Neutralizing monoclonal antibodies protect against human adenovirus type 55 infection in transgenic mice and tree shrews

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.

KEYWORDS:

• Human adenovirus type 55; neutralizing monoclonal antibodies; rhesus macaque; targeting sites; mechanism of action

Acknowledgements

We thank Yichu Liu, Xuehua Zheng, Yahai Shu in GIBH for their technical assistance. We also thank Jian Zhang, Zhi Wang and Cuie Li in the Animal Center of GIBH and Kangtian Li, Zhenxia Zheng in GMU for their assistance in animal experiments.

Disclosure statement

L.C. serves as chief scientific advisor for Guangzhou nBiomed Ltd. The remaining authors declare no competing financial interests.

Additional information

Funding

This study was partially supported by National Natural Science Foundation of China (32370998, 32300776, and 82072264), Natural Science Foundation of Guangdong Province (2021A1515011076), Foundation for Basic and Applied Basic Research of Guangzhou (2023A04J0106), and grants from State Key Laboratory of Respiratory Diseases (SKLRD-Z-202118, SKLRD-Z-202120, SKLRD-Z-202211 and SKLRD-Z-202319).