10.1021/acs.molpharmaceut.8b00093.s001
Rosemery Membreno
Rosemery
Membreno
Brendon E. Cook
Brendon E.
Cook
Kimberly Fung
Kimberly
Fung
Jason S. Lewis
Jason S.
Lewis
Brian M. Zeglis
Brian M.
Zeglis
Click-Mediated Pretargeted Radioimmunotherapy of Colorectal
Carcinoma
American Chemical Society
2018
colorectal carcinoma
PRIT
huA 33 antibody
177 Lu-DOTA-PEG 7
177 Lu-labeled Tz radioligand
tumor
huA 33-TCO Biodistribution studies
strategy
Colorectal Carcinoma Pretargeted radioimmunotherapy
dosimetry
IEDDA
vivo
Click-Mediated Pretargeted Radioimmunotherapy
ID
2018-03-05 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Click-Mediated_Pretargeted_Radioimmunotherapy_of_Colorectal_Carcinoma/5962699
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.