Takeda Development Center Americas, Inc. (TDCA), Lexington, Massachusetts.
Takeda Pharmaceutical Company, Ltd., Fujisawa, Kanagawa, Japan.
Cancer Res Commun. 2022 Jun 23;2(6):489-502. doi: 10.1158/2767-9764.CRC-21-0161. eCollection 2022 Jun.
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 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.
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.
针对免疫系统的肿瘤疗法已改善了多种肿瘤类型患者的预后，但由于肿瘤微环境（TME）中 T 细胞反应不足而导致的耐药性仍然是一个重大问题。新的治疗方法可激活先天免疫反应并缓解这种抑制作用，可能有助于克服这一障碍。TAK-676 是一种新型的干扰素基因（STING）激动剂，设计用于静脉给药。在这里，我们证明 TAK-676 剂量依赖性地触发 STING 信号通路的激活和 I 型干扰素的激活。此外，我们表明 TAK-676 是先天和适应性免疫系统的高度有效的调节剂，并且它促进树突状细胞、自然杀伤细胞和 T 细胞在临床前模型中的激活。在同种异体小鼠肿瘤模型中，TAK-676 诱导剂量依赖性细胞因子反应，并增加 TME 和肿瘤相关淋巴组织中免疫细胞的激活和增殖。我们还证明，TAK-676 给药导致明显的依赖 STING 的抗肿瘤活性，包括完全消退和持久的记忆 T 细胞免疫。我们表明 TAK-676 耐受性良好，在血浆中表现出剂量比例的药代动力学，并且在肿瘤中表现出更高的暴露。TAK-676 的静脉给药为多种肿瘤类型提供了潜在的治疗益处。TAK-676 的首次人体 I 期临床试验的进一步研究正在进行中。
TAK-676 是一种新型的系统性 STING 激动剂，可有效激活先天和适应性免疫活性，在多种同种异体肿瘤模型中产生持久的抗肿瘤反应。TAK-676 的临床研究正在进行中。
