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.

项目摘要/摘要 小细胞肺癌（SCLC）是一种高级肺神经内分泌肿瘤，占 每年在美国诊断出的所有肺癌病例中，约有16％。在大多数患者中，SCLC是转移性的 演示时间；患有广泛阶段疾病的患者预后不良，生存 可在几个月内测量，平均5年生存率<5％。新的治疗策略是拼命的 需要改善这些患者的临床结果。 一种新型抗体药物缀合物（Rovalpituzumab tesirine; rova​​-t），其靶向三角洲（例如配体3）（dll3）， 高度肿瘤选择性细胞表面蛋白在早期表现出令人印象深刻的临床益处 大细胞肺癌患者的临床试验。在可评估的DLL3+患者中 根据IHC的衡量，基线样品的总体反应率和75％的临床福利率为39％ 观察到，强调靶向DLL3的治疗潜力和DLL3评估的效用。 虽然DLL3 IHC已证明诊断效用，但目前从存档的组织中收集了此数据 标本，这可能不能用作理想的参考点，以帮助在诊所做出最佳决定 治疗时间；实际上，许多具有明显DLL3阳性的患者无法做出反应，许多患者 无法评估。一种更可靠，动态的，实时的，无创但定量的方法来评估IN 抗原表达在肿瘤上的体内状态将大大改善该诊所中该药物的患者选择。 我们建议开发包含89ZR的Rovalpituzumab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 免疫-PET图像使用非特异性胺标记和特异性马来酰亚胺生物结合。我们将 通过开发更稳定的硫醇可粘合甲基氟氟螯合剂的89ZR来改进这种方法 最大程度地减少肾脏摄取。具体目标2将集中于研究体内毒理学和 89ZR-ROVA的药理学以及FDA调查新药的准备和提交 临床试验申请。特定AIM 3的目的是89ZR-ROVA的首次人类临床试验 对于小细胞肺癌患者的PET成像，同时参加了一项临床试验 治疗性ADC ROVA-T。这项30名患者试验将集中于89ZR作为一个的临床安全性和功效 预测对Rova-T的响应指标。 该提议将加强纪念斯隆·凯特（Sloan Kettering）之间已经紧密的工作关系 科学家和临床医生和STEMCentRX，Inc。朝着89ZR标记的Rovalpituzumab开发。这 新颖的成像剂将通过允许将其用作DLL3靶向ADC的诊断值 同时的诊断工具，并充当未来放射治疗的侦察员。