文章：

全人源化抗TAG-72-IL-2融合蛋白的研发及其在实体瘤治疗中的强效抗肿瘤活性

Development and Potent Anti-Tumor Activity of a Fully Humanized Anti-TAG-72-IL-2 Fusion Protein for Therapy of Solid Tumors

原文发布日期：26 April 2025

DOI: 10.3390/cancers17091453

类型: Article

开放获取: 是

英文摘要：

Background/Objectives:Immunocytokines (ICKs) are antibody–cytokine fusion proteins that deliver cytokines directly to tumors to increase immune responses, which are otherwise absent or limited by the delivery of antibodies alone. Tumor-associated glycoprotein-72 (TAG72) is overexpressed in numerous solid tumors.Methods:An anti-TAG72-IL-2 fusion protein was expressed in mammalian cells and tested in vitro for binding and bioactivity, and in vivo in two models.Results:In vitro studies showed high antigen specificity against TAG-72-positive tumor cell lines and IL-2 activity in CD25 (IL-2R)-positive reporter cells. To study the anti-tumor activity of huCC49-IL-2 in an immunocompetent model, the TAG-72 expression was established in murine mammary and colorectal cells by transfection with murine st6galnac-I gene (mSTn). Four daily doses of anti-TAG72-IL-2 monotherapy for TAG-72-expressing orthotopic murine mammary tumors in immunocompetent mice resulted in minimal whole-body toxicity and significant tumor growth reduction mediated by tumor infiltration of IFNγ+CD8+T cells. When mammary tumors were pretreated with image-guided fractionated radiation therapy (IGRT) followed by anti-TAG72-IL-2 therapy, an improved tumor growth inhibition was observed along with an increased tumor infiltration of IFNγ+CD8+T cells and a significant reduction in Foxp3+CD4+cells. Anti-TAG72-IL-2 monotherapy in TAG-72+colorectal tumors led to a significant tumor reduction but also cures (4/7), with a rejection of rechallenges with both TAG-72-positive and -negative MC38 cells, thus demonstrating evidence of immune memory and antigen spreading.Conclusions:antiTAG-72-IL-2 therapy showed strong anti-tumor effects driven by activated CD8+T cells making it a promising approach to the treatment of TAG-72+tumors.

摘要翻译： 

背景/目的：免疫细胞因子（ICKs）是抗体-细胞因子融合蛋白，可将细胞因子直接递送至肿瘤以增强免疫反应，而单独使用抗体递送则无法产生或仅能产生有限的免疫反应。肿瘤相关糖蛋白-72（TAG72）在多种实体瘤中过度表达。方法：在哺乳动物细胞中表达抗TAG72-IL-2融合蛋白，并在体外进行结合活性和生物活性测试，同时在两种体内模型中进行评估。结果：体外研究显示，该融合蛋白对TAG-72阳性肿瘤细胞系具有高抗原特异性，并在CD25（IL-2R）阳性报告细胞中表现出IL-2活性。为研究huCC49-IL-2在免疫健全模型中的抗肿瘤活性，通过转染小鼠st6galnac-I基因（mSTn）在小鼠乳腺和结直肠细胞中建立TAG-72表达。在免疫健全小鼠中，对表达TAG-72的原位小鼠乳腺肿瘤进行为期四天的抗TAG72-IL-2单药治疗，结果显示全身毒性极小，且通过IFNγ+CD8+T细胞的肿瘤浸润介导了显著的肿瘤生长抑制。当乳腺肿瘤先接受图像引导分次放射治疗（IGRT）预处理，再进行抗TAG72-IL-2治疗时，观察到肿瘤生长抑制效果增强，同时IFNγ+CD8+T细胞的肿瘤浸润增加，Foxp3+CD4+细胞显著减少。在TAG-72阳性结直肠肿瘤中，抗TAG72-IL-2单药治疗不仅显著缩小了肿瘤，还实现了部分治愈（4/7），且对TAG-72阳性和阴性MC38细胞的再攻击均产生排斥反应，从而证明了免疫记忆和抗原扩散的存在。结论：抗TAG-72-IL-2疗法通过激活CD8+T细胞显示出强大的抗肿瘤效果，使其成为治疗TAG-72阳性肿瘤的一种有前景的方法。

原文链接：

Development and Potent Anti-Tumor Activity of a Fully Humanized Anti-TAG-72-IL-2 Fusion Protein for Therapy of Solid Tumors