A5007877117- interferon and immune responses
- Cytokine Signaling Pathways and Interactions
- Inflammation biomarkers and pathways
- Cancer Immunotherapy and Biomarkers
- Ubiquitin and proteasome pathways
- Immune Cell Function and Interaction
- Immunotherapy and Immune Responses
- Neuroblastoma Research and Treatments
- Immune cells in cancer
- Lung Cancer Research Studies
- T-cell and B-cell Immunology
- Cancer Research and Treatments
- Peptidase Inhibition and Analysis
- Ethics in Clinical Research
- NF-κB Signaling Pathways
- Pharmaceutical industry and healthcare
- CAR-T cell therapy research
- Advanced biosensing and bioanalysis techniques
- Cancer Mechanisms and Therapy
- RNA Interference and Gene Delivery
- Biomedical Ethics and Regulation
- Microscopic Colitis
- Glycosylation and Glycoproteins Research
- Cell death mechanisms and regulation
- Cancer-related gene regulation
Takeda (United States)
2016-2025
Millennium Engineering and Integration (United States)
2021
Stanford University
2006-2011
Center for Rheumatology
2008
Medical Publishing Insights & Practices (MPIP)—a partnership among pharmaceutical companies and the International Society for Publication Professionals—aims to identify ways improve transparency credibility in publishing results of industry sponsored research. This article provides guidance from MPIP on clinically relevant more informative adverse event reporting, previously identified by journal editors as a significant unmet need patient care increase publications. Our recommendations...
Activation of the stimulator interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding mechanism action in human tumors is key developing therapeutic combinations that activate effective innate immunity. Here, we report malignant pleural mesothelioma cells robustly express and are responsive agonist treatment ex vivo. Using dynamic single-cell RNA sequencing explants treated with a agonist, observed CXCR3...
Abstract Ubiquitination of eukaryotic proteins regulates a broad range cellular processes, including regulation T cell activation and tolerance. We have previously demonstrated that gene related to anergy in lymphocytes (GRAIL), ring finger ubiquitin E3 ligase, is required for the induction anergy; however, substrate(s) GRAIL ligase activity is/are unknown. In this study, we report novel prokaryotic system developed screen substrates ligases. Using screen, Rho guanine dissociation inhibitor...
The ubiquitin E3 ligase gene related to anergy in lymphocytes (GRAIL) (Rnf128) is a type 1 transmembrane protein that induces T cell through the ubiquitination activity of its cytosolic RING finger. GRAIL also contains an equally large luminal region consisting primarily uncharacterized protease-associated (PA) domain. Using two-hybrid technology screen for proteins bound PA domain we identified CD151, member tetraspanin family membrane proteins. luminal/extracellular portion both CD151 and...
Activation of naive T lymphocytes is regulated through a series discrete checkpoints that maintain unresponsiveness to self. During this multistep process, costimulatory interactions act as inducible signals allow APCs selectively mobilize cells against foreign Ags. In study, we provide evidence the anergy-associated E3 ubiquitin ligase GRAIL (gene related anergy in lymphocytes) regulates expression molecule CD40L on CD4 cells. Using its luminal protease-associated domain, binds...
The tumor microenvironment (TME) in solid tumors contains myeloid cells that modulate local immune activity. STING signaling activation these enhances type I interferon (IFN) production, inducing an innate response mobilizes adaptive immunity and reprograms immunosuppressive populations to drive antitumor immunity. Here, we generated TAK-500, cell directed antibody drug conjugate (iADC), deliver a agonist CCR2+ human enhanced activity relative non-targeted agonists. Preclinically, TAK-500...
<p>Conjugation enhances potency compared with dazostinag through selective delivery to immune cells and improved PK. <b>A,</b> Structure of STING agonist TAK-500. <b>B,</b> Receptor occupancy (RO) assessment in human (left) murine (right) whole blood; EC<sub>50</sub> values 1.757 ± 0.524 1.386 1.151 µg/mL, respectively. Data shown represent the mean five donors from a single experiment. Experiment was performed at least twice consistent results...
<p>mTAK-500 shows durable enhanced efficacy and increased activation of innate adaptive immune responses when combined with anti–PD-1 or radiation. <b>A,</b> Antitumor effect mTAK-500 without αPD-1 therapy in C57BL/6 mice bearing MC38 tumors. Data shown represent the MTVs from eight per group. <b>B,</b> Evaluation immune-cell blood, lymph nodes, tumors tumor–bearing treated αPD-1. mean five group timepoint. <b>C,</b> 8 Gy focal radiation treatment...
<p>Evaluation of CCR2 expression levels and the impact TAK-500 treatment on T NK cell activation cytokine production in vitro.</p>
<p>Gating Strategy for Murine Macrophage/Dendritic Cell Panel</p>
<p>Gating Strategy for Evaluating T and NK Cell Activation</p>
<p>TAK-500 drives activation of monocytes and induces type-I IFN response <i>in vitro.</i><b>A,</b> Evaluation classical monocyte frequency (left), (middle), CCR2 expression (right) in PBMCs treated with TAK-500 for 24 hours. Data shown indicate the results five human donors from a single experiment. Experiment was performed at least twice consistent between independent replicates. <b>B,</b> Cytokine induction whole blood after treatment represent...
<p>Evaluation of CCR2 expression in intratumoral mMDSCs within syngeneic tumor bearing mouse models via flow cytometry correlated with the antitumor response those to mTAK-500. Models evaluated include C1498, B16F10, MC38, H22, CT26, JC, and Panc02.</p>
<p>Analysis of TAK-500 iADC.</p>
<p>Binding Curves Demonstrate Species Specificity for antibody portions of TAK-500 and mTAK-500</p>
<p>Gating Strategy for Receptor Occupancy in Human Whole Blood</p>