» Articles » PMID: 32847862

Human Monoclonal Antibody Derived from Transchromosomic Cattle Neutralizes Multiple H1 Clades of Influenza A Virus by Recognizing a Novel Conformational Epitope in the Hemagglutinin Head Domain

Abstract

Influenza remains a global health risk and challenge. Currently, neuraminidase (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 nonimmunogenic antibodies in large quantities rapidly. Here, we report that 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. selection of antibody escape mutants revealed that 53C10 recognizes a novel noncontinuous epitope in the hemagglutinin (HA) head domain involving three amino acid residues, glycine (G), serine (S), and glutamic acid (E) at positions 172, 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. 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 nonimmunogenic antibodies in large scale. In the present study, transchromosomic (Tc) cattle were used for the generation of nonimmunogenic 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 nonimmunogenic MAbs and highlight the potential of MAb 53C10 in the therapeutic application against H1 influenza virus infection in humans.

Citing Articles

Emerging Threats of Highly Pathogenic Avian Influenza A (H5N1) in US Dairy Cattle: Understanding Cross-Species Transmission Dynamics in Mammalian Hosts.

Sreenivasan C, Li F, Wang D Viruses. 2024; 16(11).

PMID: 39599818 PMC: 11598956. DOI: 10.3390/v16111703.


Evolutionary analysis of Hemagglutinin and neuraminidase gene variation in H1N1 swine influenza virus from vaccine intervention in China.

Zhao X, Shen M, Cui L, Liu C, Yu J, Wang G Sci Rep. 2024; 14(1):28792.

PMID: 39567587 PMC: 11579394. DOI: 10.1038/s41598-024-80457-4.


Transchromosomic bovines-derived broadly neutralizing antibodies as potent biotherapeutics to counter important emerging viral pathogens with a special focus on SARS-CoV-2, MERS-CoV, Ebola, Zika, HIV-1, and influenza A virus.

Saied A, Nascimento M, do Nascimento Rangel A, Skowron K, Grudlewska-Buda K, Dhama K J Med Virol. 2022; 94(10):4599-4610.

PMID: 35655326 PMC: 9347534. DOI: 10.1002/jmv.27907.


Protective and pathogenic role of humoral responses in COVID-19.

Park U, Cho N J Microbiol. 2022; 60(3):268-275.

PMID: 35235178 PMC: 8890013. DOI: 10.1007/s12275-022-2037-8.


The contribution of bovines to human health against viral infections.

Saied A, Metwally A, Mohamed H, Haridy M Environ Sci Pollut Res Int. 2021; 28(34):46999-47023.

PMID: 34272669 PMC: 8284698. DOI: 10.1007/s11356-021-14941-z.

References
1.
Hause B, Collin E, Liu R, Huang B, Sheng Z, Lu W . Characterization of a novel influenza virus in cattle and Swine: proposal for a new genus in the Orthomyxoviridae family. mBio. 2014; 5(2):e00031-14. PMC: 3958797. DOI: 10.1128/mBio.00031-14. View

2.
Gardner C, Sun C, Luke T, Raviprakash K, Wu H, Jiao J . Antibody Preparations from Human Transchromosomic Cows Exhibit Prophylactic and Therapeutic Efficacy against Venezuelan Equine Encephalitis Virus. J Virol. 2017; 91(14). PMC: 5487544. DOI: 10.1128/JVI.00226-17. View

3.
Prabakaran M, Prabhu N, He F, Hongliang Q, Ho H, Qiang J . Combination therapy using chimeric monoclonal antibodies protects mice from lethal H5N1 infection and prevents formation of escape mutants. PLoS One. 2009; 4(5):e5672. PMC: 2682562. DOI: 10.1371/journal.pone.0005672. View

4.
Soundararajan V, Tharakaraman K, Raman R, Raguram S, Shriver Z, Sasisekharan V . Extrapolating from sequence--the 2009 H1N1 'swine' influenza virus. Nat Biotechnol. 2009; 27(6):510-3. DOI: 10.1038/nbt0609-510. View

5.
Brimacombe C, Grove J, Meredith L, Hu K, Syder A, Flores M . Neutralizing antibody-resistant hepatitis C virus cell-to-cell transmission. J Virol. 2010; 85(1):596-605. PMC: 3014195. DOI: 10.1128/JVI.01592-10. View