An Experimental and Modeling Approach to Study Tangential Flow Filtration Performance for mRNA Drug Substance Purification.

Following the recent COVID-19 pandemic, mRNA manufacturing processes are being actively developed and optimized to produce the next generation of mRNA vaccines and therapeutics. Herein, the performance of the tangential flow filtration (TFF) was evaluated for high-recovery, and high-purity separation of mRNA from unreacted nucleoside triphosphates (NTPs) from the in vitro transcription (IVT) reaction mixture. For the first time, the fouling model was successfully validated with TFF experimental data to describe the adsorption of mRNA on filtration membrane.

The effect of TG2-inhibitory monoclonal antibody zampilimab on tissue fibrosis in human in vitro and primate in vivo models of chronic kidney disease.

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.

Transglutaminase 2: Development of therapeutic antibodies reveals four inhibitory epitopes and confirms extracellular function in fibrotic remodelling.

Background And Purpose: Transglutaminase type 2 (TG2) catalyses formation of ε-(γ-glutamyl)-lysine bonds between proteins, including those of the extracellular matrix (ECM). Elevated extracellular TG2 leads to accelerated ECM deposition and reduced clearance that underlies tissue scarring and fibrosis. Many transglutaminase inhibitors exist and allowed for proof-of-concept studies in disease models, but their lack of specificity for the TG2 isoform, and/or poor pharmacokinetic/pharmacodynamic properties have limited their clinical application.

Integration of Transcriptome and Metabolome Provides Unique Insights to Pathways Associated With Obese Breast Cancer Patients.

Information regarding transcriptome and metabolome has significantly contributed to identifying potential therapeutic targets for the management of a variety of cancers. Obesity has profound effects on both cancer cell transcriptome and metabolome that can affect the outcome of cancer therapy. The information regarding the potential effects of obesity on breast cancer (BC) transcriptome, metabolome, and its integration to identify novel pathways related to disease progression are still elusive.

Interplay between transglutaminases and heparan sulphate in progressive renal scarring.

Transglutaminase-2 (TG2) is a new anti-fibrotic target for chronic kidney disease, for its role in altering the extracellular homeostatic balance leading to excessive build-up of matrix in kidney. However, there is no confirmation that TG2 is the only transglutaminase involved, neither there are strategies to control its action specifically over that of the conserved family-members. In this study, we have profiled transglutaminase isozymes in the rat subtotal nephrectomy (SNx) model of progressive renal scarring.

Structure of the human obesity receptor leptin-binding domain reveals the mechanism of leptin antagonism by a monoclonal antibody.

Leptin regulates energy homeostasis, fertility, and the immune system, making it an important drug target. However, due to a complete lack of structural data for the obesity receptor (ObR), leptin's mechanism of receptor activation remains poorly understood. We have crystallized the Fab fragment of a leptin-blocking monoclonal antibody (9F8), both in its uncomplexed state and bound to the leptin-binding domain (LBD) of human ObR.

Identification of a monoclonal antibody against the leptin receptor that acts as an antagonist and blocks human monocyte and T cell activation.

Nutritional status has a major impact on the immune response and this is in part mediated by leptin, a pro-inflammatory cytokine. Preliminary data suggest that antagonism of leptin may offer a therapeutic approach for the treatment of some inflammatory disorders. We have tested monoclonal antibodies (mAbs) to the human leptin receptor (ObR) for antagonist activity using a leptin signalling bioassay.