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A Humoral Immune Response Alters the Distribution of Enzyme Replacement Therapy in Murine Mucopolysaccharidosis Type I
- Source :
- Molecular Therapy: Methods & Clinical Development, Vol 8, Iss C, Pp 42-51 (2018), Molecular Therapy. Methods & Clinical Development
- Publication Year :
- 2018
- Publisher :
- Elsevier, 2018.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
lcsh:QH426-470
Hurler
Pharmacology
Article
law.invention
Scheie
03 medical and health sciences
Mucopolysaccharidosis type I
0302 clinical medicine
Immune system
law
Genetics
medicine
Lysosomal storage disease
glycosaminoglycan
lcsh:QH573-671
Molecular Biology
Kidney
biology
lcsh:Cytology
lysosomal disease
Enzyme replacement therapy
medicine.disease
3. Good health
lcsh:Genetics
030104 developmental biology
medicine.anatomical_structure
Immunology
biology.protein
Recombinant DNA
Molecular Medicine
Antibody
Iduronidase
030217 neurology & neurosurgery
alpha-l-iduronidase
Subjects
Details
- Language :
- English
- ISSN :
- 23290501
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Molecular Therapy: Methods & Clinical Development
- Accession number :
- edsair.doi.dedup.....03b3e4be0fe91d6ae9802b52e6703012