Brain delivery of biotherapeutics via receptor-mediated transcytosis across the blood–brain barrier

Abstract

The brain microvasculature represents the blood–brain barrier (BBB) in vivo and it is permeable only to small lipophilic molecules. Polar nutrients, like glucose and amino acids, are transported across the BBB via carrier-mediated transport systems. Large protein-based biotherapeutics are not able to cross the BBB, which has represented a major issue for the development of potential treatments for the central nervous system over the past several decades. The finding that proteins such as insulin and transferrin cross the BBB through receptor-mediated transcytosis (RMT) led to the idea that it may be possible to transport peptidomimetic molecules to the brain by targeting these BBB receptors. It was later demonstrated that monoclonal antibodies (MAb) targeting either insulin and transferrin BBB receptors were able to penetrate the BBB and distribute throughout the brain. A first generation of molecular Trojan horses or shuttle systems were developed, which were able to piggyback therapeutic molecules conjugated directly to these MAbs or bound to them via avidin–biotin chemistry. This technology was also applied to the delivery of genes and antisense oligonucleotides to the brain. A second generation of brain penetrating protein-based biotherapeutics was produced in a form of fusion proteins, comprised of a transport domain and a therapeutic domain. These fusion proteins were validated in various experimental models, including lysosomal storage disorders, stroke, Parkinson's and Alzheimer's disease, respectively. Clinical trials with brain penetrating fusion proteins have been completed or are in progress with valanafusp alpha and lepunafusp alfa for Hurler's syndrome (mucopolysaccharidosis type I, MPS I), with pabinafusp alfa and tividenofusp alpha for Hunter's syndrome (MPS II), and with trontinemab for Alzheimer's disease. Pabinafusp alfa was the first brain penetrating biotherapeutic approved by a regulatory agency for the treatment of Hunter MPSII syndrome. The aim of this article is to review the progress made in the brain delivery of biotherapeutics via RMT across the BBB.