Epitope-dependent mechanisms of CD27 neutralization revealed by X-ray crystallography.
CD27 is a T and B cell co-stimulatory protein of the TNF receptor superfamily dependent on the availability of the TNF-like ligand CD70. Two anti-CD27 neutralizing monoclonal antibodies were obtained from mouse hybridoma and subsequently humanized and optimized for binding the target. The two antibodies are similar in terms of their CD27-binding affinity and ability to block NF-κB signaling, however their clearance rates in monkeys are very different. The pharmacokinetics profiles could be epitope dependent. To identify the epitopes, we determined the crystal structure of the ternary complex between CD27 and the Fab fragments of these non-competing antibodies. The structure reveals the binding modes of the antibodies suggesting that their mechanisms of action are distinctly different and provides a possible explanation of the in vivo data.
['Obmolova|Galina|G|', 'Teplyakov|Alexey|A|', 'Malia|Thomas J|TJ|', 'Wunderler|Nicole|N|', 'Kwok|Deborah|D|', 'Barone|Linda|L|', 'Sweet|Raymond|R|', 'Ort|Tatiana|T|', 'Scully|Michael|M|', 'Gilliland|Gary L|GL|']
D000818:Animals D000911:Antibodies, Monoclonal D057134:Antibodies, Neutralizing D000915:Antibody Affinity D053282:CD27 Ligand D018360:Crystallography, X-Ray D004797:Enzyme-Linked Immunosorbent Assay D018985:Epitopes, B-Lymphocyte D006207:Half-Life D006801:Humans D008252:Macaca fascicularis D051379:Mice D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7
Mechanism CD27 Antibody Epitope Crystal structure