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F8-IL10: A New Potential Antirheumatic Drug Evaluated by a PET-Guided Translational Approach.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-12-24 , DOI: 10.1021/acs.molpharmaceut.8b00982 Stefan T G Bruijnen 1 , Durga M S H Chandrupatla 1 , Leonardo Giovanonni 2 , Dario Neri 3 , Danielle J Vugts , Marc C Huisman , Otto S Hoekstra , René J P Musters , Adriaan A Lammertsma , Guus A M S van Dongen , Gerrit Jansen 1 , Carla F M Molthoff , Conny J van der Laken 1
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-12-24 , DOI: 10.1021/acs.molpharmaceut.8b00982 Stefan T G Bruijnen 1 , Durga M S H Chandrupatla 1 , Leonardo Giovanonni 2 , Dario Neri 3 , Danielle J Vugts , Marc C Huisman , Otto S Hoekstra , René J P Musters , Adriaan A Lammertsma , Guus A M S van Dongen , Gerrit Jansen 1 , Carla F M Molthoff , Conny J van der Laken 1
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Antibody fragment F8-mediated interleukin 10 (IL10) delivery is a novel treatment for rheumatoid arthritis (RA). F8 binds to the extra-domain-A of fibronectin (ED-A). In this study, in vivo biodistribution and arthritis targeting of radiolabeled F8-IL10 were investigated in RA patients, followed by further animal studies. Therefore, three RA patients (DAS28 > 3.2) received 0.4 mg of 30-74 megabecquerel [124I]I-F8-IL10 for PET-CT and blood sampling. In visually identified PET-positive joints, target-to-background was calculated. Healthy mice, rats, and arthritic rats were injected with iodinated F8-IL10 or KSF-IL10 control antibody. Various organs were excised, weighed, and counted for radioactivity. Tissue sections were stained for fibronectin ED-A. In RA patients, [124I]I-F8-IL10 was cleared rapidly from the circulation with less than 1% present in blood after 5 min. PET-CT showed targeting in 38 joints (11-15 per patient) and high uptake in the liver and spleen. Mean target-to-background ratios of PET-positive joints were 2.5 ± 1.2, 1.5 times higher for clinically active than clinically silent joints. Biodistribution of radioiodinated F8-IL10 in healthy mice showed no effect of the radioiodination method. [124I]I-F8-IL10 joint uptake was also demonstrated in arthritic rats, ∼14-fold higher than that of the control antibody [124I]I-KSF-IL10 ( p < 0.001). Interestingly, liver and spleen uptake were twice as high in arthritic than in healthy rats and were related to increased (∼7×) fibronectin ED-A expression in these tissues. In conclusion, [124I]I-F8-IL10 uptake was observed in arthritic joints in RA patients holding promise for visualization of inflamed joints by PET-CT imaging and therapeutic targeting. Patient observations and, subsequently, arthritic animal studies pointed to awareness of increased [124I]I-F8-IL10 uptake in the liver and spleen associated with moderate systemic inflammation. This translational study demonstrated the value of in vivo biodistribution and PET-CT-guided imaging in development of new and potential antirheumatic drugs'.
中文翻译：
F8-IL10：一种新的潜在的抗风湿药，通过PET指导的转化方法进行了评估。
抗体片段F8介导的白介素10（IL10）传递是类风湿关节炎（RA）的一种新型治疗方法。F8结合纤连蛋白（ED-A）的域外-A。在这项研究中，对RA患者进行了放射性标记的F8-IL10的体内生物分布和关节炎靶向研究，随后进行了进一步的动物研究。因此，三名RA患者（DAS28> 3.2）接受了0.4 mg 30-74兆贝克[124I] I-F8-IL10进行PET-CT和血液采样。在视觉上确定的PET阳性关节中，计算目标到背景。给健康小鼠，大鼠和关节炎大鼠注射碘化的F8-IL10或KSF-IL10对照抗体。切下各种器官，称重，并计数放射性。对组织切片进行纤连蛋白ED-A染色。在RA患者中 [124I] I-F8-IL10从循环中迅速清除，在5分钟后血液中的含量不到1％。PET-CT显示靶向38个关节（每位患者11-15个），并且肝脏和脾脏的摄取量很高。PET阳性关节的平均靶与背景之比为2.5±1.2，比临床沉默关节高1.5倍。放射性碘化的F8-IL10在健康小鼠中的生物分布未显示放射性碘化方法的效果。在关节炎大鼠中也证实了[124I] I-F8-IL10的联合摄取，比对照抗体[124I] I-KSF-IL10的摄取高约14倍（p <0.001）。有趣的是，关节炎大鼠的肝脏和脾脏摄取量是健康大鼠的两倍，并且与这些组织中纤连蛋白ED-A表达的增加（约7倍）有关。综上所述，在RA患者的关节炎症关节中观察到[124I] I-F8-IL10的摄取，有望通过PET-CT成像和靶向治疗可视化发炎的关节。患者的观察以及随后的关节炎动物研究表明，人们意识到与中度全身性炎症相关的肝脏和脾脏中[124I] I-F8-IL10摄取的增加。这项转化研究证明了体内生物分布和PET-CT引导成像在开发新的和潜在的抗风湿药中的价值。
更新日期：2018-12-14
中文翻译：
F8-IL10：一种新的潜在的抗风湿药，通过PET指导的转化方法进行了评估。
抗体片段F8介导的白介素10（IL10）传递是类风湿关节炎（RA）的一种新型治疗方法。F8结合纤连蛋白（ED-A）的域外-A。在这项研究中，对RA患者进行了放射性标记的F8-IL10的体内生物分布和关节炎靶向研究，随后进行了进一步的动物研究。因此，三名RA患者（DAS28> 3.2）接受了0.4 mg 30-74兆贝克[124I] I-F8-IL10进行PET-CT和血液采样。在视觉上确定的PET阳性关节中，计算目标到背景。给健康小鼠，大鼠和关节炎大鼠注射碘化的F8-IL10或KSF-IL10对照抗体。切下各种器官，称重，并计数放射性。对组织切片进行纤连蛋白ED-A染色。在RA患者中 [124I] I-F8-IL10从循环中迅速清除，在5分钟后血液中的含量不到1％。PET-CT显示靶向38个关节（每位患者11-15个），并且肝脏和脾脏的摄取量很高。PET阳性关节的平均靶与背景之比为2.5±1.2，比临床沉默关节高1.5倍。放射性碘化的F8-IL10在健康小鼠中的生物分布未显示放射性碘化方法的效果。在关节炎大鼠中也证实了[124I] I-F8-IL10的联合摄取，比对照抗体[124I] I-KSF-IL10的摄取高约14倍（p <0.001）。有趣的是，关节炎大鼠的肝脏和脾脏摄取量是健康大鼠的两倍，并且与这些组织中纤连蛋白ED-A表达的增加（约7倍）有关。综上所述，在RA患者的关节炎症关节中观察到[124I] I-F8-IL10的摄取，有望通过PET-CT成像和靶向治疗可视化发炎的关节。患者的观察以及随后的关节炎动物研究表明，人们意识到与中度全身性炎症相关的肝脏和脾脏中[124I] I-F8-IL10摄取的增加。这项转化研究证明了体内生物分布和PET-CT引导成像在开发新的和潜在的抗风湿药中的价值。
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