Selective STING Activation in Intratumoral Myeloid Cells via CCR2-Directed Antibody Drug Conjugate TAK-500.

IF 8.1 1区 医学 Q1 IMMUNOLOGY Cancer immunology research Pub Date : 2025-02-07 DOI:10.1158/2326-6066.CIR-24-0103
Vicky A Appleman, Atsushi Matsuda, Michelle L Ganno, Dong Mei Zhang, Emily Rosentrater, Angel E Maldonado Lopez, Angelo Porciuncula, Tiquella Hatten, Camilla L Christensen, Samantha A Merrigan, Hong Myung Lee, Min Young Lee, Charlotte I Wang, Linlin Dong, Jian Huang, Natasha Iartchouk, Jianing Wang, He Xu, Tomoki Yoneyama, Konstantin I Piatkov, Satyajeet Haridas, Carole E Harbison, Richard C Gregory, Alexander Parent, Neil Lineberry, Chris Arendt, Kurt A Schalper, Adnan O Abu-Yousif
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引用次数: 0

Abstract

The tumor microenvironment (TME) in solid tumors contains myeloid cells that modulate local immune activity. STING signaling activation in these myeloid cells enhances local type I interferon (IFN) production, inducing an innate immune response that mobilizes adaptive immunity and reprograms immunosuppressive myeloid populations to drive antitumor immunity. Here, we generated TAK-500, an immune cell directed antibody drug conjugate (iADC), to deliver a STING agonist to CCR2+ human cells and drive enhanced antitumor activity relative to non-targeted STING agonists. Preclinically, TAK-500 triggered dose-dependent innate immune activation in vitro. In addition, a murine TAK-500 iADC surrogate enhanced innate and adaptive immune responses both in vitro and in murine tumor models. Spatially resolved analysis of CCR2 and immune cell markers in the TME of >1,000 primary human tumors showed the CCR2 protein was predominantly expressed in intratumoral myeloid cells. Collectively, these data highlight the clinical potential of delivering a STING agonist to CCR2+ cells.

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Cancer immunology research
Cancer immunology research ONCOLOGY-IMMUNOLOGY
CiteScore
15.60
自引率
1.00%
发文量
260
期刊介绍: Cancer Immunology Research publishes exceptional original articles showcasing significant breakthroughs across the spectrum of cancer immunology. From fundamental inquiries into host-tumor interactions to developmental therapeutics, early translational studies, and comprehensive analyses of late-stage clinical trials, the journal provides a comprehensive view of the discipline. In addition to original research, the journal features reviews and opinion pieces of broad significance, fostering cross-disciplinary collaboration within the cancer research community. Serving as a premier resource for immunology knowledge in cancer research, the journal drives deeper insights into the host-tumor relationship, potent cancer treatments, and enhanced clinical outcomes. Key areas of interest include endogenous antitumor immunity, tumor-promoting inflammation, cancer antigens, vaccines, antibodies, cellular therapy, cytokines, immune regulation, immune suppression, immunomodulatory effects of cancer treatment, emerging technologies, and insightful clinical investigations with immunological implications.
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