Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai, India.
Homi Bhabha National Institute, Mumbai, India.
Cancer Biother Radiopharm. 2020 Apr;35(3):177-189. doi: 10.1089/cbr.2019.2882. Epub 2020 Mar 20.
Human epidermal growth factor receptor 2 (HER2) is found to be amplified in ∼15%-20% of breast cancers. In this study, the authors report the synthesis and comparative therapeutic efficacy of Lu-CHX-A″-DTPA-trastuzumab and Lu-CHX-A″-DTPA-F(ab')-trastuzumab to determine their potential as theranostic agents for patients with breast cancer. Bivalent F(ab')-trastuzumab was produced by enzymatic digestion of trastuzumab, conjugated with p-SCN-Bn-CHX-A″-DTPA and subsequently radiolabeled with Lu. Cell viability, membrane toxicity assays, and apoptosis analysis were carried out with Lu-CHX-A″-DTPA-trastuzumab and Lu-CHX-A″-DTPA-F(ab')-trastuzumab in HER2-positive ovarian (SK-OV-3) and breast cancer (SK-BR-3 and MDA-MB-453) cells. cell binding studies showed ∼20%-25% binding of Lu-CHX-A″-DTPA-trastuzumab and Lu-CHX-A″-DTPA-F(ab')-trastuzumab to SK-OV-3, SK-BR-3, and MDA-MB-453 cells. The cells exhibited similar degree of membrane integrity and cellular toxicity when treated with same amount (activity) of Lu-CHX-A″-DTPA-F(ab')-trastuzumab and Lu-CHX-A″-DTPA-trastuzumab, and the toxicity was dose dependent. The mode of cell death was predominantly by apoptosis and necrosis with both the radioimmunoconjugates. The results indicated that the efficacy of both the radioimmunoconjugates, in terms of inducing cell death, was similar thereby ascertaining their potential as good therapeutic agents for patients with breast cancer.
人表皮生长因子受体 2（HER2）在约 15%-20%的乳腺癌中被发现扩增。在这项研究中，作者报告了 Lu-CHX-A″-DTPA-曲妥珠单抗和 Lu-CHX-A″-DTPA-F(ab')-曲妥珠单抗的合成和比较治疗效果，以确定它们作为乳腺癌患者治疗诊断试剂的潜力。双价 F(ab')-曲妥珠单抗通过曲妥珠单抗的酶促消化产生，与 p-SCN-Bn-CHX-A″-DTPA 缀合，然后用 Lu 标记。用 Lu-CHX-A″-DTPA-曲妥珠单抗和 Lu-CHX-A″-DTPA-F(ab')-曲妥珠单抗在 HER2 阳性卵巢（SK-OV-3）和乳腺癌（SK-BR-3 和 MDA-MB-453）细胞中进行细胞活力、膜毒性测定和细胞凋亡分析。细胞结合研究表明，Lu-CHX-A″-DTPA-曲妥珠单抗和 Lu-CHX-A″-DTPA-F(ab')-曲妥珠单抗与 SK-OV-3、SK-BR-3 和 MDA-MB-453 细胞的结合率约为 20%-25%。当用相同量（活性）的 Lu-CHX-A″-DTPA-F(ab')-曲妥珠单抗和 Lu-CHX-A″-DTPA-曲妥珠单抗处理时，细胞表现出相似程度的膜完整性和细胞毒性，并且毒性是剂量依赖性的。两种放射性免疫偶联物诱导细胞死亡的方式主要是凋亡和坏死。结果表明，两种放射性免疫偶联物在诱导细胞死亡方面的疗效相似，从而确定了它们作为乳腺癌患者良好治疗药物的潜力。
