Identification of Novel Carbocyclic Pyrimidine Cyclic Dinucleotide STING Agonists for Antitumor Immunotherapy Using Systemic Intravenous Route

Stimulator of Interferon
Genes (STING) plays an important role
in innate immunity by inducing type I interferon production upon infection
with intracellular pathogens. STING activation can promote increased
T-cell activation and inflammation in the tumor microenvironment,
resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides
(CDNs) are known to activate STING, and several synthetic CDN molecules
are being investigated in the clinic using an intratumoral administration
route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural
ligands with optimized properties for systemic intravenous (iv) administration.
Our studies have shown that STING activation by 15a leads
to an acute innate immune response as measured by cytokine secretion
and adaptive immune response via activation of CD8+ cytotoxic T-cells,
which ultimately provides robust antitumor efficacy.