Seiya Yamayoshi1, Atsuhiro Yasuhara1, Mutsumi Ito1, Ryuta Uraki1, Yoshihiro Kawaoka2. 1. Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan. 2. Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan; Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Japan; Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, USA. Electronic address: yoshihiro.kawaoka@wisc.edu.
Abstract
BACKGROUND: Broadly protective human monoclonal antibodies that recognize the conserved epitopes in the HA of influenza A virus are being developed as therapeutic agents. Emergence of resistant viruses must always be considered when developing therapeutic agents against influenza. OBJECTIVES: We examined human hetero-reactive mAbs against the HA stem of influenza A virus for the ease with which escape mutant viruses emerged. STUDY DESIGN: We attempted to generate the mutant viruses escaped from the hetero-reactive anti-HA stem antibodies. We also evaluated their protective efficacy, binding affinity, and epitopes. RESULTS: We obtained several human monoclonal antibodies (mAbs) that react with the HA of different HA subtypes of influenza A virus belonging to group 1. Upon attempting to generate escape mutant viruses, we found that the ease with which such viruses emerged differed among the mAbs; viruses barely escaped from two of the mAbs (clones S9-3-37 and F20C77), whereas escape from the third mAb (clone F5B7) occurred readily. Comparisons of the mAbs revealed that the HA stem epitopes, in vitro neutralization potency, binding affinity to H1-HA, and protective efficacy against lethal challenge with H1N1pdm09 virus were all comparable. CONCLUSIONS: These results demonstrate the importance of determining the ease with which escape mutant viruses emerge when evaluating anti-HA stem antibodies as antiviral agents during preclinical testing.
BACKGROUND: Broadly protective human monoclonal antibodies that recognize the conserved epitopes in the HA of influenza A virus are being developed as therapeutic agents. Emergence of resistant viruses must always be considered when developing therapeutic agents against influenza. OBJECTIVES: We examined human hetero-reactive mAbs against the HA stem of influenza A virus for the ease with which escape mutant viruses emerged. STUDY DESIGN: We attempted to generate the mutant viruses escaped from the hetero-reactive anti-HA stem antibodies. We also evaluated their protective efficacy, binding affinity, and epitopes. RESULTS: We obtained several human monoclonal antibodies (mAbs) that react with the HA of different HA subtypes of influenza A virus belonging to group 1. Upon attempting to generate escape mutant viruses, we found that the ease with which such viruses emerged differed among the mAbs; viruses barely escaped from two of the mAbs (clones S9-3-37 and F20C77), whereas escape from the third mAb (clone F5B7) occurred readily. Comparisons of the mAbs revealed that the HA stem epitopes, in vitro neutralization potency, binding affinity to H1-HA, and protective efficacy against lethal challenge with H1N1pdm09 virus were all comparable. CONCLUSIONS: These results demonstrate the importance of determining the ease with which escape mutant viruses emerge when evaluating anti-HA stem antibodies as antiviral agents during preclinical testing.
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Authors: Nicholas C Wu; Seiya Yamayoshi; Mutsumi Ito; Ryuta Uraki; Yoshihiro Kawaoka; Ian A Wilson Journal: Cell Host Microbe Date: 2018-10-10 Impact factor: 21.023