對大腸直腸癌醣抗原具有專一性之抗體藥物M1及G10研究

本論文的研究主軸是開發治療癌症之抗體藥物，所研究之抗體是以基因轉殖小鼠製造，對抗癌細胞表面的特殊醣抗原，所開發的兩株抗體分別是M1 與 G10。由於其類似於人體自然產生之抗體，安全性高及副作用低。M1抗體是一IgM 抗體，對大腸直腸癌組織具有非常高的專一性，組織切片之免疫染色結果顯示，79%的大腸直腸癌組織對M1抗體呈陽性反應，而在其他癌組織或正常組織中，極少發現此抗原之存在。因此，M1抗體極具潛力開發為大腸直腸癌治療藥物，以及癌症篩檢或診斷之工具。G10抗體是一人類IgG 抗體，其抗原決定位是一複合型第一類醣鏈結構，組織切片之免疫染色研究結果顯示G10的抗原決定位分佈於多種癌組織，50%以上的大腸直腸癌組的大腸直腸癌組織對M1抗體呈陽性反應，其生物體外抗癌活性研究顯示G10抗體經由 CDC或ADCC的機轉對於大腸直腸癌具有顯著的毒殺作用。其載瘤動物模式之體內抗癌活性試驗結果亦顯示，G10抗體單獨使用可以抑制腫瘤在生物體內的生長達50%以上；G10抗體與化療藥物Irinotecan併用，其抑制大腸直腸癌細胞生長之作用顯著高於兩者單獨使用，且副作用明顯低於Irinotecan單獨使用，並觀察到動物體內的腫瘤在開始給藥之後逐漸消失的現象。單一劑量及重複劑量毒理試驗中，試驗動物並未觀察到因投藥所造成的毒理反應。總結本研究之成果，M1及G10兩株抗體對於大腸直腸癌均具有良好的專一性，其中G10抗體具有顯著抑制大腸直腸癌細胞生長之作用，且安全性評估未發現顯著之毒性反應，極具開發為治療大腸直腸癌藥物之可行性。兩種抗體除了直接毒殺癌細胞的用途之外，也可以與其他抗癌藥物連接，製造具有導向性的標靶藥物，降低抗癌藥物的副作用，其所對應之特殊抗原亦將可望繼續進行癌症疫苗開發，進一步利用主動免疫之機制，達成治療癌症之目的。

關鍵字

單株抗體；大腸癌；醣蛋白

並列摘要

In present study, two human monoclonal antibodies, M1 and G10, were developed, which specifically recognize carbohydrate antigens expressed on colorectal cancer cell surfaces. M1 is a human IgM. In immunohistochemical studies, 79% of tested colorectal cancer tissues were stained with M1. The expression of this epitope on normal tissues and other type of cancers is limited. G10 is a human IgG, reacted specifically with a carbohydrate antigen, bound to several colorectal cancer cell lines, and displayed strong complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity on cancer cells. The antigen defined by G10, expressed in Colo205 cells, were: (i) glycosphingolipids with G10 epitope, whose reactivity was abolished upon defucosylation; (ii) glycoproteins with molecular mass range from 32 to >175 kDa, which were depleted in cells cultured in the presence of benzyl-α-GalNAc, indicating that these epitopes are O linked glycans. Immunohistological reactivity of G10 at 1 μg/ml, applied on tissue sections from colorectal and various other types of cancer, was much stronger than that with various normal cells and tissues. Growth of subcutaneous xenograft of human colonic cancer cells, Colo205 or DLD-1, in SCID mice, was strongly inhibited by administration of G10. These observations, taken together, indicate that antibody G10 provides a novel direction of immunotherapy for human colorectal cancer. Since M1 and G10 induce significant cytotoxicity on colorectal cancer cell lines, the epitopes play a critical role in the cells. That also indicates the potential of the epitopes to be good target for cancer vaccine development. This will be our next target to develop anticancer therapeutics.

並列關鍵字

monoclonal anribody ； colon cancer ； glycoprotein

參考文獻

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對大腸直腸癌醣抗原具有專一性之抗體藥物M1及G10研究

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