Cited by 37Botulinum Toxin and Related Neurological DisordersMonoclonal and Polyclonal Antibodies ResearchToxin Mechanisms and Immunotoxins

Prolonged Prophylactic Protection from Botulism with a Single Adenovirus Treatment Promoting Serum Expression of a VHH-Based Antitoxin Protein

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Mukherjee, Jean, Dmitriev, Igor, Debatis, Michelle, Tremblay, Jacqueline M., Beamer, Gillian, Kashentseva, Elena A., Curiel, David T., Shoemaker, Charles B.·2014·PLoS ONE

Abstract

Current therapies for most acute toxin exposures are limited to administration of polyclonal antitoxin serum. We have shown that VHH-based neutralizing agents (VNAs) consisting of two or more linked, toxin-neutralizing heavy-chain-only VH domains (VHHs), each binding distinct epitopes, can potently protect animals from lethality in several intoxication models including Botulinum neurotoxin serotype A1 (BoNT/A1). Appending a 14 amino acid albumin binding peptide (ABP) to an anti-BoNT/A1 heterodimeric VNA (H7/B5) substantially improved serum stability and resulted in an effective VNA serum half-life of 1 to 2 days. A recombinant, replication-incompetent, adenoviral vector (Ad/VNA-BoNTA) was engineered that induces secretion of biologically active VNA, H7/B5/ABP (VNA-BoNTA), from transduced cells. Mice administered a single dose of Ad/VNA-BoNTA, or a different Ad/VNA, via different administration routes led to a wide range of VNA serum levels measured four days later; generally intravenous > intraperitoneal > intramuscular > subcutaneous. Ad/VNA-BoNTA treated mice were 100% protected from 10 LD50 of BoNT/A1 for more than six weeks and protection positively correlated with serum levels of VNA-BoNTA exceeding about 5 ng/ml. Some mice developed antibodies that inhibited VNA binding to target but these mice displayed no evidence of kidney damage due to deposition of immune complexes. Mice were also successfully protected from 10 LD50 BoNT/A1 when Ad/VNA-BoNTA was administered up to 1.5 hours post-intoxication, demonstrating rapid appearance of the protective VNA in serum following treatment. Genetic delivery of VNAs promises to be an effective method of providing prophylactic protection and/or acute treatments for many toxin-mediated diseases.

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Crossref · 10.1371/journal.pone.0106422

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  • VNAs with an estimated serum half-life of 1-2 days (with albumin-binding) should benefit from being encoded by mRNA (Mukherjee et al, 2014).

    “Accordingly, VNAs with an estimated serum half‐life of 1–2 days (with albumin‐binding) should benefit from being encoded by mRNA (Mukherjee et al, 2014).”

    From mRNA mediates passive vaccination against infectious agents, toxins, and tumors (2017) · cites this paper as Mukherjee et al, 2014

    The Discussion (page not provided) estimates a 1–2-day serum half-life for the albumin-binding VNA in mice and says continuous genetic expression can improve VNA serum levels. The Introduction mentions RNA as a possible delivery vehicle, but the study tested adenoviral DNA delivery, not mRNA-encoded VNAs; it does not establish the claimed benefit of mRNA encoding. (LLM, conf=0.85)

    Experimental — accuracy not yet measured
  • The use of parenterally administered VNAs that potently neutralize botulinum neurotoxin serotype A (BoNT/A) has been previously reported.

    “The use of parenterally administered VNAs that potently neutralize botulinum neurotoxin serotype A (BoNT/A) has been previously reported (Mukherjee et al, 2014).”

    From mRNA mediates passive vaccination against infectious agents, toxins, and tumors (2017) · cites this paper as Mukherjee et al, 2014

  • For both VNAs, serum half-lives were calculated to be in the range of 24-36 h.

    “For both VNAs, serum half‐lives were calculated to be in the range of 24–36 h which is in line with a previous report (Mukherjee et al, 2014).”

    From mRNA mediates passive vaccination against infectious agents, toxins, and tumors (2017) · cites this paper as Mukherjee et al, 2014

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Authors
Mukherjee, J., Dmitriev, I., Debatis, M., Tremblay, J. M., Beamer, G., Kashentseva, E. A., Curiel, D. T., & Shoemaker, C. B.
Affiliations
  • Tufts University (US)
  • Washington University in St. Louis (US)
Corresponding author
Shoemaker, Charles B.
Venue
PLoS ONE
Published
2014-08-29
Volume
9
Issue
8
Pages
e106422
ISSN
1932-6203 (ISSN-L)
OpenAlex
W1978487895
Cited by
37
References
51
Citations by year
2026: 1 · 2025: 2 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 6 · 2019: 3 · 2018: 1 · 2017: 3 · 2016: 9 · 2015: 3 · 2014: 1
FWCI
3.48
Type
journal article
Language
en
Open access
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Institutes of Health (R21/R33, AI057159)
  • National Institute of Allergy and Infectious Diseases (AI057159, AI101403, U54AI057159, R21AI101403, R21/R33 AI101403)
Topics
  • Health Sciences › Medicine › Neurology › Botulinum Toxin and Related Neurological Disorders
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Immunology and Microbiology › Immunology › Toxin Mechanisms and Immunotoxins
Keywords
botulism, nanobodies, adenoviral vector, recombinant protein delivery, serum half-life, prophylactic protection, toxin neutralization, immune complex deposition, toxin-mediated disease
MeSH terms
Dependovirus, Animals, Botulinum Antitoxin, Botulism, Disease Models, Animal, Genetic Vectors, Vaccination, Mice, Antibodies, Neutralizing

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