Brain and Organ Uptake in the Rhesus Monkey in Vivo of Recombinant Iduronidase Compared to an Insulin Receptor Antibody-Iduronidase Fusion Protein.

Mucopolysaccharidosis type I (MPSI) is caused by mutations in the gene encoding the lysosomal enzyme, α-l-iduronidase (IDUA), and patients with MPSI are currently treated with IDUA enzyme replacement therapy (ERT). However, the majority of MPSI patients have severe CNS involvement, and conventional ERT does not treat the brain. The failure of ERT to treat the brain is believed to be due to the lack of IDUA transport through the blood-brain barrier (BBB). However, BBB transport of IDUA has not been directly measured, to date. BBB transport of IDUA may be enhanced by fusion of the enzyme to a monoclonal antibody (mAb) against the human insulin receptor (HIR). The HIRMAb binds the insulin receptor on the BBB to trigger transport into the brain and acts as a molecular Trojan horse to deliver IDUA to brain cells. Therefore, the purpose of the present investigation was to compare, side-by-side, the BBB transport of IDUA alone and the HIRMAb-IDUA fusion protein in the Rhesus monkey in vivo. Each protein was radio-iodinated by conjugation with the [125 I]-Bolton-Hunter reagent and injected intravenously (IV) in the primate. The uptake by brain, and peripheral organs, was measured by whole body autoradiography. The results show there is no transport of IDUA alone into the brain, but that the brain uptake of the HIRMAb-IDUA fusion protein is high, 1.2% injected dose/brain. There is comparable uptake of the IDUA and the HIRMAb-IDUA fusion protein by peripheral organs, where uptake is primarily controlled by the mannose 6-phosphate receptor. The work suggests that treatment of MPSI with the HIRMAb-IDUA fusion protein will be as effective as IDUA in peripheral organs, but offer the benefit of treatment of the central nervous system in MPSI.