Targeted delivery of Lu-177 to tumor vasculature

将 Lu-177 靶向递送至肿瘤脉管系统

基本信息

批准号：
8332296
负责人：
Joseph M Backer
金额：
$ 98.56万
依托单位：
SIBTECH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-13 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8332296
关键词：
Adjuvant Adjuvant Therapy Angiogenesis Inhibitors Animals Apoptosis Binding Blood Circulation Blood Vessels Body Surface Breast Cancer Model Businesses Cells Chelating Agents Clinical Collaborations Combined Modality Therapy Data Dependence Development Dose Doxorubicin Drug Design Drug resistance Endocytosis Endothelial Cells Engineering Environment FDA approved Goals Growth Human Image Immunocompetent Injection of therapeutic agent Lead Legitimacy Malignant Neoplasms Mammary Neoplasms Mediating Modeling Mono-S Mus Names Outcome Patients Penetration Persons Pharmaceutical Preparations Phase Phase I Clinical Trials Positron-Emission Tomography Progression-Free Survivals Proteins Radiation therapy Radioisotopes Radiolabeled Radiopharmaceuticals Receptor Signaling Recurrence Resistance Rest Role Safety Signal Transduction Site Therapeutic Time Treatment Efficacy Universities Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors base bevacizumab cancer radiation therapy cancer therapy chemotherapy cytotoxic dosimetry evidence base experience in vivo inhibitor/antagonist malignant breast neoplasm mouse model novel overexpression phase 1 study pre-clinical radiotracer receptor single photon emission computed tomography targeted delivery triple-negative invasive breast carcinoma tumor vessel regression

项目摘要

DESCRIPTION (provided by applicant): Currently available anti-angiogenic drugs inhibit VEGF/VEGFR signaling, which leads to transient vascular regression followed by rebound of drug-resistant vasculature, which significantly decrease the therapeutic efficacy of very expensive anti-angiogenic treatment. To overcome this problem, we are developing a cytotoxic 177Lu radiopharmaceutical, scVEGF/Lu. This radiopharmaceutical is based on engineered single-chain VEGF (scVEGF) and it accumulates in tumor endothelial cells via endocytosis mediated by overexpressed VEGFR-2. In Phase I we optimized the composition of scVEGF/Lu, assessed its radiotoxicity and dosimetry and performed initial therapeutic efficacy and mechanistic studies in orthotopic breast tumor models. Our results demonstrate that a single injection of a safe dose of scVEGF/Lu induces destruction of tumor vasculature sustainable for at least 30-35 days and a widespread apoptosis in tumor without significant overall radiotoxicity. In contrast, FDA-approved sunitinib and bevacizumab failed to induce sustainable destruction of tumor vasculature, suggesting potential advantages of scVEGF/Lu. In Phase II we will focus on late pre-clinical development of scVEGF/Lu as a novel component of anti- angiogenic therapy, using orthotopic mouse models of recurrent breast cancer, including a model of human triple negative breast cancer. First, we will establish the dose- and time-dependences for scVEGF/Lu-induced destruction of tumor vasculature and potential roles of overexpressed endogenous VEGF and immunocompetent environment in therapeutic efficacy of scVEGF/Lu. Next, we will establish optimal sequence for scVEGF/Lu-doxorubicin combination as adjuvant therapy for recurrent breast cancer. Considering that scVEGF is a physiologically active protein, we will also establish the safety profile for scVEGF-PEG-DOTA conjugate. We expect that by the end of Phase II of the project we will have evidence-based indications for safe use of scVEGF/Lu in adjuvant anti-angiogenic therapy for breast cancer. We will also have a GLP-grade for dosimetry studies. This data will be used for filing IND or eIND with FDA for Phase I clinical trials with scVEGF/Lu in breast cancer. We believe that this novel targeted radiopharmaceutical may provide a new line of attack on breast cancer, and eventually will be explored for treatment of other cancers.

描述（由申请人提供）：目前可用的抗血管生成药物抑制VEGF/VEGFR信号，这导致短暂性血管回归，然后抗药抗药性脉管系统反弹，这显着降低了非常昂贵的抗激发治疗的治疗功效。为了克服这个问题，我们正在开发一种细胞毒性177LU放射性药物，SCVEGF/LU。这种放射性药物基于工程的单链VEGF（SCVEGF），它通过过表达的VEGFR-2介导的内吞作用在肿瘤内皮细胞中积聚。在第一阶段，我们优化了SCVEGF/LU的组成，评估了其放射性毒性和剂量测定法，并在原位性乳腺肿瘤模型中进行了初始的治疗功效和机械研究。我们的结果表明，单一注射安全剂量的SCVEGF/LU会导致至少30-35天的可持续性肿瘤脉管系统的破坏，并且肿瘤的广泛细胞凋亡，没有明显的总体放射性毒性。相比之下，FDA批准的Sunitinib和贝伐单抗未能诱导肿瘤脉管系统的可持续破坏，这表明SCVEGF/LU的潜在优势。在第二阶段，我们将使用抗血管生成疗法的新型组成部分，使用复发性乳腺癌的原位小鼠模型，包括人类三重阴性乳腺癌的模型。首先，我们将建立用于SCVEGF/LU诱导的肿瘤脉管系统破坏的剂量和时间依赖性，以及过表达的内源性VEGF和免疫能力环境在SCVEGF/LU治疗功效中的潜在作用。接下来，我们将建立用于SCVEGF/LU-doxorubicin组合的最佳序列，作为复发性乳腺癌的辅助治疗。考虑到SCVEGF是一种生理活性蛋白，我们还将为SCVEGF-PEG-DOTA结合物建立安全性。我们预计，在该项目的第二阶段结束时，我们将有基于证据的迹象，以安全地使用SCVEGF/LU在乳腺癌辅助抗血管生成疗法中。我们还将有一个GLP级用于剂量学研究。该数据将用于乳腺癌中的I阶段临床试验，用于对I期临床试验进行IND或FDA。我们认为，这种新颖的针对性放射药物可能会对乳腺癌提供新的攻击线，并最终将探索其他癌症的治疗。