Objectif
Botulinum neurotoxins (BoNTs), the most toxic substances known, are susceptible for use as bioweapons (listed as class A agents by CDC). Currently licensed animal derived antibodies or F(ab’)2 preparations, are at a high risk of inducing adverse effects and their privately-owned stockpiles are limited. In this project, we will target the most lethal types of BoNTs: A (subtypes A1 and A2), B (B1 and B2) and E (E1). The antibodies will be directed against the C-terminus of the heavy chain and the light chain of each of these three BoNTs, as these domains contain neutralizing epitopes, according to the latest scientific data. The six corresponding immunogens will be produced in recombinant form, and utilized to immunize macaques (Macaca fascicularis), from which phage-displayed immune libraries will be built. Utilizing the phage technology, scFvs cross- reacting with A1 and A2, or B1 and B2subtypes will be panned. The best scFv from each library will be selected according to its high affinity and in vitro neutralization property. The six most neutralizing scFvs will then be super-humanized (“germline-humanized”) and expressed as IgGs, which will be tested in vivo, in a standardised model of protection and against toxins obtained from collections of clostridia strains. The project includes representatives of medical first-responders who will disseminate our results, and help create a market so that the necessary clinical studies could be performed in future. The project will offer an unequalled level of security against biothreats in Europe, based upon a family of well-tolerated and effective molecules.
Champ scientifique
Appel à propositions
FP7-SEC-2009-1
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Régime de financement
CP - Collaborative project (generic)Coordinateur
75007 Paris
France