PDF(Pubmed)
Abstract：
UNASSIGNED: Conventional chemotherapy results in severe toxic side effects due to affecting normal and cancer cells. The conjugation of chemotherapy with mAb will improve the chemotherapy selectivity towards cancer cells and at the same time will potentiate immune system to detect and kill cancer cells. The aim of the study was to prepare atezolizumab-pemetrexed conjugate using two types of linkers (linker conjugated with -NH2 of lysine amino acid in the mAb).
UNASSIGNED: This study utilizes (for the first time) the mAb atezolizumab (AtZ) to prepare a new, selective conjugate carrier for pemetrexed (PMX) by using gamma amino butyric acid (GABA) as linker for the first time in comparison to the commonly used linker polyethylene glycol (PEG) using carbodiimide (EDC) / N-hydroxysulfosuccinimide (Sulfo-NHS) zero length cross linker. Stepwise evaluation for PMX-linkers linkage as well as mAb conjugates was evaluated by FTIR, 1HNMR, DSC, LC-MS, gel-electrophoresis as well as the anticancer activity against lung cells A549.
UNASSIGNED: The work revealed that two molecules of GABA combined with PMX, which in turn conjugated with an average ratio of 4:1 with mAb, while one molecule of PEG combined with PMX, which in turn conjugated with mAb in the same average ratio. The IC 50 for the prepared PMX-GABA-AtZ conjugate was 0.048 µM, which was much lower than PMX alone, antibody AtZ alone as well as PMX-PEG-AtZ conjugate in a dose and time dependent manner.
UNASSIGNED: The potential use of such conjugate that selectively directed to the overexpressed lung cells antigen in a low dose leading to reduction of serious side effects of PMX and the cost of therapeutically AtZ mAb used.
UNASSIGNED: This study utilizes (for the first time) the mAb atezolizumab (AtZ) to prepare a new, selective conjugate carrier for pemetrexed (PMX) by using gamma amino butyric acid (GABA) as linker for the first time in comparison to the commonly used linker polyethylene glycol (PEG) using carbodiimide (EDC) / N-hydroxysulfosuccinimide (Sulfo-NHS) zero length cross linker. Stepwise evaluation for PMX-linkers linkage as well as mAb conjugates was evaluated by FTIR, 1HNMR, DSC, LC-MS, gel-electrophoresis as well as the anticancer activity against lung cells A549.
UNASSIGNED: The work revealed that two molecules of GABA combined with PMX, which in turn conjugated with an average ratio of 4:1 with mAb, while one molecule of PEG combined with PMX, which in turn conjugated with mAb in the same average ratio. The IC 50 for the prepared PMX-GABA-AtZ conjugate was 0.048 µM, which was much lower than PMX alone, antibody AtZ alone as well as PMX-PEG-AtZ conjugate in a dose and time dependent manner.
UNASSIGNED: The potential use of such conjugate that selectively directed to the overexpressed lung cells antigen in a low dose leading to reduction of serious side effects of PMX and the cost of therapeutically AtZ mAb used.
摘要：
■常规化疗由于影响正常细胞和癌细胞而导致严重的毒副作用。化疗与mAb的结合将改善化疗对癌细胞的选择性,同时将增强免疫系统以检测和杀死癌细胞。研究的目的是使用两种类型的接头(与mAb中赖氨酸氨基酸的-NH2缀合的接头)制备阿替珠单抗-培美曲塞缀合物。
■这项研究（首次）利用mAbatezolizumab（AtZ）来制备一种新的，与使用碳二亚胺（EDC）/N-羟基磺基琥珀酰亚胺（Sulfo-NHS）零长度交联剂的常用接头聚乙二醇（PEG）相比，首次使用γ氨基丁酸（GABA）作为接头用于培美曲塞（PMX）的选择性缀合载体。通过FTIR评估PMX-接头连接以及mAb缀合物的逐步评估，1HNMR,DSC,LC-MS,凝胶电泳以及对肺细胞A549的抗癌活性。
■这项工作表明，GABA的两个分子与PMX结合，反过来与mAb的平均比率为4：1，当一个分子的PEG与PMX结合时，其又以相同的平均比率与mAb缀合。制备的PMX-GABA-AtZ缀合物的IC50为0.048µM，远低于单独的PMX，以剂量和时间依赖性方式单独的抗体AtZ以及PMX-PEG-AtZ缀合物。
■以低剂量选择性地针对过表达的肺细胞抗原的这种缀合物的潜在用途导致PMX的严重副作用的减少和所使用的治疗性AtZmAb的成本。
■这项研究（首次）利用mAbatezolizumab（AtZ）来制备一种新的，与使用碳二亚胺（EDC）/N-羟基磺基琥珀酰亚胺（Sulfo-NHS）零长度交联剂的常用接头聚乙二醇（PEG）相比，首次使用γ氨基丁酸（GABA）作为接头用于培美曲塞（PMX）的选择性缀合载体。通过FTIR评估PMX-接头连接以及mAb缀合物的逐步评估，1HNMR,DSC,LC-MS,凝胶电泳以及对肺细胞A549的抗癌活性。
■这项工作表明，GABA的两个分子与PMX结合，反过来与mAb的平均比率为4：1，当一个分子的PEG与PMX结合时，其又以相同的平均比率与mAb缀合。制备的PMX-GABA-AtZ缀合物的IC50为0.048µM，远低于单独的PMX，以剂量和时间依赖性方式单独的抗体AtZ以及PMX-PEG-AtZ缀合物。
■以低剂量选择性地针对过表达的肺细胞抗原的这种缀合物的潜在用途导致PMX的严重副作用的减少和所使用的治疗性AtZmAb的成本。
