LILRB1 antibody targeting the LILRB1/HLA-G axis: Preclinical efficacy, pharmacokinetics, and safety supporting first-in-human trials

Background: LILRB1 is an inhibitory receptor expressed on T cells, B cells, NK cells, and monocytes. It binds to HLA class I molecules, with the highest affinity for HLA-G. This interaction delivers inhibitory signals that allow tumor cells to evade immune surveillance, impairing NK cell, T cell, and macrophage function. Disrupting the LILRB1/HLA-G axis is a promising strategy for restoring anti-tumor immunity. Additionally, LILRB1 may regulate T cell function independently of PD-1, suggesting potential to overcome resistance to PD-1 inhibitors. Methods: Binding affinity and specificity of LG-LILRB1 antibody were assessed via surface plasmon resonance and flow cytometry. Competitive binding assays confirmed blockade of LILRB1/HLA-G interaction. Restoration of immune cell function was evaluated using flow cytometry and western blotting. Anti-tumor efficacy was tested in human LILRB1 transgenic mice. Pharmacokinetics and toxicokinetics were studied in cynomolgus monkeys, and safety was assessed through GLP-compliant toxicology and immunotoxicity studies. Results: LG-LILRB1 antibody showed high-affinity, selective binding to LILRB1 and dose-dependent blockade of HLA-G. Functional assays revealed enhanced T cell proliferation, NK cell cytotoxicity, and macrophage phagocytosis. In vivo, LG-LILRB1 antibody significantly inhibited tumor growth (up to 88.8%) in transgenic mice bearing HLA-G-expressing tumors. Pharmacodynamic analysis showed increased infiltration and activation of CD8⁺ T cells and NK cells. Combination with PD-L1 blockade yielded synergistic anti-tumor effects. In monkeys, LG-LILRB1 antibody exhibited dose-proportional exposure and a long half-life (>12 days). No treatment-related adverse findings were observed in 4-week GLP toxicity studies. Conclusions: LG-LILRB1 antibody, a first-in-class LILRB1 blocker, restored anti-tumor immunity by disrupting the LILRB1/HLA-G axis. It enhanced immune cell function and showed strong efficacy in preclinical models. Favorable pharmacokinetics and safety support its clinical development. Combination with PD-L1 blockade further improved outcomes. These findings support LG-LILRB1 antibody as a promising candidate for cancer immunotherapy, with a Phase 1a trial currently ongoing (NCT06332755).