| Autor: |
Masanori Okaniwa, Michael H. Shaw, Christopher Arendt, Adnan O. Abu-Yousif, Joseph Conlon, Tennille D. Thelen, Pu Shi, Tary Traore, Saurabh Menon, Hojjat Bazzazi, Omid Ghasemi, Emily R. Roberts, Chris Gemski, Vaishali Shinde, Satyajeet Haridas, Luhua Shen, Jian Huang, Masato Yoshikawa, Michiyo Mochizuki, Judy Shi, Atsushi Matsuda, Vihren Kolev, Shinji Iwasaki, Vicky A. Appleman, Doanh Mai, Yosuke Sato, Elizabeth Carideo Cunniff |
| Rok vydání: |
2023 |
| Popis: |
Oncology therapies targeting the immune system have improved patient outcomes across a wide range of tumor types, but resistance due to an inadequate T-cell response in a suppressive tumor microenvironment (TME) remains a significant problem. New therapies that activate an innate immune response and relieve this suppression may be beneficial to overcome this hurdle. TAK-676 is a synthetic novel stimulator of interferon genes (STING) agonist designed for intravenous administration. Here we demonstrate that TAK-676 dose-dependently triggers activation of the STING signaling pathway and activation of type I interferons. Furthermore, we show that TAK-676 is a highly potent modulator of both the innate and adaptive immune system and that it promotes the activation of dendritic cells, natural killer cells, and T cells in preclinical models. In syngeneic murine tumor models in vivo, TAK-676 induces dose-dependent cytokine responses and increases the activation and proliferation of immune cells within the TME and tumor-associated lymphoid tissue. We also demonstrate that TAK-676 dosing results in significant STING-dependent antitumor activity, including complete regressions and durable memory T-cell immunity. We show that TAK-676 is well tolerated, exhibits dose-proportional pharmacokinetics in plasma, and exhibits higher exposure in tumor. The intravenous administration of TAK-676 provides potential treatment benefit in a broad range of tumor types. Further study of TAK-676 in first-in-human phase I trials is ongoing.Significance:TAK-676 is a novel systemic STING agonist demonstrating robust activation of innate and adaptive immune activity resulting in durable antitumor responses within multiple syngeneic tumor models. Clinical investigation of TAK-676 is ongoing. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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