Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins.
Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins.
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单克隆抗体和FC融合蛋白的药代动力学。
DOI：
10.1007/s13238-017-0408-4
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发表时间：
2018-01
期刊：
影响因子：
21.1
通讯作者：
Liu L
中科院分区：
文献类型：
--
作者：
Liu L
有许多因素可以影响单抗或Fc融合分子的药代动力学(PK)，其中主要决定因素是FcRN介导的循环。通过Fab或Fc工程，Ig G-FcRN相互作用可用于产生各种治疗性抗体，半衰期显著增强，或具有显著提高从循环中清除多余抗原的能力。单抗或Fc融合蛋白的糖基化对这些分子的PK有重大影响。MAB电荷可能是重要的，PI值为1-2个单位差的变体可能会影响PK，较低的PI值有利于较长的半衰期。大多数单抗显示靶向介导的药物处置(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也会受到抗药物抗体(ADA)反应和靶外结合的影响，这些都需要在发现阶段仔细考虑。单抗主要通过淋巴管通过对流吸收，可以方便地通过皮下途径(Sc)与透明质酸酶共制剂大剂量/体积地给药。使用食蟹猴数据和异速生长标度方法可以合理地估计单抗的人pK。
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.
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影响因子：
5.3
作者：
Datta-Mannan, Amita;Witcher, Derrick R.;Wroblewski, Victor J.
通讯作者：
Wroblewski, Victor J.
影响因子：
5.3
作者：
Datta-Mannan, Amita;Croy, Johnny E.;Wroblewski, Victor J.
通讯作者：
Wroblewski, Victor J.
DOI：
10.1124/dmd.114.059089
发表时间：
2014-11-01
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
Datta-Mannan, Amita;Wroblewski, Victor J
通讯作者：
Wroblewski, Victor J
影响因子：
4.5
作者：
Bai, Shuang;Jorga, Karin;Dresser, Mark J.
通讯作者：
Dresser, Mark J.
影响因子：
10.8
作者：
Bookbinder, L. H.;Hofer, A.;Frost, G. I.
通讯作者：
Frost, G. I.