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Antibody Epitope of Human α‐Galactosidase A Revealed by Affinity Mass Spectrometry : A Basis for Reversing Immunoreactivity in Enzyme Replacement Therapy of Fabry Disease

Antibody Epitope of Human α‐Galactosidase A Revealed by Affinity Mass Spectrometry : A Basis for Reversing Immunoreactivity in Enzyme Replacement Therapy of Fabry Disease

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KUKACKA, Zdenek, Marius Ionut IURASCU, Loredana LUPU, Hendrik RUSCHE, Mary MURPHY, Lorenzo ALTAMORE, Fabio BORRI, Stefan MAESER, Anna Maria PAPINI, Michael PRZYBYLSKI, 2018. Antibody Epitope of Human α‐Galactosidase A Revealed by Affinity Mass Spectrometry : A Basis for Reversing Immunoreactivity in Enzyme Replacement Therapy of Fabry Disease. In: ChemMedChem. 13(9), pp. 909-915. ISSN 1860-7179. eISSN 1860-7187. Available under: doi: 10.1002/cmdc.201800094

@article{Kukacka2018-05-08Antib-42514, title={Antibody Epitope of Human α‐Galactosidase A Revealed by Affinity Mass Spectrometry : A Basis for Reversing Immunoreactivity in Enzyme Replacement Therapy of Fabry Disease}, year={2018}, doi={10.1002/cmdc.201800094}, number={9}, volume={13}, issn={1860-7179}, journal={ChemMedChem}, pages={909--915}, author={Kukacka, Zdenek and Iurascu, Marius Ionut and Lupu, Loredana and Rusche, Hendrik and Murphy, Mary and Altamore, Lorenzo and Borri, Fabio and Maeser, Stefan and Papini, Anna Maria and Przybylski, Michael} }

Altamore, Lorenzo Murphy, Mary Iurascu, Marius Ionut Murphy, Mary Maeser, Stefan eng Borri, Fabio Antibody Epitope of Human α‐Galactosidase A Revealed by Affinity Mass Spectrometry : A Basis for Reversing Immunoreactivity in Enzyme Replacement Therapy of Fabry Disease Kukacka, Zdenek α‐Galactosidase (αGal) is a lysosomal enzyme that hydrolyses the terminal α‐galactosyl moiety from glycosphingolipids. Mutations in the encoding genes for αGal lead to defective or misfolded enzyme, which results in substrate accumulation and subsequent organ dysfunction. The metabolic disease caused by a deficiency of human α‐galactosidase A is known as Fabry disease or Fabry–Anderson disease, and it belongs to a larger group known as lysosomal storage diseases. An effective treatment for Fabry disease has been developed by enzyme replacement therapy (ERT), which involves infusions of purified recombinant enzyme in order to increase enzyme levels and decrease the amounts of accumulated substrate. However, immunoreactivity and IgG antibody formation are major, therapy‐limiting, and eventually life‐threatening complications of ERT. The present study focused on the epitope determination of human α‐galactosidase A against its antibody formed. Here we report the identification of the epitope of human αGal(309–332) recognized by a human monoclonal anti‐αGal antibody, using a combination of proteolytic excision of the immobilized immune complex and surface plasmon resonance biosensing mass spectrometry. The epitope peptide, αGal(309–332), was synthesized by solid‐phase peptide synthesis. Determination of its affinity by surface plasmon resonance analysis revealed a high binding affinity for the antibody (K<sub>D</sub>=39×10<sup>−9</sup> m), which is nearly identical to that of the full‐length enzyme (K<sub>D</sub>=16×10<sup>−9</sup> m). The proteolytic excision affinity mass spectrometry method is shown here to be an efficient tool for epitope identification of an immunogenic lysosomal enzyme. Because the full‐length αGal and the antibody epitope showed similar binding affinities, this provides a basis for reversing immunogenicity upon ERT by: 1) treatment of patients with the epitope peptide to neutralize antibodies, or 2) removal of antibodies by apheresis, and thus significantly improving the response to ERT. Przybylski, Michael Lupu, Loredana 2018-05-08 Kukacka, Zdenek Maeser, Stefan Borri, Fabio Iurascu, Marius Ionut 2018-06-08T09:21:47Z 2018-06-08T09:21:47Z Papini, Anna Maria Rusche, Hendrik Papini, Anna Maria Altamore, Lorenzo Przybylski, Michael Lupu, Loredana Rusche, Hendrik

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