Abstract 1942: AGX73 is an effective treatment for hepatocellular carcinoma (HCC) by selective inhibition of immunokinases that play crucial roles in the crosstalk between cancer and immune cells in the tumor microenvironment
Authors: Francis Y.F. Lee, Wenlian Wu, Zhiqiang Yang, John Tan
Journal: Cancer Research (2020)

Abstract HCC is the second leading cause of cancer-related death and the fifth-most-common cancer worldwide. Unlike almost all other tumor types, the vast majority (90%) of HCCs develop due to underlying chronic inflammation, the induction of fibrosis and/or subsequent cirrhosis. In established disease, persistent upregulation of inflammatory signals in the tumor microenvironment leads to suppression of antitumor immune response by various mechanisms such as reprogramming of tumor-associated macrophages (TAMs) and loss of critical immune cell subsets (e.g. tumor-infiltrating lymphocytes). We identified 6 key immunokinases (AXL, DDR1, DDR2, FMS, KIT and MER) that are frequently amplified in HCC and are significant predictive markers of poor outcome (TCGA). We design small molecule compounds that potently and selectively inhibit these kinases. AGX73, optimized for drug-like properties, is an orally bioavailable compound currently undergoing IND evaluation as potential clinical candidate for first-in-human trial. In in vitro assay, carried out at high ATP concentration (100 μM), AGX73 inhibited the activity of recombinant human AXL, DDR1, DDR2, FMS, KIT and MER with IC50 values of 30, 12, 0.63, 96, 54, and 40 nM, respectively, but was highly selective against a panel of 374 kinases. In an in vitro primary macrophage assays, AGX73 promoted M1 macrophage polarization and increased the secretion of IL-6 and TNFα. In contrast, AGX73 suppressed the activation of M2 macrophages and decreased the secretion of IL-10. Importantly, AGX73 prevented the reprogramming of human LPS/IFN-γ polarized M1 macrophages back to M2 macrophages. In contrast, AGX73 had no effect on the reprogramming of IL-4/IL-13 polarized M2 macrophages back to M1. In vivo, in the MC38 colon carcinoma model, AGX73 treatment reduced the number of TAMs, from 46 to 22% of the total CD45+ cells in the tumors. Moreover, the M1/M2 ratio was favorably increased, from 1.3 to 1.8. AGX73 demonstrated robust antitumor activity in multiple (11) patient-derived xenograft (PDX) models of HCC, with tumor growth inhibition (TGI) ranging 62-105% (Median = 84%) and was effective at multiple dose levels, from 30-150 mg/kg. In combination with anti-PD1 (10 mg/kg) in the MC38 model, AGX73 produced synergistic activity at multiple dose levels. In nonclinical ADME studies, AGX73 demonstrated favorable drug-like properties: including good bioavailability (F&amp;gt;50% in mouse, rat and monkey) and systemic exposure following oral administration in multiple species, acceptable metabolic stability, lack of significant drug-drug interaction liabilities (transporters, CYP inhibition, CYP induction) and excellent cardiac safety profile. IND toxicologic studies are currently in progress. Citation Format: Francis Y.F. Lee, Wenlian Wu, Zhiqiang Yang, John Tan. AGX73 is an effective treatment for hepatocellular carcinoma (HCC) by selective inhibition of immunokinases that play crucial roles in the crosstalk between cancer and immune cells in the tumor microenvironment [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1942.