Pretargeted Clinical Imaging of CA19.9 in Pancreatic Cancer

项目摘要/摘要 摘要胰腺导管腺癌是一种几乎全致命的疾病，其五年存活率仅为 6%。鉴于目前对创造新的胰腺癌治疗方式的极大关注， 发展能够安全、准确和明确地帮助早期诊断的成像技术 该病的诊断、分期和治疗监测是一个极其重要的未得到满足的临床需求。而当 长期以来，抗体一直是将诊断和治疗放射性同位素输送到 癌细胞，放射免疫结合物通常会引起严重的临床并发症：高剂量的辐射 非靶器官。为了绕过这一障碍，我们最近开发了一种方法来 利用反式环辛烯之间快速生物正交环加成的预靶向PET成像 (TCO)和四嗪(TZ)有效地将抗体的亲和力和特异性与快速 小分子药物动力学。这一方法学不仅区分了肿瘤组织中非常高的 对比度，但也只产生健康组织背景辐射剂量的一小部分 直接标记的抗体。本建议书描述了开发、临床前验证和临床 为PDAC的正电子发射计算机断层成像翻译一种预靶向策略。 我们将使用抗体5b1，这是一种针对CA19.9的全人单抗(MAb)，CA19.9是一种很好的 已确定的胰腺癌生物标记物。具体目标1(SA1)，在奖励的1-2年内执行 期间，将集中于68Ga标记TZ库的设计、合成和药代动力学评价 放射性配基，总体目标是确定四个放射性配基具有最有利的组合 稳定性、反应性和药代动力学。具体目标2(SA2)，在获奖的2-3年内执行 期间，将集中于使用这些TZ的预靶向PET成像策略的体内评估 放射性配体和5b1-TCO在三种不同的PDAC小鼠模型中的表达。不同的方法将是 根据肿瘤摄取、肿瘤与背景的活动性比率和剂量学指标进行评估，以及 这一特定目标的首要目标是确定一种适用于临床翻译的策略。特定的 AIM 3(SA3)，在授权期的3-5年期间执行，将专注于临床翻译 预靶向PET成像策略。为此，将编写一份FDA IND，并将其提交给第一批- 人体临床试验，该方法的体内表现将在一系列28名患者中进行评估 以获得初步的影像数据和基本的生物分布、代谢和安全性信息。我们 相信这项建议可能会在短期内对患有癌症的患者的临床护理产生重大影响 通过创造一种灵敏、安全和有效的诊断和治疗胰腺癌的成像方式。 此外，我们认为，这项工作也可能在未来的道路上产生长期的、变革性的影响 抗体被用于核医学，最终改善了对广泛恶性生长领域的成像。

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.