Glycan variants of a respiratory syncytial virus antibody with enhanced effector function and in vivo efficacy

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 16; pp. 5992 - 5997
• Main Authors: Hiatt, Andrew, Bohorova, Natasha, Bohorov, Ognian, Goodman, Charles, Kim, Do, Pauly, Michael H., Velasco, Jesus, Whaley, Kevin J., Piedra, Pedro A., Gilbert, Brian E., Zeitlin, Larry
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22-04-2014; National Acad Sciences
• Subjects: Animals; Antibodies; Antibodies, Monoclonal - therapeutic use; Antibodies, Neutralizing - pharmacology; Antibodies, Viral - chemistry; Antibodies, Viral - therapeutic use; Antiviral drugs; Binding sites; Biological Sciences; Complement C1q - metabolism; Enzyme-Linked Immunosorbent Assay; Female; Human respiratory syncytial virus; Humans; Immunoglobulins; Isotypes; Lung - drug effects; Lung - immunology; Lung - pathology; Lung - virology; Male; Monoclonal antibodies; Neutralization Tests; Pediatrics; Polysaccharides; Polysaccharides - metabolism; Protein Binding - drug effects; Rats; Receptors; Receptors, Fc - metabolism; Respiratory syncytial virus; Respiratory syncytial virus infections; Respiratory Syncytial Virus Infections - drug therapy; Respiratory Syncytial Virus Infections - immunology; Respiratory syncytial viruses; Respiratory Syncytial Viruses - drug effects; Respiratory Syncytial Viruses - immunology; Rodents; Sigmodontinae - immunology; Sigmodontinae - virology; Treatment Outcome; Viruses; afucosylated; glycoengineering; ADCC; immunotherapy
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1402458111

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 IgG ₁ 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 Fcγ 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 Fcγ 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.