IgG conformer's binding to amyloidogenic aggregates

Monichan Phay, Alfred T. Welzel, Angela D. Williams, Helen P. McWilliams-Koeppen, Veronika Blinder, Tiernan T. O'Malley, Alan Solomon, Dominic M. Walsh, Brian O'Nuallain

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere0137344
JournalPloS one
Volume10
Issue number9
DOIs
StatePublished - Sep 14 2015

Fingerprint

protein aggregates
Amyloid
Immunoglobulin G
Prealbumin
Intravenous Immunoglobulins
amyloid
Amyloidogenic Proteins
prealbumin
immunoglobulins
Binding Sites
Monomers
Peptides
Antibodies
Serum
blood serum
Dimers
binding sites
Blood
peptides
Plasmas

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Phay, M., Welzel, A. T., Williams, A. D., McWilliams-Koeppen, H. P., Blinder, V., O'Malley, T. T., ... O'Nuallain, B. (2015). IgG conformer's binding to amyloidogenic aggregates. PloS one, 10(9), [e0137344]. https://doi.org/10.1371/journal.pone.0137344

IgG conformer's binding to amyloidogenic aggregates. / Phay, Monichan; Welzel, Alfred T.; Williams, Angela D.; McWilliams-Koeppen, Helen P.; Blinder, Veronika; O'Malley, Tiernan T.; Solomon, Alan; Walsh, Dominic M.; O'Nuallain, Brian.

In: PloS one, Vol. 10, No. 9, e0137344, 14.09.2015.

Research output: Contribution to journalArticle

Phay, M, Welzel, AT, Williams, AD, McWilliams-Koeppen, HP, Blinder, V, O'Malley, TT, Solomon, A, Walsh, DM & O'Nuallain, B 2015, 'IgG conformer's binding to amyloidogenic aggregates', PloS one, vol. 10, no. 9, e0137344. https://doi.org/10.1371/journal.pone.0137344
Phay M, Welzel AT, Williams AD, McWilliams-Koeppen HP, Blinder V, O'Malley TT et al. IgG conformer's binding to amyloidogenic aggregates. PloS one. 2015 Sep 14;10(9). e0137344. https://doi.org/10.1371/journal.pone.0137344
Phay, Monichan ; Welzel, Alfred T. ; Williams, Angela D. ; McWilliams-Koeppen, Helen P. ; Blinder, Veronika ; O'Malley, Tiernan T. ; Solomon, Alan ; Walsh, Dominic M. ; O'Nuallain, Brian. / IgG conformer's binding to amyloidogenic aggregates. In: PloS one. 2015 ; Vol. 10, No. 9.
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