Papers In Press, published online ahead of print December 29, 2003
J. Biol. Chem, 10.1074/jbc.C300470200
Submitted on October 27, 2003
Revised on December 19, 2003
Accepted on December 23, 2003
Engineered human IgG antibodies with longer serum half-lives in primates
Paul R. Hinton, Mary G. Johlfs, Joanna M. Xiong, Kelly Hanestad, Kelly C. Ong, Chuck Bullock, Stephen Keller, Meina Tao Tang, J. Yun Tso, Max Vasquez, and Naoya Tsurushita
Protein Design Labs, Inc., Fremont, CA 94555
The neonatal Fc receptor (FcRn) plays an important role in regulating the serum half-lives of IgG antibodies. A correlation has been established between the pH-dependent binding affinity of IgG antibodies to FcRn and their serum half-lives in mice. In this study, molecular modeling was used to identify Fc positions near the FcRn binding site in a human IgG antibody that, when mutated, might alter the binding affinity of IgG to FcRn. Following mutagenesis, several IgG2 mutants with increased binding affinity to human FcRn at pH 6.0 were identified at Fc positions 250 and 428. These mutants do not bind to human FcRn at pH 7.5. A pharmacokinetics study of two mutant IgG2 antibodies with increased FcRn binding affinity indicated that they had serum half-lives in rhesus monkeys approximately twofold longer than the wild-type antibody. |
