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

开发套索肽作为免疫肿瘤学的有效内皮素受体 B 拮抗剂

• 批准号: 10259206
• 负责人: Mark J Burk
• 金额: $ 39.96万
• 依托单位: LASSOGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259206
• 关键词: 3-Dimensional; Address; Affinity; Amino Acids; Animal Model; Binding Proteins; Biological; C57BL/6 Mouse; Cancer Model; Cell Adhesion Molecules; Cells; Clinical; Clinical Trials; Cyclic GMP; Development; Diagnosis; Disease; Dose; Drug Kinetics; Endothelial Cells; Endothelin B Receptor; Endothelin Receptor; Endothelin Receptor Antagonist; G-Protein-Coupled Receptors; Human; Immune; Immune checkpoint inhibitor; Immune system; Immunocompetent; Immunooncology; Immunotherapy; In Vitro; Intercellular adhesion molecule 1; Intravenous; Lasso; Lead; Leukocytes; Malignant Neoplasms; Malignant neoplasm of ovary; Medicine; Metabolic; Mus; Normal tissue morphology; Oral; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Property; Protocols documentation; Risk Assessment; Safety; Sampling; Serum; Shapes; Source; Structure; Tail; Testing; Therapeutic; Toxic effect; Urine; anti-tumor immune response; comparative; design; effective therapy; efficacy trial; experimental study; human model; immunogenicity; improved; in silico; in vivo; in vivo evaluation; intraperitoneal; migration; mouse model; novel; novel strategies; novel therapeutics; overexpression; patient derived xenograft model; patient response; phase 1 study; plasma protein fraction; prevent; programmed cell death protein 1; receptor; response; safety testing; scale up; triple-negative invasive breast carcinoma; tumor; tumor microenvironment

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.

抽象的。免疫疗法已迅速成为越来越多的患者的有效治疗选择 癌症的数量，但这种方法的巨大潜力往往受到患者人数少的限制 由多种免疫逃逸和抑制途径引起的缓解率（10-20%） 在肿瘤微环境（TME）中运作。例如，已发现卵巢癌 在肿瘤血管系统中过度表达 B 型内皮素受体 (ETBR)，从而抑制 内皮细胞表达粘附分子（例如 ICAM-1）并阻止粘附分子的迁移 免疫细胞，例如肿瘤浸润白细胞 (TIL)，进入 TME。无瘤内 TILs的抗肿瘤免疫反应较弱，免疫治疗效果较差。 因此，ETBR 的拮抗代表了一种改善患者免疫治疗的新方法 回复率。 最近的研究表明，ETBR 在至少 50% 的组织中过度表达（>2 倍正常组织） 原发性卵巢癌 (OC) 和高达 62% 的原发性三阴性乳腺癌 (TNBC) 以及 100% 的转移性 TNBC。在肿瘤脉管系统中过度表达 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，这两者 使用少数可用的 ETBR 拮抗剂 BQ- 之一治疗后，该值显着增加。 788. 在同一实验中，双重 ETBR/ETAR 拮抗剂马西腾坦被证明 无效，表明需要选择性 ETBR 拮抗剂来增加 TIL。 不幸的是，BQ-788 仅表现出适度的选择性（与 ETAR 相比约为 200 倍）并且药物效果较差 特性，强调需要新的和改进的 ETBR 拮抗剂。 Lassogen 正在利用 lasso 肽的独特特性来创造新的 免疫肿瘤学 (IO) 应用的治疗方法。 Lasso肽体积小，高度稳定， 受限天然肽（15-25 个氨基酸），具有独特的套索状折叠 通过 3D 功能定向促进目标参与的结构。 重要的是，套索肽对某些 G 蛋白偶联受体表现出高亲和力， 因此代表了调节这一类重要的新药物的未开发来源 疾病目标。 Lassogen 正在开发 LAS-103 作为一种稳定、有效、选择性的 ETBR 拮抗剂，可增强白细胞流入 TME 并使肿瘤更容易受到 免疫疗法。在此，我们建议测试 LAS-103 的安全性、药理学和功效 用于治疗卵巢癌。