71P - Novel Dual Arginase 1/2 Inhibitor OATD-02 (OAT-1746) Improves the Efficacy of Immune Checkpoint Inhibitors (71P)

Date 08 December 2017
Event ESMO Immuno-Oncology Congress 2017
Session Lunch & Poster Display session
Topics Cervical Cancer
Gynaecologic Malignancies
Presenter Marcin Grzybowski
Citation Annals of Oncology (2017) 28 (suppl_11): xi6-xi29. 10.1093/annonc/mdx711
Authors M.M. Grzybowski1, P.S. Stańczak1, J. Pęczkowicz-Szyszka1, P. Wolska1, A.M. Zdziarska1, M. Mazurkiewicz1, J. Brzezińska2, R. Blaszczyk2, A. Gołębiowski2, P. Dobrzański1, K. Dzwonek1
  • 1Department Of Biology, OncoArendi Therapeutics SA, 02-089 - Warsaw/PL
  • 2Department Of Chemistry, OncoArendi Therapeutics SA, 02-089 - Warsaw/PL

Abstract

Background

New approach for cancer therapy using checkpoint inhibitors confirmed that reactivation of antitumor immunity can lead to strong clinical benefits including full regression. However, only a fraction of patients achieved long-lasting therapeutic effects prompting efforts to target additional effectors of antitumor immunity. Evidence from preclinical and clinical studies demonstrated that interference with multiple immune checkpoints provides a superior efficacy. Arginase promotes the immune escape of cancer cells by decreasing the level of arginine and inhibiting proliferation and activation of T cells. High arginase activity has been found in patients with a wide spectrum of cancers, both in plasma and in tumors and correlated with a poor prognosis.

Methods

IC50 was determined against the recombinant arginase 1 and 2 (ARG1/2). M2-polarized, bone marrow derived murine macrophages or CHO cells transfected with human ARG1 or ARG2 were used to assess the cellular activity. The in vivo antitumor efficacy was evaluated in syngeneic mouse models. The levels of arginine and OATD-02 (OAT-1746) in plasma and tumors were determined by LC/MS analysis.

Results

We have developed OATD-02 - a potent, selective, orally active inhibitor of ARG1 and ARG2. The compound is a low nanomolar ARG1/2 inhibitor with < 50 nM cellular activity. In vivo, OATD-02 showed good pharmacological properties and significant antitumor efficacy as a monotherapy in multiple tumor models. Combining OATD-02 with PD-L1 and IDO inhibitors exhibited greatly increased antitumor efficacy. The efficacy correlated with sustained pharmacodynamic effects: 3-6 fold increase in plasma and tumor arginine levels and suppression of tumor arginase activity. The arginine plasma levels exceeded several fold concentration required for the maximal stimulation of T cell proliferation. Induction of inflammatory markers (IFN-gamma, CD94, CD3) in tumors confirmed reversal of immunosuppression.

Conclusions

The results provide a rationale for the clinical development of OATD-02 as a cancer immunotherapy.

Clinical trial identification

Legal entity responsible for the study

OncoArendi Therapeutics SA

Funding

OncoArendi Therapeutics SA

Disclosure

M.M. Grzybowski, P.S. Stańczak, J. Pe¸czkowicz-Szyszka, P. Wolska, A.M. Zdziarska, M. Mazurkiewicz, J. Brzezińska, R. Blaszczyk, A. Gołębiowski, P. Dobrzański, K. Dzwonek: Employee of OncoArendi Therapeutics SA.