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Toxins 2018, 10(2), 84; https://doi.org/10.3390/toxins10020084

A Single Tri-Epitopic Antibody Virtually Recapitulates the Potency of a Combination of Three Monoclonal Antibodies in Neutralization of Botulinum Neurotoxin Serotype A

1
Department of Anesthesia and Perioperative Care, University of California, San Francisco Rm 3C-38, San Francisco General Hospital, 1001 Potrero Ave, San Francisco, CA 94110, USA
2
Western Regional Research Center, Agricultural Research Service, United States Department of Agriculture, Albany, CA 94710, USA
3
Molecular and Translational Sciences Division, United States Army Medical Institute of Infectious Disease, Fort Detrick, MD 21702, USA
4
U. S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702, USA
5
Department of Pathology, University of California, San Francisco, ZSFG/UCSF, Bldg 3/ Rm 211, 1001 Potrero Ave., San Francisco, CA 94158, USA
*
Authors to whom correspondence should be addressed.
Received: 14 December 2017 / Revised: 5 February 2018 / Accepted: 13 February 2018 / Published: 15 February 2018
(This article belongs to the Special Issue Botulinum Neurotoxins Antibody and Vaccine)
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Abstract

The standard of treatment for botulism, equine antitoxin, is a foreign protein with associated safety issues and a short serum half-life which excludes its use as a prophylactic antitoxin and makes it a less-than-optimal therapeutic. Due to these limitations, a recombinant monoclonal antibody (mAb) product is preferable. It has been shown that combining three mAbs that bind non-overlapping epitopes leads to highly potent botulinum neurotoxin (BoNT) neutralization. Recently, a triple human antibody combination for BoNT/A has demonstrated potent toxin neutralization in mouse models with no serious adverse events when tested in a Phase I clinical trial. However, a triple antibody therapeutic poses unique development and manufacturing challenges. Thus, potentially to streamline development of BoNT antitoxins, we sought to achieve the potency of multiple mAb combinations in a single IgG-based molecule that has a long serum half-life. The design, production, and testing of a single tri-epitopic IgG1-based mAb (TeAb) containing the binding sites of each of the three parental BoNT/A mAbs yielded an antibody of nearly equal potency to the combination. The approach taken here could be applied to the design and creation of other multivalent antibodies that could be used for a variety of applications, including toxin elimination. View Full-Text
Keywords: bi-epitopic; tri-epitopic; multivalent antibody; recombinant monoclonal antibody; botulinum neurotoxin; antitoxin; botulism; mouse neutralization assay; negative-stain electron microscopy; kinetic-exclusion analysis bi-epitopic; tri-epitopic; multivalent antibody; recombinant monoclonal antibody; botulinum neurotoxin; antitoxin; botulism; mouse neutralization assay; negative-stain electron microscopy; kinetic-exclusion analysis
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Lou, J.; Wen, W.; Conrad, F.; Meng, Q.; Dong, J.; Sun, Z.; Garcia-Rodriguez, C.; Farr-Jones, S.; Cheng, L.W.; Henderson, T.D.; Brown, J.L.; Smith, T.J.; Smith, L.A.; Cormier, A.; Marks, J.D. A Single Tri-Epitopic Antibody Virtually Recapitulates the Potency of a Combination of Three Monoclonal Antibodies in Neutralization of Botulinum Neurotoxin Serotype A. Toxins 2018, 10, 84.

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