A5032883287- Monoclonal and Polyclonal Antibodies Research
- Glycosylation and Glycoproteins Research
- Amino Acid Enzymes and Metabolism
- CAR-T cell therapy research
- Protein purification and stability
- Biosimilars and Bioanalytical Methods
- Carbohydrate Chemistry and Synthesis
- T-cell and B-cell Immunology
- Galectins and Cancer Biology
- Chronic Lymphocytic Leukemia Research
- Bacterial Genetics and Biotechnology
- Cell Adhesion Molecules Research
- Enzyme Structure and Function
- S100 Proteins and Annexins
- Glioma Diagnosis and Treatment
- Cancer-related Molecular Pathways
- Lipid Membrane Structure and Behavior
- Advanced Drug Delivery Systems
- HER2/EGFR in Cancer Research
- Diet, Metabolism, and Disease
- Protease and Inhibitor Mechanisms
- RNA and protein synthesis mechanisms
- Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- RNA Interference and Gene Delivery
- Porphyrin Metabolism and Disorders
Janssen (United States)
2021-2022
AstraZeneca (United States)
2019-2020
The University of Texas at Austin
2009-2012
University of Wisconsin–Madison
2005-2009
University of Notre Dame
2005
University of Missouri
2003
The N-linked glycan of immunoglobulin G (IgG) is indispensable for the interaction Fc domain with Fcγ receptors on effector cells and clearance target via antibody dependent cell-mediated cytotoxicity (ADCC). Escherichia coli expressed, aglycosylated domains bind FcγRs poorly cannot elicit ADCC. Using a novel bacterial display/flow cytometric library screening system we isolated variants that to FcγRI (CD64) nanomolar affinity. Binding was critically amino acid substitutions (E382V, lesser...
Binding of the Fc domain Immunoglobulin G (IgG) to Fcγ receptors on leukocytes can initiate a series signaling events resulting in antibody-dependent cell-mediated cytotoxicity (ADCC) and other important immune responses. domains lacking glycosylation at N297 have greatly diminished receptor binding lack ability robust ADCC response. Earlier structural studies with either full length or truncated glycans led proposal that these stabilize an "open" conformation recognized by receptors. We...
Monovalent bispecific IgGs cater to a distinct set of mechanisms action but are difficult engineer and manufacture because complexities associated with correct heavy light chain pairing. We have created novel design, "DuetMab," for efficient production these molecules. The platform uses knobs-into-holes (KIH) technology heterodimerization 2 chains increases the efficiency cognate pairing by replacing native disulfide bond in one CH1-CL interfaces an engineered bond. Using two pairs...
Efficacious use of therapeutic gene delivery via nanoparticles is hampered by the challenges associated with targeted to tissues interest. Systemic administration lipid nanoparticle (LNP)-encapsulated mRNA leads a protein expressed predominantly in liver and spleen. Here, LNP encapsulating was covalently conjugated an antibody, specifically binding plasmalemma vesicle-associated (PV1) as means target lung tissue. PV1-targeted LNPs demonstrated significantly increased lungs 40-fold...
The C-type lectin dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is found on the surface of cells. It can mediate between cells and T lymphocytes facilitate antigen capture presentation. Many pathogens exploit DC-SIGN binding for nefarious purposes. For example, dissemination viruses, like HIV-1. Alternatively, some microbes (e.g., Mycobacterium tuberculosis) use their ability to interact with evade immune detection. diverse roles attributed provide...
D-Glucose/D-Galactose-binding protein (GGBP) mediates chemotaxis toward and active transport of glucose galactose in a number bacterial species. GGBP, like other periplasmic binding proteins, can exist open (ligand-free) closed (ligand-bound) states. We report 0.92 angstroms resolution structure GGBP from Escherichia coli the glucose-bound state first an open, unbound form (at 1.55 resolution). These structures vary angle between two structural domains; observed difference 31 degrees arises...
Fc effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis (ADCP) are crucial to the efficacy of many antibody therapeutics. In addition IgG, antibodies IgA isotype can also promote cell killing through engagement myeloid lineage cells via interactions between IgA-Fc FcαRI (CD89). Herein, we describe a unique, tandem IgG1/IgA2 format in context trastuzumab variable domain that exhibits enhanced ADCC ADCP capabilities. The retains IgG1 FcγR binding...
Immunoglobulin E (IgE) plays a key role in allergic asthma and is clinically validated target for monoclonal antibodies. Therapeutic anti-IgE antibodies block the interaction between IgE Fc epsilon (Fcε) receptor, which eliminates or minimizes phenotype but does not typically curtail ongoing production of by B cells. We generated high-affinity (MEDI4212) that have potential to both neutralize soluble eliminate IgE-expressing B-cells through antibody-dependent cell-mediated cytotoxicity....
Antibody-mediated immune effector functions play an essential role in the anti-tumor efficacy of many therapeutic mAbs. While much effort to improve potency has focused on augmenting interaction between antibody-Fc and activating Fc-receptors expressed cells, antibody binding interactions with target antigen remains poorly understood. We show that intrinsic affinity clearly influences extent efficiency Fc-mediated mechanisms, report pivotal valence ability regulate functions. More...
Objective Immune complexes (ICs) play a critical role in the pathology of autoimmune diseases. The aim this study was to generate and characterise first-in-class anti-FcγRIIA antibody (Ab) VIB9600 (previously known as MEDI9600) that blocks IgG immune complex-mediated cellular activation for clinical development. Methods humanised optimised from IV.3 Ab. Binding affinity specificity were determined by Biacore ELISA. Confocal microscopy, Flow Cytometry-based assays binding competition used...
Systemic administration of bio-therapeutics can result in only a fraction drug reaching targeted tissues, with the majority being distributed to tissues irrelevant drug's site action. Targeted delivery specific organs may allow for greater accumulation, better efficacy, and improved safety. We investigated how targeting plasmalemma vesicle-associated protein (PV1), found endothelial caveolae lungs kidneys, promote accumulation these organs. Using ex vivo fluorescence imaging, we show that...
Urate oxidase catalyzes the oxidation of urate without involvement any cofactors. The gene encoding from Bacillus subtilis has been cloned and expressed, enzyme was purified characterized. Formation dianion is believed to be a key step in oxidative reaction. Rapid-mixing chemical quench studies provide evidence that indeed an intermediate; at 15 °C forms within mixing time rapid-quench instrument, it disappears with rate constant 8 s-1. Steady-state kinetic indicate ionizable group on pK 6.4...
Many receptors undergo ligand-induced conformational changes to initiate signal transduction. Periplasmic binding proteins (PBPs) are bacterial that exhibit dramatic upon ligand binding. These mediate a wide variety of fundamental processes including transport, chemotaxis, and quorum sensing. Despite the importance these receptors, no PBP antagonists have been identified characterized. In this study, we identify 3-O-methyl-d-glucose as an antagonist glucose/galactose-binding protein...
Despite some clinical success with antibody-drug conjugates (ADCs) in patients solid tumors and hematological malignancies, improvements ADC design are still desirable due to the narrow therapeutic window of these compounds. Tumor-targeting antibody fragments have distinct advantages over monoclonal antibodies, including more rapid tumor accumulation enhanced penetration, but subject clearance. Half-life extension technologies such as PEGylation albumin-binding domains (ABDs) been widely...
IgG antibodies are abundantly present in the vasculature but to a much lesser extent mucosal tissues. This contrasts with of IgA and IgM isotype that at high concentration secretions due active delivery by polymeric Ig receptor (pIgR). is preferred for therapeutic mAb development its long serum half-life robust Fc-mediated effector function, it utilized treat diverse array diseases antigen targets located vasculature, serosa, mucosa. As targeting luminal side tissue lack an transport...
Bacterial chemotaxis is of medical, biological, and geological significance. Despite its importance, current measurements fail to account for the speciation chemical effector protonation state bacterial surface. We hypothesize that adsorption Ni2+ onto surface Escherichia coli can influence effective concentration therefore ability induce a repellent response. By measuring response at different pH values, on was assessed. In addition, we tested effect chelating agents. Our data indicate...
The signal transduction cascade responsible for bacterial chemotaxis serves as a model understanding how cells perceive and respond to their environments. Bacteria react chemotactic signals by migrating toward attractants away from repellents. Recent data suggest that the amplification of attractant stimuli depends on receptor collaboration: occupied unoccupied chemoreceptors act together relay signals. Attractant transmission, therefore, organization into lattice signaling proteins....
Antibodies have become the fastest growing class of biological therapeutics, in part due to their exquisite specificity and ability modulate protein-protein interactions with a high potency. The relatively large size bivalency antibodies, however, limits use as therapeutics certain circumstances. Antibody fragments, such single-chain variable fragments antigen binding-fragments, emerged viable alternatives, but without further modifications these monovalent formats reduced terminal serum...
The success of chimeric antigen receptor (CAR) T-cell therapy against hematologic malignancies has altered the treatment paradigm for patients with these diseases. Nevertheless, occurrence relapse due to escape or heterogeneous expression on tumors remains a challenge first-generation CAR therapies as only single tumor can be targeted. To address this limitation and add further level tunability control therapies, adapter universal approaches use soluble mediator bridge T cells cells. Adapter...
Annexin A1 (anxA1) is an immunomodulatory protein that has been proposed as a tumor vascular target for antitumor biologic agents, yet to date the expression of anxA1 in specific indications not systematically assessed. Attempts evaluate by immunohistochemistry are complicated lack available antibodies both and bind N-terminal–truncated form previously identified vasculature. To study pattern non–small-cell lung carcinoma (NSCLC), we isolated antibody capable binding 27-346 employed it...