SIBP-03, a novel anti-HER3 antibody, exerts antitumor effects and synergizes with EGFR- and HER2-targeted drugs

Wen-jing Li1,2, Cheng-ying Xie1, Xi Zhu1, Jiao Tang1, Lei Wang1, Li-guang Lou1,2
1 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
Correspondence to: Lei Wang:, Li-guang Lou:,
DOI: 10.1038/s41401-023-01221-4
Received: 17 August 2023
Accepted: 19 December 2023
Advance online: 10 January 2024


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.
Keywords: SIBP-03; HER3; HER3-targeted therapy; neuregulin 1; EGFR; HER2

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