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

项目总结/摘要 小细胞肺癌（SCLC）是一种高级别的肺神经内分泌肿瘤， 约占美国每年诊断的所有肺癌病例的16%。在大多数患者中，SCLC是转移性的， 出现的时间;广泛期疾病的患者预后较差，生存期 可在数月内测量，平均5年生存率<5%。新的治疗策略 需要改善这些患者的临床结果。 一种靶向δ样配体3（DLL 3）的新型抗体药物缀合物（罗伐匹妥珠单抗tesirine; Rova-T）， 一种高度肿瘤选择性的细胞表面蛋白，已在早期阶段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。DLL 3+的可评价患者中 基线样本，如通过IHC测量的，39%的总体应答率和75%的临床获益率， 观察到，突出了靶向DLL 3的治疗潜力和DLL 3评估的效用。 虽然DLL 3 IHC已证明具有诊断实用性，但该数据目前是从存档组织中收集的 标本，这可能不是理想的参考点，以帮助作出最佳决定，在诊所 治疗时间;事实上，许多具有明显DLL 3阳性的患者未能应答，许多患者 无法评估。一种更可靠的，动态的，真实的时间，非侵入性的，但定量的方法来评估在 肿瘤上抗原表达的体内状态将极大地改善临床上对该试剂的患者选择。 我们提出开发包含89 Zr标记的罗伐匹妥珠单抗的免疫PET诊断剂。 具体目标1建立在有希望的初步成像数据基础上。我们已经能够获得高对比度 使用非特异性胺标记和位点特异性马来酰亚胺生物缀合的免疫PET成像。我们将 通过开发用于89 Zr的更稳定的硫醇可点击的甲砜螯合剂来改进该方法， 尽量减少肾脏摄取。具体目标2将集中于体内毒理学研究， 89 Zr-Rova的药理学以及FDA研究新药的制备和提交 申请临床试验。Specific Aim 3的目标将是89 Zr-Rova的首次人体临床试验 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30例患者的试验将重点关注89 Zr作为一种 Rova-T反应的预测因子。 这项建议将加强纪念斯隆凯特琳之间已经密切的工作关系， 科学家和临床医生以及Stemcentrx，Inc.开发89 Zr标记的rovalpituzumab。这 新的成像剂将通过使其作为一种靶向DLL 3的ADC， 作为一种现代诊断工具，并作为未来放射治疗的侦察员。

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.