8JYQ

Crystal structure of cancer-specific anti-HER2 antibody H2Mab-214 in complex with epitope peptide

Summary for 8JYQ

• Entry DOI: 10.2210/pdb8jyq/pdb
• Descriptor: H2CasMab-1 VH(S112C),SARAH, H2CasMab-1 VL,SARAH(S37C), H2CasMab-1 epitope peptide, ... (4 entities in total)
• Functional Keywords: her2, antibody, immune system
• Biological source: Mus musculus; More
• Total number of polymer chains: 6
• Total formula weight: 79470.36

Authors

Arimori, T.,Takagi, J. (deposition date: 2023-07-03, release date: 2024-03-13, Last modification date: 2024-11-13)

Primary citation

Arimori, T.,Mihara, E.,Suzuki, H.,Ohishi, T.,Tanaka, T.,Kaneko, M.K.,Takagi, J.,Kato, Y.
Locally misfolded HER2 expressed on cancer cells is a promising target for development of cancer-specific antibodies.
Structure, 32:536-549.e5, 2024

PubMed Abstract: Overexpression of human epidermal growth factor receptor 2 (HER2) in breast and gastric cancers is associated with a poor prognosis, making it an important therapeutic target. Here, we establish a novel cancer-specific anti-HER2 antibody, HMab-214. HMab-214 reacts with HER2 on cancer cells, but unlike the therapeutic antibody trastuzumab, it does not react with HER2 on normal cells in flow cytometry measurements. A crystal structure suggests that HMab-214 recognizes a structurally disrupted region in the HER2 domain IV, which normally forms a β-sheet. We show that this misfolding is inducible by site-directed mutagenesis mimicking the disulfide bond defects that also may occur in cancer cells, indicating that the local misfolding in the Cys-rich domain IV governs the cancer-specificity of HMab-214. Furthermore, we show that HMab-214 effectively suppresses tumor growth in xenograft mouse models. Our findings offer a potential strategy for developing cancer-specific therapeutic antibodies that target partially misfolded cell surface receptors.

PubMed: 38460519
DOI: 10.1016/j.str.2024.02.007

Experimental method

X-RAY DIFFRACTION (1.75 Å)