PSMA-Dye Surgical Margin Imaging During Prostatectomy

描述(由申请人提供)： 在这个多中心、多学科项目的重新分类快速通道(由于研究人员从学术界转向行业)中，我们将开发一种有针对性的光学造影剂和改进的房间光成像系统，允许对根治性前列腺切除术中暴露在切除边缘的小至0.1 mm的表面肿瘤(以及小至1 mm至5 mm的表面下肿瘤)进行实时成像。这样的肿瘤现在无法实时检测到。在所有的前列腺切除术中，30%的手术边缘会出现残留肿瘤；这类患者的局部复发、转移和死亡的风险明显更高，需要额外的放射治疗。这种造影剂是基于荧光染料Cy 7和人源化抗体HuJ-591的结合，HuJ-591是千禧制药公司的人源化抗体，目标是所有腔内前列腺癌起源的细胞。我们将合成这种药物，在组织培养和异种小鼠移植中进行测试，生产GMP，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)两个阶段。 一年的具体目标。R43的可行性部分包括：a)通过将Cy7与huJ591偶联，生产针对管腔起源的人前列腺细胞的靶向光学对比剂，b)测试房间光临床成像系统，该系统可检测手术室环境光中预期在体内肿瘤中发现的染料浓度的荧光信号，并选择以里程碑为基础的定量性能特征，以使体内成功成为可能，以及c)证明该试剂可在10秒或更短的时间内以至少2：1的信噪比被检测到，并在组织模型中以NM水平进行成像，同时保持20%的huJ591结合活性。我们用来衡量3年R44开发组件的成功的具体目标是：a)优化染料动力学，b)部署OR就绪的实时成像系统，c)生产GMP药用级结合抗体-染料，并在培养和动物中执行临床前安全测试，d)评估OR条件下的表现，以及e)量化在动物研究中通过手术获得阴性边际的能力。 如果成功，这种方法可能会导致手术中前列腺切除的阳性切缘减少，从长远来看，可以进行更有效的治疗，最终也会延伸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.