Structural basis for cooperativity of human monoclonal antibodies to meningococcal factor H-binding protein

Factor H-binding protein (fHbp) is an important antigen of Neisseria meningitidis that is capable of eliciting 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 co-operative and become bactericidal if used in combination. Several factors have been shown to influence such co-operativity, 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 antigen-binding) fragment of JAR5, a specific anti-fHbp murine monoclonal antibody known to be highly co-operative with other monoclonal antibodies. We show that JAR5 is highly synergic with monoclonal antibody (mAb) 12C1, whose structure in complex with fHbp has been previously solved. Structural analyses of the epitopes recognized by JAR5 and 12C1, and computational modeling of full-length IgG mAbs of JAR5 and 12C1 bound to the same fHbp molecule, provide insights into the spatial orientation of Fc (fragment crystallizable) regions and into the possible implications for the susceptibility of meningococci to complement-mediated killing.

Download Full-text

Structural basis of tetanus toxin neutralization by native human monoclonal antibodies

Cell Reports ◽

10.1016/j.celrep.2021.109070 ◽

2021 ◽

Vol 35 (5) ◽

pp. 109070

Author(s):

Yueming Wang ◽

Changwen Wu ◽

Jinfang Yu ◽

Shujian Lin ◽

Tong Liu ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Tetanus Toxin ◽

Structural Basis ◽

Human Monoclonal Antibodies

Download Full-text

A novel mechanism for complement-mediated killing of encapsulated Neisseria meningitidis elicited by monoclonal antibodies to factor H-binding protein (genome-derived Neisserial antigen 1870)

Molecular Immunology ◽

10.1016/j.molimm.2006.07.256 ◽

2007 ◽

Vol 44 (1-3) ◽

pp. 256

Author(s):

Jo Anne Welsch ◽

Sanjay Ram ◽

Dan M. Granoff

Keyword(s):

Monoclonal Antibodies ◽

Neisseria Meningitidis ◽

Binding Protein ◽

Factor H

Download Full-text

Functional cooperativity mediated by rationally selected combinations of human monoclonal antibodies targeting the henipavirus receptor binding protein

10.1101/2021.02.17.431743 ◽

2021 ◽

Author(s):

Michael P. Doyle ◽

Nurgun Kose ◽

Viktoriya Borisevich ◽

Elad Binshtein ◽

Moushimi Amaya ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Receptor Binding ◽

Binding Protein ◽

Severe Disease ◽

Hendra Virus ◽

Human Monoclonal Antibodies ◽

Human Mabs ◽

Viral Attachment ◽

Antigenic Sites ◽

Receptor Binding Protein

AbstractHendra virus (HeV) and Nipah virus (NiV), the prototypic members of the Henipavirus (HNV) genus, are emerging, zoonotic paramyxoviruses known to cause severe disease across six mammalian orders, including humans (Eaton et al., 2006). While several research groups have made strides in developing candidate vaccines and therapeutics against henipaviruses, such countermeasures have not been licensed for human use, and significant gaps in knowledge about the human immune response to these viruses exist. To address these gaps, we isolated a large panel of human monoclonal antibodies (mAbs) from the B cells of an individual with prior occupation-related exposure to the equine HeV vaccine (Equivac® HeV). Competition-binding and hydrogen-deuterium exchange mass spectrometry (HDX-MS) studies identified at least six distinct antigenic sites on the HeV/NiV receptor binding protein (RBP) that are recognized by human mAbs. Antibodies recognizing multiple antigenic sites potently neutralized NiV and/or HeV isolates in vitro. The most potent class of cross-reactive antibodies achieved neutralization by blocking viral attachment to the host cell receptors ephrin-B2 and ephrin-B3. Antibodies from this class mimic receptor binding by inducing a receptor-bound conformation to the HeV-RBP protein tetramer, exposing an epitope that appears to lie hidden in the interface between protomers within the HeV-RBP tetramer. Antibodies that recognize this cryptic epitope potently neutralized HeV and NiV. Flow cytometric studies using cell-surface-displayed HeV-RBP protein showed that cross-reactive, neutralizing mAbs from each of these classes cooperate for binding. In a highly stringent hamster model of NiVB infection, antibodies from both classes reduced morbidity and mortality and achieved synergistic protection in combination and provided therapeutic benefit when combined into two bispecific platforms. These studies identified multiple candidate mAbs that might be suitable for use in a cocktail therapeutic approach to achieve synergistic antiviral potency and reduce the risk of virus escape during treatment.

Download Full-text

Naturally acquired blocking human monoclonal antibodies to Plasmodium vivax reticulocyte binding protein 2b

10.1101/2020.05.12.091900 ◽

2020 ◽

Author(s):

Li-Jin Chan ◽

Anugraha Gandhirajan ◽

Lenore L. Carias ◽

Melanie H. Dietrich ◽

Oscar Vadas ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Plasmodium Vivax ◽

Papua New Guinea ◽

Binding Protein ◽

Human Monoclonal Antibodies ◽

Human Antibodies ◽

Human Transferrin Receptor ◽

Transferrin Receptor 1 ◽

Functional Inhibition ◽

Structural Mechanisms

AbstractPlasmodium vivax preferentially invades reticulocytes and recognition of these cells is mediated by P. vivax Reticulocyte Binding Protein 2b (PvRBP2b) binding to human Transferrin receptor 1 (TfR1) and Transferrin (Tf). Longitudinal cohort studies in Papua New Guinea, Thailand and Brazil show that PvRBP2b antibodies are correlated with protection against P. vivax infection and disease. Here, we isolated and characterized anti-PvRBP2b human monoclonal antibodies from two individuals in Cambodia with natural P. vivax infection. These antibodies bind with high affinities and map to different regions of PvRBP2b. Several human antibodies blocked PvRBP2b binding to reticulocytes and inhibited complex formation with human TfR1-Tf. We describe different structural mechanisms for functional inhibition, including either steric hindrance with TfR1-Tf or the reticulocyte membrane. These results show that naturally acquired human antibodies against PvRBP2b can inhibit its function which is important for P. vivax invasion.

Download Full-text

Cooperativity mediated by rationally selected combinations of human monoclonal antibodies targeting the henipavirus receptor binding protein

Cell Reports ◽

10.1016/j.celrep.2021.109628 ◽

2021 ◽

Vol 36 (9) ◽

pp. 109628

Author(s):

Michael P. Doyle ◽

Nurgun Kose ◽

Viktoriya Borisevich ◽

Elad Binshtein ◽

Moushimi Amaya ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Receptor Binding ◽

Binding Protein ◽

Human Monoclonal Antibodies ◽

Receptor Binding Protein

Download Full-text

Identification and Characterization of Functional Human Monoclonal Antibodies toPlasmodium vivaxDuffy-Binding Protein

The Journal of Immunology ◽

10.4049/jimmunol.1801631 ◽

2019 ◽

Vol 202 (9) ◽

pp. 2648-2660 ◽

Cited By ~ 11

Author(s):

Lenore L. Carias ◽

Sebastien Dechavanne ◽

Vanessa C. Nicolete ◽

Sokunthea Sreng ◽

Seila Suon ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Binding Protein ◽

Human Monoclonal Antibodies ◽

Identification And Characterization

Download Full-text

Molecular characterization of two sub-family specific monoclonal antibodies to meningococcal Factor H binding protein

Heliyon ◽

10.1016/j.heliyon.2018.e00591 ◽

2018 ◽

Vol 4 (4) ◽

pp. e00591 ◽

Cited By ~ 1

Author(s):

C. Lo Passo ◽

L. Zippilli ◽

A. Angiolillo ◽

I. Costa ◽

I. Pernice ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Molecular Characterization ◽

Binding Protein ◽

Factor H

Download Full-text

Fine Antigenic Specificity and Cooperative Bactericidal Activity of Monoclonal Antibodies Directed at the Meningococcal Vaccine Candidate Factor H-Binding Protein

Infection and Immunity ◽

10.1128/iai.00367-08 ◽

2008 ◽

Vol 76 (9) ◽

pp. 4232-4240 ◽

Cited By ~ 68

Author(s):

Peter T. Beernink ◽

Jo Anne Welsch ◽

Michal Bar-Lev ◽

Oliver Koeberling ◽

Maurizio Comanducci ◽

...

Keyword(s):

Amino Acids ◽

Monoclonal Antibodies ◽

Bactericidal Activity ◽

Binding Protein ◽

Factor H ◽

Antigenic Specificity ◽

Complement Protein ◽

Antigenic Variant ◽

Classical Complement Pathway ◽

Group B

ABSTRACT No broadly protective vaccine is available for the prevention of group B meningococcal disease. One promising candidate is factor H-binding protein (fHbp), which is present in all strains but often sparsely expressed. We prepared seven murine immunoglobulin G monoclonal antibodies (MAbs) against fHbp from antigenic variant group 2 (v.2) or v.3 (∼40% of group B strains). Although none of the MAbs individually elicited bactericidal activity with human complement, all had activity in different combinations. We used MAb reactivity with strains expressing fHbp polymorphisms and site-specific mutagenesis to identify residues that are important for epitopes recognized by six of the v.2 or v.3 MAbs and by two v.1 MAbs that were previously characterized. Residues affecting v.2 or v.3 epitopes resided between amino acids 174 and 216, which formed an eight-stranded beta-barrel in the C domain, while residues affecting the v.1 epitopes included amino acids 121 and 122 of the B domain. Pairs of MAbs were bactericidal when their respective epitopes involved residues separated by 16 to 20 Å and when at least one of the MAbs inhibited the binding of fH, a downregulatory complement protein. In contrast, there was no cooperative bactericidal activity when the distance between residues was ≥27 Å or ≤14 Å, which correlated with the inhibition of the binding of one MAb by the other MAb. Thus, a model for anti-fH MAb bactericidal activity against strains expressing low levels of fHbp requires the binding of two MAbs directed at nonoverlapping epitopes, which activates the classical complement pathway as well as inhibits fH binding. The latter increases the susceptibility of the organism to complement-mediated bacteriolysis.

Download Full-text