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

用于前列腺癌鉴别诊断的 MRI 造影剂的商业化

• 批准号: 10704488
• 负责人: SONGQI GAO
• 金额: $ 100万
• 依托单位: MOLECULAR THERANOSTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-14 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704488
• 关键词: Adverse effects; Adverse event; Amino Acids; Animal Model; Animals; Binding; Biological; Biopsy; Brain; Cancer Etiology; Cancer Patient; Canis familiaris; Carcinoma; Cessation of life; Chemistry; Clinical; Clinical Data; Clinical Management; Clinical Trials; Contrast Media; Cyclic GMP; Data; Decision Making; Detection; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Differential Diagnosis; Disease; Disease Progression; Dose; Drug Kinetics; Drug resistance; Early Diagnosis; Economics; Excretory function; Exhibits; Extracellular Matrix; FDA approved; FOLH1 gene; Fibronectins; Formulation; Funding; Future; Goals; Grant; Guidelines; Healthcare; Human; Image; Imaging technology; Institutional Review Boards; Invaded; Investments; Kidney; Kilogram; Lead; Legal patent; Lesion; Liquid substance; Location; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Methods; Mission; Modeling; Mole the mammal; Molecular; Monitor; Neoplasm Metastasis; Normal tissue morphology; Ohio; Oncoproteins; PET/CT scan; PSA screening; Patient Schedules; Patients; Pelvis; Peptides; Phase; Phase I Clinical Trials; Phase II/III Trial; Physicians; Precision therapeutics; Privatization; Procedures; Proliferating; Protocols documentation; Quality of life; Radical Prostatectomy; Rattus; Recommendation; Resolution; Risk; Safety; Secure; Sensitivity and Specificity; Signal Transduction; Site; Small Business Innovation Research Grant; Specific qualifier value; System; Therapeutic Intervention; Tissues; Toxic effect; Work; accurate diagnosis; accurate diagnostics; active method; aggressive therapy; analytical method; angiogenesis; cGMP production; cancer cell; cancer imaging; cancer risk; clinical application; clinical development; clinical diagnostics; cohort; commercialization; cost; cost effective; design; drug resistance development; epithelial to mesenchymal transition; healthy volunteer; high risk; image guided; imaging agent; imaging approach; imaging modality; improved; in vivo; manufacture; manufacturing scale-up; men; meter; molecular imaging; mortality; non-invasive imaging; noninvasive diagnosis; novel; open label; overexpression; personalized intervention; pharmacologic; phase I trial; pre-Investigational New Drug meeting; pre-clinical; pre-clinical assessment; preclinical safety; prostate biopsy; prostate cancer cell; prostate cancer risk; risk stratification; safety testing; scale up; soft tissue; stemness; theranostics; tool; treatment response; tumor

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.

摘要 前列腺癌是一种高度异质性疾病，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是结合前列腺特异性抗原(PSA) 筛查和随机的前列腺活检。不幸的是，这一策略未能揭示病变的位置和 不能准确区分浸润性和非浸润性前列腺癌。因此，大多数人 对于低风险前列腺癌，患者将接受不必要的积极治疗。因此，非政府组织的发展 对高危前列腺癌进行定位和鉴别诊断的侵入性和准确性诊断技术 提供了一种新的工具来帮助医生进行风险分层和决策，并节省了数百万 来自不必要的积极治疗的低风险癌症患者。 分子遗传学的使命是将一种新的分子成像方法商业化，这种方法 靶向一种与上皮向间充质转化(EMT)相关的癌蛋白，癌细胞干细胞， 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，在低级别肿瘤中低表达，在正常组织中不表达。这个 该项目的最终目标是将一种靶向造影剂MT218商业化，用于准确的早期 高危前列腺癌的核磁共振检测、定位和鉴别诊断。我们已经优化了 并确定了一种靶向铅的核磁共振造影剂，在各种动物体内肿瘤模型中证明了它的有效性， 并完成了临床前批次的化学、制造和控制(CMC)工作。此外， 根据FDA的IND指南，我们证明了MT218的GLP临床前安全性 呈件。MT218通过肾脏排泄显示迅速和完全清除，没有检测到大脑 在老鼠和狗身上保留，低药理风险和毒性。年，FDA批准了一种IND 2021年3月在俄亥俄州进行第一阶段临床试验。前两个剂量队列没有显示出不良反应。 并作为临床造影剂快速从体内排泄。 该SBIR项目中的拟议工作将使公司能够进行概念验证阶段 在确诊为高危前列腺癌的专利中进行临床试验。具体目标是：1)执行 开放标记2a期临床试验研究MT218在前列腺癌MRI诊断中的初步成像效果 患者；2)开发一种放大生产cGMP的液相合成工艺。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 前列腺癌的MRI空间分辨率为1毫米，减少了侵袭性前列腺活检的使用，等等 提高前列腺癌临床治疗的决策能力。它还有可能准确地 前列腺癌的非侵入性主动监测和疾病进展的及时监测 作为影像引导的焦点治疗。MT218的临床应用有望改善医疗保健和 因此，它将对PCa患者的临床、经济和社会产生重大影响。