title: A subcutaneous cellular implant for passive immunization against amyloid-β reduces brain amyloid and tau pathologies.
abstract: Passive immunization against misfolded toxic proteins is a promising approach to treat neurodegenerative disorders. For effective immunotherapy against Alzheimer's disease, recent clinical data indicate that monoclonal antibodies directed against the amyloid-β peptide should be administered before the onset of symptoms associated with irreversible brain damage. It is therefore critical to develop technologies for continuous antibody delivery applicable to disease prevention. Here, we addressed this question using a bioactive cellular implant to deliver recombinant anti-amyloid-β antibodies in the subcutaneous tissue. An encapsulating device permeable to macromolecules supports the long-term survival of myogenic cells over more than 10 months in immunocompetent allogeneic recipients. The encapsulated cells are genetically engineered to secrete high levels of anti-amyloid-β antibodies. Peripheral implantation leads to continuous antibody delivery to reach plasma levels that exceed 50 µg/ml. In a proof-of-concept study, we show that the recombinant antibodies produced by this system penetrate the brain and bind amyloid plaques in two mouse models of the Alzheimer's pathology. When encapsulated cells are implanted before the onset of amyloid plaque deposition in TauPS2APP mice, chronic exposure to anti-amyloid-β antibodies dramatically reduces amyloid-β40 and amyloid-β42 levels in the brain, decreases amyloid plaque burden, and most notably, prevents phospho-tau pathology in the hippocampus. These results support the use of encapsulated cell implants for passive immunotherapy against the misfolded proteins, which accumulate in Alzheimer's disease and other neurodegenerative disorders.
authors.affiliation: Neurodegenerative Studies Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland patrick.aebischer@epfl.ch bernard.schneider@epfl.ch bernd.bohrmann@roche.com.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Lathuilière
authors.affiliation: Neurodegenerative Studies Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Laversenne
authors.affiliation: Swiss Light Source, Paul Scherrer Institute (PSI), 5232, Villigen-PSI, Switzerland.
authors.forename: Alberto
authors.initials: A
authors.lastname: Astolfo
authors.affiliation: Pharma Research and Early Development, DTA Neuroscience, Roche Innovation Center Penzberg, F. Hoffmann-La Roche, Switzerland.
authors.forename: Erhard
authors.initials: E
authors.lastname: Kopetzki
authors.affiliation: Pharma Research and Early Development, DTA Neuroscience, Roche Innovation Center Basel, F. Hoffmann-La Roche, Switzerland.
authors.forename: Helmut
authors.initials: H
authors.lastname: Jacobsen
authors.affiliation: Swiss Light Source, Paul Scherrer Institute (PSI), 5232, Villigen-PSI, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Stampanoni
authors.affiliation: Pharma Research and Early Development, DTA Neuroscience, Roche Innovation Center Basel, F. Hoffmann-La Roche, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Bohrmann
authors.affiliation: Neurodegenerative Studies Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Bernard L
authors.initials: BL
authors.lastname: Schneider
authors.affiliation: Neurodegenerative Studies Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Aebischer
mesh_terms: D000544:Alzheimer Disease / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D004343:Drug Implants; D007116:Immunization, Passive / Q000379:methods*; D051379:Mice; D008822:Mice, Transgenic; D000066829:Neuroprotection; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D065566:Subcutaneous Absorption; D024801:Tauopathies / Q000517:prevention & control*
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D004343:Drug Implants; D010446:Peptide Fragments; D011994:Recombinant Proteins; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: Alzheimer’s disease; antibody; cellular implant; encapsulation; immunization