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

抽象的。免疫疗法已迅速成为一种有效的治疗选择 癌症的数量，但这种方法的巨大潜力往往受到患者人数的限制 多条免疫逃逸和抑制途径导致的应答率(10%-20%) 在肿瘤微环境(TME)中操作。例如，卵巢癌已被发现 内皮素受体B型(ETBR)在肿瘤血管中的过表达 内皮细胞表达黏附分子(如ICAM-1)并阻止血管内皮细胞迁移 免疫细胞，如肿瘤浸润性白细胞(TIL)，进入TME。无瘤内 TIL，抗肿瘤免疫反应弱，免疫治疗效果差。 因此，ETBR的拮抗作用代表了改善免疫治疗患者的一种新途径 应答率。 最近的研究表明，ETBR在至少50%的组织中过度表达(是正常组织的2倍) 原发卵巢癌(OC)和高达62%的原发三阴性乳腺癌(TNBC) 转移的TNBC为100%。在肿瘤血管系统中过表达ETBR的OC样本 被证明具有非常低的TIL和对免疫治疗的低反应性，这两种情况 使用为数不多的ETBR拮抗剂之一BQ治疗后，BQ- 788。在同一实验中，ETBR/ETAR双重拮抗剂Macitentan被证明是 无效，表明需要选择性的ETBR拮抗剂来增加TIL。 不幸的是，BQ-788只表现出适度的选择性(大约是Etar的200倍)，而且药物很差 属性，强调需要新的和改进的ETBR拮抗剂。 Lassogen正在利用套索多肽的独特性质来创造新的 针对免疫肿瘤学(IO)应用的治疗。套索多肽很小，高度稳定， 受限制的天然多肽(15-25个氨基酸)，具有独特的套索状折叠 通过功能的3D方向促进目标交战的结构。 重要的是，套索肽对某些G蛋白偶联受体表现出高亲和力， 因此代表了一种未开发的新药来源，这些新药调节了这一重要类别的 疾病目标。Lassogen正在开发LAS-103，作为一种稳定、高效和选择性的ETBR 一种拮抗剂，可增加白细胞进入TME并使肿瘤更容易发生 免疫疗法。在此，我们建议测试LAS-103的安全性、药理学和有效性 治疗卵巢癌。

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.