IgG Fusion Proteins for Brain Delivery of Biologics via Blood–Brain Barrier Receptor-Mediated Transport

Abstract

The treatment of neurological disorders with large-molecule biotherapeutics requires that the therapeutic drug be transported across the blood–brain barrier (BBB). However, recombinant biotherapeutics, such as neurotrophins, enzymes, decoy receptors, and monoclonal antibodies (MAb), do not cross the BBB. These biotherapeutics can be re-engineered as brain-penetrating bifunctional IgG fusion proteins. These recombinant proteins comprise two domains, the transport domain and the therapeutic domain, respectively. The transport domain is an MAb that acts as a molecular Trojan horse by targeting a BBB-specific endogenous receptor that induces receptor-mediated transcytosis into the brain, such as the human insulin receptor (HIR) or the transferrin receptor (TfR). The therapeutic domain of the IgG fusion protein exerts its pharmacological effect in the brain once across the BBB. A generation of bifunctional IgG fusion proteins has been engineered using genetically engineered MAbs directed to either the BBB HIR or TfR as the transport domain. These IgG fusion proteins were validated in animal models of lysosomal storage disorders; acute brain conditions, such as stroke; or chronic neurodegeneration, such as Parkinson’s disease and Alzheimer’s disease. Human phase I–III clinical trials were also completed for Hurler MPSI and Hunter MPSII using brain-penetrating IgG-iduronidase and -iduronate-2-sulfatase fusion protein, respectively.