James Crowe
Faculty Member
Last active: 3/31/2020

Reversion of somatic mutations of the respiratory syncytial virus-specific human monoclonal antibody Fab19 reveal a direct relationship between association rate and neutralizing potency.

Bates JT, Keefer CJ, Utley TJ, Correia BE, Schief WR, Crowe JE
J Immunol. 2013 190 (7): 3732-9

PMID: 23455501 · PMCID: PMC3608519 · DOI:10.4049/jimmunol.1202964

The role of affinity in determining neutralizing potency of mAbs directed against viruses is not well understood. We investigated the kinetic, structural, and functional advantage conferred by individual naturally occurring somatic mutations in the Ab H chain V region of Fab19, a well-described neutralizing human mAb directed to respiratory syncytial virus. Comparison of the affinity-matured Ab Fab19 with recombinant Fab19 Abs that were variants containing reverted amino acids from the inferred unmutated ancestor sequence revealed the molecular basis for affinity maturation of this Ab. Enhanced binding was achieved through mutations in the third H chain CDR (HCDR3) that conferred a markedly faster on-rate and a desirable increase in antiviral neutralizing activity. In contrast, most somatic mutations in the HCDR1 and HCDR2 regions did not significantly enhance Ag binding or antiviral activity. We observed a direct relationship between the measured association rate (Kon) for F protein and antiviral activity. Modeling studies of the structure of the Ag-Ab complex suggested the HCDR3 loop interacts with the antigenic site A surface loop of the respiratory syncytial virus F protein, previously shown to contain the epitope for this Ab by experimentation. These studies define a direct relationship of affinity and neutralizing activity for a viral glycoprotein-specific human mAb.

MeSH Terms (19)

Amino Acid Sequence Antibodies, Monoclonal Antibodies, Neutralizing Antibodies, Viral Antibody Affinity Antibody Specificity Humans Immunoglobulin Fab Fragments Immunoglobulin Variable Region Kinetics Models, Molecular Molecular Docking Simulation Mutation Neutralization Tests Protein Binding Protein Conformation Recombinant Proteins Respiratory Syncytial Virus, Human Viral Fusion Proteins

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