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

使用 89Zrrovalpituzumab（一种 DLL3 靶向单克隆抗体）对高级神经内分泌肺肿瘤进行免疫 PET 成像

• 批准号: 10078772
• 负责人: Jason S. Lewis
• 金额: $ 36.74万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078772
• 关键词: Amines; Antibodies; Antibody-drug conjugates; Antigens; Archives; Biodistribution; Biopsy; Cancer Patient; Cell Surface Proteins; Cell surface; Chelating Agents; Chemistry; Clinic; Clinical; Clinical Research; Clinical Trials; Cysteine; Data; Deferoxamine; Development; Diagnosis; Diagnostic; Disease; Dose; Drug Delivery Systems; Enrollment; Evaluable Disease; Extensive Stage; FDA approved; Future; Goals; Grant; Heterogeneity; Image; ImmunoPET; Immunoconjugates; Immunohistochemistry; Investigation; Investigational Drugs; Investigational New Drug Application; Investigational Therapies; Kidney; Label; Ligands; Lung Neuroendocrine Neoplasm; Maleimides; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Memorial Sloan-Kettering Cancer Center; Metastatic/Recurrent; Methods; Molecular; Molecular Target; Monoclonal Antibodies; Nature; Necrosis; Needle biopsy procedure; PET/CT scan; Patient Selection; Patient imaging; Patient-Focused Outcomes; Patients; Performance; Pharmacology; Pharmacology and Toxicology; Phase; Positron; Positron-Emission Tomography; Pre-Clinical Model; Preparation; Prior Therapy; Proteins; Radiation therapy; Radioimmunoconjugate; Recurrent disease; Refractory; Research Personnel; Running; Safety; Sampling; Scientist; Serum; Site; Specificity; Specimen; Stains; Sulfhydryl Compounds; Therapeutic; Therapeutic Clinical Trial; Therapeutic antibodies; Time; Tissues; Toxic effect; Tracer; Translating; Tumor Antigens; United States; Validation; Xenograft procedure; Zirconium; appropriate dose; base; cGMP production; cancer imaging; cohort; companion diagnostics; dosimetry; effusion; first-in-human; imaging agent; immunoreactivity; improved; in vivo; lead optimization; lung small cell carcinoma; novel; novel therapeutic intervention; novel therapeutics; outcome forecast; phase 1 study; preclinical imaging; predicting response; response; statistics; targeted treatment; tool; tumor; uptake

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.

项目概要/摘要 小细胞肺癌（SCLC）是一种高级别肺神经内分泌肿瘤，占 在美国，每年诊断出的肺癌病例约占所有肺癌病例的 16%。在大多数患者中，SCLC 在以下时间发生转移： 演示时间；广泛期疾病患者的生存预后较差 可以用几个月来衡量，平均 5 年生存率 <5%。新的治疗策略迫在眉睫 需要改善这些患者的临床结果。 一种针对 Delta 样配体 3 (DLL3) 的新型抗体药物偶联物（rovalpituzumab tesirine；Rova-T）， 一种高度肿瘤选择性的细胞表面蛋白，已在早期阶段表现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 测量，基线样本的总体缓解率为 39%，临床获益率为 75% 观察到，突出了靶向 DLL3 的治疗潜力和 DLL3 评估的实用性。 虽然 DLL3 IHC 已证明具有诊断实用性，但该数据目前是从存档的组织中收集的 样本，这可能无法作为帮助在诊所做出最佳决策的理想参考点 治疗时间；事实上，许多 DLL3 明显呈阳性的患者未能做出反应，并且许多患者 是不可评估的。一种更可靠、动态、实时、非侵入性且定量的方法来评估 肿瘤上抗原表达的体内状态将极大地改善患者在临床上对该药物的选择。 我们建议开发一种包含 89Zr 标记的 rova​​lpituzumab 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的基础上。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共轭的免疫 PET 图像。我们将 通过为 89Zr 开发更稳定的硫醇可点击甲基砜螯合剂来改进这种方法 尽量减少肾脏的摄取。具体目标 2 将集中于体内毒理学研究和 89Zr-Rova 的药理学以及 FDA 研究性新药的制备和提交 申请临床试验。 Specific Aim 3的目标将是89Zr-Rova的首次人体临床试验 用于同时参加一项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 名患者参与的试验将重点关注 89Zr 作为药物的临床安全性和有效性。 对 Rova-T 反应的预测因子。 该提案将加强纪念斯隆·凯特琳与纪念斯隆·凯特琳之间本已密切的工作关系 科学家和临床医生以及 Stemcentrx, Inc. 致力于开发 89Zr 标记的 rova​​lpituzumab。这 新型显像剂将通过允许 DLL3 靶向 ADC 充当 同期诊断工具并充当未来放射治疗的侦察者。