Pretargeted radioimmunotherapy (PRIT) based on the inverse electron demand Diels-Alder (IEDDA) reaction between tetrazine (Tz) and trans-cyclooctene (TCO) represents a promising strategy for leveraging the affinity and specificity of antibodies without their pharmacokinetic drawbacks. Herein, we present an investigation of the in vivo efficacy and dosimetry of a PRIT strategy for colorectal carcinoma based on the ligation between a 177Lu-labeled Tz radioligand (177Lu-DOTA-PEG7-Tz) and a TCO-bearing immunoconjugate of the huA33 antibody (huA33-TCO). Biodistribution studies in tumor-bearing mice using intervals of 24, 48, and 72 h between the administration of huA33-TCO and 177Lu-DOTA-PEG7-Tz revealed that a 24 h lag time produced the most promising in vivo results: high activity concentrations in the tumor (21.2 %ID/g ± 2.9 at 24 h postinjection), low uptake in nontarget tissues, and favorable dosimetry (an effective dose of 0.054 mSv/MBq). A subsequent longitudinal therapy study revealed striking differences between both the survival and tumor growth of the treatment and control cohorts, clearly underscoring the promise of this approach for the radiotherapy of colorectal carcinoma.

中文翻译：

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点击介导的大肠癌预靶向放射免疫疗法。

基于四嗪（Tz）和反式环辛烯（TCO）之间电子反需求Diels-Alder（IEDDA）反应的预靶向放射免疫疗法（PRIT）代表了一种利用抗体的亲和力和特异性而又没有药代动力学缺点的有前途的策略。本文中，我们基于177Lu标记的Tz放射性配体（177Lu-DOTA-PEG7-Tz）和huA33抗体的带有TCO的免疫缀合物之间的连接，对大肠癌的PRIT策略的体内功效和剂量测定进行了研究（huA33-TCO）。在荷瘤小鼠中进行huA33-TCO和177Lu-DOTA-PEG7-Tz给药之间间隔24、48和72小时的生物分布研究表明，滞后24小时产生了最有希望的体内结果：高活性浓度在肿瘤中（注射后24 h，21.2％ID / g±2.9），非目标组织的摄取低，剂量测定法有利（有效剂量为0.054 mSv / MBq）。随后的纵向疗法研究显示，治疗组和对照组的生存率和肿瘤生长之间都存在显着差异，这显然凸显了这种方法在大肠癌放射治疗中的前景。