Homogeneous antibody and CAR-T cells with improved effector functions targeting SSEA-4 glycan on pancreatic cancer
Homogeneous antibody and CAR-T cells with improved effector functions targeting SSEA-4 glycan on pancreatic cancer
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DOI：
10.1073/pnas.2114774118
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发表时间：
2021-12-14
影响因子：
11.1
通讯作者：
Wong, Chi-Huey
中科院分区：
文献类型：
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作者：
Lin, Chih-Wei;Wang, Yu-Jen;Wong, Chi-Huey
胰腺癌通常在早期阶段无症状; 5年生存率约为9%;并且缺乏有效的治疗。在这里，我们发现SSEA-4在所有胰腺癌细胞系中表达更多，但在正常胰腺细胞中检测不到; SSEA-4或与SSEA-4生物合成相关的关键酶B3 GALT 5 + ST 3GAL 2的高表达显著降低了总生存率。为了评估胰腺癌的潜在新治疗，具有用于最佳效应子功能的明确定义的Fc聚糖的均质抗体和具有设计用于靶向SSEA-4的scFv构建体的CAR-T细胞在体外和体内显示出对胰腺癌高度有效。这进一步得到以下发现的支持：与未分离的NK细胞相比，通过同质抗体分离的自然杀伤（NK）细胞亚群表现出癌细胞杀伤活性的增强。这些结果表明，通过同源抗体或CAR-T策略靶向SSEA-4可以有效抑制癌症生长，表明SSEA-4是治疗胰腺疾病的潜在免疫治疗靶标。
Pancreatic cancer is usually asymptomatic in the early stages; the 5-y survival rate is around 9%; and there is a lack of effective treatment. Here we show that SSEA-4 is more expressed in all pancreatic cancer cell lines examined but not detectable in normal pancreatic cells; and high expression of SSEA-4 or the key enzymes B3GALT5 + ST3GAL2 associated with SSEA-4 biosynthesis significantly lowers the overall survival rate. To evaluate potential new treatments for pancreatic cancer, homogeneous antibodies with a well-defined Fc glycan for optimal effector functions and CAR-T cells with scFv construct designed to target SSEA-4 were shown highly effective against pancreatic cancer in vitro and in vivo. This was further supported by the finding that a subpopulation of natural killer ( NK) cells isolated by the homogeneous antibody exhibited enhancement in cancer- cell killing activity compared to the unseparated NK cells. These results indicate that targeting SSEA-4 by homologous antibodies or CAR-T strategies can effectively inhibit cancer growth, suggesting SSEA-4 as a potential immunotherapy target for treating pancreatic disease.