Unlocking the Potential of CB-1158: Targeting Arginase to Enhance Immune-Mediated Anti-Tumor Activity

Myeloid derived suppressor cells (MDSCs) are recognized for their role in tumor immune evasion, but there are no effective treatments to counteract their immunosuppressive effects. MDSCs hinder the function of cytotoxic T-cells and Natural Killer cells by secreting arginase, an enzyme that depletes arginine levels in the tumor microenvironment, thus impairing T-cell proliferation and anti-tumor response. M2 macrophages and polymorphonuclear cells (PMNs) also contribute to immune suppression through high arginase expression. The potential of restoring arginine levels by inhibiting arginase to reactivate T-cells is highlighted.

A new inhibitor of arginase, CB-1158, has been developed with high potency and specificity, showing an IC50 of less than 100 nM in an assay. It does not directly affect cell proliferation but enhances T-cell proliferation in the presence of MDSCs in a dose-dependent manner in co-cultures with Peripheral Blood Mononuclear Cells (PBMCs) from a renal cell carcinoma patient.

CB-1158 demonstrates high oral bioavailability and significantly increases tumor arginine levels in mice with Lewis Lung Carcinoma (LLC) tumors, with a clear correlation between pharmacokinetics and pharmacodynamics. The effect is sustained with a twice-daily dosing schedule and observed across multiple models. Systemic plasma arginine levels are also significantly increased post-dosing. Notably, CB-1158 shows single agent anti-tumor efficacy in immune competent mice, but not in immunocompromised mice, suggesting an immune-mediated mechanism. This is supported by an increase in CD3+ T-cell infiltrates in treated tumors.

CB-1158 is well-tolerated in rodents, with no adverse effects on body weight or serum chemistry after prolonged dosing. It represents a novel class of arginase inhibitors targeting the immunosuppressive activity of myeloid cells in the tumor microenvironment and is under development as a new immuno-oncology approach. The combination of CB-1158 with other immune checkpoint inhibitors may offer enhanced therapeutic benefits.