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Neutralizing monoclonal antibodies protect against human adenovirus type 55 infection in transgenic mice and tree
Xinglong Liu1,2, Zhengfeng Li1, Xiao Li3
1State Key Laboratory of Respiratory Disease, CAS Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, People's Republic of China.
Abstract:
Re-emerging human adenovirus type 55 (HAdV55) has become a significant threat to public health due to its widespread circulation and the association with severe pneumonia, but an effective anti-HAdV55 agent remains unavailable. Herein, we report the generation of macaque-derived, human-like monoclonal antibodies (mAbs) protecting against HAdV55 infection with high potency. Using fluorophore-labelled HAdV55 virions as probes, we isolated specific memory B cells from rhesus macaques (Macaca mulatta) that were immunized twice with an experimental vaccine based on E1-, E3-deleted, replication-incompetent HAdV55. We cloned a total of 19 neutralizing mAbs, nine of which showed half-maximal inhibitory concentrations below 1.0 ng/ml. These mAbs recognized the hyper-variable-region (HVR) 1, 2, or 7 of viral hexon protein, or the fibre knob. In transgenic mice expressing human desmoglein-2, the major cellular receptor for HAdV55, a single intraperitoneal injection with hexon-targeting mAbs efficiently prevented HAdV55 infection, and mAb 29C12 showed protection at a dose as low as 0.004 mg/kg. Fibre-targeting mAb 28E8, however, showed protection only at a dose up to 12.5 mg/kg. In tree shrews that are permissive for HAdV55 infection and disease, mAb 29C12 effectively prevented HAdV55-caused pneumonia. Further analysis revealed that fibre-targeting mAbs blocked the attachment of HAdV55 to host cells, whereas hexon-targeting mAbs, regardless of their targeting HVRs, mainly functioned at post-attachment stage via inhibiting viral endosomal escape. Our results indicate that hexon-targeting mAbs have great anti-HAdV55 activities and warrant pre-clinical and clinical evaluation.
Insights
Researchers developed potent human-like monoclonal antibodies (mAbs) from macaques to combat human adenovirus type 55 (HAdV55) and severe pneumonia. Hexon-targeting mAbs showed high efficacy, warranting further clinical evaluation for HAdV55 infections.
Area of Science:
- Virology
- Immunology
- Infectious Diseases
Background:
- Re-emerging human adenovirus type 55 (HAdV55) causes severe pneumonia, posing a public health threat.
- Effective anti-HAdV55 agents are currently unavailable.
Purpose of the Study:
- To generate potent macaque-derived, human-like monoclonal antibodies (mAbs) against HAdV55.
- To evaluate the efficacy of these mAbs in preventing HAdV55 infection and disease.
Main Methods:
- Rhesus macaques were immunized with an HAdV55 vaccine to isolate memory B cells.
- Neutralizing mAbs targeting viral hexon protein or fibre knob were cloned and characterized.
- Efficacy was tested in transgenic mice and tree shrews.
Main Results:
- Nineteen neutralizing mAbs were generated, with nine showing sub-nanogram/mL potency.
- Hexon-targeting mAbs (e.g., mAb 29C12) demonstrated high efficacy in vivo, preventing infection and pneumonia.
- Fibre-targeting mAbs blocked viral attachment, while hexon-targeting mAbs inhibited post-attachment events like endosomal escape.
Conclusions:
- Macaque-derived mAbs offer a promising therapeutic strategy against HAdV55.
- Hexon-targeting mAbs exhibit significant anti-HAdV55 activity and are suitable for pre-clinical and clinical development.
