Abstract 3862: AB474, a potent orally bioavailable inhibitor of arginase, for the treatment of cancer
2019
Introduction: It has been demonstrated that myeloid derived suppressor cells (MDSCs) have a direct role in tumor immune evasion, and increased MDSCs are associated with reduced overall survival in several types of cancer. Elevated levels of circulating MDSCs have been shown to correlate with a blunted response to checkpoint blockade. MDSCs secrete arginase, which depletes arginine, leading to decreased T cell activity and a suppressed anti-tumor response. Here we will present the characterization of AB474, a highly potent small molecule inhibitor of arginase. Methods: Arginase inhibition was measured using a coupled enzyme assay in the presence and absence of both mouse and human serum. IC50 was determined in buffer, human plasma, and serum by LC-MS/MS quantification of ornithine, while plasma protein binding was determined by equilibrium dialysis. Tumor transcript analysis was performed on homogenized whole murine tumors using Taqman probes. Arginase inhibition by AB474 was tested on human CD4 and CD8 T cells, with proliferation and effector functions being determined in the presence of recombinant and endogenous human ARG1. Assays were performed using standard CD2/CD3/CD28 activation conditions: proliferation was measured by flow cytometry, and IFNγ secretion by ELISA. Results: AB474 inhibits arginase with low-nanomolar potency. It effectively inhibits both recombinant and endogenous arginase, while displaying low plasma protein binding across species. Pharmacokinetic characterization of AB474 demonstrated oral bioavailability in both mice and rats, displaying qualities compatible with human dosing. Measuring transcript of Arg1 in murine tumor models revealed expression in both tumor and immune compartments. Flow cytometry analysis shows ARG1+ MDSCs exist in both the tumor and periphery, with higher expression levels seen in Ly6c+ mMDSC populations. Consistent with the elevation of arginase in tumor-bearing mice, levels of arginine are decreased when compared to naive littermates. Addition of arginase to activated CD4 or CD8 T-cells results in a significant suppression of proliferation, CD3 expression, and IFNγ secretion. Addition of AB474 results in a significant restoration of normal T cell effector functions (P Conclusions: AB474 is a potent orally bioavailable inhibitor of arginase. Inhibition of arginase will block one of the primary immune-suppressive functions of MDSCs resulting in restored T cell activation and anti-tumor responses. Citation Format: Sterling C. Eckard, Yu Chen, Dana Piovesan, Nell Narasappa, Timothy W. Park, Jarek Kalisiak, Eric T. Newcomb, Manmohan R. Leleti, Divyank Soni, Elaine Ginn, Jie Chen, Dan DiRenzo, Kristen Zhang, Lixia Jin, Stephen W. Young, Matthew J. Walters, Ulrike Schindler, Jay P. Powers. AB474, a potent orally bioavailable inhibitor of arginase, for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3862.
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