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

TROP-2靶向四聚体兰比纳斯酶用于治疗三阴性乳腺癌

基本信息

批准号：
8592297
负责人：
Donglin Liu
金额：
$ 20.08万
依托单位：
IMMUNOMEDICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-03 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8592297
关键词：
A kinase anchoring protein Accounting Affinity Chromatography Aggressive behavior Amino Acid Sequence Amphibia Animal Model Binding Biological Availability Blood Body Weight decreased Breast Breast Cancer Cell Buffers Cancer cell line Cell Culture Techniques Cell Line Cells Chemistry Chimeric Proteins Clinical Trials Complex Cyclic AMP-Dependent Protein Kinases Development Dimerization Docking Dose Dose-Limiting Drug Kinetics Engineering Enzyme-Linked Immunosorbent Assay Epidermal Growth Factor Receptor Epithelial Escherichia coli Estrogen Receptors Fermentation Goals Hemorrhage Human Human Cell Line Immunoglobulin G In Vitro Integral Membrane Protein Ions Lead Malignant Neoplasms Mammalian Cell Measures Metals Monitor Morphology Mus Nude Mice Peripheral Blood Mononuclear Cell Phase Preparation Production Progesterone Receptors Property Proteins Regimen Ribonucleases Safety Serum Site Small Business Innovation Research Grant Solid Surface Therapeutic Tissues Toxic effect Treatment Efficacy Treatment Protocols Xenograft Model Xenograft procedure base cytotoxicity dimer disulfide bond human TACSTD2 protein humanized monoclonal antibodies improved in vivo interest malignant breast neoplasm mortality novel outcome forecast pre-clinical preclinical study public health relevance ranpirnase scale up self assembly targeted delivery triple-negative invasive breast carcinoma tumor tumor xenograft

项目摘要

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.

描述（由申请人提供）：三阴性乳腺癌（TNBC）是乳腺癌的一个亚类，由于缺乏有效的治疗方案，预后较差，死亡率较高。该 I 期 SBIR 申请旨在开发 E1-Rap，一种新型免疫 RNA 酶，用于治疗 TNBC。 E1-Rap 是一种 DOCK-AND-LOCKTM (DNLTM) 复合物，包含四个拷贝的 ranpirnase (Rap)，其位点特异性地连接到 hRS7 的 CH3 末端，hRS7 是一种靶向 TROP-2 的人源化单克隆抗体，TROP-2 是一种过表达的跨膜蛋白在多种上皮癌中。我们已经证明 TROP-2 存在于 TNBC 细胞表面，并且 E1-Rap 的靶向递送显着增强了 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 比之前制备的融合蛋白 (Rap-hRS7) 大大提高了效力，但对 TROP-2 阴性细胞系和人 PBMC 的毒性保持最小。在此一期应用中，我们将扩大E1-Rap的生产规模，并评估E1-Rap的体内特性，包括PK、稳定性、安全性、生物利用度以及E1-Rap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申请，旨在完成 E1-Rap 的临床前开发以进行临床试验。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Severely polarized extracellular acidity around tumour cells.

肿瘤细胞周围的细胞外酸度严重极化。

DOI：
发表时间：
2024-03-04
期刊：
影响因子：
28.1
作者：
Feng, Qiang;Bennett, Zachary;Grichuk, Anthony;Pantoja, Raymundo;Huang, Tongyi;Faubert, Brandon;Huang, Gang;Chen, Mingyi;DeBerardinis, Ralph J;Sumer, Baran D;Gao, Jinming
通讯作者：
Gao, Jinming

Trop-2-targeting tetrakis-ranpirnase has potent antitumor activity against triple-negative breast cancer.

Trop-2 靶向的 tetrakis-ranpirnase 对三阴性乳腺癌具有有效的抗肿瘤活性。