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• W2503011278 abstract "Monoclonal antibodies (mAbs) are promising vectors for delivering therapeutic radiation to cancer cells, but the slow pharmacokinetics of immunoglobulins can lead to high radiation doses to healthy organs, which has hampered the advent of targeted radiommunotherapy (RIT) in the clinic. In response, considerable attention has been dedicated to RIT strategies — including pretargeted radioimmunotherapy (PRIT) — that reduce the radiation burden to healthy tissue. PRIT harnesses the tumor-targeting properties of mAbs while avoiding their drawbacks by employing process in which we are able to radioactively label mAbs after they have accumulated at their target site in vivo. Recently, an innovative approach has emerged based on the extraordinarily selective and rapid inverse electron demand Diels-Alder cycloaddition between a tetrazine (Tz) bearing radioligand and transcyclooctene (TCO) modified mAb. This system has yielded PET images with high contrast while delivering only a small fraction of the radiation dose produced by directly labeled mAbs. Given the success of these pretargeted imaging modalities, the logical next step is to leverage this technology for the development of a safe and effective approach to PRIT. To accomplish this goal, we synthesized two novel 177Lu-labeled Tz radioligands in excellent radiochemical yield (>98%). We compared their uptake in a PRIT system with TCO-modified 5B1 — a human, anti-CA19.9 mAb — using preclinical murine models of pancreatic ductal adenocarcinoma (PDAC). Biodistribution studies in mice bearing subcutaneous xenografts indicated that 177Lu-DOTA-PEG7-Tz—the best ligand tested—had rapid (4.6 ± 0.8%ID/g at 4h) and persistent (16.8 ± 3.9%ID/g at 120h) uptake in xenografts while rapidly clearing from blood and non-target tissues. Single-dose therapy studies using 5B1-TCO and varying doses of 177Lu-DOTA-PEG7-Tz (400, 800, and 1200μCi) showed that our system elicits a dose-dependent therapeutic response in mice bearing human xenografts, the higher two doses causing marked reduction in size or complete elimination of the tumors in vivo. Moreover, dosimetry calculations indicated that, as expected, the PRIT approach reduced the effective absorbed dose of radiation relative to directly labeled 177Lu-5B1 by as much as an order of magnitude at doses that elicited an equal therapeutic response. This was particularly true in metabolic organs such as the liver, kidneys, and spleen as well as tissues such as dose-limiting tissues like blood and red marrow. In the past, several strategies for PRIT have been limited by intrinsic problems (i.e. immunogenicity or radionuclide washout due to noncovalent binding) that prevented clinical translation. We have adapted and optimized a novel PRIT system without those inherent limitations that matches or improves upon their efficacy in preclinical studies. Studies to expedite clinical translation are currently underway. Citation Format: Jacob Houghton, Rosemery Membreno, Dalya Abdel-Atti, Wolfgang W. Scholz, Brian M. Zeglis, Jason S. Lewis. Improving the efficacy of pretargeted radioimmunotherapy in preclinical murine models by utilizing bioorthogonal click chemistry. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3051." @default.
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• W2503011278 date "2016-07-15" @default.
• W2503011278 modified "2023-09-27" @default.
• W2503011278 title "Abstract 3051: Improving the efficacy of pretargeted radioimmunotherapy in preclinical murine models by utilizing bioorthogonal click chemistry" @default.
• W2503011278 doi "https://doi.org/10.1158/1538-7445.am2016-3051" @default.
• W2503011278 hasPublicationYear "2016" @default.
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