A Digital Twin to Optimize Treatment Efficacy of Targeted Alpha-particle Therapies by Antibody-Radioconjugate Cocktails Against Solid Tumors

Advanced solid tumors are incurable. Antibody-delivered targeted alpha-particle (-particle) radionuclide therapies (TAT) comprise a tumor-agnostic treatment type, due to the unparalleled killing efficacy of, and irradiation precision (4-5 cell lengths) by, -particles, as well as the selectivity in tumor cell targeting by antibody technologies. However, cells not being directly hit by -particles will likely not be killed. METHODSTo address the limited solid tumor penetration by highly specific and strongly binding antibody-radioconjugates, an experimentally informed digital twin, based on transport (diffusion/advection) first principles, was developed to describe an approach where a fraction of the administered (radio)activity is delivered by a separate type of a model -particle antibody-radioconjugate of low(er)/no affinity for the same marker. The latter was chosen because it can irradiate cells residing in the deep regions of solid tumors away from vasculature. RESULTSThe digital twin that was trained and validated on spheroids that were employed as surrogates of the avascular tumor regions, demonstrated that the investigated cocktails of antibody-radioconjugates with controlled affinities exhibited better inhibition of spheroid growth compared to the extent of growth inhibition by the high-affinity antibody-radioconjugate alone, for the same total (incubated) activity concentrations; this prediction was independent of spheroid size and/or level of expression of the targeted markers. CONCLUSIONThe findings of this study suggest that antibody-delivered TAT (that is already in the clinic) can be augmented by delivering a fraction of the same total activity by low(er) affinity antibody-radioconjugates. This combination of separate antibody-radioconjugates with variable affinities (for the same targeted marker) is a promising approach to possibly even more delay recurrence and further prolong survival of patients with advanced solid tumors.