Arginase 1/2 Inhibitor OATD-02: From Discovery to First-in-man Setup in Cancer Immunotherapy

  • Mol Cancer Ther. 2023 Jul 5;22(7):807-817. doi: 10.1158/1535-7163.MCT-22-0721.
Bartlomiej Borek  #  1 ,  Julita Nowicka  #  1 ,  Anna Gzik  #  1 ,  Marek Dziegielewski  #  1 ,  Karol Jedrzejczak  1 ,  Joanna Brzezinska  1 ,  Marcin Grzybowski  1 ,  Paulina Stanczak  1 ,  Paulina Pomper  1 ,  Agnieszka Zagozdzon  1 ,  Tomasz Rejczak  1 ,  Krzysztof Matyszewski  1 ,  Adam Golebiowski  1 ,  Jacek Olczak  1 ,  Kamil Lisiecki  1 ,  Magdalena Tyszkiewicz  1 ,  Magdalena Kania  1 ,  Sylwia Piasecka  1 ,  Anna Cabaj  1 ,  Paulina Dera  1 ,  Krzysztof Mulewski  1 ,  Jacek Chrzanowski  1 ,  Damian Kusmirek  1 ,  Elzbieta Sobolewska  1 ,  Marta Magdycz  1 ,  Lukasz Mucha  1 ,  Marek Masnyk  1 ,  Jakub Golab  2 ,  Marcin Nowotny  3 ,  Elzbieta Nowak  3 ,  Agnieszka Napiorkowska-Gromadzka  3 ,  Stanislaw Pikul  1 ,  Radoslaw Jazwiec  4 ,  Karolina Dzwonek  1 ,  Pawel Dobrzanski  1 ,  Michael Meyring  5 ,  Krzysztof Skowronek  6 ,  Piotr Iwanowski  1 ,  Zbigniew Zaslona  1 ,  Roman Blaszczyk  1
Affiliations
  • 1. Molecure S.A., Warsaw, Poland.
  • 2. Department of Immunology, Medical University of Warsaw, Warsaw, Poland.
  • 3. Laboratory of Protein Structure, International Institute of Molecular and Cell Biology, Warsaw, Poland.
  • 4. Institute of Biochemistry and Biophysics Polish Academy of Sciences, Warsaw, Poland.
  • 5. Nuvisan GmbH, Grafing, Germany.
  • 6. Biophysics and Bioanalytics Facility, International Institute of Molecular and Cell Biology, Warsaw, Poland. (RRID:SCR_021630).
  • # Contributed equally.
PMID: 36939275 DOI: 10.1158/1535-7163.MCT-22-0721
Abstract

Pharmacologic inhibition of the controlling immunity pathway Enzymes arginases 1 and 2 (ARG1 and ARG2) is a promising strategy for Cancer Immunotherapy. Here, we report the discovery and development of OATD-02, an orally bioavailable, potent arginases inhibitor. The unique pharmacologic properties of OATD-02 are evidenced by targeting intracellular ARG1 and ARG2, as well as long drug-target residence time, moderate to high volume of distribution, and low clearance, which may jointly provide a weapon against arginase-related tumor immunosuppression and ARG2-dependent tumor cell growth. OATD-02 monotherapy had an antitumor effect in multiple tumor models and enhanced an efficacy of the Other immunomodulators. Completed nonclinical studies and human pharmacokinetic predictions indicate a feasible therapeutic window and allow for proposing a dose range for the first-in-human clinical study in patients with Cancer.

Significance: We have developed an orally available, small-molecule intracellular Arginase 1 and 2 inhibitor as a potential enhancer in Cancer Immunotherapy. Because of its favorable pharmacologic properties shown in nonclinical studies, OATD-02 abolishes tumor immunosuppression induced by both arginases, making it a promising drug candidate entering clinical trials.

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