Advanced Manufacturing Process for High Performance MRI Contrast Agents

描述（申请人提供）：磁共振增强成像广泛应用于多种疾病的无创诊断。然而，由于现有钆螯合造影剂的固有特性，临床需要改进的MRI造影剂，延长循环半衰期，使血池成像具有良好的生物分布和组织特异性成像；减少Gd相关的长期安全问题；具有更大的松弛性并产生正对比度增强。Luna正在开发基于金属富勒烯的T1药物，用于血液池成像和癌症和动脉粥样硬化斑块的靶向成像。我们已经进行了大量的动物研究，证明在较低剂量下显著提高了成像灵敏度，并且没有发现急性毒性。这是一种非常有前途的新型T1造影剂平台技术。然而，为了具有成本竞争力并能够生产临床相关数量的金属富勒烯，有必要改进现有的制造工艺。Luna提议开发一种大批量的列车升华工艺，以取代现有的批量提取净化工艺，从而可以直接从生产的反应器烟尘中收集高纯度的金属富勒烯。将对现有的制造工艺进行根本性的改进，以提供可观的生产率、质量和环境效益。这些改进将克服高成本纯化所面临的挑战，这是实现基于金属富勒烯的MRI造影剂的一个重要障碍。将在拟议的生产过程之后进行体外测试，以证明物理化学和磁性不受影响。我们还将从结构-活性（弛豫）关系中推断信息，并优化弛豫特性，以最大限度地发挥我们的氢查龙制剂的临床潜力。随着稳定性研究和质量控制分析，I期结果将为进入IND的II期药代动力学、毒性和成像研究提供坚实的基础。

DESCRIPTION (provided by applicant): Contrast-enhanced magnetic resonance imaging is widely used for non-invasive diagnosis of a variety of diseases. However due to the intrinsic properties of existing gadolinium-chelate contrast agents, there exist clinical needs of improved MRI contrast agents that render extended circulatory half-life enabling blood pool imaging with favorable biodistribution and enabling tissue-specific imaging; reduce Gd associated long term safety concerns; have greater relaxivity and generate positive contrast enhancement. Luna is developing metallofullerene-based T1 agents for both blood pool imaging and targeted imaging of cancer and atherosclerotic plaque. We have conducted extensive animal studies demonstrating substantially improved imaging sensitivity at lower does, and no acute toxicity was found. It is a very promising new T1 contrast agent platform technology. However, to be cost competitive and capable of producing clinically relevant quantities, it is necessary to improve the existing manufacturing process for metallofullerenes. Luna proposes to develop a high-volume train sublimation process in place of the existing batch extraction-purification processes allowing direct collection of high purity metallofullerenes from as-produced reactor soot. Fundamental improvements will be made in existing manufacturing processes that deliver substantial productivity, quality, and environmental benefits. These improvements will overcome challenges facing the high cost purification, a significant barrier in the realization of metallofullerene-based MRI contrast agents. In vitro testing will be conducted following the proposed production process to demonstrate that the physiochemical and magnetic properties are not affected. We will also extrapolate information from the structure-activity (relaxivity) relationship and optimize the relaxivity property to maximize the clinical potential of our Hydrochalarone agents. Along with stability studies and quality control assays, the Phase I results will provide a sound foundation to proceed to Phase II for IND- enabling pharmacokinetics, toxicity and imaging studies.