Biology subjects

Townsend, C.

Publications and source records attributed to Townsend, C..

4 recordsLinked to original sources

bioRxiv2025

A Highly Potent Human Antibody Neutralizing All Serotypes of BK Polyomavirus

BK polyomavirus infection poses a significant risk to kidney transplant recipients. Reactivation of dormant virus in the transplanted kidney, triggered by immunosuppression, can lead to BK polyomavirus-associated nephropathy in up to 10% of transplants, often resulting in loss of graft function or even graft loss. Currently, there is no specific treatment that reliably prevents BK polyomavirus-associated nephropathy or halts its progression. Standard of care relies on reducing immunosuppression, allowing the immune system to gradually control the infection but at the risk of provoking rejection episodes and compromising kidney function. This study describes the discovery and characterization of an ultra-potent BK polyomavirus-neutralizing antibody, identified from a kidney transplant recipient who displayed rapid clearance of high-level BK viremia. Antibody mAb 319C07 (USAN potravitug) neutralizes all four BK polyomavirus serotypes and recognizes an epitope critical for viral cell attachment. mAb 319C07 is in clinical development for the treatment of BKPyV infection in renal transplant patients (NCT05769582).

immunology↗

bioRxiv2024

Comparison of a novel potentiator of CFTR channel activity to ivacaftor in ameliorating mucostasis caused by cigarette smoke in primary human bronchial airway epithelial cells

BackgroundCystic Fibrosis causing mutations in the gene CFTR, reduce the activity of the CFTR channel protein, and leads to mucus aggregation, airway obstruction and poor lung function. A role for CFTR in the pathogenesis of other muco-obstructive airway diseases such as Chronic Obstructive Pulmonary Disease (COPD) has been well established. The CFTR modulatory compound, Ivacaftor (VX-770), potentiates channel activity of CFTR and certain CF-causing mutations and has been shown to ameliorate mucus obstruction and improve lung function in people harbouring these CF-causing mutations. A pilot trial of Ivacaftor supported its potential efficacy for the treatment of mucus obstruction in COPD. These findings prompted the search for CFTR potentiators that are more effective in ameliorating cigarette-smoke (CS) induced mucostasis. MethodsA novel small molecule potentiator (SK-POT1), previously identified in CFTR binding studies, was tested for its activity in augmenting CFTR channel activity using patch clamp electrophysiology in HEK-293 cells, a fluorescence-based assay of membrane potential in Calu-3 cells and in Ussing chamber studies of primary bronchial epithelial cultures. Addition of cigarette smoke extract (CSE) to the solutions bathing the apical surface of Calu-3 cells and primary bronchial airway cultures was used to model COPD. Confocal studies of the velocity of fluorescent microsphere movement on the apical surface of CSE exposed airway epithelial cultures, were used to assess the effect of potentiators on CFTR-mediated mucociliary movement. ResultsWe showed that SK-POT1, like VX-770, was effective in augmenting the cyclic AMP-dependent channel activity of CFTR. SK-POT-1 enhanced CFTR channel activity in airway epithelial cells previously exposed to CSE and ameliorated mucostasis on the surface of primary airway cultures. ConclusionTogether, this evidence supports the further development of SK-POT1 as an intervention in the treatment of COPD.

physiology↗

bioRxiv2021

Structural basis for carbapenam C-alkylation by TokK, a B12-dependent radical SAM enzyme

Cobalamin- or B12-dependent radical S-adenosylmethionine (SAM) enzymes acting during carbapenem antibiotic biosynthesis carry out radical-mediated methyl transfers that underlie the therapeutic usefulness of these essential medicines. Here we present x-ray crystal structures of TokK, which are representative of this functional class, containing its two metallocofactors and determined in the presence and absence of carbapenam substrate. The structures give the first visualization of a cobalamin-dependent radical SAM methylase that employs the radical mechanism shared by a vast majority of these enzymes. The structures provide insight into the stereochemistry of initial C6 methylation and suggests that substrate positioning governs the rate of each methylation event. One Sentence SummaryStructural insight into a cobalamin-dependent radical SAM methylase that performs three sequential radical-mediated methylations to install the C6 side chain of a carbapenem antibiotic.

biochemistry↗

bioRxiv2020

MTX-COVAB, a human-derived antibody with potent neutralizing activity against SARS-CoV-2 infection in vitro and in a hamster model of COVID-19

Fast track microfluidic screening of the antibody repertoires of 12 convalescent COVID-19 donors comprising 2.8mio antibodies yielded MTX-COVAB, a human-derived monoclonal antibody with low picomolar neutralization IC50 of SARS-CoV-2. COVAB neutralization potency is on par with the Regeneron cocktail as demonstrated in a comparative neutralization assay. MTX-COVAB shows strong efficacy in vivo and binds to all currently identified clinically relevant variants of SARS-CoV-2. MTX-COVAB completes GMP manufacturing by the end of this year and will be tested in the clinic in March 2021.

immunology↗