Guiding treatment response by spatiotemporal control of α-particle deposition in solid tumors: the case for ‘affinity cocktails’ of antibody-radioconjugates

Antibody-radioconjugates are leading the investigational targeted alpha-particle (α-particle) therapies for the treatment of solid tumors that do not respond to approved therapies. Yet, there is still treatment failure in the clinic largely attributed to the heterogenous patterns of tumor irradiation by α-particles. Although α-particles are essentially impervious to resistance, attributed to the complex double-strand DNA breaks they cause while traversing cells, cells not being directly hit by α-particles will likely not be killed. The diffusion-limited poor tumor penetration of high-affinity (strongly-binding) antibody-radioconjugates combined with α-particles’ short-range in tissue (only 40-80μm), let tumor regions far from vasculature inadequately irradiated, therefore, possibly escaping treatment. METHODS To improve penetration of delivered activity within tumors, we engineered separate actinium-225 antibody-radioconjugates of variable affinities (‘affinity cocktails’) targeting the same marker on cancer cells, that were chosen based on their preferential irradiation of complementary regions of the same tumors. The cocktails comprise: (a) ‘high-affinity’ antibody-radioconjugates (as the ones on clinical trials), which mostly deliver their cargo in tumor cells close to the vasculature, where the ‘low(er)-affinity’ antibody-radioconjugates fail to deliver effective doses, due to their fast clearance; and (b) ‘low(er)-affinity’ antibody-radioconjugates, that penetrate the deeper parts of tumors farther from the vasculature, where the ‘high-affinity’ antibodies fail to reach. The efficacy of affinity cocktails was assessed in spheroids, that were employed as surrogates of tumor avascular regions, and on mice with subcutaneous xenografts of different cancer origin, expression levels and/or type of the targeted receptor: HER2 highly-expressing BT-474 breast cancer cells, HER2 moderately-expressing HEPG2 hepatoma cells, and/or HER1 low-expressing BxPC-3 pancreatic cancer cells. RESULTS Although the high-affinity antibody-radioconjugates were most lethal against cancer cells in monolayers, affinity cocktails were most effective in inhibiting spheroid growth, due to better collective spreading of the antibody-conjugates within the spheroids’ volume. On all mouse models, and for the same total injected activity, affinity cocktails resulted in the best tumor growth inhibition, even at lower tumor absorbed doses, compared to the high-affinity antibody-radioconjugates alone. CONCLUSIONS This proof-of-concept study in α-particle antibody-delivery to solid tumors demonstrates that ‘separating’ the two key processes of diffusion and reaction/binding improves treatment efficacy. This generalizable approach may augment antibody-radioconjugates already in clinical trials.