Targeted delivery of Lu-177 to tumor vasculature

将 Lu-177 靶向递送至肿瘤脉管系统

• 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
• 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

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，导致短暂性血管消退，随后耐药血管反弹，这显著降低了非常昂贵的抗血管生成治疗的疗效。为了克服这个问题，我们正在开发一种具有细胞毒性的放射性药物，scVEGF/Lu。这种放射性药物基于工程单链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累。在I期研究中，我们优化了scVEGF/Lu的组成，评估了其放射毒性和剂量学，并在原位乳腺肿瘤模型中进行了初步的治疗效果和机制研究。我们的研究结果表明，单次注射安全剂量的scVEGF/Lu诱导肿瘤血管破坏持续至少30-35天，肿瘤细胞广泛凋亡，无明显的总体放射毒性。相比之下，fda批准的舒尼替尼和贝伐单抗未能诱导肿瘤血管的持续破坏，提示scVEGF/Lu的潜在优势。在II期，我们将专注于scVEGF/Lu作为抗血管生成治疗的新成分的后期临床前开发，使用复发性乳腺癌的原位小鼠模型，包括人类三阴性乳腺癌模型。首先，我们将建立scVEGF/Lu诱导的肿瘤血管破坏的剂量和时间依赖性，以及过表达的内源性VEGF和免疫活性环境在scVEGF/Lu治疗效果中的潜在作用。接下来，我们将建立scVEGF/ lu -阿霉素联合辅助治疗复发性乳腺癌的最佳序列。考虑到scVEGF是一种具有生理活性的蛋白，我们还将建立scVEGF- peg - dota偶联物的安全性。我们预计，在项目II期结束时，我们将获得基于证据的适应症，证明scVEGF/Lu在乳腺癌辅助抗血管生成治疗中的安全使用。我们也将有glp等级用于剂量学研究。该数据将用于向FDA提交scVEGF/Lu在乳腺癌中的I期临床试验的IND或eIND。我们相信，这种新型靶向放射性药物可能为乳腺癌提供一条新的治疗途径，并最终将探索用于治疗其他癌症。