Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Victoria, Australia;
School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia.
J Nucl Med. 2024 Sep 3;65(9):1456-1462. doi: 10.2967/jnumed.123.266894.
The epidermal growth factor receptor (EGFR) protein is highly expressed in a range of malignancies. Although therapeutic interventions directed toward EGFR have yielded therapeutic responses in cancer patients, side effects are common because of normal-tissue expression of wild-type EGFR. We developed a novel tumor-specific anti-EGFR chimeric antibody ch806 labeled with Ac and evaluated its in vitro properties and therapeutic efficacy in murine models of glioblastoma and colorectal cancer. Ac-ch806 was prepared using different chelators, yielding [Ac]Ac-macropa-tzPEGSq-ch806 and [Ac]Ac-DOTA-dhPzPEG-ch806. Radiochemical yield, purity, apparent specific activity, and serum stability of Ac-ch806 were quantified. In vitro cell killing effect was examined. The biodistribution and therapeutic efficacy of Ac-ch806 were investigated in mice with U87MG.de2-7 and DiFi tumors. Pharmacodynamic analysis of tumors after therapy was performed, including DNA double-strand break immunofluorescence of γH2AX, as well as immunohistochemistry for proliferation, cell cycle arrest, and apoptosis. [Ac]Ac-macropa-tzPEGSq-ch806 surpassed [Ac]Ac-DOTA-dhPzPEG-ch806 in radiochemical yield, purity, apparent specific activity, and serum stability. [Ac]Ac-macropa-tzPEGSq-ch806 was therefore used for both in vitro and in vivo studies. It displayed a significant, specific, and dose-dependent in vitro cell-killing effect in U87MG.de2-7 cells. Ac-ch806 also displayed high tumor uptake and minimal uptake in normal tissues. Ac-ch806 significantly inhibited tumor growth and prolonged survival in both U87MG.de2-7 and DiFi models. Enhanced γH2AX staining was observed in Ac-ch806-treated tumors compared with controls. Reduced Ki-67 expression was evident in all Ac-ch806-treated tumors. Increased expression of p21 and cleaved caspase 3 was shown in U87MG.de2-7 and DiFi tumors treated with Ac-ch806. In glioblastoma and colorectal tumor models, Ac-ch806 significantly inhibited tumor growth via induction of double-strand breaks, thereby constraining cancer cell proliferation while inducing cell cycle arrest and apoptosis. These findings underscore the potential clinical applicability of Ac-ch806 as a potential therapy for EGFR-expressing solid tumors.
表皮生长因子受体 (EGFR) 蛋白在多种恶性肿瘤中高度表达。虽然针对 EGFR 的治疗干预措施在癌症患者中产生了治疗反应，但由于野生型 EGFR 在正常组织中的表达，副作用很常见。我们开发了一种新型的肿瘤特异性抗 EGFR 嵌合抗体 ch806，并用 Ac 标记，并评估了其在胶质母细胞瘤和结直肠癌小鼠模型中的体外特性和治疗效果。使用不同的螯合剂制备 Ac-ch806，得到 [Ac]Ac-macropa-tzPEGSq-ch806 和 [Ac]Ac-DOTA-dhPzPEG-ch806。Ac-ch806 的放射性化学产率、纯度、表观比活度和血清稳定性均进行了定量。检测了体外细胞杀伤效果。在 U87MG.de2-7 和 DiFi 肿瘤小鼠中研究了 Ac-ch806 的体内分布和治疗效果。对治疗后的肿瘤进行了药效学分析，包括 γH2AX 的双链 DNA 免疫荧光，以及增殖、细胞周期阻滞和凋亡的免疫组织化学分析。[Ac]Ac-macropa-tzPEGSq-ch806 的放射性化学产率、纯度、表观比活度和血清稳定性均优于 [Ac]Ac-DOTA-dhPzPEG-ch806。因此，[Ac]Ac-macropa-tzPEGSq-ch806 用于体外和体内研究。它在 U87MG.de2-7 细胞中表现出显著的、特异性的、剂量依赖性的体外细胞杀伤作用。Ac-ch806 也表现出对肿瘤的高摄取和对正常组织的低摄取。Ac-ch806 显著抑制了 U87MG.de2-7 和 DiFi 模型中的肿瘤生长并延长了生存时间。与对照组相比，在 Ac-ch806 治疗的肿瘤中观察到增强的 γH2AX 染色。在所有接受 Ac-ch806 治疗的肿瘤中，Ki-67 的表达均减少。在 U87MG.de2-7 和 DiFi 肿瘤中，p21 和 cleaved caspase 3 的表达增加。在胶质母细胞瘤和结直肠肿瘤模型中，Ac-ch806 通过诱导双链断裂显著抑制肿瘤生长，从而限制癌细胞增殖，同时诱导细胞周期阻滞和凋亡。这些发现强调了 Ac-ch806 作为一种治疗 EGFR 表达实体肿瘤的潜在疗法的临床应用潜力。
