The European AntibotABE Framework Program and Its Update: Development of Innovative Botulinum Antibodies

Toxins

卷:9

Katja Selby¹  Yagmur Derman¹  Hannu Korkeala¹  Christelle Mazuet²  Michel R. Popoff²  Christine Rasetti-Escargueil²  Thibaut Pelat³  Philippe Thullier³  Arnaud Avril³  Alexandre Fontayne⁴  Remi Urbain⁴  Dorothea Sesardic⁵  Sebastian Miethe⁶  Michael Hust⁶ 

[1] Department of Food Hygiene and Environmental Health, University of Helsinki, P.O. Box 66, FI-00014 Helsinki, Finland;

[2] Institut Pasteur, Unité des Bactéries Anaérobies et Toxines, 25 Avenue du Docteur Roux, 75015 Paris, France;

[3] Institut de Recherche Biomédicale des Armées (IRBA-CRSSA), Département de Microbiologie, Unité de Biotechnologie des Anticorps et Des Toxins, Cedex 38702 La Tronche, France;

[4] LFB Biotechnologies, Therapeutic Innovation Department, 59, Rue de Trévise, BP 2006-59011 Lille Cedex, France;

[5] National Institute for Biological Standards and Control (NIBSC), a Center of the Medicines and Healthcare Products Regulatory Agency, Division of Bacteriology, Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3QG, UK;

[6] Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig, Germany and YUMAB GmbH, Rebenring 33, Braunschweig 38106, Germany;

关键词: AntiBotABE;    botulinum;    toxin;    phage-display;    IgG;    neutralization;    botulism;    biodefense;    recombinant;    oligoclonal antibodies;   

DOI  :  10.3390/toxins9100309

来源: DOAJ

【 摘 要 】

The goal of the AntiBotABE Program was the development of recombinant antibodies that neutralize botulinum neurotoxins (BoNT) A, B and E. These serotypes are lethal and responsible for most human botulinum cases. To improve therapeutic efficacy, the heavy and light chains (HC and LC) of the three BoNT serotypes were targeted to achieve a synergistic effect (oligoclonal antibodies). For antibody isolation, macaques were immunized with the recombinant and non-toxic BoNT/A, B or E, HC or LC, followed by the generation of immune phage-display libraries. Antibodies were selected from these libraries against the holotoxin and further analyzed in in vitro and ex vivo assays. For each library, the best ex vivo neutralizing antibody fragments were germline-humanized and expressed as immunoglobulin G (IgGs). The IgGs were tested in vivo, in a standardized model of protection, and challenged with toxins obtained from collections of Clostridium strains. Protective antibody combinations against BoNT/A and BoNT/B were evidenced and for BoNT/E, the anti-LC antibody alone was found highly protective. The combination of these five antibodies as an oligoclonal antibody cocktail can be clinically and regulatorily developed while their high “humanness” predicts a high tolerance in humans.

【 授权许可】

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