pretargeted-radioimmunotherapy-based-on-inverse-electron-demand-diels

Pretargeted Radioimmunotherapy Based on the Inverse Electron Demand Diels-Alder Reaction

While radioimmunotherapy (RIT) is a promising approach for the treatment of cancer, the long pharmacokinetic half-life of radiolabeled antibodies can ...

Hunter College of The City University of New York

Graduate Center of the City University of New York

Pretargeted 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 Lu-labeled Tz radioligand (Lu-DOTA-PEG-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 Lu-DOTA-PEG-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.

Click-Mediated Pretargeted Radioimmunotherapy of Colorectal Carcinoma.

The development of immunoconjugates requires a careful balance between preserving the functionality of the antibody and modifying the immunoglobulin with the desired cargo. Herein, we describe the synthesis, development, and in vivo evaluation of a novel bifunctional dendrimeric scaffold and its application in pretargeted PET imaging. The site-specific modification of the huA33 antibody with this dendrimeric scaffold yields an immunoconjugate-huA33-DEN-TCO-decorated with ∼8 trans-cyclooctene (TCO) moieties, a marked increase compared to the ∼2 TCO/mAb of a nondendrimeric control immunoconjugate (huA33-PEG-TCO). Pretargeted PET imaging and biodistribution experiments were used to compare the in vivo performance of these two immunoconjugates in athymic nude mice bearing subcutaneous SW1222 human colorectal cancer xenografts. To this end, the mice were administered 100 μg of each immunoconjugate followed 120 h later by the injection of a tetrazine-bearing radioligand, [Cu]Cu-SarAr-Tz. Pretargeting with huA33-DEN-TCO produced excellent tumoral uptake at 24 h (8.9 ± 1.9 %ID/g), more than double that created by huA33-PEG-TCO (4.1 ± 1.3 %ID/g). Critically-and somewhat surprisingly-the attachment of the G dendrimeric structures did not hamper the in vivo behavior of the immunoconjugate, suggesting that this versatile bifunctional scaffold may have applications beyond pretargeting.

Dendrimer Scaffold for the Amplification of In Vivo Pretargeting Ligations.

Interest in targeted alpha-therapy has surged due to α-particles' high cytotoxicity. However, the widespread clinical use of this approach could be limited by on-/off-target toxicities. Here, we investigated the inverse electron-demand Diels-Alder ligation between an Ac-labeled tetrazine radioligand and a -cyclooctene-bearing anti-CA19.9 antibody (5B1) for pretargeted α-radioimmunotherapy (PRIT) of pancreatic ductal adenocarcinoma (PDAC). This alternative strategy is expected to reduce nonspecific toxicities as compared with conventional radioimmunotherapy (RIT). A side-by-side comparison of Ac-PRIT and conventional RIT using a directly Ac-radiolabeled immunoconjugate evaluates the therapeutic efficacy and toxicity of both methodologies in PDAC murine models.

Article	Year
Click-Mediated Pretargeted Radioimmunotherapy of Colorectal Carcinoma. Molecular pharmaceutics\| PubMed ID: 29502416	2018
Dendrimer Scaffold for the Amplification of In Vivo Pretargeting Ligations. Bioconjugate chemistry\| PubMed ID: 29969558	2018
Leveraging Bioorthogonal Click Chemistry to Improve Ac-Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 30352909	2019

Rosemery Membreno

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