A novel therapy for cancer micrometastases by dual targeted alpha particle radiation

Patients with advanced prostate cancer often experience bone and extraskeletal metastases, resulting in poor prognoses and reduced quality of life. Currently available treatments are not curative. Thus, there is a significant unmet need for novel treatments that can overcome therapeutic resistance. This project focused on the development and preclinical testing of a broad technology platform called DualAlpha. The novel radiopharmaceutical solution consists of radioactive radium-224 that is natural bone-seeking and targets bone metastases, and its decay product lead-212. Lead-212 is a source of highly cytotoxic alpha particles, and can be connected to a carrier molecule that specifically targets circulating cancer cells and micrometastases. The DualAlpha technology has been explored with a small molecular ligand that targets PSMA on the surface of prostate cancer cells. The targeting ligand led to rapid accumulation of lead-212 in tumour of mice, whereas free radium-224 accumulated in bones. The 212Pb-labelled ligand was retained in tumour over many hours, while it rapidly cleared from non-targeted tissues. In mice, treatment with the 212Pb-labelled carrier reduced tumour growth and improved survival compared to untreated mice. The radioligand demonstrated high tolerability with no short or long term radiotoxicity observed at therapeutic relevant doses.

The findings have been important to gain knowledge of a novel Dual Alpha technology that has the potential to prepare dual-alpha targeting solutions with 212Pb-labelled ligands or antibodies specific for a range of cancers. The project focused on a novel PSMA-targeting radioligand 212Pb-NG001 for the treatment of mCRPC. The results presented in the thesis have demonstrated that 212Pb-NG001 is a promising candidate for PSMA-TAT of mCRPC. The findings are of importance to Artbio AS, and have been used in the preclinical package for the radioligand, and are part of the documentation for regulatory authorities for approval of clinical study protocols. Recently, Artbio AS received approval for initiating a phase 0 study to explore the biodistribution and clearance of the purified 212Pb-NG001 in late-stage mCRPC patients, potentially progressing to a phase I study to investigate the safety and tolerability of the radioligand. If successful, the radioligand therapy will be of great importance to mCRPC patients. Further, the findings in the project obtain knowledge and contribute to the field of targeted alpha therapy of metastatic cancers.

The main goal of this research proposal is to achieve new knowledge, skills and methods that are going to help in the future to develop new and better pharmaceuticals necessary to attack and eliminate cancer metastases, and to plan clinical trials in the future. This include the development and the preclinical testing of a novel and broad technology platform called DualAlpha. The novel radiopharmaceuticals comprise free uncomplexed bone-seeking Radium-224 (Ra-224), targeting the stromal elements and tumour-seeking lead-212 (Pb-212 complexed with a cancer cell surface-targeting molecule (PSMA-seeking ligand or mAb)). The aim is to destroy circulating tumour cells and micrometastases in the skeleton, bone marrow and in soft tissues and at the same time minimizing normal tissue radiotoxicity in patients with metastatic prostate cancer. A conjugated chelator with a PSMA-seeking ligand or mAb will be added to the Ra-224 solution in equilibrium with Pb-212 which makes Pb-212 complexed and hence, cancer-cell targeted. This could mean the administration of substantial amounts of Pb-212 since a pure Ra-224 source will have an ingrowth of Pb-212 to 50% in about 10 h. This new technology may enhance the overall tumor targeting of radiation dose and reduce toxicity by minimising uptake of Pb-212 in normal tissues and cells. The work plan of the PhD project is divided into three strongly interconnected parts to address the formulation, production, optimization and evaluation of the novel radiopharmaceuticals. For patients the novel dual alpha targeted therapy is going to offer fewer side effects, less hospitalizations, improved quality of life, increased productivity, and most importantly, extended lives. The novel radiopharmaceuticals may be suitable for treating chemoresistant cancer metastases.