Radhakrishnan P Iyer is the co-founder and Chief Scientific Officer of Spring Bank Pharmaceuticals. He has more than 25 years’ experience in the Biotechnology industry in drug discovery and development in diverse therapeutic areas including antivirals, inflammation, and immune-oncology. He is a leading innovator in the fields of nucleic acid chemistry, bioorganic chemistry and pharmaceutical sciences with over 100 publications and 200 issued, as well as, filed US and international patents. Prior to Spring Bank, he was the co-founder and VP of Discovery of Origenix Technologies and also served as Associate Director of Antisense Discovery at Hybridon, Inc. He currently serves on the Board of Directors of Spring Bank Pharmaceuticals and is a member of the Scientific Advisory Board of Oligomerix, Inc., NY.
Introduction: Immunotherapy has emerged as a transformative approach for the treatment of cancer. Recent work has highlighted a significant role for Stimulator of Interferon Genes (STING) agonists in immunotherapy. Conceptually, the activation of STING pathway in immune cells in the tumor microenvironment and/or tumor cells could result in the induction of innate and adaptive immunity through the activation of cytotoxic T cells and NK cells for profound and durable anti-tumor response. Herein, we describe the pharmacodynamic studies of a highly potent and selective first-in-class STING agonist SB 11285 and its structural analogs in different syngeneic tumor models.
Methods: For efficacy studies, SB 11285 was administered by intravenous (i.v.), intraperitoneal (i.p.) or intratumoral (i.t.) routes in the A20 lymphoma, CT26 colon carcinoma, B16 melanoma, and 4T1 breast cancer syngeneic mouse models (10 animals/group) and tumor growth inhibition (TGI) and tumor growth delay (TGD) assessed by measurement of mean tumor volumes (MTV). To check for the induction of immune memory, SB 11285 was administered i.t., (100μg, days 1,2,4,6,8) in the A20 model, monitored for 73 days and tumor-free survivors (TFS) were re-challenged with A20 cells and followed for an additional 45 days. Abscopal antitumor effect of i.t.-administered SB 11285 (100μg, days 1,2,4,6,8) was evaluated by implantation of tumors in the left and right flanks in the
CT26 model. Next, dose-ranging studies of SB 11285 were performed using i.t. (10 to 100μg), i.p. (1 to 9mg/kg) and i.v. (1 to 9mg/kg) routes in the CT26 model. Pharmacodynamic (PD) studies of SB 11285 was carried out in the 4T1 and CT26 models by
(i) measurement of cytokines in serum,
(ii) enumeration of cytotoxic T cells, as well as, MDSCs in blood, lymph , and spleen by flow cytometry; and
(iii) immuno-histochemistry of tumor tissues.
Results: (a) In the A20 model, 9 out of 10 animals that received, i.t. SB 11285 achieved complete tumor regression with 86% TGI & 73% TGD; all TFS rejected the tumors upon re-challenge with A20 cells;
(b) In the CT26 model, SB 11285 monotherapy resulted in highly durable antitumoral response: i.t., 94% TGI & 207% TGD; i.p., 62% TGI & 49% TGD and i.v., 80% TGI & 85% TGD respectively with complete tumor regression in several animals;
(c) In the B16 melanoma pilot study, both i.v and i.p. administrations of SB 11285 resulted in 77% and 56% reduction in MTV respectively by day 11 post-treatment;
(d) In the 4T1 breast cancer model, i.p.-administered SB 11285 showed 78% reduction in MTV by 21 days post-implantation with resulting potent inhibition of tumor metastasis;
(e) i.t.-administered SB 11285 showed a profound abscopal effect in the CT26 model;
(f) SB 11285 displayed dose-dependent TGI and TGD when administered i.t., i.p., & i.v in the CT26 model;
(g) Cytokine analysis showed the induction of type I interferon and cytokines;
(h) Flow cytometric analysis of blood, lymph nodes and spleen revealed induction of CD8+ T cells, a decrease in CD4 T cells;
(j) Immuno-histochemistry of tumor tissues from SB 11285-treated groups revealed the presence of CD8+ T cells, NK cells, and macrophages.
Conclusion: SB 11285, a novel STING agonist, showed potent, and highly durable immune-mediated antitumor activity when administered by multiple routes in the syngeneic mice tumor models. IND-enabling studies are ongoing to support the clinical trials
of SB 11285 in Q4 2018.