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Nouveau format de banques d’anticorps recombinants humains pour un criblage fonctionnel à grande échelle

Abstract : Since 2000, monoclonal antibodies (mAb) have become essential and routine drugs in therapy and particularly in oncology. The field continues to grow very quickly and given the abundance of molecules available, it is increasingly important to bring innovative molecules with a high added value for therapy.Two main approaches are used to select these mAbs: hybridoma technology using normal or humanized mice; display systems such as phage-display. The major interests of phage display are the speed of mAb development, the facilities offered by E. coli and the easy access to protein engineering techniques. Typically, antibodies are first selected on their ability to bind to the antigen, and then tested for their functional efficiency in cellular models. However, only a part of the activity of antibodies is explained by their binding to the antigen, and the therapeutic activity also depends strongly on their ability to recruit the immune system (ADCC) and activate the complement cascade (CDC).This thesis project consists in the development of a new recombinant antibody library format combining the power of phage display selection with functional screening in a whole IgG format produced in eukaryotic cells. This new system is based on hybrid promoter and signal peptide regions allowing expression both in prokaryotic and eukaryotic cells, and a site-specific recombination event that exchanges the Fab between the display vector and the chromosome of an especially developed mammalian cell line resulting in the secretion of a monoclonal human antibody by the cell. The usual approach of recloning one by one from E.Coli vector to an IgG format is no more needed since it is done directly by transfection. This new system makes possible to couple selection by phage display with a direct functional screening of a large population of human monoclonal clones.
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Déborah Caucheteur. Nouveau format de banques d’anticorps recombinants humains pour un criblage fonctionnel à grande échelle. Médecine humaine et pathologie. Université Montpellier, 2018. Français. ⟨NNT : 2018MONTT012⟩. ⟨tel-02868491⟩

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