A simeprevir-inducible molecular switch for the control of cell and gene therapies.

Chemical inducer of dimerization (CID) modules can be used effectively as molecular switches to control biological processes, and thus there is significant interest within the synthetic biology community in identifying novel CID systems. To date, CID modules have been used primarily in engineering cells for in vitro applications. To broaden their utility to the clinical setting, including the potential to control cell and gene therapies, the identification of novel CID modules should consider factors such as the safety and pharmacokinetic profile of the small molecule inducer, and the orthogonality and immunogenicity of the protein components.

Humanised effector-null FcγRIIA antibody inhibits immune complex-mediated proinflammatory responses.

Objective: Immune complexes (ICs) play a critical role in the pathology of autoimmune diseases. The aim of this study was to generate and characterise a first-in-class anti-FcγRIIA antibody (Ab) VIB9600 (previously known as MEDI9600) that blocks IgG immune complex-mediated cellular activation for clinical development.

Methods: VIB9600 was humanised and optimised from the IV.

Engineering the surface properties of a human monoclonal antibody prevents self-association and rapid clearance in vivo.

Uncontrolled self-association is a major challenge in the exploitation of proteins as therapeutics. Here we describe the development of a structural proteomics approach to identify the amino acids responsible for aberrant self-association of monoclonal antibodies and the design of a variant with reduced aggregation and increased serum persistence in vivo. We show that the human monoclonal antibody, MEDI1912, selected against nerve growth factor binds with picomolar affinity, but undergoes reversible self-association and has a poor pharmacokinetic profile in both rat and cynomolgus monkeys.

Structural Characterisation Reveals Mechanism of IL-13-Neutralising Monoclonal Antibody Tralokinumab as Inhibition of Binding to IL-13Rα1 and IL-13Rα2.

Interleukin (IL)-13 is a pleiotropic T helper type 2 cytokine frequently associated with asthma and atopic dermatitis. IL-13-mediated signalling is initiated by binding to IL-13Rα1, which then recruits IL-4Rα to form a heterodimeric receptor complex. IL-13 also binds to IL-13Rα2, considered as either a decoy or a key mediator of fibrosis.

MUC5AC and inflammatory mediators associated with respiratory outcomes in the British 1946 birth cohort.

Background And Objective: Dysregulation of respiratory mucins, MUC5AC in particular, has been implicated in respiratory disease and MUC5AC expression is up-regulated in response to environmental challenges and inflammatory mediators. The aim of this study was to examine the effect of genetic variation on susceptibility to common respiratory conditions.

Methods: The association of MUC5AC and the closely linked genes MUC2 and MUC5B with respiratory outcomes was tested in the MRC National Survey of Health and Development, a longitudinal birth cohort of men and women born in 1946.

Contribution of functional variation in the IL13 gene to allergy, hay fever and asthma in the NSHD longitudinal 1946 birth cohort.

Background: Genetic variants of the two adjacent genes, IL13 and IL4 have frequently been reported as being associated with susceptibility to atopy and asthma, both in adults and children, and some studies also suggest association with lung function and chronic obstructive pulmonary disease.

Methods: In this study, we examined for the first time the effect of these variants in 2918 adults in a longitudinal birth cohort, the British National Survey of Health and Development, where there are extensive life style, developmental and environmental data. We examine two IL13 single nucleotide polymorphisms (SNPs) IL13 rs20541 (R110Q) and rs1800925 (-1024C>T) and one IL4 SNP, rs2070874 (-33C>T) with likely function.

MUC7 haplotype analysis: results from a longitudinal birth cohort support protective effect of the MUC7*5 allele on respiratory function.

The mucin MUC7 is a glycoprotein that plays a role in bacterial clearance and has candidacidal activity. There are two common allelic forms with 5 or 6 tandem repeats (TR) of a 23 amino acid motif within the highly glycosylated (mucin) domain. The MUC7*5 allele has previously been shown to be less prevalent in patients with asthma, suggesting a protective role in respiratory function.

Alpha1-antitrypsin as a risk for infant and adult respiratory outcomes in a national birth cohort.

Reduced alpha1-antitrypsin (AAT) encoded by the gene SERPINA1 is a potential risk for pulmonary disease. We investigated SERPINA1 polymorphism as a risk for infant and adult pulmonary morbidity, and adult respiratory function and its change between 43 and 53 yr. We used data on a British national representative sample (n = 5,362) studied since birth in 1946 to age 53 yr (when n = 3,035), when DNA was first obtained.

Hypervariability of the membrane-associated mucin and cancer marker MUC1.

The highly heterogeneous epithelial mucins show considerable inter-individual variability attributable to allelic variations in their tandem repeat (TR) peptide domains. Most mucins are known to show variations in repeat number but variation in the sequence of the individual TRs is not as well characterised. Here, we have studied variation in the immunodominant PDTR motif in the TR domain of the membrane-associated "cancer" mucin MUC1 by using the Minisatellite Variant Repeat-Polymerase chain reaction (MVR-PCR) technique.

Altered expression and allelic association of the hypervariable membrane mucin MUC1 in Helicobacter pylori gastritis.

Background & Aims: Infection with Helicobacter pylori causes chronic gastritis, and this confers a risk of gastric cancer. Short alleles of the membrane-bound mucin MUC1, which has a large extracellular highly glycosylated domain and is highly polymorphic due to variation in the number of tandemly repeated (TR) 20-amino acid units, have been shown to be associated with gastric cancer. Our aim was to investigate the involvement of MUC1 in chronic gastritis and, by implication, gastric cancer.

Polymorphism of the human muc genes.

Mucins encoded by the MUC genes share the common feature of having an extensive tandem repeat region that encompasses a large proportion of the coding sequence. In many of the genes this tandem repeat region shows a great deal of allelic length variation and recently studies have demonstrated person to person variation in pattern of nucleotide or amino-acid changes in the repeat units. The length and sequence variability will be discussed in this review, as will its role in disease susceptibility.

Genetic polymorphism of MUC7: allele frequencies and association with asthma.

MUC7 encodes a small salivary mucin, previously called MG2, a glycoprotein with a putative role in facilitating the clearance of oral bacteria. The central domain of this glycoprotein was previously shown to comprise five or six tandemly repeated units of 23 amino-acids which carry most of the O-linked glycans. The polymorphism of these two allelic forms (MUC7*5 or MUC7*6) has been confirmed in this study in which we have analysed a large cohort of subjects (n = 375) of various ethnic origins.

Polymorphism of human mucin genes in chest disease: possible significance of MUC2.

Most of the genes that encode epithelial mucins are highly polymorphic due to variations in the length of domains of tandemly repeated (TR) coding sequence, the part of the apomucin that is heavily glycosylated. We report here for the first time a difference in the distribution of MUC TR length alleles in chest disease. We examined the distribution of the length alleles of those MUC genes whose expression we have confirmed in the bronchial tree in an age- and sex-matched series of 50 pairs of atopic patients with and without asthma.

Variable number tandem repeat polymorphism of the mucin genes located in the complex on 11p15.5.

A family of four genes that encode major secreted mucins (MUC6, MUC2, MUC5AC and MUC5B) map to within 400 kb on chromosome 11p15.5. These genes contain long stretches of tandem repeats of sequence that encode serine- and threonine-rich domains but that otherwise show no similarity from gene to gene, and regions of unique sequence domains that do show evidence of sequence homology.

MUC3 human intestinal mucin. Analysis of gene structure, the carboxyl terminus, and a novel upstream repetitive region.

MUC3 is a large mucin glycoprotein expressed by the human intestine and gall bladder. In this manuscript, we present details of the deduced protein structure of MUC3. The MUC3 carboxyl-terminal domain is 617 residues in length, including 511 residues of a non-repetitive mucin-like domain (27% Thr, 22% Ser, and 11% Pro) and a 106-residue Cys-rich domain with homology to the epidermal growth factor (EGF) -like structural motifs found in many proteins.