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: Yona Levites, Brian O'Nuallain, Rama Devudu Puligedda, Tomas Ondrejcak, Sharad P Adekar, Cindy Chen, Pedro E Cruz, Awilda M Rosario, Sallie Macy, Alexandra J Mably, Dominic M Walsh, Ruben Vidal, Alan Solomon, Daniel Brown, Michael J Rowan, Todd E Golde, Scott K Dessain
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 35 Issue 16 Pg. 6265-76 (Apr 22 2015) ISSN: 1529-2401 [Electronic] United States
• PMID: 25904780 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 the authors 0270-6474/15/356265-12$15.00/0.

Chemical References

• Amyloid
• Amyloid beta-Peptides
• Antibodies, Monoclonal
• Immunoglobulin G

Topics

• Amyloid (drug effects, metabolism)
• Amyloid beta-Peptides (immunology)
• Animals
• Antibodies, Monoclonal (immunology, pharmacology)
• Brain (metabolism)
• Cataract (immunology)
• Cerebellar Ataxia (immunology)
• Cerebral Amyloid Angiopathy (immunology)
• Deafness (immunology)
• Dementia (immunology)
• Humans
• Immunoglobulin G (immunology, pharmacology)
• Male
• Mice
• Mice, Transgenic
• Rats