Radioimmunotherapy study of (131)I-labeled Atezolizumab in preclinical models of colorectal cancer.
Radioimmunotherapy study of (131)I-labeled Atezolizumab in preclinical models of colorectal cancer.
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DOI：
10.1186/s13550-022-00939-2
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发表时间：
2022-10-28
期刊：
影响因子：
3.2
通讯作者：
中科院分区：
文献类型：
--
作者：
程序性细胞死亡 1 配体 1 (PD-L1) 在许多肿瘤中过度表达。放射性核素标记的抗PD-L1单克隆抗体可用于PD-L1过表达癌症的成像和治疗。在这里，我们描述了 131I 标记的 Atezolizumab（131I-Atezolizumab，靶向 PD-L1）作为 PD-L1 过度表达的结直肠癌的治疗剂。 131I-Atezolizumab 通过 Iodogen 法制备。通过流式细胞术、蛋白质印迹和细胞结合实验测定不同人结直肠细胞中PD-L1的表达水平。通过免疫反应分数测定 131I-Atezolizumab 对 PD-L1 高表达细胞的免疫反应性。采用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑(MTT)法检测不同浓度131I-Atezolizumab对PD-L1高表达和低表达细胞的杀伤能力。对两种人类结直肠癌模型进行了切伦科夫发光成像 (CLI) 和 131I-Atezolizumab 放射免疫治疗 (RIT)。通过成像评估 131I-Atezolizumab 的分布和肿瘤靶向性。以肿瘤体积和生存时间作为评价131I-Atezolizumab抗肿瘤效果的指标。细胞结合实验测定的PD-L1体外表达水平与流式细胞术和western blot的数据相关。 131I-Atezolizumab 可在体外特异性结合 PD-L1 高表达细胞，以反映 PD-L1 的表达水平。 PD-L1 高表达 RKO 细胞与 131I-Atezolizumab 的免疫反应分数为 52.2%。 131I-Atezolizumab对PD-L1高表达细胞的杀伤能力高于低表达细胞。 CLI证明肿瘤的特异性摄取水平取决于PD-L1的表达水平。 131I-Atezolizumab RIT 对 PD-L1 高表达的 RKO 荷瘤小鼠显示出活性依赖性肿瘤抑制作用。与未治疗的小鼠（27 天）相比，131I-Atezolizumab (37 MBq) 可以延长小鼠的中位生存时间（34 天）（P = 0.027）。尽管131I-Atezolizumab单效（37MBq）也能抑制PD-L1低表达的HCT8荷瘤小鼠的肿瘤（P < 0.05），但不能延长小鼠的生存期（P = 0.29）。 131I-Atezolizumab 可用作筛查 PD-L1 表达水平的 CLI 试剂。它可以作为PD-L1过表达肿瘤的放射免疫治疗药物靶点。在线版本包含可在 10.1186/s13550-022-00939-2 获取的补充材料。
Programmed cell death 1 ligand 1(PD-L1) is overexpressed in many tumors. The radionuclide-labeled anti-PD-L1 monoclonal antibody can be used for imaging and therapy of PD-L1 overexpressing cancer. Here, we described 131I-labeled Atezolizumab (131I-Atezolizumab, targeting PD-L1) as a therapeutic agent for colorectal cancer with PD-L1 overexpression. 131I-Atezolizumab was prepared by the Iodogen method. The expression levels of PD-L1 in different human colorectal cells were determined by flow cytometry, western blot and cell binding assay. The immunoreactivity of 131I-Atezolizumab to PD-L1 high-expressing cells was determined by immunoreactive fraction. The killing abilities of different concentrations of 131I-Atezolizumab on cells with high and low expression of PD-L1 were detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Cerenkov luminescence imaging (CLI) and radioimmunotherapy (RIT) of 131I-Atezolizumab were performed on two human colorectal cancer models. The distribution and tumor targeting of 131I-Atezolizumab were evaluated by imaging. Tumor volume and survival time were used as indicators to evaluate the anti-tumor effect of 131I-Atezolizumab. The expression level of PD-L1 in vitro determined by the cell binding assay was related to the data of flow cytometry and western blot. 131I-Atezolizumab can specifically bind to PD-L1 high-expressing cells in vitro to reflect the expression level of PD-L1. Immunoreactive fraction of PD-L1 high-expressing RKO cells with 131I-Atezolizumab was 52.2%. The killing ability of 131I-Atezolizumab on PD-L1 high-expressing cells was higher than that of low-expressing cells. CLI proved that the specific uptake level of tumors depends on the expression level of PD-L1. Effect of 131I-Atezolizumab RIT showed an activity-dependent tumor suppressor effect on RKO tumor-bearing mice with high PD-L1 expression. 131I-Atezolizumab (37 MBq) can improve the median survival time of mice (34 days), compared to untreated mice (27 days) (P = 0.027). Although a single activity(37 MBq) of 131I-Atezolizumab also inhibited the tumors of HCT8 tumor-bearing mice with low PD-L1 expression (P < 0.05), it could not prolong the survival of mice(P = 0.29). 131I-Atezolizumab can be used as a CLI agent for screening PD-L1 expression levels. It may be used as a radioimmunotherapy drug target for PD- L1 overexpressing tumors. The online version contains supplementary material available at 10.1186/s13550-022-00939-2.
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