上海科技大学知识管理系统

Receptors and their ligands are important therapeutic targets for about one third of
marketed drugs. We describe here an epitope-guided approach for selection of novel
antibodies that modulate cellular signaling of targeted receptors. We chose CXC
chemokine receptor 2 (CXCR2) in the G-protein coupled receptor superfamily as
receptor and a CXCR2 N-terminal peptide for antibody selection. We obtain a highly
selective, tight-binding antibody from a 1011-member antibody library using
combinatorial enrichment. Structural and Hydrogen-Deuterium-Exchange mass
spectrometry analyses demonstrate antibody interaction with an N-terminal region of
CXCR2 that is part of the interleukin-8 epitope. The antibody strongly inhibits
interleukin-8-induced and CXCR2-mediated neutrophil chemotaxis in vitro and
alleviates the hCXCR2-dependent Experimental Autoimmune Encephalomyelitis
symptoms in vivo. Inappropriate neutrophil migration accompanies many diseases
including inflammatory bowel disease, glomerulonephritis, allergic asthma, chronic
obstructive pulmonary disease, and cancer. Thus, this potent new antibody has potential
for development as a therapeutic agent, akin to anti-TNF antibodies. However, an
important difference here is that the antibody targets the chemokine receptor and
competes with natural ligand, rather than targeting the ligand itself.