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

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Abstract

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.

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Abbreviations

ASA:

arylsulfatase A

CNS:

central nervous system

CRIM:

cross-reacting immunological material

ERT:

enzyme replacement therapy

LSD:

lysosomal storage disease

M6P:

mannose 6-phosphate

M6PR:

M6P receptor

MLD:

metachromatic leukodystrophy

pNCS:

p-nitrocatechol sulfate

PNS:

peripheral nervous system

rhASA:

recombinant human ASA

Sap B:

saposin B

TDC:

taurodeoxycholate

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Acknowledgments

We would like to thank A. Fluharty, P. Fredman, D. Hartmann, and P. Saftig for providing Sap B and antibodies. This work was supported by the European Leukodystrophy Foundation (ELA).

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Authors and Affiliations

  1. Institut für Physiologische Chemie, Rheinische Friedrich-Wilhelms-Universität, Nussallee 11, D-53115, Bonn, Germany

    Ulrich Matzner, Frank Matthes & Volkmar Gieselmann

  2. Zymenex A/S, Roskildevej 12C, DK-3400, Hillerød, Denmark

    Carl Eistrup & Jens Fogh

  3. Zymenex A/S Dalenum 13, S-18170, Lidingö, Sweden

    Cecilia Weigelt & Claes Andersson

Authors
  1. Ulrich Matzner
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  2. Frank Matthes
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  3. Cecilia Weigelt
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  4. Claes Andersson
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  5. Carl Eistrup
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  7. Volkmar Gieselmann
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Correspondence to Ulrich Matzner.

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Matzner, U., Matthes, F., Weigelt, C. et al. Non-inhibitory antibodies impede lysosomal storage reduction during enzyme replacement therapy of a lysosomal storage disease. J Mol Med 86, 433–442 (2008). https://doi.org/10.1007/s00109-008-0309-3

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  • DOI: https://doi.org/10.1007/s00109-008-0309-3

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