Novel Quaternary Ammonium Salt‐Linked STING Agonist Antibody‐Drug Conjugate: Synergistic Activation of Tumor Immunity with Mitigated Off‐Target Toxicity

Novel Quaternary Ammonium Salt‐Linked STING Agonist Antibody‐Drug Conjugate: Synergistic Activation of Tumor Immunity with Mitigated Off‐Target Toxicity

Abstract Immune‐stimulating antibody conjugate (ISACs) incorporating STING agonists as payloads leverage both the targeting capability of the Fab region and the Fc region‐mediated tumor antigen‐dependent immune activation. Herein, a novel class of ISACs is reported, generated by engineering a quater...

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Main Authors: Yu Long, Borui Tang, Fei Xie, Lianqi Liu, Yangyihua Zhou, Jingwen Dong, Jianfeng Wang, Cuicui Sun, Yuting Wang, Ruoqi Li, Na Zhang, Liping Li, Longlong Luo, Junhai Xiao, Wu Zhong, Dian Xiao, Hongbin Deng, Xinbo Zhou
Format: Article
Language:English
Published: Wiley 2025-08-01
Series:Advanced Science
Subjects:
antitumor immunity
diABZI STING agonist 3
immune‐stimulating antibody conjugates
quaternary ammonium salt‐linker
stimulator of interferon genes
Online Access:https://doi.org/10.1002/advs.202502270
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Summary:Abstract Immune‐stimulating antibody conjugate (ISACs) incorporating STING agonists as payloads leverage both the targeting capability of the Fab region and the Fc region‐mediated tumor antigen‐dependent immune activation. Herein, a novel class of ISACs is reported, generated by engineering a quaternary ammonium‐cleavable linker to conjugate diABZI STING agonist 3 (dSA3) with the HER2‐targeting antibody Trastuzumab. The optimized ISAC (TZ‐dSA3‐12) demonstrated high potency, stability, enhanced solubility, and reduced off‐target toxicity. The data showed that TZ‐dSA3‐12 potently activates the STING pathway in the tumor microenvironment through the synergistic action of the Fab and Fc regions of antibodies (activity switch‐on). In contrast, TZ‐dSA3‐12 exhibited ≈75 fold lower activity than dSA3 in normal immune cells, where activation relies solely on the Fc region without Fab‐mediated tumor antigen binding (activity switch‐off). Furthermore, systemic administration of TZ‐dSA3‐12 at a dose (1 mg kg−1) elicited robust and sustained antitumor effect in a manner dependent on the activation of innate immunity and adaptive immunity, including macrophages, dendritic cells (DCs) and CD8+ T cells, while minimizing systemic cytokine release. Notably, TZ‐dSA3‐12 also induced immunological memory to combat the growth of rechallenged tumors. This innovative quaternary ammonium‐linked STING agonist‐ISAC represents a promising avenue for the future development of STING‐targeted immunotherapy.
ISSN:2198-3844

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