A5022926968- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- Protein purification and stability
- RNA and protein synthesis mechanisms
- Toxin Mechanisms and Immunotoxins
- T-cell and B-cell Immunology
- Ferroptosis and cancer prognosis
- CAR-T cell therapy research
- Protein Structure and Dynamics
- Immunotherapy and Immune Responses
- Biochemical and Structural Characterization
- Immunodeficiency and Autoimmune Disorders
- Ion Transport and Channel Regulation
- Enzyme Structure and Function
- Psoriasis: Treatment and Pathogenesis
- Peptidase Inhibition and Analysis
- Advanced Biosensing Techniques and Applications
- Alzheimer's disease research and treatments
- Immune Response and Inflammation
- Cancer-related molecular mechanisms research
- Circular RNAs in diseases
- Ion Channels and Receptors
- Ubiquitin and proteasome pathways
- Chronic Lymphocytic Leukemia Research
- Ion channel regulation and function
Janssen (United States)
2013-2024
Zhongshan People's Hospital
2023
Springhouse
2021
Roche (Switzerland)
2018
Ludwig-Maximilians-Universität München
2018
JK Research (United States)
2017-2018
Janssen (Switzerland)
2015
Janssen (Belgium)
2012-2014
Johnson & Johnson (United States)
2004-2014
The University of Texas Medical Branch at Galveston
2004
Durable influenza protection Vaccines are indispensable for the control and prevention of influenza, but there several challenges to efficacy. Some individuals respond poorly vaccination, virus variation makes targeting optimal antigens difficult. Broadly neutralizing antibodies one solution, they have their own pitfalls, including limited cross-reactivity both A B strains need repeated injections. Now, Laursen et al. developed multidomain with breadth potency. Administered intranasally mice...
Protein aggregation is of great concern to pharmaceutical formulations and has been implicated in several diseases. We engineered an anti-IL-13 monoclonal antibody CNTO607 for improved solubility. Three structure-based engineering approaches were employed this study: (i) modifying the isoelectric point (pI), (ii) decreasing overall surface hydrophobicity (iii) re-introducing N-linked carbohydrate moiety within a complementarity-determining region (CDR) sequence. A mutant was identified with...
ABSTRACT To assess the state of art in antibody 3D modeling, 11 unpublished high‐resolution x‐ray Fab crystal structures from diverse species and covering a wide range antigen‐binding site conformations were used as benchmark to compare Fv models generated by seven structure prediction methodologies. The participants included: Accerlys Inc, Chemical Computer Group (CCG), Schrodinger, Jeff Gray's lab at John Hopkins University, Macromoltek, Astellas Pharma/Osaka University Prediction...
A blinded study to assess the state of art in three-dimensional structure modeling variable region (Fv) antibodies was conducted. Nine unpublished high-resolution x-ray Fab crystal structures covering a wide range antigen-binding site conformations were used as benchmark compare Fv models generated by four prediction methodologies. The methodologies included two homology strategies independently developed CCG (Chemical Computer Group) and Accerlys Inc, fully automated antibody servers: PIGS...
Microtubule-associated protein tau becomes abnormally phosphorylated in Alzheimer's disease and other tauopathies forms aggregates of paired helical filaments (PHF-tau). AT8 is a PHF-tau-specific monoclonal antibody that commonly used marker neuropathology because its recognition tau. Previous reports described the epitope to include pS202/pT205. Our studies support extend previous findings by also identifying pS208 as part binding epitope. We characterized phosphoepitope through both...
The use of consensus design to produce stable proteins has been applied numerous structures and classes proteins. Here, we describe the engineering novel FN3 domains from two different proteins, namely human fibronectin tenascin-C, as potential alternative scaffold biotherapeutics. resulting were found be robustly expressed in Escherichia coli, soluble highly stable, with melting temperatures 89 78°C, respectively. X-ray crystallography was used confirm that approach led a structure...
Some antibodies have a tendency to self-associate leading precipitation at relatively low concentrations. CNTO607, monoclonal antibody, precipitates irreversibly in phosphate-buffered saline concentrations above 13 mg/ml. Previous mutagenesis work based on the Fab crystal structure pinpointed three residue fragment heavy chain CDR-3, (99)FHW(100a), as an aggregation epitope that is anchored by two salt bridges. Biophysical characterization of variants reveals F99 and W100a, but not H100,...
To assess the state-of-the-art in antibody structure modeling, a blinded study was conducted. Eleven unpublished Fab crystal structures were used as benchmark to compare Fv models generated by seven prediction methodologies. In first round, each participant submitted three non-ranked complete for target. second CDR-H3 modeling performed context of correct environment provided with removed. this report we describe reference and present our assessment models. Some essential sources errors...
Treating and preventing infections by antimicrobial-resistant bacterial pathogens is a worldwide problem. Pathogens such as Staphylococcus aureus produce an array of virulence determinants, making it difficult to identify single targets for the development vaccines or monoclonal therapies. We described human-derived anti-S. antibody (mAb)-centyrin fusion protein ("mAbtyrin") that simultaneously multiple adhesins, resists proteolysis protease GluV8, avoids Fc engagement S. IgG-binding...
The Protein Data Bank (PDB) is the global archive for structural information on macromolecules, and a popular resource researchers, teachers, students, amassing more than one million unique users each year. Crystallographic structure models in PDB (more 100,000 entries) are optimized against crystal diffraction data geometrical restraints. This process of crystallographic refinement typically ignored hydrogen bond (H-bond) distances as source information. However, H-bond restraints can...
To support antibody therapeutic development, the crystal structures of a set 16 germline variants composed 4 different kappa light chains paired with heavy have been determined. All four antigen-binding fragments (Fabs) same complementarity-determining region (CDR) H3 that was reported in an earlier Fab structure. The structure analyses include comparisons overall structures, canonical CDRs and VH:VL packing interactions. CDR conformations for most part are tightly clustered, especially ones...
Single-chain fragment variable (scFv) domains play an important role in antibody-based therapeutic modalities, such as bispecifics, multispecifics and chimeric antigen receptor T cells or natural killer cells. However, scFv exhibit lower stability increased risk of aggregation due to transient dissociation ("breathing") inter-molecular reassociation the two (VL VH). We designed a novel strategy, referred stapling, that introduces disulfide bonds between linker minimize breathing. named...
Engineering of fragment crystallizable (Fc) domains therapeutic immunoglobulin (IgG) antibodies to eliminate their immune effector functions while retaining other Fc characteristics has numerous applications, including blocking antigens on gamma (Fcγ) receptor-expressing cells. We previously reported a human IgG2 variant termed IgG2σ with barely detectable activity in antibody-dependent cellular cytotoxicity, phagocytosis, complement activity, and Fcγ receptor binding assays. Here, we extend...
Abstract CD19 is a transmembrane protein expressed on malignant B cells, but not in other lineages or tissues, which makes it an attractive target for monoclonal antibody‐mediated immunotherapy. Anti‐CD19 antibody B43 was utilized bispecific T‐cell engager (BiTE) blinatumomab that demonstrated potency the treatment of relapsed acute lymphoblastic leukemia. To gain insight into mechanism action antibody, crystal structure Fab determined complex with and unbound form. The revealed binding...
Immunostimulatory receptors belonging to the tumor necrosis factor receptor (TNFR) superfamily are emerging as promising targets for cancer immunotherapies. To optimize agonism of therapeutic antibodies these receptors, Fc engineering was applied facilitate clustering cell surface TNFRs activate downstream signaling pathways. One strategy is identify mutations that antibody multimerization on directly. From analyses crystal packing IgG1 structures, we identified a novel set mutations, T437R...
Fragment crystallizable (Fc) region of immunoglobulin G (IgG) antibody binds to specific Fc receptors (FcγRs) control effector functions. Currently, engineered Fc-FcγR interactions are validated with a static conformation derived from the crystal structure. However, computational evidence suggests that conformational variability Fcs plays an important role in receptor recognition. Here we elucidate flexibility IgG1, IgG2, and IgG1 mutations (M255Y/S257T/T259E) solution by small-angle X-ray...
Abstract Acid-sensing ion channels (ASICs) are proton-gated cation critical for neuronal functions. Studies of ASIC1, a major ASIC isoform and proton sensor, have identified acidic pocket, an extracellular region enriched in residues, as key participant channel gating. While binding to this by the venom peptide psalmotoxin modulates gating, molecular structural mechanisms gating modulation small molecules poorly understood. Here, combining functional, crystallographic, computational...
Gas6 (growth-arrest-specific gene 6) is a vitamin K-dependent protein known to activate the Axl family of receptor tyrosine kinases. It an important regulator thrombosis and many other biological functions. The C-terminus binds receptors consists two laminin-like globular domains LG1 LG2. has been reported that Ca2+-binding site at junction LG2 hydrophobic patch domain are for binding [Sasaki, Knyazev, Cheburkin, Gohring, Tisi, Ullrich, Timpl Hohenester (2002) J. Biol. Chem. 277,...