Commercialization of an MRI contrast agent for differential diagnosis of prostate cancer

摘要 前列腺癌是一种高度异质性的疾病，是男性癌症死亡的第二大原因 在美国。目前评估前列腺癌风险的方法结合前列腺特异性抗原（PSA） 筛查和随机前列腺活检。不幸的是，这种策略未能揭示病变的位置和 不能准确区分侵袭性和非侵袭性前列腺癌。结果，大多数 患者将接受不必要的低风险前列腺癌积极治疗。因此，发展非 用于定位和区分高风险前列腺癌的侵入性准确诊断成像技术 提供了一种新工具来帮助医生进行风险分层和决策，并避免数百万 患有低风险癌症的患者免受不必要的积极治疗。 分子治疗诊断学的使命是将一种新颖的分子成像方法商业化，该方法 靶向与上皮间质转化 (EMT)、癌细胞干性相关的癌蛋白， 血管生成、增殖和转移。癌蛋白在肿瘤中高表达 高危前列腺癌的细胞外基质，低级别肿瘤的细胞外基质含量低，正常组织中无。的 该项目的最终目标是将靶向造影剂 MT218 商业化，以实现准确的早期检查 通过 MRI 检测、定位和鉴别诊断高危前列腺癌。我们已经优化了 并确定了一种领先的靶向 MRI 造影剂，证明其在各种动物体内肿瘤模型中有效， 并完成了临床前批次的化学、制造和控制（CMC）工作。而且， 我们根据 FDA 的 IND 指南证明了 MT218 的 GLP 临床前安全性 提交。 MT218已显示出通过肾脏排泄的快速和完全清除，没有检测到大脑 在大鼠和狗中保留性好，药理风险和毒性低。 IND 于 2017 年获得 FDA 批准 2021 年 3 月在俄亥俄州进行 1 期临床试验。前两个给药组没有显示出不良反应 并能快速从体内排泄，作为临床造影剂。 该 SBIR 项目中的拟议工作将使公司能够进行概念验证阶段 2a 已证实患有高危前列腺癌的专利的临床试验。具体目标是 1) 执行 开放标签 2a 期临床试验，旨在研究 MT218 在前列腺癌诊断 MRI 中的初始成像效果 病人； 2) 开发用于放大 cGMP 生产的液相合成程序。成功 我们成像技术的发展有可能准确检测、定位和诊断 MRI 空间分辨率 < 1 毫米的前列腺癌，减少侵入性前列腺活检的使用等 改善前列腺癌临床管理的决策。它还具有准确的潜力 对前列腺癌进行无创主动监测并及时监测疾病进展 作为图像引导焦点治疗。 MT218的临床应用有望改善医疗保健和 PCa 患者的生活质量，因此将产生非常显着的临床、经济和社会影响。

Abstract Prostate cancer is a highly heterogeneous disease and the second most cause of cancer death of men in the USA. Current methods to assess prostate cancer risk combine prostate specific antigen (PSA) screening and random prostate biopsy. Unfortunately, this strategy fails to reveal the lesion’s location and does not accurately differentiate between invasive and non-invasive prostate cancers. As a result, most patients will receive unnecessary active treatment for low-risk prostate cancer. Thus, development of non- invasive and accurate diagnostic imaging technology to localize and differentiate high-risk prostate cancer offers a new tool to assist physicians in risk-stratification and decision-making, and to spare millions of patients with low-risk cancer from unnecessary aggressive treatment. The mission of Molecular Theranostics is to commercialize a novel molecular imaging approach that targets an oncoprotein associated with epithelial-to-mesenchymal transition (EMT), cancer cell stemness, angiogenesis, proliferation, and metastasis. The oncoprotein has a high expression in the tumor extracellular matrix of high-risk prostate cancer, low in low-grade tumor, and none in normal tissues. The ultimate goal of this project is to commercialize a targeted contrast agent, MT218, for accurate early detection, localization, and differential diagnosis of high-risk prostate cancer with MRI. We have optimized and identified a lead targeted MRI contrast agent, proven it effective in various animal in vivo tumor models, and completed the chemistry, manufacturing and control (CMC) work for the preclinical batches. Moreover, we demonstrated the GLP preclinical safety of MT218 according to the FDA’s guidelines for an IND submission. MT218 has shown rapid and complete clearance via renal excretion, with no detectable brain retention, and low pharmacological risk and toxicity in rats and dogs. An IND was approved by the FDA in March 2021 for phase 1 clinical trial in Ohio. The first two dosing cohorts have shown no adverse effects and rapid excretion from the body as the clinical contrast agents. The proposed work in this SBIR project will allow the company to carry out the proof-of-concept phase 2a clinical trial in the patents with confirmed high-risk prostate cancer. The specific aims are 1) to perform open-label phase 2a clinical trial to investigate initial imaging efficacy of MT218 in diagnostics MRI in PCa patients; 2) to develop a liquid phase synthetic procedure for scale-up cGMP production. Successful development of our imaging technology has the potential to accurately detect, localize, and diagnose prostate cancer with MRI’s < 1 mm spatial resolution, reduce the use of invasive prostate biopsy, and so improve decision-making in clinical management of prostate cancer. It also has the potential for accurate non-invasive Active Surveillance of prostate cancer and timely monitoring of disease progression, as well as image-guided focal therapy. Clinical application of MT218 promises to improve the healthcare and the quality of life of PCa patients, and will thus have highly significant clinical, economic and societal impact.