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单克隆抗体和 Fc 融合蛋白的药代动力学。

Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins.

机构信息

Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, MRL, West Point, PA, 19486, USA.

出版信息

Protein Cell. 2018 Jan;9(1):15-32. doi: 10.1007/s13238-017-0408-4. Epub 2017 Apr 19.

Abstract

There are many factors that can influence the pharmacokinetics (PK) of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediated recycling. Through Fab or Fc engineering, IgG-FcRn interaction can be used to generate a variety of therapeutic antibodies with significantly enhanced half-life or ability to remove unwanted antigen from circulation. Glycosylation of a mAb or Fc-fusion protein can have a significant impact on the PK of these molecules. mAb charge can be important and variants with pI values of 1-2 unit difference are likely to impact PK with lower pI values being favorable for a longer half-life. Most mAbs display target mediated drug disposition (TMDD), which can have significant consequences on the study designs of preclinical and clinical studies. The PK of mAb can also be influenced by anti-drug antibody (ADA) response and off-target binding, which require careful consideration during the discovery stage. mAbs are primarily absorbed through the lymphatics via convection and can be conveniently administered by the subcutaneous (sc) route in large doses/volumes with co-formulation of hyaluronidase. The human PK of a mAb can be reasonably estimated using cynomolgus monkey data and allometric scaling methods.

摘要

有许多因素会影响单抗或 Fc 融合分子的药代动力学(PK),主要决定因素是 FcRn 介导的再循环。通过 Fab 或 Fc 工程,IgG-FcRn 相互作用可用于产生各种治疗性抗体,显著延长半衰期或从循环中清除不需要的抗原的能力。单抗或 Fc 融合蛋白的糖基化对这些分子的 PK 有显著影响。单抗的电荷可能很重要,pI 值相差 1-2 个单位的变体可能会影响 PK,较低的 pI 值有利于延长半衰期。大多数单抗显示靶介导的药物处置(TMDD),这可能对临床前和临床研究的研究设计产生重大影响。单抗的 PK 也可能受到抗药物抗体(ADA)反应和脱靶结合的影响,这在发现阶段需要仔细考虑。单抗主要通过淋巴系统通过对流吸收,可通过皮下(sc)途径大剂量/体积给药,并与透明质酸酶联合给药。可使用食蟹猴数据和同种异体标度方法合理估计单抗的人体 PK。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7499/5777971/8e251f7d42e7/13238_2017_408_Fig1_HTML.jpg

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