Structural basis of QX007N neutralizing interleukin-33 for asthma and COPD treatment.

Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is upregulated in various inflammatory and allergic diseases, including asthma and chronic obstructive pulmonary disease (COPD). In this study, we report the generation and functional characterization of QX007N, a humanized monoclonal antibody that specifically neutralizes IL-33. QX007N shows high neutralization activities against IL-33-mediated signaling. In B-hIL-33 humanized mice, QX007N significantly suppressed ovalbumin (OVA)-specific IgE levels in serum and attenuated acute allergic inflammation in lung cells. Crystal structures of the QX007N-Fab (2.62 Å) and its complex with IL-33 (2.60 Å) were determined. Structural comparison of the QX007N-Fab/IL-33 complex with published antibody/IL-33 complexes and the IL-33/suppression of tumorigenicity 2 (ST2) complex reveals that QX007N-Fab recognizes epitope 2 on IL-33 and sterically inhibits ST2 binding, thereby preventing assembly of the IL-33/ST2/IL-1RAcP signaling complex and downstream signal transduction. These findings establish QX007N as a promising therapeutic candidate for asthma and COPD.