title: Antibody-Mediated Targeting of Tau In Vivo Does Not Require Effector Function and Microglial Engagement.
abstract: The spread of tau pathology correlates with cognitive decline in Alzheimer's disease. In vitro, tau antibodies can block cell-to-cell tau spreading. Although mechanisms of anti-tau function in vivo are unknown, effector function might promote microglia-mediated clearance. In this study, we investigated whether antibody effector function is required for targeting tau. We compared efficacy in vivo and in vitro of two versions of the same tau antibody, with and without effector function, measuring tau pathology, neuron health, and microglial function. Both antibodies reduced accumulation of tau pathology in Tau-P301L transgenic mice and protected cultured neurons against extracellular tau-induced toxicity. Only the full-effector antibody enhanced tau uptake in cultured microglia, which promoted release of proinflammatory cytokines. In neuron-microglia co-cultures, only effectorless anti-tau protected neurons, suggesting full-effector tau antibodies can induce indirect toxicity via microglia. We conclude that effector function is not required for efficacy, and effectorless tau antibodies may represent a safer approach to targeting tau.
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Seung-Hye
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Claire E
authors.initials: CE
authors.lastname: Le Pichon
authors.affiliation: AC Immune SA, 1015 Lausanne, Switzerland.
authors.forename: Oskar
authors.initials: O
authors.lastname: Adolfsson
authors.affiliation: AC Immune SA, 1015 Lausanne, Switzerland.
authors.forename: Valérie
authors.initials: V
authors.lastname: Gafner
authors.affiliation: AC Immune SA, 1015 Lausanne, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Pihlgren
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Lin
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Hilda
authors.initials: H
authors.lastname: Solanoy
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Brendza
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Ngu
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Oded
authors.initials: O
authors.lastname: Foreman
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Ruby
authors.initials: R
authors.lastname: Chan
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Ernst
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: DiCara
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Isidro
authors.initials: I
authors.lastname: Hotzel
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Karpagam
authors.initials: K
authors.lastname: Srinivasan
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: David V
authors.initials: DV
authors.lastname: Hansen
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Jasvinder
authors.initials: J
authors.lastname: Atwal
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Bumbaca
authors.affiliation: AC Immune SA, 1015 Lausanne, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pfeifer
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Watts
authors.affiliation: AC Immune SA, 1015 Lausanne, Switzerland. Electronic address: andreas.muhs@acimmune.com.
authors.forename: Andreas
authors.initials: A
authors.lastname: Muhs
authors.affiliation: Genentech, South San Francisco, CA 94080, USA. Electronic address: kscearcelevie@gmail.com.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Scearce-Levie
authors.affiliation: Genentech, South San Francisco, CA 94080, USA. Electronic address: ayalon.gai@gene.com.
authors.forename: Gai
authors.initials: G
authors.lastname: Ayalon
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques / Q000379:methods; D016207:Cytokines / Q000378:metabolism; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D000906:Antibodies; D016207:Cytokines; D016875:tau Proteins