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.

Mucopolysaccharidoses and the blood–brain barrier

“…The brain delivery of biologics using the RMT processes has long been studied by making a drug conjugation to receptor ligands of RMT across the BBB [ 56 – 60 ]. There are several RMT processes exist at the BBB, including the low-density lipoprotein receptor, insulin-like growth factor receptor, insulin receptor, and transferrin receptor (TfR) [ 58 , 60 – 63 ]. The latter two RMT systems are the ones most extensively studied for the delivery of lysosomal enzymes across the BBB [ 59 , 60 , 62 , 64 – 66 ].…”

“…There are several RMT processes exist at the BBB, including the low-density lipoprotein receptor, insulin-like growth factor receptor, insulin receptor, and transferrin receptor (TfR) [ 58 , 60 – 63 ]. The latter two RMT systems are the ones most extensively studied for the delivery of lysosomal enzymes across the BBB [ 59 , 60 , 62 , 64 – 66 ]. Their cellular uptake processes are driven by the clathrin-mediated endocytotic process of the receptors available at the luminal surface of the brain endothelial cells.…”

“…Furthermore, in addition to the affinity and the availability of innate RMT systems, the bidirectional nature of transcellular transport may need to manage for effective delivery. As evidence suggests [ 58 – 60 , 78 ], transcytosis across the BBB is a bi-directional process. While TfR exerts ligand-independent transcytosis in brain endothelial cells [ 68 ], any conventional antibody targeting TfR, regardless of its affinity, behaves indistinguishably from endogenous ligand transferrin in terms of bi-directional transportation.…”

“…Kucharz et al showed that receptor-mediated transcytosis via TfR primarily occurs at post-capillary venules due to the perivascular space, which allows for less diffusion resistance [ 100 ]. However, it is unknown whether these findings apply to other receptors such as insulin receptor, insulin-like growth factor receptor-1, low-density lipoprotein receptor (LDLR), or CD98hc, which have been attempted to utilize for BBB transport [ 60 , 63 , 80 , 101 ].…”

“…In addition to TfR-mediated brain delivery, there are multiple studies using the insulin receptor intrinsically expressed in the brain endothelial cells to deliver lysosomal enzymes across the BBB. These studies include hexosaminidase (Tay-Sachs disease), palmitoyl-protein thioesterase-1 (Batten disease type 1), acid sphingomyelinase (Niemann-Pick type A and B), and β-galactosidase-1 (GM1-gangliosidosis) [ 60 , 104 ]. These studies further open an avenue of RMT of lysosomal enzymes across the BBB.…”