GSK’s systemic STING agonist could overcome delivery hurdles

GlaxoSmithKline plc (LSE:GSK; NYSE:GSK) researchers have developed a STING agonist that can be delivered systemically as opposed to intratumorally, which can overcome challenges of accessing hard to reach tumors or cancers that have spread.

At least two companies have unencapsulated compounds that activate STING (TMEM173), which triggers CD8+ T cells to initiate tumor cell killing, in clinical testing. Merck & Co. Inc. (NYSE:MRK) and Aduro Biotech Inc. (NASDAQ:ADRO) each have STING agonists in Phase I trials, but recent data showed Aduro's compound led to treatment discontinuations in patients with advanced solid tumors or lymphomas. Merck's compound led to treatment-related adverse events in combination and monotherapy arms, but no discontinuations as monotherapy.

Other companies such as Codiak BioSciences Inc. (Cambridge, Mass.) and Synlogic Inc. (NASDAQ:SYBX) are developing a new generation of STING agonists with delivery mechanisms designed to increase cell type-specific rather than indiscriminate uptake of STING agonists, which could reduce systemic toxicity (see "Codiak's Exosomes Could Offer New Tack to STING Agonism").

However, all of these therapeutics are injected directly to the tumor. Previous studies of STING agonists have suggested that potency is a limiting factor for systemic delivery.

In a Nature paper, the GSK team identified a small molecule, amidobenzimidazole, that outcompeted STING's natural ligand, cyclic GMP-AMP (cGAMP), for binding to the receptor. A dimeric compound that linked two amidobenzimidazole molecules bound STING with an IC50 of 20 nM.

Treatment of mouse peripheral blood mononuclear cells (PBMCs) showed that an optimized dimeric amidobenzimidazole STING agonist induced STING activation and secretion of interferon β (IFNβ) with 400 times more potency than cGAMP.

In a mouse model of colon cancer, IV delivery of the STING agonist increased survival and decreased tumor growth compared with vehicle, with eight out of 10 mice achieving full tumor regression by day 43.

GSK plans to begin clinical testing of the dimeric amidobenzimidazole STING agonist next year to treat solid tumors.

The STING pathway is increasingly being recognized for its role in multiple disease areas, including autoimmune, infectious and aging-related diseases (see "Sensor Sensibility").