Drug Discovery Science and Technology, Abbvie Bioresearch Center, Worcester, MA, USA.
Generate Biomedicines, Cambridge, MA, USA.
Adv Rheumatol. 2022 May 27;62(1):17. doi: 10.1186/s42358-022-00247-2.
To assess the ability of monoclonal antibodies (mAbs) specific for fibronectin extra-domain A (FnEDA) to target diseased tissues of mouse collagen induced arthritis (mCIA) models. To explore the parameters of the targeting exhibited by anti-FnEDA mAbs including timing and location.
Targeting capabilities of anti-FnEDA mAbs were demonstrated by biodistribution study where i.v. injected antibodies were detected by conjugated near-infrared (NIR) fluorophore, I label and immunohistochemistry (IHC) of the injected antibody. Location of FnEDA expression in both mCIA and human RA tissue were mapped by IHC. Quantification of anti-FnEDA mAbs targeted to disease tissue was measured by whole-body autoradiography (WBA). Timing of the targeting was interrogated with fluorescent and confocal microscopy using anti-FnEDA mAbs labeled with different fluorophores and injected at different times.
Anti-FnEDA mAbs show specific targeting to diseased paws of mCIA animal. The targeting was focused on inflamed synovium which is consistent with FnEDA expression profile in both mCIA and human RA tissues. Anti-FnEDA mAbs accumulated in diseased tissue at pharmacologically relevant concentrations, the targeting was sustained for up to 14 days and FnEDA was able to support targeting of multiple doses of anti-FnEDA mAbs given 5 days apart.
FnEDA is specifically upregulated in the inflamed tissues of mCIA. Antibodies specific for FnEDA can be useful as molecular delivery vehicles for disease specific targeting of payloads to inflamed joint tissue.
评估针对纤维连接蛋白外显子 A（FnEDA）的单克隆抗体（mAbs）靶向小鼠胶原诱导关节炎（mCIA）模型病变组织的能力。探索抗 FnEDA mAbs 表现出的靶向参数，包括时间和位置。
通过生物分布研究证明抗 FnEDA mAbs 的靶向能力，其中通过连接近红外（NIR）荧光团、I 标记和注射抗体的免疫组织化学（IHC）检测静脉注射的抗体。通过 IHC 绘制 mCIA 和人类 RA 组织中 FnEDA 表达的位置。通过全身放射自显影（WBA）测量针对疾病组织的抗 FnEDA mAbs 的定量靶向。通过使用不同荧光团标记的抗 FnEDA mAbs 并在不同时间注射进行荧光和共聚焦显微镜检查来探究靶向的时间。
抗 FnEDA mAbs 特异性靶向 mCIA 动物的患病爪子。靶向集中在发炎的滑膜上，这与 mCIA 和人类 RA 组织中的 FnEDA 表达谱一致。抗 FnEDA mAbs 在药理学相关浓度下积聚在患病组织中，靶向可持续长达 14 天，并且 FnEDA 能够支持相隔 5 天给予的多剂量抗 FnEDA mAbs 的靶向。
FnEDA 在 mCIA 的发炎组织中特异性上调。针对 FnEDA 的抗体可用作分子递送载体，将有效载荷靶向特定于炎症关节组织。
