A nanobody-based therapeutic targeting Nipah virus limits viral escape

Ariel Isaacs^#^{1

2}, Guillermo Valenzuela Nieto^#^{3

4}, Xinghai Zhang^#⁵, Naphak Modhiran^{1

2}, Jennifer Barr⁶, Nazia Thakur^{7

8}, Yu Shang Low¹, Rhys H Parry¹, James B Barnes⁹, Ronald Jara^{4

10}, Johanna Himelreichs⁴, Yanfeng Yao⁵, Camila Deride⁴, Barbara Barthou-Gatica⁴, Constanza Salinas-Rebolledo⁴, Pamela Ehrenfeld¹¹, Jun Jet Hen¹, Noah Hayes¹, Devina Paramitha¹, Mahali S Morgan¹, Christopher L D McMillan^{1

2}, Martina L Jones¹², Trent P Munro¹², Alexander A Khromykh^{1

2}, Patrick C Reading⁹, Paul R Young^{1

2

12}, Keith J Chappell^{1

2

12}, Yi Shi¹³, Dalan Bailey⁷, Glenn A Marsh⁶, Sandra Chiu^{14

15}, Alejandro Rojas-Fernandez¹⁶, Daniel Watterson^{17

18}

Affiliations

¹ School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia.
² Australian Infectious Disease Research Centre, Global Virus Network Centre of Excellence, Brisbane, Queensland, Australia.
³ Healthcare Science Faculty, Universidad San Sebastián, Valdivia, Chile.
⁴ Institute of Medicine, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile.
⁵ CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
⁶ CSIRO, Health and Biosecurity, Australian Centre for Disease Preparedness, Geelong, Victoria, Australia.
⁷ The Pirbright Institute, Surrey, UK.
⁸ Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁹ WHO Collaborating Centre for Reference and Research on Influenza, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
¹⁰ Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, Valdivia, Chile.
¹¹ Laboratory of Cellular Pathology, Institute of Anatomy, Histology and Pathology, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile.
¹² The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland, Australia.
¹³ CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
¹⁴ Department of Laboratory Medicine, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Heifei, China. qiux@ustc.edu.cn.
¹⁵ Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. qiux@ustc.edu.cn.
¹⁶ Institute of Medicine, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile. alejandro.rojas@uach.cl.
¹⁷ School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia. d.watterson@uq.edu.au.
¹⁸ Australian Infectious Disease Research Centre, Global Virus Network Centre of Excellence, Brisbane, Queensland, Australia. d.watterson@uq.edu.au.

^# Contributed equally.

PMID: 40629166
DOI: 10.1038/s41594-025-01598-2

A nanobody-based therapeutic targeting Nipah virus limits viral escape

Ariel Isaacs et al. Nat Struct Mol Biol. 2025.

. 2025 Jul 8.

doi: 10.1038/s41594-025-01598-2. Online ahead of print.

Authors

Affiliations

¹ School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia.
² Australian Infectious Disease Research Centre, Global Virus Network Centre of Excellence, Brisbane, Queensland, Australia.
³ Healthcare Science Faculty, Universidad San Sebastián, Valdivia, Chile.
⁴ Institute of Medicine, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile.
⁵ CAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
⁶ CSIRO, Health and Biosecurity, Australian Centre for Disease Preparedness, Geelong, Victoria, Australia.
⁷ The Pirbright Institute, Surrey, UK.
⁸ Nuffield Department of Medicine, University of Oxford, Oxford, UK.
⁹ WHO Collaborating Centre for Reference and Research on Influenza, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
¹⁰ Institute of Biochemistry and Microbiology, Faculty of Sciences, Universidad Austral de Chile, Valdivia, Chile.
¹¹ Laboratory of Cellular Pathology, Institute of Anatomy, Histology and Pathology, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile.
¹² The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland, Australia.
¹³ CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
¹⁴ Department of Laboratory Medicine, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Heifei, China. qiux@ustc.edu.cn.
¹⁵ Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, China. qiux@ustc.edu.cn.
¹⁶ Institute of Medicine, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile. alejandro.rojas@uach.cl.
¹⁷ School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia. d.watterson@uq.edu.au.
¹⁸ Australian Infectious Disease Research Centre, Global Virus Network Centre of Excellence, Brisbane, Queensland, Australia. d.watterson@uq.edu.au.

^# Contributed equally.

PMID: 40629166
DOI: 10.1038/s41594-025-01598-2

Abstract

Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic henipaviruses without approved human vaccines or therapies. Here, we report on a highly potent bispecific therapeutic that combines an anti-fusion glycoprotein nanobody with an anti-receptor-binding glycoprotein (RBP) antibody to deliver a dual-targeting biologic that is resistant to viral escape. We show that the nanobody, DS90, engages a unique, conserved site within the fusion glycoprotein of NiV and HeV and provides neutralization and complete protection from NiV disease. Bispecific engineering of DS90 with the anti-RBP monoclonal antibody m102.4 results in neutralization, elimination of viral escape and superior protection from NiV disease compared to leading monovalent approaches. These findings carry implications for the development of cross-neutralizing immunotherapies that limit the emergence of henipaviral escape mutants.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

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A nanobody-based therapeutic targeting Nipah virus limits viral escape

Affiliations

A nanobody-based therapeutic targeting Nipah virus limits viral escape

Authors

Affiliations

Abstract

Conflict of interest statement

References

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