Novel Class of STING Agonists for Immuno-oncology
Sreerupa Challa1, Shenghua Zhou1, Anjaneyulu Sheri1, Samantha Delaney1, Rayomand Gimi1,
Seetharamaiyer Padmanabhan1, Geeta Meher1, Diane Schmidt, 1Dillon Cleary1, Santosh Khedkar2, Nezam Afdhal1, and Radhakrishnan Iyer1
1Spring Bank Pharmaceuticals, Inc., 113 Cedar Street, Milford, MA 01757, USA;
2ChemBio Discovery Solutions, Lexington, MA 02421, USA
Immunotherapy has emerged as a transformative approach for the treatment of cancer. Indeed, the activation of Stimulator of Interferon Genes (STING) pathway in immune calls within the tumor microenvironment (TME) can induce the production of Interferons and cytokines for innate and adaptive immunity against cancer. Therefore, the combination of STING agonists with other agents is expected to provide synergistic anti-cancer response against multiple cancers.
Methods and Results: Using structure-guided drug design, a library of nucleotide compounds was evaluated using reporter assays in SZ14 HEK cells. Following SAR studies, a lead compound SB 11285 was identified as a highly potent STING agonist that cause: (a) induction of IRF with an EC50 of 2 nM, and NF-kB with an EC50 of 200 nM in THP-1 cells, (b) secretion of type I and III Interferons, (c) expression of PRRs and ISGs, (d) modulation of BAX and BCL2 levels for apoptosis in selective cell lines. In the mouse lymphoma tumor model, the administration of SB 11285 (100 g, i.t., days 3,4 6, 8 and 10 post study-start [ss]), showed highly potent anti-tumor activity. When SB 11285 was used in combination with cyclophosphamide (100 mg/kg, i.p., days 1 and 2 post ss), a highly durable antitumor response resulted with 9 out of 10 animals achieving complete response in 60 days post ss. In the SB 11285-treated groups, the presence of CD8 T cells and NK cells in the TME correlated with the induction of innate and adaptive immune response for anti-tumor activity.
Conclusion: We have discovered a highly potent first-in-class STING agonist SB 11285 that shows excellent safety and anti-tumor activity in syngeneic mouse models. SB 11285 is being advanced for additional preclinical studies for application in immuno-oncology.
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