A protective bispecific antibody targets both Nipah virus surface glycoproteins and limits viral escape

Ariel Isaacs; Guillermo Valenzuela; Xinghai Zhang; Naphak Modhiran; Jennifer A. Barr; Nazia Thakur; Yu Shang Low; Rhys H. Parry; James B. Barnes; Ronald Jara; Johanna Himelreichs; Yanfeng Yao; Camila Deride; Barbara Barthou-Gatica; Constanza Salinas-Rebolledo; Pamela Ehrenfeld; Jun Jet Hen; Noah Hayes; Devina Paramitha; Mahali S. Morgan; Christopher L. D. McMillan; Martina L. Jones; Trent P. Munro; Alexander A. Khromykh; Patrick C. Reading; Paul R. Young; Keith  Joseph Chappell; Yi Shi; Dalan Bailey; Glenn A. Marsh

doi:10.1101/2025.03.11.642517

MicrobiologybioRxivMar 11, 2025

Preprint

A protective bispecific antibody targets both Nipah virus surface glycoproteins and limits viral escape

Ariel Isaacs iD, Guillermo Valenzuela iD, Xinghai Zhang iD, Naphak Modhiran iD, Jennifer A. Barr iD, Nazia Thakur iD, Yu Shang Low iD, Rhys H. Parry iD, James B. Barnes, Ronald Jara iD, Johanna Himelreichs, Yanfeng Yao iD, Camila Deride, Barbara Barthou-Gatica, Constanza Salinas-Rebolledo iD, Pamela Ehrenfeld iD, Jun Jet Hen, Noah Hayes, Devina Paramitha iD, Mahali S. Morgan iD, Christopher L. D. McMillan iD, Martina L. Jones iD, Trent P. Munro iD, Alexander A. Khromykh iD, Patrick C. Reading iD, , Daniel Watterson iD

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 (F) nanobody with an anti-receptor binding protein (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 prefusion F of NiV and HeV, and provides neutralization and complete protection from NiV disease. Bispecific engineering of DS90 with the anti-RBP mAb 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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