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
{"title":"通过ccr2导向抗体药物偶联物TAK-500在瘤内髓细胞中选择性激活STING。","authors":"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","doi":"10.1158/2326-6066.CIR-24-0103","DOIUrl":null,"url":null,"abstract":"<p><p>The tumor microenvironment in solid tumors contains myeloid cells that modulate local immune activity. Stimulator of IFN gene (STING) signaling activation in these myeloid cells enhances local type-I IFN production, inducing an innate immune response that mobilizes adaptive immunity and reprograms immunosuppressive myeloid populations to drive antitumor immunity. In this study, we generated TAK-500, an immune cell-directed antibody-drug conjugate, to deliver a STING agonist to CCR2+ human cells and drive enhanced antitumor activity relative to nontargeted STING agonists. Preclinically, TAK-500 triggered dose-dependent innate immune activation in vitro. In addition, a murine TAK-500 immune cell-directed antibody-drug conjugate surrogate enhanced innate and adaptive immune responses both in in vitro and murine tumor models. Spatially resolved analysis of CCR2 and immune cell markers in the tumor microenvironment of >1,000 primary human tumors showed that 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.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"661-679"},"PeriodicalIF":8.1000,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046323/pdf/","citationCount":"0","resultStr":"{\"title\":\"Selective STING Activation in Intratumoral Myeloid Cells via CCR2-Directed Antibody-Drug Conjugate TAK-500.\",\"authors\":\"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\",\"doi\":\"10.1158/2326-6066.CIR-24-0103\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>The tumor microenvironment in solid tumors contains myeloid cells that modulate local immune activity. 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Selective STING Activation in Intratumoral Myeloid Cells via CCR2-Directed Antibody-Drug Conjugate TAK-500.
The tumor microenvironment in solid tumors contains myeloid cells that modulate local immune activity. Stimulator of IFN gene (STING) signaling activation in these myeloid cells enhances local type-I IFN production, inducing an innate immune response that mobilizes adaptive immunity and reprograms immunosuppressive myeloid populations to drive antitumor immunity. In this study, we generated TAK-500, an immune cell-directed antibody-drug conjugate, to deliver a STING agonist to CCR2+ human cells and drive enhanced antitumor activity relative to nontargeted STING agonists. Preclinically, TAK-500 triggered dose-dependent innate immune activation in vitro. In addition, a murine TAK-500 immune cell-directed antibody-drug conjugate surrogate enhanced innate and adaptive immune responses both in in vitro and murine tumor models. Spatially resolved analysis of CCR2 and immune cell markers in the tumor microenvironment of >1,000 primary human tumors showed that 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.
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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