ADU-S100 disodium salt

ADU-S100 disodium salt (MIW815 disodium salt) is an activator of stimulatory interferon gene (STING) protein with a K_d of 4.61±0.42μM[1]. The mechanism of action of ADU-S100 disodium salt is to activate the STING pathway by simulating the effect of cyclic GMP-AMP (cGAMP), thereby inducing the production of inflammatory cytokines such as IFN-β^[2]. ADU-S100 disodium salt shows higher anti-tumor ability than endogenous ML cGAMP ^[3].

In vitro, ADU-S100 disodium salt (0-100µM) treated glioblastoma (GBM) cells without toxicity, but in the presence of PBMC, ADU-S100 produced immune-mediated cytotoxicity against GBM cells at 12.5 and It is effective between 50µM and less effective at 100µM^[4]. ADU-S100 disodium salt stimulated the THP-1 Dual cell line for 48 hours, and the EC₅₀ values of activated cell IRF 3 and NF-κB pathways were 3.031 and 4.839µg/mL respectively ^[5].

In vivo, ADU-S100 disodium salt (50µg) was administered via intracranial injection to GL 261 and CT-2A tumor model mice 3 days after treatment, causing suppression of microglia and T cell populations, as well as NK and inflammatory responses. In the infiltration of immune cells, the proportion of T cells recovered 7 days after treatment and increased compared with the baseline level ^[4]. ADU-S100 disodium salt (20 or 40µg) was treated by subcutaneous injection in colon cancer model mice, which effectively inhibited the growth of CT-26 tumors, significantly increased the number of lymphocytes, and prevented tumor metastasis to liver and spleen tissues^[6].

References:

[1]Jekle A, Thatikonda S, Stevens S, et al. Abstract 4520: Preclinical characterization of ALG-031048, a novel STING agonist with potent anti-tumor activity in mice[C]//Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24.

[2]Jneid B, Bochnakian A, Hoffmann C, et al. Selective STING stimulation in dendritic cells primes antitumor T cell responses[J]. Science Immunology, 2023, 8(79): eabn6612.

[3]Corrales L, et al. Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity[J]. Cell Rep. 2015 May 19;11(7):1018-30. 

[4]Berger G, Knelson E H, Jimenez-Macias J L, et al. STING activation promotes robust immune response and NK cell–mediated tumor regression in glioblastoma models[J]. Proceedings of the National Academy of Sciences, 2022, 119(28): e2111003119.

[5]Ji N, Wang M, Tan C. Liposomal delivery of MIW815 (ADU-S100) for potentiated STING activation[J]. Pharmaceutics, 2023, 15(2): 638.

[6]Zaidi A H, Kelly R J, Gorbunova A, et al. Intratumoral immunotherapy with STING agonist, ADU-S100, induces CD8+ T-cell mediated anti-tumor immunity in an esophageal adenocarcinoma model[J]. Oncotarget, 2021, 12(4): 292.

ADU-S100 disodium salt（MIW815 disodium salt）是干扰素基因刺激蛋白（STING）的激活剂，K_d为4.61±0.42μM^[1]。ADU-S100 disodium salt的作用机制是通过模拟环状GMP-AMP（cGAMP）的作用，激活STING途径，进而诱导IFN-β等炎症性细胞因子的产生^[2]。ADU-S100 disodium salt比内源性ML cGAMP显示出更高的抗肿瘤能力^[3]。

在体外，ADU-S100 disodium salt（0-100µM）处理胶质母细胞瘤（GBM）细胞没有毒性，但在PBMC存在下，ADU-S100对GBM细胞产生了免疫介导的细胞毒性，在12.5和50 µM之间有效，而在100µM时效果降低^[4]。ADU-S100 disodium salt刺激THP-1 Dual细胞系48h，活化细胞IRF 3和NF-κ B途径的EC₅₀值分别为3.031、4.839µg/mL^[5]。

在体内，ADU-S100 disodium salt（50µg）通过颅内注射给予GL 261和CT-2A肿瘤模型小鼠，治疗后3d，引起了小胶质细胞和T细胞群体的抑制，以及NK和炎性免疫细胞的浸润，治疗后7d，T细胞比例恢复，与基线水平相比有所增加^[4]。ADU-S100 disodium salt（20 or 40µg）通过皮下注射治疗结肠癌模型小鼠，有效地抑制了CT-26肿瘤生长，显著增加了淋巴细胞的数量，且阻止了肿瘤转移到肝、脾组织中^[6]。