Abstract 636: ABT-863: The next generation anti-CCR8 immuno-oncology antibody therapeutic

Abstract The chemokine receptor CCR8 has come into focus based on its upregulation on immune suppressive Tregs within the tumor microenvironment in a range of solid tumors, eg breast, colon, and lung cancers. This finding has spurred efforts to develop CCR8 targeting antibodies (mAbs) that can selectively target and deplete this Treg population to augment the antitumor immune response and the efficacy of cancer therapies, including checkpoint inhibitors. To date, the development of several clinical antibodies primarily focuses on the depletion of CCR8-expressing Tregs through enhanced Antibody Dependent Cellular Cytotoxicity and Antibody-Dependent Cellular Phagocytosis. While these antibodies have been reported to compete with CCL1, CCR8’s endogenous ligand, the simple inhibition of the receptor, without a depletion mechanism, has failed to demonstrate tumor suppression in mouse models. Overall, the impact of CCR8 expression on the Treg phenotype and its involvement in cancer progression remains to be fully elucidated. Abilita Therapeutics has instead focused on maximizing the inhibition of CCR8 function by developing potent inverse agonists based on single domain heavy chain antibody (VHH) scaffolds that engage the receptor’s orthosteric pocket in the transmembrane domain to inhibit both CCL1 agonism and ligand-independent signaling. Our development candidate ABT-863 was discovered using Abilita’s proprietary Enabled Membrane Protein (EMP) platform. EMP technology was leveraged to generate a stabilized CCR8 variant, which was key to llama immunization, protein-based antibody selections, and affinity maturation of the humanized VHH. ABT-863 is formatted as a bivalent VHH-Fc fusion that demonstrates excellent affinity, selectivity, and an optimal developability profile. In preclinical studies using human CCR8 knock-in mice, ABT-863 demonstrated significant tumor growth inhibition in both the MC38 (murine colon carcinoma) and CMT167 (murine lung carcinoma) models. Remarkably, an Fc effector-null version of the antibody demonstrated efficacy in absence of Treg depleting activity, both as monotherapy or in synergy with anti-PD1, which contrasts with what others have reported. Because of its distinct pharmacology, this mechanism may offer more robust modulation of the TME and immune responses, potentially enhancing therapeutic efficacy, while avoiding unnecessary safety risks of depleting Tregs in healthy tissues or other CCR8-expressing cell types. In conclusion, ABT-863 is a differentiated first-in-class inverse agonist antibody with the potential to provide superior efficacy, improved safety and more favorable patient outcomes. Citation Format: Pia Kuss, Karen Chiang, Alexander Alexandrov, Le Li, Riccardo Contu, Christopher Roth, Anke Kretz-Rommel, Mauro Mileni. ABT-863: The next generation anti-CCR8 immuno-oncology antibody therapeutic [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 636.