Selective plasma pharmacokinetics and brain uptake in the mouse of enzyme fusion proteins derived from species-specific receptor-targeted antibodies

Abstract

Enzymes may be re-engineered for brain drug targeting as an IgG-enzyme fusion protein, where the IgG is a monoclonal antibody (MAb) against an endogenous blood–brain barrier (BBB) receptor transporter, such as the insulin receptor or transferrin receptor (TfR). Iduronate 2-sulfatase (IDS) is fused to the heavy chain of a genetically engineered MAb against the human insulin receptor (HIR). Neither the HIRMAb alone, nor the HIRMAb–IDS fusion protein, is delivered across the BBB in the mouse, owing to lack of cross-reactivity of the HIRMAb with the insulin receptor in the mouse. The uptake of the HIRMAb–IDS fusion protein in peripheral organs exceeds that of the HIRMAb, which is attributed to uptake mediated via the mannose-6 phosphate receptor in non-brain organs. In contrast to the lack of BBB transport of the HIRMAb–IDS fusion protein, there is high BBB penetration in the mouse of an IDS fusion protein and a chimeric MAb against the mouse TfR. The comparison of the brain distribution of two different IgG-IDS fusion proteins, with different reactivity for an endogenous BBB receptor, illustrates the difference in brain targeting of a biopharmaceutical caused by the targeting properties of the IgG domain of the fusion protein.