Molecular Fluorescence-Guided Surgery Platform

分子荧光引导手术平台

• 批准号: 8649029
• 负责人: KEITH D. PAULSEN
• 金额: $ 55.02万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-08 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649029
• 关键词: Advanced Development; Aminolevulinic Acid; Animal Model; Animals; Binding; Biological; Biological Assay; Biological Markers; Biomedical Engineering; Cell Surface Receptors; Clinical; Clinical Trials; Contrast Media; Detection; Development; Development Plans; Discipline of Nuclear Medicine; Disease; Dose; Drug Kinetics; Engineering; Epidermal Growth Factor Receptor; Excision; Fluorescence; Fluorescent Dyes; Glioma; Human; Image; Injection of therapeutic agent; Institution; Intellectual Property; Investigational Drugs; Malignant Neoplasms; Methods; Microscope; Modality; Molecular; Molecular Probes; New Drug Approvals; North America; Nuclear; Operative Surgical Procedures; Oral; Outcome; Pathway interactions; Patients; Peptide Synthesis; Peptides; Pharmaceutical Preparations; Phase; Positioning Attribute; Positron-Emission Tomography; Procedures; Process; Production; Proteins; Recurrence; Research Infrastructure; Resected; Risk; Series; Signal Transduction; Specificity; Specimen; Strategic Planning; Surgical Oncology; Technology; Testing; Time; Toxicity Tests; Tracer; Translations; Xenograft procedure; absorption; base; brain tumor resection; cost; cost effective; efficacy testing; experience; fluorescence imaging; fluorophore; in vivo; industry partner; medical schools; molecular imaging; neurosurgery; novel; oncology; pre-clinical; primary outcome; protoporphyrin IX; public health relevance; single photon emission computed tomography; success; tumor

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.

描述（由申请人提供）：该学术-工业合作伙伴关系 (AIP) 旨在开发和翻译分子靶向光学荧光显像剂，按照 GMP 生产，用于指导 0 期临床试验中的手术切除。虽然指导肿瘤外科手术的技术的最新进展将建立一个有效的管道，令人印象深刻，但在术中确定生物边缘方面仍然存在重大限制 的疾病。基于高级神经胶质瘤中原卟啉 IX 产生的荧光引导手术切除凸显了该方法的潜在前景，因为术中荧光成像（具有红色和红外通道）现在可以在徕卡和蔡司制造的最先进的手术显微镜上实现。尽管取得了这些快速进展，但指导外科手术所需的分子示踪剂的开发仍然缺乏。该应用的基础和所提出的 AIP 的基本原则是，为了实现手术期间荧光引导的承诺，需要一种具有成本效益、风险稀释的方法和具有成本效益的测试造影剂开发。测试将以 0 期微剂量研究中的手术测试终点进行，信号检测和结合特异性是 0 期试验的主要结果。快速测试至关重要，因为大多数药物都不会成功，我们需要一种策略来减少早期快速评估靶向功效所需的时间、成本和风险。 人体手术试验。这种管道流程的创建将极大地加速分子引导肿瘤外科手术的范式转变，这将彻底改变可能的手术以及将产生的手术结果。达特茅斯学院（工程学院和医学院）、Affibody AB 和 LI-COR 之间拟议的 AIP 汇集了 3 个合作伙伴，他们拥有知识产权 (IP)、专业知识和基础设施来开发、测试和 推进用于手术指导的分子靶向荧光示踪剂。我们将推进的第一个药物将是一种 Affibody 分子（由 Affibody, AB 在动物中创建并进行广泛表征，目前正在进行人体核成像研究），靶向表皮生长因子受体 (EGFR)，与荧光染料（由 LI-COR 系统开发供人类使用）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，在必要的动物模型中完成单次给药毒性测试，并且根据 FDA 的探索性研究新药 (eIND) 批准，将在达特茅斯进行首次人体 0 期剂量递增研究。