中国科学院上海药物研究所李铁海团队报道了3D-MPL和QS-21联合佐剂增强Globo h基疫苗的抗肿瘤免疫。相关研究成果发表在2024年12月16日出版的国际学术期刊《德国应用化学》。

Globo H是一种在各种人类恶性肿瘤中过表达的特异性碳水化合物抗原，作为抗癌疫苗开发的抗原靶标引起了人们的极大兴趣。尽管已经设计了几种基于Globo H的碳水化合物疫苗，但有效获得Globo H六糖抗原和开发增强抗肿瘤免疫的强效佐剂仍然具有挑战性。

该文中，研究人员报道了一种简化的化学酶法来制备这种六糖抗原，该方法依赖于通过立体收敛[2+3]策略化学合成Gb5五糖，随后进行酶促α-岩藻糖基化，以轻松组装α1,2-岩藻糖残基。另外，通过整合立体控制糖基化、区域选择性酰化、位点特异性磷酸化和简单的全局脱保护，开发了一种有效合成3-O-脱酰基单磷酰脂质a（3D-MPL）的模块化组装方法。

在高效构建Globo H-CRM197偶联物后，研究人员对Globo H-CR M197进行了系统的免疫学评估，该偶联物由各种佐剂和佐剂组合配制而成，包括皂苷QS-21、合成3D-MPL和α-半乳糖神经酰胺衍生物S34。

结果显示，用QS-21和3D-MPL佐剂的Globo H-CRM197偶联物在小鼠中引起了强烈的IgG2a和IgG3抗体反应和Th1细胞免疫。此外，该制剂诱导的抗体与Globo H阳性MCF-7癌症细胞有效结合，并表现出优异的补体依赖性细胞毒性和抗体依赖性细胞吞噬作用，有望进一步开发有效的抗癌疫苗。

附：英文原文

Title: Enhanced Antitumor Immunity of a Globo H-Based Vaccine Enabled by the Combination Adjuvants of 3D-MPL and QS-21

Author: Wenjing Ma, Zhuojia Xu, Changcai Teng, Chang Cao, Ruixue Wu, Xiao Meng, Qiang Sui, Qi Gao, Chengli Zong, Tiehai Li

Issue&Volume: 2024-12-16

Abstract: Globo H, a specific carbohydrate antigen overexpressed on various human malignancies, has attracted considerable interest as an antigenic target for anticancer vaccine development. Despite several Globo H-based carbohydrate vaccines that have been designed, efficient access to Globo H hexasaccharide antigen and development of powerful adjuvants for enhancing antitumor immunity remain challenging. Herein, we reported a streamlined chemoenzymatic approach to prepare this hexasaccharide antigen, relying on chemical synthesis of Gb5 pentasaccharide by a stereoconvergent [2+3] strategy and subsequent enzymatic α-fucosylation to easily install α1,2-fucose residue. Separately, a modular assembly approach to efficiently synthesize 3-O-deacyl-monophosphoryl lipid A (3D-MPL) was developed by the integration of stereocontrolled glycosylation, regioselective acylation, site-specific phosphorylation, and facile global deprotection. After efficient construction of Globo H-CRM197 conjugate, we conducted systematic immunological evaluations of Globo H-CRM197 formulated with various adjuvants and adjuvant combinations, comprising saponin QS-21, synthetic 3D-MPL and α-galactosylceramide derivative S34. The results revealed that Globo H-CRM197 conjugate adjuvanted with QS-21 and 3D-MPL elicited robust IgG2a and IgG3 antibody responses and Th1 cellular immunity in mice. Moreover, antibodies induced by this formulation effectively bound to Globo H-positive MCF-7 cancer cells and exhibited superior complement-dependent cytotoxicity and antibody-dependent cellular phagocytosis, holding promise for further development of effective anticancer vaccines.

DOI: 10.1002/anie.202418948

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202418948