Pretargeted Clinical Imaging of CA19.9 in Pancreatic Cancer

胰腺癌中 CA19.9 的预靶向临床成像

• 批准号: 10215431
• 负责人: Jason S. Lewis
• 金额: $ 68.92万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-10 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215431
• 关键词: Affinity; Antibodies; Antibody Specificity; Award; Background Radiation; Biodistribution; Biological Markers; Blood; Blood Tests; Clinical; Clinical Trials; Companions; Complication; Cyclooctenes; Data; Development; Diagnosis; Diagnostic; Discipline of Nuclear Medicine; Disease; Drug Kinetics; Early Diagnosis; Evaluation; Excretory function; Genetically Engineered Mouse; Goals; Growth; Health; Human; Image; Imaging Device; Imaging Techniques; Imaging technology; Investigation; Label; Laboratories; Lead; Leadership; Libraries; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Metabolism; Methodology; Modality; Monitor; Organ; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Performance; Pharmacy (field); Positron; Positron-Emission Tomography; Prognosis; Radiation; Radiation Dose Unit; Radioactive; Radioimmunoconjugate; Radioisotopes; Radiopharmaceuticals; Reaction; Reporting; Safety; Series; Serum; Site; Staging; Stratification; Surface Antigens; Survival Rate; Technology; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; Tumor Tissue; Validation; Whole Blood; Work; Xenograft Model; Xenograft procedure; base; cancer cell; cancer diagnosis; clinical Diagnosis; clinical care; clinical imaging; clinical translation; cycloaddition; design; dosimetry; first-in-human; fluorodeoxyglucose; human monoclonal antibodies; imaging approach; imaging modality; imaging platform; improved; in vivo; in vivo evaluation; member; mouse model; noninvasive diagnosis; novel; novel strategies; novel therapeutics; pancreas imaging; pancreatic cancer model; pancreatic cancer patients; pancreatic ductal adenocarcinoma model; pre-clinical; radioligand; residence; risk minimization; serial imaging; small molecule; targeted imaging; theranostics; treatment planning; treatment strategy; tumor; uptake; vector; Affinity; Antibodies; Antibody Specificity; Award; Background Radiation; Biodistribution; Biological Markers; Blood; Blood Tests; Clinical; Clinical Trials; Companions; Complication; Cyclooctenes; Data; Development; Diagnosis; Diagnostic; Discipline of Nuclear Medicine; Disease; Drug Kinetics; Early Diagnosis; Evaluation; Excretory function; Genetically Engineered Mouse; Goals; Growth; Health; Human; Image; Imaging Device; Imaging Techniques; Imaging technology; Investigation; Label; Laboratories; Lead; Leadership; Libraries; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Metabolism; Methodology; Modality; Monitor; Organ; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Performance; Pharmacy (field); Positron; Positron-Emission Tomography; Prognosis; Radiation; Radiation Dose Unit; Radioactive; Radioimmunoconjugate; Radioisotopes; Radiopharmaceuticals; Reaction; Reporting; Safety; Series; Serum; Site; Staging; Stratification; Surface Antigens; Survival Rate; Technology; Testing; Therapeutic; Therapeutic Uses; Time; Tissues; Tumor Tissue; Validation; Whole Blood; Work; Xenograft Model; Xenograft procedure; base; cancer cell; cancer diagnosis; clinical Diagnosis; clinical care; clinical imaging; clinical translation; cycloaddition; design; dosimetry; first-in-human; fluorodeoxyglucose; human monoclonal antibodies; imaging approach; imaging modality; imaging platform; improved; in vivo; in vivo evaluation; member; mouse model; noninvasive diagnosis; novel; novel strategies; novel therapeutics; pancreas imaging; pancreatic cancer model; pancreatic cancer patients; pancreatic ductal adenocarcinoma model; pre-clinical; radioligand; residence; risk minimization; serial imaging; small molecule; targeted imaging; theranostics; treatment planning; treatment strategy; tumor; uptake; vector

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease with a 5-year survival of only 6%. Given the tremendous current focus on the creation of new treatment modalities for pancreatic cancer, the development of imaging technologies that can safely, accurately, and unambiguously aid in the early diagnosis, staging, and treatment monitoring of the disease is a vitally important unmet clinical need. While antibodies have long been attractive vectors for the delivery of diagnostic and therapeutic radioisotopes to cancer cells, radioimmunoconjugates often give rise to a critical clinical complication: high radiation doses to non-target organs. In order to circumvent this obstacle, we have recently developed a methodology for pretargeted PET imaging that harnesses the rapid bioorthogonal cycloaddition between trans-cyclooctene (TCO) and tetrazine (Tz) to effectively combine the affinity and specificity of antibodies with the rapid pharmacokinetics of small molecules. This methodology not only distinguishes tumor tissue with very high contrast, but also produces only a fraction of the background radiation dose to healthy tissue compared to directly labeled antibodies. This proposal describes the development, preclinical validation, and clinical translation of a pretargeted strategy for the PET imaging of PDAC. We will employ the antibody 5B1, a fully human monoclonal antibody (mAb) which targets CA19.9, a well- established biomarker for pancreatic cancer. Specific Aim 1 (SA1), executed during Years 1-2 of the award period, will be focused on the design, synthesis, and pharmacokinetic evaluation of a library of 68Ga-labeled Tz radioligands with the overall goal of identifying four radioligands with the most favorable combination of stability, reactivity, and pharmacokinetics. Specific Aim 2 (SA2), executed during Years 2-3 of the award period, will be centered on the in vivo evaluation of pretargeted PET imaging strategies employing these Tz radioligands and 5B1-TCO in three different murine models of PDAC. The different methodologies will be evaluated based on tumoral uptake, tumor-to-background activity ratios, and dosimetry metrics, and the overarching goal of this specific aim is the identification of a strategy suitable for clinical translation. Specific Aim 3 (SA3), executed during Years 3-5 of the award period, will be focused on the clinical translation of a pretargeted PET imaging strategy. To this end, an FDA IND will be prepared and submitted for the first-in- human clinical trial, and the in vivo performance of the methodology will be evaluated in a series of 28 patients to obtain preliminary imaging data and fundamental biodistribution, metabolism, and safety information. We believe that this proposal could have a significant near-term impact on the clinical care of patients with pancreatic cancer by creating a sensitive, safe, and effective diagnostic and theranostic imaging modality. Furthermore, we contend that this work could also have a long-term, transformational effect on the way antibodies are used in nuclear medicine, ultimately improving the imaging of a wide field of malignant growths.

项目摘要/摘要 胰腺导管腺癌（PDAC）是一种几乎统一的致命疾病，只有5年的生存率 6％。鉴于当前的巨大关注胰腺癌的新治疗方式， 发展成像技术，这些技术可以在早期安全，准确和明确的帮助 疾病的诊断，分期和治疗监测是至关重要的未满足临床需求。尽管 长期以来，抗体一直是将诊断和治疗性放射性同位素传递给 癌细胞，放射免疫偶联物通常会引起严重的临床并发症：高辐射剂量至 非目标器官。为了规避这一障碍，我们最近开发了一种方法。 预先设定的宠物成像，利用反式环烯之间的快速生物正交环载条 （TCO）和四嗪（TZ）有效地结合了抗体的亲和力和特异性 小分子的药代动力学。这种方法不仅区分了很高的肿瘤组织 对比，但与 直接标记为抗体。该建议描述了发展，临床前验证和临床 PDAC PET成像的有预定策略的翻译。 我们将采用抗体5b1，一种完全人类的单克隆抗体（MAB），该抗体靶向Ca19.9（一种）。 建立的胰腺癌生物标志物。特定的目标1（SA1），在奖励的1 - 2年内执行 时期将集中于68GA标记的TZ库的设计，合成和药代动力学评估 放射性配体的总体目标是识别四个具有最有利组合的放射线 稳定性，反应性和药代动力学。特定的目标2（SA2），在奖励的2 - 3年内执行 时期将集中于对使用这些TZ的有预定宠物成像策略的体内评估 PDAC的三种不同鼠模型中的放射性物和5B1-TCO。不同的方法将是 根据肿瘤摄取，肿瘤与背景的活性比和剂量测量指标进行评估，并且 这个特定目标的总体目标是确定适合临床翻译的策略。具体的 AIM 3（SA3）在奖励期的3 - 5年内执行，将重点介绍 有预定的宠物成像策略。为此，将准备FDA IND并提交第一次 人类临床试验以及该方法的体内性能将在一系列28例患者中进行评估 获得初步成像数据和基本生物分布，代谢和安全信息。我们 相信该提案可能会对患者的临床护理产生重大影响 胰腺癌通过创建一种敏感，安全和有效的诊断和疗法成像方式。 此外，我们认为这项工作也可能对方式产生长期的变革影响 抗体用于核医学，最终改善了广泛的恶性增长的成像。