Tiquella Hatten
A5066205474- interferon and immune responses
- Cytokine Signaling Pathways and Interactions
- Immune cells in cancer
- Cancer Immunotherapy and Biomarkers
- Monoclonal and Polyclonal Antibodies Research
- Toxoplasma gondii Research Studies
- Ubiquitin and proteasome pathways
- HER2/EGFR in Cancer Research
- Cancer therapeutics and mechanisms
- Immunotherapy and Immune Responses
- Inflammation biomarkers and pathways
- Cancer, Hypoxia, and Metabolism
- Immune Response and Inflammation
Takeda (United States)
2020-2025
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...
Objectives: Certain immune cells in the tumor microenvironment (TME), such as myeloid-derived suppressor cells, regulatory T and type II macrophages, are considered immunosuppressive. Tumors with high levels of infiltration by these associated poor patient prognosis resistance to therapy. Thus, modulating one or more immunosuppressive (IICs) TME may release an brake on cytotoxic effector enabling them kill cancer cells. A biologic, targeting a surface antigen specific IIC types, therefore...
<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>
<p>Gating Strategy for Receptor Occupancy in Murine Whole Blood</p>
<p>Complete loss of receptor-mediated TAK-500 and mTAK-500 activity observed on human murine peripheral blood monocytes lacking cell surface CCR2 expression</p>
<p>Gating Strategy for Monocyte Activation in PBMCs</p>