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Increased Brain Penetration and Potency of a Therapeutic Antibody Using a Monovalent Molecular Shuttle

2014; Cell Press; Volume: 81; Issue: 1 Linguagem: Inglês

10.1016/j.neuron.2013.10.061

1097-4199

Jens Niewoehner, Bernd Bohrmann, Ludovic Collin, Eduard Urich, Hadassah Sade, Peter Maier, Petra Rueger, Jan Olaf Stracke, Wilma Lau, Alain C. Tissot, Hansruedi Loetscher, Anirvan Ghosh, Per‐Ola Freskgård,

Lipid Membrane Structure and Behavior

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.