A protective bispecific antibody targets both Nipah virus surface glycoproteins and limits viral escape
Isaacs, A.; Valenzuela Nieto, G.; Zhang, X.; Modhiran, N.; Barr, J.; Thakur, N.; Low, Y. S.; Parry, R.; Barnes, J. B.; Jara, R.; Himelreichs, J.; Yao, Y.; Deride, C.; Barthou-Gatica, B.; Salinas-Rebolledo, C.; Pamela, E.; Hen, J. J.; Hayes, N.; Paramitha, D.; Morgan, M. S.; McMillan, C. L.; Jones, M. L.; Munro, T.; Khromykh, A.; Reading, P.; Young, P.; Chappell, K.; Shi, Y.; Bailey, D.; Marsh, G. A.; Chiu, S.; Rojas-Fernandez, A.; Watterson, D.
Show 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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