A generic method for design of oligomer-specific antibodies.

Antibodies that preferentially and specifically target pathological oligomeric protein and peptide assemblies, as opposed to their monomeric and amyloid counterparts, provide therapeutic and diagnostic opportunities for protein misfolding diseases. Unfortunately, the molecular properties associated...

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Autores principales:	Kristoffer Brännström, Malin Lindhagen-Persson, Anna L Gharibyan, Irina Iakovleva, Monika Vestling, Mikael E Sellin, Thomas Brännström, Ludmilla Morozova-Roche, Lars Forsgren, Anders Olofsson
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/85bdb2aa8c704054b936e00b43b5987b
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spelling	oai:doaj.org-article:85bdb2aa8c704054b936e00b43b5987b2021-11-18T08:28:49ZA generic method for design of oligomer-specific antibodies.1932-620310.1371/journal.pone.0090857https://doaj.org/article/85bdb2aa8c704054b936e00b43b5987b2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24618582/?tool=EBIhttps://doaj.org/toc/1932-6203Antibodies that preferentially and specifically target pathological oligomeric protein and peptide assemblies, as opposed to their monomeric and amyloid counterparts, provide therapeutic and diagnostic opportunities for protein misfolding diseases. Unfortunately, the molecular properties associated with oligomer-specific antibodies are not well understood, and this limits targeted design and development. We present here a generic method that enables the design and optimisation of oligomer-specific antibodies. The method takes a two-step approach where discrimination between oligomers and fibrils is first accomplished through identification of cryptic epitopes exclusively buried within the structure of the fibrillar form. The second step discriminates between monomers and oligomers based on differences in avidity. We show here that a simple divalent mode of interaction, as within e.g. the IgG isotype, can increase the binding strength of the antibody up to 1500 times compared to its monovalent counterpart. We expose how the ability to bind oligomers is affected by the monovalent affinity and the turnover rate of the binding and, importantly, also how oligomer specificity is only valid within a specific concentration range. We provide an example of the method by creating and characterising a spectrum of different monoclonal antibodies against both the Aβ peptide and α-synuclein that are associated with Alzheimer's and Parkinson's diseases, respectively. The approach is however generic, does not require identification of oligomer-specific architectures, and is, in essence, applicable to all polypeptides that form oligomeric and fibrillar assemblies.Kristoffer BrännströmMalin Lindhagen-PerssonAnna L GharibyanIrina IakovlevaMonika VestlingMikael E SellinThomas BrännströmLudmilla Morozova-RocheLars ForsgrenAnders OlofssonPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 3, p e90857 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Kristoffer Brännström Malin Lindhagen-Persson Anna L Gharibyan Irina Iakovleva Monika Vestling Mikael E Sellin Thomas Brännström Ludmilla Morozova-Roche Lars Forsgren Anders Olofsson A generic method for design of oligomer-specific antibodies.
description	Antibodies that preferentially and specifically target pathological oligomeric protein and peptide assemblies, as opposed to their monomeric and amyloid counterparts, provide therapeutic and diagnostic opportunities for protein misfolding diseases. Unfortunately, the molecular properties associated with oligomer-specific antibodies are not well understood, and this limits targeted design and development. We present here a generic method that enables the design and optimisation of oligomer-specific antibodies. The method takes a two-step approach where discrimination between oligomers and fibrils is first accomplished through identification of cryptic epitopes exclusively buried within the structure of the fibrillar form. The second step discriminates between monomers and oligomers based on differences in avidity. We show here that a simple divalent mode of interaction, as within e.g. the IgG isotype, can increase the binding strength of the antibody up to 1500 times compared to its monovalent counterpart. We expose how the ability to bind oligomers is affected by the monovalent affinity and the turnover rate of the binding and, importantly, also how oligomer specificity is only valid within a specific concentration range. We provide an example of the method by creating and characterising a spectrum of different monoclonal antibodies against both the Aβ peptide and α-synuclein that are associated with Alzheimer's and Parkinson's diseases, respectively. The approach is however generic, does not require identification of oligomer-specific architectures, and is, in essence, applicable to all polypeptides that form oligomeric and fibrillar assemblies.
format	article
author	Kristoffer Brännström Malin Lindhagen-Persson Anna L Gharibyan Irina Iakovleva Monika Vestling Mikael E Sellin Thomas Brännström Ludmilla Morozova-Roche Lars Forsgren Anders Olofsson
author_facet	Kristoffer Brännström Malin Lindhagen-Persson Anna L Gharibyan Irina Iakovleva Monika Vestling Mikael E Sellin Thomas Brännström Ludmilla Morozova-Roche Lars Forsgren Anders Olofsson
author_sort	Kristoffer Brännström
title	A generic method for design of oligomer-specific antibodies.
title_short	A generic method for design of oligomer-specific antibodies.
title_full	A generic method for design of oligomer-specific antibodies.
title_fullStr	A generic method for design of oligomer-specific antibodies.
title_full_unstemmed	A generic method for design of oligomer-specific antibodies.
title_sort	generic method for design of oligomer-specific antibodies.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/85bdb2aa8c704054b936e00b43b5987b
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A generic method for design of oligomer-specific antibodies.

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