title: A human monoclonal IgG that binds aβ assemblies and diverse amyloids exhibits anti-amyloid activities in vitro and in vivo.
abstract: Alzheimer's disease (AD) and familial Danish dementia (FDD) are degenerative neurological diseases characterized by amyloid pathology. Normal human sera contain IgG antibodies that specifically bind diverse preamyloid and amyloid proteins and have shown therapeutic potential in vitro and in vivo. We cloned one of these antibodies, 3H3, from memory B cells of a healthy individual using a hybridoma method. 3H3 is an affinity-matured IgG that binds a pan-amyloid epitope, recognizing both Aβ and λ Ig light chain (LC) amyloids, which are associated with AD and primary amyloidosis, respectively. The pan-amyloid-binding properties of 3H3 were demonstrated using ELISA, immunohistochemical studies, and competition binding assays. Functional studies showed that 3H3 inhibits both Aβ and LC amyloid formation in vitro and abrogates disruption of hippocampal synaptic plasticity by AD-patient-derived soluble Aβ in vivo. A 3H3 single-chain variable fragment (scFv) retained the binding specificity of the 3H3 IgG and, when expressed in the brains of transgenic mice using an adeno-associated virus (AAV) vector, decreased parenchymal Aβ amyloid deposition in TgCRND8 mice and ADan (Danish Amyloid) cerebral amyloid angiopathy in the mouse model of FDD. These data indicate that naturally occurring human IgGs can recognize a conformational, amyloid-specific epitope and have potent anti-amyloid activities, providing a rationale to test their potential as antibody therapeutics for diverse neurological and other amyloid diseases.
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, Florida 32610, dessains@mlhs.org levites.yona@ufl.edu.
authors.forename: Yona
authors.initials: Y
authors.lastname: Levites
authors.affiliation: The Laboratory of Neurodegenerative Research, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115.
authors.forename: Brian
authors.initials: B
authors.lastname: O'Nuallain
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, Pennsylvania 19096.
authors.forename: Rama Devudu
authors.initials: RD
authors.lastname: Puligedda
authors.affiliation: Trinity College Institute of Neuroscience and Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland.
authors.forename: Tomas
authors.initials: T
authors.lastname: Ondrejcak
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, Pennsylvania 19096.
authors.forename: Sharad P
authors.initials: SP
authors.lastname: Adekar
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, Pennsylvania 19096.
authors.forename: Cindy
authors.identifier: http://orcid.org/0000-0001-8796-7983
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, Florida 32610.
authors.forename: Pedro E
authors.initials: PE
authors.lastname: Cruz
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, Florida 32610.
authors.forename: Awilda M
authors.initials: AM
authors.lastname: Rosario
authors.affiliation: University of Tennessee Graduate School of Medicine, Knoxville, Tennessee 37920.
authors.forename: Sallie
authors.initials: S
authors.lastname: Macy
authors.affiliation: The Laboratory of Neurodegenerative Research, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115.
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Mably
authors.affiliation: The Laboratory of Neurodegenerative Research, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115.
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
authors.affiliation: Department of Pathology and Laboratory Medicine and the Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, and.
authors.forename: Ruben
authors.identifier: http://orcid.org/0000-0002-5803-3871
authors.initials: R
authors.lastname: Vidal
authors.affiliation: University of Tennessee Graduate School of Medicine, Knoxville, Tennessee 37920.
authors.forename: Alan
authors.initials: A
authors.lastname: Solomon
authors.affiliation: Department of Pathology and Laboratory Medicine, Lehigh Valley Health Network, Allentown, Pennsylvania 18103.
authors.forename: Daniel
authors.identifier: http://orcid.org/0000-0002-5822-7975
authors.initials: D
authors.lastname: Brown
authors.affiliation: Trinity College Institute of Neuroscience and Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Rowan
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, College of Medicine, University of Florida, Gainesville, Florida 32610.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, Pennsylvania 19096, dessains@mlhs.org levites.yona@ufl.edu.
authors.forename: Scott K
authors.identifier: http://orcid.org/0000-0002-4331-6799
authors.initials: SK
authors.lastname: Dessain
mesh_terms: D000682:Amyloid / Q000187:drug effects / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002386:Cataract / Q000276:immunology; D002524:Cerebellar Ataxia / Q000276:immunology; D016657:Cerebral Amyloid Angiopathy / Q000276:immunology; D003638:Deafness / Q000276:immunology; D003704:Dementia / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G
keywords: Alzheimer's disease; IVIG; amyloid; amyloid beta; animal study; antibody