Antibody-mediated neutralization of cytomegalovirus: modulation of efficacy induced through the IgG constant region.
Antibodies can neutralize the infectious properties of human cytomegalovirus (CMV). In vivo, the major neutralization determinants are located on glycoprotein B (gB). Recombinant human antibodies, that carry different constant regions (IgG1, IgG3 and the synthetic variant IgG3mA) against two of these epitopes were investigated for their ability to recruit the complement cascade for destruction of the virus. It was shown that all variants of an antibody against the antigenic domain (AD)-2 epitope displayed a similar neutralization activity despite the fact that improved C1q binding was observed for IgG3 and IgG3mA over the IgG1 variant. In contrast, an antibody against the AD-1 epitope carrying the normal IgG3 constant region, was less efficient than its IgG1 counterpart in neutralizing the virus in the absence of complement. However, it restored its activity in the presence of complement to the level of the naturally occurring IgG1 version. The same antibody was substantially more potent in neutralizing the virus in the presence of complement if it carried the IgG3mA constant region. This demonstrates the importance of the constant domain for the biological activity of AD-1 specific antibodies, a factor that should be taken into account when using antibody-based therapeutics or when inducing antibodies by vaccination.
Furebring
Christina
C
Department of Immunotechnology, Lund University, Lund, Sweden.
Speckner
Andrea
A
Mach
Michael
M
Sandlie
Inger
I
Norderhaug
Lars
L
Borrebaeck
Carl A K
CA
Turesson
Heléne
H
Ohlin
Mats
M
D000914:Antibodies, Viral / Q000276:immunology*; D001483:Base Sequence; D003165:Complement System Proteins / Q000502:physiology; D003587:Cytomegalovirus / Q000276:immunology*; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology*; D008969:Molecular Sequence Data; D009500:Neutralization Tests; D011994:Recombinant Proteins / Q000276:immunology; D014407:Tumor Cells, Cultured
D000914:Antibodies, Viral; D007127:Immunoglobulin Constant Regions; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D003165:Complement System Proteins