發展抗乳癌疫苗與醣脂佐劑之應用

Development of Globo H anti-breast cancer vaccines with novel glycolipid adjuvants

黃彥霖(Yen-Lin Huang)

指導教授 ： 翁啟惠

共同指導教授 ： 吳宗益 ； 陳鈴津(Alice Lin-Tsing Yu)

國立臺灣大學/生命科學院/生化科學研究所/碩士(2008年)

https://doi.org/10.6342/NTU.2008.00891

摘要

癌症的發生與轉移常伴隨著細胞表面異常的醣化現象。至今發現許多和腫瘤發展高度相關的醣抗原以醣蛋白或醣脂質的形式存在。其中由六個單醣所組成的Globo H (Fucα1→2Galβ1→3 GalNAcβ1→3Galα1→4Galβ1→4Glu)是由Hakamori 教授於1984年從乳癌細胞所分離出。而1995才由Danishefsky教授以glycal assembly方式首先合成出來。Globo H 大多表現在表皮類癌細胞上，而僅微量表現在正常組織中的分泌管道。所以科學家便根據Globo H表現的特異性設計疫苗及免疫療法來針對前列腺癌、乳癌、直腸癌、或卵巢癌。至今，雖然全世界還未有已核准的醣類抗癌疫苗，但在臨床實驗中已發現許多有潛力的疫苗能增加癌症患者的存活率。不過最終目標還是希望能徹底預防癌症術後的復發。因此，我們希望能依據前人的研究基礎來開發更有效的癌症疫苗。
在我們的研究中發現，若將此抗原接上蛋白及在佐劑的加成下可產生抗體。且對於異體移植癌細胞(4T1)的老鼠也觀察到有延遲腫瘤生長的效果。如果再藉由有系統的調整疫苗組成、佐劑種類、劑量、醣抗原比例、與時程，可望大幅提升免疫力來達到預防癌症的效果。最後，本研究團隊也正著手於相關醣抗原與新型載體的開發，以期望能發展出更有效的抗癌疫苗。

關鍵字

乳癌 ； 疫苗 ； 醣脂質 ； 佐劑

並列摘要

Aberrant glycosylation is often a hallmark during tumor progression and correlates with poor prognosis. Diverse tumor associated antigens existed in the form of glycolipids or glycoproteins have been characterized. Globo H (Fucα1→2Galβ1→3 GalNAcβ1→3Galα1→4Galβ1→4Glu) hexasaccharide was first isolated from metastatic breast cancer cells by Hakomori in 1984 and initially synthesized by Danishefsky using glycal assembly strategy in 1995. Globo H was present on most cancers of epithelial origin, but only minimal expression on normal secretory tissue which is not readily accessible to immune system. Taking advantage of the exclusive expression signature, Globo H has been an attractive target for immunotherapy against prostate, breast, colon and ovarian cancers. Although, numerous vaccines are undergoing clinical evaluation and some shows improved survival rate in patients, the ultimate goal is to prevent the tumor recurrence. Therefore, we aim to develop a more effective vaccine and adjuvant against a variety of cancers.
Here we reported the promising carbohydrate based vaccine enhanced antibody production and delayed tumorigenesis in xenograft studies. Overall, systematic optimization with respect to formulation, adjuvant, dosage, glycan/protein ratio and timing of immunization regimen may further improve the protection against tumors. Finally, conjugation of diverse carbohydrate antigens to various carriers or dendrimer will be planned in the near further.

並列關鍵字

breast cancer ； vaccine ； glycolipid ； adjuvants

參考文獻

1. Meezan, E., Wu, H. C., Black, P. H., and Robbins, P. W. Comparative studies on carbohydrate containing membrane components of normal and virus transformed mouse fibroblasts. Biochemistry 1969, 8, 2518-2524.

2. Turner, G. A. N-glycosylation of serum proteins in disease and its investigation using lectins. Clin. Chirn. Acta. 1992, 208, 149-171.

3. Gabius, H. J. Biological information transfer beyond the genetic code: the sugar code. Naturwissenschaften. 2000, 87, 108-121.

4. Shriver, Z., Raguram, S., and Sasisekharan, R. Glycomics: a pathway to a class of new and improved therapeutics. Nat. Rev. Drug. Disc. 2004, 3, 863-873.

5. Pacino, G. Osinaga, E., Charpin, C., Mistro, D., Barque, J. P., and Roseto, A. Purification and characterization of a breast cancer associated glycoprotein not expressed in normal breast and identified by monoclonal antibody. Br. J. Cancer. 1991, 63, 390-398.