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

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

in Adverse events / Affinity / Amino acids / Animals / Antibodies, Monoclonal - therapeutic use / antibody engineering / Antiinfectives and antibacterials / Antimicrobial agents / Antitoxins / botulinum neurotoxin / Botulinum toxin / Botulinum Toxins - immunology / Botulism / Botulism - immunology / Cattle / Chemotherapy / Epitopes / Female / Food contamination / Humans / Libraries / Mice / Molecular evolution / Monoclonal antibodies / Mosaics / Neurotoxins / Neutralization / oligoclonal antibodies / recombinant antibodies / Serogroup / serotype C botulism / serotype D botulism / Serotypes / Toxins / Yeast

2021

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

2021

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

2021

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Journal Article

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

Yan, Shude,

Geren, Isin N.,

Marks, James D.,

Lou, Jianlong,

Conrad, Fraser,

Smith, Theresa J.,

Wen, Wei-Hua,

Sun, Zhengda,

Skerry, Janet C.,

Brown, Jennifer L.,

Smith, Leonard A.,

Dong, Jianbo,

Garcia-Rodriguez, Consuelo,

Knopp, Kristeene A.,

Farr-Jones, Shauna

2021

Overview

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.

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Publisher

MDPI AG,MDPI

Subject

Adverse events

/ Affinity

/ Amino acids

/ Animals

/ Antibodies, Monoclonal - therapeutic use

/ antibody engineering

/ Antiinfectives and antibacterials