Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
Mol Pharm. 2022 Oct 3;19(10):3586-3599. doi: 10.1021/acs.molpharmaceut.2c00203. Epub 2022 May 31.
Surgery remains the only potentially curative treatment option for pancreatic cancer, but resections are made more difficult by infiltrative disease, proximity of critical vasculature, peritumoral inflammation, and dense stroma. Surgeons are limited to tactile and visual cues to differentiate cancerous tissue from normal tissue. Furthermore, translating preoperative images to the intraoperative setting poses additional challenges for tumor detection, and can result in undetected and unresected lesions. Thus, pancreatic ductal adenocarcinoma (PDAC) has high rates of incomplete resections, and subsequently, disease recurrence. Fluorescence-guided surgery (FGS) has emerged as a method to improve intraoperative detection of cancer and ultimately improve surgical outcomes. Initial clinical trials have demonstrated feasibility of FGS for PDAC, but there are limited targeted probes under investigation for this disease, highlighting the need for development of additional novel biomarkers to reflect the PDAC heterogeneity. MUCIN16 (MUC16) is a glycoprotein that is overexpressed in 60-80% of PDAC. In our previous work, we developed a MUC16-targeted murine antibody near-infrared conjugate, termed AR9.6-IRDye800, that showed efficacy in detecting pancreatic cancer. To build on the translational potential of this imaging probe, a humanized variant of the AR9.6 fluorescent conjugate was developed and investigated herein. This conjugate, termed huAR9.6-IRDye800, showed equivalent binding properties to its murine counterpart. Using an optimized dye:protein ratio of 1:1, studies demonstrated high tumor to background ratios in MUC16-expressing tumor models, and delineation of tumors in a patient-derived xenograft model. Safety, biodistribution, and toxicity studies were conducted. These studies demonstrated that huAR9.6-IRDye800 was safe, did not yield evidence of histological toxicity, and was well tolerated . The results from this work suggest that AR9.6-IRDye800 is an efficacious and safe imaging agent for identifying pancreatic cancer intraoperatively through fluorescence-guided surgery.
手术仍然是胰腺癌唯一有治愈可能的治疗选择，但由于浸润性疾病、关键脉管系统的临近、肿瘤周围炎症和致密基质的存在，使得切除术变得更加困难。外科医生只能依靠触觉和视觉线索来区分癌组织和正常组织。此外，将术前图像转化为术中环境会给肿瘤检测带来额外的挑战，导致无法检测和无法切除的病变。因此，胰腺导管腺癌（PDAC）的不完全切除率很高，随后疾病复发率也很高。荧光引导手术（FGS）已成为提高术中癌症检测能力并最终改善手术结果的一种方法。初步临床试验已经证明了 FGS 对 PDAC 的可行性，但针对这种疾病的靶向探针数量有限，这凸显了开发额外的新型生物标志物以反映 PDAC 异质性的必要性。MUCIN16（MUC16）是一种在 60-80%的 PDAC 中过度表达的糖蛋白。在我们之前的工作中，我们开发了一种 MUC16 靶向的小鼠抗体近红外缀合物，称为 AR9.6-IRDye800，该缀合物在检测胰腺癌方面显示出了疗效。为了进一步开发这种成像探针的转化潜力，我们在此开发并研究了一种 AR9.6 荧光缀合物的人源化变体。这种缀合物称为 huAR9.6-IRDye800，与人源化的 AR9.6 抗体具有相同的结合特性。使用优化的染料：蛋白比为 1:1，研究表明在 MUC16 表达的肿瘤模型中，huAR9.6-IRDye800 具有高肿瘤与背景的比值，并在患者来源的异种移植模型中描绘了肿瘤。还进行了安全性、生物分布和毒性研究。这些研究表明，huAR9.6-IRDye800 是一种安全、没有组织学毒性证据且耐受良好的成像剂。这项工作的结果表明，AR9.6-IRDye800 是一种有效的、安全的成像剂，可通过荧光引导手术术中识别胰腺癌。
