開發可以一步驟增殖並武裝T 細胞之雙功能抗體以進行腫瘤專一性治療

TMUIR > College of Pharmacy > Master Program for Clinical Pharmacogenomics and Pharmacoproteomics > Dissertations/Theses > Item 987654321/61123

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Title:	開發可以一步驟增殖並武裝T 細胞之雙功能抗體以進行腫瘤專一性治療 Development of the bispecific antibody to one-step expand and arm T cells for selective tumor therapy
Authors:	蔡宜珊 Tsai, Yi-Shan
Contributors:	臨床藥物基因體學暨蛋白質體學碩士學位學程莊國祥
Keywords:	anti-EGFR x anti-CD3;活體外分化和增生CD3+ T細胞;細胞毒殺 anti-EGFR x anti-CD3;differentiated and expanded T cell ex vivo;cytotoxicity
Date:	2016
Issue Date:	2021-11-21 20:40:22 (UTC+8)
Abstract:	T細胞治療為癌症之一種新興療法；然而，傳統T 細胞缺乏腫瘤專一性，為使其具有專一性則須花費過長時間培育或因利用基因轉殖技術隱藏基因突變潛在問題。為克服這些問題，我們希望開發一新型雙功能抗體，於活體外一步驟快速武裝T細胞成腫瘤專一性（arm-T），藉此提升臨床上癌症病患的腫瘤治療效果，並且更進一步利用雙功能抗體增生分化T 細胞，達到簡單且低免疫源性之治療。研究結果顯示我們成功利用基因工程建構新型雙功能抗體，anti-EGFR x anti-CD3 BsAb，並利用流式細胞儀確定其具有結合腫瘤和T細胞之雙邊功能，在活體外T細胞毒殺腫瘤實驗證實，arm-T細胞相較於傳統T細胞毒殺EGFR+大腸癌細胞之能力由3.8%提升至27%（E:T=5:1）及1.2%提升至45% （E:T=10:1）且在SCID小鼠腫瘤抑制實驗中arm-T細胞也大幅提升腫瘤抑制能力，更重要是成功利用含雙功能抗體之生長液於活體外分化增生人類之CD3+CD8+T細胞並同時間進行武裝動作，在活體外T細胞毒殺腫瘤實驗中證實，以此方式所增生之T 細胞其毒殺能力優於傳統OKT3培養法。本研究利用雙功能抗體於T細胞療法中快速達成高度腫瘤專一性且低免疫性之一種再現性佳的腫瘤治療模式。 Adoptive cell transfer is personalized immunotherapy for human cancer. However, conventional T cell therapy lacks of tumor specificity or make it specificity by long-term ex vivo culture. Although CAR-T solve the problem, virus transfection is other worries in the future. Additionally, so far differentiated and expanded T cell by adding murine antibody, OKT3, it may enhance human anti-mouse antibody response. To overcome these problems, we develop the bispecific antibody to one-step expand and arm T cells for selective tumor therapy, then improve quality of life. In our study, we successfully have developed a novel bispecific antibody, anti-EGFRxanti-CD3 BsAb, proved bilateral function by flow cytometry. In vitro cytotoxicity test, the ability of arm-T is raise up to 27% from 3.8% at E/T ratio 5:1 and 45% from 1.2% at E/T ratio 10:1 .In vivo, arm-T also significantly suppress tumor growth in SCID mice. Finally, we successfully differentiate and expand PBMC to CD3+CD8+T cell by adding our anti-EGFR x anti-CD3 BsAb in culture medium, at the same time, arming CD3+T cell in one step. The cytotoxicity show higher efficiency than traditional expended way （by OKT3）. In summary, our study provide a highly and rapidly tumor specificity and low toxicity way in adoptive T cell therapy.
Description:	碩士指導教授：莊國祥
Data Type:	thesis
Appears in Collections:	[Master Program for Clinical Pharmacogenomics and Pharmacoproteomics] Dissertations/Theses

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