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.
Authors
- Michelle L. Ganno (ORCID: https://orcid.org/0009-0001-3322-0670)
- Neil Lineberry (ORCID: https://orcid.org/0000-0001-9156-4423)
- Carole E. Harbison (ORCID: https://orcid.org/0000-0003-1696-3859)
- Camilla L. Christensen (ORCID: https://orcid.org/0009-0007-3313-2615)
- Natasha Iartchouk (ORCID: https://orcid.org/0009-0003-3706-0947)
- Satyajeet Haridas
- Atsushi Matsuda
- Jian Huang
- Kurt A. Schalper (ORCID: https://orcid.org/0000-0001-5692-4833)
- Tomoki Yoneyama (ORCID: https://orcid.org/0000-0002-2207-3505)
- Adnan O. Abu‐Yousif (ORCID: https://orcid.org/0000-0002-7670-0041)
- Chris Arendt
- Richard C. Gregory (ORCID: https://orcid.org/0000-0002-5041-1882)
- Vicky A. Appleman (ORCID: https://orcid.org/0000-0002-9132-1322)
- Angelo Porciuncula (ORCID: https://orcid.org/0000-0002-8001-3121)
- Tiquella Hatten (ORCID: https://orcid.org/0009-0006-8570-8535)
- Jianing Wang (ORCID: https://orcid.org/0009-0003-4168-7873)
- Linlin Dong (ORCID: https://orcid.org/0000-0002-7944-8582)
- Emily Rosentrater
- Charlotte I. Wang (ORCID: https://orcid.org/0009-0000-3512-8635)
- Samantha A. Merrigan
- Alexander Parent (ORCID: https://orcid.org/0000-0001-6419-3719)
- Hong Myung Lee
- Min Young Lee (ORCID: https://orcid.org/0000-0001-7542-4818)
- He Xu
- Angel E. Maldonado Lopez
- Konstantin I. Piatkov (ORCID: https://orcid.org/0009-0004-9337-6329)
- Dong Mei Zhang
Institutions
- Johnson & Johnson (United States) (US)
- Yale University (US)
- Dana-Farber Cancer Institute (US)
- NovaRx (United States) (US)
- DMH Associates (United States) (US)
- Takeda (United States) (US)
- Millennium Engineering and Integration (United States) (US)
- Takeda (Japan) (JP)
Publication Details
- Journal
- Cancer Immunology Research
- Published
- 2025-02-07
- DOI
- https://doi.org/10.1158/2326-6066.cir-24-0103
- Citations
- 7
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 5.58