A research team led by Prof. FENG Wei at the Institute of Biophysics of the Chinese Academy of Sciences, in collaboration with QX Biopharmaceuticals, has identified the molecular mechanism by which the humanized monoclonal antibody QX007N neutralizes interleukin-33 (IL-33). IL-33 is a key regulator of immune responses that is implicated in inflammatory and allergic diseases, such as asthma and chronic obstructive pulmonary disease (COPD).

The study, published in Structure on September 18, shows that QX007N effectively inhibits IL-33's biological activity, revealing how the antibody interferes with IL-33 receptor signaling.

The researchers first evaluated the activity of QX007N in cellular systems. The antibody strongly inhibited signaling triggered by IL-33 and showed potent neutralizing activity across multiple experimental assays. They also assessed its efficacy in B-hIL-33 humanized mice with acute allergic airway inflammation. The results demonstrated that QX007N can suppress IL-33-driven allergic inflammation in vivo.

To elucidate the molecular basis of QX007N-mediated neutralization, the researchers determined high-resolution crystal structures of the QX007N antigen-binding fragment (Fab) alone and its complex with IL-33, with resolutions of 2.62 Å and 2.60 Å, respectively. Structural analysis revealed that QX007N recognizes epitope 2 on IL-33, which partially overlaps with the ST2-binding surface.

Further structural comparison showed that QX007N binding would sterically interfere with the productive assembly of the IL-33/ST2/IL-1RAcP signaling complex. Biochemical competition experiments further demonstrated that QX007N interferes with the interaction between IL-33 and ST2. Together, these findings suggest that QX007N primarily neutralizes IL-33 by preventing the formation of the functional receptor signaling complex and blocking downstream signal transduction.

Integrating structural, biochemical, cellular, and in vivo analyses provides a molecular framework for understanding QX007N's neutralizing mechanism. These results establish QX007N as a potent, epitope-2-directed, IL-33-neutralizing antibody, supporting its development as a therapeutic candidate for asthma, COPD, and other inflammatory diseases driven by dysregulated IL-33 signaling.