Abstract 6025: ABBV-514: an afucosylated CCR8 specific antibody that targets and eliminates key immunosuppressive tumor regulatory T cells

Abstract Regulatory T cells (Tregs) have long been appreciated as a key suppressive cell type that limits anti-tumor immunity, yet it has been challenging to find an effective approach to target this important cell population. CCR8 has recently emerged as a promising target due to its enhanced expression on tumor Tregs compared to other Treg and T effector cell populations. A greater abundance of CCR8+ Tregs is also correlated with poor clinical outcomes in several solid tumor indications. Here we report the discovery and comprehensive preclinical characterization of ABBV-514, a human CCR8 specific afucosylated hIgG1 antibody and a functionally similar mouse CCR8 specific mIgG2a surrogate antibody. Both ABBV-514 and the mouse surrogate specifically bind to and robustly deplete CCR8 expressing cells via ADCC without inhibiting CCL1-stimulated signaling. The mouse surrogate selectively depletes CCR8+ intratumoral Tregs and has strong monotherapy activity in a variety of in vivo syngeneic tumor models including models that are insensitive to anti-PD-1 treatment. We have used scRNAseq and TCRseq studies to provide novel insights into the mechanisms behind the anti-tumor immune response mediated by the CCR8 mouse surrogate ± anti-PD-1 combination therapy. The transcriptional and phenotypic profiles of intratumoral CD8+ T cells are greatly altered upon CCR8+ tumor Treg depletion compared to anti-PD-1. Tumor Treg depletion upon anti-CCR8 treatment leads to enrichment of a distinct effector memory-like CD8+ T cell population with dramatically enhanced Granzyme K expression and reduced expression of exhaustion associated transcripts including TOX and Lag-3. This population is further augmented with anti-CCR8/anti-PD-1 combination therapy. Similarly, ABBV-514 binds human or cyno CCR8 expressing cells and mediates ADCC of CCR8+ Tregs in vitro. ABBV-514 is currently being evaluated in a Phase I clinical trial, both as a monotherapy and in combination with budigalimab, a PD-1-blocking antibody (NCT05005403). Together, these data highlight ABBV-514 as a therapeutic approach to enhance anti-tumor immunity. WF was an employee of AbbVie at the time of the study. All other authors are current employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: Amanda Schmidt Paustian, Linlin Guo, Weiguo Feng, Ryan Duggan, Mitra Bhattacharyya, Andrew McCluskey, Kelsey Gallant, Christopher Negron, Michael McDevitt, Cyril Ramathal, Diana Chen, Maulik Patel, Heath Smith, Keith Hamel, Julie Wilsbacher. ABBV-514: an afucosylated CCR8 specific antibody that targets and eliminates key immunosuppressive tumor regulatory T cells [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 6025.