Targeted delivery of Lu-177 to tumor vasculature

描述(申请人提供)：目前可用的抗血管生成药物抑制血管内皮生长因子/血管内皮生长因子受体信号，这会导致一过性血管退化，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，我们正在开发一种细胞毒性的177Lu放射性药物，scVEGF/Lu。这种放射性药物以工程单链血管内皮生长因子(ScVEGF)为基础，通过高表达的VEGFR-2介导的内吞作用在肿瘤内皮细胞中蓄积。在第一阶段，我们优化了单链血管内皮生长因子/Lu的组成，评估了其放射毒性和剂量学特性，并在原位乳腺肿瘤模型上进行了初步的治疗效果和机制研究。我们的结果表明，单次注射安全剂量的scVEGF/Lu可导致肿瘤血管的破坏，至少持续30-35天，并导致肿瘤内广泛的细胞凋亡，而没有明显的整体放射毒性。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，这表明scVEGF/Lu具有潜在的优势。在第二阶段，我们将专注于scVEGF/Lu作为抗血管生成治疗的新成分的临床前晚期开发，使用复发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关系，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-阿霉素联合治疗复发乳腺癌的最佳方案。考虑到scVEGF是一种具有生理活性的蛋白质，我们还将建立scVEGF-PEG-DOTA结合物的安全性模型。我们期望到该项目第二阶段结束时，我们将有证据表明，在乳腺癌的辅助抗血管生成治疗中，scVEGF/Lu是安全使用的。我们还将有一个GLP级的剂量学研究。这些数据将用于向FDA提交IND或EIND，用于scVEGF/Lu治疗乳腺癌的I期临床试验。我们相信，这种新颖的靶向放射性药物可能为乳腺癌提供一条新的攻击线，并最终将被探索用于其他癌症的治疗。 公共卫生相关性：为了提高抗血管生成治疗的有效性，有必要维持肿瘤血管的消退和抑制血管反弹。为此，我们开发了一种新型的177Lu放射性药物，scVEGF/Lu，它可以在肿瘤内皮细胞中传递致命剂量的177Lu。在原位乳腺癌模型中，scVEGF/Lu可导致肿瘤血管的破坏和肿瘤细胞的广泛凋亡，且无明显的整体放射毒性。在这个项目中，我们将评估单链血管内皮生长因子/Lu作为一种新的抗血管生成治疗成分的潜力，这可能会对三阴性乳腺癌的预后产生重大影响。我们期望这项研究将为安全使用单项或联合治疗乳腺癌的单项或联合治疗提供循证适应症。我们相信，这种新颖的靶向放射性药物可能为乳腺癌提供一条新的攻击线，并最终将被探索用于其他癌症的治疗。

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.