Alternatively Spliced EDA Domain of Fibronectin Is a Target for Pharmacodelivery Applications in Inflammatory Bowel Disease
Alternatively Spliced EDA Domain of Fibronectin Is a Target for Pharmacodelivery Applications in Inflammatory Bowel Disease
复制标题
DOI：
10.1097/mib.0000000000000440
复制
发表时间：
2015-08-01
影响因子：
4.9
通讯作者：
Neri, Dario
中科院分区：
文献类型：
--
作者：
Bootz, Franziska;Schmid, Anja Sophie;Neri, Dario
基于抗体的细胞因子到疾病部位的药物递送已被广泛研究用于各种适应症，但不用于治疗炎性肠病。在这里，我们报告说，选择性剪接的EDA结构域的纤连蛋白，血管生成和组织重塑的标志物，表达在葡聚糖硫酸钠小鼠模型的结肠炎和炎症性肠病患者，而在大多数正常成人组织几乎检测不到。F8抗体的放射性标记制剂，特异于纤连蛋白的EDA结构域，显示出选择性定位于结肠炎小鼠的炎症部位，如放射自显影分析所示。将F8抗体与各种鼠有效载荷（白细胞介素-4、白细胞介素-12的p40亚基、白细胞介素-13）的融合蛋白给予患有结肠炎的小鼠。IL 12 p40-F8介导的抗炎活性与环孢菌素相当，而F8-IL 4不抑制结肠炎，F8-IL 13使炎症状况恶化。
The antibody-based pharmacodelivery of cytokines to sites of disease has been extensively studied for various indications but not for the treatment of inflammatory bowel diseases. Here, we report that the alternatively spliced EDA domain of fibronectin, a marker of angiogenesis and of tissue remodeling, is expressed in the dextran sodium sulfate mouse model of colitis and in patients with inflammatory bowel conditions, while being virtually undetectable in most normal adult tissues. Radiolabeled preparations of the F8 antibody, specific to the EDA domain of fibronectin, were shown to selectively localize to sites of inflammation in mice with colitis, as revealed by autoradiographic analysis. Fusion proteins of the F8 antibody with various murine payloads (interleukin-4, the p40 subunit of interleukin-12, interleukin-13) were administered to mice with colitis. IL12p40-F8 mediated an anti-inflammatory activity, which was comparable with the one of cyclosporine, whereas F8-IL4 did not inhibit colitis and F8-IL13 worsened the inflammatory conditions.