Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California.
Jules Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, California.
Mol Cancer Ther. 2024 Jun 4;23(6):890-903. doi: 10.1158/1535-7163.MCT-23-0465.
Epithelial membrane protein-2 (EMP2) is upregulated in a number of tumors and therefore remains a promising target for mAb-based therapy. In the current study, image-guided therapy for an anti-EMP2 mAb was evaluated by PET in both syngeneic and immunodeficient cancer models expressing different levels of EMP2 to enable a better understanding of its tumor uptake and off target accumulation and clearance. The therapeutic efficacy of the anti-EMP2 mAb was initially evaluated in high- and low-expressing tumors, and the mAb reduced tumor load for the high EMP2-expressing 4T1 and HEC-1-A tumors. To create an imaging agent, the anti-EMP2 mAb was conjugated to p-SCN-Bn-deferoxamine (DFO) and radiolabeled with 89Zr. Tumor targeting and tissue biodistribution were evaluated in syngeneic tumor models (4T1, CT26, and Panc02) and human tumor xenograft models (Ramos, HEC-1-A, and U87MG/EMP2). PET imaging revealed radioactive accumulation in EMP2-positive tumors within 24 hours after injection, and the signal was retained for 5 days. High specific uptake was observed in tumors with high EMP2 expression (4T1, CT26, HEC-1-A, and U87MG/EMP2), with less accumulation in tumors with low EMP2 expression (Panc02 and Ramos). Biodistribution at 5 days after injection revealed that the tumor uptake ranged from 2 to approximately 16%ID/cc. The results show that anti-EMP2 mAbs exhibit EMP2-dependent tumor uptake with low off-target accumulation in preclinical cancer models. The development of improved anti-EMP2 Ab fragments may be useful to track EMP2-positive tumors for subsequent therapeutic interventions.
上皮膜蛋白 2（EMP2）在许多肿瘤中上调，因此仍然是 mAb 为基础治疗的有前途的靶点。在目前的研究中，通过 PET 评估了针对抗 EMP2 mAb 的图像引导治疗，该 mAb 在表达不同水平 EMP2 的同源和免疫缺陷癌症模型中进行评估，以更好地了解其肿瘤摄取和脱靶积累和清除。抗 EMP2 mAb 的治疗效果最初在高表达和低表达肿瘤中进行了评估，mAb 减少了高 EMP2 表达的 4T1 和 HEC-1-A 肿瘤的肿瘤负荷。为了制备成像剂，将抗 EMP2 mAb 与 p-SCN-Bn-去铁胺（DFO）缀合，并与 89Zr 放射性标记。在同源肿瘤模型（4T1、CT26 和 Panc02）和人肿瘤异种移植模型（Ramos、HEC-1-A 和 U87MG/EMP2）中评估了肿瘤靶向和组织生物分布。PET 成像显示，注射后 24 小时内放射性物质在 EMP2 阳性肿瘤中积累，信号保留了 5 天。在高 EMP2 表达的肿瘤（4T1、CT26、HEC-1-A 和 U87MG/EMP2）中观察到高特异性摄取，在低 EMP2 表达的肿瘤（Panc02 和 Ramos）中摄取较少。注射后 5 天的生物分布显示，肿瘤摄取范围为 2%至约 16%ID/cc。结果表明，抗 EMP2 mAbs 在临床前癌症模型中表现出 EMP2 依赖性肿瘤摄取，并且脱靶积累低。开发改进的抗 EMP2 Ab 片段可能有助于跟踪 EMP2 阳性肿瘤，以进行后续的治疗干预。
