Publication
Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle.
Niewoehner Jens, Bohrmann Bernd, Collin Ludovic, Urich Eduard, Sade Hadassah, Maier Peter, Rueger Petra, Stracke Jan Olaf, Lau Wilma, Tissot Alain C, Loetscher Hansruedi, Ghosh Anirvan, Freskgård Per-Ola
Abstract
Although biotherapeutics have vast potential for treating brain disorders, their use has been limited due to low exposure across the blood-brain barrier (BBB). We report that by manipulating the binding mode of an antibody fragment to the transferrin receptor (TfR), we have developed a Brain Shuttle module, which can be engineered into a standard therapeutic antibody for successful BBB transcytosis. Brain Shuttle version of an anti-Aβ antibody, which uses a monovalent binding mode to the TfR, increases β-Amyloid target engagement in a mouse model of Alzheimer's disease by 55-fold compared to the parent antibody. We provide in vitro and in vivo evidence that the monovalent binding mode facilitates transcellular transport, whereas a bivalent binding mode leads to lysosome sorting. Enhanced target engagement of the Brain Shuttle module translates into a significant improvement in amyloid reduction. These findings have major implications for the development of biologics-based treatment of brain disorders.