Fluorophore-Conjugated Antibodies for Imaging and Resection of GI Tumors

描述（由申请人提供）：我们提议在加州圣地亚哥大学（学术合作伙伴）和抗癌公司的研究人员之间建立一个独特的学术-工业合作伙伴关系。（工业合作伙伴）开发和验证荧光团缀合抗体用于胃肠道肿瘤的手术导航和腹腔镜定位。拟议的研究将开发用于小鼠模型研究的先进成像技术、方法和工具，这些技术、方法和工具将可用于临床，以开发荧光引导的癌症手术。假设荧光团标记的抗肿瘤特异性抗原的抗体将改善原发性和转移性胰腺癌和结肠癌的可视化，检测和切除。具体目的1利用特异于肿瘤抗原CA 19 -9、CEA或两者的组合的荧光团标记的单克隆抗体来促进胰腺癌和结肠癌的肿瘤边缘和转移病灶的成像和切除。我们将使用荧光标记的抗肿瘤抗原CA 19 -9和CEA的单克隆抗体或两者的组合，以评估在人胰腺癌和结肠癌的原位转移性裸鼠模型中的体内肿瘤负荷，并促进原位和转移性病变的完全切除。将对荧光团偶联的单克隆抗体进行毒性、给药和组织分布研究。具体目标2我们将比较几种不同的荧光团在我们的人胰腺癌小鼠模型中的体内给药反应、体内信号持续时间、体内光漂白和体内信号背景比。荧光团在其体内初始荧光发射强度、荧光信号的持续时间、上覆组织的散射和吸收以及随着长时间暴露于强光而丧失荧光强度的倾向（称为光漂白的现象）方面可以变化很大。由于荧光团之间的这些差异，选择具有适当波长和信号强度的稳定荧光团用于体内使用至关重要。我们将在我们的人胰腺癌原位移植裸鼠模型中检查绿色（480-520 nm）、黄色（550-570 nm）、红色（610-650 nm）和远红（680-710 nm）范围内的几种不同荧光团，以确定用于人类荧光引导癌症手术的潜在临床用途的最佳荧光团候选物。具体目标3：利用荧光腹腔镜检查改善在正常腹腔镜照明下看不到的原发性和转移性胃肠道癌的可视化。通过腹腔镜在手术前清楚地区分所有荧光标记的癌组织的能力可以消除不必要的剖腹手术造成的发病率，并指导胰腺癌和结肠癌的后续治疗。我们将使用由上述目标确定的抗体和荧光团的最佳组合，以比较荧光腹腔镜与传统腹腔镜下腹腔镜手术期间肿瘤检测的程度。 公共卫生相关性：在美国，结肠直肠癌和胰腺癌一起构成癌症相关死亡的第三和第四大常见原因。对于这两种疾病，原发性和转移性肿瘤的完整检测对患者的预后至关重要。我们的目标是利用不断发展的荧光成像技术来开发结直肠癌和胰腺癌术中分期的新方法，并提高我们在手术时实现真正切除的能力。

DESCRIPTION (provided by applicant): We propose a unique academic-industrial partnership between investigators at the University of California San Diego (Academic Partner) and AntiCancer, Inc. (Industrial Partner) to develop and validate the use of fluorophore-conjugated antibodies for surgical navigation and laparoscopic localization of gastrointestinal tumors. The proposed research will develop advanced imaging technology, methods and tools for mouse-model studies that will be translatable to the clinic to develop fluorescence-guided cancer surgery. Hypothesis Fluorophore-labeled antibodies against tumor-specific antigens will improve visualization, detection, and resection of primary and metastatic pancreatic and colon cancer. Specific Aim 1 Utilization of fluorophore-labeled monoclonal antibody specific for the tumor antigen CA19-9, CEA, or a combination of both to facilitate imaging and resection of tumor margins and metastatic lesions in pancreatic and colon cancer. We will use fluorescent-conjugated monoclonal antibodies against tumor antigen CA19-9 and CEA or a combination of both to evaluate tumor burden in vivo in an orthotopic metastatic nude mouse model of human pancreatic and colon cancer and to facilitate the complete resection of orthotopic and metastatic lesions. Toxicity, dosing, and tissue distribution studies will be performed for fluorophore-conjugated monoclonal antibodies. Specific Aim 2 We will compare several different fluorophores for in vivo dosing response, in vivo signal duration, in vivo photobleaching, and in vivo signal-to-background ratio in our mouse models of human pancreatic cancer. Fluorophores can vary greatly in their in vivo intensity of initial fluorescence emission, duration of fluorescence signal, scatter and absorption by overlying tissues and propensity for loss of fluorescence intensity with prolonged exposure to bright light, a phenomenon known as photobleaching. Due to these differences between fluorophores, it is of vital importance to choose a stable fluorophore with appropriate wavelength and signal intensity for in vivo use. We will examine several different fluorophores in the green (480-520 nm), yellow (550-570 nm), red (610-650 nm), and far-red (680-710 nm) ranges in our orthotopic metastastic nude mouse models of human pancreatic cancer to determine the optimal fluorophore candidates for potential clinical use for fluorescence guided cancer surgery in humans. Specific Aim 3 Utilization of fluorescence laparoscopy to improve visualization of primary and metastatic GI cancers not otherwise seen under normal laparoscopic lighting. The ability to clearly distinguish all fluorescently-labeled cancerous tissue pre-operatively via laparoscopy can eliminate the morbidity from an unnecessary laparotomy and direct subsequent treatment of pancreatic and colon cancer. We will use the optimal combination of antibodies and fluorophores as determined by the aims listed above to compare the extent of tumor detection during laparoscopy under fluorescence versus traditional laparoscopy. PUBLIC HEALTH RELEVANCE: Colorectal and pancreatic cancers together comprise the third and fourth most common causes of cancer- related death in the United States. For both diseases the complete detection of primary and metastatic tumor is critical to patient outcomes. Our goal is to utilize the growing technology of fluorescence imaging to both develop new methods of intraoperative staging for colorectal and pancreatic cancer and to improve our ability to achieve true resection at the time of surgery.