A Rationally Designed Humanized Antibody Selective for Amyloid Beta Oligomers in Alzheimer’s Disease

Abstract Advances in the understanding of Alzheimer’s disease (AD) suggest that pathogenesis is not directly related to plaque burden, but rather to soluble toxic amyloid-beta oligomers (AßO). Therapeutic antibodies targeting Aß monomers and/or plaque have shown limited efficacy and dose-limiting ad...

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Autores principales:	Ebrima Gibbs, Judith M. Silverman, Beibei Zhao, Xubiao Peng, Jing Wang, Cheryl L. Wellington, Ian R. Mackenzie, Steven S. Plotkin, Johanne M. Kaplan, Neil R. Cashman
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7e17d617f44d4cba8b63f9167f89ea62
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spelling	oai:doaj.org-article:7e17d617f44d4cba8b63f9167f89ea622021-12-02T15:09:24ZA Rationally Designed Humanized Antibody Selective for Amyloid Beta Oligomers in Alzheimer’s Disease10.1038/s41598-019-46306-52045-2322https://doaj.org/article/7e17d617f44d4cba8b63f9167f89ea622019-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-46306-5https://doaj.org/toc/2045-2322Abstract Advances in the understanding of Alzheimer’s disease (AD) suggest that pathogenesis is not directly related to plaque burden, but rather to soluble toxic amyloid-beta oligomers (AßO). Therapeutic antibodies targeting Aß monomers and/or plaque have shown limited efficacy and dose-limiting adverse events in clinical trials. These findings suggest that antibodies capable of selectively neutralizing toxic AßO may achieve improved efficacy and safety. To this end, we generated monoclonal antibodies against a conformational Aß epitope predicted by computational modeling to be presented on toxic AßO but not monomers or fibrils. The resulting lead antibody, PMN310, showed the desired AßO-selective binding profile. In vitro, PMN310 inhibited AßO propagation and toxicity. In vivo, PMN310 prevented AßO-induced loss of memory formation and reduced synaptic loss and inflammation. A humanized version (huPMN310) compared favorably to other Aß-directed antibodies showing a lack of adverse event-associated binding to Aß deposits in AD brains, and greater selective binding to AßO-enriched AD brain fractions that contain synaptotoxic Aß species. Systemic administration of huPMN310 in mice resulted in brain exposure and kinetics comparable to those of other therapeutic human monoclonal antibodies. Greater selectivity for AßO and the potential to safely administer high doses of huPMN310 are expected to result in enhanced safety and therapeutic potency.Ebrima GibbsJudith M. SilvermanBeibei ZhaoXubiao PengJing WangCheryl L. WellingtonIan R. MackenzieSteven S. PlotkinJohanne M. KaplanNeil R. CashmanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-14 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ebrima Gibbs Judith M. Silverman Beibei Zhao Xubiao Peng Jing Wang Cheryl L. Wellington Ian R. Mackenzie Steven S. Plotkin Johanne M. Kaplan Neil R. Cashman A Rationally Designed Humanized Antibody Selective for Amyloid Beta Oligomers in Alzheimer’s Disease
description	Abstract Advances in the understanding of Alzheimer’s disease (AD) suggest that pathogenesis is not directly related to plaque burden, but rather to soluble toxic amyloid-beta oligomers (AßO). Therapeutic antibodies targeting Aß monomers and/or plaque have shown limited efficacy and dose-limiting adverse events in clinical trials. These findings suggest that antibodies capable of selectively neutralizing toxic AßO may achieve improved efficacy and safety. To this end, we generated monoclonal antibodies against a conformational Aß epitope predicted by computational modeling to be presented on toxic AßO but not monomers or fibrils. The resulting lead antibody, PMN310, showed the desired AßO-selective binding profile. In vitro, PMN310 inhibited AßO propagation and toxicity. In vivo, PMN310 prevented AßO-induced loss of memory formation and reduced synaptic loss and inflammation. A humanized version (huPMN310) compared favorably to other Aß-directed antibodies showing a lack of adverse event-associated binding to Aß deposits in AD brains, and greater selective binding to AßO-enriched AD brain fractions that contain synaptotoxic Aß species. Systemic administration of huPMN310 in mice resulted in brain exposure and kinetics comparable to those of other therapeutic human monoclonal antibodies. Greater selectivity for AßO and the potential to safely administer high doses of huPMN310 are expected to result in enhanced safety and therapeutic potency.
format	article
author	Ebrima Gibbs Judith M. Silverman Beibei Zhao Xubiao Peng Jing Wang Cheryl L. Wellington Ian R. Mackenzie Steven S. Plotkin Johanne M. Kaplan Neil R. Cashman
author_facet	Ebrima Gibbs Judith M. Silverman Beibei Zhao Xubiao Peng Jing Wang Cheryl L. Wellington Ian R. Mackenzie Steven S. Plotkin Johanne M. Kaplan Neil R. Cashman
author_sort	Ebrima Gibbs
title	A Rationally Designed Humanized Antibody Selective for Amyloid Beta Oligomers in Alzheimer’s Disease
title_short	A Rationally Designed Humanized Antibody Selective for Amyloid Beta Oligomers in Alzheimer’s Disease
title_full	A Rationally Designed Humanized Antibody Selective for Amyloid Beta Oligomers in Alzheimer’s Disease
title_fullStr	A Rationally Designed Humanized Antibody Selective for Amyloid Beta Oligomers in Alzheimer’s Disease
title_full_unstemmed	A Rationally Designed Humanized Antibody Selective for Amyloid Beta Oligomers in Alzheimer’s Disease
title_sort	rationally designed humanized antibody selective for amyloid beta oligomers in alzheimer’s disease
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/7e17d617f44d4cba8b63f9167f89ea62
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A Rationally Designed Humanized Antibody Selective for Amyloid Beta Oligomers in Alzheimer’s Disease

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