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.

摘要 开发所需的生物标志物，以定义膜铁转运蛋白靶点的参与和对 用于临床翻译的下游信号传导 铁是生命所必需的，但也是剧毒的。因此，铁的获取、运输、储存和利用 受到严格管制。铁调素是铁的主要调节剂;它控制从饮食中摄取铁， 通过与铁转运蛋白ferroportin的相互作用从铁储存中释放。 铁调素产生功能障碍可导致严重的健康问题，包括β-地中海贫血和遗传性 血色病在这两种疾病中，低铁调素水平增加肠铁吸收并增加释放 从网状内皮系统回收的铁，这会导致巨噬细胞铁的消耗，相对较低 血清铁蛋白水平升高，肝脏铁浓度增加，游离铁释放到循环中，引起器官功能障碍。 损害如果不治疗，铁继续积累，相当一部分患者最终 达到有毒的铁超负荷水平 铁超载疾病患者目前的治疗组合放血，输血 和/或铁螯合剂。放血和输血不方便， 需要住院治疗，而螯合疗法与相当大的毒性有关。因此，有一个重要的 需要更安全和耐受性更好的新治疗方法。 由于铁调素复杂的4-二硫键结构、不溶性、聚集潜力和快速清除， 它不适合作为治疗，并且已经提出铁调素模拟物作为潜在的治疗剂。克服 铁调素的物理化学限制，Protagonist工程更强大，稳定，可溶性和有效的 使用有目的地构建的基于结构的药物设计环境（VeclampTM）的替代支架。 在SBIR I期提案期间，在优化效力后开发了铁调素模拟物PTG-300， 稳定性、溶解性和其它物理化学性质。第二阶段SBIR提案的总体目标是 开发用于表征体内靶向接合的方法，包括药代动力学和 描述PTG-300与膜铁转运蛋白结合以及结合如何影响 下游生物标志物和功效。这些生物标志物将用于辅助剂量选择并提供早期- 阶段性临床概念验证。 具体目标是：1）开发方法来表征目标接合（TE）的程度， 2）开发药效学（PD）生物标志物，其描述了膜铁转运蛋白参与对 下游信号传导，3）将TE和对PD生物标志物的影响与临床前模型中的功效相关联， 地中海贫血，4）提供关于PTG-300的临床效用的进一步机制数据。 这些都是实现我们最终目标的重要步骤，即在晚期临床试验中证明临床获益。 审判本研究中开发的生物标志物将允许评估机制特异性和疾病- 相关参数指导临床设计。