Pharmacokinetic Properties of 2nd-Generation Fibroblast Growth Factor-1 Mutants for Therapeutic Application

Fibroblast growth factor-1 (FGF-1) is an angiogenic factor with therapeutic potential for the treatment of ischemic disease. FGF-1 has low intrinsic thermostability and is characteristically formulated with heparin as a stabilizing agent. Heparin, however, adds a number of undesirable properties that negatively impact safety and cost. Mutations that increase the thermostability of FGF-1 may obviate the need for heparin in formulation and may prove to be useful “2nd-generation” forms for therapeutic use. We report a pharmacokinetic (PK) study in rabbits of human FGF-1 in the presence and absence of heparin, as well as three mutant forms having differential effects upon thermostability, buried reactive thiols, and heparin affinity. The results support the hypothesis that heparan sulfate proteoglycan (HSPG) in the vasculature of liver, kidney and spleen serves as the principle peripheral compartment in the distribution kinetics. The addition of heparin to FGF-1 is shown to increase endocrine-like properties of distribution. Mutant forms of FGF-1 that enhance thermostability or eliminate buried reactive thiols demonstrate a shorter distribution half-life, a longer elimination half-life, and a longer mean residence time (MRT) in comparison to wild-type FGF-1. The results show how such mutations can produce useful 2nd-generation forms with tailored PK profiles for specific therapeutic application.

成纤维细胞生长因子-1（Fibroblast growth factor-1, FGF-1）是一种具备缺血性疾病治疗潜力的血管生成因子。FGF-1本征热稳定性较低，通常会与肝素配伍作为稳定剂。然而，肝素会引入诸多不良特性，对制剂的安全性与成本产生负面影响。能够提升FGF-1热稳定性的突变，可免除制剂中对肝素的需求，有望成为具有应用价值的“第二代”治疗用形式。本研究报道了一项在家兔中开展的人源FGF-1药代动力学（pharmacokinetic, PK）研究，分别设置了有无肝素的组别，同时纳入了三种对热稳定性、包埋反应性巯基及肝素亲和力具有不同调控效果的突变体。研究结果支持以下假说：肝脏、肾脏与脾脏血管系统中的硫酸乙酰肝素蛋白聚糖（heparan sulfate proteoglycan, HSPG）是分布动力学过程中的主要外周隔室。向FGF-1中添加肝素可使其分布呈现类内分泌特性。相较于野生型FGF-1，能够提升热稳定性或消除包埋反应性巯基的FGF-1突变体，展现出更短的分布半衰期、更长的消除半衰期以及更长的平均驻留时间（mean residence time, MRT）。本研究结果阐明了此类突变如何可制备出具备定制化药代动力学特征、可用于特定治疗场景的第二代FGF-1制剂形式。