Selective antibody intervention of Toll like Receptor 4 activation through Fc gamma receptor tethering [Immunology]

April 15th, 2014 by Shang, L., Daubeuf, B., Triantafilou, M., Olden, R., Depis, F., Raby, A.–C., Herren, S., Dos Santos, A., Malinge, P., Dunn–Siegrist, I., Benmkaddem, S., Geinoz, A., Magistrelli, G., Rousseau, F., Buatois, V., Salgado–Pires, S., Reit

Inflammation is mediated mainly by leukocytes which express both toll-like receptor 4 (TLR4) and Fc gamma receptors (FcγR). 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 FcγR 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 trafficks into glycolipoprotein microdomains, forming concentrated protein platforms that include FcγRs. This clustering produces a microenvironment allowing anti-TLR4 antibodies to co-engage TLR4 and FcγRs, increasing their avidity and thus substantially increasing their inhibitory potency. Tethering of antibodies to both TLR4 and FcγRs proves valuable at 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.