22GE

The structure of HER2-r40-trastuzumab-pertuzumab

Summary for 22GE

• Entry DOI: 10.2210/pdb22ge/pdb
• EMDB information: 68256
• Descriptor: Receptor tyrosine-protein kinase erbB-2, Pertuzumab FAB LIGHT CHAIN, Pertuzumab FAB HEAVY CHAIN, ... (7 entities in total)
• Functional Keywords: r40 (rabbit-derived), human epidermal growth factor receptor 2 (her2), her2-r40-trastuzumab-pertuzumab, protein binding/immune system, protein binding-immune system complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 7
• Total formula weight: 227336.59

Authors

Liu, C.,Ren, Y.,Yang, H.,Xu, Y. (deposition date: 2026-01-09, release date: 2026-10-28)

Primary citation

Liu, C.,Ren, Y.,Luo, X.,Zhou, P.,Du, X.,Wang, Q.,Han, X.,Xu, Y.,Wang, P.,Zhao, D.,Yang, H.
Inhibition of HER2 signaling and breast cancer cell growth with a novel antibody targeting HER2 ECD III/IV.
Plos One, 21:e0338127-e0338127, 2026

PubMed Abstract: Human epidermal growth factor receptor 2 (HER2), a ligand-independent tyrosine kinase receptor belonging to the EGFR family, serves as a key oncogenic driver in breast, gastric, and several other solid tumors. Although anti-HER2 therapies have substantially improved survival outcomes-particularly in breast and gastric cancers-treatment resistance and cancer recurrence remain major clinical challenges. Thus, developing novel antibodies exhibiting complementary effects to the current anti-HER2 therapies could provide additional therapeutic benefits. Here, we describe two novel HER2-targeting monoclonal antibodies, m66 (murine-derived) and r40 (rabbit-derived), which inhibit breast cancer cell proliferation in vitro. Of the two, antibody r40 exhibits stronger suppression of the PI3K/AKT and MAPK signaling pathways compared to m66. Moreover, the addition of r40 to the combination of trastuzumab and pertuzumab leads to a significantly enhanced inhibitory effect. We also determined the cryo-EM structures of the HER2-m66-trastuzumab ternary complex and the HER2-r40-trastuzumab-pertuzumab tetrameric complex, at overall resolutions of 3.2 Å and 3.1 Å, respectively. Structural analyses reveal that m66 recognizes an epitope overlapping with that of pertuzumab, whereas r40 binds within the HER2 ECD III/IV-a region distinct from the binding sites of both trastuzumab and pertuzumab. These findings identify r40 as a promising therapeutic candidate for use in combination with trastuzumab and pertuzumab in the treatment of HER2-positive breast cancer.

PubMed: 41538393
DOI: 10.1371/journal.pone.0338127

Experimental method

ELECTRON MICROSCOPY (3.1 Å)