title: Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle.
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.
authors.affiliation: Pharma Research and Early Development, Large Molecule Research, F. Hoffmann-La Roche, Penzberg 82377, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Niewoehner
authors.affiliation: Pharma Research and Early Development, Neuroscience Discovery and Translation Area, F. Hoffmann-La Roche, Basel 4070, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Bohrmann
authors.affiliation: Pharma Research and Early Development, Neuroscience Discovery and Translation Area, F. Hoffmann-La Roche, Basel 4070, Switzerland.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Collin
authors.affiliation: Pharma Research and Early Development, Neuroscience Discovery and Translation Area, F. Hoffmann-La Roche, Basel 4070, Switzerland.
authors.forename: Eduard
authors.initials: E
authors.lastname: Urich
authors.affiliation: Pharma Research and Early Development, Large Molecule Research, F. Hoffmann-La Roche, Penzberg 82377, Germany.
authors.forename: Hadassah
authors.initials: H
authors.lastname: Sade
authors.affiliation: Pharma Research and Early Development, Large Molecule Research, F. Hoffmann-La Roche, Penzberg 82377, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Maier
authors.affiliation: Pharma Research and Early Development, Large Molecule Research, F. Hoffmann-La Roche, Penzberg 82377, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Rueger
authors.affiliation: Pharma Research and Early Development, Large Molecule Research, F. Hoffmann-La Roche, Penzberg 82377, Germany.
authors.forename: Jan Olaf
authors.initials: JO
authors.lastname: Stracke
authors.affiliation: Pharma Research and Early Development, Large Molecule Research, F. Hoffmann-La Roche, Penzberg 82377, Germany.
authors.forename: Wilma
authors.initials: W
authors.lastname: Lau
authors.affiliation: Pharma Research and Early Development, Large Molecule Research, F. Hoffmann-La Roche, Penzberg 82377, Germany.
authors.forename: Alain C
authors.initials: AC
authors.lastname: Tissot
authors.affiliation: Pharma Research and Early Development, Neuroscience Discovery and Translation Area, F. Hoffmann-La Roche, Basel 4070, Switzerland.
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Loetscher
authors.affiliation: Pharma Research and Early Development, Neuroscience Discovery and Translation Area, F. Hoffmann-La Roche, Basel 4070, Switzerland. Electronic address: anirvan.ghosh@roche.com.
authors.forename: Anirvan
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Pharma Research and Early Development, Neuroscience Discovery and Translation Area, F. Hoffmann-La Roche, Basel 4070, Switzerland. Electronic address: per-ola.freskgard@roche.com.
authors.forename: Per-Ola
authors.initials: PO
authors.lastname: Freskgård
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D018448:Models, Immunological; D053764:Presenilin-1 / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology*; D011990:Receptors, Transferrin / Q000276:immunology / Q000378:metabolism; D057127:Single-Chain Antibodies / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D057900:Transcytosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D018942:Macrolides; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011990:Receptors, Transferrin; D057127:Single-Chain Antibodies; C040929:bafilomycin A1