Targeted delivery of Lu-177 to tumor vasculature

描述（由申请人提供）：目前可用的抗血管生成药物抑制VEGF/VEGFR信号传导，这导致短暂的血管消退，随后是耐药血管系统的反弹，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，我们正在开发一种细胞毒性177 Lu放射性药物，scVEGF/Lu。这种放射性药物基于工程单链VEGF（scVEGF），并且其通过由过表达的VEGFR-2介导的内吞作用在肿瘤内皮细胞中积累。在第一阶段，我们优化了scVEGF/Lu的组成，评估了其放射毒性和剂量测定，并在原位乳腺肿瘤模型中进行了初步治疗功效和机制研究。我们的研究结果表明，单次注射安全剂量的scVEGF/Lu诱导肿瘤血管系统的破坏可持续至少30-35天，并在肿瘤中引起广泛的细胞凋亡，而没有显著的总体放射毒性。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可持续破坏，这表明scVEGF/Lu的潜在优势。 在II期，我们将集中于scVEGF/Lu作为抗血管生成疗法的新组分的晚期临床前开发，使用复发性乳腺癌的原位小鼠模型，包括人三阴性乳腺癌模型。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治疗功效中的潜在作用。接下来，我们将建立scVEGF/Lu-doxorubicin组合作为复发性乳腺癌辅助治疗的最佳序列。考虑到scVEGF是一种生理活性蛋白，我们还将建立scVEGF-PEG-DOTA缀合物的安全性特征。我们预计，到项目II期结束时，我们将获得scVEGF/Lu在乳腺癌辅助抗血管生成治疗中安全使用的循证指征。我们还将为剂量测定研究提供GLP等级。这些数据将用于向FDA提交IND或eIND，用于scVEGF/Lu在乳腺癌中的I期临床试验。我们相信，这种新型的靶向放射性药物可能会为乳腺癌提供一种新的攻击路线，并最终将被探索用于治疗其他癌症。 公共卫生相关性：为了提高抗血管生成治疗的疗效，有必要维持肿瘤血管消退并抑制血管反弹。为此，我们开发了一种新的177 Lu放射性药物scVEGF/Lu，其在肿瘤内皮细胞中递送致死剂量的177 Lu。在乳腺癌原位模型中，scVEGF/Lu诱导肿瘤血管的破坏和肿瘤中广泛的细胞凋亡，而没有显著的总体放射毒性。在这个项目中，我们将评估scVEGF/Lu作为抗血管生成治疗的新组分的潜力，这可能对三阴性乳腺癌的结果产生重大影响。我们期望这项研究将为scVEGF/Lu作为乳腺癌的单药或联合辅助治疗的安全使用提供循证指征。我们相信，这种新型的靶向放射性药物可能会为乳腺癌提供一种新的攻击路线，并最终将被探索用于治疗其他癌症。

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. PUBLIC HEALTH RELEVANCE: To increase the efficacy anti-angiogenic therapy, it is necessary to sustain tumor vascular regression and to inhibit vascular rebound. For this, we develop a novel 177Lu radiopharmaceutical, scVEGF/Lu, which delivers lethal doses of 177Lu in tumor endothelial cells. In orthotopic models of breast cancer, scVEGF/Lu induces destruction of tumor vasculature and widespread apoptosis in tumor, without significant overall radiotoxicity. In this project we will evaluate the potential of scVEGF/Lu as a novel component of anti-angiogenic therapy that could make a significant impact on outcome of triple negative breast cancer. We expect that this study will provide evidence-based indications for safe use of scVEGF/Lu as a mono- or combination therapy as adjuvant therapy for 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.