Abstract 6349: Targeting the CXCR3 pathway with a novel peptide drug candidate mobilizes the immune system to enhance anti-tumor immunity

Abstract

Abstract Immune-checkpoint inhibitor (ICI) therapy releases the molecular “brakes” on the immune system thereby promoting robust anti-tumor immune responses. However, many patients do not respond to ICI therapy due to development of primary and secondary resistance, and this population represents a large unmet medical need. The critical role of C-X-C motif chemokine receptor 3 (CXCR3) signaling in eliciting an effective response to anti-PD-1 therapy has been recently demonstrated. The CXCR3 chemokine system is instrumental in effector cell recruitment to the tumor and augments intratumoral CD8+ T cell proliferation and function, which are key mechanisms driving anti-tumor immunity and responses to ICI therapy. We used our proprietary peptide discovery platform to identify a unique microbiome-derived peptide, SG-3-00802, from bacterial strains associated with response to anti-PD1 inhibitors in patients with melanoma. We subsequently determined that CXCR3 is the target receptor for SG-3-00802 and demonstrated that SG-3-00802 enhanced the activity of CXCR3 in the presence of its endogenous ligands CXCL9/CXCL10/CXCL11. Optimization of SG-3-00802 pharmacological properties led to the selection of a novel drug development candidate SG-3-00802DC with improved potency and PK properties. Mechanistically, it increases CXCR3 activation by CXCL11 by greater than 10-fold from a nM to a pM range. As a positive allosteric modulator, SG-3-00802DC can potentially alter the conformation of the primary orthosteric binding site of CXCR3 and enhance the binding affinity of CXCL11, causing increased CXCR3 signaling activity, which is known to drive TIL infiltration that improves overall survival in mouse tumor models and cancer patients. Supporting this concept, we demonstrated that SG-3-00802DC showed anti-tumor activity in pre-clinical mouse tumor models, alone and in combination with anti-PD-1, improved overall survival and increased recruitment of CXCR3+ effector cells into the tumor microenvironment. Numerous strategies are currently undergoing clinical evaluation to improve long-lasting disease control in broader patient populations by combining ICIs with approved and novel therapeutic agents and procedures. SG-3-00802DC, with its well validated and unique mechanism of action to safely target the CXCR3-driven anti-tumor immune response offers a novel orthogonal approach complementary not only to immunotherapies, but also as a combination strategy with chemotherapy or radiotherapy. Citation Format: Dhwani Haria, Jina Lee, Justy Guagua, Archana Nagaraja, Kyle Roskamp, Bum-Yeol Hwang, Divya Ravichandar, Michi Willcoxon, Todd DeSantis, Karim Dabbagh, Helena Kiefel. Targeting the CXCR3 pathway with a novel peptide drug candidate mobilizes the immune system to enhance anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6349.