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J Virol . Human Monoclonal Antibody Derived from Transchromosomic (Tc) Cattle Neutralizes Multiple H1 Clades of Influenza A Virus by Recognizing a Novel Conformational Epitope in the HA Head Domain

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  • J Virol . Human Monoclonal Antibody Derived from Transchromosomic (Tc) Cattle Neutralizes Multiple H1 Clades of Influenza A Virus by Recognizing a Novel Conformational Epitope in the HA Head Domain


    J Virol


    . 2020 Aug 26;JVI.00945-20.
    doi: 10.1128/JVI.00945-20. Online ahead of print.
    Human Monoclonal Antibody Derived from Transchromosomic (Tc) Cattle Neutralizes Multiple H1 Clades of Influenza A Virus by Recognizing a Novel Conformational Epitope in the HA Head Domain


    Rongyuan Gao 1 , Chithra C Sreenivasan 1 , Zizhang Sheng 2 , Ben M Hause 3 , Bin Zhou 4 , David E Wentworth 4 , Travis Clement 3 , Dana Rausch 3 , Colin Brunick 5 , Jane Christopher-Hennings 3 6 , Hua Wu 7 , Christoph L Bausch 7 , Eddie J Sullivan 7 , Adam D Hoppe 8 9 , Victor C Huber 9 5 6 , Dan Wang 10 9 6 , Feng Li 10 9 6



    Affiliations

    Abstract

    Influenza remains a global health risk and challenge. Currently, NA inhibitors are extensively used to treat influenza, but their efficacy is compromised by the emergence of drug resistant variants. Neutralizing antibodies targeting influenza A virus surface glycoproteins are critical components of influenza therapeutic agents and may provide alternative strategies to the existing countermeasures. However, the major hurdle for the extensive application of antibody therapies lies in the difficulty of generating non-immunogenic antibodies in large quantities rapidly. Here, we report one human monoclonal antibody (mAb), 53C10, isolated from transchromosomic (Tc) cattle exhibits potent neutralization and hemagglutination inhibition titers against different clades of H1N1 subtype influenza A viruses. In vitro selection of antibody escape mutants reveals that 53C10 recognizes a novel non-continuous epitope in the HA head domain involving three amino acid residues, glycine (G), Serine (S) and glutamic acid (E) at positions172, 207 and 212, respectively. The results of our experiments supported a critical role for substitution of arginine at position 207 (S207R) in mediating resistance to 53C10, while substitutions at either G172E or E212A did not alter antibody recognition and neutralization. The E212A mutation may provide structural stability for the epitope, while the substitution G172E probably compensates for loss of fitness introduced by S207R. Our results offer novel insights into the mechanism of action of mAb 53C10 and indicate its potential role in therapeutic treatment of H1 influenza virus infection in humans.IMPORTANCE Respiratory diseases caused by influenza viruses still pose a serious concern to global health and neutralizing antibodies constitute a promising area of antiviral therapeutics. However, the potential application of antibodies is often hampered by the challenge in generating non-immunogenic antibodies in large scale. In the present study, the transchromosomic (Tc) cattle were used for the generation of non-immunogenic monoclonal antibodies (mAbs) and characterization of such mAbs revealed one monoclonal antibody 53C10, exhibiting a potent neutralization activity against H1N1 influenza viruses. Further characterization of the neutralization-escape mutant generated using this mAb, showed that three amino acid substitutions in the HA head domain contributed to the resistance. These findings emphasize the importance of Tc cattle in the production of non-immunogenic mAbs and highlight the potential of 53C10 mAb in the therapeutic application against H1 influenza virus infection in humans.


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