Non-inhibitory antibodies impede lysosomal storage reduction during enzyme replacement therapy of a lysosomal storage disease

• Published in: Journal of molecular medicine (Berlin, Germany) Vol. 86; no. 4; pp. 433 - 442
• Main Authors: Matzner, Ulrich, Matthes, Frank, Weigelt, Cecilia, Andersson, Claes, Eistrup, Carl, Fogh, Jens, Gieselmann, Volkmar
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.04.2008; Springer; Springer Nature B.V
• Subjects: Animals; Antibodies - metabolism; Binding Sites; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cells, Cultured; Cerebroside-Sulfatase - genetics; Cerebroside-Sulfatase - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; General aspects; Genetic Therapy; Human Genetics; Humans; Internal Medicine; Kidney - cytology; Leukodystrophy, Metachromatic - metabolism; Leukodystrophy, Metachromatic - therapy; Lysosomal Storage Diseases - metabolism; Lysosomal Storage Diseases - therapy; Medical sciences; Mice; Mice, Knockout; Molecular Medicine; Neurology; Original Article; Receptor, IGF Type 2 - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Sulfoglycosphingolipids - metabolism; Metachromatic leukodystrophy; Arylsulfatase A; Mouse model; Lysosomal storage disease; Enzyme replacement therapy; Animal model; Replacement therapy; Conservation; Lysosome; Lipids; Esterases; Sphingolipidosis; Enzymopathy; Reduction; Degenerative disease; Lipoidosis; Cerebroside-sulfatase; Nervous system diseases; Antibody; Enzyme; Rodentia; Metabolic diseases; Enzyme replacement therapy· Arylsulfatase A, Mouse model; Genetic disease; Cerebral disorder; Medicine; Vertebrata; Metachromatic leukodystrophy· Lysosomal storage disease; Mammalia; Storage; Mouse; Central nervous system disease; Hydrolases; Sulfuric ester hydrolases
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-008-0309-3

Enzyme replacement therapy is a treatment option for several lysosomal storage disorders. We reported previously that treatment of a knockout mouse model of the sphingolipid storage disease metachromatic leukodystrophy (MLD) by intravenous injection of recombinant human arylsulfatase A (rhASA) reduces sulfatide storage and improves nervous system pathology and function. Here, we show that treated mice can develop anti-rhASA antibodies, which impede sulfatide clearance without inhibiting enzyme activity. The neutralizing effect of antibodies was reproduced in cell culture models of MLD by demonstrating that mouse immune serum reduces the ability of rhASA to clear sulfatide from cultured ASA-deficient Schwann and kidney cells. We show that reduced clearance is due to an antibody-mediated blockade of mannose 6-phosphate receptor-dependent enzyme uptake, retargeting of rhASA from sulfatide-storing cells to macrophages, intracellular misrouting of rhASA, and reduction of enzyme stability. Induction of immunotolerance to rhASA by transgenic expression of an active site mutant of human ASA restores sulfatide clearance in mice. The data indicate that the influence of non-inhibitory antibodies must be more intensively considered in evaluating the therapeutic efficacy of enzyme replacement in lysosomal storage disorders in general and in patients without cross-reacting material specifically.