Human IgG1, IgG3, and IgG3 Hinge-Truncated Mutants Show Different Protection Capabilities against Meningococci Depending on the Target Antigen and Epitope Specificity.
We compared the bactericidal activity of recombinant sets of chimeric IgG monoclonal antibodies against two important outer membrane meningococcal vaccine antigens: PorA and factor H binding protein (FHbp). The sets contained human Fc portions from IgG1, IgG3, and two IgG3 mutants (IgG3m15 and IgGm17) with hinge regions of 15 and 17 amino acids encoded by hinge exons h2 and h1, respectively (human IgG3 has a hinge region of 62 amino acids encoded by hinge exons h1, h2, h3, and h4, while human IgG1 has a hinge region of only 15 amino acids encoded by one hinge exon) and mouse V regions. IgG1 showed higher bactericidal activity than IgG3 when directed against PorA (an abundant antigen), while IgG3 was more bactericidal than IgG1 when directed against FHbp (a sparsely and variably distributed antigen). On the other hand, the IgG3 hinge-truncated antibodies IgG3m15 and IgGm17 showed higher bactericidal activity than both IgG1 and IgG3 regardless of the target antigen. Thus, the Fc region of IgG3 antibodies appears to have an enhanced complement-activating function, independent of their long hinge region, compared to IgG1 antibodies. The greater activity of the truncated IgG3 hinge mutants indicates that the long hinge of IgG3 seems to downregulate through an unknown mechanism the inherent increased complement-activating capability of IgG3 Fc when the antibody binds to a sparse antigen.
Center for Immunobiology and Vaccine Development, UCSF Benioff Children's Hospital Oakland Research Institute, Oakland, California, USA.
S
S
Giuntini
Center for Immunobiology and Vaccine Development, UCSF Benioff Children's Hospital Oakland Research Institute, Oakland, California, USA.
D M
DM
Granoff
Center for Immunobiology and Vaccine Development, UCSF Benioff Children's Hospital Oakland Research Institute, Oakland, California, USA.
P T
0000-0001-5734-083X
PT
Beernink
Division of Infectious Disease Control, Department of Bacteriology and Immunology, Norwegian Institute of Public Health, Oslo, Norway.
O
O
Ihle
Division of Infectious Disease Control, Department of Bacteriology and Immunology, Norwegian Institute of Public Health, Oslo, Norway.
D
D
Bratlie
T E
0000-0001-8877-8519
TE
Michaelsen
D000328:Adult; D000818:Animals; D000907:Antibodies, Bacterial / Q000235:genetics / Q000276:immunology*; D000942:Antigens, Bacterial / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology; D001770:Blood Bactericidal Activity; D003167:Complement Activation; D000939:Epitopes / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D051379:Mice; D009345:Neisseria meningitidis / Q000276:immunology*; D018272:Porins / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology
D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D000939:Epitopes; D007074:Immunoglobulin G; D018272:Porins; D011994:Recombinant Proteins; C484699:factor H-binding protein, Neisseria meningitidis; C057699:porin protein, Neisseria