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

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.