High antibody titer in an adult with Pompe disease affects treatment with alglucosidase alfa

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Abstract

Clinical trials have demonstrated beneficial effects of enzyme replacement therapy (ERT) with alglucosidase alfa in infants, children and adults with Pompe disease. Recent studies have shown that high antibody titers can occur in patients receiving ERT and counteract the effect of treatment. This particularly occurs in those patients with classic-infantile Pompe disease that do not produce any endogenous acid α-glucosidase (CRIM-negative). It is still unclear to what extent antibody formation affects the outcome of ERT in adults with residual enzyme activity.

We present the case of a patient with adult-onset Pompe disease. He was diagnosed at the age of 39 years by enzymatic testing (10.7% residual activity in fibroblasts) and DNA analysis (genotype: c.-32-13T>G/p.Trp516X). Infusion-associated reactions occurred during ERT and the patient's disease progressed. Concurrently, the antibody titer rose to a similarly high level as reported for some CRIM-negative patients with classic-infantile Pompe disease.

Using newly developed immunologic-assays we could calculate that approximately 40% of the administered alglucosidase alfa was captured by circulating antibodies. Further, we could demonstrate that uptake of alglucosidase alfa by cultured fibroblasts was inhibited by admixture of the patient's serum.

This case demonstrates that also patients with an appreciable amount of properly folded and catalytically active endogenous acid α-glucosidase can develop antibodies against alglucosidase alfa that affect the response to ERT.

Introduction

Pompe disease (glycogen storage disease type II, acid α-glucosidase deficiency, or acid maltase deficiency; OMIM 232300) was the first disease to be identified as a lysosomal storage disorder [1]. Acid α-glucosidase deficiency results in lysosomal accumulation of glycogen in all tissues, most notable in skeletal muscle [2], [3], [4]. Patients with a slowly progressive form of this disease typically present with skeletal muscle weakness in the limb-girdle region and/or respiratory insufficiency. Severely affected infants present as floppy babies due to generalized muscle weakness and have hypertrophic cardiomyopathy from birth on [5], [6].

Enzyme replacement therapy (ERT) has become available for the treatment of six lysosomal storage disorders; Gaucher disease, Fabry disease, MPS I, MPS II, MPS VI and Pompe disease. The registration of alglucosidase alfa (Myozyme®) for the treatment of Pompe disease dates from 2006.

Antibody formation against the administered enzyme is a well-known side effect of ERT [7], [8], [9], [10], [11]. In Gaucher disease about 15% of the patients start to produce antibodies within the first year of ERT while antibody formation is rarely associated with clinical deterioration [7], [8], [12]. In Fabry disease the majority of patients develop antibodies, but alarming effects have not been reported although the lowering of the plasma GL-3 level stalled in some sero-positive patients [9]. The majority of patients with these conditions become tolerant after prolonged treatment.

Compared to Gaucher and Fabry diseases the experience with antibody formation in Pompe disease is modest, but the currently available data indicate that the majority of Pompe patients on ERT develop antibodies against alglucosidase alfa [13], [14], [15]. A recent study clearly shows that infants who lack endogenous enzyme production (CRIM-negative patients) more readily develop high antibody titers than those who are CRIM-positive. Long-term studies (up to 3 years follow-up) suggest that sustained high antibody titers affect treatment outcome [16].

Data on the long term effects of ERT in adults with Pompe disease are still scarce, but the first findings are hopeful in that ERT seems to halt disease progression and results in gain of muscle strength and pulmonary function in the best responders [15], [17], [18], [19], [20], [21], [22]. Thus far, it is unknown whether sustained antibody titers occur in adults with Pompe disease, who are all CRIM-positive, and whether high titers affect the response to treatment.

This case report concerns a 50-year-old male with adult-onset Pompe disease who started to experience infusion-associated reactions (IARs) during ERT with alglucosidase alfa. He had a continuous rise of antibody titer and his disease progressed. The aim of our study was to develop methods for measuring and evaluating the height of the immune response and its effect on treatment outcome.

Section snippets

Patient history

The male patient (patient 1 in this report; see Table 1) presented at the age of 29 years with low back pain and a mild lumbar lordosis. The family history was negative for muscular and neurological diseases. Over the following decade his disease progressed. Bending over and climbing stairs became difficult due to a slowly progressive limb-girdle myopathy. He was diagnosed with Pompe disease at the age of 39 years. At the age of 49 years the patient was referred to our center (Erasmus MC, the

Enzymatic and molecular diagnosis

The baseline characteristics of the patient discussed in this report (patient 1) and three reference cases (patients 2, 3 and 4) are presented in Table 1. Patient 1 had an acid α-glucosidase activity of 9.4 nmol 4 MU/h mg protein in fibroblasts and 2.9 nmol 4 MU/h mg protein in leucocytes. DNA analysis revealed compound heterozygosity for c.-32-13T>G/p.Trp516X (Table 1). c.-32-13T>G is the most common mutation among Caucasians with attenuated forms of Pompe disease and is characterized by the

Discussion

Antibody formation is frequently encountered in patients who regularly receive protein infusions to combat the manifestations of a genetically determined protein deficiency. In Pompe disease, early anecdotal reports have mentioned the finding of high antibody titers in 2 of 3 children receiving the very first formulas of recombinant human acid α-glucosidase produced in CHO cells and suggested a correlation between antibody formation and CRIM status [36]. ‘CRIM-positive’ are the patients who

Acknowledgments

Our special thanks go to the patients who participated in this study and to the research nurses for patient care and blood sample collection. The authors thank Ruud Koppenol and Tom de Vries Lentsch for preparing the photographic artwork. Financial support was obtained from ZonMw—the Netherlands Organization for Health Research and Development [project no. 152001005], from the European Union, 7th Frame Program “EUCLYD—a European Consortium for Lysosomal Storage Diseases” (health F2/2008 grant

References (39)

  • C.I. van Capelle et al.

    Eight years experience with enzyme replacement therapy in two children and one adult with Pompe disease

    Neuromuscul. Disord.

    (2008)
  • O.P. Van Diggelen et al.

    A fluorimetric enzyme assay for the diagnosis of Morquio disease type A (MPS IV A)

    Clin. Chim. Acta

    (1990)
  • A. Amalfitano et al.

    Recombinant human acid alpha-glucosidase enzyme therapy for infantile glycogen storage disease type II: results of a phase I/II clinical trial

    Genet. Med.

    (2001)
  • T. Ohashi et al.

    Reduced alpha-Gal A enzyme activity in Fabry fibroblast cells and Fabry mice tissues induced by serum from antibody positive patients with Fabry disease

    Mol. Genet. Metab.

    (2008)
  • H.G. Hers

    alpha-Glucosidase deficiency in generalized glycogen storage disease (Pompe's disease)

    Biochem. J.

    (1963)
  • R. Hirschhorn et al.

    Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency

  • A.G. Engel et al.
  • H.M. Van den Hout et al.

    The natural course of infantile Pompe's disease: 20 original cases compared with 133 cases from the literature

    Pediatrics

    (2003)
  • P.S. Kishnani et al.

    A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease

    J. Pediatr.

    (2006)
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