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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。