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

> **NIH NIH R43** · LASSOGEN, INC. · 2021 · $399,609

## Abstract

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.

## Key facts

- **NIH application ID:** 10259206
- **Project number:** 1R43CA257077-01A1
- **Recipient organization:** LASSOGEN, INC.
- **Principal Investigator:** Mark J Burk
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $399,609
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10259206

## Citation

> US National Institutes of Health, RePORTER application 10259206, Development of Lasso Peptides as Potent Endothelin Receptor B Antagonists for Immuno-oncology (1R43CA257077-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10259206. Licensed CC0.

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