Abstract 4423: XMT-2056, a HER2-targeted STING agonist antibody-drug conjugate, exhibits ADCC function that synergizes with STING pathway activation and contributes to anti-tumor responses

Abstract XMT-2056 is a systemically administered Immunosynthen STING agonist antibody-drug conjugate (ADC) that targets a novel HER2 epitope and induces complete tumor regressions with a single dose in multiple tumor models. We have previously shown that XMT-2056 delivers its STING agonist payload into tumor cells and FcγRI (CD64)-expressing myeloid cells, activating STING signaling in both cell types, leading to type I interferon (IFN) and anti-tumor innate immune responses. Here, we demonstrate that XMT-2056 exhibits ADCC (antibody-dependent cell-mediated cytotoxicity) function, which synergizes with STING pathway activation and induces potent cancer cell-killing activity in co-cultures of HER2-expressing cancer cells and FcγRIII+ (CD16+) immune cells. We show that both XMT-2056 and HT-19 (the unconjugated parental antibody) retain significant cancer cell-killing activity in an Fc-dependent manner in PBMC co-cultures depleted of FcγRI-expressing myeloid cells. This activity is abrogated by co-depletion of FcγRIII+ immune cells, illustrating the ADCC function of XMT-2056. In this setting, XMT-2056 cancer cell-killing activity was significantly increased compared to HT-19, suggesting that the STING payload contributes to the differential activity observed with XMT-2056 treatment. Indeed, co-treatment of cancer cell and immune cell co-cultures with HT-19 and free STING agonist payload enhanced the anti-tumor responses, although to a lesser extent than XMT-2056, suggesting a synergy between the ADCC function and STING pathway activation. Consistently, XMT-2056 treatment of HER2-expressing cancer cells co-cultured with unstimulated CD56+/FcγRIII+ NK cells induced granzyme b and IFN-γ cytokine production, expression of NK cell activation markers, and cancer cell-killing activity. The ADCC activity of HT-19 was comparable to that of trastuzumab in NK cell co-cultures. Finally, we found that depletion of FcγRI+ cells inhibited the cancer cell-killing activity of XMT-2056 in cancer cell and PBMC co-cultures more substantially compared to depletion of FcγRIII+ cells or CD56+ NK cells, indicating a greater contribution of myeloid cells to the XMT-2056 mechanism of action in this setting. Notably, XMT-2056 was capable of engaging both FcγRI+ myeloid cells and FcγRIII+ NK cells, activating both STING-mediated innate immune responses and ADCC function in triple cultures with HER2-expressing cancer cells. Collectively, our data reveal a synergy between ADCC function and STING pathway induction both mediated by XMT-2056, which enhances the cancer cell-killing activity of FcγRIII+ cells. This additional mechanism of action of XMT-2056 can potentially impact the overall anti-tumor immune responses in tumors infiltrated by FcγRIII+ cells. Citation Format: Jahna Soomer-James, Marc Damelin, Naniye Malli. XMT-2056, a HER2-targeted STING agonist antibody-drug conjugate, exhibits ADCC function that synergizes with STING pathway activation and contributes to anti-tumor responses. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4423.