A Four-Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotypes C and D

Consuelo Garcia-Rodriguez; Shude Yan; Isin N. Geren; Kristeene A. Knopp; Jianbo Dong; Zhengda Sun; Jianlong Lou; Fraser Conrad; Wei-Hua Wen; Shauna Farr-Jones; Theresa J. Smith; Jennifer L. Brown; Janet C. Skerry; Leonard A. Smith; James D. Marks

doi:10.3390/toxins13090641

Toxins (Sep 2021)

A Four-Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotypes C and D

Consuelo Garcia-Rodriguez,
Shude Yan,
Isin N. Geren,
Kristeene A. Knopp,
Jianbo Dong,
Zhengda Sun,
Jianlong Lou,
Fraser Conrad,
Wei-Hua Wen,
Shauna Farr-Jones,
Theresa J. Smith,
Jennifer L. Brown,
Janet C. Skerry,
Leonard A. Smith,
James D. Marks

Affiliations

Consuelo Garcia-Rodriguez: Department of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USA
Shude Yan: Department of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USA
Isin N. Geren: Department of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USA
Kristeene A. Knopp: Department of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USA
Jianbo Dong: Department of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USA
Zhengda Sun: Department of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USA
Jianlong Lou: Department of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USA
Fraser Conrad: Department of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USA
Wei-Hua Wen: Department of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USA
Shauna Farr-Jones: Department of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USA
Theresa J. Smith: Molecular and Translational Sciences Division, United States Army Medical Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USA
Jennifer L. Brown: Ke’aki Technologies LLC, United States Army Medical Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USA
Janet C. Skerry: Ke’aki Technologies LLC, United States Army Medical Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USA
Leonard A. Smith: Medical Countermeasures Technology, United States Army Medical Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USA
James D. Marks: Department of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USA

DOI: https://doi.org/10.3390/toxins13090641
Journal volume & issue: Vol. 13, no. 9
p. 641

Abstract

Read online

Human botulism can be caused by botulinum neurotoxin (BoNT) serotypes A to G. Here, we present an antibody-based antitoxin composed of four human monoclonal antibodies (mAbs) against BoNT/C, BoNT/D, and their mosaic toxins. This work built on our success in generating protective mAbs to BoNT /A, B and E serotypes. We generated mAbs from human immune single-chain Fv (scFv) yeast-display libraries and isolated scFvs with high affinity for BoNT/C, BoNT/CD, BoNT/DC and BoNT/D serotypes. We identified four mAbs that bound non-overlapping epitopes on multiple serotypes and mosaic BoNTs. Three of the mAbs underwent molecular evolution to increase affinity. A four-mAb combination provided high-affinity binding and BoNT neutralization of both serotypes and their mosaic toxins. The mAbs have potential utility as therapeutics and as diagnostics capable of recognizing and neutralizing BoNT/C and BoNT/D serotypes and their mosaic toxins. A derivative of the four-antibody combination (NTM-1634) completed a Phase 1 clinical trial (Snow et al., Antimicrobial Agents and Chemotherapy, 2019) with no drug-related serious adverse events.

Published in Toxins

ISSN: 2072-6651 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine
Website: http://www.mdpi.com/journal/toxins/

About the journal

Abstract

Keywords