Developing the required biomarkers that define ferroportin target engagement and impact on downstream signaling for clinical translation

开发所需的生物标志物来定义铁转运蛋白靶点参与和对临床转化下游信号传导的影响

• 批准号: 9762166
• 负责人: David Y Liu
• 金额: $ 69.32万
• 依托单位: PROTAGONIST THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762166
• 关键词: Adverse effects; Affect; Agonist; Binding; Biological Markers; Blood Circulation; Blood Transfusion; Characteristics; Chelation Therapy; Clinical; Clinical Trials; Data; Development; Diet; Disease; Disease model; Disulfides; Dose; Drug Design; Drug Kinetics; Engineering; Environment Design; Erythropoiesis; Ferritin; Genetic Diseases; Half-Life; Health; Hemochromatosis; Hemoglobinopathies; Hereditary hemochromatosis; Homeostasis; Hormones; Hospitals; Human; Injectable; Intestines; Iron; Iron Chelating Agents; Iron Chelation; Iron Overload; Life; Life Extension; Liver; Measurement; Methods; Nature; Needles; Organ; Pain-Free; Pathway interactions; Patients; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Physiological; Pre-Clinical Model; Production; Property; Research; Reticuloendothelial System; Rodent Model; Safety; Serum; Signal Transduction; Small Business Innovation Research Grant; Solubility; Splenomegaly; Structure; Techniques; Technology; Thalassemia; Therapeutic; Toxic effect; Translating; Translations; Treatment Protocols; Venous blood sampling; Visit; base; beta Thalassemia; clinical translation; clinically relevant; compliance behavior; design; drug candidate; hepcidin; improved; in vivo; innovation; iron absorption; macrophage; metal transporting protein 1; mimetics; novel; patient population; pharmacodynamic biomarker; pharmacokinetics and pharmacodynamics; pre-clinical; receptor; scaffold; uptake

Abstract Developing the required biomarkers that define ferroportin target engagement and impact on downstream signaling for clinical translation Iron is essential for life, but is also highly toxic. Consequently, iron acquisition, transport, storage and utilization are tightly regulated. Hepcidin is the master regulator of iron; it controls the uptake of iron from diet and the release from iron stores through its interaction with the iron transporter ferroportin. Dysfunctional hepcidin production can cause serious health issues, including β-thalassemia and hereditary hemochromatosis. In both diseases, low hepcidin levels increase intestinal iron absorption and increase release of recycled iron from the reticuloendothelial system, which causes depletion of macrophage iron, relatively lower levels of serum ferritin, increased liver iron concentration, and free iron release into the circulation, causing organ damage. Without treatment, iron continues to accumulate, and a considerable proportion of patients eventually reach toxic iron-overload levels. Patients with iron overload diseases are currently treated with combinations of phlebotomy, blood transfusions and/or iron chelators, depending on the disease. Phlebotomy and blood transfusions are inconvenient and require hospital visits, while chelation therapy is associated with considerable toxicity. Thus, there is a significant need for new treatments that are safer and better tolerated. Because of hepcidin's complicated 4-disulfide structure, insolubility, aggregation potential and rapid clearance, it is unsuitable as a treatment and hepcidin mimetics have been proposed as potential therapeutics. To overcome the physicochemical limitations of hepcidin, Protagonist engineered more potent, stable, soluble and efficacious alternative scaffolds using a purposefully built structure-based drug design environment (Vectrix™). During the SBIR Phase I proposal, the hepcidin mimetic PTG-300 was developed after optimizing potency, stability, solubility and other physicochemical properties. The overall objective of this Phase II SBIR proposal is to develop methods for characterizing in vivo target engagement, including pharmacokinetic and pharmacodynamic methods to characterize the binding of PTG-300 to ferroportin and how binding affects downstream biomarkers and efficacy. These biomarkers will be used to aid dose selections and to provide early- stage clinical proof-of-concept. The specific objectives are to: 1) develop methods to characterize the extent of target engagement (TE) of ferroportin, 2) develop pharmacodynamic (PD) biomarkers that describe the effect of ferroportin engagement on downstream signaling, 3) correlate the TE and effect on PD biomarkers with efficacy in a preclinical model of thalassemia, 4) provide further mechanistic data on the clinical utility of PTG-300. These are important steps towards our ultimate objective of demonstrating clinical benefit in late-stage clinical trials. The biomarkers developed in this study will permit the assessment of mechanism-specific and disease- related parameters to guide clinical design.

抽象的 开发定义铁杆素目标参与并影响的必需的生物标志物 临床翻译的下游信号传导 铁对生命至关重要，但也是剧毒。因此，采集铁，运输，存储和利用 受到严格调节。肝素是铁的主要调节剂；它控制了饮食中铁的吸收和 通过与铁转运蛋白铁蛋白的相互作用从铁储存中释放。 功能失调的肝素产生可能引起严重的健康问题 血色素沉着病。在这两种疾病中，低肝素水平都会增加肠铁的抽象并增加释放 网状内皮系统的再生铁，导致巨噬细胞耗尽，相对较低 血清铁蛋白的水平，肝铁浓度升高和自由铁释放到循环中，导致器官 损害。没有治疗，铁继续积累，并且最终患者的考虑比例很大 达到有毒的铁超载水平。 铁超负荷疾病的患者目前接受了静脉切开术，输血的组合治疗 和/或铁螯合剂，具体取决于疾病。静脉切开术和输血是不方便的， 需要医院就诊，而螯合疗法与考虑的毒性有关。那是一个重要的 需要安全耐受性更好的新治疗方法。 由于肝素素的4-硫化物结构复杂，无法溶解，聚集潜力和快速清除率， 它不适合治疗，并且已经提出了肝素模拟物作为潜在疗法。克服 主角肝素的身体局限 使用有目的建立的基于结构的药物设计环境（Vectrix™）的替代脚手架。 在SBIR I期提案中，肝素模拟PTG-300是在优化效力后开发的 稳定性，溶解度和其他物理特性。该阶段II SBIR提案的总体目标是 开发表征体内靶向参与的方法，包括药代动力学和 表征PTG-300与铁托蛋白的结合以及结合如何影响的药物学方法 下游生物标志物和效率。这些生物标志物将用于帮助剂量选择，并提供早期 - 阶段临床概念验证。 具体目标是：1）开发方法来表征目标参与程度（TE）的程度 铁蛋白，2）开发描述铁蛋白互动作用的药效（PD）生物标志物 下游信号传导，3）将TE和对PD生物标志物的影响与在临床前模型中的有效性相关联 Thalassexia，4）提供了有关PTG-300临床实用性的进一步机械数据。 这些是朝着我们在晚期临床中证明临床益处​​的最终目标的重要步骤 试验。这项研究中开发的生物标志物将允许评估机理特异性和疾病 - 指导临床设计的相关参数。