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.

Original languageEnglish
Pages (from-to)42-51
Number of pages10
JournalMolecular Therapy - Methods and Clinical Development
StatePublished - Mar 16 2018


  • Hurler
  • Scheie
  • alpha-L-iduronidase
  • glycosaminoglycan
  • lysosomal disease


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