Gabriëls Ruben Y, van der Waaij Anne M, Linssen Matthijs D, Dobosz Michael, Volkmer Pia, Jalal Sumreen, Robinson Dominic, Hermoso Marcela A, Lub-de Hooge Marjolijn N, Festen Eleonora A M, Kats-Ugurlu Gursah, Dijkstra Gerard, Nagengast Wouter B
Department of Gastroenterology and Hepatology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
Gut. 2024 Aug 8;73(9):1454-1463. doi: 10.1136/gutjnl-2023-331696.
Improving patient selection and development of biological therapies such as vedolizumab in IBD requires a thorough understanding of the mechanism of action and target binding, thereby providing individualised treatment strategies. We aimed to visualise the macroscopic and microscopic distribution of intravenous injected fluorescently labelled vedolizumab, vedo-800CW, and identify its target cells using fluorescence molecular imaging (FMI).
Forty three FMI procedures were performed, which consisted of macroscopic in vivo assessment during endoscopy, followed by macroscopic and microscopic ex vivo imaging. In phase A, patients received an intravenous dose of 4.5 mg, 15 mg vedo-800CW or no tracer prior to endoscopy. In phase B, patients received 15 mg vedo-800CW preceded by an unlabelled (sub)therapeutic dose of vedolizumab.
FMI quantification showed a dose-dependent increase in vedo-800CW fluorescence intensity in inflamed tissues, with 15 mg (153.7 au (132.3-163.7)) as the most suitable tracer dose compared with 4.5 mg (55.3 au (33.6-78.2)) (p=0.0002). Moreover, the fluorescence signal decreased by 61% when vedo-800CW was administered after a therapeutic dose of unlabelled vedolizumab, suggesting target saturation in the inflamed tissue. Fluorescence microscopy and immunostaining showed that vedolizumab penetrated the inflamed mucosa and was associated with several immune cell types, most prominently with plasma cells.
These results indicate the potential of FMI to determine the local distribution of drugs in the inflamed target tissue and identify drug target cells, providing new insights into targeted agents for their use in IBD.
NCT04112212.
改善炎症性肠病（IBD）患者的选择以及维多珠单抗等生物疗法的研发，需要深入了解其作用机制和靶点结合情况，从而提供个性化治疗策略。我们旨在通过荧光分子成像（FMI）可视化静脉注射的荧光标记维多珠单抗（vedo - 800CW）的宏观和微观分布，并确定其靶细胞。
进行了43次FMI操作，包括在内镜检查期间进行宏观体内评估，随后进行宏观和微观体外成像。在A阶段，患者在内镜检查前静脉注射4.5毫克、15毫克vedo - 800CW或不注射示踪剂。在B阶段，患者在接受未标记的（亚）治疗剂量维多珠单抗后，再接受15毫克vedo - 800CW。
FMI定量显示，炎症组织中vedo - 800CW荧光强度呈剂量依赖性增加，与4.5毫克（55.3任意单位（33.6 - 78.2））相比，15毫克（153.7任意单位（132.3 - 163.7））是最合适的示踪剂剂量（p = 0.0002）。此外，当在未标记的维多珠单抗治疗剂量后给予vedo - 800CW时，荧光信号下降了61%，表明炎症组织中的靶点饱和。荧光显微镜和免疫染色显示，维多珠单抗穿透炎症黏膜并与多种免疫细胞类型相关，最显著的是浆细胞。
这些结果表明FMI在确定药物在炎症靶组织中的局部分布以及识别药物靶细胞方面具有潜力，为IBD中靶向药物的使用提供了新的见解。
NCT04112212。
