Characterization of a Novel Transmembrane Activating STING Agonist using Genetically Humanized Mice

Area of Science:

• Immunology
• Pharmacology
• Molecular Biology

Background:

• STING (STimulator of INterferon Genes) is a key pattern recognition receptor involved in innate immunity.
• Pharmacologic STING agonists can enhance vaccine efficacy and antitumor responses, but clinical translation remains limited.
• Distinct cellular responses are linked to cytosolic versus transmembrane STING activation, with limited tools for studying the latter in vivo.

Purpose of the Study:

• To synthesize novel STING agonists effective against various STING protein variants.
• To develop and validate a genetically humanized mouse model for in vivo testing of human-selective STING agonists.
• To investigate the in vivo effects of transmembrane STING agonism using a novel agonist (INI3069).

Main Methods:

• Synthesis of novel STING agonists targeting both allelic variants and transmembrane domains.
• Generation of genetically humanized STING mice expressing human STING protein.
• In vivo evaluation of the lead agonist INI3069 for its mechanism, immune effects, and therapeutic potential.

Main Results:

• INI3069, a novel transmembrane STING agonist, was synthesized and demonstrated efficacy in humanized mice.
• INI3069 exhibits distinct molecular and immune effects compared to conventional STING agonists.
• INI3069 enhanced antibody responses to co-administered antigens and demonstrated antitumor efficacy.

Conclusions:

• This study presents the first in vivo examination of transmembrane STING agonism.
• INI3069 represents a potential novel vaccine adjuvant and oncological therapeutic.
• The developed humanized mouse model is suitable for evaluating human-selective STING agonists in vivo.