Immunotherapy has rapidly emerged as an effective treatment option for a growingnumber of cancers, yet the vast potential of this approach is often limited by low patientresponse rates (10-20%) caused by multiple immune escape and suppression pathways thatoperate in the tumor microenvironment (TME). For example, ovarian cancer has been found tooverexpress endothelin receptor type B (ETBR) in the tumor vasculature, which suppressesendothelial cell expression of adhesion molecules (e.g., ICAM-1) and prevents migration ofimmune cells, such as tumor infiltrating leukocytes (TILs), into the TME. Without intra-tumoralTILs, the anti-tumor immune response is weak and immunotherapy efficacy is poor.Antagonism of ETBR thus represents a novel approach to improve immunotherapy patientresponse rates.Recent studies have shown ETBR is overexpressed (>2x normal tissue) in at least 50% ofprimary 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 vasculaturewere shown to have very low TILs and low response to immunotherapy, both of whichdramatically 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 beineffective, indicating that selective ETBR antagonists are required to increase TILs.Unfortunately, BQ-788 displays only modest selectivity (ca. 200x vs ETAR) and has poor drugproperties, underscoring the need for new and improved ETBR antagonists.Lassogen is leveraging the unique properties of lasso peptides in order to create noveltherapeutics for immuno-oncology (IO) applications. Lasso peptides are small, highly stable,constrained natural peptides (15-25 amino acids) possessing a distinctive lariat-like foldedstructure 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 ofdisease targets. Lassogen is developing LAS-103 as a stable, potent, and selective ETBRantagonist that enhances leukocyte influx into the TME and renders tumors more susceptible toimmunotherapy. Herein, we propose to test the safety, pharmacology, and efficacy of LAS-103for treating ovarian cancer. Lassogen is developing new ways to diagnose and treat serious diseases through a novel class of natural compounds called lasso peptides. Lasso peptides display a unique 3D shape that looks like a "lasso", with a ring, loop, and tail that engender these remarkable molecules with high stability and potent biological activities. Lassogen's most advanced product, LAS-103, is a lasso peptide that is designed to enhance the ability of our own immune systems to attack and destroy ovarian cancer and other devastating malignancies. 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