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

Toxins
Jianlong LouJames D Marks

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 multivale...Continue Reading

References

Aug 1, 1996·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·R G HibbsK T McKee
Oct 23, 1998·Nature Structural Biology·D B LacyR C Stevens
Dec 20, 2000·The Journal of Immunology : Official Journal of the American Association of Immunologists·R SchoonjansN Mertens
Aug 15, 2002·Proceedings of the National Academy of Sciences of the United States of America·A NowakowskiJ D Marks
Apr 23, 2004·Biological Procedures Online·Melanie OhiThomas Walz
Dec 24, 2004·Proceedings of the National Academy of Sciences of the United States of America·Carol E O'Hear, Jefferson Foote
Feb 3, 2006·The New England Journal of Medicine·Stephen S ArnonCharles L Hatheway
Dec 19, 2006·Nature Biotechnology·Consuelo Garcia-RodriguezJames D Marks
Apr 5, 2007·Nature Protocols·Stefanie Kaech, Gary Banker
Jun 10, 2008·Toxicology·Luisa W ChengJ Mark Carter
Jun 10, 2008·The Journal of Pharmacology and Experimental Therapeutics·Fetweh H Al-SaleemLance L Simpson
Feb 17, 2010·Protein Engineering, Design & Selection : PEDS·J LouJ D Marks
Apr 30, 2010·Expert Opinion on Biological Therapy·Jean-Emmanuel Kurtz, Patrick Dufour
Dec 15, 2010·Protein Engineering, Design & Selection : PEDS·C Garcia-RodriguezJ D Marks
Sep 8, 2011·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Ryan P FaganWajahat Khalil
Sep 1, 2012·Protein Engineering, Design & Selection : PEDS·R CastoldiC Sustmann
Dec 4, 2013·International Immunopharmacology·Yulia VugmeysterSheldon S Leung

❮ Previous
Next ❯

Citations

Jun 24, 2020·Sensors·Mark H Smith, Daniel Fologea
Oct 9, 2019·Antimicrobial Agents and Chemotherapy·Doris M SnowMilan T Tomic
Nov 30, 2018·Toxins·Jianlong Lou, James D Marks
Apr 6, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Sébastien BrierMichel R Popoff

❮ Previous
Next ❯

Methods Mentioned

BETA
electron microscopy
X-ray
PCR
electrophoresis
equilibrium titration
immunoprecipitation assay
Assay
ELISA

Clinical Trials Mentioned

NCT02779140
NCT03046550

Software Mentioned

KinExA Pro
Graphpad Prism
NIH Image J

Related Concepts

Related Feeds

Antibody Specificity

Antibodies produced by B cells are highly specific for antigen as a result of random gene recombination and somatic hypermutation and affinity maturation. As the main effector of the humoral immune system, antibodies can neutralize foreign cells. Find the latest research on antibody specificity here.