Pretargeted radioimmunotherapy based on the inverse electron demand Diets-Alder reaction Journal Article


Authors: Membreno, R.; Cook, B. E.; Zeglis, B. M.
Article Title: Pretargeted radioimmunotherapy based on the inverse electron demand Diets-Alder reaction
Abstract: While radioimmunotherapy (RIT) is a promising approach for the treatment of cancer, the long pharmacokinetic half-life of radiolabeled antibodies can result in high radiation doses to healthy tissues. Perhaps not surprisingly, several different strategies have been developed to circumvent this troubling limitation. One of the most promising of these approaches is pretargeted radioimmunotherapy (PRIT). PRIT is predicated on decoupling the radionuclide from the immunoglobulin, injecting them separately, and then allowing them to combine in vivo at the target tissue. This approach harnesses the exceptional tumor-targeting properties of antibodies while skirting their pharmacokinetic drawbacks, thereby lowering radiation doses to non-target tissues and facilitating the use of radionuclides with half-lives that are considered too short for use in traditional radioimmunoconjugates. Over the last five years, our laboratory and others have developed an approach to in vivo pretargeting based on the inverse electron-demand Diels-Alder (IEDDA) reaction between trans-cyclooctene (TCO) and tetrazine (Tz). This strategy has been successfully applied to pretargeted positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging with a variety of antibody-antigen systems. In a pair of recent publications, we have demonstrated the efficacy of IEDDA-based PRIT in murine models of pancreatic ductal adenocarcinoma and colorectal carcinoma. In this protocol, we describe protocols for PRIT using a 177 Lu-DOTAlabeled tetrazine radioligand ([ 177 Lu]Lu-DOTA-PEG7-Tz) and a TCO-modified variant of the colorectal cancer targeting huA33 antibody (huA33- TCO). More specifically, we will describe the construction of huA33-TCO, the synthesis and radiolabeling of [ 177 Lu]Lu-DOTA-PEG7-Tz, and the performance of in vivo biodistribution and longitudinal therapy studies in murine models of colorectal carcinoma. © 2019 Journal of Visualized Experiments.
Keywords: chemistry; radioimmunotherapy; a33 antigen; hua33; pretargeted radioimmunotherapy; pretargeting; lutetium-177; tetrazine; trans-cyclooctene; inverse electron demand diels-alder reaction; issue 143
Journal Title: Journal of Visualized Experiments
Volume: 2019
Issue: 143
ISSN: 1940-087X
Publisher: MYJoVE Corporation  
Date Published: 2019-01-29
Start Page: e59041
Language: English
DOI: 10.3791/59041
PUBMED: 30774125
PROVIDER: scopus
PMCID: PMC7169957
DOI/URL:
Notes: Source: Scopus
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  1. Brian Zeglis
    88 Zeglis
  2. Brendon Ellery Cook
    7 Cook