A Four-Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotypes C and D
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 a...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-09-01
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| Series: | Toxins |
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| Online Access: | https://www.mdpi.com/2072-6651/13/9/641 |
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doaj-a25047536f784a189fd6ca0fc69595fc |
|---|---|
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 A Four-Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotypes C and D Toxins botulinum neurotoxin oligoclonal antibodies serotype C botulism serotype D botulism recombinant antibodies antibody engineering |
| author_facet |
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 |
| author_sort |
Consuelo Garcia-Rodriguez |
| title |
A Four-Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotypes C and D |
| title_short |
A Four-Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotypes C and D |
| title_full |
A Four-Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotypes C and D |
| title_fullStr |
A Four-Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotypes C and D |
| title_full_unstemmed |
A Four-Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotypes C and D |
| title_sort |
four-monoclonal antibody combination potently neutralizes multiple botulinum neurotoxin serotypes c and d |
| publisher |
MDPI AG |
| series |
Toxins |
| issn |
2072-6651 |
| publishDate |
2021-09-01 |
| description |
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. |
| topic |
botulinum neurotoxin oligoclonal antibodies serotype C botulism serotype D botulism recombinant antibodies antibody engineering |
| url |
https://www.mdpi.com/2072-6651/13/9/641 |
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doaj-a25047536f784a189fd6ca0fc69595fc2021-09-26T01:33:39ZengMDPI AGToxins2072-66512021-09-011364164110.3390/toxins13090641A Four-Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotypes C and DConsuelo Garcia-Rodriguez0Shude Yan1Isin N. Geren2Kristeene A. Knopp3Jianbo Dong4Zhengda Sun5Jianlong Lou6Fraser Conrad7Wei-Hua Wen8Shauna Farr-Jones9Theresa J. Smith10Jennifer L. Brown11Janet C. Skerry12Leonard A. Smith13James D. Marks14Department of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USADepartment of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USADepartment of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USADepartment of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USADepartment of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USADepartment of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USADepartment of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USADepartment of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USADepartment of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USADepartment of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USAMolecular and Translational Sciences Division, United States Army Medical Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USAKe’aki Technologies LLC, United States Army Medical Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USAKe’aki Technologies LLC, United States Army Medical Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USAMedical Countermeasures Technology, United States Army Medical Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USADepartment of Anesthesia & Perioperative Care, University of California, San Francisco, Zuckerberg San Francisco General Hospital and Trauma Center, 1001 Potrero Avenue, San Francisco, CA 94110, USAHuman 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.https://www.mdpi.com/2072-6651/13/9/641botulinum neurotoxinoligoclonal antibodiesserotype C botulismserotype D botulismrecombinant antibodiesantibody engineering |