BASEL, Switzerland--A new method for transporting molecules across the blood-brain barrier was published recently in Neuron that might provide some hope for future treatment of Alzheimer’s disease. The method in question uses Roche’s Brain Shuttle technology, which proved capable of delivering investigational antibodies from the blood to the brain in preclinical mouse models of Alzheimer’s.
“Thanks to our sophisticated protein engineering we were able to design a system that exploits natural transport mechanisms to significantly increase the transfer of investigational antibodies into the brain in preclinical models,” said Luca Santarelli, head of Neuroscience, Ophthalmology and Rare Diseases at Roche Pharma Early Research and Development. “Using Roche’s Brain Shuttle technology, the target engagement of investigational antibodies in the brain in a preclinical model was increased by over 50-fold compared to the parent antibody.”
Roche’s Brain Shuttle technology creates antibodies that can cross the blood-brain barrier by binding to one of the protein receptors found on its surface, specifically by engaging the natural transferrin receptor (TfR) in a specific mode, triggering a process known as receptor-mediated transcytosis to transport molecules into the brain. As noted in the paper, it has been shown that either modulating the affinity of anti-TfR antibodies or using a peptide as a transferrin ligand can improve brain exposure.”
The scientists tested this technology with an anti-amyloid beta antibody, “which uses a monovalent binding mode to the TfR” and “increases Beta-amyloid target engagement in a mouse model of Alzheimer’s disease by 55-fold compared to the parent antibody.” The team saw in-vitro and in-vivo evidence that this binding mode supports antibody transport across the blood-brain barrier, “whereas a bivalent binding mode leads to lysosome sorting.” As a result, they saw a significant reduction in the presence of amyloid in the brain of the mouse model.
“The efficacy of the Brain Shuttle technology in preclinical models suggests that this approach could deliver therapeutic molecules across the BBB. We will continue to investigate the potential of the Brain Shuttle technology to transport a variety of molecules such as growth factors, antibodies, peptides and oligonucleotides across the BBB,” Anirvan Ghosh, head of Neuroscience Discovery at Roche Pharma Early Research and Development, said in a press release.
The blood-brain barrier inhibits the transfer of molecules between the bloodstream and the central nervous system, and while various efforts have managed to successfully find ways to enable small molecules to pass the barrier, large molecules such as antibodies remain a challenge. As noted in the recent Neuron paper, “Increased Brain Penetration and Potency of a Therapeutic Antibody Using a Monovalent Molecular Shuttle,” “many of the leading therapies being developed for Alzheimer’s disease rely on antibodies that target the Beta-amyloid protein, but only around 0.1 percent to 0.2 percent of the antibody crosses into the brain.”
“If we are able to clinically validate the preclinical results observed with the Brain Shuttle technology, it could lead us to a way to test investigational drugs in a variety of brain disorders,” Per-Ola Freskgard, preclinical project leader for the Brain Shuttle technology platform at Roche Pharma Early Research and Development, commented in a statement.
Ghosh says that they have also tested this technology with other antibodies, though the bulk of their focus has been on the amyloid antibody, and initial experiments seem to be effective.
“We’re quite interested in examining whether we can use the technology to deliver other cargos into the brain,” says Ghosh, noting that they are looking into applying this technology with growth factor, oligoneucleotides and peptides, as well as in other neurodegenerative indications.