Abstract 1689P
Background
Arginases play important roles in the metabolic pathways determining the fitness of both immune and tumour cells. ARG1 expressed by the myeloid cells in the tumour microenvironment (TME) contributes to the suppression of the effector functions of T and NK cells by a local L-arginine depletion, while ARG2 constitutes a cell-autonomous and regulator of cytotoxic and regulatory T lymphocytes. ARG2 is highly expressed in various cancers and its significant role in cancer has recently emerged as ARG2 levels correlate with malignant phenotype and poor prognosis. These observations unveil arginases and especially ARG2 as well-validated and promising therapeutic targets. OATD-02 is the only dual inhibitor, which due to its unique pharmacokinetic properties and the ability to target intracellular ARG2, can address the benefit of arginase inhibition in cancer.
Methods
The inhibitory activity of OATD-02 was determined in vitro using recombinant human ARG1 and ARG2, as well as in cellular systems using primary hepatocytes and macrophages. In vivo, its antitumor activity was evaluated in murine syngeneic models of colorectal and renal carcinomas (CT26 and Renca, respectively), as well as in a leukaemia xenograft model (K562).
Results
OATD-02 is a potent dual arginase inhibitor with a cellular activity necessary for targeting ARG2. Compared to the inhibitor with only extracellular activity, we have shown improved antitumor efficacy in the CT26 model and immunomodulatory effect reflected by Treg inhibition in the RCC Renca model. Importantly, OATD-02 had a superior activity when combined with other immunotherapeutics. Finally, OATD-02 showed a significant ARG2-dependent anticancerous effect on the human CML cells.
Conclusions
OATD-02 is a potent small-molecule arginase inhibitor with optimal drug-like properties. Thanks to excellent activity against intracellular ARG2, long drug-target residence time, high volume of distribution and slow clearance, OATD-02 significantly differs from other arginase inhibitors. OATD-02 represents a very promising drug candidate for the combined treatment of tumours and is the only pharmacological tool, which can effectively address the benefits of arginase inhibition. OATD-02 will enter the clinical trials in 2022.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Molecure SA.
Funding
The National Centre for Research and Development (Poland).
Disclosure
M.M. Grzybowski, R. Blaszczyk, P. Pomper, P.S. Stanczak, B. Borek, A. Gzik, J. Nowicka, M. Mlącki: Financial Interests, Personal, Full or part-time Employment: Molecure SA. K. Jędrzejczak, T. Rejczak, N.C. Guner-Chalimoniuk, A. Kikulska, J. Olczak: Financial Interests, Full or part-time Employment: Molecure SA. J. Pęczkowicz-Szyszka: Financial Interests, Stocks/Shares: Molecure SA. K. Dzwonek, P. Dobrzanski: Financial Interests, Advisory Role: Molecure SA. A. Gołębiowski, Z. Zasłona: Financial Interests, Member of the Board of Directors: Molecure SA.