In vivo optical imaging of early osteoarthritis using an antibody specific to damaged arthritic cartilage.
In vivo optical imaging of early osteoarthritis using an antibody specific to damaged arthritic cartilage.
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DOI：
10.1186/s13075-015-0898-5
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发表时间：
2015-12-25
影响因子：
4.9
通讯作者：
Nissim A
中科院分区：
文献类型：
--
作者：
Lim NH;Vincent TL;Nissim A
由于缺乏特异性、敏感的血清和放射学生物标志物来早期诊断骨关节炎 (OA) 以及在临床试验中监测疾病活动的细微变化，这阻碍了 OA 治疗方法的开发。我们之前表明，1-11E 是一种针对 II 型胶原蛋白的人类单链片段变量 (scFv)，经过活性氧化剂 (ROS-CII) 的翻译后修饰，仅与关节炎软骨结合。在这里，我们测试 1-11E 作为实验性 OA 早期疾病的放射学生物标志物的有效性。小鼠 OA 是由成年雄性小鼠内侧半月板 (DMM) 不稳定引起的。术后 2 至 8 周，使用 Cy5.5 标记的 1-11E 和阴性对照 scFv、C7 对不稳定或假手术的膝盖进行免疫组织化学分析。在关节内注射 Cy5.5 标记的 scFv 或静脉注射 Cy5.5 标记的全长单克隆抗体 (mAb) 后，在 DMM 后 4 周和 8 周拍摄前瞻性体内光学图像。早在 DMM 后 4 周，通过组织学评估早期软骨退化时，1-11E 的特异性软骨染色就很明显。 DMM 后 4 周和 8 周，局部关节内注射 Cy5.5 标记的 scFv (n = 7) 后拍摄的前瞻性体内光学图像显示，局部给药至膝关节后，Cys5.5-1-11E scFv 在体内具有特异性保留（组织半衰期 >78 小时，n = 7，信噪比(信噪比) > 2.1)。还观察到 Cys-5.5-1-11E-mAb 对 DMM 膝关节的特异性定位 (SNR >1.65) (p<<0.01，n=8，SNR >1.65)。在这两种情况下，SNR 都随着 DMM 后时间的推移而增加。 1-11E 与早期骨关节炎软骨特异性结合，可用作局部或全身递送后的放射线生物标志物，以促进 OA 的早期诊断和监测疾病进展。
The lack of specific and sensitive serum and radiographic biomarkers for early diagnosis of osteoarthritis (OA) as well as for monitoring subtle changes in disease activity in clinical trials has hampered the development of treatments for OA. We previously showed that 1-11E, a human single chain fragment variable (scFv) specific to collagen type II that has been post-translationally modified by reactive oxidants (ROS-CII), binds exclusively to arthritic cartilage. Here we test the validity of 1-11E as a radiographic biomarker for early disease in experimental OA. Murine OA was induced by destabilisation of the medial meniscus (DMM) in adult male mice. Immunohistochemistry of destabilised or sham-operated knees was performed from 2 to 8 weeks post-surgery with Cy5.5-labelled 1-11E and negative control scFv, C7. Prospective in vivo optical images were taken 4 and 8 weeks post-DMM following intra-articular injection of Cy5.5-labelled scFvs, or intravenous injection of Cy5.5-labelled full length monoclonal antibodies (mAbs). Specific cartilage staining with 1-11E was apparent as early as 4 weeks post-DMM at the time of earlier cartilage degradation assessed by histology. Prospective in vivo optical images taken 4 and 8 weeks post-DMM following local intra-articular injection of Cy5.5-labelled scFv (n = 7) showed specific in vivo retention of Cys5.5-1-11E scFv following local administration into the knee joint (tissue half-life >78 hours, n = 7, signal to noise ratio (SNR) > 2.1). Specific localization of Cys-5.5-1-11E-mAb to DMM knees (SNR >1.65) was also observed (p < 0.01, n = 8, SNR >1.65). In both cases the SNR increased with time post-DMM. 1-11E binds specifically to early osteoarthritic cartilage and can be used as a radiographic biomarker following local or systemic delivery to facilitate early diagnosis and monitor disease progression in OA.