Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran; Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
Biomed Pharmacother. 2023 Oct;166:115292. doi: 10.1016/j.biopha.2023.115292. Epub 2023 Aug 12.
Patients receiving high-dose methotrexate (HDMTX) for malignancies are exposed to diverse complications, including nephrotoxicity, hepatotoxicity, mucositis, myelotoxicity, neurological symptoms, and death. Glucarpidase is a recombinant carboxypeptidase G2 (CPG2) that converts MTX into nontoxic metabolites. In this study, the role of vector type, gene optimization, orientation, and host on the expression of CPG2 is investigated. The effectiveness of various therapeutic regimens containing glucarpidase is classified and perspectives on the dose adjustment based on precision medicine are provided. Conjugation with cell-penetrating peptides, human serum albumin, and polymers such as PEG and dextran for delivery, higher stability, and production of the biobetter variants of CPG2 is highlighted. Conjugation of CPG2 to F(ab՜) or scFv antibody fragments against tumor-specific antigens and the corresponding prodrugs for tumor-targeted drug delivery using the antibody-directed enzyme prodrug therapy (ADEPT) is communicated. Trials to reduce the off-target effects and the possibility of repeated ADEPT cycles by adding pro-domains sensitive to tumor-overexpressed proteases, antiCPG2 antibodies, CPG2 mutants with immune-system-unrecognizable epitopes, and protective polymers are reported. Intracellular cpg2 gene expression by gene-directed enzyme prodrug therapy (GDEPT) and the concerns regarding the safety and transfection efficacy of the GDEPT vectors are described. A novel bifunctional platform using engineered CAR-T cell micropharmacies, known as Synthetic Enzyme-Armed KillER (SEAKER) cells, expressing CPG2 to activate prodrugs at the tumor niche is introduced. Taken together, integrated data in this review and recruiting combinatorial strategies in novel drug delivery systems define the future directions of ADEPT, GDEPT, and SEAKER cell therapy and the placement of CPG2 therein.
接受高剂量甲氨蝶呤 (HDMTX) 治疗恶性肿瘤的患者会面临多种并发症，包括肾毒性、肝毒性、黏膜炎、骨髓抑制、神经症状和死亡。葡醛内酯酶是一种重组羧肽酶 G2 (CPG2)，可将 MTX 转化为无毒代谢物。在这项研究中，研究了载体类型、基因优化、方向和宿主对 CPG2 表达的影响。对包含葡醛内酯酶的各种治疗方案的有效性进行了分类，并根据精准医学提供了剂量调整的观点。强调了通过细胞穿透肽、人血清白蛋白以及聚乙二醇 (PEG) 和葡聚糖等聚合物进行递送、提高稳定性以及生产 CPG2 的生物改良变体。将 CPG2 与针对肿瘤特异性抗原的 F(abʹ) 或 scFv 抗体片段缀合，并使用抗体导向酶前药治疗 (ADEPT) 进行针对肿瘤的药物递送的相应前药，也进行了沟通。报告了通过添加对肿瘤过表达蛋白酶敏感的原结构域、抗 CPG2 抗体、具有免疫系统不可识别表位的 CPG2 突变体和保护性聚合物来减少脱靶效应和重复 ADEPT 循环的可能性的试验。描述了通过基因定向酶前药治疗 (GDEPT) 进行细胞内 cpg2 基因表达以及对 GDEPT 载体的安全性和转染效率的关注。引入了一种使用表达 CPG2 以在肿瘤部位激活前药的工程化 CAR-T 细胞微粒药，称为合成酶武装杀伤器 (SEAKER) 细胞的新型双功能平台。总之，本综述中的综合数据以及在新型药物递送系统中招募组合策略定义了 ADEPT、GDEPT 和 SEAKER 细胞治疗的未来方向以及 CPG2 在其中的位置。
