曲妥珠单抗和帕妥珠单抗组合已被批准用于治疗 HER2 阳性转移性乳腺癌患者。然而，曲妥珠单抗和帕妥珠单抗组合并未显示出 HER2 阳性转移性胃癌患者总生存期的改善。我们开发了一种新的 HER2 靶向单克隆抗体 HLX22，与曲妥珠单抗一样靶向 HER2 亚结构域 IV，但具有非重叠表位。我们检查了这种新型 HER2 抗体在胃细胞系、细胞系来源的异种移植物 (CDX) 和患者来源的异种移植物 (PDX) 模型中的抗肿瘤作用。HLX22 与 HLX02（曲妥珠单抗生物类似药）联合使用可诱导 HER2/HER2 同二聚体的增强HER2/EGFR 异二聚体内化，最终导致涉及 STAT3、P70 S6 和 AKT 的信号转导减少； FGF-FGFR-PI3K-MTOR、EGF-EGFR-RAS、TGF-β-SMAD、PLCG 的基因表达和有利于胃癌细胞系 NCI-N87 中肿瘤发生、增殖、进展、迁移和存活的细胞周期进展相关通路也减少了。这些不同但互补的作用促成了 HLX22 和 HLX02 组合在胃癌细胞系 CDX 和 PDX 中的协同抗肿瘤功效。此外，HLX22与HLX02联合在体外和体内均表现出比HLX02和HLX11（潜在的帕妥珠单抗生物类似药）联合治疗更强的抗肿瘤功效。这些结果表明HLX22和HLX02共同靶向HER2子结构域IV的非竞争性抗体的应用可能对目前对曲妥珠单抗治疗反应欠佳的胃癌患者有实质性益处。© 2024。作者。

Trastuzumab and pertuzumab combination has been approved for the treatment of patients with HER2-positive metastatic breast cancer. However, trastuzumab and pertuzumab combination did not show improvement in overall survival in patients with HER2-positive metastatic gastric cancer.We developed a new HER2-targeted monoclonal antibody, HLX22, targeting HER2 subdomain IV as trastuzumab but with non-overlapping epitopes. We examined the antitumor effects of this novel HER2-antibody in gastric cell lines and cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models.HLX22 in combination with HLX02 (trastuzumab biosimilar) induced enhancement of HER2/HER2 homodimers and HER2/EGFR heterodimers internalization, which ultimately led to the reduction in signal transductions involving STAT3, P70 S6, and AKT; gene expressions of FGF-FGFR-PI3K-MTOR, EGF-EGFR-RAS, TGF-β-SMAD, PLCG and cell cycle progression related pathways that favor tumor development, proliferation, progression, migration and survival in gastric cancer cell line NCI-N87 were also reduced. These differing but complementary actions contributed to the synergistic antitumor efficacy of the HLX22 and HLX02 combination in gastric cancer cell lines, CDX and PDX. In addition, HLX22 in combination with HLX02 demonstrated stronger antitumor efficacy than HLX02 and HLX11 (a potential pertuzumab biosimilar) combination treatment both in vitro and in vivo.These results suggested that the application of non-competing antibodies HLX22 and HLX02 targeting HER2 subdomain IV together may be of substantial benefit to gastric cancer patients who currently respond suboptimal to trastuzumab therapy.© 2024. The Author(s).