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)是最重要的治疗药物之一 在过去的二十年中出现，现在是多发性骨髓瘤(MM)的主干 治疗。第一类PI，Bortezomib(BTZ)，靶向泛素蛋白酶体途径 (UPP)，它在诱导浆细胞凋亡和抑制 Mm增长。尽管PI作为一种普遍的作用机制(MOA)和强势 Pis bortezomib、ixazomib和carfilzomib治疗实体癌的临床前结果 到目前为止，由于显著的剂量限制毒性(DLT)，适应症大多未获成功 以及极其狭窄的治疗窗口。因为整个坚实的癌症患者群体 治疗-对绩效指标的天真，能够以有针对性的方式提供BTZ的技术，从而 绕过其DLT，将是非常可取的，特别是在顽固的迹象，如 三阴性乳腺癌(TNBC) 我们开发了一种新的抗体药物结合物(ADC)平台，可以控制 共价偶联PI在靶向癌细胞中的药物释放。此外，我们的ADC平台 药物负荷比FDA批准的最先进的ADC高出数倍，如 Enhertu®和Trodelvy®。到目前为止，我们已经在低HER2乳腺癌模型中证明了 我们的PI负载ADC的迭代性能可以超过T-Dxd，T-Dxd是Enhertu的生物类似物。 在12个月的时间里，我们打算合成和表征这些PI加载的ADC的库 目标和载药量各不相同。通过使用体外筛选它们的结合亲和力， 细胞内化和潜力，我们将筛选这个库中表现最好的候选者。 在各种低表达的TNBC小鼠模型中，进一步的体内PK/BD和疗效研究将 使我们能够找到一个最佳的PI负载的ADC领先候选人来推进。这件事成功了 项目将通过发现至少一名WTx-ABC首席候选人来确定，该候选人可以 进一步开发用于临床应用的第二阶段SBIR。