Neutralizing monoclonal antibodies protect against human adenovirus type 55 infection in transgenic mice and tree shrews
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
|---|---|
| Enthalten in: |
Emerging microbes & infections - 13(2024), 1 vom: 17. Feb., Seite 2307513 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Liu, Xinglong [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 05.02.2024 Date Revised 05.02.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1080/22221751.2024.2307513 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM367307677 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM367307677 | ||
| 003 | DE-627 | ||
| 005 | 20240205232044.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240119s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1080/22221751.2024.2307513 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1281.xml |
| 035 | |a (DE-627)NLM367307677 | ||
| 035 | |a (NLM)38240267 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Liu, Xinglong |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Neutralizing monoclonal antibodies protect against human adenovirus type 55 infection in transgenic mice and tree shrews |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 05.02.2024 | ||
| 500 | |a Date Revised 05.02.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Human adenovirus type 55; neutralizing monoclonal antibodies; rhesus macaque; targeting sites; mechanism of action | |
| 650 | 7 | |a Antibodies, Neutralizing |2 NLM | |
| 650 | 7 | |a Antibodies, Viral |2 NLM | |
| 650 | 7 | |a Antibodies, Monoclonal |2 NLM | |
| 650 | 7 | |a Viral Proteins |2 NLM | |
| 700 | 1 | |a Li, Zhengfeng |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xiao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xiaoyan |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Yali |e verfasserin |4 aut | |
| 700 | 1 | |a Su, Wan |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Yutong |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Weixuan |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Xikui |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Nana |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Xianmiao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Zhichao |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Wenkuan |e verfasserin |4 aut | |
| 700 | 1 | |a He, Jun |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Qu, Linbing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Rong |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Ling |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Liqiang |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Emerging microbes & infections |d 2012 |g 13(2024), 1 vom: 17. Feb., Seite 2307513 |w (DE-627)NLM249608804 |x 2222-1751 |7 nnns |
| 773 | 1 | 8 | |g volume:13 |g year:2024 |g number:1 |g day:17 |g month:02 |g pages:2307513 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1080/22221751.2024.2307513 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 13 |j 2024 |e 1 |b 17 |c 02 |h 2307513 | ||