Receptor occupancy assays applied in clinical studies provide insights into pharmacokinetic-pharmacodynamic relationships for therapeutic antibodies. When measured by different assays, however, ...receptor occupancy results can be controversial, as was observed for nivolumab, a monoclonal antibody targeting programmed cell death 1 (PD-1) receptor. We suggested an explanation of results obtained and a mechanistic approach based on specific features of the receptor occupancy assays: measurement of the free or bound receptor, normalized to the baseline or at each time point. The approach was evaluated against controversial clinical data on PD-1 receptor occupancy by nivolumab. It was shown that receptor occupancy measured by different assays might vary substantially if the internalization rate of the bound receptor is higher than the rate of degradation of the free receptor. Equations proposed in this work can be applied in quantitative systems pharmacology models to describe target receptor occupancy by different therapeutic antibodies.
Abnormal tau metabolism followed by formation of tau deposits causes a number of neurodegenerative diseases called tauopathies including Alzheimer's disease. Hyperphosphorylation of tau protein ...precedes tau aggregation and is a topic of interest for the development of pharmacological interventions to prevent pathology progression at early stages. The development of a mathematical model of multisite phosphorylation of tau would be helpful for searching for the targets of pharmacological interventions and candidates for biomarkers of pathology progression. In the present study, we for the first time developed a model of multisite phosphorylation of tau protein and elucidated the relative contribution of kinases to phosphorylation of distinct sites. The model describes phosphorylation of tau or PKA-prephosphorylated tau by GSK3β and CDK5 and dephosphorylation by PP2A, accurately reproducing the data for short-term kinetics of tau (de)phosphorylation. Our results suggest that kinase inhibition may more specifically prevent tau hyperphosphorylation, e.g., on PHF sites, which are key biomarkers of pathological changes in Alzheimer's disease. The main features of our model are partial phosphorylation of tau residues and merging of random and sequential mechanisms of multisite phosphorylation within the framework of the probability-based approach assuming independent phosphorylation events.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BackgroundBispecific antibodies (bsAb) might have superior additional mechanisms of action compared to monovalent ones. Not only bsAbs with two binding sites are available, but also tetravalent ...(novel antibody CTX8371). Additional binding sites might impact antibody pharmacodynamics. We developed a translational PK/RO model of tetravalent bispecific antibody CTX8371 to predict PK, receptor occupancy (RO) and investigate potential effects of bispecific binding on the RO.MethodsPK was described by conventional 2-compartment model. Binding of bsAb to PD1 and PDL1 on T cells in plasma and tumor and on malignant cells in tumor, including cis-binding with tri-, tetra- and pentameric complexes formation was described. Parameters were identified with published data for cynomolgus monkeys,1 translation to the human was made using a common allometric scaling approach.ResultsPredicted median CI of CTX8371 trough concentrations in plasma were 24.69 ug/ml 2.26; 92.31 (3 mg/kg Q3W), 45.29 ug/ml 7.07; 148.31 (3 mg/kg Q2W), 151.06 ug/ml 23.62; 494.66 (10 mg/kg Q2W) and 100.54 5.09; 439.64 (20 mg/kg Q4W). Predicted PD1 trough RO on T cells in plasma and tumor, and PDL1 trough RO on T cells in plasma was high (>90%) for all simulated multiple doses. Predicted PDL1 trough RO in tumor was lower (figure 1), median CI 63.4% 23.38; 82.94 (3 mg/kg Q3W) - 88.77% 63.06;95.72 (10 mg/kg Q2W). Doses of 80% RO on T cells in blood are 0.01 and 0.2 mg/kg for PD1 and PDL1, correspondingly.Predicted PD1 RO for simulated single and multiple doses are consistent with RO during canonical Nivolumab treatment.2 For the low doses (<1 mg/kg) increased avidity of CTX8371 is observed: for 0.1 mg/kg Q2W predicted trough PD1 RO on T cells in blood is 87% with cis binding to PDL1 (as for CTX8371), and 77% - without (as for Nivolumab). Predicted through PDL1 RO on T cells in blood is 56% with cis binding to PD1 and 49% - without. The effect increases with lower doses.Internalization of PD1-antibody complexes in model might explain the observed PD1 loss without any additional effects introduction.ConclusionsFirst-in-human dose estimated by RO simulations in blood (0.01 - 0.2 mg/kg) corresponds to those selected for clinical trial (0.1 mg/kg).3 Increased avidity is observed for low doses of CTX8371 due to the multimeric bsAb complexes formation. PD1 loss demonstrated in vivo for cynomolgus monkeys1 might be described by the internalization of bsAb-Target complexes only.ReferencesDiana I. Albu, Xianzhe Wang, Yan Qin, Vivian Li, Purushothama Nanjappa, Amy Daniel Ulumben, Ruturaj Jadhav, Jason Kong, Austin Ablicki, Neal Schilling, Thomas Schuetz, Susan Kalled, Bing Gong, Nelly Kuklin; Abstract 3431: Dose range finding study in non-human primates confirms the unique mechanism of action of CTX-8371, a novel bispecific antibody blocking PD-1 and PD-L1. Cancer Res 15 June 2022; 82 (12_Supplement): 3431.Shchelokov D, Demin O Jr. Receptor occupancy assessment and interpretation in terms of quantitative systems pharmacology: nivolumab case study. MAbs. 2023 Jan-Dec;15(1):2156317.https://investors.compasstherapeutics.com/static-files/41b77ecc-0138–4ced-80a0–65230716f867Abstract 480 Figure 1Simulated PDL1 RO on tumor cell during multiple dose treatment with CTX8371.
BackgroundThe minimal anticipated biological effect level (MABEL) approach is recommended for the selection of safe clinical starting dose for T-cell engagers (TCE). The approach allows to estimate ...the minimal recommended starting dose (MRSD) by setting predicted drug exposure in humans less than concentration of the drug resulting in desirable percentage of maximal pharmacological activity (PA) observed in vitro (in the range of 10%-50%, e.g. EC20). However, this method may lead to low MRDS and multiple dose escalations, resulting in sub-therapeutic doses for patients.1 The aim of our work was to predict MRSD for HPN536, a TCE targeting mesothelin, using mechanistic translational pharmacokinetic (PK), receptor occupancy (RO), PA modeling and compare it with MRSD calculated using MABEL.MethodsTwo mechanistic models were developedtranslational PK/RO/PA model and in vitro model of HPN536. In vitro model describes data on T-cell dependent cytotoxicity, cytokine secretion (IFNg, TNFa), and T-cell activation (% of CD25+ cells) in presence of various HPN536 concentrations.2 PK/RO/PA model describes PK in cynomolgus monkey and its translation to human, distribution of TCE into the tumor (ovarian cancer was considered), and PA (cytotoxicity, T-cells activation and cytokine secretion) based on EC50 values identified in the in vitro model. PA in both models depends on a number of timers of HPN536 bound with CD3 and mesothelin in immunological synapse between T-cell and cancer cell rather than on HPN536 concentration as in MABEL approach.ResultsData on HPN536 PK in cynomolgus monkey was fitted two-compartmental PK model.2 PK data in cancer patients were described with adequate precision using standard allometric scaling exponents without fitting.3 Predictions of the starting dose by MABEL approach based on EC50 (nM) identified by in vitro experiments and mechanistic modeling based on EC50 (number of trimers) fitted by in vitro model are presented in table 1. Mechanistic modeling predicted higher dose than MABEL: ranges based on all assays are 170 – 3150 ng/kg vs 0.9 – 22.6 ng/kg, respectively.ConclusionsThe starting dose chosen for HPN536 first-in-human trial was 6 ng/kg which is in the range predicted by MABEL approach.4 However, doses recommended by mechanistic modeling are higher, e.g., 50% PA is observed in the model at doses around 1000 ng/kg or greater. This prediction is validated by the fact that maximal tolerated dose in HPN536 first-in-human trial was not reached even at dose 3600 ng/kg.ReferencesSaber H, Del Valle P, Ricks T, Leighton J. An FDA oncology analysis of CD3 bispecific constructs and first-in-human dose selection. Regul Toxicol Pharmacol. 2017 Nov;90:144–152.Molloy M, Austin R, Lemon D, et al. Preclinical Characterization of HPN536, a Trispecific, T-Cell-Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors. Clin Cancer Res. 2021 Mar 1;27(5):1452–1462.Haraya K, Tachibana T, Nezu J. Quantitative prediction of therapeutic antibody pharmacokinetics after intravenous and subcutaneous injection in human. Drug Metab Pharmacokinet. 2017 Aug;32(4):208–217.Harpoon Therapeutics Investor Presentation February 2022.Abstract 1167 Table 1Doses predicted by MABEL or modeling based on various in vitro assays.
A better understanding of human metabolism and its relationship with diseases is an important task in human systems biology studies. In this paper, we present a high‐quality human metabolic network ...manually reconstructed by integrating genome annotation information from different databases and metabolic reaction information from literature. The network contains nearly 3000 metabolic reactions, which were reorganized into about 70 human‐specific metabolic pathways according to their functional relationships. By analysis of the functional connectivity of the metabolites in the network, the bow‐tie structure, which was found previously by structure analysis, is reconfirmed. Furthermore, the distribution of the disease related genes in the network suggests that the IN (substrates) subset of the bow‐tie structure has more flexibility than other parts.
BackgroundALX148 is a fusion protein comprised of a high-affinity CD47 blocker linked to an inactive immunoglobulin Fc region. Optimal doses selection is increasingly important in clinical setup and ...can be guided by an assessment of target receptor occupancy (RO) and pharmacodynamics (PD) effect in the site of action. However, direct measurement of RO and PD effect in the tumor tissue is challenging. A mechanistic pharmacokinetic (PK)-PD model was developed to predict CD47 occupancy and PD effect in tumor tissues for ALX148.MethodsThe developed semi-mechanistic PK/RO/PD model describes the PK of ALX148 and its distribution to non-Hodgkin lymphoma tumor tissues (lymph nodes, spleen, and bone marrow). The model includes non-linear clearance of ALX148 due to target CD47 receptor binding and further internalization of the complex. CD47 RO was described on red blood cells and tumor cells taking into account the number of cells and CD47 expression (molecules per cell). Parameters were fitted against clinical PK and in vitro data. In vitro data on stimulation of phagocytosis by ALX148 in the presence of antibodies inducing antibody-dependent cellular phagocytosis (ADCP) was used to estimate the RO-PD relationship. Clinical data on RO in the periphery was used for model validation.ResultsThe model successfully described dose-dependence ALX148 clinical PK and RO data. Predicted trough median CD47 occupancy in the spleen, lymph nodes, and bone marrow during the treatment with 10 mg/kg QW ALX148 was 98% (95% confidence bands: 95%–99%), whereas 30 mg/kg Q2W resulted in 99% CD47 occupancy (95% confidence bands: 98%–99%). ADCP of cancer cells was predicted to be increased by ~1.8 times during the treatment with both regimens of ALX148: 10 mg/kg QW and 30 mg/kg Q2W. Dose 3 mg/kg resulted in the lower induction of ADCP than 10 mg/kg: 1.6 vs 1.8 (p-value < 0.001).ConclusionsThe model was successfully calibrated and validated against both in vitro and clinical data on ALX148. It was predicted that 10 mg/kg QW is an optimal dose of ALX148 to occupy more than 90% of CD47 in the tumor tissues to achieve maximal induction of phagocytosis caused by ADCP stimulating antibodies such as rituximab. This approach can be applied for the optimal dose selection of other anti-CD47 agents taking into account their specific features as binding properties, size, etc.
Cell and cYTOkine CONcentrations DataBase (CYTOCON DB) is a project undertaken by the InSysBio team and aimed at the development of a database that allows collecting, processing, and visualizing ...publicly available in vivo human data on baseline concentrations of cells, cytokines, chemokines, and other molecules. Besides manual curation, an important feature of CYTOCON is that most values found in papers are converted from a huge variety of original units (i.e., mg/ml and number of cells per mm2 of biopsy surface section) to unified units: “pM” for cytokine and “kcell/L” for cell concentration. These features of the database can help researchers facilitate the creation and calibration of quantitative systems pharmacology (QSP) models. Possible applications can be: estimation of the average value or variability of the cell, cytokine or chemokine concentrations for patient groups with different characteristics, such as age, gender, disease severity, disease subtype, etc.; and analysis of correlations among the cell, cytokine, or chemokine concentrations in patients with different characteristics, such as severity of the disease.
For many years, clinical research in Alzheimer’s disease (AD) has focused on attempts to identify the most explicit biomarker, namely amyloid beta. Unfortunately, the numerous therapies that have ...been developed have failed in clinical practice. AD arises as a consequence of multiple factors, and as such it requires a more mechanistic analytical approach than statistical modeling. Quantitative systems pharmacology modeling is a valuable tool for drug development. It utilizes in vitro data for the calibration of parameters, embeds them into physiologically based structures, and explores translation between animals and humans. Such an approach allows for a quantitative study of the dynamics of the interactions between multiple factors or variables. Here, we present an overview of the quantitative translational model in AD, which embraces current preclinical and clinical data. The previously published description of amyloid physiology has been updated and joined with a model for tau pathology and multiple intraneuronal processes responsible for cellular transport, metabolism, or proteostasis. In addition, several hypotheses regarding the best correlates of cognitive deterioration have been validated using clinical data. Here, the amyloid hypothesis was unable to predict the aducanumab clinical trial data, whereas simulations of cognitive impairment coupled with tau seeding or neuronal breakdown (expressed as caspase activity) matched the data. A satisfactory validation of the data from multiple preclinical and clinical studies was followed by an attempt to predict the results of combinatorial treatment with targeted immunotherapy and activation of autophagy using rapamycin. The combination is predicted to yield better efficacy than immunotherapy alone.
BackgroundLymphodepleting chemotherapy is typically to patients prior to cell infusion to promote expansion, persistence, and function of adoptively transferred engineered T-cells. Various regimens ...and doses of are used. Lymphodepletion therapy works by multiple mechanisms, including the elimination of sinks for homeostatic cytokines, such as interleukin-7 (IL-7) and interleukin-15 (IL-15), caused by depletion of endogenous lymphocytes. We applied semi-mechanistic mathematical modeling to compare different lymphodepletion regimens by simulating absolute lymphocyte count (ALC) and IL-7 and IL-15 levels in patients at the time of engineered T-cell infusion (table 1).MethodsThe developed mathematical model describes pharmacokinetics (PK) of the 2 drugs fludarabine and cyclophosphamide, their effects on lymphocyte (T-cells) depletion, and contribution of T-cells in the degradation of IL-7 and IL-15. PK models and parameters of fludarabine and cyclophosphamide were taken from published models.1 2 These models were updated to describe the impact of creatinine clearance (CrCl) on the clearance of both drugs, and were validated against PK data in patients with renal impairment. Fludarabine and cyclophosphamide effects on ALC, IL7 and IL15 were fitted and validated against clinical data reported on monotherapies and their combination.3–7 ResultsTwo regimens similar to regimen 3 but with a reduced dose of fludarabine were tested for patients with mild and moderate renal impairment. The most effective regimen in patients with normal renal function was regimen 1 (fludarabine 30 mg/m2/day for 4 days and cyclophosphamide 1800 mg/m2/day for 2 days) followed by regimen 6 (fludarabine 30 mg/m2/day for 3 days and cyclophosphamide 500 mg/m2/day for 3 days). Regimen 1 resulted in the lowest ALC at the time of T-cell infusion (median = 0.032*109 cell/L). The highest IL-7 level was observed for regimen 1 (median = 28.93 pg/mL), whereas the highest IL-15 level was observed for regimen 6 (median = 19.693 pg/mL). Regimen 2, consisting of two doses of cyclophosphamide, showed substantially higher ALC and lower levels of IL-7 and IL-15. Regimens for patients with renal impairment showed almost the same ALC and cytokine levels as regimen 3.ConclusionsThe most effective regimen of lymphodepletion in terms of ALC decrease and cytokines increase was predicted to be fludarabine 30 mg/m2/day for 4 days and cyclophosphamide 1800 mg/m2/day for 2 days. However, there was no substantial difference between tested regimens except regimen 2 showed the lowest efficacy.ReferencesSalinger, et al. A limited sampling schedule to estimate individual pharmacokinetic parameters of fludarabine in hematopoietic cell transplant patients. Clin Cancer Res. 2009 Aug 15;15(16):5280–7.Chen, et al. Nonlinear pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide in patients with metastatic breast cancer receiving high-dose chemotherapy followed by autologous bone marrow transplantation. Drug Metab Dispos. 1997 May;25(5):544–51.Ramachandran, et al. Systemic and local immunity following adoptive transfer of NY-ESO-1 SPEAR T cells in synovial sarcoma. J Immunother Cancer. 2019 Oct 24;7(1):276.Condomines, et al. Functional regulatory T cells are collected in stem cell autografts by mobilization with high-dose cyclophosphamide and granulocyte colony-stimulating factor. J Immunol. 2006 Jun 1;176(11):6631–9.McCune, et al. Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients. Cancer Chemother Pharmacol. 2015 Jul;76(1):85–96.Kochenderfer, et al. Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels. J Clin Oncol. 2017 Jun 1;35(16):1803–1813.Heczey, et al. CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma. Mol Ther. 2017 Sep 6;25(9):2214–2224.Abstract 338 Table 1Regimens simulated by the model.
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