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Protection against lethal HAdV-4 challenge in STAT1 mice by novel human monoclonal antibodies
Xinyi Zhang1,2, Zhongge Zhu3, Peijie Zhai1,2
1College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
Introduction:
Human adenovirus serotype 4 (HAdV-4) is an epidemic pathogen associated with severe acute respiratory disease (ARD) in both pediatric and adult populations. Currently, no available vaccine or therapeutic interventions specifically targeting adenoviruses are available.
Methods:
In this study, we isolated peripheral blood mononuclear cells (PBMCs) from HAdV-4 infected donors and generated fully human monoclonal antibodies using single-cell PCR technology. The antibodies were first characterized for their neutralization efficacy both in vitro and in vivo. Subsequently, we predicted key functional residues through structural modeling of antigen-antibody complexes and validated their roles via mutagenesis studies. Finally, the mechanism of intracellular neutralization of antibodies was explored.
Results:
Through systematic screening, we successfully isolated seven antibodies with specific binding activity, among which monoclonal antibodies (mAbs) 2CF4 and 4AC3 exhibited potent neutralizing capacity against HAdV-4. Notably, we modeled adenoviral lethality using Stat1-/- transgenic mice, mAb 2CF4 conferred full protection against HAdV-4 infection in Stat1-/- transgenic mice. We identified critical amino acid residues, R99, R102 and T104 aa, of mAb 2CF4 by structural prediction of the antigen-antibody complex. Furthermore, the mAb 2CF4 neutralize the HAdV-4 through the interaction with the widely expressed cytoplasmic Fc-binding protein TRIM21.
Discussion:
Overall, mAb 2CF4 represents a promising candidate for safe and effective prophylactic and therapeutic strategies against HAdV-4 infection.
Insights
Human adenovirus serotype 4 (HAdV-4) causes severe respiratory illness. Researchers developed a monoclonal antibody (mAb) 2CF4 that effectively neutralizes HAdV-4 in preclinical models, offering a potential new treatment.
Area of Science:
- Virology
- Immunology
- Structural Biology
Background:
- Human adenovirus serotype 4 (HAdV-4) is a significant cause of epidemic acute respiratory disease (ARD) in children and adults.
- Current therapeutic options and vaccines specifically targeting HAdV-4 are lacking.
Purpose of the Study:
- To develop and characterize fully human monoclonal antibodies (mAbs) with neutralizing activity against HAdV-4.
- To elucidate the mechanism of action and identify key residues involved in antibody-mediated HAdV-4 neutralization.
Main Methods:
- Isolation of peripheral blood mononuclear cells (PBMCs) from HAdV-4 infected donors.
- Generation of mAbs using single-cell PCR technology.
- In vitro and in vivo neutralization assays, structural modeling, site-directed mutagenesis, and exploration of intracellular neutralization mechanisms.
Main Results:
- Seven specific antibodies were isolated, with mAbs 2CF4 and 4AC3 demonstrating potent HAdV-4 neutralization.
- mAb 2CF4 provided complete protection in Stat1-/- mice challenged with HAdV-4.
- Structural analysis identified critical residues (R99, R102, T104) in mAb 2CF4, and its neutralization mechanism involves interaction with TRIM21.
Conclusions:
- mAb 2CF4 is a highly effective neutralizing antibody against HAdV-4.
- mAb 2CF4 demonstrates significant potential as a prophylactic and therapeutic agent for HAdV-4 infections.
