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Abstract：
Etiological and genetic drivers of osteosarcoma (OS) are not well studied and vary from one tumor to another; making it challenging to pursue conventional targeted therapy. Recent studies have shown that cation independent mannose-6-phosphate/insulin-like growth factor-2 receptor (IGF2R) is consistently overexpressed in almost all of standard and patient-derived OS cell lines, making it an ideal therapeutic target for development of antibody-based drugs. Monoclonal antibodies, targeting IGF2R, can be conjugated with alpha- or beta-emitter radionuclides to deliver cytocidal doses of radiation to target IGF2R expression in OS. This approach known as radioimmunotherapy (RIT) can therefore be developed as a novel treatment for OS. In addition, OS is one of the common cancers in companion dogs and very closely resembles human OS in clinical presentation and molecular aberrations. In this study, we have developed human antibodies that cross-react with similar affinities to IGF2R proteins of human, canine and murine origin. We used naïve and synthetic antibody Fab-format phage display libraries to develop antibodies to a conserved region on IGF2R. The generated antibodies were radiolabeled and characterized in vitro and in vivo using human and canine OS patient-derived tumors in SCID mouse models. We demonstrate specific binding to IGF2R and tumor uptake in these models, as well as binding to tumor tissue of canine OS patients, making these antibodies suitable for further development of RIT for OS.
摘要：
骨肉瘤（OS）的病因和遗传驱动因素尚未得到很好的研究，并且因肿瘤而异；这使得追求常规靶向治疗具有挑战性。最近的研究表明，阳离子非依赖性甘露糖-6-磷酸/胰岛素样生长因子-2受体（IGF2R）在几乎所有的标准和患者来源的OS细胞系中始终过表达。使其成为开发基于抗体的药物的理想治疗靶标。单克隆抗体,靶向IGF2R，可以与α-或β-发射体放射性核素缀合以递送杀细胞剂量的辐射以靶向OS中的IGF2R表达。因此，这种称为放射免疫疗法（RIT）的方法可以开发为OS的新型治疗方法。此外,OS是伴侣犬中常见的癌症之一，在临床表现和分子畸变方面与人类OS非常相似。在这项研究中,我们已经开发了与人类IGF2R蛋白具有相似亲和力的交叉反应的人类抗体，犬和鼠的起源。我们使用天然和合成抗体Fab格式噬菌体展示文库来开发针对IGF2R上保守区域的抗体。在SCID小鼠模型中使用人和犬OS患者来源的肿瘤在体外和体内对产生的抗体进行放射性标记和表征。我们在这些模型中证明了与IGF2R的特异性结合和肿瘤摄取，以及与犬OS患者的肿瘤组织结合，使这些抗体适合于进一步开发用于OS的RIT。
