A human monoclonal IgG that binds Aβ assemblies and diverse amyloids exhibits anti-amyloid activities in vitro and in vivo

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)6265-6276
Number of pages12
JournalJournal of Neuroscience
Volume35
Issue number16
DOIs
StatePublished - Apr 22 2015

Fingerprint

Amyloid
Immunoglobulin G
Alzheimer Disease
Antibodies
Epitopes
In Vitro Techniques
Cerebral Amyloid Angiopathy
Amyloidogenic Proteins
Light
Single-Chain Antibodies
Dependovirus
Neuronal Plasticity
Hybridomas
Transgenic Mice
B-Lymphocytes
Enzyme-Linked Immunosorbent Assay
Pathology
Brain
Therapeutics
Serum

Keywords

  • Alzheimer’s disease
  • Amyloid
  • Amyloid beta
  • Animal study
  • Antibody
  • IVIG

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Levites, Y., O’Nuallain, B., Puligedda, R. D., Ondrejcak, T., Adekar, S. P., Chen, C., ... Dessain, S. K. (2015). A human monoclonal IgG that binds Aβ assemblies and diverse amyloids exhibits anti-amyloid activities in vitro and in vivo. Journal of Neuroscience, 35(16), 6265-6276. https://doi.org/10.1523/JNEUROSCI.5109-14.2015

A human monoclonal IgG that binds Aβ assemblies and diverse amyloids exhibits anti-amyloid activities in vitro and in vivo. / Levites, Yona; O’Nuallain, Brian; Puligedda, Rama Devudu; Ondrejcak, Tomas; Adekar, Sharad P.; Chen, Cindy; Cruz, Pedro E.; Rosario, Awilda M.; Macy, Sallie; Mably, Alexandra J.; Walsh, Dominic M.; Vidal, Ruben; Solomon, Alan; Brown, Daniel; Rowan, Michael J.; Golde, Todd E.; Dessain, Scott K.

In: Journal of Neuroscience, Vol. 35, No. 16, 22.04.2015, p. 6265-6276.

Research output: Contribution to journalArticle

Levites, Y, O’Nuallain, B, Puligedda, RD, Ondrejcak, T, Adekar, SP, Chen, C, Cruz, PE, Rosario, AM, Macy, S, Mably, AJ, Walsh, DM, Vidal, R, Solomon, A, Brown, D, Rowan, MJ, Golde, TE & Dessain, SK 2015, 'A human monoclonal IgG that binds Aβ assemblies and diverse amyloids exhibits anti-amyloid activities in vitro and in vivo', Journal of Neuroscience, vol. 35, no. 16, pp. 6265-6276. https://doi.org/10.1523/JNEUROSCI.5109-14.2015
Levites, Yona ; O’Nuallain, Brian ; Puligedda, Rama Devudu ; Ondrejcak, Tomas ; Adekar, Sharad P. ; Chen, Cindy ; Cruz, Pedro E. ; Rosario, Awilda M. ; Macy, Sallie ; Mably, Alexandra J. ; Walsh, Dominic M. ; Vidal, Ruben ; Solomon, Alan ; Brown, Daniel ; Rowan, Michael J. ; Golde, Todd E. ; Dessain, Scott K. / A human monoclonal IgG that binds Aβ assemblies and diverse amyloids exhibits anti-amyloid activities in vitro and in vivo. In: Journal of Neuroscience. 2015 ; Vol. 35, No. 16. pp. 6265-6276.
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T1 - A human monoclonal IgG that binds Aβ assemblies and diverse amyloids exhibits anti-amyloid activities in vitro and in vivo

AU - Levites, Yona

AU - O’Nuallain, Brian

AU - Puligedda, Rama Devudu

AU - Ondrejcak, Tomas

AU - Adekar, Sharad P.

AU - Chen, Cindy

AU - Cruz, Pedro E.

AU - Rosario, Awilda M.

AU - Macy, Sallie

AU - Mably, Alexandra J.

AU - Walsh, Dominic M.

AU - Vidal, Ruben

AU - Solomon, Alan

AU - Brown, Daniel

AU - Rowan, Michael J.

AU - Golde, Todd E.

AU - Dessain, Scott K.

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N2 - 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.

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