title: Combined treatment with a BACE inhibitor and anti-Aβ antibody gantenerumab enhances amyloid reduction in APPLondon mice.
abstract: Therapeutic approaches for prevention or reduction of amyloidosis are currently a main objective in basic and clinical research on Alzheimer's disease. Among the agents explored in clinical trials are anti-Aβ peptide antibodies and secretase inhibitors. Most anti-Aβ antibodies are considered to act via inhibition of amyloidosis and enhanced clearance of existing amyloid, although secretase inhibitors reduce the de novo production of Aβ. Limited information is currently available on the efficacy and potential advantages of combinatorial antiamyloid treatment. We performed a chronic study in APPLondon transgenic mice that received treatment with anti-Aβ antibody gantenerumab and BACE inhibitor RO5508887, either as mono- or combination treatment. Treatment aimed to evaluate efficacy on amyloid progression, similar to preexisting amyloidosis as present in Alzheimer's disease patients. Mono-treatments with either compound caused a dose-dependent reduction of total brain Aβ and amyloid burden. Combination treatment with both compounds significantly enhanced the antiamyloid effect. The observed combination effect was most pronounced for lowering of amyloid plaque load and plaque number, which suggests effective inhibition of de novo plaque formation. Moreover, significantly enhanced clearance of pre-existing amyloid plaques was observed when gantenerumab was coadministered with RO5508887. BACE inhibition led to a significant time- and dose-dependent decrease in CSF Aβ, which was not observed for gantenerumab treatment. Our results demonstrate that combining these two antiamyloid agents enhances overall efficacy and suggests that combination treatments may be of clinical relevance.
authors.affiliation: Roche Pharmaceutical Research & Early Development, DTA Neuroscience, helmut.jacobsen@roche.com bernd.bohrmann@roche.com.
authors.forename: Helmut
authors.initials: H
authors.lastname: Jacobsen
authors.affiliation: Roche Pharmaceutical Research & Early Development, DTA Neuroscience.
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
authors.affiliation: Pharmaceutical Sciences, and.
authors.forename: Antonello
authors.initials: A
authors.lastname: Caruso
authors.affiliation: Small Molecule Research, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland, and.
authors.forename: Robert
authors.initials: R
authors.lastname: Narquizian
authors.affiliation: Small Molecule Research, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland, and.
authors.forename: Hans
authors.initials: H
authors.lastname: Hilpert
authors.affiliation: Pharmaceutical Sciences, and.
authors.forename: Bjoern
authors.identifier: http://orcid.org/0000-0003-0782-6190
authors.initials: B
authors.lastname: Jacobsen
authors.affiliation: reMYND, 3001 Leuven, Belgium.
authors.forename: Dick
authors.identifier: http://orcid.org/0000-0002-2638-8336
authors.initials: D
authors.lastname: Terwel
authors.affiliation: reMYND, 3001 Leuven, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Tanghe
authors.affiliation: Roche Pharmaceutical Research & Early Development, DTA Neuroscience, helmut.jacobsen@roche.com bernd.bohrmann@roche.com.
authors.forename: Bernd
authors.initials: B
authors.lastname: Bohrmann
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004791:Enzyme Inhibitors; C571128:gantenerumab; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
keywords: Alzheimer's disease; Aβ-antibody; BACE; amyloidosis; tg-APP mouse