Abstract 1629: IO-202, a first-in-class LILRB4 antagonist antibody, activates dendritic cells and inhibits solid tumor growth in preclinical studies

Abstract

Abstract LILRB4, also known as ILT3, is an immune inhibitory transmembrane protein found on monocytes and antigen presenting cells, including dendritic cells (DCs). LILRB4 upregulation in DCs induces a tolerogenic phenotype that facilitates the generation of antigen-specific T regulatory cells. LILRB4 is also expressed on acute myeloid leukemia (AML) with monocytic differentiation, in which it promotes T cell suppression and tumor infiltration. IO-202 is a first-in-class LILRB4 antagonist antibody that is being evaluated in a Phase I trial (NCT04372433) for the treatment of AML and chronic myelomonocytic leukemia (CMML). RNA-seq data from TCGA database indicates that LILRB4 expression is upregulated in many solid tumor types. Therefore, the therapeutic potential of IO-202 in solid tumors was investigated in this study. Using computational biology approaches, we found that high LILRB4 expression in solid tumors from TCGA database is associated with macrophage infiltration in the tumor microenvironment. Flow cytometric analysis of cancer patients' blood and tumor samples confirmed LILRB4 expression on tumor-associated macrophages (TAMs) and on monocytic myeloid-derived suppressor cells (M-MDSCs) and DCs in tumor and periphery. These data raised the hypothesis that LILRB4 functions as a myeloid checkpoint and contributes to tumor immune evasion, not only in AML, but also in many solid tumor types. LILRB4 is not present in rodents. As such, the functional activity and anti-tumor efficacy of IO-202 were evaluated using human primary immune cells and immunocompetent LILRB4 transgenic mice, respectively. In healthy donor monocyte-derived DCs, IO-202 treatment promoted DC maturation, activation and an antigen presenting phenotype, as well as enhanced their ability to activate allogeneic T cells. In the radiation therapy (RT)-resistant Lewis lung carcinoma (LLC) syngeneic model, IO-202 in combination with RT resulted in tumor growth inhibition, which was associated with changes in the relative abundance of tumor-infiltrating immune cells, evidenced by a reduction in M-MDSCs and an increase in T cells, along with increased T cell activation. In conclusion, our data suggest that LILRB4 functions as a myeloid checkpoint in multiple cancer types and that IO-202, the first-in-class LILRB4 antagonist antibody, enhances dendritic cell function and T cell activation in vitro and anti-tumor immunity in a solid tumor model in vivo. These data demonstrate the therapeutic potential of IO-202 as a myeloid checkpoint inhibitor for solid tumors. Citation Format: Maria José Costa, Tao Huang, Jing-Tyan Ma, Caroline Bonnans, Azita Tabrizi, Xiaoling C. Liao, Paul Woodard, Benjamin P. Chen, Ching-Cheng Hsu, Mi Deng, Cheng Cheng Zhang, An Song. IO-202, a first-in-class LILRB4 antagonist antibody, activates dendritic cells and inhibits solid tumor growth in preclinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1629.