9T3S

Structure of human HER2 in complex with EPS226 Fab

Summary for 9T3S

• Entry DOI: 10.2210/pdb9t3s/pdb
• EMDB information: 55518
• Descriptor: EPS226 Fab HC, EPS226 Fab LC, Receptor tyrosine-protein kinase erbB-2 (3 entities in total)
• Functional Keywords: antibody fab, complex, cancer, extracellular domain., antitumor protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 3
• Total formula weight: 121670.60

Authors

Birtley, J.,Regan, L.,Johnson, R.M.,Soni, K.,Pye, V.E.,Fitzgerald, K. (deposition date: 2025-10-29, release date: 2026-03-11, Last modification date: 2026-04-15)

Primary citation

Marano, F.,McKenzie, C.,Birtley, J.R.,Hussain, S.A.,Macleod, O.,Goodacre, A.,Wu, S.,Amin, O.E.,Faulkner, N.,Devlin, J.,Regan, L.,Soni, K.,Johnson, R.M.,Pye, V.E.,Wilson, T.,Hardaker, E.,FitzGerald, K.
Elucidating the relationship between affinity and potency in the performance of therapeutic IgE.
Sci Rep, 16:-, 2026

PubMed Abstract: IgE antibodies exert strong immunostimulatory effects and their anti-tumour effectiveness is currently being assessed in clinical trials. The high affinity of IgE for FcεRI may result in the binding of exogenously delivered antibody to effector cells prior to antigen engagement, potentially leading to IgE being presented multivalently to cancer cells. With the presumed higher avidity of antigen binding it is unclear whether increasing monovalent affinity of IgE improves anti-tumour functionality. To address this, we affinity-matured an anti-HER2 IgE, generating 12 clones with increased affinity for HER2. These clones were more potent than the parental antibody in inducing mast cell degranulation, with the most potent, EPS 232, achieving enhanced antibody-dependent cytotoxicity and phagocytosis of HER2-expressing cancer cells. EPS 232 delivered superior tumour growth inhibition in vivo, including in models expressing ultra-low levels of HER2, and it promoted greater infiltration of T cells and macrophages into tumours. These findings suggest that for therapeutic IgE, increasing antigen-binding affinity can lead to functional enhancements.

PubMed: 41912649
DOI: 10.1038/s41598-026-43772-6

Experimental method

ELECTRON MICROSCOPY (3 Å)