Globo 系列抗原異構物之合成與 Globo 系列抗體專一性之研究

Abstract

現有的癌症藥物由於專一性不足,在攻擊癌症細胞的同時,亦會造成大量的 正常細胞死亡,引起強烈的副作用。近年來,有許多研究團隊致力於發展具有高 專一性的癌症藥物,以降低治療時所產生的副作用,同時提升疾病治癒率。 SSEA-3、SSEA-4 以及 Globo H 為在多種癌症細胞上具有高表現度的醣抗原, 且在正常細胞中並未被發現,因此這三種抗原可用來作為藥物辨識癌症細胞的標 的物。本實驗室先前研發的 Globo H-DT 疫苗即可誘發針對 SSEA-3、SSEA-4 及 Globo H 三種醣抗原之抗體,引起自體免疫反應,以消滅癌症細胞。 近年研究發現,在豬隻以及小鼠的體內都有 iso-Gb3 抗原的存在,此抗原的 結構與 Gb3 極為相近,其差異僅在還原端半乳糖單醣的接合位置,Gb3 是利用 α1-4 鍵結乳糖上的半乳糖,而 iso-Gb3 則是利用 α1-3 鍵結。為了釐清人體內是 否有 iso-Globo 系列抗原的存在,本篇論文利用化學結合生物酵素合成的方法, 取得 iso-Globo H 以及 iso-SSEA-4 之標準品,用以比對人體細胞與癌症細胞中是 否有 iso-Globo H 或 iso-SSEA-4 抗原之存在。其次,我們亦藉由合成的 iso-Globo 系列抗原來了解 Globo-H 以及 SSEA-4 抗體是否會辨認 iso-Globo H 與 iso-SSEA- 4 抗原,以確定此系列抗體的專一性。 本篇論文的目的在於發展更快速且更有效率合成 iso-Globo H 以及 iso-SSEA- 4 的路徑,以協助我們了解 iso-Globo 系列抗原是否有參與在癌症疾病發展的行 為中,同時測試抗體對於 Globo 系列抗原以及 iso-Globo 系列抗原的辨別能力。 透過本篇論文的研究,我們期許能更了解癌症發展的機制,以優化我們所研發的 癌症疫苗,同時開發新的治療方法。

The presence of non-specific activity in the conventional cancer drugs often damage both cancer cells and normal cells at the same time and, thus, cause severe side effect. To reduce the side effect and boost the efficacy, many research teams devote great efforts in developing new anti-cancer drugs with high specificity. The glyco-antigens, SSEA-3, SSEA-4 and Globo H, are overexpressed on cancer cells but not on normal cells and, thus, can be used as targets to distinguish between normal cells and cancer cells for the development of anti-cancer drugs. The Globo H-DT vaccine developed in our laboratory for cancer treatment in 2013 is capable of simultaneously inducing immune response and eliciting antibodies against SSEA-3, SSEA-4 and Globo H. The iso-Gb3 antigen was found in pigs and murine. The structure of this antigen is very similar to that of Gb3. The difference is only at the linkage of the galactose monosaccharide at the Cl-position. Gb3 is a terminal galactose α1-4 links to lactose, and iso-Gb3 is α1-3 linkage. In this study, the chemoenzymatic methods were applied to rapidly and efficiently synthesize iso-Globo H and iso-SSEA-4 as standards to clarify whether iso-Globo series antigens are expressed on normal and/or cancer cells and to test whether Globo H and SSEA-4 antibodies can recognize the iso- Globo series antigens. Our results suggested anti-Globo series antibodies could distinguish between Globo series and iso-Globo series antigens and demonstrated how iso-Globo series glycans are involved in cancer progression.