Enzyme therapy and immune response in relation to CRIM status: the Dutch experience in classic infantile Pompe disease

Abstract

BackgroundEnzyme-replacement therapy (ERT) in Pompe disease—an inherited metabolic disorder caused by acid α-glucosidase deficiency and characterized in infants by generalized muscle weakness and cardiomyopathy—can be complicated by immune responses. Infants that do not produce any endogenous acid α-glucosidase, so-called CRIM-negative patients, reportedly develop a strong response. We report the clinical outcome of our Dutch infants in relation to their CRIM status and immune response.MethodsEleven patients were genotyped and their CRIM status was determined. Antibody formation and clinical outcome were assessed for a minimum of 4 years.ResultsERT was commenced between 0.1 and 8.3 months of age, and patients were treated from 0.3 to 13.7 years. All patients developed antibodies. Those with a high antibody titer (above 1:31,250) had a poor response. The antibody titers varied substantially between patients and did not strictly correlate with the patients’ CRIM status. Patients who started ERT beyond 2 months of age tended to develop higher titers than those who started earlier. All three CRIM-negative patients in our study succumbed by the age of 4 years seemingly unrelated to the height of their antibody titer.ConclusionAntibody formation is a common response to ERT in classic infantile Pompe disease and counteracts the effect of treatment. The counteracting effect seems determined by the antibody:enzyme molecular stoichiometry. The immune response may be minimized by early start of ERT and by immune modulation, as proposed by colleagues. The CRIM-negative status itself seems associated with poor outcome.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-014-9707-6) contains supplementary material, which is available to authorized users.

Profile of alglucosidase alfa in the treatment of Pompe disease: safety, efficacy, and patient acceptability

“…These patients are less prone to immune reactions against rhGAA with usually low antibody titer and typically a better clinical outcome. 40 However, high doses of therapeutic rhGAA (20-40 mg/kg once a week to biweekly application) can also trigger an immune reaction against ERT in species with only mild mutation of GAA. 41 Immunomodulatory therapy is a therapeutic approach to reduce the impact of neutralizing antibodies.…”

The role of antibodies in enzyme treatments and therapeutic strategies

“…In addition, the CRIM negative group showed earlier, higher and more sustained antibody responses. Others subsequently revealed similar outcomes, demonstrating the disastrous effect of CRIM-status or IgG antibody-titer [30]; also in CRIM-positive patients higher antibody titers are associated with a reduced clinical response [31]. CRIM status was predicted by mutation-type in the corresponding GAA gene in a cohort of 243 patients [32].…”

Sustained immune tolerance induction in enzyme replacement therapy–treated CRIM-negative patients with infantile Pompe disease

“…CRIM-negative cases from across the globe have demonstrated their susceptibility to the development of high rhGAA IgG titers (2,7,32,33). However, unlike other prognostic factors, such as degree of existing damage at baseline, underlying genotype, differences in skeletal muscle fiber-type distribution, ACE and ACTN3 genotyping, and defective autophagy, immunogenicity is an avertable complication (34).…”

“…A role for omalizumab in preventing the development of an IgG response cannot be excluded in this case. Therefore, we believe that CRIM-negative ERT monotherapy cases who did not develop HSAT represent a smaller subset compared with CRIM-negative cases reported from across the globe with higher susceptibility to the development of high rhGAA IgG titers (2,7,32,33). Currently, there is no way to predict CRIM-negative cases who would not develop HSAT/SIT, and this can be a confounding factor while interpreting the efficacy of this ITI protocol.…”

“…Antibodies that develop against a therapeutic protein may alter its pharmacokinetic profile, diminish its pharmacodynamics, and compromise clinical benefits (1)(2)(3)(4)(5)(6). Pompe disease (OMIM # 232300, glycogen storage disease II) is an autosomal recessive lysosomal storage disorder treated via enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA, alglucosidase alfa), a treatment that has faced significant challenges posed by its immunogenicity in this patient population (2,7). Variants in the GAA gene lead to deficiency of acid α-glucosidase (GAA, α-1, 4-glucosidase), resulting in progressive accumulation of lysosomal glycogen, particularly in skeletal, cardiac, and smooth muscle tissues.…”