement therapy (ERT) with recombinant human alpha-glucosidase (rhGAA).MethodsThree patients (two cross-reactive immunologic material (CRIM) negative) with high sustained antibodies received a three-week treatment protocol with Rituximab and Bortezomib, followed by daily Rapamycin and monthly IVIG. Patients received 40 mg/kg/week rhGAA. Antibody titers were measured using ELISA. Neutralizing effects on cellular uptake were determined. Clinical efficacy was measured in terms of (ventilator-free) survival, reduction in left ventricular mass index (LVMI) and improvement in motor function.ResultsBefore immunomodulation anti-rhGAA antibody titers ranged from 1:156,250 to 1:781,250 and at last assessment from 1:31,250 to 1:156,250. Neutralizing effects of anti-rhGAA antibody titers (observed in two patients) disappeared. Infusion-associated reactions were no longer present. Immunomodulation resulted in substantial increases of aspartate transaminase, alanine transaminase, and creatine kinase levels. The two CRIM-negative patients who could walk at start of immunomodulation maintained their ability to walk; the patient who had lost this ability did not regain it.ConclusionsTo some extent, the immunomodulation protocol used in our study reduced antibody titers, but it did not eliminate them. Overall, there have been few reports on secondary immunomodulation, and various protocols have been applied. Future research should seek to identify the most successful immunomodulation protocol in patients with high sustained titers.
Highlights
Pompe disease (Glycogen Storage Disease type II, OMIM #232300), an autosomal recessive lysosomal storage disorder caused by deficiency of acid-α-glucosidase (GAA), results in lysosomal glycogen accumulation in all cell types, but mainly in muscle cells [1]
We studied the effects of secondary immunomodulation on anti-Recombinant human alpha-glucosidase (rhGAA) antibody titer formation, the cellular uptake of GAA, the depletion and repopulation of B cells, and clinical outcome using a protocol combining Rituximab, Bortezomib, Rapamycin and Intravenous Immunoglobulin (IVIG)
In patient 1, anti-rhGAA antibodies were first detected at one month of Enzyme replacement therapy (ERT)
Summary
Pompe disease (Glycogen Storage Disease type II, OMIM #232300), an autosomal recessive lysosomal storage disorder caused by deficiency of acid-α-glucosidase (GAA), results in lysosomal glycogen accumulation in all cell types, but mainly in muscle cells [1]. Classic infantile patients have less than 1% of enzyme activity in Enzyme replacement therapy (ERT) with recombinant human alpha-glucosidase (rhGAA, alglucosidase alfa, Myozyme) has improved prognosis for patients by improving survival and improving motor outcome. Cross-reactive immunologic material (CRIM negative) patients (who produce no GAA protein) are more likely to form higher anti-rhGAA antibodies titers than CRIM-positive infantile patients (who produce inactive GAA protein). Despite reports that antibody formation can be prevented successfully by primary immunomodulation (i.e., using a combination of Rituximab (RTX), Methotrexate (MTX) and intravenous immunoglobulin (IVIG) before the first ERT dose) [8, 19,20,21], some patients still develop high anti-rhGAA antibody titers [21,22,23]
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