Extending Half-life by Indirect Targeting of the Neonatal Fc Receptor (FcRn) Using a Minimal Albumin Binding Domain
Extending Half-life by Indirect Targeting of the Neonatal Fc Receptor (FcRn) Using a Minimal Albumin Binding Domain
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DOI：
10.1074/jbc.m110.164848
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发表时间：
2011-02-18
影响因子：
4.8
通讯作者：
Ekblad, Caroline
中科院分区：
文献类型：
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作者：
Andersen, Jan Terje;Pehrson, Rikard;Ekblad, Caroline
工程化的小蛋白、肽和化学药物候选物的治疗和诊断效率受到体内血清半衰期短的阻碍。因此，迫切需要制定策略来调整其生物分布和血清持久性。一种有吸引力的方法是利用血清白蛋白或IgG的异常长的循环半衰期，这归因于与新生儿Fc受体（FcRn）的pH依赖性相互作用，从而使这些蛋白质免于细胞内降解。在这里，我们提出的分子证据表明，一个最小的白蛋白结合结构域（ABD）来自链球菌蛋白G可用于有效的半衰期延长通过间接靶向FcRn。我们表明，ABD，和ABD重组融合的亲和体分子，在与白蛋白的复合物不干扰严格的pH依赖性FcRn-白蛋白结合动力学。在IgG存在下获得相同的结果。在大鼠中进行的体内研究证实，与ABD融合的临床相关的人表皮生长因子2（HER 2）靶向亲和体分子具有与血清白蛋白相似的半衰期和生物分布特征。所描述的概念验证可广泛适用于延长短寿命生物或化学药物的体内半衰期，最终导致增强的治疗或诊断效率、更有利的给药方案和改善的患者依从性。
The therapeutic and diagnostic efficiency of engineered small proteins, peptides, and chemical drug candidates is hampered by short in vivo serum half-life. Thus, strategies to tailor their biodistribution and serum persistence are highly needed. An attractive approach is to take advantage of the exceptionally long circulation half-life of serum albumin or IgG, which is attributed to a pH-dependent interaction with the neonatal Fc receptor (FcRn) rescuing these proteins from intracellular degradation. Here, we present molecular evidence that a minimal albumin binding domain (ABD) derived from streptococcal protein G can be used for efficient half-life extension by indirect targeting of FcRn. We show that ABD, and ABD recombinantly fused to an Affibody molecule, in complex with albumin does not interfere with the strictly pH-dependent FcRn-albumin binding kinetics. The same result was obtained in the presence of IgG. An in vivo study performed in rat confirmed that the clinically relevant human epidermal growth factor 2 (HER2)-targeting Affibody molecule fused to ABD has a similar half-life and biodistribution profile as serum albumin. The proof-of-concept described may be broadly applicable to extend the in vivo half-life of short lived biological or chemical drugs ultimately resulting in enhanced therapeutic or diagnostic efficiency, a more favorable dosing regimen, and improved patient compliance.