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Publication Abstract from PubMed

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, H(2)Mab-214. H(2)Mab-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 H(2)Mab-214 recognizes a structurally disrupted region in the HER2 domain IV, which normally forms a beta-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 H(2)Mab-214. Furthermore, we show that H(2)Mab-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.

Locally misfolded HER2 expressed on cancer cells is a promising target for development of cancer-specific antibodies.,Arimori T, Mihara E, Suzuki H, Ohishi T, Tanaka T, Kaneko MK, Takagi J, Kato Y Structure. 2024 May 2;32(5):536-549.e5. doi: 10.1016/j.str.2024.02.007. Epub 2024 , Mar 8. PMID:38460519^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.