Antibody-Based Targeted Delivery of Interleukin-22 Promotes Rapid Clinical Recovery in Mice With DSS-Induced Colitis
Antibody-Based Targeted Delivery of Interleukin-22 Promotes Rapid Clinical Recovery in Mice With DSS-Induced Colitis
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DOI：
10.1097/mib.0000000000000851
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发表时间：
2016-09-01
影响因子：
4.9
通讯作者：
Neri, Dario
中科院分区：
文献类型：
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作者：
Bootz, Franziska;Ziffels, Barbara;Neri, Dario
工作背景：我们最近描述了选择性剪接的纤连蛋白外域A作为溃疡性结肠炎中基于抗体的药物递送应用的靶点的潜力。在这里，我们报告的克隆和治疗特性的新的抗体为基础的融合蛋白，包括F8抗体特异性的外域A和鼠白细胞介素（IL）-22，一个球状细胞因子属于IL-10家族。IL 22在结肠炎中的保护功能以前已经描述过，因为这种细胞因子诱导抗微生物，增殖和抗凋亡途径，防止组织损伤和促进上皮修复。方法：两个融合蛋白，包括IL 22，融合在N-或在C-末端的F8抗体的双抗体格式，在哺乳动物细胞中表达。在葡聚糖硫酸钠诱导的结肠炎小鼠模型中通过放射自显影术和在同基因小鼠畸胎癌模型中通过定量生物分布分析评估了2种融合蛋白的放射性标记制剂定位于疾病部位的能力。治疗活性进行了评估，在小鼠与葡聚糖硫酸钠诱导的结肠炎，接受静脉注射的抗体-细胞因子融合蛋白。结果：这两种融合蛋白能够选择性地积累在该网站的疾病。在N-末端具有细胞因子部分的融合蛋白（IL 22-F8）在靶向选择性和治疗功效方面均表现出比C-末端融合更好的结果。用IL 22-F8治疗的小鼠显示出更快的临床症状恢复与对照组相比，改善宏观和微观形态的colon.Conclusions：IL 22-F8是一个有前途的生物制药候选药物治疗溃疡性结肠炎。
Background: We have recently described the potential of the alternatively spliced extradomain A of fibronectin as a target for antibody-based pharmacodelivery applications in ulcerative colitis. Here, we report on the cloning and therapeutic properties of novel antibody-based fusion proteins, comprising the F8 antibody specific to extradomain A and murine interleukin (IL)-22, a globular cytokine belonging to the IL10 family. A protective function for IL22 in colitis has previously been described, as this cytokine induces antimicrobial, proliferative, and antiapoptotic pathways, preventing tissue damage and promoting epithelial repair.Methods: Two fusion proteins comprising IL22, fused at the N- or at the C-terminus of the F8 antibody in diabody format, were expressed in mammalian cells. The ability of radiolabeled preparations of the 2 fusion proteins to localize at sites of disease was assessed by autoradiography in a murine model of dextran sodium sulfate-induced colitis and by quantitative biodistribution analysis in a syngeneic mouse teratocarcinoma model. Therapeutic activity was assessed in mice with dextran sodium sulfate-induced colitis, which received intravenous injections of antibody-cytokine fusion proteins.Results: Both fusion proteins were able to selectively accumulate at the site of disease. The fusion protein with the cytokine moiety at the N-terminal extremity (IL22-F8) exhibited better results than the C-terminal fusion, both in terms of targeting selectivity and therapeutic efficacy. Mice treated with IL22-F8 showed a more rapid recovery from clinical symptoms compared with controls and improved macroscopic and microscopic morphology of the colon.Conclusions: IL22-F8 is a promising biopharmaceutical drug candidate for the treatment of ulcerative colitis.