Chen Kai, Si Yingnan, Ou Jianfa, Guan Jia-Shiung, Kim Seulhee, Ernst Patrick, Zhang Ya, Zhou Lufang, Han Xiaosi, Liu Xiaoguang Margaret
Department of Biomedical Engineering, University of Alabama at Birmingham (UAB), 1825 University Blvd, Birmingham, AL 35294, USA.
Department of Medicine, University of Alabama at Birmingham, 703 19th Street South, Birmingham, AL 35294, USA.
Pharmaceuticals (Basel). 2021 May 2;14(5):427. doi: 10.3390/ph14050427.
Meningiomas are primary tumors of the central nervous system with high recurrence. It has been reported that somatostatin receptor 2 (SSTR2) is highly expressed in most meningiomas, but there is no effective targeted therapy approved to control meningiomas. This study aimed to develop and evaluate an anti-SSTR2 antibody-drug conjugate (ADC) to target and treat meningiomas. The meningioma targeting, circulation stability, toxicity, and anti-tumor efficacy of SSTR2 ADC were evaluated using cell lines and/or an intracranial xenograft mouse model. The flow cytometry analysis showed that the anti-SSTR2 mAb had a high binding rate of >98% to meningioma CH157-MN cells but a low binding rate of <5% to the normal arachnoidal AC07 cells. The In Vivo Imaging System (IVIS) imaging demonstrated that the Cy5.5-labeled ADC targeted and accumulated in meningioma xenograft but not in normal organs. The pharmacokinetics study and histological analysis confirmed the stability and minimal toxicity. In vitro anti-cancer cytotoxicity indicated a high potency of ADC with an IC value of <10 nM. In vivo anti-tumor efficacy showed that the anti-SSTR2 ADC with doses of 8 and 16 mg/kg body weight effectively inhibited tumor growth. This study demonstrated that the anti-SSTR2 ADC can target meningioma and reduce the tumor growth.
脑膜瘤是中枢神经系统的原发性肿瘤,具有高复发性。据报道,生长抑素受体2(SSTR2)在大多数脑膜瘤中高表达,但尚无获批的有效靶向治疗方法来控制脑膜瘤。本研究旨在开发和评估一种抗SSTR2抗体药物偶联物(ADC),用于靶向治疗脑膜瘤。使用细胞系和/或颅内异种移植小鼠模型评估了SSTR2 ADC的脑膜瘤靶向性、循环稳定性、毒性和抗肿瘤疗效。流式细胞术分析表明,抗SSTR2单克隆抗体与脑膜瘤CH157-MN细胞的结合率>98%,但与正常蛛网膜AC07细胞的结合率<5%。体内成像系统(IVIS)成像显示,Cy5.5标记的ADC靶向并积聚在脑膜瘤异种移植瘤中,而不在正常器官中。药代动力学研究和组织学分析证实了其稳定性和最小毒性。体外抗癌细胞毒性表明ADC具有高效能,IC值<10 nM。体内抗肿瘤疗效表明,体重剂量为8和16 mg/kg的抗SSTR2 ADC有效抑制了肿瘤生长。本研究表明,抗SSTR2 ADC可靶向脑膜瘤并减少肿瘤生长。