SB 11285, a Novel Canonical Purine-Pyrimidine Cyclic Dinucleotide, is a Systemically Bioavailable STING Agonist for Cancer Immunotherapy

Abstract

SummarySB 11285, a novel cell-permeable, canonical 3,5, purine-pyrimidine cyclic dinucleotide has been developed as a potent systemically bioavailable STING agonist currently in clinical trials. The stimulator of Interferon genes (STING) pathway, crucial for cytosolic DNA sensing and innate immunity, presents a promising avenue for novel cancer immunotherapies. Discussed here is the discovery and development of SB11285, a potent activator of the STING pathway, belonging to the canonical class of 3,5 purine-pyrimidine (PuPy) cyclic dinucleotides (CDNs). SB11285 exhibits superior potency and cell permeability compared to non-canonical 2,3-CDNs and demonstrates robust antitumor activity in in vivo syngeneic mouse tumor models, resulting in complete tumor regression, and durable immunological memory. Combination with checkpoint inhibitors and cytotoxic agents further enhances its efficacy. The anti-tumor effects of SB 11285 rely on the induction of CD8+ T cells, activated macrophages, and NK cells in the tumor microenvironment (TME), for efficient tumor killing and fostering profound and durable anti-tumor response. Our findings underscore the potential of functionalized canonical 3,5-Pu-Py CDNs, exemplified by SB11285, as safe and potent STING agonists for multiple routes of administration in cancer therapy. Currently, SB11285 administered intravenously (IV), is undergoing evaluation as the first systemically administered CDN analog in human clinical trials across various tumor types.