Improving Protein Delivery and Circulation via FcRn Ligands

通过 FcRn 配体改善蛋白质递送和循环

基本信息

批准号：
8508265
负责人：
FRANCIS C. SZOKA
金额：
$ 17.65万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/8508265
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

项目摘要

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.

描述（由申请人提供）：许多挑战阻碍了蛋白质作为药物的更广泛使用，包括：它们从循环中快速消除以及需要通过注射给药蛋白质。克服这些限制的策略可以减少给药频率并提高患者的便利性和依从性。工程蛋白质与 MHC I 类新生儿 Fc 受体 (FcRn) 相互作用是一种有前途的策略，可以改善循环时间并实现蛋白质给药的替代途径。 FcRn 在多种器官和组织中表达，在 IgG 保护中发挥独特作用 IgG 跨上皮屏障的分解代谢和/或运输。已通过噬菌体展示鉴定出以中等亲和力结合 FcRn 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实现肺部蛋白质递送。我们将研究影响 FcRn 结合肽修饰蛋白的循环时间和上皮转胞吞作用的因素，作为改善蛋白循环和实现肺部蛋白递送的一般策略。将积极追求三个具体目标。目标 1. (A) 合成 FcRn 的肽配体并确认它们结合并由 FcRn 转运； (B) 基于目标 1A 中鉴定的序列在大肠杆菌中生成重组 FcRn 结合融合蛋白，并表征它们与 FcRn 的相互作用。目标 2. 确定人 FcRn 转基因小鼠模型中 FcRn 结合、体内循环时间、肺吸收和肺滞留之间的关系。目标 3. 评估 FcRn 结合肽修饰的人生长激素 (hGH) 在生长激素缺乏的小鼠模型中的治疗潜力。我们的研究将更好地理解控制 FcRn 配体附着的货物的内化和转胞吞作用的因素。这项研究的成功可以促进新的基于蛋白质的疗法的开发，这种疗法具有便捷的给药途径，可以极大地改善儿童和老年人等有问题的患者群体的治疗。