Synthesis and immunological properties of N-modified GM3 antigens as therapeutic cancer vaccines
Synthesis and immunological properties of N-modified GM3 antigens as therapeutic cancer vaccines
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DOI：
10.1021/jm0494422
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发表时间：
2005-02-10
影响因子：
7.3
通讯作者：
Guo, ZW
中科院分区：
文献类型：
--
作者：
Pan, YB;Chefalo, P;Guo, ZW
肿瘤相关三糖抗原GM 3的免疫耐受问题严重阻碍了其在肿瘤疫苗开发中的应用。为了解决这一问题，合成了一系列GM 3衍生物的钥孔血蓝蛋白（KLH）缀合物，并筛选出作为治疗性癌症疫苗。首先，通过高度收敛的方法制备不同N-酰化的GM 3类似物的β-连接的异头叠氮化物。接着，在叠氮基的选择性还原之后，将戊烯酰基连接至碳水化合物抗原的还原末端。然后将接头臭氧分解以得到醛官能团，允许抗原通过还原胺化与KLH缀合。最后，在C57 BL/6小鼠中通过评估由GM 3类似物诱导的特异性抗体的滴度来研究所得糖缀合物的免疫学性质。虽然KLH-GM 3引起低水平的免疫应答，但N-丙酰基、N-丁酰基、N-异丁酰基和N-苯乙酰基GM 3的KLH缀合物诱导与多种同种型的抗体的稳健的免疫反应，表明显著改善的和T细胞依赖性的免疫应答，其导致同种型转换、亲和力成熟和免疫“记忆”的诱导。这表明GM 3 PhAc-KLH是一种有前途的候选疫苗，用于以GM 3为主要靶点的癌症糖工程免疫治疗。
The problem of immunotolerance to GM3, an important tumor-associated trisaccharide antigen, seriously hinders its usage in cancer vaccine development. To solve this problem, the keyhole limpet hemocyanin (KLH) conjugates of a series of GM3 derivatives were synthesized and screened as therapeutic cancer vaccines. First, the beta-linked anomeric azides of differently N-acylated GM3 analogues were prepared by a highly convergent procedure. Next, a pentenoyl group was linked to the reducing end of the carbohydrate antigens following selective reduction of the azido group. The linker was thereafter ozonolyzed to give an aldehyde functionality permitting the conjugation of the antigens to KLH via reductive amination. Finally, the immunological properties of the resultant glycoconjugates were studied in C57BL/6 mice by assessing the titers of specific antibodies induced by the GM3 analogues. While KLH-GM3 elicited low levels of immune response, the KLH conjugates of N-propionyl, N-butanoyl, N-isobutanoyl, and N-phenylacetyl GM3s induced robust immune reactions with antibodies of multiple isotypes, indicating significantly improved and T-cell dependent immune responses that lead to isotype switching, affinity maturation, and the induction of immunological "memory". It was suggested that GM3PhAc-KLH is a promising vaccine candidate for glycoengineered immunotherapy of cancer with GM3 as the primary target.