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Background Chemokine receptor 8 (CCR8) is selectively upregulated on immunosuppressive regulatory T cells (Tregs) within the tumor microenvironment (TME) across multiple solid tumors, including breast, colon, and lung cancers. CCR8+ Tregs contribute significantly to immune evasion and resistance to immune checkpoint blockade, posing a hurdle for effective cancer immunotherapy. Existing therapeutic strategies target CCR8+ Tregs through Fc-mediated Treg depletion mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) or phagocytosis (ADCP). Antibodies lacking effector function have failed to demonstrate preclinical efficacy, highlighting an incomplete understanding of CCR8’s role in Treg biology. Abilita’s novel approach that addresses the role of CCR8 signaling in Tregs delivered an antibody that acts as a potent inverse agonist to block both CCL1-dependent and basal receptor signaling. Leveraging this new MOA, ABT-863 demonstrated anti-tumor efficacy without the need for Treg depletion.Methods ABT-863 is a bivalent VHH-Fc fusion antibody discovered using Abilita’s proprietary Enabled Membrane Protein (EMP) platform. ABT-863’s binding affinity, epitope, selectivity, pharmacology, and developability were extensively characterized in vitro. In vivo efficacy and immune modulation were evaluated using human CCR8 knock-in mice implanted with lung (CMT167) or colon (MC38) carcinoma. Studies included monotherapy and combination with anti-PD1, complemented by comprehensive immune phenotyping and cytokine profiling.Results ABT-863 displayed potent and highly selective CCR8 binding with novel pharmacological properties. Revealed by cryo-EM analysis, ABT-863’s VHH warhead engages deep within the transmembrane domain orthosteric pocket. This not only blocks activation by CCL1 but also prevents basal, ligand-independent activation. Treatment with ABT-863 led to tumor growth inhibition in vivo. Remarkably, an Fc-effector null variant retained anti-tumor efficacy despite lacking Treg depleting activity, challenging the prevalent paradigm. When combined with anti-PD1, ABT-863 showed synergistic significant tumor suppression. Immune phenotyping of ABT-863 Fcnull treated mice revealed a significant increase in activated CD8+ T cells and early exhausted CD8+ T cells in both blood and tumors. Cytokine and chemokine blood analysis demonstrated elevated circulating levels of IL-10, previously linked to reinvigoration of exhausted CD8+ T cells and enhanced anti-tumor immunity.Conclusions ABT-863 is a first-in-class CCR8 inverse agonist antibody that promotes the anti-tumor response, modulating Treg suppressive activity, without cell depletion, offering a novel and potentially safer MoA. ABT-863 could represent a transformative immunotherapy approach targeting CCR8+ Tregs in solid tumors by coupling its robust anti-tumor activity, and its synergy with PD-1 blockade, with the potential differentiation for a better safety profile and a broader therapeutic window compared to other clinical candidates.Ethics Approval The animal studies have been conducted with a CRO, and have been approved by their internal IACUC.