Monoclonal Antibodies with Identical Fc Sequences Can Bind to FcRn Differentially with Pharmacokinetic Consequences

新生儿Fc受体 单克隆抗体 体内 化学 体外 抗体 生物化学 血浆蛋白结合 药代动力学 离解常数 受体 分子生物学 免疫球蛋白G 药理学 生物 免疫学 生物技术
作者
Weirong Wang,Ping Lü,Yulin Fang,Lora Hamuro,Tamara Pittman,Brian I. Carr,Jerome Hochman,Thomayant Prueksaritanont
出处
期刊:Drug Metabolism and Disposition [American Society for Pharmacology & Experimental Therapeutics]
卷期号:39 (9): 1469-1477 被引量:157
标识
DOI:10.1124/dmd.111.039453
摘要

The neonatal Fc receptor (FcRn) is a key determinant of IgG homeostasis. It binds to the Fc domain of IgG in a strictly pH-dependent manner and protects IgG from lysosomal degradation. The impact of FcRn salvage pathway on IgG monoclonal antibody (mAb) pharmacokinetics (PK) has been well established. In this report, a set of mAbs with wild-type human Fc sequences but different Fab domains were used to examine the potential impact of Fab domain on in vitro FcRn binding and in vivo PK. We were surprised to find that mAbs with the same wild-type human Fc sequences but different Fab domains were shown to bind FcRn with considerable differences in both the binding at acidic pH and the dissociation at neutral pH, suggesting that the Fab domain may also have an impact on FcRn interaction. For these mAbs, no relationship between the FcRn binding affinity at acidic pH and in vivo PK was found. Instead, an apparent correlation between the in vitro FcRn dissociation at neutral pH and the in vivo PK in human FcRn mice, nonhuman primates and humans was observed. Our results suggested that the Fab domain of mAbs can affect their interaction with FcRn and thus their pharmacokinetic properties and that in vitro FcRn binding/dissociation assays can be a useful screening tool for pharmacokinetic assessment of mAbs with wild-type Fc sequences.
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