Harnessing ⁶⁴ Cu/ ⁶⁷ Cu for a theranostic approach to pretargeted radioimmunotherapy

Abstract

Over the past decade, theranostic imaging has emerged as a powerful clinical tool in oncology for identifying patients likely to respond to targeted therapies and for monitoring the response of patients to treatment. Herein, we report a theranostic approach to pretargeted radioimmunotherapy (PRIT) based on a pair of radioisotopes of copper: positron-emitting copper-64 (64Cu, t1/2 = 12.7 h) and beta particle-emitting copper-67 (67Cu, t1/2 = 61.8 h). This strategy is predicated on the in vivo ligation between a trans-cyclooctene (TCO)-bearing antibody and a tetrazine (Tz)-based radioligand via the rapid and bioorthogonal inverse electron-demand Diels–Alder reaction. Longitudinal therapy studies were conducted in a murine model of human colorectal carcinoma using an immunoconjugate of the huA33 antibody modified with TCO (huA33-TCO) and a 67Cu-labeled Tz radioligand ([67Cu]Cu-MeCOSar-Tz). The injection of huA33-TCO followed 72 h later by the administration of 18.5, 37.0, or 55.5 MBq of [67Cu]Cu-MeCOSar-Tz produced a dose-dependent therapeutic response, with the median survival time increasing from 68 d for the lowest dose to >200 d for the highest. Furthermore, we observed that mice that received the highest dose of [67Cu]Cu-MeCOSar-Tz in a fractionated manner exhibited improved hematological values without sacrificing therapeutic efficacy. Dual radionuclide experiments in which a single administration of huA33-TCO was followed by separate injections of [64Cu]Cu-MeCOSar-Tz and [67Cu]Cu-MeCOSar-Tz revealed that the positron emission tomography images produced by the former accurately predicted the efficacy of the latter. In these experiments, a correlation was observed between the tumoral uptake of [64Cu]Cu-MeCOSar-Tz and the subsequent therapeutic response to [67Cu]Cu-MeCOSar-Tz.

Enzyme mediated incorporation of zirconium-89 or copper-64 into a fragment antibody for same day imaging of epidermal growth factor receptor

“…Another potential advantage of using copper-64 based imaging agents is that they can be used to predict dosimetry for the same conjugate labeled with copper-67, a potentially therapeutic β --emitting radionuclide (t 1/2 = 62 h). 49,62 The ability to obtain suitable images in 1 -3 hours post injection suggest diagnostic imaging with 68 Ga, a positron-emitting radionuclide that is available from a generator and has a radioactive half-life of 68 minutes, could be feasible. The DFOSq chelator can also be used to coordinate to 68 Ga III .…”

Radioimmunotherapy for solid tumors: spotlight on Glypican-1 as a radioimmunotherapy target

“… 55 Pre-targeting approaches are also being investigated preclinically and clinically 56 – 58 ; however, the benefits of a shorter half life need to be weighed against reduced uptake to the tumor. 59 …”

Clickable Radiocomplexes With Trivalent Radiometals for Cancer Theranostics: In vitro and in vivo Studies

“…Several groups have been reporting on the synthesis of tetrazine containing DOTA-based chelators in the last years upon functionalization with different pegylated linkers and albumin-binding moieties aiming to improve their pharmacokinetic behavior for imaging and therapeutic purposes (20)(21)(22)(23). Recently, the theranostic couple 64 Cu and 67 Cu (positron and β − emitter, respectively) were used in pre-targeted radioimmunotherapy (PRIT) and demonstrated an excellent correlation between the uptake observed in the PET scans and the dose-dependent therapeutic response (24).…”