@article {1556,
	title = {Engineering human IgG1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates.},
	journal = {Journal of Immunology},
	volume = {182},
	year = {2009},
	month = {2009 Jun 15},
	pages = {7663-71},
	abstract = {<p>The pH-dependent binding of Igs to the neonatal FcR (FcRn) plays a critical role in the in vivo homeostasis of IgGs. Modulating the interaction between Fc and FcRn through protein engineering is one method for improving the pharmacokinetics of therapeutic Abs. Recent studies disputed the direct relationship between increasing FcRn affinity and improved pharmacokinetic properties. In this work, we studied the pharmacokinetics of two human IgG1 Fc variants in cynomolgus monkey to further clarify the affinity-pharmacokinetic relationship. First, we report a number of novel Fc point mutations and combination variants, including some with primate-specific FcRn-binding improvements. By studying these variants along with some previously described variants across a wide range of affinities, we discovered a direct correlation of pH 6 affinity improvements with neutral pH improvements, suggesting that all of the tested variants exhibit similar pH dependency in FcRn binding. We then evaluated the pharmacokinetics of variants N434A and N434W, which, respectively, gave approximately 4- and 80-fold improvements in pH 6-binding affinity to both human and nonhuman primate FcRn. Surprisingly, clearance of N434W was similar to that of wild type. N434W is the first variant studied in primates that exhibits significant binding to FcRn at pH 7.4, and its clearance substantiates the principle that too much affinity improvement, i.e., beyond that of N434W, does not yield improved pharmacokinetics. In contrast, N434A exhibited a approximately 2-fold decrease in clearance in cynomolgus monkey, supporting the notion that modest increases in pH 6 FcRn affinity can result in improved pharmacokinetics in primates.</p>
},
	keywords = {Amino Acid Sequence, Animals, Antibody Affinity, Fc, Histocompatibility Antigens Class I, Humans, Hydrogen-Ion Concentration, Immunoglobulin G, Macaca fascicularis, Mice, Models, Molecular, Mutation, Protein Structure, Quaternary, Receptors, Recombinant Proteins},
	issn = {1550-6606},
	doi = {10.4049/jimmunol.0804182},
	author = {Yeung, Yik Andy and Leabman, Maya K and Marvin, Jonathan S and Qiu, Julia and Adams, Camellia W and Lien, Samantha and Starovasnik, Melissa A and Lowman, Henry B}
}
