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首页> 外文期刊>International journal of oncology >Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy
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Preclinical evaluation of a novel engineered recombinant human anti-CD44v6 antibody for potential use in radio-immunotherapy

机译：新型工程重组人抗CD44v6抗体在放射免疫治疗中的潜在临床应用价值

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CD44v6 is overexpressed in a variety of cancers, rendering it a promising target for radio-immunotherapy (RIT). In this study, we have characterized a novel engineered recombinant monoclonal anti-CD44v6 antibody, AbN44v6, and assessed its potential for use in RIT using either~(177)Lu or~(131)I as therapeutic radionuclides. In vitro affinity and specificity assays characterized the binding of the antibody labeled with~(177)Lu,~(125)I or~(131)I. The therapeutic effects of~(177)Lu-AbN44v6 and~(131)I-AbN44v6 were investigated using two in vitro 3D tumor models with different CD44v6 expression. Finally, the normal tissue biodistribution and dosimetry for~(177)Lu-AbN44v6 and~(125)I-AbN44v6/~(131)I-AbN44v6 were assessed in vivo using a mouse model. All AbN44v6 radioconjugates demonstrated CD44v6-specific binding in vitro . In the in vitro 3D tumor models, dose-dependent therapeutic effects were observed with both~(177)Lu-AbN44v6 and~(131)I-AbN44v6, with a greater significant therapeutic effect observed on the cells with a higher CD44v6 expression. Biodistribution experiments demonstrated a greater uptake of~(177)Lu-AbN44v6 in the liver, spleen and bone, compared to~(125)I-AbN44v6, whereas~(125)I-AbN44v6 demonstrated a longer circulation time. In dosimetric calculations, the critical organs for~(177)Lu-AbN44v6 were the liver and spleen, whereas the kidneys and red marrow were considered the critical organs for~(131)I-AbN44v6. The effective dose was in the order of 0.1 mSv/MBq for both labels. In conclusion, AbN44v6 bound specifically and with high affinity to CD44v6. Furthermore, in vitro RIT demonstrated growth inhibition in a CD44v6-specific activity-dependent manner for both radioconjugates, demonstrating that both~(177)Lu-AbN44v6 and~(131)I-AbN44v6 may be promising RIT candidates. Furthermore, biodistribution and dosimetric analysis supported the applicability of both conjugates for RIT. The CD44v6-specific therapeutic effects observed with radiolabeled AbN44v6 in the 3D tumor models in vitro , combined with the beneficial dosimetry in vivo , render AbN44v6 a potential candidate for RIT.
机译：CD44v6在多种癌症中过表达，使其成为放射免疫疗法（RIT）的有希望的靶标。在这项研究中，我们已经表征了一种新型工程重组单克隆抗CD44v6抗体AbN44v6，并使用〜（177）Lu或〜（131）I作为治疗性放射性核素评估了其在RIT中使用的潜力。体外亲和力和特异性测定表征了用〜（177）Lu，〜（125）I或〜（131）I标记的抗体的结合。使用两种具有不同CD44v6表达的体外3D肿瘤模型研究了〜（177）Lu-AbN44v6和〜（131）I-AbN44v6的治疗效果。最后，使用小鼠模型在体内评估〜（177）Lu-AbN44v6和〜（125）I-AbN44v6 /〜（131）I-AbN44v6的正常组织生物分布和剂量。所有AbN44v6放射性结合物在体外均显示CD44v6特异性结合。在体外3D肿瘤模型中，使用〜（177）Lu-AbN44v6和〜（131）I-AbN44v6均观察到剂量依赖性的治疗效果，对CD44v6表达较高的细胞具有更大的显着治疗效果。生物分布实验表明，与（125）I-AbN44v6相比，肝脏，脾脏和骨骼中〜（177）Lu-AbN44v6的摄取量更大，而〜（125）I-AbN44v6的循环时间更长。在剂量计算中，〜（177）Lu-AbN44v6的关键器官是肝脏和脾脏，而肾脏和红骨髓被认为是〜（131）I-AbN44v6的关键器官。两种标记的有效剂量均为0.1 mSv / MBq。总之，AbN44v6与CD44v6特异性结合且具有高亲和力。此外，体外RIT对两种放射性缀合物均以CD44v6特异性活性依赖性方式显示出生长抑制作用，表明〜（177）Lu-AbN44v6和〜（131）I-AbN44v6都可能是有希望的RIT候选药物。此外，生物分布和剂量分析支持了两种缀合物对RIT的适用性。放射性标记的AbN44v6在体外3D肿瘤模型中观察到的CD44v6特异性治疗作用，再结合体内有益的​​剂量测定，使AbN44v6成为RIT的潜在候选者。

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