A fully human monoclonal antibody possesses antibody-dependent cellular cytotoxicity (ADCC) activity against the H1 subtype of influenza A virus by targeting a conserved epitope at the HA1 protomer interface

Rongyuan Gao; Zhao Wang; Tirth Uprety; Chithra C Sreenivasan; Zizhang Sheng; Ben M Hause; Colin Brunick; Hua Wu; Thomas Luke; Christoph L Bausch; Eddie J Sullivan; Adam D Hoppe; Victor C Huber; Dan Wang; Feng Li

doi:10.1002/jmv.28901

A fully human monoclonal antibody possesses antibody-dependent cellular cytotoxicity (ADCC) activity against the H1 subtype of influenza A virus by targeting a conserved epitope at the HA1 protomer interface

J Med Virol. 2023 Jul;95(7):e28901. doi: 10.1002/jmv.28901.

Authors

Rongyuan Gao¹, Zhao Wang¹, Tirth Uprety², Chithra C Sreenivasan², Zizhang Sheng³, Ben M Hause⁴, Colin Brunick⁵, Hua Wu⁶, Thomas Luke⁶, Christoph L Bausch⁶, Eddie J Sullivan⁶, Adam D Hoppe⁷, Victor C Huber⁵, Dan Wang², Feng Li²

Affiliations

¹ Department of Biology and Microbiology, South Dakota State University, Brookings, South Dakota, USA.
² Department of Veterinary Science, Maxwell H. Gluck Equine Research Center, University of Kentucky, Lexington, Kentucky, USA.
³ Zuckerman Mind Brian Behavior Institute, Columbia University, New York, New York, USA.
⁴ Research and Development Division, Cambridge Technologies Inc, Worthington, Minnesota, USA.
⁵ Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota, USA.
⁶ SAB Biotherapeutics, Sioux Falls, South Dakota, USA.
⁷ Department of Chemistry and Biochemistry, South Dakota State University, Brookings, South Dakota, USA.

PMID: 37394780
DOI: 10.1002/jmv.28901

Abstract

The Diversitab^TM system produces target specific high titer fully human polyclonal IgG immunoglobulins from transchromosomic (Tc) bovines shown to be safe and effective against multiple virulent pathogens in animal studies and Phase 1, 2 and 3 human clinical trials. We describe the functional properties of a human monoclonal antibody (mAb), 38C2, identified from this platform, which recognizes recombinant H1 hemagglutinins (HAs) and induces appreciable antibody-dependent cellular cytotoxicity (ADCC) activity in vitro. Interestingly, 38C2 monoclonal antibody demonstrated no detectable neutralizing activity against H1N1 virus in both hemagglutination inhibition and virus neutralization assays. Nevertheless, this human monoclonal antibody induced appreciable ADCC against cells infected with multiple H1N1 strains. The HA-binding activity of 38C2 was also demonstrated in flow cytometry using Madin-Darby canine kidney cells infected with multiple influenza A H1N1 viruses. Through further investigation with the enzyme-linked immunosorbent assay involving the HA peptide array and 3-dimensional structural modeling, we demonstrated that 38C2 appears to target a conserved epitope located at the HA1 protomer interface of H1N1 influenza viruses. A novel mode of HA-binding and in vitro ADCC activity pave the way for further evaluation of 38C2 as a potential therapeutic agent to treat influenza virus infections in humans.

Keywords: antibody-dependent cellular cytotoxicity; epitope; hemagglutinin (HA) protein; human monoclonal antibody; influenza; transchromosomic cattle.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Monoclonal
Antibodies, Viral
Antibody-Dependent Cell Cytotoxicity
Cattle
Dogs
Epitopes
Hemagglutinin Glycoproteins, Influenza Virus
Humans
Immunoglobulin G
Influenza A Virus, H1N1 Subtype*
Influenza A virus*
Influenza, Human*
Protein Subunits

Substances

Epitopes
Antibodies, Monoclonal
Protein Subunits
Antibodies, Viral
Hemagglutinin Glycoproteins, Influenza Virus
Immunoglobulin G

Grants and funding

P20 GM103443/GM/NIGMS NIH HHS/United States