Biology subjects

Kuznetsov, M.

Publications and source records attributed to Kuznetsov, M..

4 recordsLinked to original sources

bioRxiv2026

Antibody co-administration robustly improves proton therapy with radiosensitizing nanoparticles: a mathematical modeling study

Radiosensitizing nanoparticles represent a promising approach for enhancing the efficacy of proton radiotherapy; however, their performance is constrained by restricted penetration into tumor tissue, resulting in preferential perivascular accumulation. Here, we develop a spatially distributed mathematical model of a growing tumor undergoing proton therapy with intravenously administered radiosensitizing nanoparticles to investigate treatment optimization strategies. Using physiologically plausible parameter ranges informed by our own experimental measurements and published data, we demonstrate that co-administration of targeted nanoparticles with antibodies binding to the same tumor receptors can overcome transport-induced localization and promote a more uniform intratumoral redistribution of nanoparticles before irradiation. Population-level simulations across heterogeneous parameter sets suggest that moderate antibody doses consistently prolong tumor regrowth time, whereas higher antibody doses produce a pronounced and robust increase in tumor cure probability under a single high-dose irradiation regimen representative of preclinical settings. A key conceptual result of our analysis is the asymmetric risk associated with antibody co-administration. In contrast to antibody--drug conjugates, for which excessive dosing of unconjugated antibodies may severely compromise therapeutic efficacy, co-administration of antibodies with nanoparticle-based radiosensitizers constitutes a "safe-by-design" strategy with respect to tumor cell kill in the modeled single high-dose irradiation setting: although excessive antibody doses may yield suboptimal outcomes, they cannot reduce tumor cell kill below that achieved with targeted nanoparticles administered without antibodies. These findings identify antibody-mediated spatial redistribution of radiosensitizing nanoparticles as a favorable strategy that is expected to provide robust therapeutic benefit despite substantial variability in tumor characteristics.

cancer biology↗

bioRxiv2025

Lymphocytes and monocytes undergo swift suppression of IL-10R, IL-6R, and IL-2Rβγ signaling under high concentrations of different cytokines

The JAK-STAT signaling pathway is fundamental for immune system regulation. It involves phosphorylation of several types of STAT proteins in response to binding of cytokines to immune cell receptors. Traditionally, the immune signaling studies focus on measuring the levels of phosphorylated STATs (pSTATs) following individual cytokine application. We developed an experimental approach, based on multiparametric flow cytometry, to simultaneously measure the levels of five pSTATs after 15 minutes of cell treatment with high doses of individual cytokines and their paired combinations. Analysis of our experimental data involving peripheral blood mononuclear cells from healthy donors reveals systematic suppression of IL-10R, IL-6R, and IL-2R{beta}{gamma} signaling in T cells, B cells, NK cells, and monocytes. This suppression is mediated by at least all tested cytokines that do not induce relevant pSTATs by themselves. Remarkably, the cytokines with negligible own signaling do act as prominent selective signaling suppressors. In contrast, the signaling of IFNAR, IFNGR, IL-4R, and IL-2R{beta}{gamma} remains largely unaffected by co-application of other cytokines. We propose that this pattern of signaling suppression represents an evolutionary developed mechanism enhancing the promptness, specialization, and efficiency of the immune response, while increased concentration of cytokines serves as a danger signal of inefficient response. We hypothesize that selective signaling suppression arises from the differential sensitivity of conformations of cytokine-receptor complexes to the increase of cell surface tension and stiffness, which is caused by effects following the binding of cytokines to membrane-associated molecules, including glycocalyx elements. While the rewiring of immune cell signaling should represent a powerful evolutionary tool for augmentation of adaptive response, it should also lead to the prolonged suppression of counteracting signaling pathways, culminating in cytokine release syndrome and contributing to autoimmune diseases.

immunology↗

bioRxiv2025

Ligand Discrimination in Immune Cells: Signal Processing Insights into Immune Dysfunction in ER+ Breast Cancer

Prior studies have shown that approximately 40% of estrogen receptor positive (ER+) breast cancer (BC) patients harbor immune signaling defects in their blood at diagnosis, and the presence of these defects predicts overall survival. Therefore, it is of interest to quantitatively characterize and measure signaling errors in immune signaling systems in these patients. Here we propose a novel approach combining communication theory and signal processing concepts to model ligand discrimination in immune cells in the peripheral blood. We use the model to measure the specificity of ligand discrimination in the presence of molecular noise by estimating the probability of error, which is the probability of making a wrong ligand identification. We apply our model to the JAK/STAT signaling pathway using high dimensional spectral flow cytometry measurements of transcription factors, including phosphorylated STATs and SMADs, in immune cells stimulated with several cytokines (IFN{gamma}, IL-2, IL-6, IL-4, and IL-10) from 19 ER+ breast cancer patients and 32 healthy controls. In addition, we apply our model to 10 healthy donor samples treated with a clinically approved JAK1/2 inhibitor. Our results show reduced ligand identification accuracy and higher levels of molecular noise in BC patients as compared to healthy controls, which may indicate altered immune signaling and the potential for immune cell dysfunction in these patients. Moreover, the inhibition of JAK1/2 produces ligand misidentification and molecular noise rates similar to, or even greater than, those observed in breast cancer. These results suggest a means to improve the use of signaling kinase inhibitor therapies by identifying patients with favorable ligand discrimination specificity profiles in their immune cells. One Sentence SummaryWe use a communication model to measure ligand discrimination errors in immune cells and molecular noise in cytokine signaling in ER+ breast cancer patients as compared to healthy controls.

cancer biology↗

bioRxiv2024

Mathematical Modeling Unveils Optimization Strategies for Targeted Radionuclide Therapy of Blood Cancers

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 225Ac-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. SignificanceMathematical modeling yields general principles for optimization of targeted radionuclide therapy in mouse models of multiple myeloma that can be extrapolated on another cancer models and on clinical setting.

cancer biology↗