University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

MassBiologics; Department of Biochemistry and Molecular Pharmacology; Department of Neurology

Publication Date

4-17-2013

Document Type

Article

Subjects

Antibodies, Monoclonal; Superoxide Dismutase; Amyotrophic Lateral Sclerosis

Disciplines

Biochemistry | Immunology and Infectious Disease | Immunoprophylaxis and Therapy | Nervous System Diseases | Neurology

Abstract

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.

Rights and Permissions

Citation: PLoS One. 2013 Apr 17;8(4):e61210. doi: 10.1371/journal.pone.0061210. Print 2013. Link to article on publisher's site

Comments

Copyright: © 2013 Broering et al. 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 credited.

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

PloS one

PubMed ID

23613814

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