Paquette Michel, Vilera-Perez Luis-Guillermo, Beaudoin Simon, Ekindi-Ndongo Nadia, Boudreaut Pierre-Luc, Bonin Marc-Andre, Battista Marie-Claude, Bentourkia M'hamed, Lopez Angel F, Lecomte Roger, Marsault Eric, Guérin Brigitte, Sabbagh Robert, Leyton Jeffrey V
Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences (FMHS), Centre hospitalier universitaire de Sherbrooke (CHUS), Université de Sherbrooke (UdeS), Sherbrooke, Québec, Canada.
Department of Pathology, FMHS, CHUS, UdeS, Sherbrooke, Québec, Canada.
Oncoimmunology. 2017 May 19;6(10):e1331195. doi: 10.1080/2162402X.2017.1331195. eCollection 2017.
Despite the high interest and concern due to an increasing incidence and death rate, patients who develop muscle invasive bladder cancer (MIBC) have few options available. However, the past decade has produced many candidate bladder tumor-specific markers but further development of these markers is still needed for creating effective targeted medications to solve this urgent need. Interleukin-5 receptor α-subunit (IL-5Rα) has recently been reported to be involved in MIBC progression. Thus, we aimed to validate IL-5Rα as a target for antibody-conjugates to better manage patients with MIBC. Patients were recruited and their tumors were processed for IL-5Rα immunohistochemical analysis. NOD/SCID mice were also heterotopically implanted with the human MIBC HT-1376 and HT-B9 cell lines and established xenografts immunohistochemically evaluated for IL-5Rα and compared against patient tumors. Using the mAb A14, an antibody-drug conjugate (ADC) and a radiolabeled immunoconjugate (RIC) were developed by conjugating to vinblastine and to the positron emitter copper-64 (Cu), respectively. As a proof-of-concept for ADC and RIC efficacy, cytotoxicity and positron emission tomography (PET) imaging in tumor-bearing mice were performed, respectively. In addition, as rapid internalization and accumulation are important components for effective antibody-conjugates, we evaluated these aspects in response to IL-5 and Cu-A14 treatments. Our findings suggest that although IL-5Rα protein expression is preferentially increased in MIBC, it is rapid IL-5Rα-mediated internalization allowing vinblastine-A14 to have cytotoxic activity and Cu-A14 to detect MIBC tumors . This is the first report to elucidate the potential of IL-5Rα as an attractive MIBC target for antibody-conjugate applications.
尽管肌肉浸润性膀胱癌（MIBC）的发病率和死亡率不断上升，引发了高度关注，但罹患该疾病的患者可选择的治疗方案却寥寥无几。然而，在过去十年间已出现了许多候选膀胱肿瘤特异性标志物，但仍需进一步研发这些标志物，以开发出有效的靶向药物来满足这一迫切需求。白细胞介素-5受体α亚基（IL-5Rα）最近被报道与MIBC的进展有关。因此，我们旨在验证IL-5Rα作为抗体偶联物的靶点，以便更好地治疗MIBC患者。招募患者并对其肿瘤进行IL-5Rα免疫组织化学分析。还将人MIBC HT-1376和HT-B9细胞系异位植入NOD/SCID小鼠体内，建立异种移植模型，对其进行IL-5Rα免疫组织化学评估，并与患者肿瘤进行比较。利用单克隆抗体A14，分别通过与长春碱和正电子发射体铜-64（Cu）偶联，开发了一种抗体药物偶联物（ADC）和一种放射性标记免疫偶联物（RIC）。作为ADC和RIC疗效的概念验证，分别在荷瘤小鼠中进行了细胞毒性和正电子发射断层扫描（PET）成像。此外，由于快速内化和积累是有效抗体偶联物的重要组成部分，我们评估了IL-5和Cu-A14处理对此的影响。我们的研究结果表明，尽管IL-5Rα蛋白表达在MIBC中优先增加，但正是IL-5Rα介导的快速内化使得长春碱-A14具有细胞毒性活性，Cu-A14能够检测MIBC肿瘤。这是第一份阐明IL-5Rα作为抗体偶联物应用中具有吸引力的MIBC靶点潜力的报告。
