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

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

doi:10.1016/j.neuron.2013.10.061

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

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

Affiliations

¹ Pharma Research and Early Development, Large Molecule Research, F. Hoffmann-La Roche, Penzberg 82377, Germany.
² Pharma Research and Early Development, Neuroscience Discovery and Translation Area, F. Hoffmann-La Roche, Basel 4070, Switzerland.
³ Pharma Research and Early Development, Neuroscience Discovery and Translation Area, F. Hoffmann-La Roche, Basel 4070, Switzerland. Electronic address: [email protected].
⁴ Pharma Research and Early Development, Neuroscience Discovery and Translation Area, F. Hoffmann-La Roche, Basel 4070, Switzerland. Electronic address: [email protected].

PMID: 24411731
DOI: 10.1016/j.neuron.2013.10.061

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.

Publication types

Video-Audio Media

MeSH terms

Alzheimer Disease / genetics
Alzheimer Disease / pathology
Alzheimer Disease / therapy
Amyloid beta-Peptides / immunology
Amyloid beta-Peptides / metabolism*
Amyloid beta-Protein Precursor / genetics
Animals
Blood-Brain Barrier / drug effects
Blood-Brain Barrier / metabolism*
Brain / drug effects
Brain / immunology
Brain / metabolism*
Cell Line, Transformed
Disease Models, Animal
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Humans
Lysosomes / drug effects
Lysosomes / metabolism
Macrolides / pharmacology
Mice
Mice, Transgenic
Models, Immunological
Presenilin-1 / genetics
Protein Binding / drug effects
Protein Binding / immunology
Protein Transport / drug effects
Protein Transport / physiology*
Receptors, Transferrin / immunology
Receptors, Transferrin / metabolism
Single-Chain Antibodies / metabolism*
Single-Chain Antibodies / pharmacology
Single-Chain Antibodies / therapeutic use
Subcellular Fractions / drug effects
Subcellular Fractions / metabolism
Time Factors
Transcytosis / drug effects
Transcytosis / genetics
Transcytosis / immunology

Substances

Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Enzyme Inhibitors
Macrolides
PSEN1 protein, human
Presenilin-1
Receptors, Transferrin
Single-Chain Antibodies
bafilomycin A1