Engineered human IgG antibodies with longer serum half-lives in primates.
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 2-fold longer than the wild-type antibody.
Hinton
Paul R
PR
Protein Design Labs, Inc, Fremont, California 94555, USA. phinton@pdl.com
Johlfs
Mary G
MG
Xiong
Joanna M
JM
Hanestad
Kelly
K
Ong
Kelly C
KC
Bullock
Chuck
C
Keller
Stephen
S
Tang
Meina Tao
MT
Tso
J Yun
JY
Vásquez
Max
M
Tsurushita
Naoya
N
D000818:Animals; D000906:Antibodies / Q000737:chemistry; D001665:Binding Sites; D001666:Binding Sites, Antibody; D001667:Binding, Competitive; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D015395:Histocompatibility Antigens Class I; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000097:blood* / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D020128:Inhibitory Concentration 50; D007668:Kidney / Q000166:cytology; D008253:Macaca mulatta; D008958:Models, Molecular; D016296:Mutagenesis; D009154:Mutation; D011485:Protein Binding; D011961:Receptors, Fc / Q000737:chemistry; D013997:Time Factors
D000906:Antibodies; D018076:DNA, Complementary; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; C100688:Fc receptor, neonatal