Molecular Fluorescence-Guided Surgery Platform

描述（由申请人提供）：该学术-工业合作伙伴关系（AIP）致力于开发和翻译分子靶向光学荧光成像剂，该成像剂是GMP生产的，用于在0期临床试验中指导手术切除。虽然最近在肿瘤外科手术指导技术方面的进展将建立一个有效的管道，这给人留下了深刻的印象，但在术中确定生物学边缘方面仍然存在重大局限性 疾病。基于高级别胶质瘤中原卟啉IX产生的放射性引导手术切除突出了该方法的潜在前景，以至于具有红色和红外通道的术中荧光成像现在可以在徕卡和蔡司制造的最先进的手术显微镜上使用。尽管这些快速的进步，分子示踪剂的发展，所需的指导外科手术一直缺乏。本申请的基础和所提出的AIP的基本原则是，需要一种成本效益高、风险稀释的方法和成本效益高的测试造影剂开发，以实现手术期间荧光引导的承诺。将在0期微量给药研究中的手术试验终点进行试验，信号检测和结合特异性是0期试验的主要结局。快速检测至关重要，因为大多数药物不会成功，我们需要一种策略来减少早期快速评估靶向疗效所需的时间、成本和风险。 人体手术试验创建这样一个管道过程将大大加速向分子引导的外科肿瘤学的范式转变，这将彻底改变可能的手术和手术结果。达特茅斯（工程和医学院），Affibody AB和LI-COR之间的拟议AIP汇集了3个拥有知识产权（IP），专业知识和基础设施的合作伙伴，以开发，测试和 先进的分子靶向荧光示踪剂用于手术指导。我们将推进的第一种药物将是一种靶向表皮生长因子受体（EGFR）的抗体分子（由Affibody，AB在动物中创建并广泛表征，目前正在进行人体核成像研究），该受体与荧光染料（由LI-COR系统开发，用于人体使用）结合，具有近红外吸收和发射光谱。该化合物将在GMP条件下通过肽合成进行开发和生产，将在必要的动物模型中完成单次给药毒性试验，并将在FDA的探索性研究新药（eIND）批准下，在达特茅斯进行首次人体0期剂量递增研究。

DESCRIPTION (provided by applicant): This Academic-Industrial Partnership (AIP) for the development and translation of molecularly-targeted optically-fluorescent imaging agents, GMP-produced for guiding surgical resection in phase 0 clinical trials. While recent advances in the technology for guiding surgical oncology will establish an efficient pipeline have been impressive, significant limitations remain in determining, intraoperatively, the biological margins of disease. Fluorescence-guided surgical resection based on protoporphyrin IX production in high-grade gliomas has highlighted the potential promise of the approach to the extent that intraoperative fluorescence imaging, with both red and infrared channels, is now available on state-of-the-art surgical microscopes manufactured by Leica and Zeiss. Despite these rapid advances, development of the molecular tracers that are required to guide surgical procedures has been lacking. The basis of this application and the underlying tenet of the proposed AIP are that a cost-effective, risk-diluted approach to and cost-effective testing contrast agent development and are needed in order to realize the promise of fluorescence-guidance during surgery. The testing will be carried out with end-points of surgical testing in phase 0 micro dosing studies signal detection and binding specificity being the primary outcomes from the phase 0 trials. Rapid testing is critical because most agents will not be successful, and we need a strategy to reduce the time, cost and risk required to quickly assess targeting efficacy in early human surgical trials. Creation of such a pipeline process stands to accelerate dramatically the paradigm shift to molecular-guided surgical oncology that will revolutionize both the procedures that are possible and the surgical outcomes that will result. The proposed AIP between Dartmouth (Engineering and Medical Schools), Affibody AB, and LI-COR brings together 3 partners who have the intellectual property (IP), expertise and infrastructure to develop, test and advance molecularly-targeted fluorescent tracers for surgical guidance. The first agent we will advance will be an affibody molecule (created and extensively characterized in animals by Affibody, AB, and currently undergoing nuclear imaging studies in humans) targeted to the epidermal growth factor receptor (EGFR) conjugated with a fluorescent dye (systematically developed by LI-COR for human use) with absorption and emission spectra in the near infrared. The compound will be developed and produced through peptide synthesis under GMP conditions, single administration toxicity testing in requisite animal models will be completed, and a first-in-human phase 0 dose escalation study will be pursued at Dartmouth under exploratory investigational new drug (eIND) approval from the FDA.