El-Emir E, Dearling J L J, Huhalov A, Robson M P, Boxer G, Neri D, van Dongen G A M S, Trachsel E, Begent R H J, Pedley R B
1Cancer Research UK Targeting and Imaging Group, Department of Oncology, Royal Free and University College Medical School (UCL), Hampstead Campus, Rowland Hill Street, London NW3 2PF, UK.
Br J Cancer. 2007 Jun 18;96(12):1862-70. doi: 10.1038/sj.bjc.6603806. Epub 2007 May 22.
Angiogenesis is a characteristic feature of tumours and other disorders. The human monoclonal antibody L19- SIP targets the extra domain B of fibronectin, a marker of angiogenesis expressed in a range of tumours. The aim of this study was to investigate whole body distribution, tumour localisation and the potential of radioimmunotherapy with the L19-small immunoprotein (SIP) in colorectal tumours. Two colorectal tumour models with highly different morphologies, the SW1222 and LS174T xenografts, were used in this study. Localisation and retention of the L19-SIP antibody at tumour vessels was demonstrated using immunohistochemistry and Cy3-labelled L19-SIP. Whole body biodistribution studies in both tumour models were carried out with (125)I-labelled L19-SIP. Finally, (131)I-labelled antibody was used to investigate the potential of radioimmunotherapy in SW1222 tumours. Using immunohistochemistry, we confirmed extra domain B expression in the tumour vasculature. Immunofluorescence demonstrated localisation and retention of injected Cy3-labelled L19-SIP at the abluminal side of tumour vessels. Biodistribution studies using a (125)I-labelled antibody showed selective tumour uptake in both models. Higher recorded values for localisation were found in the SW1222 tumours than in the LS174T (7.9 vs 6.6 %ID g(-1)), with comparable blood clearance for both models. Based on these results, a radioimmunotherapy study was performed in the SW1222 xenograft using (131)I-Labelled L19-SIP (55.5 MBq), which showed selective tumour uptake, tumour growth inhibition and improved survival. Radio- and fluorescence-labelled L19-SIP showed selective localisation and retention at vessels of two colorectal xenografts. Furthermore, (131)I-L19-SIP shows potential as a novel treatment of colorectal tumours, and provides the foundation to investigate combined therapies in the same tumour models.
血管生成是肿瘤和其他疾病的一个特征。人单克隆抗体L19 - SIP靶向纤连蛋白的额外结构域B，纤连蛋白是在一系列肿瘤中表达的血管生成标志物。本研究的目的是研究L19 - 小免疫蛋白（SIP）在结直肠癌中的全身分布、肿瘤定位及放射免疫治疗潜力。本研究使用了两种形态差异很大的结直肠癌模型，即SW1222和LS174T异种移植瘤。采用免疫组织化学和Cy3标记的L19 - SIP证明了L19 - SIP抗体在肿瘤血管处的定位和滞留。用（125）I标记的L19 - SIP对两种肿瘤模型进行了全身生物分布研究。最后，用（131）I标记的抗体研究SW1222肿瘤的放射免疫治疗潜力。通过免疫组织化学，我们证实了肿瘤脉管系统中额外结构域B的表达。免疫荧光显示注射的Cy3标记的L19 - SIP在肿瘤血管的腔外侧定位和滞留。使用（125）I标记抗体的生物分布研究显示两种模型中肿瘤均有选择性摄取。SW1222肿瘤的定位记录值高于LS174T（7.9对6.6 %ID g-1），两种模型的血液清除率相当。基于这些结果，使用（131）I标记的L19 - SIP（55.5 MBq）对SW1222异种移植瘤进行了放射免疫治疗研究，结果显示肿瘤有选择性摄取、肿瘤生长受抑制且生存期延长。放射性和荧光标记的L19 - SIP在两种结直肠癌异种移植瘤的血管处均显示出选择性定位和滞留。此外，（131）I - L19 - SIP显示出作为结直肠癌新治疗方法的潜力，并为在相同肿瘤模型中研究联合疗法奠定了基础。
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