9MTX

CryoEM structure of extracellular domain of human HER2 complexed with nano-bodies 29E09

Summary for 9MTX

• Entry DOI: 10.2210/pdb9mtx/pdb
• EMDB information: 48615
• Descriptor: Nanobody VHH 29E09, receptor protein-tyrosine kinase (2 entities in total)
• Functional Keywords: nanobodies, vhh, her2, complex, cancer, transferase
• Biological source: Lama glama (llama); More
• Total number of polymer chains: 2
• Total formula weight: 82768.55

Authors

Bruch, E.M.,Rak, A. (deposition date: 2025-01-12, release date: 2025-11-19, Last modification date: 2026-01-21)

Primary citation

De Tavernier, E.,Kim, P.S.,Bruch, E.M.,Cortez-Retamozo, V.F.,Timmerman, L.,Flynn, A.L.,Van Overbeke, W.,Tirode, F.,Cintra Barbosa-Lorenzi, V.,Piepenhagen, P.,Dinh-Le, T.,Luna, E.,Li, A.,Baker, A.,Rak, A.,Pao, L.I.,Vintem, A.P.B.
TPP-45142-an Anti-HER2 T cell Engager-Designed for Selective HER2-Low Cancer Immunotherapy.
Mol.Cancer Ther., 2026

PubMed Abstract: The standard of care for patients with HER2-positive cancers is well established, but a significant unmet need exists for patients with HER2-low tumors, who do not meet the eligibility criteria for trastuzumab, and for patients with HER2-positive tumors, who are refractory to trastuzumab treatment. Therefore, in this study, we developed a NANOBODY® domain-based HER2-targeting, T cell receptor (TCR)αβ-based T cell engager (TCE) molecule-TPP-45142; it recognizes a HER2 epitope distinct from that recognized by trastuzumab and pertuzumab and redirects T cells to kill HER2-low cancers such as breast, gastric, and gastroesophageal junction adenocarcinoma (GEJ) cancers. TPP-45142 mediated potent T cell-dependent cytotoxicity against HER2-low cancer cell lines in vitro and inhibited in vivo tumor growth of HER2-low breast cancer xenografts. TPP-45142 was highly selective toward tumor cells expressing low HER2 levels than toward normal cardiac cells and exhibited a favourable therapeutic index as per a cytokine release assay. Thus, TPP-45142, with an improved safety profile, is a promising next-generation TCE for treating challenging HER2-low cancers.

PubMed: 41504346
DOI: 10.1158/1535-7163.MCT-25-0654

Experimental method

ELECTRON MICROSCOPY (3.06 Å)