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Conception, synthèse et étude de conjugués peptidiques multimériques pour la reconnaissance sélective des cellules cancéreuses

Abstract : Despite significant progresses in the antitumoral therapy field, actual treatments suffer from major issues. The antitumoral immunotherapy became, in the last decades, an ideal alternative to improve the treatment of patients with cancer. There is still few available treatments nowadays and numbers of issues persist (side effects, production cost …). In this context, we are interested in the design of new bimodal structures called Antibody-Recruiting Molecules able to bind selectively to cancer cells and recruit endogen antibodies to induce the cells destruction by immune response without a preimmunization of the patient. The goal of my thesis was to synthesize an affine and selective cell binding module. To this end, we first chose ligands already used in targeted antitumoral therapies, presented in a multivalent fashion to try to improve the binding to their target. Secondly, we identified new peptidic ligands for cancer cells by using the Phage Display technique. The final ARM molecules combining the tumoral-binding module and the antibody-binding module (selected from another work in our team) were finally synthesized. We analyzed with flow cytometry their ability to interact with the cell and their ability to recruit endogen antibodies present in the human serum. We observed the formation of a ternary complex between cells, ARM and antibodies, a key step to induce a potent immune response. These studies allow us to select the best architecture.
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Benjamin Liet. Conception, synthèse et étude de conjugués peptidiques multimériques pour la reconnaissance sélective des cellules cancéreuses. Biochimie [q-bio.BM]. Université Grenoble Alpes, 2019. Français. ⟨NNT : 2019GREAV040⟩. ⟨tel-02613953⟩

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