Actinium Ac 225-DOTA-Daratumumab

Targeted radionuclide therapy (TRT) is based on injections of cancer-specific molecules conjugated with radioactive nuclides. Despite the specificity of this treatment, it is not devoid of side effects limiting its use and is especially harmful for rapidly proliferating organs well perfused by blood, like bone marrow. Optimization of radioconjugate administration accounting for toxicity constraints can increase treatment efficacy. Based on our experiments on a disseminated multiple myeloma mouse model treated by 225Ac-DOTA-daratumumab, we developed a mathematical model, investigation of which highlighted the following principles for optimization of TRT: (i) Nuclide-to-antibody ratio importance. The density of radioconjugates on cancer cells determines the density of radiation energy deposited in them. A low labeling ratio as well as accumulation of unlabeled antibodies and antibodies attached to decay products in the bloodstream can mitigate cancer radiation damage due to excessive occupation of specific receptors by antibodies devoid of radioactive nuclides. (ii) Cancer-binding capacity–based dosing. The total number of specific receptors on cancer cells is a critical factor for treatment optimization, and its estimation may allow increasing treatment efficacy close to its theoretical limit. Injection of doses significantly exceeding cancer-binding capacity should be avoided because radioconjugates remaining in the bloodstream have a negligible efficacy-to-toxicity ratio. (iii) Particle range–guided multi-dosing. The use of short-range particle emitters and high-affinity antibodies can allow for robust treatment optimization via initial saturation of cancer-binding capacity, enabling redistribution of further injected radioconjugates and deposited doses toward still viable cells that continue expressing specific receptors.

Mathematical modeling yields general principles for optimization of TRT in mouse models of multiple myeloma that can be extrapolated to other cancer models and clinical settings.