Kuznetsov Maxim, Adhikarla Vikram, Caserta Enrico, Wang Xiuli, Shively John E, Pichiorri Flavia, Rockne Russell C
Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States.
Department of Hematologic Malignancies Translational Science, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States.
bioRxiv. 2024 May 23:2024.05.22.595377. doi: 10.1101/2024.05.22.595377.
Targeted radionuclide therapy 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 radioconjugates administration accounting for toxicity constraints can increase treatment efficacy. Based on our experiments on disseminated multiple myeloma mouse model treated by Ac-DOTA-daratumumab, we developed a mathematical model which investigation highlighted the following principles for optimization of targeted radionuclide therapy. 1) Nuclide to antibody ratio importance. The density of radioconjugates on cancer cells determines the density of radiation energy deposited in them. 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. 2) Cancer binding capacity-based dosing. The rate of binding of drug to cancer cells depends on the total number of their specific receptors, which therefore can be estimated from the pharmacokinetic curve of diagnostic radioconjugates. Injection of doses significantly exceeding cancer binding capacity should be avoided since radioconjugates remaining in the bloodstream have negligible efficacy to toxicity ratio. 3) Particle range-guided multi-dosing. The use of short-range particle emitters and high-affinity antibodies allows for robust treatment optimization via initial saturation of cancer binding capacity, enabling redistribution of further injected radioconjugates and deposited dose towards still viable cells that continue expressing specific receptors.
靶向放射性核素治疗基于注射与放射性核素偶联的癌症特异性分子。尽管这种治疗具有特异性，但并非没有副作用，这些副作用限制了其应用，并且对像骨髓这样血液灌注良好的快速增殖器官尤其有害。考虑到毒性限制来优化放射性偶联物的给药可以提高治疗效果。基于我们对用Ac-DOTA-达雷妥尤单抗治疗的播散性多发性骨髓瘤小鼠模型所做的实验，我们开发了一个数学模型，该模型的研究突出了以下靶向放射性核素治疗优化原则。1）核素与抗体比例的重要性。癌细胞上放射性偶联物的密度决定了沉积在其中的辐射能量密度。低标记率以及未标记抗体和附着在血流中衰变产物上的抗体的积累，可能会因缺乏放射性核素的抗体过度占据特异性受体而减轻癌症辐射损伤。2）基于癌症结合能力的给药。药物与癌细胞的结合速率取决于其特异性受体的总数，因此可以从诊断性放射性偶联物的药代动力学曲线进行估算。应避免注射明显超过癌症结合能力的剂量，因为留在血流中的放射性偶联物的疗效与毒性之比可忽略不计。3）粒子射程引导的多次给药。使用短程粒子发射体和高亲和力抗体，通过最初使癌症结合能力饱和，可以实现强大的治疗优化，使进一步注射的放射性偶联物和沉积剂量重新分布到仍在表达特异性受体的存活细胞上。
