Radiotheranostic host:guest pretargeting with Pb-203 and Pb-212

Project Summary For monoclonal antibody(mAb)-based radiopharmaceuticals to widely impact precision nuclear medicine, strategies that both improve the convenience and reduce the radiation burden to non-target organs are urgently needed. Compared to direct-labeling strategies, pretargeting makes mAb-based nuclear imaging and targeted radionuclide therapy (TRT) safer, but it has yet to realize its potential impact on clinical precision nuclear medicine. However, the modest successes and inherent limitations of existing pretargeting platforms have defined that a successful platform needs: 1) to be nonimmunogenic, 2) designed to be modular and tunable to any mAb and radionuclide, and 3) to avoid clearing agents. To date, no platform has met these criteria, and there remains a critical need for pretargeting strategies to improve precision nuclear medicine. The long-term goal of this proposal is to develop a host:guest pretargeting platform that utilizes curcubit[7]uril (CB7) “hosts” and adamantane (Adma) radioligand “guests” for nuclear imaging and TRT with elementally- matched 203Pb (imaging) and 212Pb (therapy). CB7-Adma host:guest pretargeting is based on nonimmunogenic molecules, uses a modular approach, and can achieve high uptake in target tissues using mAb targeting vectors with lag times that nullify the need for clearing agents. Thus, it is hypothesized that this platform will address the shortcomings of other platforms yielding a translatable radiotheranostic approach to cancer treatment. Specific Aim 1 of this proposal is the “Development and evaluation of 203/212Pb-labeled radioligands for pretargeting.” To achieve this goal, a library of radioligands will be synthesized and evaluated in vitro as well as in vivo, optimizing the parameters of the host:guest pretargeting approach and comparing the dosimetry to a direct-labeling strategy in order to demonstrate the platform’s suitability for clinical translation Specific Aim 2 is the “Evaluation of 212Pb pretargeted alpha-TRT in murine xenograft models.” Using the strategies for pretargeting developed in Specific Aim 1 as well as a fractionated dosing approach, we will establish the efficacy of our host:guest pretargeting for alpha-TRT. We will also compare the dosimetry, therapeutic index, therapeutic efficacy, and radiological toxicity to analogous approaches with directly-labeled mAbs in a mouse model of cancer to validate the advantages. Successfully achieving the aims of the proposed studies will lead to the development and validation of a next generation pretargeting platform that is suitable for future translational studies and demonstrate its potential as an innovative theranostic application for TRT. The platform will be a robust, safe, and convenient alternative to direct-labeling strategies for mAbs that is widely applicable to precision nuclear medicine in human disease.