Biology subjects

DeBonis, J.

Publications and source records attributed to DeBonis, J..

3 recordsLinked to original sources

bioRxiv2025

Factors Influencing Monoclonal Antibody Pharmacokinetics Across Varying Immune Perturbations

The development of continuous-release devices or injectables for the long-term delivery of biologics is of great interest, especially monoclonal antibodies (mAbs) that require frequent, high-dose injections. Preclinical testing of these technologies in murine models is necessary for clinical translation; however, xenogeneic responses to the mAb and foreign body responses to the implants or injectables can confound results. Immune system knockout (KO) models that affect immune cells are often used in these experiments, but the effects of KO models on mAb pharmacokinetics (PK) are not well characterized. Here, we investigated the PK profile of the human mAb 3BNC117 after intravenous, subcutaneous, and intraperitoneal injections in four mouse strains: BL6, BCD, RAG2, and NSG mice. Noncompartmental analysis was used to quantify differences in PK between each mouse strain. Strikingly, both BL6 and NSG mice exhibited significantly higher mAb clearance compared to the other two strains. To better understand these differences, we developed a minimally physiological based PK model of mAb PK and estimated model parameters using nonlinear mixed effects modeling. The fitted model parameters illustrated how specific processes change in each strain, including the change in clearance rates over time in BL6 and differences in mAb lymphatic uptake in NSG mice. We then used simple allometric scaling relationships to assess which strains were reasonably predictive of human mAb PK. NSG and BL6 mice were found to be unpredictive of human PK, unlike RAG2 and BCD mice. Overall, these results highlight the importance of selecting an appropriate KO strain for preclinical mAb evaluation and demonstrate that RAG2 and BCD strains are suitable mouse models for investigation of mAb PK. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC="FIGDIR/small/651349v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@138af32org.highwire.dtl.DTLVardef@763196org.highwire.dtl.DTLVardef@1b17331org.highwire.dtl.DTLVardef@10199e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Uncovering the Interleukin-12 Pharmacokinetic Desensitization Mechanism and Its Consequences with Mathematical Modeling

The cytokine interleukin-12 (IL-12) is a potential immunotherapy because of its ability to induce a Th1 immune response. However, success in the clinic has been limited due to a phenomenon called IL-12 desensitization - the trend where repeated exposure to IL-12 leads to reduced IL-12 concentrations (pharmacokinetics) and biological effects (pharmacodynamics). Here, we investigated IL-12 pharmacokinetic desensitization via a modeling approach to (i) validate proposed mechanisms in literature and (ii) develop a mathematical model capable of predicting IL-12 pharmacokinetic desensitization. Two potential causes of IL-12 pharmacokinetic desensitization were identified: increased clearance or reduced bioavailability of IL-12 following repeated doses. Increased IL-12 clearance was previously proposed to occur due to the upregulation of IL-12 receptor on T-cells that causes increased receptor-mediated clearance in the serum. However, our model with this mechanism, the accelerated-clearance model, failed to capture trends in clinical trial data. Alternatively, our novel reduced-bioavailability model assumed that upregulation of IL-12 receptor on T-cells in the lymphatic system leads to IL-12 sequestration, inhibiting the transport to the blood. This model accurately fits IL-12 pharmacokinetic data from three clinical trials, supporting its biological relevance. Using this model, we analyzed the model parameter space to illustrate that IL-12 desensitization occurs over a robust range of parameter values and to identify the conditions required for desensitization. We next simulated local, continuous IL-12 delivery and identified several methods to mitigate systemic IL-12 exposure. Ultimately, our results provide quantitative validation of our proposed mechanism and allow for accurate prediction of IL-12 pharmacokinetics over repeated doses.

bioengineering↗

bioRxiv2022

Dynamic Kinetic Models Capture Cell-Free Metabolism for Improved Butanol Production

Cell-free systems are useful tools for prototyping metabolic pathways and optimizing the production of various bioproducts. Mechanistically-based kinetic models are uniquely suited to analyze dynamic experimental data collected from cell-free systems and provide vital qualitative insight. However, to date, dynamic kinetic models have not been applied with rigorous biological constraints or trained on adequate experimental data to the degree that they would give high confidence in predictions and broadly demonstrate the potential for widespread use of such kinetic models. In this work, we construct a large-scale dynamic model of cell-free metabolism with the goal of understanding and optimizing butanol production in a cell-free system. Using a novel combination of parameterization methods, the resultant model captures experimental metabolite measurements across two experimental conditions for nine metabolites at timepoints between 0 and 24 hours. We present analysis of the model predictions, provide recommendations for butanol optimization, and identify the aldehyde/alcohol dehydrogenase as the primary bottleneck in butanol production. Sensitivity analysis further reveals the extent to which various parameters are constrained, and our approach for probing valid parameter ranges can be applied to other modeling efforts.

synthetic biology↗