Correction to: The 2019 World Molecular Imaging Congress (WMIC) and Molecular Imaging and Biology (MIB) Awards.

The Commercial Innovation of the Year Award went to Emile Beaulieu of Photon etc. for their work.

Pretargeted radioimmunotherapy and SPECT imaging of peritoneal carcinomatosis using bioorthogonal click chemistry: probe selection and first proof-of-concept.

: Pretargeted radioimmunotherapy (PRIT) based upon bioorthogonal click chemistry has been investigated for the first time in the context of peritoneal carcinomatosis using a CEA-targeting 35A7 mAb bearing -cyclooctene (TCO) moieties and several Lu-labeled tetrazine (Tz) radioligands. Starting from three Tz probes containing PEG linkers of varying lengths between the DOTA and Tz groups (. PEG = 3, 7, or 11, respectively, for Tz-, Tz-, and Tz-), we selected [Lu]Lu-Tz as the most appropriate for pretargeted SPECT imaging and demonstrated its efficacy in tumor growth control.

Dual Radionuclide Theranostic Pretargeting.

Recent years have played witness to the advent of nuclear theranostics: the synergistic use of "matched pair" radiopharmaceuticals for diagnostic imaging and targeted radiotherapy. In this investigation, we report the extension of this concept to in vivo pretargeting based on the rapid and bioorthogonal inverse electron demand Diels-Alder reaction between tetrazine (Tz) and -cyclooctene (TCO). We demonstrate that a single injection of a TCO-modified immunoconjugate can be used as a platform for pretargeted PET imaging and radiotherapy via the sequential administration of a pair of Tz-bearing radioligands labeled with the positron-emitting radiometal copper-64 ( ≈ 12.

Toward the Optimization of Click-Mediated Pretargeted Radioimmunotherapy.

Pretargeted radioimmunotherapy (PRIT) based on the inverse electron demand Diels-Alder reaction has shown promise in murine models of disease, yet the radiation dosimetry of this approach must be optimized to make it a viable clinical option. To this end, we have leveraged two recent developments in pretargeted imaging-dendritic scaffolds and masking agents-to improve the dosimetric profile of a proof-of-concept PRIT system that is based on the huA33 antibody, a Lu-labeled tetrazine radioligand ([Lu]Lu-DOTA-PEG-Tz), and a mouse model of A33 antigen-expressing colorectal carcinoma. Pretargeting using an huA33 immunoconjugate bearing a trans-cyclooctene-decorated dendritic scaffold (huA33-DEN-TCO) produced significantly higher tumoral activity concentrations at 120 h post-injection (23.

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 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).

Leveraging Bioorthogonal Click Chemistry to Improve Ac-Radioimmunotherapy of Pancreatic Ductal Adenocarcinoma.

Purpose: 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.

Dendrimer Scaffold for the Amplification of In Vivo Pretargeting Ligations.

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).

Click-Mediated Pretargeted Radioimmunotherapy of Colorectal Carcinoma.

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.

Pretargeted Imaging and Therapy.

In vivo pretargeting stands as a promising approach to harnessing the exquisite tumor-targeting properties of antibodies for nuclear imaging and therapy while simultaneously skirting their pharmacokinetic limitations. The core premise of pretargeting lies in administering the targeting vector and radioisotope separately and having the 2 components combine within the body. In this manner, pretargeting strategies decrease the circulation time of the radioactivity, reduce the uptake of the radionuclide in healthy nontarget tissues, and facilitate the use of short-lived radionuclides that would otherwise be incompatible with antibody-based vectors.

Establishment of the In Vivo Efficacy of Pretargeted Radioimmunotherapy Utilizing Inverse Electron Demand Diels-Alder Click Chemistry.

The pretargeting system based on the inverse electron demand Diels-Alder reaction (IEDDA) between trans-cyclooctene (TCO) and tetrazine (Tz) combines the favorable pharmacokinetic properties of radiolabeled small molecules with the affinity and specificity of antibodies. This strategy has proven to be an efficient method for the molecularly targeted delivery of pharmaceuticals, including isotopes for radiological imaging. Despite encouraging results from in vivo PET imaging studies, this promising system has yet to be thoroughly evaluated for pretargeted radioimmunotherapy (PRIT).

Pretargeted PET Imaging Using a Site-Specifically Labeled Immunoconjugate.

In recent years, both site-specific bioconjugation techniques and bioorthogonal pretargeting strategies have emerged as exciting technologies with the potential to improve the safety and efficacy of antibody-based nuclear imaging. In the work at hand, we have combined these two approaches to create a pretargeted PET imaging strategy based on the rapid and bioorthogonal inverse electron demand Diels-Alder reaction between a (64)Cu-labeled tetrazine radioligand ((64)Cu-Tz-SarAr) and a site-specifically modified huA33-trans-cyclooctene immunoconjugate ((ss)huA33-PEG12-TCO). A bioconjugation strategy that harnesses enzymatic transformations and strain-promoted azide-alkyne click chemistry was used to site-specifically append PEGylated TCO moieties to the heavy chain glycans of the colorectal cancer-targeting huA33 antibody.