对炎症性肠病的诊断和治疗应用,α4β7整合素和TNFα的放射免疫成像。
Radioimmune Imaging of α4β7 Integrin and TNFα for Diagnostic and Therapeutic Applications in Inflammatory Bowel Disease.
发表日期:2023 Mar 02
作者:
Alberto Signore, Rita Bonfiglio, Michela Varani, Filippo Galli, Giuseppe Campagna, Manuel Desco, Lorena Cussó, Maurizio Mattei, Andreas Wunder, Filippo Borri, Maria T Lupo, Elena Bonanno
来源:
CLINICAL PHARMACOLOGY & THERAPEUTICS
摘要:
使用放射性标记的单克隆抗体成像技术可以通过非侵入性方式提供分子信息,用于癌症和慢性炎症疾病治疗的最佳方案规划和治疗反应监测。在本研究中,我们的主要目标是评估以放射性标记的抗α4β7整合素或抗TNFα mAb进行的治疗前扫描是否能预测未标记的抗α4β7整合素或抗TNFα mAb的治疗效果。为此,我们开发了两种放射性药物以研究炎症性肠病的治疗靶点表达,用于治疗决策。用锶鉻酸盐-99m成功高效稳定地标记了抗α4β7整合素和抗TNFα mAb。 Dextran硫酸钠诱导的结肠炎被用作小鼠炎症性肠病的模型,并通过平面和SPECT / CT图像进行体内和体外评估放射性标记的mAb的肠道摄取。这些研究使我们能够定义最佳成像策略,并验证了mAb在体内与其靶点的特异性结合。将四个不同区域的肠道摄取与免疫组化(IHC)得分(部分和全局)进行比较。然后,为了评估治疗前的生物标记表达,在初始炎症性肠病中,另一组经DSS处理的小鼠于DSS注射第2天接受放射性标记的mAb注射(以量化肠道中的靶标)然后接受单一治疗剂量未标记的抗α4β7整合素或抗TNFα mAb治疗。体内和体外放射性标记的mAb的肠道摄取与免疫组化(IHC)得分之间表现出良好的相关性。未标记的α4β7整合素和抗TNFα处理的小鼠显示了放射性标记的mAb的肠道摄取和治疗后组织学评分之间的反向相关性,证明只有α4β7整合素或TNFα表达高的小鼠才会从未标记的mAb治疗中受益。
Imaging using radiolabelled monoclonal antibodies can provide, non-invasively, molecular information which allows for the planning of the best treatment and for monitoring the therapeutic response in cancer, as well as in chronic inflammatory diseases. In the present study, our main goal was to evaluate if a pre-therapy scan with radiolabelled anti-α4β7 integrin or radiolabelled anti-TNFα mAb could predict therapeutic outcome with unlabelled anti-α4β7 integrin or anti-TNFα mAb. To this aim, we developed two radiopharmaceuticals to study the expression of therapeutic targets for inflammatory bowel diseases (IBD), to be used for therapy decision making. Both anti-α4β7 integrin and anti-TNFα mAbs were successfully radiolabelled with technetium-99m with high labelling efficiency and stability. Dextran sulfate sodium (DSS)-induced colitis was used as a model for murine IBD and the bowel uptake of radiolabelled mAbs was evaluated ex vivo and in vivo by planar and SPECT/CT images. These studies allowed us to define best imaging strategy and to validate the specificity of mAb binding in vivo to their targets. Bowel uptake in four different regions was compared to immunohistochemistry (IHC) score (partial and global). Then, to evaluate the biomarker expression prior to therapy administration, in initial IBD, another group of DSS-treated mice was injected with radiolabelled mAb on day 2 of DSS administration (to quantify the presence of the target in the bowel) and then injected with a single therapeutic dose of unlabelled anti-α4β7 integrin or anti-TNFα mAb. Good correlation was demonstrated between bowel uptake of radiolabelled mAb and immunohistochemistry (IHC) score, both in vivo and ex vivo. Mice treated with unlabelled α4β7 integrin and anti-TNFα showed an inverse correlation between the bowel uptake of radiolabelled mAb and the histological score after therapy, proving that only mice with high α4β7 integrin or TNFα expression will benefit of therapy with unlabelled mAb.