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Neuron. 2014 Jan 8;81(1):49-60. doi: 10.1016/j.neuron.2013.10.061.

Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle.

Author information

  • 1Pharma Research and Early Development, Large Molecule Research, F. Hoffmann-La Roche, Penzberg 82377, Germany.
  • 2Pharma Research and Early Development, Neuroscience Discovery and Translation Area, F. Hoffmann-La Roche, Basel 4070, Switzerland.
  • 3Pharma Research and Early Development, Neuroscience Discovery and Translation Area, F. Hoffmann-La Roche, Basel 4070, Switzerland. Electronic address: anirvan.ghosh@roche.com.
  • 4Pharma Research and Early Development, Neuroscience Discovery and Translation Area, F. Hoffmann-La Roche, Basel 4070, Switzerland. Electronic address: per-ola.freskgard@roche.com.

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.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24411731
[PubMed - indexed for MEDLINE]
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