Chakravarty Rubel, Chakraborty Sudipta, Sarma Haladhar Dev, Nair K V Vimalnath, Rajeswari Ardhi, Dash Ashutosh
Isotope Production and Applications Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India.
Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India.
J Labelled Comp Radiopharm. 2016 Jul;59(9):354-63. doi: 10.1002/jlcr.3413. Epub 2016 Jun 5.
Radiolabelled monoclonal antibodies (mAbs) are increasingly being utilized in cancer theranostics, which is a significant move toward tailored treatment for individual patients. Cetuximab is a recombinant, human-mouse chimeric IgG1 mAb that binds to the epidermal growth factor receptor with high affinity. We have optimized a protocol for formulation of clinically relevant doses (2.22 GBq) of (90) Y-labelled Cetuximab and (177) Lu-labelled Cetuximab by conjugation of the mAb with a suitable bifunctional chelator, N-[(R)-2-amino-3-(paraisothiocyanato-phenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N',N″,N″-pentaacetic acid (CHX-A″-DTPA). The radioimmunoconjugates demonstrated reasonably high specific activity (1.26 ± 0.27 GBq/mg for (90) Y-CHX-A″-DTPA-Cetuximab and 1.14 ± 0.15 GBq/mg for (177) Lu-CHX-A″-DTPA-Cetuximab), high radiochemical purity (>95%) and appreciable in vitro stability under physiological conditions. Preliminary biodistribution studies with both (90) Y-CHX-A″-DTPA-Cetuximab and (177) Lu-CHX-A″-DTPA-Cetuximab in Swiss mice bearing fibrosarcoma tumours demonstrated significant tumour uptake at 24-h post-injection (p.i.) (16%ID/g) with good tumour-to-background contrast. The results of the biodistribution studies were further corroborated by ex vivo Cerenkov luminescence imaging after administration of (90) Y-CHX-A″-DTPA-Cetuximab in tumour-bearing mice. The tumour uptake at 24 h p.i. was significantly reduced with excess unlabelled Cetuximab, suggesting that the uptake was receptor mediated. The results of this study hold promise, and this strategy should be further explored for clinical translation.
放射性标记的单克隆抗体（mAb）越来越多地用于癌症诊疗，这是朝着为个体患者量身定制治疗迈出的重要一步。西妥昔单抗是一种重组人鼠嵌合IgG1单克隆抗体，能与表皮生长因子受体高亲和力结合。我们通过将单克隆抗体与合适的双功能螯合剂N-[(R)-2-氨基-3-(对异硫氰酸苯基)丙基]-反式-(S,S)-环己烷-1,2-二胺-N,N,N',N″,N″-五乙酸（CHX-A″-DTPA）偶联，优化了一种用于配制临床相关剂量（约2.22 GBq）的（90）Y标记西妥昔单抗和（177）Lu标记西妥昔单抗的方案。放射性免疫偶联物表现出相当高的比活度（（90）Y-CHX-A″-DTPA-西妥昔单抗为1.26±0.27 GBq/mg，（177）Lu-CHX-A″-DTPA-西妥昔单抗为1.14±0.15 GBq/mg）、高放射化学纯度（>95%）以及在生理条件下可观的体外稳定性。用（90）Y-CHX-A″-DTPA-西妥昔单抗和（177）Lu-CHX-A″-DTPA-西妥昔单抗对患有纤维肉瘤肿瘤的瑞士小鼠进行的初步生物分布研究表明，注射后24小时（p.i.）肿瘤摄取显著（约16%ID/g），肿瘤与背景对比度良好。在荷瘤小鼠中给予（90）Y-CHX-A″-DTPA-西妥昔单抗后，通过离体切伦科夫发光成像进一步证实了生物分布研究的结果。注射后24小时肿瘤摄取因过量未标记的西妥昔单抗而显著降低，表明摄取是受体介导的。本研究结果很有前景，该策略应进一步探索用于临床转化。
