TROP-2-targeted tetrameric ranpirnase for therapy of triple-negative breast cance

描述（由申请人提供）：三阴性乳腺癌（TNBC）是乳腺癌的一个亚群，由于缺乏有效的治疗方案，预后差，死亡率高。该I期SBIR申请旨在开发用于治疗TNBC的新型免疫酶E1-Rap。E1-Rap是一种DOCK-AND-LOCKTM （DNLTM）复合物，包括四个拷贝的ranpirnase （Rap）位点特异性地连接到hRS7的ch3末端，hRS7是一种针对TROP-2的人源化单克隆抗体，TROP-2是一种在多种上皮癌中过表达的跨膜蛋白。我们发现TROP-2存在于TNBC细胞表面，靶向递送E1-Rap显著增强了TROP-2阳性细胞系中Rap的结合、内化和细胞毒性。更重要的是，E1-Rap比先前制备的融合蛋白（Rap-hRS7）的效力大大提高，但对trop -2阴性细胞系和人PBMC的毒性保持最小。在这个I期应用中，我们将扩大E1-Rap的生产，并评估E1-Rap的体内特性，包括PK、稳定性、安全性、生物利用度和E1-Rap在人类TNBC异种移植模型中的治疗活性。这些I期目标的成功实现将导致II期申请，旨在完成E1-Rap临床试验的临床前开发。

DESCRIPTION (provided by applicant): Triple-negative breast cancer (TNBC) is a subset of breast cancers with poor prognosis and high mortality due to the lack of effective therapeutic regimens. This Phase I SBIR application is to develop E1-Rap, a novel immunoRNases, for treating TNBC. E1-Rap is a DOCK-AND-LOCKTM (DNLTM) complex, comprising four copies of ranpirnase (Rap) site-specifically tethered to the CH3-terminus of hRS7, a humanized monoclonal antibody targeting TROP-2, a transmembrane protein over-expressed in diverse epithelial cancers. We have shown that TROP-2 is present on the surface of TNBC cells, and targeted delivery of E1-Rap significantly enhances the binding, internalization, and cytotoxicity of Rap in TROP-2-positive cell lines. More importantly, E1-Rap has greatly improved the potency over the previously made fusion protein (Rap-hRS7), but maintained minimal toxicity to TROP-2-negative cell lines and human PBMC. In this Phase I application, we will scale up the production of E1-Rap and evaluate the in vivo properties of E1-Rap, including PK, stability, safety, bioavailability, and the therapeutic activity of E1-Rap in human TNBC xenograft models. Successful accomplishments of these Phase I goals will lead to a Phase II application aimed to complete the preclinical development of E1-Rap for clinical trials.