A5068861651- Phagocytosis and Immune Regulation
- Cell Adhesion Molecules Research
- Pancreatitis Pathology and Treatment
- Erythrocyte Function and Pathophysiology
- Cell death mechanisms and regulation
- Caveolin-1 and cellular processes
- Hippo pathway signaling and YAP/TAZ
- Cellular Mechanics and Interactions
- RNA Research and Splicing
- Angiogenesis and VEGF in Cancer
- interferon and immune responses
- Monoclonal and Polyclonal Antibodies Research
- Melanoma and MAPK Pathways
- Cancer-related Molecular Pathways
- Complement system in diseases
- Advanced Breast Cancer Therapies
- Protease and Inhibitor Mechanisms
- Lung Cancer Treatments and Mutations
- Immune cells in cancer
- Adenosine and Purinergic Signaling
- Cancer Mechanisms and Therapy
- Neuroblastoma Research and Treatments
- Molecular Biology Techniques and Applications
- Hepatitis C virus research
- Calpain Protease Function and Regulation
Bristol-Myers Squibb (United States)
2021-2024
University of California, San Diego
2006-2020
Moores Cancer Center
2006
Scripps Research Institute
2004-2005
Hepatitis C virus (HCV) infection is one of the major causes chronic hepatitis, liver cirrhosis, which subsequently leads to hepatocellular carcinoma (HCC). The overexpression angiogenic factors has been demonstrated in HCC. In this study, we investigated potential HCV gene expression inducing angiogenesis. Our results show that stabilization hypoxia-inducible factor 1alpha (HIF-1alpha). We further was mediated via oxidative stress induced by expression. activation NF-kappaB, STAT-3,...
Caspase-8 is a proapoptotic protease that suppresses neuroblastoma metastasis by inducing programmed cell death. Paradoxically, caspase-8 can also promote migration among nonapoptotic cells; here, we show when apoptosis compromised. Migration enhanced recruitment to the cellular machinery following integrin ligation. catalytic activity not required for caspase-8-enhanced migration; rather, interacts with multiprotein complex include focal adhesion kinase and calpain 2 (CPN2), enhancing...
In normal cells, binding of the transmembrane protein CD47 to signal regulatory protein-α (SIRPα) on macrophages induces an antiphagocytic signal. Tumor cells hijack this pathway and overexpress evade immune destruction. Macrophage antitumor activity can be restored by simultaneously blocking CD47-SIRPα signaling axis inducing a prophagocytic via tumor-opsonizing antibodies. We identified novel, fully human mAb (BMS-986351) that binds SIRPα with high affinity. BMS-986351 demonstrated broad...
CD47 is the only 5-transmembrane (5-TM) spanning receptor of immune system. Its extracellular domain (ECD) a cell surface marker self that binds SIRPα and inhibits macrophage phagocytosis, cancer immuno-therapy approaches in clinical trials are focused on blocking CD47/SIRPα interaction. We present crystal structure full length bound to function-blocking antibody B6H12. ECD tethered TM via six-residue peptide linker (114RVVSWF119) forms an extended loop (SWF loop), with fundamental role...
The growth of new blood vessels from pre-existing vascular elements, or angiogenesis, involves coordinated signals to the adhesion, migration, and survival machinery within target endothelial cell. Agents that interfere with any these processes may therefore influence angiogenesis. Here, we describe angiogenesis assay in chick chorioallantoic membrane (CAM). CAM is a useful tool studying because 1) it amenable both intravascular topical administration study agents, 2) relatively rapid assay,...
Abstract Historically, phenotypic-based drug discovery has yielded a high percentage of novel drugs while uncovering new tumor biology. CC-671 was discovered using phenotypic screen for compounds that preferentially induced apoptosis in triple-negative breast cancer cell lines sparing luminal lines. Detailed vitro kinase profiling shows potently and selectively inhibits two kinases—TTK CLK2. Cellular mechanism action studies demonstrate the phosphorylation KNL1 SRp75, direct TTK CLK2...
Despite tyrosine sulfation being a relatively common post-translational modification (PTM) on the secreted proteins of higher eukaryotic organisms, there have been surprisingly few reports this occurring in recombinant monoclonal antibodies (mAbs) expressed by mammalian cell lines and even less information regarding its potential impact mAb efficacy stability. This discrepancy is likely due to extreme lability using many mass spectrometry methods typically used within biopharmaceutical...
ABSTRACT Chlamydia trachomatis infection is the most common cause of bacterial sexually transmitted diseases. Infection urogenital tract by C. causes chronic inflammation and related clinical complications. Unlike other invasive bacteria that induce a rapid cytokine/chemokine production, chlamydial induces delayed inflammatory response proinflammatory chemokine production dependent on growth. We present data here to show lipid metabolism required for growth contributes -induced production....
Cluster of differentiation 47 (CD47) is a transmembrane protein highly expressed in tumor cells that interacts with signal regulatory alpha (SIRPα) and triggers "don't eat me" to the macrophage, inhibiting phagocytosis enabling escape from immunosurveillance. The CD47-SIRPα axis has become an important target for cancer immunotherapy. To date, advancement CD47-targeted modalities hindered by ubiquitous expression target, often leading rapid drug elimination hematologic toxicity including...
<p>Effect of BMS-986351, alone or in combination with rituximab, on the proportion phagocytic macrophages ABC (<b>A</b>) and GCB (<b>B</b>) cell lines. ABC, activated B cell; GCB, germinal center cell.</p>
<p>Gene expression data from TCGA across four indications (COAD = colon adenocarcinoma, DLBC diffuse large B-cell lymphoma, HNSC head and neck cancer, READ rectal adenocarcinoma) with each point one patient units shown as the log<sub>2</sub>(normalized counts+1). The left panel of (<b>A</b>) shows that absolute level SIRPα (<i>x</i>-axis) is comparable to often correlated CD163 gene (<i>y</i>-axis). right a representative marker myeloid...
<p>Modeling of interactions between the CD47 F-G loop and SIRPα IgV domain, with position ESE haplotype residues highlighted (magenta).</p>
<div>Abstract<p>In normal cells, binding of the transmembrane protein CD47 to signal regulatory protein-α (SIRPα) on macrophages induces an antiphagocytic signal. Tumor cells hijack this pathway and overexpress evade immune destruction. Macrophage antitumor activity can be restored by simultaneously blocking CD47-SIRPα signaling axis inducing a prophagocytic via tumor-opsonizing antibodies. We identified novel, fully human mAb (BMS-986351) that binds SIRPα with high affinity....
<p>Cross-reactivity of BMS-986351 in human (<b>A</b>), cynomolgus monkey (<b>B</b>), rat (<b>C</b>), and mouse (<b>D</b>). <b>E,</b> Immunophenotyping by multiparameter flow cytometry monkeys shows that most CD14-positive cells (monocytes) also bind BMS-986351. <b>F,</b> Proportion live expressing CD14 humans monkeys. <b>G,</b> Binding specific lymphoid myeloid cell subsets. Pharmacokinetic profiles...
<p>Cross-reactivity of BMS-986351 in human (<b>A</b>), cynomolgus monkey (<b>B</b>), rat (<b>C</b>), and mouse (<b>D</b>). <b>E,</b> Immunophenotyping by multiparameter flow cytometry monkeys shows that most CD14-positive cells (monocytes) also bind BMS-986351. <b>F,</b> Proportion live expressing CD14 humans monkeys. <b>G,</b> Binding specific lymphoid myeloid cell subsets. Pharmacokinetic profiles...
<p>Baseline CD47 expression by flow cytometry in colorectal cancer cell lines (A) and DLBCL (B).</p>
<p>Enhanced phagocytosis in OCI-Ly3 cells is achieved when BMS-986351 combined with rituximab.</p>
<p>Enhanced phagocytosis in OCI-Ly3 cells is achieved when BMS-986351 combined with rituximab.</p>
<p>Lack of BMS-986351 effect on NK-mediated ADCC tumors cells (A), autologous normal monocytes and unactivated CD4 (B), ADCP activity T (C).</p>