Glycan variants of a respiratory syncytial virus antibody with enhanced effector function and in vivo efficacy.
Article Details
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Hiatt A, Bohorova N, Bohorov O, Goodman C, Kim D, Pauly MH, Velasco J, Whaley KJ, Piedra PA, Gilbert BE, Zeitlin L
Glycan variants of a respiratory syncytial virus antibody with enhanced effector function and in vivo efficacy.
Proc Natl Acad Sci U S A. 2014 Apr 22;111(16):5992-7. doi: 10.1073/pnas.1402458111. Epub 2014 Apr 7.
- PubMed ID
- 24711420 [ View in PubMed]
- Abstract
Respiratory syncytial virus (RSV) can cause devastating lower respiratory tract infections in preterm infants or when other serious health problems are present. Immunoprophylaxis with palivizumab (Synagis), a humanized IgG1 mAb, is the current standard of care for preventing RSV infection in at-risk neonates. We have explored the contribution of effector function to palivizumab efficacy using a plant-based expression system to produce palivizumab N-glycan structure variants with high homogeneity on different antibody isotypes. We compared these isotype and N-glycoform variants with commercially available palivizumab with respect to both in vitro receptor and C1q binding and in vivo efficacy. Whereas the affinity for antigen and neutralization activity of each variant were indistinguishable from those of palivizumab, their Fcgamma receptor binding profiles were very different, which was reflected in either a reduced or enhanced ability to influence the RSV lung titer in challenged cotton rats. Enhanced Fcgamma receptor binding was associated with reduced viral lung titers compared with palivizumab, whereas abrogation of receptor binding led to a drastic reduction in efficacy. The results support the hypotheses that classic antibody neutralization is a minor component of efficacy by palivizumab in the cotton rat and that antibody-dependent cell-mediated cytotoxicity activity can significantly enhance the efficacy of this antiviral mAb.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Palivizumab Complement C1q subcomponent subunit A Protein Humans UnknownNot Available Details Palivizumab Complement C1q subcomponent subunit B Protein Humans UnknownNot Available Details Palivizumab Complement C1q subcomponent subunit C Protein Humans UnknownNot Available Details Palivizumab Complement C1r subcomponent Protein Humans UnknownNot Available Details Palivizumab High affinity immunoglobulin gamma Fc receptor I Protein Humans UnknownNot Available Details Palivizumab Low affinity immunoglobulin gamma Fc region receptor II-b Protein Humans UnknownNot Available Details Palivizumab Low affinity immunoglobulin gamma Fc region receptor III-A Protein Humans UnknownNot Available Details Palivizumab Low affinity immunoglobulin gamma Fc region receptor III-B Protein Humans UnknownNot Available Details