OATD-02 Validates the Benefits of Pharmacological Inhibition of Arginase 1 and 2 in Cancer.

Simple Summary: Arginase 1 and 2 are drivers of multiple immunosuppressive mechanisms and tumour-specific metabolic adaptations. Pharmacological inhibition of extracellular ARG1 has shown antitumour efficacy in various syngeneic tumour models, however, the importance of ARG2 as a therapeutic target has only been demonstrated by genetic deletion studies. This is the first study validating the benefits of pharmacological inhibition of ARG2 in cancer. Our work describes OATD-02 as a potent dual ARG1/ARG2 inhibitor with a cellular activity (necessary for targeting ARG2) exhibiting immunomodulatory and direct antitumour efficacy in animal models. Our results present OATD-02 as an attractive option for combination with other immunotherapeutics, such as PD-1/PD-L1 antibodies or IDO1 inhibitors, especially in the therapy of particularly resistant hypoxic tumours. The presented findings provided the rationale for planning first-in-human clinical trials for OATD-02 in cancer patients. Background: Arginases play essential roles in metabolic pathways, determining the fitness of both immune and tumour cells. Along with the previously validated role of ARG1 in cancer, the particular significance of ARG2 as a therapeutic target has emerged as its levels correlate with malignant phenotype and poor prognosis. These observations unveil arginases, and specifically ARG2, as well-validated and promising therapeutic targets. OATD-02, a new boronic acid derivative, is the only dual inhibitor, which can address the benefits of pharmacological inhibition of arginase 1 and 2 in cancer. Methods: The inhibitory activity of OATD-02 was determined using recombinant ARG1 and ARG2, as well as in a cellular system using primary hepatocytes and macrophages. In vivo antitumor activity was determined in syngeneic models of colorectal and kidney carcinomas (CT26 and Renca, respectively), as well as in an ARG2-dependent xenograft model of leukaemia (K562). Results: OATD-02 was shown to be a potent dual (ARG1/ARG2) arginase inhibitor with a cellular activity necessary for targeting ARG2. Compared to a reference inhibitor with predominant extracellular activity towards ARG1, we have shown improved and statistically significant antitumor efficacy in the CT26 model and an immunomodulatory effect reflected by Treg inhibition in the Renca model. Importantly, OATD-02 had a superior activity when combined with other immunotherapeutics. Finally, OATD-02 effectively inhibited the proliferation of human K562 leukemic cells both in vitro and in vivo. Conclusions: OATD-02 is a potent small-molecule arginase inhibitor with optimal drug-like properties, including PK/PD profile. Excellent activity against intracellular ARG2 significantly distinguishes OATD-02 from other arginase inhibitors. OATD-02 represents a very promising drug candidate for the combined treatment of tumours, and is the only pharmacological tool that can effectively address the benefits of ARG1/ARG2 inhibition. OATD-02 will enter clinical trials in cancer patients in 2022. [ABSTRACT FROM AUTHOR]