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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Published inToxins Vol. 13; no. 9; p. 641
Main Authors Garcia-Rodriguez, Consuelo, Yan, Shude, Geren, Isin N, Knopp, Kristeene A, Dong, Jianbo, Sun, Zhengda, Lou, Jianlong, Conrad, Fraser, Wen, Wei-Hua, Farr-Jones, Shauna, Smith, Theresa J, Brown, Jennifer L, Skerry, Janet C, Smith, Leonard A, Marks, James D
Format Journal Article
LanguageEnglish
Published Switzerland MDPI AG 10.09.2021
MDPI
Subjects
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
Yeasts
antibody engineering
serotype D botulism
serotype C botulism
mouse neutralization assay
oligoclonal antibodies
recombinant antibodies
botulinum antitoxin
botulinum neurotoxin
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Abstract 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.
AbstractList 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.
Author Yan, Shude
Smith, Theresa J
Skerry, Janet C
Lou, Jianlong
Conrad, Fraser
Wen, Wei-Hua
Sun, Zhengda
Knopp, Kristeene A
Brown, Jennifer L
Geren, Isin N
Dong, Jianbo
Garcia-Rodriguez, Consuelo
Smith, Leonard A
Marks, James D
Farr-Jones, Shauna
AuthorAffiliation 4 Medical Countermeasures Technology, United States Army Medical Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USA; leonard.a.smith@comcast.net
3 Ke’aki Technologies LLC, United States Army Medical Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USA; jennifer.l.brown436.ctr@mail.mil (J.L.B.); jcskerry@gmail.com (J.C.S.)
2 Molecular and Translational Sciences Division, United States Army Medical Institute of Infectious Diseases (USAMRIID), Fort Detrick, MD 21702, USA; terrys2much@comcast.net
1 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; maconsuelo.gr@gmail.com (C.G.-R.); shudeyan@yahoo.com (S.Y.); isin.geren@medeniyet.edu.tr (I.N.G.); Kristeeneknopp@gmail.com (K.A.K.); jianbodong@gmail.com (J.D.); zhengda_sun@hotmail.com (Z.S.); jianlong.lou@ucsf.edu (J.L.); fraser.conrad@ucsf.edu (F.C.); wei.
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– name: 1 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; maconsuelo.gr@gmail.com (C.G.-R.); shudeyan@yahoo.com (S.Y.); isin.geren@medeniyet.edu.tr (I.N.G.); Kristeeneknopp@gmail.com (K.A.K.); jianbodong@gmail.com (J.D.); zhengda_sun@hotmail.com (Z.S.); jianlong.lou@ucsf.edu (J.L.); fraser.conrad@ucsf.edu (F.C.); wei.wen@ucsf.edu (W.-H.W.); shauna.farr-jones@ucsf.edu (S.F.-J.)
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  orcidid: 0000-0003-4130-6332
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  givenname: Janet C
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  givenname: Leonard A
  surname: Smith
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  orcidid: 0000-0003-0562-3517
  surname: Marks
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  organization: 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
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Keywords antibody engineering
serotype D botulism
serotype C botulism
mouse neutralization assay
oligoclonal antibodies
recombinant antibodies
botulinum antitoxin
botulinum neurotoxin
Language English
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Snippet 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...
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StartPage 641
SubjectTerms 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
Yeasts
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Title A Four-Monoclonal Antibody Combination Potently Neutralizes Multiple Botulinum Neurotoxin Serotypes C and D
URI https://www.ncbi.nlm.nih.gov/pubmed/34564645
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https://search.proquest.com/docview/2576904419
https://pubmed.ncbi.nlm.nih.gov/PMC8472335
https://doaj.org/article/a25047536f784a189fd6ca0fc69595fc
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