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Dissecting the mechanism of action of an anti-TLR4 antibody

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Defense Thèse de doctorat : Univ. Genève, 2015 - Sc. 4778 - 2015/04/14
Abstract In order to treat Toll-like receptor 4 (TLR4)-mediated diseases, Hu 15C1, an antagonist antibody directed against human TLR4 has been developed. The potency of this antibody is enhanced by the co-engagement of TLR4 and Fc gamma receptors (FcγR), an intriguing mode of action that does not involve FcγR downstream signaling. In this thesis, we have explored the contribution of both the Fv and Fc regions to the efficacy of Hu 15C1. First, by using a structural approach, we have showed that the antibody antagonizes TLR4 by preventing the dimerization of the receptor. Second, by using different antibody formats and FcγR blockers, we observed that the co-engagement of TLR4 and FcγR mediates an avidity effect, a mechanism which is not only influenced by the affinity of the antibody to its receptors but also by their density at the cell surface. Taken together, our results allow the prediction of Hu 15C1 efficacy in different disease settings.
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URN: urn:nbn:ch:unige-749359
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LOYAU, Jeremy. Dissecting the mechanism of action of an anti-TLR4 antibody. Université de Genève. Thèse, 2015. https://archive-ouverte.unige.ch/unige:74935

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Deposited on : 2015-08-31

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