Abstract
The immune response to exogenous protein has been shown to reduce therapeutic efficacy in animal models of enzyme replacement therapy. A previously published study demonstrated an immunosuppressive regimen which successfully induced immune tolerance to α-l-iduronidase in canines with mucopolysaccharidosis I. The two key requirements for success were high-affinity receptor-mediated enzyme uptake, conferred by mannose 6-phosphate conjugation, and immunosuppression with low-dose antigen exposure. In this study, we attempted to induce immune tolerance to phenylalanine ammonia-lyase by producing a recombinant mannose 6-phosphate conjugated form and administering it to normal dogs according to the previously published tolerance induction regimen. We found that the recombinant conjugated enzyme was stable, could bind to the mannose 6-phosphate receptor with high affinity, and its uptake into fibroblast cells was mediated by this receptor. However, at the end of a tolerance induction period, all dogs demonstrated an antigen-specific immune response when challenged with increasing doses of unconjugated phenylalanine ammonia-lyase. The average time to seroconvert was not significantly different among three separate groups of test animals (n = 3 per group) and was not significantly different from one group of control animals (n = 3). None of the nine test group animals developed immune tolerance to the enzyme using this method. This suggests that high-affinity cellular uptake mediated by the mannose 6-phosphate receptor combined with a previously studied tolerizing regimen is not sufficient to induce immune tolerance to an exogenous protein and that other factors affecting antigen distribution, uptake, and presentation are likely to be important.
Competing interests: None declared
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Acknowledgments
This study was supported by a grant from BioMarin Pharmaceutical, Inc., which also provided RtPAL for this study. We thank Catalina Guerra, Jenny Dancourt, and Barbara Villareal for their technical assistance.
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Communicated by: Gregory Enns
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Synopsis
We produced mannose 6-phosphate-conjugated recombinant phenylalanine ammonia-lyase (PAL), administered it to normal dogs using a previously published tolerizing regimen, and found that, despite demonstrated M6P receptor binding and cellular uptake, all test animals failed to develop immune tolerance to PAL and produced a marked antibody response.
Competing Interest Statement
The coauthors TL, BZ, PT, SC, JF, and JFL are employees of BioMarin Pharmaceutical. EDK is a former employee of BioMarin and is now Chief Executive Officer of Ultragenyx Corporation.
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Vera, M. et al. (2012). Mannose 6-Phosphate Conjugation Is Not Sufficient to Allow Induction of Immune Tolerance to Phenylalanine Ammonia-Lyase in Dogs. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports - Case and Research Reports, 2012/5. JIMD Reports, vol 8. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2012_162
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DOI: https://doi.org/10.1007/8904_2012_162
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