Abstract 312: Comprehensive characterization of DT-7012, a differentiated CCR8-depleting antibody for the treatment of solid tumors

Abstract Background: CCR8 is a chemokine G-protein coupled receptor predominantly expressed on tumor-resident regulatory T cells (Tregs), which suppress anti-tumor immunity. DT-7012 is a highly differentiated, fully humanized monoclonal antibody designed to deplete CCR8+ Tregs through Fc-mediated mechanisms, including antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). This study aimed to characterize the binding properties, effector functions, and Treg-depleting activity of DT-7012 to support its clinical development, planned for early 2025. Methods: Binding assays: The binding affinity of DT-7012 to human CCR8 was assessed using flow cytometry on a variety of CCR8-expressing cell lines and native Tregs. Specificity against native circulating immune cells as well as membrane and secreted targets have been investigated. Functional assays: ADCC and ADCP activities were evaluated using gene reporter assays or various target:effector killing assays. Treg depletion: Ex vivo studies were conducted using blood samples from patients with non-small cell lung cancer (NSCLC) to quantify DT-7012-mediated depletion of CCR8+ Tregs. Results: DT-7012 displayed high-affinity binding to human CCR8 and selectively recognized CCR8 without cross-reactivity to other targets including chemokine receptors. In vitro, DT-7012 induced robust ADCC and ADCP activities on all tested CCR8-expressing cells, including in presence of CCL1. Ex vivo treatment with DT-7012 resulted in significant depletion of CCR8+ Tregs from NSCLC patient samples without affecting other immune cell populations. Together, these results demonstrate the high potency and selectivity of DT-7012. Preliminary safety studies confirmed the good tolerability of DT-7012 in rat and monkey. Additional data are ongoing and will be presented. Conclusions: DT-7012 exhibits high-affinity binding to CCR8, potent Fc-mediated effector functions, and selective depletion of CCR8+ Tregs in NSCLC patient samples as well as a good safety profile. These findings highlight the therapeutic potential of DT-7012 as a novel strategy to enhance anti-tumor immunity and support its upcoming clinical development. Citation Format: Hélène Lelièvre, Mélanie Frauli, Maria Dolorès Garcia Fernandez, Dounia Chraa, Luc Baron, Aurélie Janvier, Iseulys Richert, Solène Rose, Katia Saulnier, Malaury Schappler, Christel Franchet, Orphée Blanchard, Thibaut Brugat, Stephan Schann, Nathalie Lenne. Comprehensive characterization of DT-7012, a differentiated CCR8-depleting antibody for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 312.