Preclinical studies of SB 11285, a novel STING agonist for immuno-oncology.

Abstract

e14616 Background: The activation of innate and adaptive immunity via Stimulator of Interferon Genes (STING) signaling is a potentially transformative immuno-therapeutic strategy in cancer. We report here in vivo efficacy and safety studies of SB 11285. Methods: Tumor Growth Inhibition (TGI) and Tumor Growth Delay (TGD) studies in syngeneic mouse models were initiated when mean tumor volume (MTV) reached 100mm3: A20 Lymphoma: (10 animals/Group); (A) Saline; (B) 100µg SB 11285, intratumoral (i.t.), days 3,4,6,8,10; (C) 100mg/kg Cyclophosphamide, intraperitoneal (i.p), days 1,2; and (D) combination of cyclophosphamide+SB 11285. CT26 Colon Carcinoma experimental design is shown in Table. Re-challenge study was initiated in tumor-free animals in A20 lymphoma model on day 73, and monitored for an additional 45 days. Presence of activated immune cells intumor tissues was evaluated by immuno-histochemistry. Cytokine response was evaluated in serum after a single i.p. injection of SB 11285 at 10mg/kg. Maximum Tolerated Dose (MTD) in mice was determined by daily i.p. injection of SB 11285 for 10 days. Results: A20 model: % TGI in the treatment groups were—A, 0; B, 86; C, 98, and D, 93; % TGD, day 70: A, 0; B, 64; C, 156; D, 288. In D, day 73, 90% of animals remained tumor-free. CT26 model: Table 1 shows MTV on day 19 and %TGD on day 43; Re-challenge study. All animals from the SB 11285-treated groups remained completely tumor-free on day 45 compared to control group (MTV,1666 mm3); Immuno-histochemistry of SB 11285-treated groups, revealed the infiltration of CD8+T and NK cells into tumor and surrounding tissues; Cytokine analysis did not show systemic inflammatory response; MTD of SB 11285 was 16 mg/kg/day. Conclusions: SB 11285, a novel STING agonist, showed very potent, and highly durable immune response-mediated anti-tumor activity. SB 11285 was well tolerated, safe, and is being advanced to IND-enabling studies. [Table: see text]