Proteasome Inhibitor-Loaded Antibody Drug Conjugates with High Drug Loading For Targeted Treatment of Triple Negative Breast Cancers

负载蛋白酶体抑制剂的高载药量抗体药物偶联物用于三阴性乳腺癌的靶向治疗

• 批准号: 10822628
• 负责人: Yivan Jiang
• 金额: $ 30万
• 依托单位: WINDOW THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10822628
• 关键词: Address; Affinity; Antibodies; Antibody-drug conjugates; Apoptosis; Architecture; Binding; Biodistribution; Biological Assay; Blood; Bortezomib; Breast Cancer Model; Breast Cancer cell line; Cancer Model; Cancer Patient; Cardiotoxicity; Cell Line; Cell Survival; Cells; Circulation; Clinical; Confocal Microscopy; Coupled; Couples; Dose; Dose Limiting; Drug Kinetics; ERBB2 gene; Esters; Evaluation; Event; Exhibits; FDA approved; Flow Cytometry; Fluorescence; Freeze Drying; Freezing; Government; Growth; Half-Life; In Vitro; Label; Libraries; Malignant Neoplasms; Maximum Tolerated Dose; Mediating; Monitor; Monoclonal Antibodies; Mucin 1 protein; Multiple Myeloma; Mus; Names; Nature; Pathway interactions; Performance; Persons; Pharmaceutical Preparations; Phase; Plasma Cells; Polymers; Prodrugs; Proteasome Inhibition; Proteasome Inhibitor; Proteins; SN-38; Safety; Site; Small Business Innovation Research Grant; Solid; Technology; Therapeutic; Time; Toxic effect; Trastuzumab; Treatment Efficacy; Tumor Burden; Ubiquitin; Vertebral column; analog; antibody libraries; cancer cell; clinical application; cyanine; delivery vehicle; drug discovery; efficacy study; improved; in vivo; lead candidate; lead optimization; liquid chromatography mass spectrometry; mouse model; multicatalytic endopeptidase complex; new technology; novel; orthotopic breast cancer; patient population; pre-clinical; receptor; response; screening; side effect; stem; success; targeted treatment; triple-negative invasive breast carcinoma; tumor

Project Summary/Abstract Proteasome inhibitors (PIs) are one of the most important classes of therapeutics to have emerged in the past two decades and now serve as the backbone of multiple myeloma (MM) treatment. The first-in-class PI, bortezomib (Btz), targets the ubiquitin proteasome pathway (UPP), which has led to tremendous efficacy in inducing plasma cell apoptosis and in inhibiting MM growth. Despite the universal nature of PI as a mechanism of action (MoA) and strong preclinical results, the clinical use of the PIs bortezomib, ixazomib, and carfilzomib for solid cancer indications have been largely unsuccessful thus far due to significant dose-limiting toxicity (DLT) and exceedingly narrow therapeutics window. As the entire solid cancer patient population is treatment-naïve to PIs, technologies that can deliver Btz in a targeted manner, thereby circumventing its DLTs, would be highly desirable especially in recalcitrant indications such as triple negative breast cancer (TNBC). We have developed a novel Antibody Drug Conjugate (ADC) platform that enables controlled drug release of a covalently conjugated PI in targeted cancer cells. Additionally, our ADC platform has drug loadings multi-fold higher than what is used in state-of-the-art FDA approved ADCs like Enhertu® and Trodelvy®. Thus far, we have shown in a low HER2 breast cancer model that an iteration of our PI-loaded ADC can outperform T-Dxd, a biosimilar of Enhertu. Over 12 months, we intend to synthesize and characterize a library of these PI-loaded ADCs with varying targets and drug loadings. By use of in vitro screening of their binding affinities, cellular internalization, and potency, we will screen this library for best performing candidates. Further in vivo PK/BD and efficacy studies in various low-expression TNBC mouse models will enable us to find an optimal PI-loaded ADC lead candidate to push forward. Success of this project will be determined by the discovery of at least one WTx-ABC lead candidate that can be further developed for clinical application with a Phase II SBIR.

项目概要/摘要 蛋白酶体抑制剂 (PI) 是最重要的治疗药物之一 在过去二十年中出现，现在成为多发性骨髓瘤 (MM) 的支柱 一流的 PI 硼替佐米 (Btz) 靶向泛素蛋白酶体途径。 （UPP），在诱导浆细胞凋亡和抑制浆细胞凋亡方面具有巨大功效 尽管 PI 作为一种作用机制 (MoA) 具有普遍性和很强的增长性。 临床前结果、PI 硼替佐米、伊沙佐米和卡非佐米治疗实体癌的临床应用 由于显着的剂量限制毒性（DLT），迄今为止的适应症基本上不成功 由于整个实体癌症患者群体的治疗窗口极其狭窄。 对 PI 来说是未经治疗的技术，可以有针对性地提供 Btz，从而 规避其 DLT 是非常可取的，尤其是在顽固的适应症中，例如 三阴性乳腺癌（TNBC）。 我们开发了一种新型抗体药物偶联物 (ADC) 平台，可实现受控 此外，我们的 ADC 平台还可以在靶向癌细胞中释放共价结合的 PI。 其载药量比 FDA 批准的最先进 ADC（例如 Enhertu® 和 Trodelvy® 迄今为止，我们已经在低 HER2 乳腺癌模型中证明了这一点。 我们的 PI 加载 ADC 的迭代可以超越 Enhertu 的生物仿制药 T-Dxd。 我们打算在 12 个月内综合并表征这些 PI 加载 ADC 的库 具有不同的靶点和药物负载量通过体外筛选它们的结合亲和力， 细胞内化和效力，我们将在该库中筛选表现最佳的候选者。 在各种低表达 TNBC 小鼠模型中进行进一步的体内 PK/BD 和功效研究将 使我们能够找到最佳的 PI 负载 ADC 候选药物来推动这一目标的成功。 项目将通过发现至少一个 WTx-ABC 主要候选药物来确定 通过 II 期 SBIR 进一步开发用于临床应用。