Abstract
Factor H binding protein (fHbp) is an important antigen of Neisseria meningitidis that is able to elicit a robust protective immune response in humans. Previous studies on the interactions of fHbp with antibodies revealed that some anti-fHbp monoclonal antibodies that are unable to trigger complement-mediated bacterial killing in vitro, are highly cooperative and become bactericidal if used in combination. Several factors have been shown to influence such cooperativity, including IgG subclass and antigen density. To investigate the structural basis of the anti-fHbp antibody synergy, we determined the crystal structure of the complex between fHbp and the Fab fragment of JAR5, a specific anti-fHbp murine monoclonal antibody known to be highly cooperative with other monoclonal antibodies. We show that JAR5 is highly synergic with mAb 12C1, whose structure in complex with fHbp has been previously solved. Structural analyses of the epitopes recognized by JAR5 and 12C1, and computational modelling of full-length IgG mAbs of JAR5 and 12C1 bound to the same fHbp molecule provide insights on the spatial orientation of Fc regions and on the possible implications for the susceptibility of meningococci to complement-mediated killing.
Highlights
Factor H-binding protein is a surface-exposed meningococcal lipoprotein that binds human complement factor H and is one of the recombinant protein components of Bexsero® and Trumenba®, two recently licensed vaccines against serogroup B meningococcus [1]
In the case of an antigen such as Factor H binding protein (fHbp), which is present on the surface of virtually all pathogenic meningococcal strains [10], efficient C1q engagement by a multiple copies of the same monoclonal antibodies (mAbs) can occur under conditions of high expression levels, which ensure a sufficient antigen density on the bacterial surface
The interface between fHbp and JAR5 is formed by 21 fHbp and 30 JAR5 residues, which contribute a total of ~800 and ~700 Å2 of surface area to the interaction surface
Summary
Factor H-binding protein (fHbp) is a surface-exposed meningococcal lipoprotein that binds human complement factor H (fH) and is one of the recombinant protein components of Bexsero® and Trumenba®, two recently licensed vaccines against serogroup B meningococcus [1]. Anti-fHbp antibodies can elicit complement-mediated bactericidal activity [2] and inhibit the binding of fH to the bacterial surface. Both mechanisms contribute to the susceptibility of meningococci to complement-mediated killing [3]. The classical complement pathway is triggered when antigen-bound immunoglobulins bind the Complement component 1 (C1) complex formed by the C1q, C1r and C1s subunits [5]. While C1q binds a single Fc with low affinity, the more avid stable binding of two or more of the six globular heads activates the serine protease subunits C1r and C1s, which in turn initiates the downstream reactions of the classical cascade, resulting in bacteriolysis. The ability of two or more distinct mAbs which bind simultaneously to non-overlapping epitopes on the same antigen molecule could in principle efficiently activate the C1 complex even under conditions of low antigen density [4, 11]
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