A5007007815- Monoclonal and Polyclonal Antibodies Research
- Cancer, Stress, Anesthesia, and Immune Response
- Protein purification and stability
- Cancer, Hypoxia, and Metabolism
- Melanoma and MAPK Pathways
- T-cell and B-cell Immunology
- Immunotherapy and Immune Responses
- Cytokine Signaling Pathways and Interactions
- interferon and immune responses
- Microfluidic and Capillary Electrophoresis Applications
- Cancer Immunotherapy and Biomarkers
- Cell Adhesion Molecules Research
- Immune Cell Function and Interaction
- Psoriasis: Treatment and Pathogenesis
- NF-κB Signaling Pathways
- Synthesis of Tetrazole Derivatives
- Advanced Biosensing Techniques and Applications
- Receptor Mechanisms and Signaling
- Computational Drug Discovery Methods
- Cancer Mechanisms and Therapy
- Cell death mechanisms and regulation
- Synthesis and biological activity
- Biosimilars and Bioanalytical Methods
- Quinazolinone synthesis and applications
- Glycosylation and Glycoproteins Research
Boehringer Ingelheim (United States)
2011-2023
Boehringer Ingelheim (Spain)
2021
Boehringer Ingelheim (United Kingdom)
2017
Institute of Chemical Technology
2015
Amgen (United States)
2015
University of Delaware
2015
Eli Lilly (United States)
2015
Boehringer Ingelheim (Taiwan)
2015
Hexal (Germany)
2015
University of New Hampshire
2015
The acquisition of reliable kinetic parameters for the characterization biomolecular interactions is an important component drug discovery and development process. While several benchmark studies have explored variability rate constants obtained from multiple laboratories biosensors, a direct comparison these instruments' performance has not been undertaken, systematic factors contributing to data systems discussed. To address questions, panel ten high-affinity monoclonal antibodies was...
Herein, we describe the generation and characterization of BI 655066, a novel, highly potent neutralizing anti-interleukin-23 (IL23) monoclonal antibody in clinical development for autoimmune conditions, including psoriasis Crohn's disease. IL23 is key driver differentiation, maintenance, activity number immune cell subsets, T helper 17 (Th17) cells, which are believed to mediate pathogenesis several immune-mediated disorders. Thus, neutralization an attractive therapeutic approach....
Practically, IgG charge can contribute significantly to thermodynamic nonideality, and hence solubility viscosity. Biologically, isomers exhibit differences in clearance potency. It has been known since the 1930s that all immunoglobulins carry a weak negative physiological solvents. However, there no systematic exploration of this fundamental property. Accurate measurements have made using membrane confined electrophoresis two solvents (pH 5.0 pH 7.4) on panel twelve mAb IgGs, as well their...
Deficiency of interleukin (IL)-36 receptor antagonist (DITRA) syndrome is a rare autosomal recessive disease caused by mutations in IL36RN. IL-36R cell surface and member the IL1R family that involved inflammatory responses triggered skin other epithelial tissues. Accumulating evidence suggests signaling may play role pathogenesis psoriasis. Therapeutic intervention offers an innovative treatment paradigm for targeting cell-mediated diseases such as life-threatening psoriasis variant called...
Aggregation is mediated by local unfolding to allow aggregation “hot spot(s)” become solvent exposed and available associate with a hot spot on another partially unfolded protein. Historically, the of either crystallizable fragment (Fc) or antigen binding (Fab) regions given monoclonal antibody (MAb) has been implicated in aggregation, differing results across different proteins. The present work focuses separately quantifying kinetics isolated Fc, Fab, intact MAb as function pH under...
A novel inhibitor of p38 mitogen-activated protein kinase (p38), CMPD1, identified by high-throughput screening, is characterized herein. Unlike the inhibitors described previously, this substrate selective and noncompetitive with ATP. In steady-state kinetics experiments, CMPD1 was observed to prevent p38α-dependent phosphorylation (Kiapp = 330 nM) splice variant kinase-activated 2 (MK2a) that contains a docking domain for p38α p38β, but it did not ATF-2 > 20 μM). addition kinetic studies,...
We report on the structure-activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor p38alpha MAP kinase which has advanced into human clinical trials for treatment autoimmune diseases. Thermal denaturation was used to establish molecular binding affinities this class inhibitors. The tert-butyl group remains a critical element by occupying lipophilic domain in is exposed upon rearrangement activation...
The Fc (fragment crystallizable) is a common structural region in immunoglobulin gamma (IgG) proteins, IgG-based multi-specific platforms, and Fc-fusion platform technologies. Changes conformational stability, protein-protein interactions, aggregation of NS0-produced human Fc1 were quantified experimentally as function pH (4 to 6) temperature (30 77°C), using combination differential scanning calorimetry, laser light scattering, size-exclusion chromatography, capillary electrophoresis. was...
CX3CR1 has been identified as a highly attractive target for several therapeutic interventions. Despite this potential, no potent antagonists, either small molecule or monoclonal antibody, have identified. Here we describe the lead finding and engineering approach that to identification of BI 655088, biotherapeutic antagonist CX3CR1. 655088 is that, upon dosing, significantly inhibits plaque progression in standard mouse model atherosclerosis. represents novel selective could reduce...
Weak protein-protein interactions may be important to binding cooperativity. A panel of seven fluorescently labeled tracer monoclonal IgG antibodies, differing in variable (V) and constant (C) region sequences, were sedimented increasing concentrations unlabeled IgGs identical, similar, different backgrounds. IgG::IgG attractive detected characterized by global analysis the hydrodynamic nonideality coefficient, k
Activation of TRAILR2 has emerged as an important therapeutic concept in cancer treatment. agonistic molecules have only had limited clinical success, to date, due either lack efficacy or hepatotoxicity. BI 905711 is a novel tetravalent bispecific antibody targeting both and CDH17 represents liver-sparing agonist specifically designed overcome the disadvantages previous strategies. Here, we show that effectively triggered apoptosis broad panel CDH17-positive colorectal tumor cells vitro....
The p38 mitogen-activated protein kinase (p38) pathway is required for the production of proinflammatory cytokines (TNFalpha and IL-1) that mediate chronic inflammatory phases several autoimmune diseases. Potent inhibitors, such as slow tight-binding inhibitor BIRB 796, have recently been reported to block TNFalpha IL-1beta. Here we analyze downstream signaling complexes molecular mechanisms, provide new insight into function development novel inhibitors pathway. Catalysis, functions,...
Antibodies with pH-dependent binding to both target antigens and neonatal Fc receptor (FcRn) provide an alternative tool conventional neutralizing antibodies, particularly for therapies where reduction in antigen level is challenging due high burden. However, the requirements optimal kinetic framework extent of pH dependence these antibodies maximize clearance from circulation are not well understood. We have identified a series naturally-occurring affinity properties. By vivo studies...
Abstract Despite some impressive clinical results with immune checkpoint inhibitors, the majority of patients cancer do not respond to these agents, in part due immunosuppressive mechanisms tumor microenvironment. High levels adenosine tumors can suppress cell function, and strategies target pathway involved its production have emerged. CD73 is a key enzyme production. This led us identify novel humanized antagonistic antibody, mAb19, distinct binding properties. mAb19 potently inhibits...
It has been reported that the diaryl urea class of p38α inhibitors binds to p38 map kinase with both high affinity and slow binding kinetics (Pargellis et al. Nat. Struct. Biol. 2002, 9, 268−272). The this is believed be result an allosteric pocket adjacent active site. use traditional kinetic equilibrium methods measure compounds created many challenges for determination structure-activity relationships (SAR). thermal denaturation method provides a means measuring high-affinity...
Label-free optical biosensors are powerful tools in drug discovery for the characterization of biomolecular interactions. In this study, we describe use four routinely used biosensor platforms our laboratory to evaluate binding affinity and kinetics ten high-affinity monoclonal antibodies (mAbs) against human proprotein convertase subtilisin kexin type 9 (PCSK9). While both Biacore T100 ProteOn XPR36 derived from well-established Surface Plasmon Resonance (SPR) technology, former has flow...
Purpose: Semaphorin 3A (Sema3A) is an axonal guidance molecule that inhibits angiogenesis by vasorepulsion and blocks revascularization in the ischemic retina. BI-X intravitreal anti-Sema3A agent under clinical investigation patients with proliferative diabetic retinopathy (PDR) macular ischemia (DMI). Methods: Surface plasmon resonance was used to determine binding affinity of human murine Sema3A. In vitro, retinal microvascular endothelial cells (HRMECs) were assess effects on cell...