9WWH

Crystal structure of IL-33 and antibody Tozorakimab fab binary complex

Summary for 9WWH

• Entry DOI: 10.2210/pdb9wwh/pdb
• Descriptor: Tozorakimab-Heavy chain, Tozorakimab-Light chain, Interleukin-33 (109-270) (3 entities in total)
• Functional Keywords: il-33, antibody, tozorakimab, cytokine/immune system, cytokine-immune system complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 127862.78

Authors

Wang, X.Q.,Chen, J.,Wang, Y. (deposition date: 2025-09-23, release date: 2026-03-18)

Primary citation

Chen, J.,Wang, Y.,Wang, X.
Structures of clinical antibodies bound to IL-33 uncover two distinct epitopes underlying differential efficacy.
Mabs, 18:2639673-2639673, 2026

PubMed Abstract: Interleukin-33 (IL-33), an alarmin cytokine of the IL-1 family, drives type 2 inflammation through signaling via the ST2 and IL-1RAcP receptors, making it a critical therapeutic target for inflammatory diseases such as asthma and chronic obstructive pulmonary disease. Current therapeutic strategies have primarily focused on antibodies that target IL-33 or ST2 to disrupt their specific interaction. However, the structural mechanisms underlying antibody-mediated neutralization of IL-33 remain poorly understood. Here, we report the structures of three antibodies in clinical trial - etokimab, itepekimab, and tozorakimab - complexed with IL-33, determined by X-ray crystallography and cryo-electron microscopy. Structural analysis reveals two distinct neutralizing epitopes on IL-33, termed Epitope 1 at IL-33/ST2 binding Site 1 and Epitope 2 at IL-33/ST2 binding Site 2. Tozorakimab, which targets Epitope 1, completely blocks ST2 engagement by sterically occluding the ST2 D1-D2 domain-binding interface. In contrast, etokimab and itepekimab, which recognize Epitope 2, interfere with IL-33 recognition of the ST2 D3 domain and thereby only partially inhibit ST2 binding. These structural and biochemical findings provide a molecular explanation for the differential efficacy of the three antibodies in inhibiting IL-33 signaling in cellular assays. Collectively, our results provide valuable insights into the molecular determinants of efficacy for existing IL-33 therapeutics and offer a structural framework for the rational design of next-generation IL-33 targeted inhibitors.

PubMed: 41765683
DOI: 10.1080/19420862.2026.2639673

Experimental method

X-RAY DIFFRACTION (3.51 Å)