Targeting Immunokinases in HCC: The Therapeutic Potential of AGX73 in Modulating Tumor-Immune Cell Dynamics

Hepatocellular carcinoma (HCC) is a prevalent and deadly cancer, predominantly caused by chronic inflammation and fibrosis. A significant number of HCC cases are linked to the persistent presence of inflammatory signals, which hinder the body's immune response by altering the behavior of tumor-associated macrophages (TAMs) and depleting vital immune cells. Key immunokinases, including AXL, DDR1, DDR2, FMS, KIT, and MER, have been identified as biomarkers for poor prognosis in HCC and are targeted by newly developed small molecule compounds.

One such compound, AGX73, is being evaluated for its potential therapeutic use against HCC. It has shown to be an effective oral drug candidate with high selectivity in inhibiting the aforementioned immunokinases. In vitro studies have demonstrated AGX73's ability to promote M1 macrophage polarization and reduce M2 macrophage activation, thereby influencing the balance of immune responses within the tumor microenvironment. In animal models, AGX73 has been shown to decrease TAMs and improve the M1/M2 ratio, leading to significant tumor growth inhibition across various patient-derived xenograft models.

Furthermore, AGX73 has displayed promising results when combined with anti-PD1 therapy, indicating a synergistic effect. Nonclinical studies have also highlighted AGX73's favorable pharmacokinetic properties, such as good bioavailability and metabolic stability, as well as its safety profile, including the absence of significant drug interactions and a positive cardiac safety assessment. Current toxicological studies for IND are underway, and the findings are expected to further support AGX73's development as a novel therapeutic agent for HCC.

Reference: Francis Y.F. Lee et al., "AGX73: A promising therapeutic approach for hepatocellular carcinoma through selective targeting of immunokinases pivotal in tumor-immune cell interactions" [abstract]. Proceedings of the Annual Meeting of the American Association for Cancer Research, 2020.