Improving Protein Delivery and Circulation via FcRn Ligands

通过 FcRn 配体改善蛋白质递送和循环

• 批准号: 8353495
• 负责人: FRANCIS C. SZOKA
• 金额: $ 22.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8353495
• 关键词: Affect; Affinity; Amino Acid Sequence; Binding; Binding Proteins; Biological Assay; Blood Circulation; Catabolism; Cells; Child; Chimeric Proteins; Development; Dose; Drug Delivery Systems; Drug Kinetics; Elderly; Epithelial; Epithelial Cells; Escherichia coli; Frequencies; Goals; Human; Immunoglobulin G; Injection of therapeutic agent; Ligand Binding; Ligands; Lung; MHC Class I Genes; Mediating; Methods; Modeling; Mus; Organ; Patients; Peptides; Phage Display; Pharmaceutical Preparations; Property; Protein Engineering; Proteins; Pulmonary Circulation; Recombinant Proteins; Recombinants; Recycling; Research; Role; Route; Somatropin; Surface Plasmon Resonance; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Translating; absorption; base; growth hormone deficiency; human disease; improved; in vivo; macromolecule; mouse model; neonatal Fc receptor; novel; patient population; polypeptide; protein B; protein aminoacid sequence; success; therapeutic protein; transcytosis

DESCRIPTION (provided by applicant): A number of challenges impede the more widespread use of proteins as drugs including: their rapid elimination from circulation and the need to dose proteins via injection. Strategies that overcome these limitations could decrease dosing frequency and improve patient convenience and compliance. Engineering proteins to interact with the MHC Class I-like neonatal Fc receptor (FcRn) represents a promising strategy to improve circulation time and enable alternative routes of protein administration. FcRn is expressed in several organs and tissues in which it serves a distinct role in the protection of IgG from catabolism and/or transport of IgG across epithelial barriers. Peptide sequences that bind to FcRn with moderate affinity have been identified by phage display and may be amenable for incorporation into proteins in order to improve their pharmacokinetic properties and enable pulmonary protein delivery. We will investigate factors that affect the circulation time and epithelial transcytosis of FcRn binding peptide-modified proteins as a general strategy to improve protein circulation and enable pulmonary protein delivery. Three specific aims will be aggressively pursued. Aim 1. (A) Synthesize peptides ligands for FcRn and confirm they bind and are transported by FcRn; (B) Generate recombinant FcRn binding fusion proteins in E. coli based upon sequences identified in Aim 1A and characterize their interaction with FcRn. Aim 2. Determine the relationship between FcRn binding, in vivo circulation time, pulmonary absorption, and pulmonary retention in a human FcRn transgenic mouse model. Aim 3. Evaluate the therapeutic potential of FcRn binding peptide-modified human growth hormone (hGH) in a murine model of growth hormone deficiency. Our studies will generate a better understanding of the factors that control internalization and transcytosis of cargos attached to an FcRn ligand. Success in this research could enable the development of new protein-based therapies with convenient routes of administration that could greatly improve treatment in problematic patient populations such as children and the elderly. PUBLIC HEALTH RELEVANCE: Improved PK and Delivery of Protein Modified with FcRn Binding Ligands Project Relevance Our goal is to engineer proteins to interact with FcRn and use them to define factors that affect FcRn mediated protein circulation and pulmonary absorption. Successful completion of the plan would result in a novel method to improve protein delivery and pharmacokinetics that could be translated into improved protein therapeutics for treating human disease.

描述（由申请人提供）：许多挑战阻碍了蛋白质作为药物的广泛使用，包括：它们从循环中快速消除和通过注射剂量蛋白质的需求。克服这些限制的策略可以降低给药频率并提高患者的便利性和依从性。与MHC类似I类新生儿FC受体（FCRN）相互作用的工程蛋白是改善循环时间并实现蛋白质给药的替代途径的有前途的策略。 FCRN在几个器官和组织中表达，其中它在保护IgG中起着独特的作用 从分解代谢和/或IgG跨上皮屏障的运输。通过噬菌体显示，已经鉴定出与中等亲和力结合的肽序列，并且可能适合掺入蛋白质中，以改善其药代动力学特性并启用肺蛋白质递送。我们将研究影响FCRN结合肽改性蛋白的循环时间和上皮转胞胞菌的因素，作为改善蛋白质循环并实现肺蛋白递送的一般策略。将积极追求三个具体目标。 AIM 1。（a）合成肽配体的FCRN，并确认它们结合并通过FCRN运输； （b）基于在AIM 1A中鉴定的序列并表征其与FCRN的相互作用，在大肠杆菌中生成重组FCRN结合蛋白。 AIM 2。确定人体FCRN转基因小鼠模型中FCRN结合，体内循环时间，肺部吸收和肺部保留之间的关系。 AIM 3。在生长激素缺乏症的鼠模型中评估FCRN结合肽修饰的人类生长激素（HGH）的治疗潜力。我们的研究将更好地理解控制与FCRN配体相关的cargos的内在化和跨介症的因素。这项研究的成功可以使新的基于蛋白质的疗法的发展具有方便的管理途径，从而可以大大改善有问题的患者人群（例如儿童和老年人）的治疗方法。 公共卫生相关性：改善PK和通过FCRN结合配体项目的蛋白质的递送项目相关性，我们的目标是设计与FCRN相互作用，并使用它们来定义影响FCRN介导的蛋白质循环和肺部吸收的因素。该计划的成功完成将导致一种新的方法来改善蛋白质递送和药代动力学，该方法可以转化为改善治疗人类疾病的蛋白质疗法。