Getting oriented with antibodies.
Neisseria meningitidis is a Gram-negative bacterium capable of causing deadly invasive disease. Two recently developed vaccines against N. meningitidis serogroup B include recombinant factor H binding protein (fHbp), a surface protein that meningococci use to evade the host immune system. Many anti-fHbp monoclonal antibodies (mAbs) produced against fHbp fail to trigger complement-mediated bacteriolysis when used alone in vitro, but are highly synergistic and bactericidal when used in combination. This opened the door to defining the structural basis by which mAbs activate complement synergistically when binding to different epitopes on the same antigen, a story that is told by Malito et al. in a recent issue of the Biochemical Journal. Using two separate crystal structures of fHbp bound to Fabs from synergistic mAbs, they were able to model the structure of both full length antibodies bound simultaneously to fHbp. This revealed that the bound antibodies orient their Fc domains 115-130 Å apart, a distance that is compatible with multivalent C1q binding. The need for a precise orientation of Fc domains in order to efficiently activate effector functions is an emerging theme across multiple fields, and its implications could have broad impacts on vaccinology and immunotherapy.
['Klontz|Erik H|EH|', 'Sundberg|Eric J|EJ|']
D000907:Antibodies, Bacterial D000911:Antibodies, Monoclonal D000942:Antigens, Bacterial D001426:Bacterial Proteins D001666:Binding Sites, Antibody D015922:Complement C1q D018360:Crystallography, X-Ray D004357:Drug Synergism D004359:Drug Therapy, Combination D000939:Epitopes D007140:Immunoglobulin Fab Fragments D007141:Immunoglobulin Fc Fragments D009345:Neisseria meningitidis D011485:Protein Binding
antibodies Neisseria meningitidis vaccine factor H binding protein effector functions crystallography