Pretargeted Clinical Imaging of CA19.9 in Pancreatic Cancer

项目概要/摘要 胰腺导管腺癌（PDAC）是一种几乎一致致死的疾病， 百分之六鉴于目前对胰腺癌新治疗模式的巨大关注， 发展成像技术，可以安全，准确，明确地帮助早期 该疾病的诊断、分期和治疗监测是一个极其重要的未满足的临床需求。而 抗体长期以来一直是有吸引力的载体，用于将诊断和治疗性放射性同位素递送至 癌细胞，放射免疫缀合物通常引起严重的临床并发症：高辐射剂量， 非靶器官。为了克服这一障碍，我们最近开发了一种方法， 利用反式环辛烯之间的快速生物正交环加成的预靶向PET成像 (TCO)和四嗪（Tz），以有效地将抗体的亲和力和特异性与快速免疫反应联合收割机结合。 小分子的药代动力学。这种方法不仅区分肿瘤组织与非常高的 对比度，但也只产生一小部分的背景辐射剂量的健康组织相比， 直接标记抗体。本提案描述了开发、临床前验证和临床 PDAC的PET成像的预靶向策略的翻译。 我们将使用抗体5 B1，一种靶向CA 19.9的全人单克隆抗体（mAb），一种良好的抗肿瘤抗体。 胰腺癌的生物标志物具体目标1（SA 1），在奖励的第1-2年执行 期间，将集中在设计，合成和药代动力学评价库的68镓标记的Tz 放射性配体，总体目标是鉴定具有以下最有利组合的四种放射性配体 稳定性、反应性和药代动力学。具体目标2（SA 2），在奖励的第2-3年执行 期间，将集中在体内评价的预靶向PET成像策略，采用这些Tz 放射性配体和5 B1-TCO在三种不同的PDAC鼠模型中的作用。不同的方法将是 基于肿瘤摄取、肿瘤与背景活性比和剂量测定指标进行评价， 这一特定目标的首要目标是确定适合临床翻译的策略。具体 目标3（SA 3），在奖励期的第3-5年执行，将专注于临床翻译， 预先靶向PET成像策略。为此，将准备并提交FDA IND，用于首次临床试验。 人体临床试验，并将在一系列28名患者中评价该方法的体内性能 以获得初步的成像数据和基本的生物分布、代谢和安全性信息。我们 我相信，这一建议可能会对患者的临床护理产生重大的近期影响， 通过创建一个敏感，安全和有效的诊断和治疗诊断成像模式，胰腺癌。 此外，我们认为，这项工作也可能有一个长期的，变革性的影响， 抗体被用于核医学，最终改善了广泛的恶性肿瘤的成像。

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.