Abstract 6735: A systemically administered non-nucleotide STING agonist in albumin nanoformulation with potent antitumor activity and low toxicity
Authors: Tao Jinsong , Zhao Hongyi , Liu Zhongwei , Wen Hanning , Li Chengyi , Li Qiuxia , He Miao , Wen Bo , Gao Wei , Sun Duxin 
Published: March 2024

Background: Stimulator of interferon genes (STING), a dimeric transmembrane adapter protein, plays a pivotal role in regulating tumor immune microenvironment and has been explored as a therapeutic strategy against tumors. Most STING agonists were tested in clinical trials using intratumoral injection with limited systemic efficacy. Several systemically administered STING agonists have progressed to clinical trials, with their efficacy yet to be determined, while their systemic toxicity may limit their application. Our study aimed to develop a novel systemically administrated non-nucleotide STING agonist formulated within albumin nanoparticles, demonstrating potent antitumor activity and low systemic toxicity.

Methods & Results: We synthesized a novel non-nucleotide small molecule STING dimer ZSA-51D. The acid form of ZSA-51D exhibited a high binding affinity (EC 50: 1.3 nM) to human STING. ZSA-51D demonstrated potent STING activation in THP1-BlueTM ISG cells, with an EC50 of 5.1 nM. To enable systemic delivery, ZSA-51D was encapsulated in albumin nanoparticles (nano ZSA-51D) with a particle size of 115 nm. Surprisingly, nano ZSA-51D exhibited a tenfold increase in STING activation (EC50 of 0.44 nM) compared to free ZSA-51D. Furthermore, nano ZSA-51D demonstrated sevenfold greater activation of bone marrow-derived dendritic cells (EC 50 of 3.5 nM), and eightfold enhanced repolarization of bone marrow-derived macrophages (EC 50 of 4.2 nM) from M2 to M1 compared to free ZSA-51D. The in-vivo anticancer efficacy was evaluated on MC-38 and KPC 6620 xenograft in C57BL/6 mice using intravenous administration of ZSA-51D (1 mg/kg) or nano ZSA-51D, in combination with PD-1 antibody (α-PD1, 100 μg) for 5 dose every 3 days. The results revealed that nano ZSA-51D exhibited superior anticancer effects compared to free ZSA-51D. Remarkedly, nano ZSA-51D, in combination with α-PD1, completely eradicated cancer in the MC-38 xenograft model. These cured mice completely rejected the rechallenge with MC38 cells 120 days after the initial tumor inoculation, indicating potent and long-term anticancer immune memory for anticancer activity. In addition, we performed the toxicity evaluation of nano ZSA-51D and free ZSA-51D at the same dose regime as the efficacy study. Nano ZSA-51D shows no hematological and liver toxicity. However, free ZSA-51D has a sever local inflammation after injections, whereas nano ZSA-51D has no local toxicity.

Conclusion: In this study, we developed a novel systemically administered non-nucleotide sting agonist formulated within albumin nanoparticles. Nano ZSA-51, in combination with α-PD1, demonstrated superior anticancer efficacy and low toxicity, holding the potential for future clinical trials. The significantly enhanced STING activation and in vivo efficacy of nano ZSA-51D warrant further investigation into its underlying mechanisms.

Citation Format: Jinsong Tao, Hongyi Zhao, Zhongwei Liu, Hanning Wen, Chengyi Li, Qiuxia Li, Miao He, Bo Wen, Wei Gao, Duxin Sun. A systemically administered non-nucleotide STING agonist in albumin nanoformulation with potent antitumor activity and low toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6735.