posted on 2024-09-16, 11:53authored byBartlomiej Borek, Julita Nowicka, Anna Gzik, Marek Dziegielewski, Karol Jedrzejczak, Joanna Brzezinska, Marcin Grzybowski, Paulina Stanczak, Paulina Pomper, Agnieszka Zagozdzon, Tomasz Rejczak, Krzysztof Matyszewski, Adam Golebiowski, Jacek Olczak, Kamil Lisiecki, Magdalena Tyszkiewicz, Magdalena Kania, Sylwia Piasecka, Anna Cabaj, Paulina Dera, Krzysztof Mulewski, Jacek Chrzanowski, Damian Kusmirek, Elzbieta Sobolewska, Marta Magdycz, Lukasz Mucha, Marek Masnyk, Jakub Golab, Marcin Nowotny, Elzbieta Nowak, Agnieszka Napiorkowska-Gromadzka, Stanislaw Pikul, Radoslaw Jazwiec, Karolina Dzwonek, Pawel Dobrzanski, Michael Meyring, Krzysztof Skowronek, Piotr Iwanowski, Zbigniew Zaslona, Roman Blaszczyk
Allometric scaling of human volume of distribution (V-SAfu)
History
ARTICLE ABSTRACT
Pharmacological 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 pharmacological 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 non-clinical 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 cancer patients.