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了前列腺特异性抗原（PSA）联合收割机 筛查和随机前列腺活检。不幸的是，这种策略无法揭示病变的位置， 不能准确区分侵袭性和非侵袭性前列腺癌。结果大部分 患者将接受不必要的低风险前列腺癌的积极治疗。因此，发展非 侵入性和准确的诊断成像技术，以定位和区分高危前列腺癌 提供了一个新的工具，以协助医生在风险分层和决策，并节省数百万美元， 低风险癌症患者免受不必要的积极治疗。 分子治疗学的使命是将一种新的分子成像方法商业化， 靶向与上皮细胞向间质细胞转化（EMT），癌细胞干细胞， 血管生成、增殖和转移。癌蛋白在肿瘤中有高表达 高风险前列腺癌的细胞外基质，低级别肿瘤中低，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，用于准确的早期诊断。 使用MRI检测、定位和鉴别诊断高危前列腺癌。我们优化了 并鉴定了一种铅靶向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、生产和控制（CMC）工作。此外，委员会认为， 我们根据FDA的IND指南证明了MT218的GLP临床前安全性 成绩. MT218通过肾脏排泄显示出快速和完全的清除， 在大鼠和犬中的保留和低药理学风险和毒性。一种IND于年获得FDA批准， 2021年3月在俄亥俄州进行1期临床试验。前两个给药队列未显示不良反应 并且作为临床造影剂从体内快速排泄。 SBIR项目中的拟议工作将允许公司进行概念验证阶段 2a在确诊高危前列腺癌患者中进行的临床试验。具体目标是：（1）执行 一项旨在研究MT218在PCa诊断MRI中的初始成像疗效的开放标签IIa期临床试验 2）开发用于放大cGMP生产的液相合成方法。成功 我们的成像技术的发展有可能准确地检测，定位和诊断 前列腺癌与MRI的< 1毫米的空间分辨率，减少使用侵入性前列腺活检，等等 改善前列腺癌临床管理决策。它也有可能准确地 前列腺癌的非侵入性主动监测和疾病进展的及时监测，以及 作为图像引导的局部治疗。MT218的临床应用有望改善医疗保健， PCa患者的生活质量，因此将具有非常显著的临床、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.