METHODS: The binding of DB-1310 to Her3 and other HER families were measured by ELISA and SPR. The competition of binding epitope for DB-1310 and patritumab was tested by FACS. The sensitivity of breast, lung, prostate and colon cancer cell lines to DB-1310 was evaluated by in vitro cell killing assay. In vivo growth inhibition study evaluated the sensitivity of DB-1310 to Her3 + breast, lung, colon and prostate cancer xenograft models. The safety profile was also measured in cynomolgus monkey.
RESULTS: DB-1310 binds HER3 via a novel epitope with high affinity and internalization capacity. In vitro, DB-1310 exhibited cytotoxicity in numerous HER3 + breast, lung, prostate and colon cancer cell lines. In vivo studies in HER3 + HCC1569 breast cancer, NCI-H441 lung cancer and Colo205 colon cancer xenograft models showed DB-1310 to have dose-dependent tumoricidal activity. Tumor suppression was also observed in HER3 + non-small cell lung cancer (NSCLC) and prostate cancer patient-derived xenograft (PDX) models. Moreover, DB-1310 showed stronger tumor growth-inhibitory activity than patritumab deruxtecan (HER3-DXd), which is another HER3 ADC in clinical development at the same dose. The tumor-suppressive activity of DB-1310 synergized with that of EGFR tyrosine kinase inhibitor, osimertinib, and exerted efficacy also in osimertinib-resistant PDX model. The preclinical assessment of safety in cynomolgus monkeys further revealed DB-1310 to have a good safety profile with a highest non severely toxic dose (HNSTD) of 45 mg/kg.
CONCLUSIONS: These finding demonstrated that DB-1310 exerted potent antitumor activities against HER3 + tumors in in vitro and in vivo models, and showed acceptable safety profiles in nonclinical species. Therefore, DB-1310 may be effective for the clinical treatment of HER3 + solid tumors.
方法:通过ELISA和SPR测量DB-1310与Her3和其他HER家族的结合。通过FACS测试DB-1310和帕特单抗的结合表位的竞争。乳房的敏感性,肺,通过体外细胞杀伤试验评估了DB-1310的前列腺癌和结肠癌细胞系。体内生长抑制研究评估了DB-1310对Her3+乳腺的敏感性,肺,结肠癌和前列腺癌异种移植模型。还在食蟹猴中测量了安全性特征。
结果:DB-1310通过具有高亲和力和内化能力的新型表位结合HER3。体外,DB-1310在许多HER3+乳腺中表现出细胞毒性,肺,前列腺癌和结肠癌细胞系。HER3+HCC1569乳腺癌的体内研究,NCI-H441肺癌和Colo205结肠癌异种移植模型显示DB-1310具有剂量依赖性杀肿瘤活性。在HER3+非小细胞肺癌(NSCLC)和前列腺癌患者来源的异种移植物(PDX)模型中也观察到肿瘤抑制。此外,DB-1310显示出比派妥克替康(HER3-DXd)更强的肿瘤生长抑制活性,这是在相同剂量下临床开发中的另一种HER3ADC。DB-1310的抑瘤活性与EGFR酪氨酸激酶抑制剂协同作用,奥希替尼,并在奥希替尼耐药的PDX模型中发挥作用。食蟹猴的安全性的临床前评估进一步显示,DB-1310具有良好的安全性,最高非严重毒性剂量(HNSTD)为45mg/kg。
结论:这些发现表明,DB-1310在体外和体内模型中对HER3+肿瘤具有有效的抗肿瘤活性,并在非临床物种中显示出可接受的安全性。因此,DB-1310可有效用于HER3+实体瘤的临床治疗。