A5076882042- Monoclonal and Polyclonal Antibodies Research
- Immune Cell Function and Interaction
- T-cell and B-cell Immunology
- Biochemical and Molecular Research
- Immunotherapy and Immune Responses
- Rheumatoid Arthritis Research and Therapies
- Asthma and respiratory diseases
- Allergic Rhinitis and Sensitization
- Systemic Lupus Erythematosus Research
- Immune Response and Inflammation
- Malaria Research and Control
- Cytomegalovirus and herpesvirus research
- NF-κB Signaling Pathways
- Food Allergy and Anaphylaxis Research
- HER2/EGFR in Cancer Research
- Immunodeficiency and Autoimmune Disorders
- Inflammatory Bowel Disease
- Influenza Virus Research Studies
- Inhalation and Respiratory Drug Delivery
- Mosquito-borne diseases and control
- Toxin Mechanisms and Immunotoxins
- Biosimilars and Bioanalytical Methods
- RNA modifications and cancer
- Cytokine Signaling Pathways and Interactions
- Chronic Lymphocytic Leukemia Research
UCB Pharma (United Kingdom)
2007-2021
UCB Pharma (Belgium)
2012-2014
Royal Berkshire NHS Foundation Trust
2014
Inflammation Research Foundation
2012
University College Birmingham
2010-2012
Imperial College London
1996-1998
St Mary's Hospital
1996-1998
National Institute for Medical Research
1992
The integrin CD103 is highly expressed at mucosal sites, but its role in immune regulation remains poorly understood. We have analyzed the functional of intestinal using T cell transfer model colitis. Our results show no mandatory for expression on cells either development or CD4+CD25+ regulatory (T reg) cell–mediated control However, wild-type were unable to prevent colitis immune-deficient recipients lacking CD103, demonstrating a nonredundant host reg regulation. Non–T restricted...
Inhibitors of tumor necrosis factor α (TNFα) have demonstrated significant efficacy in chronic inflammatory diseases, including Crohn's disease (CD). To further elucidate the mechanisms action these agents, we compared anti-TNFα agents certolizumab pegol, infliximab, adalimumab, and etanercept several vitro systems. The ability each agent to neutralize soluble membrane-bound TNFα; mediate cytotoxicity, affect apoptosis activated human peripheral blood lymphocytes monocytes; induce...
Abstract Tumour necrosis factor (TNF) is a cytokine belonging to family of trimeric proteins; it has been shown be key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF the target several successful biologic drugs, attempts design small molecule therapies directed this have not led approved products. Here we report discovery potent inhibitors that stabilise an asymmetrical form soluble trimer, compromising signalling inhibiting functions vitro vivo....
Abstract Tumour necrosis factor (TNF) is a trimeric protein which signals through two membrane receptors, TNFR1 and TNFR2. Previously, we identified small molecules that inhibit human TNF by stabilising distorted trimer reduce the number of receptors bound to from three two. Here present biochemical structural characterisation molecule-stabilised TNF-TNFR1 complex, providing insights into how can alter signalling function. We demonstrate inhibitors binding affinity third molecule. In support...
Interleukin-6 (IL-6) is a critical regulator of the immune system and has been widely implicated in autoimmune disease. Here, we describe discovery characterization olokizumab, humanized antibody to IL-6. Data from structural biology, cell biology primate pharmacology demonstrate therapeutic potential targeting IL-6 at "Site 3", blocking interaction with signaling co-receptor gp130.
Cytidine triphosphate (CTP) synthetase 1 (CTPS1) deficiency is caused by a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X). CTPS1-deficient patients display severe bacterial and viral infections. CTPS1 responsible for CTP nucleotide de novo production involved in DNA/RNA synthesis. Herein, we characterized depth lymphocyte defects associated with deficiency. Immune phenotyping performed 7 showed absence or low numbers of mucosal-associated T cells, invariant NKT...
Tumor necrosis factor (TNF) is a pleiotropic cytokine belonging to family of trimeric proteins with both proinflammatory and immunoregulatory functions. TNF key mediator in autoimmune diseases during the last couple decades several biologic drugs have delivered new therapeutic options for patients suffering from chronic such as rheumatoid arthritis inflammatory bowel disease. Attempts design small molecule therapies directed this not led approved products yet. Here we report discovery...
The CTP nucleotide is a key precursor of nucleic acids metabolism essential for DNA replication. De novo production relies on synthetases 1 and 2 (CTPS1 CTPS2) that catalyze the conversion UTP into CTP. synthetase activity high in proliferating cells including cancer cells; however, respective roles CTPS1 CTPS2 cell proliferation are not known. By inactivation
Abstract We have recently described the development of a series small-molecule inhibitors human tumour necrosis factor (TNF) that stabilise an open, asymmetric, signalling-deficient form soluble TNF trimer. Here, we describe generation, characterisation, and utility monoclonal antibody selectively binds with high affinity to asymmetric trimer–small molecule complex. The helps define molecular dynamics apo trimer, reveals mode action specificity small inhibitors, acts as chaperone in solving...
Certolizumab pegol (CZP) is a PEGylated Fab′ fragment of humanized monoclonal immunoglobulin G (IgG)1 antibody that binds to human tumor necrosis factor alpha (TNFα) with high affinity. As for many antibodies (mAbs), nonclinical safety assessment CZP has been constrained because its limited species cross-reactivity and recognition only nonhuman primate TNFα, which presents particular challenges assessing reproductive developmental safety. To comprehensively assess the potential liability...
Rationale: IL-13 is an important cytokine implicated in the pathogenesis of allergic asthma and attractive target for inhaled therapeutic.Objective: To investigate efficacy CDP7766, a nebulized anti–IL-13 monoclonal antibody Fab fragment, model cynomolgus macaques naturally sensitized to Ascaris suum.Methods: CDP7766 was using vibrating-membrane nebulizer on basis eFlow technology. The aerosol generated analyzed determine particle size profile biophysical functional properties CDP7766....
SUMMARY Cloned lines of the four rodent Plasmodium species can be differentiated by RFLP pattern generated following Southern blotting and probing with PCsv4.1, a probe derived from P. chabaudi genomic library. Groups CBA/Ca mice were inoculated simultaneously cloned two parasite or strains. Six mixed three strain infections using malaria initiated. The composition population in each group was determined qualitatively semi-quantitatively analysis DNA purified daily blood samples, thereby...
Influenza A/Beijing/32/92 (H3N2) haemagglutinin (HA)-specific short-term CD4+ T cell lines were generated from six unrelated HLA-DR0701, 1501 positive adults (aged 27-60 years) 3 months following administration of an influenza subunit vaccine containing HA A/Beijing/32/92. Epitope recognition was examined using 118 A/Beijing/32/92-specific 16mer peptides which overlapped by 11 residues and spanned the entire molecule. Following vaccination donors recognized identical peptides. The selected...
Novel molecules that specifically target human TNFα in rheumatoid arthritis pose problems for preclinical assessment of efficacy. In this study collagen antibody-induced (CAIA) has been induced transgenic mice to provide a novel model optimised the evaluation targeting TNFα. Tg1278TNFko lack murine and are heterozygous multiple copies transgene is expressed under normal physiological control. To establish CAIA, II monoclonal antibody cocktail (CAb) at 2, 4 or 8 mg was injected i.p. on Day 0...
In this study we demonstrate that immunization of H-2(b) mice with the allergen Der p 1 induces MHC class II restricted T cells proliferate to residues 15-29 (p15-29) and murine II-associated invariant chain derived peptide (CLIP). from naive those immunized CLIP fail respond either or p15-29. cell lines clones reactive p15-29 strongly in response splenic antigen-presenting (APC) normal but show reduced proliferation APC deficient mice. Furthermore, isolated primed expanded on spleen absence...
Cells spontaneously secreting IgG or IgM (ISC) are present at a high level in the blood of patients with systemic lupus erythematosus (SLE). By use magnetic-bead techniques, mononuclear cells from such and healthy donors were fractionated according to expression CD19 CD38 cell fractions then cultured absence added mitogen/antigen for 5/6 days. Supernatant determined and, addition, experiments ISC enumerated both before after culture. Much immunoglobulin-producing capacity unfractionated...
ABSTRACT The CTP nucleotide is a key precursor of nucleic acids metabolism essential for DNA replication. De novo production relies on synthetases 1 and 2 (CTPS1 2) that catalyze the conversion UTP into CTP. synthetase activity high in proliferating cells including cancer cells, however, respective roles CTPS1 CTPS2 cell proliferation are not known. By inactivation and/or complementation experiments, we showed both differentially required proliferation. was more efficient promoting than...