Immuno-PET imaging of high-grade neuroendocrine lung tumors using 89Zr-rovalpituzumab, a DLL3-targeting monoclonal antibody

项目摘要/摘要 小细胞肺癌(SCLC)是一种高级别的肺神经内分泌肿瘤，占 在美国每年确诊的所有肺癌病例中，约有16%。在大多数患者中，小细胞肺癌在 出现的时间；广泛期疾病的患者预后差，存活率低。 可以用几个月来衡量，平均5年存活率为5%。新的治疗策略正在不顾一切地 需要改善这些患者的临床结果。 一种针对Delta like配体3(DLL3)的新型抗体药物结合物(rovalPituzumab tesiine；RoVA-T)， 一种高度肿瘤选择性的细胞表面蛋白，在早期阶段已显示出令人印象深刻的临床益处 广泛期小细胞肺癌患者的临床试验。在可评估的DLL3+患者中 根据IHC的测量，基线样本的总应答率为39%，临床受益率为75% 观察，强调了靶向DLL3的治疗潜力和DLL3评估的实用性。 虽然DLL3IHC已经证明了诊断的实用性，但这些数据目前是从存档的组织中收集的 标本，这些标本可能不是帮助临床做出最佳决定的理想参照点 治疗时间；事实上，许多明显DLL3阳性的患者没有反应，许多患者 是不可评估的。一种更可靠、动态、实时、非侵入性但定量的方法来评估智能 肿瘤表面抗原表达的体内状态将极大地改善临床上对该制剂的患者选择。 我们建议开发一种含有89Zr标记的罗伐珠单抗的免疫-PET诊断试剂。 具体目标1建立在有希望的初步成像数据的基础上。我们已经能够获得高对比度 使用非特异胺标记和特定部位马来酰亚胺生物标记的免疫-PET图像。我们会 通过开发更稳定的硫醇可点击的甲基亚砜螯合剂来改进这一方法 将肾脏摄取降至最低。具体目标2将集中在体内毒理学和 89Zr-Rova的药理作用及FDA研究新药的制备和提交 临床试验申请书。特指目标3的目标将是89Zr-Rova的首个人体临床试验 对于同时参加临床试验的小细胞肺癌患者的PET成像 治疗性ADC Rova-T。这项有30名患者参加的试验将集中于89Zr作为一种药物的临床安全性和有效性。 对Rova-T反应的预测因子 这一提议将加强斯隆·凯特林纪念馆之间本已密切的工作关系 科学家、临床医生和Stemcentx，Inc.正在开发89Zr标记的rovalPituzumab。这 新型显像剂将通过允许DLL3靶向ADC作为 当时的诊断工具，并作为未来放射治疗的童子军。

PROJECT SUMMARY/ABSTRACT Small cell lung cancer (SCLC), is a high-grade pulmonary neuroendocrine tumor that accounts for ~16% of all lung cancer cases diagnosed annually in the United States. In most patients, SCLC is metastatic at the time of presentation; patients with extensive stage disease have a poor prognosis with survival measureable in months, and an average 5-year survival of <5%. New therapeutic strategies are desperately needed to improve clinical outcomes for these patients. A novel antibody drug conjugate (rovalpituzumab tesirine; Rova-T) targeting Delta like ligand 3 (DLL3), a highly tumor-selective cell surface protein, has demonstrated impressive clinical benefit in early phase clinicial trials in patients with extensive stage small cell lung cancer. Among evaluable patients with DLL3+ baseline samples, as measured by IHC, a 39% overall response rate and 75% clinical benefit rate were observed, highlighting both the therapeutic potential for targeting DLL3 and the utility of DLL3 assessment. While DLL3 IHC has demonstrated diagnostic utility, this data is presently collected from archived tissue specimens, which may not serve as ideal reference points to help make the best decisions in the clinic at the time of treatment; indeed, many patients with apparent DLL3 positivity failed to respond and many patients were not evaluable. A more reliable, dynamic, real time, non-invasive yet quantitative method to evaluate the in vivo status of antigen expression on tumors will greatly improve patient selection for this agent in the clinic. We propose development of an immuno-PET diagnostic agent comprising 89Zr labeled rovalpituzumab. Specific Aim 1 builds upon promising preliminary imaging data. We are already able to obtain high-contrast immune-PET images using non-specific amine labeling and site-specific maleimide bioconjugation. We will improve upon this approach by developing more stable thiol-clickable methylsuflone chelators for 89Zr to minimize kidney uptake. Specific Aim 2 will be centered on the study of the in vivo toxicology and pharmacology of 89Zr-Rova as well as the preparation and submission of an FDA Investigational New Drug application for the clinical trial. The goal of Specific Aim 3 will be the first-in-human clinical trial of 89Zr-Rova for the PET imaging of patients with small cell lung cancer concurrently enrolled on a clinical trial of the therapeutic ADC Rova-T. This 30-patient trial will be focused on the clinical safety and efficacy of 89Zr as a predictor of response to Rova-T. This proposal will strengthen the already close working relationship between Memorial Sloan Kettering scientists and clinicians and Stemcentrx, Inc. toward the development of 89Zr-labeled rovalpituzumab. This novel imaging agent will render diagnostic value to the DLL3-targeting ADC by allowing it to serve as a contemporaneous diagnostic tool and act as a scout for future radiotherapeutics.