601 Development of improved small molecule STING agonists suitable for systemic administration

Autor: Magdalena Zastawna, Marcin Leś, Peter Littlewood, Karolina Wiatrowska, Izabela Strojny, Raghuram Tangirala, Katarzyna Wójcik-Jaszczyńska, Monika Dobrzańska, Tushar Mahajan, Stefan Chmielewski, Karolina Gluza, Kamil Kuś, Ewelina Gabor-Worwa, Urszula Głowniak-Kwitek, Magdalena Zawadzka, Justyna Jabłońska, Aleksandra Poczkaj, Maciej Rogacki, David Synak, Wojciech Schonemann, Jolanta Mazurek, Katarzyna Banaszak, Karol Zuchowicz, Krzysztof Brzózka, Katarzyna Wnuk-Lipinska, Mirosława Gładysz, Marek Wronowski, Urszula Kulesza, Luigi Stasi, Lukasz Piotr Dudek
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Journal for ImmunoTherapy of Cancer, Vol 8, Iss Suppl 3 (2020)
ISSN: 2051-1426
Popis: Background Stimulator of Interferon Genes (STING) is a major player in the activation of robust innate immune response leading to initiation and enhancement of tumor-specific adaptive immunity. Several clinical and pre-clinical programs have shown that activation of the STING pathway triggers immune-mediated antitumor response. Although vast majority of programs focus on development of analogues of the endogenous STING ligands, their chemical nature and stability often limit their use to local administration. Herein, we present recent results from the development of our selective non-nucleotide, non-macrocyclic, small molecule direct STING agonists, suitable for systemic administration, characterized by improved activity in human immune cells. Methods Binding to recombinant STING protein was examined using FTS, MST, FP and crystallography studies. Phenotypic screen was performed in THP-1 Dual reporter cells. Mouse bone marrow-derived dendritic cells (BMDC) were obtained from C57BL/6 mice and differentiated with mIL-4 and mGM-CSF. STING agonists were administered into BALB/c mice and cytokine release was measured in plasma. Additionally, mice were inoculated with CT26 murine colon carcinoma or EMT6 murine breast carcinoma cells and the compound was administered, followed by the regular tumor growth and body weight monitoring. Results Ryvu’s small-molecule agonists demonstrate strong binding affinity to recombinant STING proteins across all tested species. The compounds bind to all human STING protein variants and trigger pro-inflammatory cytokine release from human immune cells regardless of the STING haplotype. Moreover, new generation of developed agonists show significantly improved binding to human protein as well as in vitro activity on human cells. Systemic, intravenous in vivo administration leads to a dose-dependent upregulation of STING-dependent pro-inflammatory cytokines, which results in a dose-dependent antitumor efficacy observed in CT26 and EMT6 mouse cancer models, leading to complete tumor remissions in all treated animals. Furthermore, observed efficacy is accompanied by development of a lasting immunological response demonstrated by lack of tumor engraftment or a delayed tumor growth in cured animals challenged with repeated inoculation of cancer cells. Conclusions New generation Ryvu’s STING agonists are strong and selective activators of STING-dependent signaling in both mouse and human immune cells promoting anti-tumor immunity. Treatment with Ryvu’s small-molecule STING agonists leads to engagement of the immune system which results in a complete tumor remission and development of immunological memory of the cancer antigens. The compounds show good selectivity and ADME properties enabling development for systemic administration. In addition developed compounds maintain small functional handles amenable to linker attachment making the series suitable for versatile development as single agents, for combinations with immunotherapies or as targeted agents.
Databáze: OpenAIRE
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