Pharmacokinetics of humanized monoclonal anti-tumor necrosis factor-{alpha} antibody and its neonatal Fc receptor variants in mice and cynomolgus monkeys
- PMID: 20071453
- DOI: 10.1124/dmd.109.031310
Pharmacokinetics of humanized monoclonal anti-tumor necrosis factor-{alpha} antibody and its neonatal Fc receptor variants in mice and cynomolgus monkeys
Abstract
The neonatal Fc receptor (FcRn) plays a critical role in maintaining homeostasis of IgG antibodies. Recent studies have shown that the FcRn-IgG interaction can be modulated to alter the pharmacokinetics of the antibody. This has been achieved by altering amino acid residues in the FcRn-binding domain of the antibody, resulting in a change in the pH-dependent binding affinity of the antibody to FcRn. The purpose of this study was to examine the impact of the pH-dependent FcRn binding affinity on the pharmacokinetics of the antibody with changes in the Asn434 residue. Two anti-tumor necrosis factor-alpha monoclonal antibody (mAb) FcRn variants (N434A and N434H) were engineered, and pharmacokinetic studies of the two FcRn variants together with the wild type (WT) were conducted in mice and cynomolgus monkeys. N434A, which had binding properties to murine FcRn similar to those of the WT, had the same pharmacokinetic profile as the WT in mice. N434H, with the highest binding affinity to murine FcRn at pH 7.4, had a faster clearance (16.1 ml/day/kg) and a lower bioavailability (61.3%) compared with the WT (5.07 ml/day/kg, 73.2%) and N434A (5.90 ml/day/kg, 72.4%) in mice. N434A and N434H, which had higher binding affinity at pH 6.0 to monkey FcRn with comparable affinity at pH 7.4, had significantly higher areas under the serum concentration-time curve from time 0 to day 7 than the WT (749 +/- 71.9 and 819 +/- 81.5 versus 592 +/- 56.8 microg/ml . day) in monkeys. Thus, increasing the binding affinity of mAbs to FcRn at pH 6.0 while keeping a low binding affinity at pH 7.4 improves the pharmacokinetics of these molecules.
Similar articles
-
Engineering human IgG1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates.J Immunol. 2009 Jun 15;182(12):7663-71. doi: 10.4049/jimmunol.0804182. J Immunol. 2009. PMID: 19494290
-
Humanized IgG1 variants with differential binding properties to the neonatal Fc receptor: relationship to pharmacokinetics in mice and primates.Drug Metab Dispos. 2007 Jan;35(1):86-94. doi: 10.1124/dmd.106.011734. Epub 2006 Oct 18. Drug Metab Dispos. 2007. PMID: 17050651
-
Modeling approach to investigate the effect of neonatal Fc receptor binding affinity and anti-therapeutic antibody on the pharmacokinetic of humanized monoclonal anti-tumor necrosis factor-α IgG antibody in cynomolgus monkey.Eur J Pharm Sci. 2014 Jan 23;51:51-8. doi: 10.1016/j.ejps.2013.08.033. Epub 2013 Aug 31. Eur J Pharm Sci. 2014. PMID: 23999033
-
Are endosomal trafficking parameters better targets for improving mAb pharmacokinetics than FcRn binding affinity?Mol Immunol. 2013 Dec;56(4):660-74. doi: 10.1016/j.molimm.2013.05.008. Epub 2013 Aug 2. Mol Immunol. 2013. PMID: 23917469 Review.
-
Current strategies in antibody engineering: Fc engineering and pH-dependent antigen binding, bispecific antibodies and antibody drug conjugates.Biotechnol J. 2012 Dec;7(12):1444-50. doi: 10.1002/biot.201200250. Epub 2012 Nov 1. Biotechnol J. 2012. PMID: 23125076 Review.
Cited by
-
A single chimpanzee-human neutralizing monoclonal antibody provides post-exposure protection against type 1 and type 2 polioviruses.J Clin Virol. 2015 Apr;65:32-7. doi: 10.1016/j.jcv.2015.01.023. Epub 2015 Feb 3. J Clin Virol. 2015. PMID: 25766984 Free PMC article.
-
Subcutaneous bioavailability of therapeutic antibodies as a function of FcRn binding affinity in mice.MAbs. 2012 Jan-Feb;4(1):101-9. doi: 10.4161/mabs.4.1.18543. MAbs. 2012. PMID: 22327433 Free PMC article.
-
Population pharmacokinetic modeling of LY2189102 after multiple intravenous and subcutaneous administrations.AAPS J. 2014 Sep;16(5):1009-17. doi: 10.1208/s12248-014-9623-6. Epub 2014 Jun 11. AAPS J. 2014. PMID: 24912797 Free PMC article.
-
Discovery and characterization of COVA322, a clinical-stage bispecific TNF/IL-17A inhibitor for the treatment of inflammatory diseases.MAbs. 2016;8(1):141-9. doi: 10.1080/19420862.2015.1093266. Epub 2015 Sep 22. MAbs. 2016. PMID: 26390837 Free PMC article. Clinical Trial.
-
Evaluation of a catenary PBPK model for predicting the in vivo disposition of mAbs engineered for high-affinity binding to FcRn.AAPS J. 2012 Dec;14(4):850-9. doi: 10.1208/s12248-012-9395-9. Epub 2012 Sep 7. AAPS J. 2012. PMID: 22956476 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources