Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins.
10.1007/s13238-017-0408-4
- Author:
Liming LIU
1
Author Information
1. Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, MRL, West Point, PA, 19486, USA. liming_liu2@merck.com.
- Publication Type:Journal Article
- Keywords:
Fc-fusion protein;
FcRn;
anti-drug antibody (ADA);
glycosylation;
human PK prediction;
monoclonal antibody (mAb);
pharmacokinetics;
target-mediated drug disposition (TMDD)
- MeSH:
Absorption, Physiological;
Animals;
Antibodies, Monoclonal;
pharmacokinetics;
Dose-Response Relationship, Immunologic;
Humans;
Receptors, Fc;
metabolism;
Recombinant Fusion Proteins;
pharmacokinetics;
Tissue Distribution
- From:
Protein & Cell
2018;9(1):15-32
- CountryChina
- Language:English
-
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.
