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Locally Misfolded HER2 Expressed on Cancer Cells is a Promising Target for Development of Cancer-Specific Antibodies

40 Pages Posted: 11 Sep 2023 Publication Status: Under Review

See all articles by Takao Arimori

Takao Arimori

Osaka University

Emiko Mihara

Osaka University - Laboratory of Protein Synthesis and Expression

Hiroyuki Suzuki

Tohoku University - Graduate School of Medicine

Tomokazu Ohishi

Institute of Microbial Chemistry (BIKAKEN)

Tomohiro Tanaka

Tohoku University - Graduate School of Medicine

Mika Kato Kaneko

Tohoku University - Graduate School of Medicine

Junichi Takagi

Osaka University - Laboratory of Protein Synthesis and Expression

Yukinari Kato

Tohoku University - Graduate School of Medicine

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Abstract

Overexpression of human epidermal growth factor receptor 2 (HER2) in breast and gastric cancers is known to be associated with poor prognosis, making it an attractive therapeutic target.  Here, we established a novel cancer-specific anti-HER2 antibody, H2Mab-214. H2Mab-214 reacted with HER2 on cancer cells, but unlike the therapeutic antibody trastuzumab, did not react with HER2 on normal cells in flow cytometry. Using X-ray crystallography, we revealed that H2Mab-214 recognizes a structurally disrupted portion in the HER2 domain IV, which normally forms a β-sheet. This misfolding was shown to be inducible by site-directed mutagenesis mimicking the disulfide bond defects that may occur in cancer cells, indicating that the local misfolding in the Cys-rich domain IV governs the cancer-specificity of H2Mab-214. Furthermore, we showed that H2Mab-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.

Keywords: Cancer-specific monoclonal antibody, Human epidermal growth factor receptor 2, breast cancer, Misfolding, Crystal structure, Trastuzumab, Xenograft model, Anti-tumor effect, Fv-clasp

Suggested Citation

Arimori, Takao and Mihara, Emiko and Suzuki, Hiroyuki and Ohishi, Tomokazu and Tanaka, Tomohiro and Kaneko, Mika Kato and Takagi, Junichi and Kato, Yukinari, Locally Misfolded HER2 Expressed on Cancer Cells is a Promising Target for Development of Cancer-Specific Antibodies. Available at SSRN: https://ssrn.com/abstract=4565236 or http://dx.doi.org/10.2139/ssrn.4565236
This version of the paper has not been formally peer reviewed.

Takao Arimori (Contact Author)

Osaka University ( email )

Emiko Mihara

Osaka University - Laboratory of Protein Synthesis and Expression ( email )

Hiroyuki Suzuki

Tohoku University - Graduate School of Medicine ( email )

Tomokazu Ohishi

Institute of Microbial Chemistry (BIKAKEN) ( email )

Tomohiro Tanaka

Tohoku University - Graduate School of Medicine ( email )

Mika Kato Kaneko

Tohoku University - Graduate School of Medicine ( email )

Junichi Takagi

Osaka University - Laboratory of Protein Synthesis and Expression ( email )

Yukinari Kato

Tohoku University - Graduate School of Medicine ( email )

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