Li Wen-Jing, Xie Cheng-Ying, Zhu Xi, Tang Jiao, Wang Lei, Lou Li-Guang
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Acta Pharmacol Sin. 2024 Apr;45(4):857-866. doi: 10.1038/s41401-023-01221-4. Epub 2024 Jan 10.
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.
HER3（人表皮生长因子受体3）通过与表皮生长因子受体（EGFR）或HER2异源二聚化发挥作用，在激活磷酸肌醇3激酶（PI3K）和AKT信号传导中起重要作用，这是促进肿瘤细胞存活的关键途径。HER3是癌症治疗的一个有前景的靶点，几种针对HER3的抗体已进入临床试验。在本研究中，我们对一种新型抗HER3单克隆抗体SIBP-03进行了特性分析。SIBP-03（0.01 - 10μg/mL）特异性地且呈浓度依赖性地阻断神经调节蛋白（NRG）依赖性和非依赖性HER3激活，减弱HER3介导的下游信号传导并抑制细胞增殖。这种抗肿瘤活性至少部分依赖于SIBP-03诱导的细胞介导的细胞毒性和细胞吞噬作用。重要的是，SIBP-03在体外和体内增强了EGFR或HER2靶向药物（西妥昔单抗或曲妥珠单抗）的抗肿瘤活性。这种协同作用的潜在机制包括对HER3介导的下游信号传导的抑制增强。总体而言，这些结果表明，目前正在中国进行I期临床试验的SIBP-03可能为携带激活型HER3的癌症患者提供一种新的治疗选择，特别是作为联合治疗策略的一部分。
