Excessive activation of Toll-like receptor 4 (TLR4)/MD-2 by lipopolysaccharide (LPS) causes septic shock. We previously produced an inhibitory antibody, HT52, against LPS-induced human TLR4 activation independently of LPS binding of MD-2. Consistent with the hypothesis that HT52 recognizes the epitopes inherent to inhibitory antibodies, we generated an HT52-crossblockable antibody and revealed the relationship between its inhibitory activity and the anti-TLR4 antibody epitope. Leucine-rich repeat 2 was identified as an inhibitory epitope, and Phe75, Ser76 and Pro79 as antigenic determinants. These findings provide a way to design therapeutic antibodies targeted to TLR4 that are distinct from LPS analog antagonists targeting MD-2.
ASJC Scopus subject areas