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Leucine‐rich repeat 2 of human Toll‐like receptor 4 contains the binding site for inhibitory monoclonal antibodies
Author(s) -
Tsukamoto Hiroki,
Ukai Ippo,
Yamagata Yuki,
Takeuchi Shino,
Kubota Kanae,
Kozakai Sao,
Suzuki Naoto,
Kimoto Masao,
Tomioka Yoshihisa
Publication year - 2015
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2015.11.018
Subject(s) - epitope , monoclonal antibody , inhibitory postsynaptic potential , tlr4 , antibody , toll like receptor , receptor , chemistry , lipopolysaccharide , antigen , microbiology and biotechnology , biology , immunology , biochemistry , innate immune system , endocrinology
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 Phe 75 , Ser 76 and Pro 79 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.