ABSTRACT
Fibrotic remodeling is the primary driver of functional loss in chronic kidney disease, with no specific anti-fibrotic agent available for clinical use. Transglutaminase 2 (TG2), a wound response enzyme that irreversibly crosslinks extracellular matrix proteins causing dysregulation of extracellular matrix turnover, is a well-characterized anti-fibrotic target in the kidney. We describe the humanization and characterization of two anti-TG2 monoclonal antibodies (zampilimab [hDC1/UCB7858] and BB7) that inhibit crosslinking by TG2 in human in vitro and rabbit/cynomolgus monkey in vivo models of chronic kidney disease. Determination of zampilimab half-maximal inhibitory concentration (IC50) against recombinant human TG2 was undertaken using the KxD assay and determination of dissociation constant (Kd) by surface plasmon resonance. Efficacy in vitro was established using a primary human renal epithelial cell model of tubulointerstitial fibrosis, to assess mature deposited extracellular matrix proteins. Proof of concept in vivo used a cynomolgus monkey unilateral ureteral obstruction model of chronic kidney disease. Zampilimab inhibited TG2 crosslinking transamidation activity with an IC50 of 0.25 nM and Kd of <50 pM. In cell culture, zampilimab inhibited extracellular TG2 activity (IC50 119 nM) and dramatically reduced transforming growth factor-ß1-driven accumulation of multiple extracellular matrix proteins including collagens I, III, IV, V, and fibronectin. Intravenous administration of BB7 in rabbits resulted in a 68% reduction in fibrotic index at Day 25 post-unilateral ureteral obstruction. Weekly intravenous administration of zampilimab in cynomolgus monkeys with unilateral ureteral obstruction reduced fibrosis at 4 weeks by >50%, with no safety signals. Our data support the clinical investigation of zampilimab for the treatment of kidney fibrosis.
Subject(s)
Disease Models, Animal , Fibrosis , GTP-Binding Proteins , Macaca fascicularis , Protein Glutamine gamma Glutamyltransferase 2 , Renal Insufficiency, Chronic , Transglutaminases , Animals , Humans , Fibrosis/drug therapy , Rabbits , Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/pathology , Transglutaminases/antagonists & inhibitors , Transglutaminases/metabolism , GTP-Binding Proteins/antagonists & inhibitors , GTP-Binding Proteins/metabolism , GTP-Binding Proteins/immunology , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized/pharmacology , Male , Kidney/pathology , Kidney/drug effects , Kidney/metabolismABSTRACT
Introduction: Vaccines alone do not control pandemics, but vaccinations. The hope of COVID-19 pandemic control is hinged on vaccinations and other public health measures. This systematic review/meta-analysis (SR/MA) investigated the factors that inform coronavirus vaccine uptake globally in an attempt to improve COVID-19 immunization. Method: The PRISMA 2020 methodology was used for this review. A total of 2902 articles were identified from electronic databases and other sources. After screening, 33 articles were included in the review and quantitative meta-analysis. Comprehensive meta-analysis software version 3 was used for the meta-analysis. Results: We observed that vaccine effectiveness, side effects and the proportion of acquaintances vaccinated significantly influenced respondents' COVID-19 immunization decision. Also, associations of vaccine effectiveness, smaller risks to serious side effects, free and voluntary vaccinations and fewer vaccine doses, and longer duration to wanning were observed. We also observed variations in vaccine hesitancy trends in studies carried out in Asia, Europe, America, and Africa. Conclusion: Wanning and acquaintance's vaccination status as factors to vaccination are insights the present paper is bringing to the limelight. Health promotion and COVID-19 vaccination planning are crucial for enhancing vaccine uptake.
Subject(s)
COVID-19 , Coronavirus , Humans , COVID-19 Vaccines , Pandemics , COVID-19/prevention & control , VaccinationABSTRACT
Introduction: Vaccines alone do not control pandemics, but vaccinations. The hope of COVID-19 pandemic control is hinged on vaccinations and other public health measures. This systematic review/meta-analysis (SR/MA) investigated the factors that inform coronavirus vaccine uptake globally in an attempt to improve COVID-19 immunization. Method: The PRISMA 2020 methodology was used for this review. A total of 2902 articles were identified from electronic databases and other sources. After screening, 33 articles were included in the review and quantitative meta-analysis. Comprehensive meta-analysis software version 3 was used for the meta-analysis. Results: We observed that vaccine effectiveness, side effects and the proportion of acquaintances vaccinated significantly influenced respondents' COVID-19 immunization decision. Also, associations of vaccine effectiveness, smaller risks to serious side effects, free and voluntary vaccinations and fewer vaccine doses, and longer duration to wanning were observed. We also observed variations in vaccine hesitancy trends in studies carried out in Asia, Europe, America, and Africa. Conclusion: Wanning and acquaintance's vaccination status as factors to vaccination are insights the present paper is bringing to the limelight. Health promotion and COVID-19 vaccination planning are crucial for enhancing vaccine uptake
Subject(s)
Humans , Male , Female , COVID-19 Vaccines , COVID-19ABSTRACT
A number of novel fused thiophene derivatives have been prepared and identified as potent inhibitors of MEK. The SAR data of selected examples and the in vivo profiling of compound 13 h demonstrates the functional activity of this class of compounds in HT-29 PK/PD models.
Subject(s)
Chemistry, Pharmaceutical/methods , MAP Kinase Kinase Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Thiophenes/chemistry , Animals , Cell Line, Tumor , Crystallography, X-Ray/methods , Drug Design , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Phosphorylation , Static Electricity , Structure-Activity Relationship , Time FactorsABSTRACT
Identifying protein-ligand binding interactions is a key step during early-stage drug discovery. Existing screening techniques are often associated with drawbacks such as low throughput, high sample consumption, and dynamic range limitations. The increasing use of fragment-based drug discovery (FBDD) demands that these techniques also detect very weak interactions (mM K(D) values). This paper presents the development and validation of a fully automated screen by mass spectrometry, capable of detecting fragment binding into the millimolar K(D) range. Low sample consumption, high throughput, and wide dynamic range make this a highly attractive, orthogonal approach. The method was applied to screen 157 compounds in 6 h against the anti-apoptotic protein target Bcl-x(L). Mass spectrometry results were validated using STD-NMR, HSQC-NMR, and ITC experiments. Agreement between techniques suggests that mass spectrometry offers a powerful, complementary approach for screening.
