mp8b00093_si_001.pdf (3.53 MB)
Click-Mediated Pretargeted Radioimmunotherapy of Colorectal Carcinoma
journal contribution
posted on 2018-03-05, 00:00 authored by Rosemery Membreno, Brendon E. Cook, Kimberly Fung, Jason S. Lewis, Brian M. ZeglisPretargeted 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.