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

描述(申请人提供)：三阴性乳腺癌(TNBC)是乳腺癌的一个子集，由于缺乏有效的治疗方案，预后差，死亡率高。这一阶段的SBIR应用是为了开发一种新型的免疫核糖核酸酶E1-Rap，用于治疗TNBC。E1-Rap是一种DOCK-and-LOCKTM(DNLTM)复合体，由四个拷贝的Rap(Rap)组成，Rap特异性地连接到hRS7的CH3末端，是针对trp-2的人源化单抗，trop-2是一种在各种上皮性癌症中过度表达的跨膜蛋白。我们已经证明，trp-2存在于TNBC细胞的表面，并且靶向递送E1-Rap显著增强了trp-2阳性细胞系中Rap的结合、内化和细胞毒性。更重要的是，与先前制备的融合蛋白(Rap-hRS7)相比，E1-Rap的效价大大提高，但对trop-2阴性细胞系和人PBMC的毒性保持在最低水平。在这一阶段的应用中，我们将扩大E1-Rap的生产，并评估E1-Rap的体内性质，包括PK、稳定性、安全性、生物利用度以及在人TNBC异种移植模型中的治疗活性。这些第一阶段目标的成功实现将导致第二阶段的应用，旨在完成用于临床试验的E1-Rap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.