title: IgG Conformer's Binding to Amyloidogenic Aggregates.
abstract: Amyloid-reactive IgGs isolated from pooled blood of normal individuals (pAbs) have demonstrated clinical utility for amyloid diseases by in vivo targeting and clearing amyloidogenic proteins and peptides. We now report the following three novel findings on pAb conformer's binding to amyloidogenic aggregates: 1) pAb aggregates have greater activity than monomers (HMW species > dimers > monomers), 2) pAbs interactions with amyloidogenic aggregates at least partially involves unconventional (non-CDR) interactions of F(ab) regions, and 3) pAb's activity can be easily modulated by trace aggregates generated during sample processing. Specifically, we show that HMW aggregates and dimeric pAbs present in commercial preparations of pAbs, intravenous immunoglobulin (IVIg), had up to ~200- and ~7-fold stronger binding to aggregates of Aβ and transthyretin (TTR) than the monomeric antibody. Notably, HMW aggregates were primarily responsible for the enhanced anti-amyloid activities of Aβ- and Cibacron blue-isolated IVIg IgGs. Human pAb conformer's binding to amyloidogenic aggregates was retained in normal human sera, and mimicked by murine pAbs isolated from normal pooled plasmas. An unconventional (non-CDR) component to pAb's activity was indicated from control human mAbs, generated against non-amyloid targets, binding to aggregated Aβ and TTR. Similar to pAbs, HMW and dimeric mAb conformers bound stronger than their monomeric forms to amyloidogenic aggregates. However, mAbs had lower maximum binding signals, indicating that pAbs were required to saturate a diverse collection of binding sites. Taken together, our findings strongly support further investigations on the physiological function and clinical utility of the inherent anti-amyloid activities of monomeric but not aggregated IgGs.
authors.affiliation: The Laboratory of Neurodegenerative Research, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Monichan
authors.initials: M
authors.lastname: Phay
authors.affiliation: The Conway Institute, University College Dublin, Belfield, Dublin, Republic of Ireland.
authors.forename: Alfred T
authors.initials: AT
authors.lastname: Welzel
authors.affiliation: Human Immunology and Cancer Program, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, United States of America.
authors.forename: Angela D
authors.initials: AD
authors.lastname: Williams
authors.affiliation: Human Immunology and Cancer Program, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, United States of America.
authors.forename: Helen P
authors.initials: HP
authors.lastname: McWilliams-Koeppen
authors.affiliation: The Laboratory of Neurodegenerative Research, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Veronika
authors.initials: V
authors.lastname: Blinder
authors.affiliation: The Laboratory of Neurodegenerative Research, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Tiernan T
authors.initials: TT
authors.lastname: O'Malley
authors.affiliation: Human Immunology and Cancer Program, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, United States of America.
authors.forename: Alan
authors.initials: A
authors.lastname: Solomon
authors.affiliation: The Laboratory of Neurodegenerative Research, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Dominic M
authors.initials: DM
authors.lastname: Walsh
authors.affiliation: The Laboratory of Neurodegenerative Research, Brigham and Women's Hospital, Harvard Institutes of Medicine, Boston, Massachusetts, United States of America; The Conway Institute, University College Dublin, Belfield, Dublin, Republic of Ireland; Human Immunology and Cancer Program, University of Tennessee Graduate School of Medicine, Knoxville, Tennessee, United States of America.
authors.forename: Brian
authors.initials: B
authors.lastname: O'Nuallain
mesh_terms: D000682:Amyloid / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D051379:Mice; D066263:Protein Aggregation, Pathological / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D000682:Amyloid; D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G