Rim Yeri Alice, Yi Hyoju, Kim Youngkyun, Park Narae, Jung Hyerin, Kim Juryun, Jung Seung Min, Park Sung-Hwan, Ju Ji Hyeon
CiSTEM laboratory, Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul. 137-701, South Korea.
1] CiSTEM laboratory, Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul. 137-701, South Korea [2] Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul. 137-701, Republic of Korea.
Sci Rep. 2014 Nov 6;4:6935. doi: 10.1038/srep06935.
Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA4Ig, abatacept) is a B7/CD28 costimulation inhibitor that can ward off the immune response by preventing the activation of naïve T cells. This therapeutic agent is administered to patients with autoimmune diseases such as rheumatoid arthritis. Its antiarthritic efficacy is satisfactory, but the limitations are the necessity for frequent injection and high cost. Minicircles can robustly express the target molecule and excrete it outside the cell as an indirect method to produce the protein of interest in vivo. We inserted the sequence of abatacept into the minicircle vector, and by successful in vivo injection the host was able to produce the synthetic protein drug. Intravenous infusion of the minicircle induced spontaneous production of CTLA4Ig in mice with collagen-induced arthritis. Self-produced CTLA4Ig significantly decreased the symptoms of arthritis. Injection of minicircle CTLA4Ig regulated Foxp3(+) T cells and Th17 cells. Parental and mock vectors did not ameliorate arthritis or modify the T cell population. We have developed a new concept of spontaneous protein drug delivery using a minicircle vector. Self in vivo production of a synthetic protein drug may be useful when biological drugs cannot be injected because of manufacturing or practical problems.
细胞毒性T淋巴细胞相关抗原4免疫球蛋白融合蛋白（CTLA4Ig，阿巴西普）是一种B7/CD28共刺激抑制剂，可通过阻止幼稚T细胞的激活来抵御免疫反应。这种治疗剂用于治疗类风湿性关节炎等自身免疫性疾病患者。其抗关节炎疗效令人满意，但局限性在于需要频繁注射且成本高昂。微小环能够强有力地表达靶分子并将其分泌到细胞外，作为在体内产生目标蛋白的一种间接方法。我们将阿巴西普序列插入微小环载体中，通过在体内成功注射，宿主能够产生合成蛋白药物。静脉输注微小环可诱导胶原诱导性关节炎小鼠自发产生CTLA4Ig。自身产生的CTLA4Ig显著减轻了关节炎症状。注射微小环CTLA4Ig可调节Foxp3(+) T细胞和Th17细胞。亲本载体和空载体均未改善关节炎或改变T细胞群体。我们利用微小环载体开发了一种自发蛋白药物递送的新概念。当由于制造或实际问题无法注射生物药物时，体内自身产生合成蛋白药物可能会很有用。
