研發以醣抗原為基礎之抗乳癌疫苗

Abstract

中文摘要 Hakomori在1984年以單株抗體Mbr1分離並鑑定Globo H的組成為Fucα1→2Galβ1→3GalNAcβ1→3Galα1→4Galβ1→4Gluβ1→R。在上皮細胞癌，例如：乳癌、肺癌、前列腺癌、胰臟癌、胃癌、卵巢癌…等，都有發現Globo H的過量表現。正常細胞只有少數的分泌管道組織會有微量Globo H的表現。由於Globo H在正常細胞與癌細胞表現量有顯著的差異，因此，有潛力發展為抗癌疫苗。研究發現，初期的癌症幹細胞表面除了有Globo H的表現，還有大量的SSEA-3與SSEA-4表現。此兩種醣抗原也隸屬於Globo-系列。此外，SSEA-3與SSEA-4不只在癌症幹細胞有表現，在癌症細胞中也有表現。 對此新發現，我們利用這三種醣抗原搭配白喉毒素突變體 (DT-CRM 197) 以及佐劑來設計新的抗乳癌疫苗，期望可以增加癌症疫苗的效能。我們的研究發現，Globo H-DT可以誘發大量可辨識Globo H, SSEA-3, and SSEA-4 的抗體。利用SSEA-DT產生的抗體有很高的專一性。另一方面，SSEA-3以白喉毒素突變體為載體蛋白所製成的疫苗，與Globo H以及SSEA-4相比，由於缺少岩藻醣(fucose)或唾液酸(sialic acid)，產生的抗體專一性則較差。令人興奮的是，這三種疫苗所產生的IgG都遠高於IgM，因此，此一疫苗的持久性是令人期待的。 本論文也利用樹突狀高分子來增加醣抗原在載體蛋白上的表現量，希望可以藉由提高醣抗原的密度，來提升免疫系統對醣抗原的辨識能力。期許從醣抗原的選擇以及提高醣抗原的表現量，搭配適當的醣脂佐劑及載體蛋白能設計出最有效的疫苗。

Abstract Globo H was first isolated and identified by the monoclonal antibody, MBr1 in 1984 by Hakomori et al. It was found minor expressed in normal human mammary gland epithelia but over-expressed on breast cancer, lung cancer, prostate cancer, pancreas cancer, stomach cancer, and ovary cancer and just minor expressed in normal human mammary gland epithelia. Based on the significant difference between normal cells and cancer cells, Globo H was considered to be a good candidate for carbohydrate-based anti-cancer vaccine. Recently, Globo H, SSEA-3, and SSEA-4, especially the later two, were found largely on cancer stem cells. They are also belong to globo-series. These two antigens have provided a new direction for cancer stem cell targeting vaccine design. In this study, these three antigens were combined with DT-CRM197 and adjuvant, respectively. Globo H-DT induced large amount of antibodies not only anti-Globo H but also anti-SSEA-3 and anti-SSEA-4 antibodies. SSEA-4-DT induced antibodies with high spcificity. On the other hand, SSEA-3-DT which lack of fucose or sialic acid showed low specificity. More interestingly, all these three vaccines can induce much higher IgG titer than IgM., these vaccine with long-term protective efficiency is worth waiting for. . These results are very exciting, and synthesize of different glycodendrimer vaccines are ongoing. By changing and increasing the density of carbohydrate antigen, we expect to develop a more efficiency carbohydrate-based anti-cancer vaccine in the very near future.