The development of novel Sigma-2 targeted alpha-emitting radioligand astatine-211-MM3 as a potential radiotherapeutic for breast cancer

Objectives The Sigma-2 receptor is a unique therapeutic target in cancer due to its preferential expression in rapidly dividing cells, and to a lesser extent in dormant cells, compared to healthy tissue. Targeting the Sigma-2 receptor with an alpha emitting radioconjugate provides a new strategy for delivering high doses of radiation selectively to cancer cells with a potential lethality irrespective of cell cycle status unlike conventional therapies. In this work we report the pre-clinical evaluation of ²¹¹At-MM3 in breast cancer models.

Methods ²¹¹At-MM3 was synthesized from stannylated precursor and was purified by HPLC. The dissociation constant (K_d) of ²¹¹At-MM3 was determined using live EMT-6 breast cancer cells. The therapeutic effect of ²¹¹At-MM3 was tested on EMT6, MDA-MB-231 and MCF-7 breast cancer cells, assessed by cell viability measured 72 hrs post treatment. In vivo biodistribution in balb/c mice bearing EMT6 xenografts was measured after intravenous administration of 10 microCuries ²¹¹At-MM3; animals were sacrificed at 5 minutes, 1 and 2 hours, after radiotracer administration.

Results ²¹¹At-MM3 was produced in adequate quantities and cell binding assays showed high affinity for the Sigma-2 receptor and cytotoxicity was observed in all breast cancer cell lines tested. In vivo biodistribution resulted in high tumor targeting with an average of 4.93% injected dose/gram in the tumor at 2 hours and a tumor/muscle ratio of 4.

Conclusions ²¹¹At-MM3 retains high affinity for the Sigma-2 receptor in vitro and in vivo with promising tumor targeting capabilities. In vitro cytotoxicity experiments reveal therapeutic efficacy across multiple breast cancer cell lines and collectively this work establishes the proof of concept for ²¹¹At-MM3 as a potential alpha-emitting radiotherapeutic meriting further exploration.

Research Support Funding and Support: This research was supported by the Department of Energy DE-FOA-0001075 as part of the multi-disciplinary research and training program in Breast Cancer Molecular Imaging and Targeted Radiochemistry at the University of Pennsylvania.