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We searched for cell-surface-associated proteins overexpressed on B cell chronic lymphocytic leukemia (CLL) to use as therapeutic antibody targets. Antibodies binding the immunosuppressive molecule CD200 were identified by cell panning of an antibody phage display library derived from rabbits immunized with primary CLL cells. B cells from 87 CLL patients exhibited 1.6- to 5.4-fold cellsurface up-regulation of CD200 relative to normal B cells. An effect of increased CD200 expression by CLL cells on the immune system was evaluated in mixed lymphocyte reactions. Addition of primary CLL but not normal B cells to macrophages and T cells down-regulated the Th1 response, as seen by a 50-95% reduction in secreted IL-2 and IFN-γ. Antibodies to CD200 prevented downregulation of the Th1 response in most B cell CLL samples evaluated, indicating abrogation of the CD200/CD200R interaction can be sufficient to restore the Th1 response. A disease-progression-associated shift of the immune response from Th1 to Th2 has been observed in numerous cancers. Because this cytokine shift is also believed to promote the induction of regulatory T cells, reverting the immune response to Th1 through direct targeting of the cancer cells may provide therapeutic benefits in CLL by encouraging a cytotoxic T cell response.

BackgroundChemokine 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.MethodsABT-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.ResultsABT-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.ConclusionsABT-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 ApprovalThe animal studies have been conducted with a CRO, and have been approved by their internal IACUC.

To differentiate into T cells, immature thymocytes must engage, through their antigen-specific T-cell receptor, peptides derived from self proteins presented by cortical epithelial cells in the thymus, a process called positive selection. Despite this requirement for self-recognition during development, mature T cells do not normally show autoreactivity. Mice injected in the thymus with procainamide-hydroxylamine, a metabolite of procainamide, develop autoimmune features resembling drug-induced lupus. Here, we show that when thymocytes undergo positive selection in the presence of procainamide-hydroxylamine, they fail to establish unresponsiveness to low affinity selecting self antigens, resulting in systemic autoimmunity.

Drug-induced lupus is a side effect of deliberate ingestion of various medications, but its etiology, underlying mechanisms, and pathogenesis are puzzling. In vivo metabolic transformation of lupus-inducing drugs to reactive products explains how a heterogeneous set of drugs can mediate the same disease syndrome. Evidence has accumulated that drugs are transformed by extracellular oxidation from reactive oxygen species and myeloperoxidase produced when neutrophils are activated, maximizing the in situ accumulation of reactive drug metabolites within lymphoid compartments. The metabolite of procainamide, procainamide hydroxylamine, displays diverse biologic properties, but no apparent autoimmune effect has been observed. However, when procainamide hydroxylamine was introduced into the thymus of young adult normal mice, a delayed but robust autoimmune response developed. Disruption of central T-cell tolerance by intrathymic procainamide hydroxylamine resulted in the production of chromatin-reactive T cells that apparently drove the autoantibody response in the periphery. Drug-induced autoantibodies in this mouse model were remarkably similar to those in patients with procainamide-induced lupus. Therefore, this system has considerable promise to provide insight into the initiating events in drug-induced lupus and may provide a paradigm for how other xenobiotics might induce systemic autoimmunity.