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PLoS One. 2016 Aug 25;11(8):e0161446. doi: 10.1371/journal.pone.0161446. eCollection 2016.

Development of Germline-Humanized Antibodies Neutralizing Botulinum Neurotoxin A and B.

Author information

1
Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Braunschweig, Germany.
2
Institut Pasteur, Unité des Bactéries anaérobies et Toxines, Paris, France.
3
National Institute for Biological Standards and Control (NIBSC), Division of Bacteriology, Potters Bar, United Kingdom.
4
Institut de Recherche Biomédicale des Armées (IRBA) Département des Maladies Infectieuses, Unité Interaction Hôte-Pathogène, Brétigny-sur-Orge, France.
5
LFB Biotechnologies, Therapeutic Innovation Department, Lille, France.

Abstract

Botulinum neurotoxins (BoNTs) are counted among the most toxic substances known and are responsible for human botulism, a life-threatening disease characterized by flaccid muscle paralysis that occurs naturally by food poisoning or colonization of the gastrointestinal tract by BoNT-producing clostridia. To date, 7 serologically distinct serotypes of BoNT (serotype A-G) are known. Due to the high toxicity of BoNTs the Centers for Disease Control and Prevention (CDC) have classified BoNTs as category A agent, including the six biological agents with the highest potential risk of use as bioweapons. Well tolerated antibodies neutralizing BoNTs are required to deal with the potential risk. In a previous work, we described the development of scFv and scFv-Fc (Yumab) from macaque origin (Macaca fascicularis) neutralizing BoNT/A and B by targeting the heavy and light chain of each serotype. In the present study, we humanized the macaque antibodies SEM120-IIIC1 (anti-BoNT/A light chain), A1HC38 (anti-BoNT/A heavy chain), BLC3 (anti-BoNT/B light chain) and B2-7 (anti-BoNT/B heavy chain) by germline-humanization to obtain a better potential immunotolerance in humans. We increased the Germinality Index (GI) of SEM120-IIIC1 to 94.5%, for A1HC38, to 95% for BLC3 and to 94.4% for B2-7. Furthermore, the neutralization efficacies of the germline-humanized antibodies were analyzed in lethal and non-lethal in vivo mouse assays as full IgG. The germline-humanized IgGs hu8SEM120-IIIC1, hu8A1HC38, hu8BLC3 and hu8B2-7 were protective in vivo, when anti-heavy and anti-light chain antibodies were combined. The synergistic effect and high humanness of the selected IgGs makes them promising lead candidates for further clinical development.

PMID:
27560688
PMCID:
PMC4999263
DOI:
10.1371/journal.pone.0161446
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Competing Interests: André Frenzel has a part time contract with YUMAB GmbH. Remi Urbain and Alexandre Fontayne are employed by LFB Biotechnologies. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

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