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Poster display session

3717 - Development of OAT-1746, a Novel Arginase 1 and 2 Inhibitor for Cancer Immunotherapy

Date

10 Sep 2017

Session

Poster display session

Topics

Clinical Research;  Cancers in Adolescents and Young Adults (AYA);  Immunotherapy

Presenters

Paulina Stanczak

Citation

Annals of Oncology (2017) 28 (suppl_5): v403-v427. 10.1093/annonc/mdx376

Authors

P.S. Stanczak1, M.M. Grzybowski1, P. Wolska1, A.M. Zdziarska1, M. Mazurkiewicz1, R. Blaszczyk2, J. Nowicka2, A. Sosnowska3, K. Ramji3, D. Nowis4, J. Golab3, A. Golebiowski2, P. Dobrzanski1, K. Dzwonek1

Author affiliations

  • 1 Department Of Biology, OncoArendi Therapeutics SA, 02-089 - Warsaw/PL
  • 2 Department Of Chemistry, OncoArendi Therapeutics SA, 02-089 - Warsaw/PL
  • 3 Department Of Immunology, Medical University of Warsaw, 02-097 - Warsaw/PL
  • 4 Genomic Medicine, Medical University of Warsaw, 02-097 - Warsaw/PL
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Resources

Abstract 3717

Background

Clinical success of PD-1/PD-L1 and CTLA-4 checkpoint inhibitors demonstrated that reactivation of anti-tumor immunity provides strong clinical benefits including curative responses. However, only a fraction of patients demonstrate long-lasting therapeutic effects prompting efforts to target additional pathways regulating antitumor immune response. Depletion of arginine inhibits proliferation and activation of T cells and is an important mechanism of immunosuppression. High plasma and tumor arginase (ARG) activity has been found in patients with a wide spectrum of cancers correlating with a poor prognosis. Therefore, we developed ARG inhibitors and report the immunoregulatory and antitumor activity of the lead compound (OAT-1746) alone or in combination.

Methods

The IC50 of the compounds was determined against the recombinant ARG1/2. M2-polarized, bone marrow derived murine macrophages and CHO cells transfected with human ARG1 were used to assess the cellular activity. Murine and human CD4+/CD8+ T cells were negatively isolated and incubated with anti-CD3/CD28 beads to trigger proliferation, CD3ζ levels were measured. The in vivo antitumor efficacy was evaluated in syngeneic mouse models after oral administration at 50 mg/kg bid.

Results

We have developed potent, selective, orally active inhibitors of ARG1 and 2. Our lead compound, OAT-1746, has a low nanomolar activity against ARG1/2 and < 50 nM cellular activity. It reversed the ARG1-inhibited proliferation of human and murine T cells and restored CD3ζ expression in ex vivo assays. In vivo, OAT-1746 showed good pharmacological properties with significant antitumor efficacy in multiple tumor models as a monotherapy and in combinations with checkpoint inhibitors and gemcitabine. The efficacy correlated with sustained PD effects: suppression of tumor arginase activity and 3-6 fold increase in plasma and tumor arginine concentrations that exceeded those required for the maximal stimulation of T cell proliferation. Induction of inflammatory markers in tumors confirmed reversal of immunosuppression. No toxicity was observed after multiple oral dosing in mono- or combinatorial therapies.

Conclusions

These results support the clinical development of OAT-1746 for cancer therapy.

Clinical trial identification

Legal entity responsible for the study

OncoArendi Therapeutics SA

Funding

The research was supported by the National Science and Research Development (NCBIR) STRATEGMED programme 2/265503/3/NCBIR/15

Disclosure

All authors have declared no conflicts of interest.

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