Molecular Fluorescence-Guided Surgery Platform

描述(由申请人提供)：该学术-产业合作伙伴关系(AIP)用于开发和翻译分子靶向光学荧光显像剂，GMP-生产用于指导0期临床试验中的手术切除。虽然指导外科肿瘤学的技术的最新进展将建立一条有效的管道，但在确定手术中的生物学界限方面仍然存在重大限制。 疾病的威胁。基于产生原卟啉IX的高级别胶质瘤的荧光引导手术切除突出了这种方法的潜在前景，以至于术中具有红色和红外通道的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。尽管取得了这些快速的进展，但指导外科手术所需的分子示踪剂的开发一直缺乏。这一应用的基础和拟议的AIP的基本原则是，为了实现手术中荧光引导的承诺，需要一种具有成本效益、风险稀释和成本效益的检测造影剂开发方法。测试将在0阶段的外科测试的终点进行，微剂量研究、信号检测和结合特异性是0阶段试验的主要结果。快速检测是至关重要的，因为大多数试剂不会成功，我们需要一种策略来减少在早期快速评估靶向效果所需的时间、成本和风险 人体外科试验。这种流水线过程的建立将极大地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程序和将产生的手术结果。达特茅斯(工程和医学院)、附属机构AB和Li-COR之间拟议的AIP将拥有知识产权(IP)、专业知识和基础设施的3个合作伙伴聚集在一起，以开发、测试和 先进的分子靶向荧光示踪剂，用于外科手术指导。我们将推进的第一个试剂将是一种仿体分子(通过ApiBody AB创建并在动物中广泛表征，目前正在进行人类核成像研究)，目标是与具有近红外吸收和发射光谱的荧光染料(由Li-COR系统开发用于人类)结合的表皮生长因子受体(EGFR)。该化合物将在GMP条件下通过肽合成进行开发和生产，在必要的动物模型中完成单次给药毒性测试，并将在FDA批准的探索性研究新药(EIND)下在达特茅斯进行首个人类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.