Combined, yet Separate: cocktails of carriers (not drugs) for α-particle therapy of solid tumors expressing moderate-to-low levels of targetable markers

Alpha-particle radionuclide-antibody conjugates are being clinically evaluated against solid cancers expressing moderate levels of the targeted markers, with promising results. These findings are attributed to the high killing power of alpha-particles in spite of the expected decrease in antibody tumor uptake, that reduces tumor absorbed doses. However, when tumor absorbed doses are reduced, addressing the heterogeneities in delivery of alpha-particles within solid tumors (i.e. enabling uniform irradiation patterns) becomes critical: to maintain efficacy, the fewer alpha-particles delivered within tumors need to traverse/hit as many different cancer cells as possible. This proof-of-concept study describes an approach to complement the antibody- targeted radiotherapy by using a separate carrier to deliver a fraction of the injected radioactivity to tumor regions geographically different than those affected by the antibody; collectively, the two carriers should distribute the alpha-particle emitters, Actinium-225 in particular, more uniformly within tumors maintaining efficacy. Methods We monitored the extent(s) of tumor growth inhibition, onset delay of spontaneous metastases and/or survival on orthotopic MDA-MB-213 and MDA-MB-436 triple negative breast cancer mouse models and on an ectopic BxPC3 pancreatic cancer mouse model, treated systemically with the two separate carriers. Tumors were chosen to express different (but low) levels of HER1, utilized as a model antibody-targeted marker. Results Independent of tumor origin and/or resistance to chemotherapy, the two separate carriers: (a) improved the ‘primary’ tumor growth inhibition, (b) eliminated the formation of spontaneous metastases, and/or (c) prolonged survival, at lower or comparable tumor delivered doses relative to the antibody alone, without noticeable off-target toxicities. Conclusion This tumor-agnostic strategy is timely and could be used to enhance the efficacy of existing alpha-particle radionuclide-antibody treatments without increasing, possibly even reducing, the total administered radioactivity.