A Single Tri-Epitopic Antibody Virtually Recapitulates the Potency of a Combination of Three Monoclonal Antibodies in Neutralization of Botulinum Neurotoxin Serotype A
Jianlong Lou,
Weihua Wen,
Fraser Conrad,
Qi Meng,
Jianbo Dong,
Zhengda Sun,
Consuelo Garcia-Rodriguez,
Shauna Farr-Jones,
Luisa W. Cheng,
Thomas D. Henderson,
Jennifer L. Brown,
Theresa J. Smith,
Leonard A. Smith,
Anthony Cormier,
James D. Marks
Affiliations
Jianlong Lou
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
Weihua Wen
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
Fraser Conrad
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
Qi Meng
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
Jianbo Dong
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
Zhengda Sun
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
Consuelo Garcia-Rodriguez
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
Shauna Farr-Jones
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
Luisa W. Cheng
Western Regional Research Center, Agricultural Research Service, United States Department of Agriculture, Albany, CA 94710, USA
Thomas D. Henderson
Western Regional Research Center, Agricultural Research Service, United States Department of Agriculture, Albany, CA 94710, USA
Jennifer L. Brown
Molecular and Translational Sciences Division, United States Army Medical Institute of Infectious Disease, Fort Detrick, MD 21702, USA
Theresa J. Smith
Molecular and Translational Sciences Division, United States Army Medical Institute of Infectious Disease, Fort Detrick, MD 21702, USA
Leonard A. Smith
U. S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702, USA
Anthony Cormier
Department of Pathology, University of California, San Francisco, ZSFG/UCSF, Bldg 3/ Rm 211, 1001 Potrero Ave., San Francisco, CA 94158, USA
James D. Marks
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
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.
