4:27 PM
Aug 17, 2017
 |  BC Innovations  |  Targets & Mechanisms


How anti-GRP78 antibodies could help therapeutic mAbs get through the BBB

Biogen Inc. has discovered antibodies in patients with a rare CNS autoimmune disease that could provide a new way to deliver mAbs across the blood-brain barrier, an application with wide-reaching ramifications for neurologic drug development.

The inability to concentrate therapeutic antibodies in the brain has long dogged drug makers, particularly in Alzheimer’s disease, where insufficient levels of anti-β amyloid antibodies is proposed as one cause of their failure to clear senile plaques.

Biogen’s Richard Ransohoff, a lead author on the study, told BioCentury that after IV administration only 1 out of 1,000 antibody molecules makes it across the barrier. “It would be valuable to be able to get those antibodies into the brain at higher levels,” and to get them in deeper, he said. Ransohoff is VP and Research Unit Head, Neuroimmunology, Acute Neurology and Pain.

Ransohoff said that other diseases in Biogen’s pipeline that may benefit from increased transit of mAbs into the brain include Parkinson’s disease, frontal temporal dementia and other tauopathies.

In studying the pathogenesis of neuromyelitis optica (NMO), his team and its academic collaborators identified two antibodies targeting the heat shock protein GRP78, and found the molecules specifically bind brain endothelial cells and make the BBB leakier.

Although Biogen hasn’t disclosed how it intends to pursue the findings, Ransohoff sees potential for using the discovery to deliver mAbs to the brain.

“I would make a bispecific and try it out as a shuttle first, before doing anything else.” The idea is to use a compound that binds GRP78 with one arm and the therapeutic target with the other. The anti-GRP78 arm would open up the barrier, allowing the antibodies through so the therapeutic arm can reach its target.


ProductHuman mAb against GRP78 or bispecific comprising the GRP78 antibody and a therapeutic mAb
ConceptTargeting GRP78 transiently decreases levels of the tight junction protein CLDN5, increasing permeability of the blood-brain barrier (BBB) and facilitating delivery of large molecule therapies to the brain
DiseaseCNS diseases
CompetitionTransferrin receptor-mediated transcytosis across the BBB; siRNAs against tight junction proteins
DifferentiationDifferent mechanism of BBB entry; amenable to a bispecific approach where the two components have identical PK/PD

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