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Open AccessArticle

Camelid VHHs Fused to Human Fc Fragments Provide Long Term Protection Against Botulinum Neurotoxin A in Mice

1
Department of Genetics and Bacteria Molecular Biology, Gamaleya Research Center of Epidemiology and Microbiology, 18 Gamaleya Street, Moscow 123098, Russia
2
Department of Bacteriology, Gamaleya Research Center of Epidemiology and Microbiology, 18 Gamaleya Street, Moscow 123098, Russia
3
Department of Medical Microbiology, Gamaleya Research Center of Epidemiology and Microbiology, 18 Gamaleya Street, Moscow 123098, Russia
*
Author to whom correspondence should be addressed.
Toxins 2019, 11(8), 464; https://doi.org/10.3390/toxins11080464
Received: 11 July 2019 / Revised: 29 July 2019 / Accepted: 2 August 2019 / Published: 7 August 2019
(This article belongs to the Section Bacterial Toxins)
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Abstract

The bacterium Clostridium botulinum is the causative agent of botulism—a severe intoxication caused by botulinum neurotoxin (BoNT) and characterized by damage to the nervous system. In an effort to develop novel C. botulinum immunotherapeutics, camelid single-domain antibodies (sdAbs, VHHs, or nanobodies) could be used due to their unique structure and characteristics. In this study, VHHs were produced using phage display technology. A total of 15 different monoclonal VHHs were selected based on their comlementarity-determining region 3 (CDR3) sequences. Different toxin lethal dose (LD50) challenges with each selected phage clone were conducted in vivo to check their neutralizing potency. We demonstrated that modification of neutralizing VHHs with a human immunoglobulin G (IgG)1 Fc (fragment crystallizable) fragment (fusionbody, VHH-Fc) significantly increased the circulation time in the blood (up to 14 days). At the same time, VHH-Fc showed the protective activity 1000 times higher than monomeric form when challenged with 5 LD50. Moreover, VHH-Fcs remained protective even 14 days after antibody administration. These results indicate that this VHH-Fc could be used as an effective long term antitoxin protection against botulinum type A. View Full-Text
Keywords: camelid single-domain antibodies; VHH; Clostridium botulinum; toxin neutralization; phage display; dimers; Fc fragments camelid single-domain antibodies; VHH; Clostridium botulinum; toxin neutralization; phage display; dimers; Fc fragments
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Godakova, S.A.; Noskov, A.N.; Vinogradova, I.D.; Ugriumova, G.A.; Solovyev, A.I.; Esmagambetov, I.B.; Tukhvatulin, A.I.; Logunov, D.Y.; Naroditsky, B.S.; Shcheblyakov, D.V.; Gintsburg, A.L. Camelid VHHs Fused to Human Fc Fragments Provide Long Term Protection Against Botulinum Neurotoxin A in Mice. Toxins 2019, 11, 464.

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