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Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：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联合治疗HER2阳性转移性胃癌患者的总生存期没有改善.
方法：我们开发了一种新的HER2靶向单克隆抗体，HLX22，靶向HER2亚结构域IV作为曲妥珠单抗，但具有非重叠表位。我们检查了这种新型HER2抗体在胃细胞系和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。
结果：HLX22与HLX02（曲妥珠单抗生物仿制药）联合诱导HER2/HER2同源二聚体和HER2/EGFR异源二聚体内化的增强，最终导致涉及STAT3，P70S6和AKT的信号转导减少；FGF-FGFR-PI3K-MTOR的基因表达，EGF-EGFR-RAS,TGF-β-SMAD,PLCG和细胞周期进展相关的途径，有利于肿瘤的发展，扩散,programming,胃癌细胞系NCI-N87的迁移和存活也降低。这些不同但互补的作用有助于HLX22和HLX02组合在胃癌细胞系中的协同抗肿瘤功效，CDX和PDX。此外,HLX22与HLX02的组合在体外和体内表现出比HLX02和HLX11(潜在的帕妥珠单抗生物类似物)组合治疗更强的抗肿瘤功效。
结论：这些结果表明，靶向HER2亚结构域IV的非竞争性抗体HLX22和HLX02一起应用可能对目前对曲妥珠单抗治疗反应欠佳的胃癌患者具有实质性益处。
方法：我们开发了一种新的HER2靶向单克隆抗体，HLX22，靶向HER2亚结构域IV作为曲妥珠单抗，但具有非重叠表位。我们检查了这种新型HER2抗体在胃细胞系和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。
结果：HLX22与HLX02（曲妥珠单抗生物仿制药）联合诱导HER2/HER2同源二聚体和HER2/EGFR异源二聚体内化的增强，最终导致涉及STAT3，P70S6和AKT的信号转导减少；FGF-FGFR-PI3K-MTOR的基因表达，EGF-EGFR-RAS,TGF-β-SMAD,PLCG和细胞周期进展相关的途径，有利于肿瘤的发展，扩散,programming,胃癌细胞系NCI-N87的迁移和存活也降低。这些不同但互补的作用有助于HLX22和HLX02组合在胃癌细胞系中的协同抗肿瘤功效，CDX和PDX。此外,HLX22与HLX02的组合在体外和体内表现出比HLX02和HLX11(潜在的帕妥珠单抗生物类似物)组合治疗更强的抗肿瘤功效。
结论：这些结果表明，靶向HER2亚结构域IV的非竞争性抗体HLX22和HLX02一起应用可能对目前对曲妥珠单抗治疗反应欠佳的胃癌患者具有实质性益处。
