A5102794383- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- Microbial Natural Products and Biosynthesis
- Carbohydrate Chemistry and Synthesis
- Viral Infectious Diseases and Gene Expression in Insects
- Toxin Mechanisms and Immunotoxins
- Protein purification and stability
- Immune Cell Function and Interaction
- Genomics and Phylogenetic Studies
- vaccines and immunoinformatics approaches
- T-cell and B-cell Immunology
- Transgenic Plants and Applications
- Adrenal and Paraganglionic Tumors
- Adenosine and Purinergic Signaling
- Pharmacological Effects of Natural Compounds
- Protein Degradation and Inhibitors
- Protease and Inhibitor Mechanisms
- Biochemical and biochemical processes
- Protein Structure and Dynamics
- Eosinophilic Esophagitis
- Cancer, Hypoxia, and Metabolism
- Pain Mechanisms and Treatments
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Receptor Mechanisms and Signaling
- Plant-Microbe Interactions and Immunity
AstraZeneca (United Kingdom)
2019-2020
AstraZeneca (Canada)
2020
University of Cambridge
2005-2008
Abstract In response to infections and irritants, the respiratory epithelium releases alarmin interleukin (IL)-33 elicit a rapid immune response. However, little is known about regulation of IL-33 following its release. Here we report that biological activity at receptor ST2 rapidly terminated in extracellular environment by formation two disulphide bridges, resulting an extensive conformational change disrupts binding site. Both reduced (active) bonded (inactive) forms can be detected lung...
SAbPred is a server that makes predictions of the properties antibodies focusing on their structures. Antibody informatics tools can help improve our understanding immune responses to disease and aid in design engineering therapeutic molecules. single platform containing multiple applications which can: number align sequences; automatically generate antibody variable fragment homology models; annotate such models with estimated accuracy alongside sequence structural including potential...
Interleukin (IL)-13 is a pleiotropic T helper type 2 cytokine frequently associated with asthma and atopic dermatitis. IL-13-mediated signalling initiated by binding to IL-13Rα1, which then recruits IL-4Rα form heterodimeric receptor complex. IL-13 also binds IL-13Rα2, considered as either decoy or key mediator of fibrosis. IL-13-neutralising antibodies act preventing and/or IL-13Rα2. Tralokinumab (CAT-354) an human IgG4 monoclonal antibody that has shown clinical benefit in patients asthma....
Antibodies represent essential tools in research and diagnostics are rapidly growing importance as therapeutics. Commonly used methods to obtain novel antibodies typically yield several candidates capable of engaging a given target. The development steps that follow, however, usually performed with only one or few since they can be resource demanding, thereby increasing the risk failure overall antibody discovery program. In particular, insufficient solubility, which may lead aggregation...
Abstract Uncontrolled self-association is a major challenge in the exploitation of proteins as therapeutics. Here we describe development structural proteomics approach to identify amino acids responsible for aberrant monoclonal antibodies and design variant with reduced aggregation increased serum persistence vivo. We show that human antibody, MEDI1912, selected against nerve growth factor binds picomolar affinity, but undergoes reversible has poor pharmacokinetic profile both rat...
The H3 loop in the Complementarity Determining Region of antibodies plays a key role their ability to bind diverse space potential antigens. It is also exceptionally difficult model computationally causing significant hurdle for silico development antibody biotherapeutics. In this article, we show that most H3s have unique structural characteristics which may explain why they are so challenging model. We found over 75% loops do not sub-Angstrom neighbor non-antibody world. Also, comparison...
Antibodies can undergo a variety of covalent and non-covalent degradation reactions that have adverse effects on efficacy, safety, manufacture storage. We had identified an antibody to Angiopoietin 2 (Ang2 mAb) neutralizes Ang2 binding its receptor in vitro inhibits tumor growth vivo. Despite favorable pharmacological activity, the mAb preparations were heterogeneous, aggregated rapidly poorly expressed. Here, we report engineering variable constant domains generate with reduced propensity...
Antibodies are an important class of therapeutics that have significant clinical impact for the treatment severe diseases. Computational tools to support antibody drug discovery been developing at increasing rate over last decade and typically rely upon a predetermined co-crystal structure bound antigen structural predictions. Here, we show example successful in silico affinity maturation hybridoma derived antibody, AB1, using just homology model fragment variable region protein-protein...
Abstract P2X4 is a ligand-gated ion channel implicated in neuropathic pain. Drug discovery efforts targeting have been unsuccessful largely because of the difficulty engineering specificity and selectivity. Here, we describe for first time generation panel diverse monoclonal antibodies (mAbs) to human mouse P2X4, capable both positive negative modulation function. The affinity-optimised anti-P2X4 mAb IgG#151-LO showed exquisite selectivity induced potent complete block currents....
C5a is a potent anaphylatoxin that modulates inflammation through the C5aR1 and C5aR2 receptors. The molecular interactions between C5a-C5aR1 receptor are well defined, whereas C5a-C5aR2 poorly understood. Here, we describe generation of human antibody, MEDI7814, neutralizes C5adesArg binding to receptors, without affecting complement-mediated bacterial cell killing. Unlike other anti-C5a mAbs described, this antibody has been shown inhibit effects by blocking both crystal structure in...
Abstract Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor (serpin) that regulates fibrinolysis, cell adhesion and motility via its interactions with plasminogen activators vitronectin. PAI-1 has been shown to play role in number of diverse pathologies including cardiovascular diseases, obesity cancer therefore an attractive therapeutic target. However the multiple patho-physiological roles PAI-1, understanding relative contributions these any one disease setting, make...
Significance Insertion/deletion (InDel) mutations play key roles in genome and protein evolution. Despite their prominence evolutionary history, the potential of InDels for changing function engineering by directed evolution remains unexplored. Instead point mutagenesis is widely used. Here we create antibody libraries containing demonstrate that affinity maturation can be achieved this way, establishing an alternative to mutation strategies employed all previous vitro selections. These...
Abstract The aminotransferase (BtrR), which is involved in the biosynthesis of butirosin, a 2‐deoxystreptamine (2‐DOS)‐containing aminoglycoside antibiotic produced by Bacillus circulans, catalyses pyridoxal phosphate (PLP)‐dependent transamination reaction both 2‐deoxy‐ scyllo ‐inosose to ‐inosamine and amino‐dideoxy‐ 2‐DOS. high‐resolution crystal structures PLP‐ PMP‐bound forms BtrR from B. circulans were solved at resolutions 2.1 Å 1.7 with R factor / free values 17.4/20.6 19.9/21.9,...
Monoclonal antibodies are a commercially successful class of drug molecules and there now growing number coupled to toxic payloads, which demonstrate clinical efficacy. Determining the precise epitope therapeutic is beneficial in understanding structure–activity relationship drug, but many cases not done due structural complexity of, particular, conformational protein epitopes. Using immunotoxin CAT-8015 as test case, this study demonstrates that new methodology, hybrid β-lactamase display,...
High levels of protein expression are key to the successful development and manufacture a therapeutic antibody. Here, we describe two related antibodies, Ab001 Ab008, where shows markedly lower level relative Ab008 when stably expressed in Chinese hamster ovary cells. We use single-gene vectors structural analysis show that reduced titer is associated with VL CDR2 Ab001. adopted approaches improve First, used mutagenesis change single amino-acid residues back equivalent but this resulted...
To aid in the discovery and development of peptides proteins as therapeutic agents, a virtual screen can be used to predict trends direct workflow. We have developed Parasol Protocol, dynamic method implemented using AMBER MD package, for computational site-directed mutagenesis. This tool mutate between any pair amino acids computationally expedient, automated manner. demonstrate potential this methodology, we employed protocol investigate test case involving stapled peptides, demonstrated...