A retrospective analysis of the potential impact of IgG antibodies to agalsidase β on efficacy during enzyme replacement therapy for Fabry disease

Bénichou, Bernard; Goyal, Sunita; Sung, Crystal; Norfleet, Andrea M.; O’Brien, Fanny

doi:10.1016/j.ymgme.2008.10.004

Cited by 92 publications

(93 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We envision the ␣-NAGAL EL molecule would have little immunogenicity in Fabry disease patients (who make typical amounts ␣-NAGAL glycoprotein and are thus immunologically tolerant toward ␣-NAGAL). Consistent with this, heterozygous female Fabry disease patients (with one wild-type copy of the GLA gene) do not make the comparable immune responses as their hemizygous male counterparts against injected enzyme during enzyme replacement therapy (24,25).…”

Section: Discussionmentioning

confidence: 87%

Interconversion of the Specificities of Human Lysosomal Enzymes Associated with Fabry and Schindler Diseases

Tomašić

Metcalf

Guce

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

The human lysosomal enzymes ␣-galactosidase (␣-GAL, EC 3.2.1.22) and ␣-N-acetylgalactosaminidase (␣-NAGAL, EC 3.2.1.49) share 46% amino acid sequence identity and have similar folds. The active sites of the two enzymes share 11 of 13 amino acids, differing only where they interact with the 2-position of the substrates. Using a rational protein engineering approach, we interconverted the enzymatic specificity of ␣-GAL and ␣-NAGAL. The engineered ␣-GAL (which we call ␣-GAL SA ) retains the antigenicity of ␣-GAL but has acquired the enzymatic specificity of ␣-NAGAL. Conversely, the engineered ␣-NAGAL (which we call ␣-NAGAL EL ) retains the antigenicity of ␣-NAGAL but has acquired the enzymatic specificity of the ␣-GAL enzyme. Comparison of the crystal structures of the designed enzyme ␣-GAL SA to the wild-type enzymes shows that active sites of ␣-GAL SA and ␣-NAGAL superimpose well, indicating success of the rational design. The designed enzymes might be useful as non-immunogenic alternatives in enzyme replacement therapy for treatment of lysosomal storage disorders such as Fabry disease.

show abstract

Section: Discussionmentioning

confidence: 87%

Interconversion of the Specificities of Human Lysosomal Enzymes Associated with Fabry and Schindler Diseases

Tomašić

Metcalf

Guce

et al. 2010

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…At baseline and every 6 weeks, serum titers of IgG antibodies to agalsidase beta were determined. 11,17 Patients were considered seropositive when a positive signal on enzyme-linked immunosorbent assay was confirmed by radioimmunoprecipitation. Antibody titers were reported as the inverse of the highest serum dilution that yielded a positive enzyme-linked immunosorbent assay signal.…”

Section: Safety Assessmentsmentioning

confidence: 99%

Evaluation of a low dose, after a standard therapeutic dose, of agalsidase beta during enzyme replacement therapy in patients with Fabry disease

Lubanda

Anijalg

Bzdúch

et al. 2009

Genetics in Medicine

Self Cite

View full text Add to dashboard Cite

Purpose: Fabry disease, a genetic deficiency of ␣-galactosidase A, is characterized by pathogenic cellular accumulation of globotriaosylceramide. During clinical trials, recombinant human ␣-galactosidase A (agalsidase beta; Fabrazyme®, Genzyme Corporation, Cambridge, MA), infused intravenously at 1.0 mg/kg every 2 weeks for 6 months, cleared or reduced globotriaosylceramide in renal, cardiac, and dermal microvascular endothelia and other cells, with results sustained for up to 5 years in most patients evaluated. This study explored whether a lower dose could maintain globotriaosylceramide clearance achieved with 1.0 mg/kg. Methods: Cellular globotriaosylceramide levels were assessed histologically in kidney and skin biopsies from 21 adult Fabry males treated for 6 months at 1.0 mg/kg/2 weeks followed by 18 months at 0.3 mg/kg/2 weeks. Results: In kidney interstitial capillary endothelium, the primary endpoint, globotriaosylceramide clearance was achieved in 100% of patients with 1.0 mg/kg and maintained in 90% with 0.3 mg/kg. In seven other renal cell types and superficial dermal capillary endothelium, globotriaosylceramide reduction or clearance was maintained with 0.3 mg/kg in ϳ70% of patients. Conclusions: A lower dose of agalsidase beta may be sufficient in some, but not all, patients with Fabry disease to maintain the cellular globotriaosylceramide clearance achieved with 1.0 mg/kg/2 weeks. Long-term clinical effects of transitioning to the lower dose have not been evaluated. Genet Med 2009:11(4):256 -264.

show abstract

“…2,3 Recent studies suggested that infusion of recombinant enzyme may lead to formation of antibodies, resulting in short-term acute complications, 2 as well as deleterious long-term effects by therapy inhibition, resulting in severely decreased Gb3 and lyso-Gb3 depletion. [4][5][6][7] Reduced lyso-Gb3 clearance, as a marker of disease progression, may be accompanied by a deterioration of clinical manifestations and symptoms in affected patients. Until now, only indirect associations between ERT inhibition and end-organ manifestations have been shown, in that elevated lyso-Gb3 levels of inhibition-positive patients were associated with left ventricular mass (LV mass ) and the formation of whitematter lesions.…”

mentioning

confidence: 99%

Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

Lenders

Stypmann

Duning

et al. 2016

Journal of the American Society of Nephrology

106

113

View full text Add to dashboard Cite

Fabry disease (FD) is a progressive multisystemic disorder, treatable with recombinant enzyme replacement therapy (agalsidase). However, recent studies suggest an endogenous inhibition of agalsidase in patients with FD, as reported for other lysosomal storage diseases. To assess the clinical consequences of serum-mediated agalsidase inhibition in affected patients, we determined the agalsidase inhibition status of 168 patients (68 male) with FD and compared outcomes of inhibition-positive patients with those of inhibition-negative patients. The assessment included clinical events during time on agalsidase, determination of renal and cardiac function, and evaluation of FD-related symptoms. The frequency of serum-mediated agalsidase inhibition was 40% in agalsidase-treated males. Inhibition did not depend on the compound initially used (agalsidase-a or -b). Agalsidase inhibition was associated with higher lysoglobotriaosylceramide levels and worse disease severity scores in patients. Compared with agalsidase inhibition-negative men, agalsidase inhibition-positive men showed greater left ventricular mass (P=0.02) and substantially lower renal function (difference in eGFR of about -30 ml/min per 1.73 m 2 ; P=0.04), which was confirmed by a longitudinal 5-year retrospective analysis. Additionally, affected patients presented more often with FD-typical symptoms, such as diarrhea, fatigue, and neuropathic pain, among others. Therefore, patients with poor clinical outcome on agalsidase should be tested for agalsidase inhibition. Future studies are warranted to determine if affected patients with FD benefit from acute reduction of anti-agalsidase antibodies or long-term immune modulation therapies to suppress agalsidase inhibition and to identify mechanisms that minimize antibody generation against agalsidase.

show abstract

A retrospective analysis of the potential impact of IgG antibodies to agalsidase β on efficacy during enzyme replacement therapy for Fabry disease

Cited by 92 publications

References 24 publications

Interconversion of the Specificities of Human Lysosomal Enzymes Associated with Fabry and Schindler Diseases

Interconversion of the Specificities of Human Lysosomal Enzymes Associated with Fabry and Schindler Diseases

Evaluation of a low dose, after a standard therapeutic dose, of agalsidase beta during enzyme replacement therapy in patients with Fabry disease

Serum-Mediated Inhibition of Enzyme Replacement Therapy in Fabry Disease

Contact Info

Product

Resources

About