肿瘤细胞治疗研究
英文原题：Design and development of dual targeting CAR protein for the development of CAR T-cell therapy against KRAS mutated pancreatic ductal adenocarcinoma using computational approaches.
Design and development of dual targeting CAR protein for the development of CAR T-cell therapy against KRAS mutated pancreatic ductal adenocarcinoma using computational approaches.
突变 KRAS 促进多种癌症的增殖、转移和侵袭性，包括胰腺导管腺癌（PDAC）、非小细胞肺癌（NSCLC）和结直肠腺癌（CRC）。
突变型KRAS可促进多种癌症的增殖、转移和侵袭性，包括胰腺导管腺癌（PDAC）、非小细胞肺癌（NSCLC）和结直肠腺癌（CRC）。针对突变KRAS的治疗手段有限；索托拉西布和阿达格拉西布是目前仅有的获FDA批准、用于治疗KRAS G12C突变NSCLC的药物。嵌合抗原受体（CAR）T细胞疗法已成为治疗血液系统恶性肿瘤的有效策略，并正拓展至PDAC等实体瘤。已有研究报道，间皮素（MSLN）和癌胚抗原（CEA）在KRAS突变型PDAC中均高表达。当前PDAC的多项临床CAR T细胞研究主要聚焦于这两种肿瘤抗原，但尚未报道同时靶向二者的策略。本研究采用多种生物信息学方法设计并开发了一种新型双靶向CAR蛋白，包括功能分析（抗原性、致敏性、抗原结合位点及信号级联）、质量分析（理化性质、二维和三维结构预测、优化与验证）、分子对接及计算机模拟克隆。结果显示，所设计的CAR蛋白可分别与MSLN和CEA特异性结合，具有显著的结合亲和力；预测结果还显示该蛋白稳定且无致敏性。此外，蛋白质相互作用网络提示，所设计CAR各结构域均参与T细胞介导的抗肿瘤反应。总之，本研究通过计算方法设计并开发了针对KRAS突变型PDAC、同时靶向MSLN和CEA的CAR蛋白，并建议未来将该CAR导入T细胞，在体外和体内研究中评估其治疗效力。
Mutant KRAS promotes the proliferation, metastasis, and aggressiveness of various cancers including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal adenocarcinoma (CRC) respectively. Mutant KRAS therapeutics are limited, while Sotorasib and Adagrasib were the only FDA-approved drugs for the treatment of KRAS G12C mutated NSCLC. Chimeric antigen receptor (CAR) T-cell therapy has been emerged as an effective strategy against hematological malignancies and being extended towards solid cancers including PDAC. mesothelin (MSLN) and Carcinoembryonic Antigen (CEA) were reported to be highly overexpressed in KRAS-mutated PDAC. Meanwhile, in clinical trials, several CAR T-cell therapy studies are mainly focused towards these two cancer antigens in PDAC, however, the dual targeting of these two neoantigens is not reported. In the present study, we have designed and developed a novel dual-targeting CAR protein by employing various bioinformatics approaches such as functional analysis (antigenicity, allergenicity, antigen binding sites & signalling cascades), qualitative analysis (physicochemical, prediction, refinement & validation of 2D and 3D structures), molecular docking, and in silico cloning. Our results revealed that the designed CAR protein specifically binds with both MSLN & CEA with significant binding affinities, and was predicted to be stable & non-allergenic. Additionally, the protein-protein interaction network reveals the T-cell mediated antitumor responses of each domain in the designed CAR. Conclusively, we have designed and developed a dual targeting (MSLN & CEA) CAR protein towards KRAS-mutated PDAC using computational approaches. Alongside, we further recommend to engineer this designed CAR in T-cells and evaluating their therapeutic efficiency in in vitro and in vivo studies in the near future.
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