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
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.
