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

项目总结/摘要 蛋白酶体抑制剂（PI）是最重要的一类治疗药物， 在过去的二十年中出现，现在是多发性骨髓瘤（MM）的支柱 治疗第一类PI，硼替佐米（Btz），靶向泛素蛋白酶体途径 (UPP)，这导致了在诱导浆细胞凋亡和抑制浆细胞凋亡方面的巨大功效。 MM增长尽管PI作为一种作用机制（MoA）具有普遍性， 临床前结果，PI硼替佐米、ixazomib和卡非佐米治疗实体癌的临床用途 迄今为止，由于显著的剂量限制性毒性（DLT）， 和非常狭窄的治疗窗口。因为整个实体癌患者群体 对PI未经治疗，可以靶向方式递送Btz的技术， 规避其DLT，将是非常可取的，特别是在非预期适应症， 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， 在靶向癌细胞中共价缀合的PI的药物释放。此外，我们的ADC平台 具有比在最先进的FDA批准的ADC中使用的高数倍的载药量， Enhertu®和Trodelvy®。到目前为止，我们已经在低HER 2乳腺癌模型中表明， 我们的PI负载ADC的迭代可以优于Enhertu的生物仿制药T-Dxd。 在12个月的时间里，我们打算合成和表征这些PI负载ADC的库 具有不同的靶点和载药量。通过体外筛选它们的结合亲和力， 细胞内化和效力，我们将筛选这个库中表现最好的候选物。 在各种低表达TNBC小鼠模型中的进一步体内PK/BD和功效研究将在以下方面进行： 使我们能够找到一个最佳的PI负载ADC领导候选人，以推动前进。成功的这项 项目将通过发现至少一个WTx-ABC领导候选人来确定， 进一步开发用于II期SBIR的临床应用。

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.