ProstaFluor FDA Trial for Real-Time Margin Detection During Prostatectomy

描述（由申请人提供）：在这个为期5年的学术-工业合作伙伴关系中，一个经验丰富的团队和合作伙伴，包括康奈尔大学，范德比尔特大学，Intuitive Surgical， LI COR和Sand Hill研究所，将推动一种前列腺靶向荧光造影剂，在之前的R44项目中展示，允许实时检测动物残留肿瘤，通过FDA批准用于人类。未满足的需求是，由于手术边缘的前列腺肿瘤无法实时检测到，因此在所有前列腺切除术中，边缘残留肿瘤的发生率为30%。这类患者局部复发、转移和死亡的风险明显较高，也需要放射治疗。相比之下，即使是前列腺外肿瘤延伸的患者，如果在手术中清除肿瘤边缘，情况也会好转。我们建议利用我们的经验和我们的动物验证剂来合成，获得FDA的IND批准，并在96名人类受试者中进行I/II期试验我们的靶向荧光偶联物。我们的试剂由商用LICOR荧光染料和康奈尔大学和千禧制药公司的人源抗体（huJ-591）制成。靶向抗体可标记所有腔内起源的前列腺细胞，并在先前的资助中证明，在动物中对前列腺细胞产生4-12倍的对比。直觉外科公司是一家价值100亿美元的机器人手术公司，该设备将使用该公司的荧光敏感手术系统在现场进行测试。该基金的项目负责人此前已经开发并商业化了基础光学技术，他(1)在斯坦福大学共同开发了第一个体内荧光素酶成像系统，并共同创立了Xenogen，(2)他开发了T- Stat(R)，这是FDA批准的第一个用于组织血流量不足的检测系统。其他团队成员合成了用于商业用途的染料偶联物，并通过FDA批准管理基于抗体的药物配方。公司合作伙伴LiCor（使用近红外设备和染料的自动化测序仪器和试剂的全球领导者）和Sand Hill Institute（在抗体配方方面经验丰富）以及Intuitive Surgical，在造影剂和FDA批准方面提供成熟的商业转化经验。这些团队将配制并合成该药物，从而向FDA提交IND申请并进行人体临床试验。可选择的路径将每个阶段的风险降到最低。如果成功，商业染料将准备与主要手术工具合作伙伴进行三期多中心试验，这是一条昂贵且必要的市场推广之路。主要成像公司（西门子、菲利普斯、通用电气等）也有分子成像项目，该合同代理将适合这些项目。可能会采用一种成功的显像剂。预计将利用叶状II型受体和其他靶点扩展到卵巢癌，包括与其他小组开发的其他靶向抗体一起使用。我们预计，这将是许多实时手术为目标的光学造影剂在人类受试者中的第一个。立即应用的领域是前列腺癌术中淋巴扩散的检测，以及使用叶酸检测卵巢癌。我们预计这种用于治疗癌症的设备的市场规模将达到每年数亿美元。表格SF-424摘要

DESCRIPTION (provided by applicant): In this 5 year academic-industrial partnership to FDA approval, an experienced team and partners including Cornell, Vanderbilt, Intuitive Surgical, LI COR, and Sand Hill Institute, will move a prostate-targeted fluorescent contrast agent, demonstrated in a prior R44 project to allow real time detection of residual tumor in animals, through FDA approval to human use. The unmet need is that because prostate tumor at the surgical margin is undetectable in real time, residual tumor at the margin occurs in 30% of all prostatectomies. Such patients have a significantly higher risk of local recurrence, metastasis, and death, and also require radiation therapy. In contrast, even patients with extra prostatic extension of tumors do better when the margins are made clean of tumor during surgery. We propose to leverage our experience and our animal proven agent to synthesize, receive FDA IND approval on, and Phase I/II test our targeted fluorescent conjugate in a pilot study in 96 human subjects. Our agent is made from a commercial LICOR fluorescent dye, and a humanized antibody from Cornell and Millennium Pharmaceuticals (huJ-591). The targeted antibody tags all prostate cells of luminal origin, and was demonstrated in prior funding to produce 4-12 fold contrast for prostate cells over nearby tissues in animals. The device will be tested a sites using a fluorescence-sensitive surgery system from Intuitive Surgical, a $10 billion robotic surgery company. The PI of this grant has previously developed and commercialized fundamental optical technologies he (1) co-developed the first in vivo luciferase imaging system at Stanford and co-founded Xenogen, and (2) he developed T- Stat(R), the first FDA approved detection system for insufficient blood flow to tissue. Other team members have synthesized dye conjugates for commercial use, and managed antibody based drug formulation through FDA approval. The corporate partners, LiCor (a world leader in automated sequencing instruments and reagents using near infrared devices and dyes) and Sand Hill Institute (experienced at antibody formulation), and Intuitive Surgical, provide proven commercial translational experience in contrast agents and FDA approval. These groups will formulate and synthesize the agent, leading to FDA IND filing and human clinical testing. Alternative paths minimize risks at each stage. If successful, the commercial dye will be readied for Phase III multi-center trial with a major surgical tool partner, a costly and required path to market introduction. Major imaging companies (Siemens, Phillips, GE, and others) also have molecular imaging programs, into which this contract agent will fit. A successful imaging agent would likely be adopted. Extensions to ovarian cancer using the foliate type II receptor, and other targets, are envisioned, including use with other targeting antibodies developed by other groups. We anticipate that this will be among the first of many real-time surgery-targeting optical contrast agents in human subjects. Areas with immediate application are the detection of lymphatic spread intraoperatively for prostate cancer, as well as for ovarian cancer using a Folate. We expect that the market for such a device in cancer could reasonably be in the hundreds of millions of dollars/year. Form SF-424 Abstract