Abstract
HER3 (human epidermal growth factor receptor 3) acts through heterodimerization with EGFR (epidermal growth factor receptor) or HER2 to play an essential role in activating phosphoinositide 3-kinase (PI3K) and AKT signaling—a crucial pathway that promotes tumor cell survival. HER3 is a promising target for cancer therapy, and several HER3-directed antibodies have already entered into clinical trials. In this study we characterized a novel anti-HER3 monoclonal antibody, SIBP-03. SIBP-03 (0.01−10 μg/mL) specifically and concentration-dependently blocked both neuregulin (NRG)-dependent and -independent HER3 activation, attenuated HER3-mediated downstream signaling and inhibited cell proliferation. This antitumor activity was dependent, at least in part, on SIBP-03–induced, cell-mediated cytotoxicity and cellular phagocytosis. Importantly, SIBP-03 enhanced the antitumor activity of EGFR- or HER2-targeted drugs (cetuximab or trastuzumab) in vitro and in vivo. The mechanisms underlying this synergy involve increased inhibition of HER3-mediated downstream signaling. Collectively, these results demonstrated that SIBP-03, which is currently undergoing a Phase I clinical trial in China, may offer a new treatment option for patients with cancers harboring activated HER3, particularly as part of a combinational therapeutic strategy.
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Acknowledgements
This research was supported by grants from the Science and Technology Commission of Shanghai Municipality (No 18DZ2293200) and the Yunnan Province Sciences and Technology plan (No 202102AA310026).
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LGL conceived and designed the research. WJL and CYX performed the experiments. WJL, CYX, LW, and LGL contributed to the acquisition and analysis of the data. WJL prepared the figures, tables, and manuscript. XZ and JT partly supervised the research. LW and LGL revised and approved the manuscript. All authors approved the final manuscript.
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Li, Wj., Xie, Cy., Zhu, X. et al. SIBP-03, a novel anti-HER3 antibody, exerts antitumor effects and synergizes with EGFR- and HER2-targeted drugs. Acta Pharmacol Sin 45, 857–866 (2024). https://doi.org/10.1038/s41401-023-01221-4
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DOI: https://doi.org/10.1038/s41401-023-01221-4