PSMA-Dye Surgical Margin Imaging During Prostatectomy

描述（由申请人提供）： 在这次快速重新提交重新分类（由于研究人员从学术界转移到工业界）的多中心，多学科项目，我们将开发一种靶向光学造影剂和改进的室内光成像系统，可以对小至0.1 mm的表面肿瘤进行实时成像（以及小至1 mm至5 mm深度的皮下肿瘤）在根治性椎间盘切除术中暴露于切除边缘。这样的肿瘤现在在真实的时间内是无法检测到的。30%的乳腺癌切除术患者会出现手术边缘的残留肿瘤;这些患者局部复发、转移和死亡的风险明显更高，需要额外的放射治疗。造影剂是基于Cy 7（一种荧光染料）和huJ-591（一种来自Millennium Pharmaceuticals的人源化抗体）的结合，靶向所有前列腺腔来源的细胞。我们将合成这种药物，在组织培养和异种移植小鼠中进行测试，GMP生产，并进行临床前安全性研究。根据NCI/BIP PAR-03-125，本项目分为可行性（R43）和开发（R44）阶段。 1年的具体目标。R43可行性组成部分是：a）通过将Cy 7缀合至huJ 591来产生对管腔来源的人前列腺细胞特异的靶向光学造影剂，B）测试室内光临床成像系统，所述室内光临床成像系统检测来自预期在体内肿瘤中发现的染料浓度的手术室环境光中的荧光信号，选择基于里程碑的性能特征，以使体内成功成为可能，和c）证明该试剂可以在10秒或更短时间内以至少2：1的信噪比检测，并在组织模型中以nM水平成像，同时保留20%huJ591结合活性。我们将衡量3年R44开发组件成功与否的具体目标是：a）优化染料动力学，B）部署OR就绪实时成像系统，c）生产GMP药物级缀合抗体染料，并在培养物和动物中进行临床前安全性测试，和d）评估OR条件下的性能，和e）在动物研究中定量手术获得阴性边缘的能力。 如果成功的话，这种方法可能会导致在手术切除术中减少阳性边缘，并且从长远来看，允许更有效的治疗，最终扩展到乳腺癌和黑色素瘤。

DESCRIPTION (provided by applicant): In this fast-track re-submission for re-classification (due to investigator move from academia to industry) of a multi-center, multi-disciplinary project, we will develop a targeted optical contrast agent and improved roomlight imaging system which allow for real-time imaging of surface tumors as small as 0.1 mm (and subsurface tumors as small as 1 mm to a depth of 5 mm) exposed at the excisional margin during radical prostatectomy surgery. Such tumors are now undetectable in real time. Residual tumor at the surgical margin occurs in 30% of all prostatectomies; such patients have a significantly higher risk of local recurrence, metastasis, and death, and require additional radiation therapy. The contrast agent is based on a conjugation of a Cy 7, a fluorescent dye, and huJ-591, a humanized antibody from Millennium Pharmaceuticals targeted to all cells of luminal prostate origin. We will synthesize this agent, test in tissue culture and xenograft mouse, GMP manufacture, and perform pre-clinical safety studies. This project divides into feasibility (R43) and development (R44) phases, in response to NCI/BIP PAR-03-125. Specific aims of the 1 yr. R43 feasibility component are: a) to produce a targeted optical contrast agent specific for human prostate cells of luminal origin by conjugating Cy 7 to huJ591, b) to test a room-light clinical imaging system that detects a fluorescent signal in operating room ambient light from at a dye concentration expected to be found in tumors in vivo, with quantitative, milestone-based performance characteristics selected so as to make success in vivo likely, and c) to demonstrate that this agent can be detected with a signal to noise of at least 2:1 in 10 seconds or less, and imaged at nM levels in tissue models, while retaining 20% huJ591 binding activity. This specific aims by which we will measure the success of the 3 year R44 development component are: a) to optimize dye kinetics, b) to deploy an OR-ready real-time imaging system, c) to produce a GMP pharmaceutical grade conjugated antibody-dye, and to perform pre-clinical safety testing in culture and in animals, and d) to evaluate performance in OR conditions, and e) quantitate the ability to surgically obtain negative margins in animal studies. If successful, this approach may lead to fewer positive margins during surgical prostatectomy and, in the long term, allow for more effective treatment, with ultimate extension to breast cancer and melanoma as well.