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Selective antibody intervention of Toll-like receptor 4 activation through Fc receptor tethering

Shang, L;Daubeuf, B;Triantafilou, M;Olden, R;Dpis, F;Raby, AC;Herren, S;Dos Santos, A;Malinge, P;Dunn-Siegrist, I;Benmkaddem, S;Geinoz, A;Magistrelli, G;Rousseau, F;Buatois, V;Salgado-Pires, S;Reith, W;Monteiro, R;Pugin, J;Leger, O;Ferlin, W;Kosco-Vilbo

Inflammation is mediated mainly by leukocytes that express both Toll-like receptor 4 (TLR4) and Fc receptors (FcR). Dysregulated activation of leukocytes via exogenous and endogenous ligands of TLR4 results in a large number of inflammatory disorders that underlie a variety of human diseases. Thus, differentially blocking inflammatory cells while sparing structural cells, which are FcR-negative, represents an elegant strategy when targeting the underlying causes of human diseases. Here, we report a novel tethering mechanism of the Fv and Fc portions of anti-TLR4 blocking antibodies that achieves increased potency on inflammatory cells. In the presence of ligand (e.g. lipopolysaccharide (LPS)), TLR4 traffics into glycolipoprotein microdomains, forming concentrated protein platforms that include FcRs. This clustering produces a microenvironment allowing anti-TLR4 antibodies to co-engage TLR4 and FcRs, increasing their avidity and thus substantially increasing their inhibitory potency. Tethering of antibodies to both TLR4 and FcRs proves valuable in ameliorating inflammation in vivo. This novel mechanism of action therefore has the potential to enable selective intervention of relevant cell types in TLR4-driven diseases.