The blood-brain barrier severely limits the delivery of large molecules like antibodies to the brain, with only a minuscule fraction entering the CNS after intravenous injection. Urs Langen, Lab Head at Roche, gave the audience an overview of the company’s brainshuttle technology as a potential solution to this salient problem.
When antibodies are injected IV into the circulation, only a small fraction of the antibodies reach the brain. An experiment on monkeys showed that one out of 3,300 antibodies injected into non-human primates ends up in the brain. The brainshuttle platform uses a Fab fragment targeting a transferrin receptor, enabling efficient transport of therapeutic antibodies and other cargoes into the brain via receptor-mediated transcytosis.
The brain shuttle not only works in mice but also in non-human primates, where there is an increased exposure of IgGs in the brain when using the brainshuttle. Clinical data also backed the brainshuttle’s capabilities; it showed an eightfold increase in CSF to plasma ratio for a brainshuttle compared to an IgG.
Langen pointed out that monovalent brain shuttle formats are significantly more effective for brain delivery than bivalent ones. He attributed this to the fact that monovalent formats pass through sorting tubules for transcytosis, while bivalent formats are degraded in lysosomes. Additionally, the functionality of antibodies is preserved post-delivery, including Fc receptor activation and microglial engagement.
Roche has focused its efforts on developing blood-brain barrier organoids using human cells for high-throughput screening. These organoids mimic the BBB structure and allow testing of brain shuttle variants, and only human-targeted brainshuttles showed uptake, confirming specificity.
Furthermore, Langen and his team are focused on cargo expansion applications. The brainshuttle can deliver not only antibodies but also enzymes and antisense oligonucleotides (ASOs). According to Langen, this could potentially allow intravenous administration of ASOs for CNS diseases, improving patient convenience and distribution within the brain. However, they are still working on improving delivery into the deeper brain regions.
