The European AntibotABE Framework Program and Its Update: Development of Innovative Botulinum Antibodies
Christine Rasetti-Escargueil,
Arnaud Avril,
Sebastian Miethe,
Christelle Mazuet,
Yagmur Derman,
Katja Selby,
Philippe Thullier,
Thibaut Pelat,
Remi Urbain,
Alexandre Fontayne,
Hannu Korkeala,
Dorothea Sesardic,
Michael Hust,
Michel R. Popoff
Affiliations
Christine Rasetti-Escargueil
Institut Pasteur, Unité des Bactéries Anaérobies et Toxines, 25 Avenue du Docteur Roux, 75015 Paris, France
Arnaud Avril
Institut de Recherche Biomédicale des Armées (IRBA-CRSSA), Département de Microbiologie, Unité de Biotechnologie des Anticorps et Des Toxins, Cedex 38702 La Tronche, France
Sebastian Miethe
Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig, Germany and YUMAB GmbH, Rebenring 33, Braunschweig 38106, Germany
Christelle Mazuet
Institut Pasteur, Unité des Bactéries Anaérobies et Toxines, 25 Avenue du Docteur Roux, 75015 Paris, France
Yagmur Derman
Department of Food Hygiene and Environmental Health, University of Helsinki, P.O. Box 66, FI-00014 Helsinki, Finland
Katja Selby
Department of Food Hygiene and Environmental Health, University of Helsinki, P.O. Box 66, FI-00014 Helsinki, Finland
Philippe Thullier
Institut de Recherche Biomédicale des Armées (IRBA-CRSSA), Département de Microbiologie, Unité de Biotechnologie des Anticorps et Des Toxins, Cedex 38702 La Tronche, France
Thibaut Pelat
Institut de Recherche Biomédicale des Armées (IRBA-CRSSA), Département de Microbiologie, Unité de Biotechnologie des Anticorps et Des Toxins, Cedex 38702 La Tronche, France
Remi Urbain
LFB Biotechnologies, Therapeutic Innovation Department, 59, Rue de Trévise, BP 2006-59011 Lille Cedex, France
Alexandre Fontayne
LFB Biotechnologies, Therapeutic Innovation Department, 59, Rue de Trévise, BP 2006-59011 Lille Cedex, France
Hannu Korkeala
Department of Food Hygiene and Environmental Health, University of Helsinki, P.O. Box 66, FI-00014 Helsinki, Finland
Dorothea Sesardic
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
Michael Hust
Technische Universität Braunschweig, Institut für Biochemie, Biotechnologie und Bioinformatik, Abteilung Biotechnologie, Spielmannstr. 7, 38106 Braunschweig, Germany and YUMAB GmbH, Rebenring 33, Braunschweig 38106, Germany
Michel R. Popoff
Institut Pasteur, Unité des Bactéries Anaérobies et Toxines, 25 Avenue du Docteur Roux, 75015 Paris, France
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.
