A Novel PET Imaging based Companion Diagnostic

摘要 高流失率--特别是在药物开发的后期--导致了估计的20亿美元 将一种药物推向市场的成本。此外，许多进入市场的药物只对 患者的子集。目前，缺乏能够更好地识别反应的靶向特异性生物标记物。 病人。因此，包括抗血管生成药物在内的许多主流治疗方法的益处仍然存在。 有限的。这大大增加了医疗系统的成本，因为不必要的治疗是 不太可能对特定的治疗有反应。因此，发展一种以无创PET成像为基础 伴随诊断(CD)使用治疗剂本身的放射性标记版本，将有助于分层 并改善疾病转归。这是因为裁谈会将：1)提供目标的量化措施 在治疗时在患者肿瘤中的表达以选择患者；以及ii)使治疗性 调整，包括在治疗周期期间增加/减少目标流行率；以及三)允许 当成像显示正在进行的治疗失败时，及时切换到替代治疗。 我们建议测试开发[18F]标记的Cys标记的血管内皮细胞生长的可行性 因子-3s(VEGF-3s)作为一种新型的无创PET成像CD，将与VEGF-3s一起使用，一种新的(和 通过靶向干扰硫酸肝素蛋白多糖(HSPG)产生的血管内皮生长因子拮抗剂 血管内皮生长因子-A 165的结合残基。拟议的CD将基于由N-末端15- 含有半胱氨酸残基的AA融合标签(cVEGF-3S)，用于位点特异性的18F放射性标记。A正向[18F] 来自患者肿瘤部位的cVEGF-3S PET信号将证实VEGF靶向VEGFRs的流行。 仅限3S。因此，与现有的靶向血管内皮生长因子相比，联合应用CD的血管内皮生长因子-3将具有显著的临床优势 为个别患者提供精准医疗的药物。 我们将在这项提案中建立[18F]cysVEGF-3s的靶标特异性，这将是定量的 具有里程碑意义的IND支持研究进入第二阶段。

Abstract High attrition rates - particularly at the late stage of drug development – contribute to the estimated $2.0B cost of bringing a drug to the market. Furthermore, many of the drugs that reach the market benefit only a subset of patients. Currently, there is a lack of target-specific biomarkers that can better identify responsive patients. Consequently, the benefits from many mainstay treatments, including anti-angiogenic drugs, are still limited. This adds significant costs to the healthcare system by the unnecessary treatment of patients that are not likely to respond to a specific therapy. Therefore, the development of a non-invasive PET imaging-based companion diagnostic (CD) using a radio-labeled version of the therapeutic agent itself, will help stratify patients and improve disease outcomes. This is because the CD will i) provide quantitative measures of target expression in patient tumors at the time of treatment to select patients; and ii) enable the staging of therapeutic modulation, including increase/decrease of target prevalence during the treatment cycle; and iii) allow for timely switches to alternative treatment when imaging shows the failure of the ongoing therapy. We propose to test the feasibility of developing a [18 F] labeled cys-tagged vascular endothelial growth factor-3S (VEGF-3S) as a novel non-invasive PET-imaging based CD, to be used with VEGF-3S, a novel (and patented) VEGF antagonist generated through targeted disruption of 3 heparin sulfate proteoglycan (HSPG) binding residues in VEGF-A 165. The proposed CD will be based on VEGF-3S engineered with N-terminal 15- aa fusion tag containing cysteine residue (cVEGF-3S) for site-specific 18F radiolabeling. A positive [18F] cVEGF-3S PET signal from tumor sites in a patient will confirm the prevalence of VEGFRs targeted by VEGF- 3S only. Thus, VEGF-3S with the CD will have significant clinical advantages over the existing VEGF targeted drugs providing precision medicine to individual patients. We will establish the target specificity of [18F] cysVEGF-3S in this proposal which will be the quantitative milestone to progress to Phase II for IND enabling studies.