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.

项目摘要/摘要 蛋白酶体抑制剂（PI）是具有 在过去的二十年中出现，现在充当多发性骨髓瘤（MM）的骨干 治疗。第一类PI硼替佐米（BTZ）靶向泛素蛋白酶体途径 （UPP），这导致了诱导的血浆细胞凋亡和抑制 MM增长。尽管PI是一种行动机理（MOA）和强大的性质 临床前结果，PIS Bortezomib，Ixazomib和Carfilzomib的临床用途用于固体癌 到目前为止，由于明显的剂量限制毒性（DLT），迹象在很大程度上没有成功 和极其狭窄的治疗窗口。由于整个癌症患者人数是 对PI的治疗，可以以目标方式提供BTZ的技术 规避其DLT，是非常需要的 三重阴性乳腺癌（TNBC）。 我们已经开发了一种新型的抗体药物缀合物（ADC）平台，该平台可控制 在靶向癌细胞中共价连接的PI的药物释放。此外，我们的ADC平台 药物负荷比最先进的FDA批准的ADC（例如 EnherTu®和Trodelvy®。那遥远，我们已经在低HER2乳腺癌模型中显示了 我们加载的ADC的迭代可以胜过T-DXD，这是一种生物仿制药。 在12个月的时间里，我们打算合成并表征这些PI-LOADCS的库 具有不同的靶标和药物负荷。通过使用其结合亲和力的体外筛选， 蜂窝内在化和效力，我们将筛选此库以最佳性能候选者。 在各种低表达TNBC小鼠模型中，进一步的体内PK/BD和效率研究将 使我们能够找到一个最佳的PI-PI ADC铅候选人，以推动前进。成功的成功 项目将通过发现至少一个WTX-ABC首席候选人来确定 进一步开发用于II期SBIR的临床应用。