Click-Mediated Pretargeted Radioimmunotherapy of Colorectal Carcinoma

Pretargeted radioimmunotherapy (PRIT) based on the inverse electron demand Diels–Alder (IEDDA) reaction between tetrazine (Tz) and <i>trans</i>-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 <i>in vivo</i> efficacy and dosimetry of a PRIT strategy for colorectal carcinoma based on the ligation between a <sup>177</sup>Lu-labeled Tz radioligand (<sup>177</sup>Lu-DOTA-PEG<sub>7</sub>-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 <sup>177</sup>Lu-DOTA-PEG<sub>7</sub>-Tz revealed that a 24 h lag time produced the most promising <i>in vivo</i> 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.