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Quantitative systems pharmacology model of GITR-mediated T cell dynamics in tumor microenvironment.
No full textT cell interaction in the tumor microenvironment is a key component of immuno-oncology therapy. Glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) is expressed on immune cells including regulatory T cells (Tregs) and effector T cells (Teffs). Preclinical data suggest that agonism of GITR in combination with Fc-γ receptor-mediated depletion of Tregs results in increased intratumoral Teff:Treg ratio and tumor shrinkage. A novel quantitative systems pharmacology (QSP) model was developed for the murine anti-GITR agonist antibody, DTA-1.mIgG2a, to describe the kinetics of intratumoral Tregs and Teffs in Colon26 and A20 syngeneic mouse tumor models. It adequately captured the time profiles of intratumoral Treg and Teff and serum DTA-1.mIgG2a and soluble GITR concentrations in both mouse models, and described the response differences between the two models. The QSP model provides a quantitative understanding of the trade-off between maximizing Treg depletion versus Teff agonism, and offers insights to optimize drug design and dose regimen
The physician factor and anatomical site in 8846 consecutive mediastinal lymph node aspirations in a cross-sectional study.
No full textMediastinal lymph node fine needle aspiration (MLN-FNA) is a common procedure; however, the physician factor in pathological category, and anatomical site are not routinely assessed. Cytology reports for endobronchial ultrasound (EBUS)/endoscopic ultrasound (EUS) MLN-FNA specimens (8846) were retrieved for July 2012-Dec 2019, classified by hierarchical free text string match algorithm into 51 diagnostic categories, four mutually exclusive diagnostic groups (benign |suspicious |malignant |insufficient), and 24 anatomical sites. Pathologist and submitting physician/surgeon bias were assessed using logistic regression and funnel plots|control charts centered on the group median (diagnostic/capture) rate. Eleven pathologists and seven submitting physician/surgeon were involved in more than 250 specimens each. Overall, the MLN-FNAs were benign|suspicious|malignant|insufficient in 46%|4%|25%|24% of specimens. Percent malignant (number of samples) varied by station; 7| 4R| 4L| 2R| 10R| 11R| 11L were respectively 21
Predicting crystal form stability under real-world conditions
No full textThe physicochemical properties of molecular crystals, such as solubility, stability, compactability, melting behaviour and bioavailability, depend on their crystal form. In silico crystal form selection has recently come much closer to realization because of the development of accurate and affordable free-energy calculations. Here we redefine the state of the art, primarily by improving the accuracy of free-energy calculations, constructing a reliable experimental benchmark for solid–solid free-energy differences, quantifying statistical errors for the computed free energies and placing both hydrate crystal structures of different stoichiometries and anhydrate crystal structures on the same energy landscape, with defined error bars, as a function of temperature and relative humidity. The calculated free energies have standard errors of 1–2 kJ mol−1 for industrially relevant compounds, and the method to place crystal structures with different hydrate stoichiometries on the same energy landscape can be extended to other multi-component systems, including solvates. These contributions reduce the gap between the needs of the experimentalist and the capabilities of modern computational tools, transforming crystal structure prediction into a more reliable and actionable procedure that can be used in combination with experimental evidence to direct crystal form selection and establish control
An end is in sight: A perspective on PCR as an endpoint for Chagas disease treatment trials
No full textNovel therapies for chronic indeterminate Chagas disease (CICD) are needed, but trials are limited by the absence of tests to detect infection and early treatment efficacy. This perspective highlights the shortfalls and strengths of polymerase chain reaction (PCR) as a study endpoint for anti-parasitic drug development. Serologic reversion, the gold standard test of cure, may take decades to occur in adults and therefore is challenging as an endpoint for drug development. Use of PCR as a marker of infection and treatment response has notable limitations due to low parasitemia in CICD, fluctuations in circulating (versus tissue) parasite burden, strain differences, and assay performance. It is, however, rapidly responsive to therapy, and technological advances have improved detection of different strains and may allow for parasite quantification. Until we have more sensitive tests for parasitological clearance, PCR as a measure of treatment failure may be the best available efficacy endpoint to accelerate early development of much-needed novel therapies. Adequately designed clinical studies are needed to correlate PCR clearance with clinical outcomes and to identify novel biomarkers predictive of clinical outcomes in patients with CICD. Public-private partnerships and health authority engagement are paramount to identify feasible trial endpoints and deliver promising new drug candidates for Chagas disease
Generation of bioactivity-tailored FK506/FK520 analogs by CRISPR editing in Streptomyces tsukubaensis
No full textFor a potential application of FK506 in the treatment of acute kidney failure only the FKBP12 binding capability of the compound is required while the immunosuppressive activity via calcineurin binding is considered as a likely risk to the patients. The methoxy-groups at C13 and C15 are thought to have significant influence on the immunosuppressive activity of the molecule. Consequently, FK506 analogs with different functionalities at C13 and C15 were generated by targeted CRISPR editing of the AT domains in module 7 and 8 of the biosynthetic assembly line in Streptomyces tsukubaensis. In addition, the corresponding FK520 (C21 ethyl derivative of FK506) analogs could be obtained by media adjustments. The compounds were tested for their bioactivity in regards to FKBP12 binding, BMP potentiation and calcineurin sparing. 15-desmethoxy FK506 was superior to the other tested analogs by retaining its high potency towards FKBP12 binding and BMP potentiation, while calcineurin inhibition was abolishe
Structural and biophysical comparisons of the pomalidomide- and CC-220-induced interactions of SALL4 with cereblon.
No full textThe design of cereblon-binding molecular glues (MGs) that selectively recruit a desired protein while excluding teratogenic SALL4 is an area of significant interest when designing therapeutic agents. Previous studies show that SALL4 is degraded in the presence of IKZF1 degraders pomalidomide, and to a lesser extent by CC-220. To expand our understanding of the molecular basis for the interaction of SALL4 with cereblon, we performed biophysical and structural studies demonstrating that SALL4 zinc finger domains one and two (ZF1-2) interact with cereblon (CRBN) in a unique manner. ZF1 interacts with the N-terminal domain of cereblon and ZF2 binds as expected in the C-terminal IMiD-binding domain. Both ZF1 and ZF2 contribute to the potency of the interaction of ZF1-2 with CRBN:MG complexes and the affinities of SALL4 ZF1-2 for the cereblon:CC-220 complex are less potent than for the corresponding pomalidomide complex. Structural analysis provides a rationale for understanding the reduced affinity of SALL4 for cereblon in the presence of CC-220, which engages both ZF1 and ZF2. These studies further our understanding of the molecular glue-mediated interactions of zinc finger-based proteins with cereblon and may provide structural tools for the prospective design of compounds with reduced binding and degradation of SALL4
Modular and tunable alternative surfactants for biopharmaceuticals provide insights into Surfactant's Structure-Function relationship.
No full textSurface-induced aggregation of protein therapeutics is opposed by employing surfactants, which are ubiquitously used in drug product development, with polysorbates being the gold standard. Since poloxamer 188 is currently the only generally accepted polysorbate alternative, but cannot be ubiquitously applied, there is a strong need to develop surfactant alternatives for protein biologics that would complement and possibly overcome known drawbacks of existing surfactants. Yet, a severe lack of structure-function relationship knowledge complicates the development of new surfactants. Herein, we perform a systematic analysis of the structure-function relationship of three classes of novel alternative surfactants. Firstly, the mode of action is thoroughly characterized through tensiometry, calorimetry and MD simulations. Secondly, the safety profiles are evaluated through cell-based in vitro assays. Ultimately, we could conclude that the alternative surfactants investigated possess a mode of action and safety profile comparable to polysorbates. Moreover, the biophysical patterns elucidated here can be exploited to precisely tune the features of future surfactant designs
Decentralized clinical trial design using blood microsampling technology for serum bioanalysis.
No full textBackground: Alternatives to phlebotomy in clinical trials increase options for patients and clinicians by simplifying and increasing accessibility to clinical trials. The authors investigated the technical and logistical considerations of one technology compared with phlebotomy. Methodology: Paired samples were collected from 16 donors via a second-generation serum gel microsampling device and conventional phlebotomy. Microsamples were subject to alternative sample handling conditions and were evaluated for quality, clinical testing and proteome profiling. Results: Timely centrifugation of blood serum microsamples largely preserved analyte stability. Conclusion: Centrifugation timing of serum microsamples impacts the quality of specific clinical chemistry and protein biomarkers. Microsampling devices with remote centrifugation and refrigerated shipping can decrease patient burden, expand clinical trial populations and aid clinical decisions
Towards implementing virtual control groups in nonclinical safety studies: Workshop report and roadmap to implementation
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Energy partitioning of pharmaceutical cocrystal structures
No full textActive pharmaceutical ingredients (APIs) and selected coformers were studied in crystalline self-environment, in selected co-crystal structures, and gas phase. To obtain comparable geometries from experimental crystal structures, we rely on fast quantum mechanical GFN2-XTB molecule-in-cluster optimizations. Optimized crystal structures are first analysed in terms of molecule-pair interaction energies, by subdividing a cluster generated from asymmetric unit content through space-group symmetry into pairs of molecules. Accurate energies are then obtained by single-point molecular orbital (MO/MO) two layer “ONIOM” energy partitioning, comparing the same molecules in different crystal environments. Clusters approximate the local environment of a crystal structure for ONIOM. The pre-processor program BAERLAUCH (Acta Cryst A 2012) was used to set up all cluster computations. Solid-state computations using dispersion-corrected density functional theory provide reference results. ONIOM partitioned energies shed light on the driving force of co-crystal formation, with the energy gain from the complementarity of molecule-pair wavefunctions in such structures being the main driving force. It follows that improving prediction of co-crystal structure formation beyond current approaches, e.g. COSMO-RS1 excess enthalpies, statistics from structural databases or full crystal structure prediction is possible by finding complementary molecule-pairs through conformational sampling, as ultimately exemplified