Novel regulatory mechanism of human Toll-like receptor 4 function by the inhibitory monoclonal antibody

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In this study, novel inhibitory monoclonal antibodies against human Toll-like receptor 4 (TLR4), which are potential leading antibodies for anti-sepsis antibody drugs, were developed. These antibodies inhibited the production of proinflammatory cytokines, the upregulation of costimulatory molecules and the activation of NF-kappaB in lipopolysaccharide (LPS)-stimulated cells such as human peripheral blood mononuclear cells. The inhibitory activities were mediated by novel mechanism that is the induction of inactive TLR4 oligomerization, the inhibition of LPS-induced TLR4 internalization, but not the inhibition of TLR4-LPS binding. In addition, the epitope to which the binding of antibody inhibits the TLR4 function was found on extracellular domain of TLR4 independently of MD-2. Identification and chracterization of this epitope may provide a promising drug discovery target sturucture for the development of anti-septic antibody drugs.