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A Humoral Immune Response Alters the Distribution of Enzyme Replacement Therapy in Murine Mucopolysaccharidosis Type I

Antibodies against recombinant proteins can significantly reduce their effectiveness in unanticipated ways. We evaluated the humoral response of mice with the lysosomal storage disease mucopolysaccharidosis type I treated with weekly intravenous recombinant human alpha-l-iduronidase (rhIDU). Unlike...

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Autores principales: Le, Steven Q., Kan, Shih-hsin, Clarke, Don, Sanghez, Valentina, Egeland, Martin, Vondrak, Kristen N., Doherty, Terence M., Vera, Moin U., Iacovino, Michelina, Cooper, Jonathan D., Sands, Mark S., Dickson, Patricia I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684429/
https://www.ncbi.nlm.nih.gov/pubmed/29159202
http://dx.doi.org/10.1016/j.omtm.2017.09.008
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author Le, Steven Q.
Kan, Shih-hsin
Clarke, Don
Sanghez, Valentina
Egeland, Martin
Vondrak, Kristen N.
Doherty, Terence M.
Vera, Moin U.
Iacovino, Michelina
Cooper, Jonathan D.
Sands, Mark S.
Dickson, Patricia I.
author_facet Le, Steven Q.
Kan, Shih-hsin
Clarke, Don
Sanghez, Valentina
Egeland, Martin
Vondrak, Kristen N.
Doherty, Terence M.
Vera, Moin U.
Iacovino, Michelina
Cooper, Jonathan D.
Sands, Mark S.
Dickson, Patricia I.
author_sort Le, Steven Q.
collection PubMed
description Antibodies against recombinant proteins can significantly reduce their effectiveness in unanticipated ways. We evaluated the humoral response of mice with the lysosomal storage disease mucopolysaccharidosis type I treated with weekly intravenous recombinant human alpha-l-iduronidase (rhIDU). Unlike patients, the majority of whom develop antibodies to recombinant human alpha-l-iduronidase, only approximately half of the treated mice developed antibodies against recombinant human alpha-l-iduronidase and levels were low. Serum from antibody-positive mice inhibited uptake of recombinant human alpha-l-iduronidase into human fibroblasts by partial inhibition compared to control serum. Tissue and cellular distributions of rhIDU were altered in antibody-positive mice compared to either antibody-negative or naive mice, with significantly less recombinant human alpha-l-iduronidase activity in the heart and kidney in antibody-positive mice. In the liver, recombinant human alpha-l-iduronidase was preferentially found in sinusoidal cells rather than in hepatocytes in antibody-positive mice. Antibodies against recombinant human alpha-l-iduronidase enhanced uptake of recombinant human alpha-l-iduronidase into macrophages obtained from MPS I mice. Collectively, these results imply that a humoral immune response against a therapeutic protein can shift its distribution preferentially into macrophage-lineage cells, causing decreased availability of the protein to the cells that are its therapeutic targets.
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spelling pubmed-56844292017-11-20 A Humoral Immune Response Alters the Distribution of Enzyme Replacement Therapy in Murine Mucopolysaccharidosis Type I Le, Steven Q. Kan, Shih-hsin Clarke, Don Sanghez, Valentina Egeland, Martin Vondrak, Kristen N. Doherty, Terence M. Vera, Moin U. Iacovino, Michelina Cooper, Jonathan D. Sands, Mark S. Dickson, Patricia I. Mol Ther Methods Clin Dev Article Antibodies against recombinant proteins can significantly reduce their effectiveness in unanticipated ways. We evaluated the humoral response of mice with the lysosomal storage disease mucopolysaccharidosis type I treated with weekly intravenous recombinant human alpha-l-iduronidase (rhIDU). Unlike patients, the majority of whom develop antibodies to recombinant human alpha-l-iduronidase, only approximately half of the treated mice developed antibodies against recombinant human alpha-l-iduronidase and levels were low. Serum from antibody-positive mice inhibited uptake of recombinant human alpha-l-iduronidase into human fibroblasts by partial inhibition compared to control serum. Tissue and cellular distributions of rhIDU were altered in antibody-positive mice compared to either antibody-negative or naive mice, with significantly less recombinant human alpha-l-iduronidase activity in the heart and kidney in antibody-positive mice. In the liver, recombinant human alpha-l-iduronidase was preferentially found in sinusoidal cells rather than in hepatocytes in antibody-positive mice. Antibodies against recombinant human alpha-l-iduronidase enhanced uptake of recombinant human alpha-l-iduronidase into macrophages obtained from MPS I mice. Collectively, these results imply that a humoral immune response against a therapeutic protein can shift its distribution preferentially into macrophage-lineage cells, causing decreased availability of the protein to the cells that are its therapeutic targets. American Society of Gene & Cell Therapy 2017-10-05 /pmc/articles/PMC5684429/ /pubmed/29159202 http://dx.doi.org/10.1016/j.omtm.2017.09.008 Text en © 2017 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Le, Steven Q.
Kan, Shih-hsin
Clarke, Don
Sanghez, Valentina
Egeland, Martin
Vondrak, Kristen N.
Doherty, Terence M.
Vera, Moin U.
Iacovino, Michelina
Cooper, Jonathan D.
Sands, Mark S.
Dickson, Patricia I.
A Humoral Immune Response Alters the Distribution of Enzyme Replacement Therapy in Murine Mucopolysaccharidosis Type I
title A Humoral Immune Response Alters the Distribution of Enzyme Replacement Therapy in Murine Mucopolysaccharidosis Type I
title_full A Humoral Immune Response Alters the Distribution of Enzyme Replacement Therapy in Murine Mucopolysaccharidosis Type I
title_fullStr A Humoral Immune Response Alters the Distribution of Enzyme Replacement Therapy in Murine Mucopolysaccharidosis Type I
title_full_unstemmed A Humoral Immune Response Alters the Distribution of Enzyme Replacement Therapy in Murine Mucopolysaccharidosis Type I
title_short A Humoral Immune Response Alters the Distribution of Enzyme Replacement Therapy in Murine Mucopolysaccharidosis Type I
title_sort humoral immune response alters the distribution of enzyme replacement therapy in murine mucopolysaccharidosis type i
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684429/
https://www.ncbi.nlm.nih.gov/pubmed/29159202
http://dx.doi.org/10.1016/j.omtm.2017.09.008
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