Palmitate-derivatized human IL-2: a potential anticancer immunotherapeutic of low systemic toxicity.
Palmitate-derivatized human IL-2: a potential anticancer immunotherapeutic of low systemic toxicity.
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棕榈酸酯衍生的人IL-2：潜在的抗癌免疫治疗性，对低全身毒性。
DOI：
10.1007/s00262-012-1364-8
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发表时间：
2013-03
影响因子：
5.8
通讯作者：
Zheng, Guoxing
中科院分区：
文献类型：
--
作者：
Chou, Sharon H.;Shetty, Aditya V.;Geng, Yajun;Xu, Lipeng;Munirathinam, Gnanasekar;Pipathsouk, Anne;Tan, Isaiah;Morris, Timothy;Wang, Bin;Chen, Aoshuang;Zheng, Guoxing
重组人IL-2（rhIL-2）是一种有效的细胞因子和FDA批准的抗癌药物。然而，其临床应用受到严重毒性的限制，主要与全身给药相关，过量的蛋白质自由分布在全身。我们推测，rhIL-2的替代形式，允许更多的限制性定位可能发挥更强的抗肿瘤疗效和更低的毒性。在这里，我们已经测试了棕榈酸衍生的rhIL-2的效用。rhIL-2与N-羟基琥珀酰亚胺棕榈酸酯反应。脂质化rhIL-2（pIL-2）与细胞混合后，能自发地从溶液转移到细胞表面。接下来，以两种方式评估pIL-2的抗癌功效。对于过继性T细胞疗法，将抗肿瘤细胞毒性T细胞（CTL）用pIL-2蛋白质转移（“涂染”）并注射到携带淋巴瘤的小鼠中。对于原位治疗，将pIL-2瘤内注射到携带黑素瘤的小鼠中。测定肿瘤生长和IL-2相关毒性。在淋巴瘤模型中，用pIL-2涂敷抗肿瘤CTL显著增加了它们的活力和滴度。在黑色素瘤模型中，瘤内注射pIL-2，而不是rhIL-2，增加脾脏中活化的CD 8 + T细胞（IFN-γ+）的数量，减少肺转移，延长治疗小鼠的生存期。此外，虽然以过高剂量（10次注射10000 IU/小鼠）重复瘤内注射rhIL-2引起明显的血管渗漏综合征，但使用pIL-2的相同方案未引起可检测的毒性。pIL-2可以自发地从溶液转移到细胞表面，从而可以绕过rhIL-2的现有限制，从而作为一种更有效和耐受性更好的抗癌药物。
Recombinant human IL-2 (rhIL-2) is a potent cytokine and FDA-approved anti-cancer drug. However, its clinical use has been limited by severe toxicity, associated primarily with systemic administration with excess protein distributing freely throughout the body. We hypothesized that rhIL-2 in alternate forms permitting more restricted localization may exert stronger antitumor efficacy and less toxicity. Here, we have tested the utility of palmitate-derivatized rhIL-2. rhIL-2 was reacted with N-hydroxysuccinimide palmitate ester. The resultant lipidated rhIL-2 (pIL-2), when mixed with cells, could spontaneously transfer from solution to cell surfaces. Next, anticancer efficacy of pIL-2 was assessed in two modalities. For adoptive T cell therapy, antitumor cytotoxic T cells (CTLs) were protein transferred (“painted”) with pIL-2 and injected into mice bearing lymphoma. For in situ therapy, pIL-2 was injected intratumorally into mice bearing melanoma. Tumor growth and IL-2-associated toxicity were determined. In the lymphoma model, painting of the antitumor CTLs with pIL-2 markedly increased their viability and titer. In the melanoma model, intratumoral injection of pIL-2, but not rhIL-2, increased the number of activated CD8+ T cells (IFN-γ+) in the spleen, reduced lung metastasis and prolonged the survival of treated mice. Moreover, while repeated intratumoral injection of rhIL-2 at an excessively high dose (10 injections of 10000 IU/mouse) caused marked vascular leakage syndrome, the same regimen using pIL-2 caused no detectable toxicity. Transferring spontaneously from solution to cell surfaces, pIL-2 may bypass the current limitations of rhIL-2 and, thus, serve as a more effective and tolerable anticancer drug.
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影响因子：
3.9
作者：
Mustafa, A;McKallip, RJ;Nagarkatti, M
通讯作者：
Nagarkatti, M
影响因子：
11.2
作者：
Chen, Aoshuang;Liu, Shanrong;Zheng, Guoxing
通讯作者：
Zheng, Guoxing
影响因子：
4.4
作者：
Liu, Shanrong;Breiter, Deborah R.;Chen, Aoshuang
通讯作者：
Chen, Aoshuang
影响因子：
2.2
作者：
KIM, SA;PEACOCK, JS
通讯作者：
PEACOCK, JS
影响因子：
2.2
作者：
COLSKY, AS;PEACOCK, JS
通讯作者：
PEACOCK, JS