骨肉瘤的治疗急需新的治疗方法。靶向放射核素治疗（TRT）和放射免疫治疗（RIT）是有希望的方法，可以将治疗放射线精确地传递到肿瘤部位。我们先前开发了一种完全人源抗体，命名为IF3，可以结合胰岛素样生长因子2受体（IGF2R）。IF3被用于TRT，在骨肉瘤的临床前模型中有效抑制了肿瘤生长。然而，IF3在小鼠体内的相对短半衰期增加了对其改进的需求。我们按已知增强抗体在人血清中半衰期的氨基酸替代生成了一种Fc改良版本的IF3，称为IF3δ。在本研究中，我们确认了IF3δ与IGF2R的特异性结合，与野生型IF3的纳摩尔亲和力相似。此外，IF3δ显示出与人和鼠新生儿Fc受体（FcRn）结合，表明存在FcRn介导的内吞和回收的潜力。小鼠的体内分布研究显示，与野生型IF3相比，IF3δ在脾脏和骨骼中的积累更高，可能是由于小鼠脾脏IGF2R的异常表达。因此，小鼠异种移植模型中的药代动力学数据可能无法准确反映其在犬和人类患者中的行为。然而，这些发现表明IF3和IF3δ都是骨肉瘤RIT的有希望的选择。

Novel therapeutic approaches are much needed for the treatment of osteosarcoma. Targeted radionuclide therapy (TRT) and radioimmunotherapy (RIT) are promising approaches that deliver therapeutic radiation precisely to the tumor site. We have previously developed a fully human antibody, named IF3, that binds to insulin-like growth factor 2 receptor (IGF2R). IF3 was used in TRT to effectively inhibit tumor growth in osteosarcoma preclinical models. However, IF3's relatively short half-life in mice raised the need for improvement. We generated an Fc-engineered version of IF3, termed IF3δ, with amino acid substitutions known to enhance antibody half-life in human serum. In this study, we confirmed the specific binding of IF3δ to IGF2R with nanomolar affinity, similar to wild-type IF3. Additionally, IF3δ demonstrated binding to human and mouse neonatal Fc receptors (FcRn), indicating the potential for FcRn-mediated endocytosis and recycling. Biodistribution studies in mice showed a higher accumulation of IF3δ in the spleen and bone than wild-type IF3, likely attributed to abnormal spleen expression of IGF2R in mice. Therefore, the pharmacokinetics data from mouse xenograft models may not precisely reflect their behavior in canine and human patients. However, the findings suggest both IF3 and IF3δ as promising options for the RIT of osteosarcoma.