Long‐Circulating Nanobody Confers Durable Prophylaxis against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Infection
Breakthrough infections in vaccinated population and continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants make it imperative to develop more efficacious medical countermeasures. Previously, an anti‐SARS‐CoV‐2 nanobody, Nanosota‐3A, that neutralizes the infect...
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| Format: | Article |
| Language: | English |
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Wiley-VCH
2025-08-01
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| Series: | Advanced NanoBiomed Research |
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| Online Access: | https://doi.org/10.1002/anbr.202400214 |
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| author | Geetha Jyothi Vaskuri Gang Ye Fan Bu Dong Yang Colleen B. Jonsson Hailey Turner‐Hubbard Sydney Winecke Alise Mendoza Fang Li Chalet Tan |
| author_facet | Geetha Jyothi Vaskuri Gang Ye Fan Bu Dong Yang Colleen B. Jonsson Hailey Turner‐Hubbard Sydney Winecke Alise Mendoza Fang Li Chalet Tan |
| author_sort | Geetha Jyothi Vaskuri |
| collection | DOAJ |
| description | Breakthrough infections in vaccinated population and continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants make it imperative to develop more efficacious medical countermeasures. Previously, an anti‐SARS‐CoV‐2 nanobody, Nanosota‐3A, that neutralizes the infection of live Omicron BA.1 with picomolar potency, is identified. Herein, Nanosota‐3A is fused with the crystallizable fragment (Fc) domain of human IgG1 that contains M252Y/S254T/T256E (YTE) substitutions, named Nanosota‐3A‐Fc‐YTE. Compared to Nanosota‐3A‐Fc, Nanosota‐3A‐Fc‐YTE exhibits identical binding to the SARS‐CoV‐2 spike protein yet displays eightfold higher binding affinity for human neonatal Fc receptor (hFcRn) at pH 6.0. In hFcRn transgenic mice, the half‐life of Nanosota‐3A‐Fc and Nanosota‐3A‐Fc‐YTE is 5.1 days and 24.8 days, respectively. The mice are challenged with intranasal exposure of Omicron B.1.1.529 virus 55 days after a single dose of Nanosota‐3A fusions (20 mg kg−1) is administered. Compared to the untreated controls, the lung viral titers in mice receiving Nanosota‐3A‐Fc‐YTE are reduced by 104.7‐fold (p = 0.007) with 50% of the mice free of detectable virus. By contrast, Nanosota‐3A‐Fc‐treated mice show only 3.5‐fold reduction in the viral titers (p = 0.41). The durable protection conferred by a single dose of Nanosota‐3A‐Fc‐YTE administered nearly 2 months prior to the virus exposure demonstrates the promise of long‐circulating nanobodies as powerful prophylactics against SARS‐CoV‐2. |
| format | Article |
| id | doaj-art-79a9e7b1acd04efb9262b4b4e7885e2b |
| institution | Kabale University |
| issn | 2699-9307 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley-VCH |
| record_format | Article |
| series | Advanced NanoBiomed Research |
| spelling | doaj-art-79a9e7b1acd04efb9262b4b4e7885e2b2025-08-20T03:59:45ZengWiley-VCHAdvanced NanoBiomed Research2699-93072025-08-0158n/an/a10.1002/anbr.202400214Long‐Circulating Nanobody Confers Durable Prophylaxis against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron InfectionGeetha Jyothi Vaskuri0Gang Ye1Fan Bu2Dong Yang3Colleen B. Jonsson4Hailey Turner‐Hubbard5Sydney Winecke6Alise Mendoza7Fang Li8Chalet Tan9Department of Pharmaceutical Sciences University of Tennessee Health Science Center Memphis TN 38163 USADepartment of Pharmacology University of Minnesota Medical School Minneapolis MN 55455 USADepartment of Pharmacology University of Minnesota Medical School Minneapolis MN 55455 USARegional Biocontainment Laboratory University of Tennessee Health Science Center Memphis TN 38163 USADepartment of Pharmaceutical Sciences University of Tennessee Health Science Center Memphis TN 38163 USADepartment of Pharmacology University of Minnesota Medical School Minneapolis MN 55455 USADepartment of Pharmacology University of Minnesota Medical School Minneapolis MN 55455 USADepartment of Pharmacology University of Minnesota Medical School Minneapolis MN 55455 USADepartment of Pharmacology University of Minnesota Medical School Minneapolis MN 55455 USADepartment of Pharmaceutical Sciences University of Tennessee Health Science Center Memphis TN 38163 USABreakthrough infections in vaccinated population and continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants make it imperative to develop more efficacious medical countermeasures. Previously, an anti‐SARS‐CoV‐2 nanobody, Nanosota‐3A, that neutralizes the infection of live Omicron BA.1 with picomolar potency, is identified. Herein, Nanosota‐3A is fused with the crystallizable fragment (Fc) domain of human IgG1 that contains M252Y/S254T/T256E (YTE) substitutions, named Nanosota‐3A‐Fc‐YTE. Compared to Nanosota‐3A‐Fc, Nanosota‐3A‐Fc‐YTE exhibits identical binding to the SARS‐CoV‐2 spike protein yet displays eightfold higher binding affinity for human neonatal Fc receptor (hFcRn) at pH 6.0. In hFcRn transgenic mice, the half‐life of Nanosota‐3A‐Fc and Nanosota‐3A‐Fc‐YTE is 5.1 days and 24.8 days, respectively. The mice are challenged with intranasal exposure of Omicron B.1.1.529 virus 55 days after a single dose of Nanosota‐3A fusions (20 mg kg−1) is administered. Compared to the untreated controls, the lung viral titers in mice receiving Nanosota‐3A‐Fc‐YTE are reduced by 104.7‐fold (p = 0.007) with 50% of the mice free of detectable virus. By contrast, Nanosota‐3A‐Fc‐treated mice show only 3.5‐fold reduction in the viral titers (p = 0.41). The durable protection conferred by a single dose of Nanosota‐3A‐Fc‐YTE administered nearly 2 months prior to the virus exposure demonstrates the promise of long‐circulating nanobodies as powerful prophylactics against SARS‐CoV‐2.https://doi.org/10.1002/anbr.202400214Fc engineeringFcRnhalf‐life extensionnanobodypharmacokineticspre‐exposure prophylaxis |
| spellingShingle | Geetha Jyothi Vaskuri Gang Ye Fan Bu Dong Yang Colleen B. Jonsson Hailey Turner‐Hubbard Sydney Winecke Alise Mendoza Fang Li Chalet Tan Long‐Circulating Nanobody Confers Durable Prophylaxis against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Infection Advanced NanoBiomed Research Fc engineering FcRn half‐life extension nanobody pharmacokinetics pre‐exposure prophylaxis |
| title | Long‐Circulating Nanobody Confers Durable Prophylaxis against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Infection |
| title_full | Long‐Circulating Nanobody Confers Durable Prophylaxis against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Infection |
| title_fullStr | Long‐Circulating Nanobody Confers Durable Prophylaxis against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Infection |
| title_full_unstemmed | Long‐Circulating Nanobody Confers Durable Prophylaxis against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Infection |
| title_short | Long‐Circulating Nanobody Confers Durable Prophylaxis against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Infection |
| title_sort | long circulating nanobody confers durable prophylaxis against severe acute respiratory syndrome coronavirus 2 omicron infection |
| topic | Fc engineering FcRn half‐life extension nanobody pharmacokinetics pre‐exposure prophylaxis |
| url | https://doi.org/10.1002/anbr.202400214 |
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