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.
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
Erik H
EH
Klontz
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A. esundberg@ihv.umaryland.edu.|Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.|Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, U.S.A.
Eric J
EJ
Sundberg
D000907:Antibodies, Bacterial / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology*; D000942:Antigens, Bacterial / Q000737:chemistry* / Q000276:immunology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000276:immunology; D001666:Binding Sites, Antibody; D015922:Complement C1q / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry* / Q000276:immunology; D007141:Immunoglobulin Fc Fragments / Q000737:chemistry* / Q000276:immunology; D009345:Neisseria meningitidis / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D011485:Protein Binding
D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D007141:Immunoglobulin Fc Fragments; C484699:factor H-binding protein, Neisseria meningitidis; D015922:Complement C1q
Neisseria meningitidis; antibodies; crystallography; effector functions; factor H binding protein; vaccine