Development of Lasso Peptides as Potent Endothelin Receptor B Antagonists for Immuno-oncology

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Abstract. Immunotherapy has rapidly emerged as an effective treatment option for a growing number of cancers, yet the vast potential of this approach is often limited by low patient response rates (10-20%) caused by multiple immune escape and suppression pathways that operate in the tumor microenvironment (TME). For example, ovarian cancer has been found to overexpress endothelin receptor type B (ETBR) in the tumor vasculature, which suppresses endothelial cell expression of adhesion molecules (e.g., ICAM-1) and prevents migration of immune cells, such as tumor infiltrating leukocytes (TILs), into the TME. Without intra-tumoral TILs, the anti-tumor immune response is weak and immunotherapy efficacy is poor. Antagonism of ETBR thus represents a novel approach to improve immunotherapy patient response rates. Recent studies have shown ETBR is overexpressed (>2x normal tissue) in at least 50% of primary ovarian cancers (OC) and up to 62% of primary triple negative breast cancers (TNBC) and 100% of metastatic TNBC. OC samples that overexpress ETBR in the tumor vasculature were shown to have very low TILs and low response to immunotherapy, both of which dramatically increased upon treatment with one of the few available ETBR antagonists, BQ- 788. In the same experiments, a dual ETBR/ETAR antagonist, macitentan, was shown to be ineffective, indicating that selective ETBR antagonists are required to increase TILs. Unfortunately, BQ-788 displays only modest selectivity (ca. 200x vs ETAR) and has poor drug properties, underscoring the need for new and improved ETBR antagonists. Lassogen is leveraging the unique properties of lasso peptides in order to create novel therapeutics for immuno-oncology (IO) applications. Lasso peptides are small, highly stable, constrained natural peptides (15-25 amino acids) possessing a distinctive lariat-like folded structure that facilitates target engagement through a 3D orientation of functionality. Importantly, lasso peptides have displayed high affinity for certain G protein-coupled receptors, and thus represent an untapped source of new medicines that modulate this important class of disease targets. Lassogen is developing LAS-103 as a stable, potent, and selective ETBR antagonist that enhances leukocyte influx into the TME and renders tumors more susceptible to immunotherapy. Herein, we propose to test the safety, pharmacology, and efficacy of LAS-103 for treating ovarian cancer.