Multistate design of influenza antibodies improves affinity and breadth against seasonal viruses

Influenza is a yearly threat to global public health. Rapid changes in influenza surface proteins resulting from antigenic drift and shift events make it difficult to readily identify antibodies with broadly neutralizing activity against different influenza subtypes with high frequency, specifically...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2019-01, Vol.116 (5), p.1597-1602
Main Authors: Sevy, Alexander M., Wu, Nicholas C., Gilchuk, Iuliia M., Parrish, Erica H., Burger, Sebastian, Yousif, Dina, Nagel, Marcus B. M., Schey, Kevin L., Wilson, Ian A., Crowe, James E., Meiler, Jens
Format: Article
Language:English
Subjects:
Affinity
Amino Acid Sequence
Antibodies
Antibodies, Neutralizing - immunology
Antibodies, Viral - immunology
Antigenic drift
Antigens
Binding
Biological Sciences
Computer applications
Crystallography, X-Ray - methods
Design
Design optimization
Electrostatic properties
HA protein
Health risks
Hemagglutinin Glycoproteins, Influenza Virus - immunology
Humans
Immunoglobulins
Influenza
Influenza A virus - immunology
Influenza, Human - immunology
Mutants
Proteins
Public health
Redesign
Seasons
Viruses
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Summary:Influenza is a yearly threat to global public health. Rapid changes in influenza surface proteins resulting from antigenic drift and shift events make it difficult to readily identify antibodies with broadly neutralizing activity against different influenza subtypes with high frequency, specifically antibodies targeting the receptor binding domain (RBD) on influenza HA protein. We developed an optimized computational designmethod that is able to optimize an antibody for recognition of large panels of antigens. To demonstrate the utility of this multistate design method, we used it to redesign an antiinfluenza antibody against a large panel of more than 500 seasonal HA antigens of the H1 subtype. As a proof of concept, we tested this method on a variety of known antiinfluenza antibodies and identified those that could be improved computationally. We generated redesigned variants of antibody C05 to the HA RBD and experimentally characterized variants that exhibited improved breadth and affinity against our panel. C05 mutants exhibited improved affinity for three of the subtypes used in design by stabilizing the CDRH3 loop and creating favorable electrostatic interactions with the antigen. These mutants possess increased breadth and affinity of binding while maintaining high-affinity binding to existing targets, surpassing a major limitation up to this point.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1806004116