Dissecting the mechanism of action of an anti-TLR4 antibody

Diplôme Thèse Dissecting the mechanism of action of an anti-TLR4 antibody eng 2015-04-14 author Loyau Jeremy 740713 director Hartley Oliver 0000-0002-2283-8379 507767 10.13097/archive-ouverte/unige:74935 urn:nbn:ch:unige-749359 Sc. 4778 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. Dewey 616.07 137 Département de pathologie et immunologie 21F false 8e9146a8-56a5-4db4-b8da-bab5a05d0f76 Thesis Restricted Thesis_JLOYAU.pdf 4407886 application/pdf 0896a08ed5a4abac8a38f970541d806d7ac8bc2d58c0621cdcd670ead37c6f0a restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

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Dissecting the mechanism of action of an anti-TLR4 antibody				2015	992	6

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Loyau, Jeremy