Analysis of a family of antibodies with different half-lives in mice fails to find a correlation between affinity for FcRn and serum half-life.
In this study we analyzed mouse FcRn binding to different recombinant chimeric antibodies with human constant regions. This system has the advantage that in vivo half-life in animals expressing the receptor can be directly correlated with receptor binding kinetics. The goal was to determine which FcRn binding parameters, if any, correlate with the serum half-life of antibodies. We used a BIAcore surface plasmon resonance (SPR) device to study kinetic properties at different pHs and concentrations. The data were analyzed using a new model, the dual bivalent analyte model (DBVA), which postulates that there are two types of FcRn bound to the chip, one low affinity and one high affinity. In addition, it takes into consideration the possibility that the ligand, immunoglobulin G (IgG), can exist as both monomer and as higher molecular forms. While some antibodies bind to FcRn with different kinetics, including antibodies that differ only by containing the kappa or lambda light chain--a result which itself is unexpected--we cannot identify a single FcRn binding parameter that directly correlates with Ab half-life. Importantly, we demonstrate that some IgGs with higher affinity for FcRn do not have extended in vivo half-lives.
Gurbaxani
Brian
B
Department of Microbiology, Immunology and Molecular Genetics, Molecular Biology Institute, University of California, Los Angeles, CA 90049, USA. buw8@cdc.gov
Dela Cruz
Linh L
LL
Chintalacharuvu
Koteswara
K
Morrison
Sherie L
SL
D000818:Animals; D000906:Antibodies / Q000097:blood*; D000915:Antibody Affinity; D005260:Female; D006207:Half-Life; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007074:Immunoglobulin G / Q000097:blood; D007145:Immunoglobulin kappa-Chains / Q000097:blood; D007146:Immunoglobulin lambda-Chains / Q000097:blood; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018448:Models, Immunological; D011961:Receptors, Fc / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000097:blood; D020349:Surface Plasmon Resonance
D000906:Antibodies; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; C100688:Fc receptor, neonatal