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Research ArticleArticle

Glycemic Control and Chronic Dosing of Rhesus Monkeys with a Fusion Protein of Iduronidase and a Monoclonal Antibody Against the Human Insulin Receptor

Ruben J. Boado, Eric Ka-Wai Hui, Jeff Zhiqiang Lu and William M. Pardridge
Drug Metabolism and Disposition October 2012, 40 (10) 2021-2025; DOI: https://doi.org/10.1124/dmd.112.046375
Ruben J. Boado
Department of Medicine, University of California Los Angeles, Los Angeles, California (R.J.B., W.M.P.); and, ArmaGen Technologies, Inc., Santa Monica, California (R.J.B., E.K.-W.H., J.Z.L.)
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Eric Ka-Wai Hui
Department of Medicine, University of California Los Angeles, Los Angeles, California (R.J.B., W.M.P.); and, ArmaGen Technologies, Inc., Santa Monica, California (R.J.B., E.K.-W.H., J.Z.L.)
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Jeff Zhiqiang Lu
Department of Medicine, University of California Los Angeles, Los Angeles, California (R.J.B., W.M.P.); and, ArmaGen Technologies, Inc., Santa Monica, California (R.J.B., E.K.-W.H., J.Z.L.)
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William M. Pardridge
Department of Medicine, University of California Los Angeles, Los Angeles, California (R.J.B., W.M.P.); and, ArmaGen Technologies, Inc., Santa Monica, California (R.J.B., E.K.-W.H., J.Z.L.)
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Abstract

Hurler's syndrome, or mucopolysaccharidosis type I, is a lysosomal storage disorder caused by mutations in the gene encoding the lysosomal enzyme iduronidase (IDUA). The disease affects both peripheral tissues and the central nervous system (CNS). Recombinant IDUA treatment does not affect the CNS, because IDUA does not cross the blood-brain barrier (BBB). To enable BBB penetration, human IDUA was re-engineered as an IgG-IDUA fusion protein, where the IgG domain is a genetically engineered monoclonal antibody (MAb) against the human insulin receptor (HIR). The HIRMAb penetrates the brain from the blood via transport on the endogenous BBB insulin receptor and acts as a molecular Trojan horse to deliver the fused IDUA to the brain. Before human testing, the HIRMAb-IDUA fusion protein was evaluated in a 6-month weekly dosing toxicology study at doses of 0, 3, 9, and 30 mg/kg/week of the fusion protein administered to 40 rhesus monkeys. The focus of the present study is the effect of chronic high dose administration of this fusion protein on plasma glucose and long-term glycemic control. The results show that the HIRMAb has weak insulin agonist activity and causes hypoglycemia at the high dose, 30 mg/kg, after intravenous infusion in normal saline. When dextrose is added to the saline infusion solution, no hypoglycemia is observed at any dose. An intravenous glucose tolerance test performed at the end of the 6 months of chronic treatment showed no change in glucose tolerance at any dose of the HIRMAb-IDUA fusion protein.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant U44-NS064602].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.112.046375.

  • ABBREVIATIONS:

    BBB
    blood-brain barrier
    CNS
    central nervous system
    CSF
    cerebrospinal fluid
    HIR
    human insulin receptor
    HIRMAb
    MAb against HIR
    IDUA
    iduronidase
    HIRMAb-IDUA
    fusion protein of HIRMAb and IDUA
    MAb
    monoclonal antibody.

  • Received April 21, 2012.
  • Accepted July 20, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (10)
Drug Metabolism and Disposition
Vol. 40, Issue 10
1 Oct 2012
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Research ArticleArticle

GLUCOSE CONTROL AND INSULIN RECEPTOR MONOCLONAL ANTIBODY

Ruben J. Boado, Eric Ka-Wai Hui, Jeff Zhiqiang Lu and William M. Pardridge
Drug Metabolism and Disposition October 1, 2012, 40 (10) 2021-2025; DOI: https://doi.org/10.1124/dmd.112.046375

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Research ArticleArticle

GLUCOSE CONTROL AND INSULIN RECEPTOR MONOCLONAL ANTIBODY

Ruben J. Boado, Eric Ka-Wai Hui, Jeff Zhiqiang Lu and William M. Pardridge
Drug Metabolism and Disposition October 1, 2012, 40 (10) 2021-2025; DOI: https://doi.org/10.1124/dmd.112.046375
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