Identification of Human Monoclonal Antibodies Specific for Human SOD1 Recognizing Distinct Epitopes and Forms of SOD1

Mutations in the gene encoding human SOD1 (hSOD1) can cause amyotrophic lateral sclerosis (ALS) yet the mechanism by which mutant SOD1 can induce ALS is not fully understood. There is currently no cure for ALS or treatment that significantly reduces symptoms or progression. To develop tools to under...

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Main Authors:	Broering, Teresa J., Wang, Hongyan, Boatright, Naomi K., Wang, Yang, Baptista, Katherine, Shayan, Gilda, Garrity, Kerry A., Kayatekin, Can, Bosco, Daryl A., Matthews, C. Robert, Ambrosino, Donna M., Xu, Zuoshang, Babcock, Gregory J.
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629177/

id	pubmed-3629177
recordtype	oai_dc
spelling	pubmed-36291772013-04-23 Identification of Human Monoclonal Antibodies Specific for Human SOD1 Recognizing Distinct Epitopes and Forms of SOD1 Broering, Teresa J. Wang, Hongyan Boatright, Naomi K. Wang, Yang Baptista, Katherine Shayan, Gilda Garrity, Kerry A. Kayatekin, Can Bosco, Daryl A. Matthews, C. Robert Ambrosino, Donna M. Xu, Zuoshang Babcock, Gregory J. Research Article Mutations in the gene encoding human SOD1 (hSOD1) can cause amyotrophic lateral sclerosis (ALS) yet the mechanism by which mutant SOD1 can induce ALS is not fully understood. There is currently no cure for ALS or treatment that significantly reduces symptoms or progression. To develop tools to understand the protein conformations present in mutant SOD1-induced ALS and as possible immunotherapy, we isolated and characterized eleven unique human monoclonal antibodies specific for hSOD1. Among these, five recognized distinct linear epitopes on hSOD1 that were not available in the properly-folded protein but were available on forms of protein with some degree of misfolding. The other six antibodies recognized conformation-dependent epitopes that were present in the properly-folded protein with two different recognition profiles: three could bind hSOD1 dimer or monomer and the other three were specific for hSOD1 dimer only. Antibodies with the capacity to bind hSOD1 monomer were able to prevent increased hydrophobicity when mutant hSOD1 was exposed to increased temperature and EDTA, suggesting that the antibodies stabilized the native structure of hSOD1. Two antibodies were tested in a G93A mutant hSOD1 transgenic mouse model of ALS but did not yield a statistically significant increase in overall survival. It may be that the two antibodies selected for testing in the mouse model were not effective for therapy or that the model and/or route of administration were not optimal to produce a therapeutic effect. Therefore, additional testing will be required to determine therapeutic potential for SOD1 mutant ALS and potentially some subset of sporadic ALS. Public Library of Science 2013-04-17 /pmc/articles/PMC3629177/ /pubmed/23613814 http://dx.doi.org/10.1371/journal.pone.0061210 Text en © 2013 Broering et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Broering, Teresa J. Wang, Hongyan Boatright, Naomi K. Wang, Yang Baptista, Katherine Shayan, Gilda Garrity, Kerry A. Kayatekin, Can Bosco, Daryl A. Matthews, C. Robert Ambrosino, Donna M. Xu, Zuoshang Babcock, Gregory J.
spellingShingle	Broering, Teresa J. Wang, Hongyan Boatright, Naomi K. Wang, Yang Baptista, Katherine Shayan, Gilda Garrity, Kerry A. Kayatekin, Can Bosco, Daryl A. Matthews, C. Robert Ambrosino, Donna M. Xu, Zuoshang Babcock, Gregory J. Identification of Human Monoclonal Antibodies Specific for Human SOD1 Recognizing Distinct Epitopes and Forms of SOD1
author_facet	Broering, Teresa J. Wang, Hongyan Boatright, Naomi K. Wang, Yang Baptista, Katherine Shayan, Gilda Garrity, Kerry A. Kayatekin, Can Bosco, Daryl A. Matthews, C. Robert Ambrosino, Donna M. Xu, Zuoshang Babcock, Gregory J.
author_sort	Broering, Teresa J.
title	Identification of Human Monoclonal Antibodies Specific for Human SOD1 Recognizing Distinct Epitopes and Forms of SOD1
title_short	Identification of Human Monoclonal Antibodies Specific for Human SOD1 Recognizing Distinct Epitopes and Forms of SOD1
title_full	Identification of Human Monoclonal Antibodies Specific for Human SOD1 Recognizing Distinct Epitopes and Forms of SOD1
title_fullStr	Identification of Human Monoclonal Antibodies Specific for Human SOD1 Recognizing Distinct Epitopes and Forms of SOD1
title_full_unstemmed	Identification of Human Monoclonal Antibodies Specific for Human SOD1 Recognizing Distinct Epitopes and Forms of SOD1
title_sort	identification of human monoclonal antibodies specific for human sod1 recognizing distinct epitopes and forms of sod1
description	Mutations in the gene encoding human SOD1 (hSOD1) can cause amyotrophic lateral sclerosis (ALS) yet the mechanism by which mutant SOD1 can induce ALS is not fully understood. There is currently no cure for ALS or treatment that significantly reduces symptoms or progression. To develop tools to understand the protein conformations present in mutant SOD1-induced ALS and as possible immunotherapy, we isolated and characterized eleven unique human monoclonal antibodies specific for hSOD1. Among these, five recognized distinct linear epitopes on hSOD1 that were not available in the properly-folded protein but were available on forms of protein with some degree of misfolding. The other six antibodies recognized conformation-dependent epitopes that were present in the properly-folded protein with two different recognition profiles: three could bind hSOD1 dimer or monomer and the other three were specific for hSOD1 dimer only. Antibodies with the capacity to bind hSOD1 monomer were able to prevent increased hydrophobicity when mutant hSOD1 was exposed to increased temperature and EDTA, suggesting that the antibodies stabilized the native structure of hSOD1. Two antibodies were tested in a G93A mutant hSOD1 transgenic mouse model of ALS but did not yield a statistically significant increase in overall survival. It may be that the two antibodies selected for testing in the mouse model were not effective for therapy or that the model and/or route of administration were not optimal to produce a therapeutic effect. Therefore, additional testing will be required to determine therapeutic potential for SOD1 mutant ALS and potentially some subset of sporadic ALS.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629177/
_version_	1611970903867916288

Identification of Human Monoclonal Antibodies Specific for Human SOD1 Recognizing Distinct Epitopes and Forms of SOD1

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