Isaacs Ariel, Nieto Guillermo Valenzuela, Zhang Xinghai, Modhiran Naphak, Barr Jennifer, Thakur Nazia, Low Yu Shang, Parry Rhys H, Barnes James B, Jara Ronald, Himelreichs Johanna, Yao Yanfeng, Deride Camila, Barthou-Gatica Barbara, Salinas-Rebolledo Constanza, Ehrenfeld Pamela, Hen Jun Jet, Hayes Noah, Paramitha Devina, Morgan Mahali S, McMillan Christopher L D, Jones Martina L, Munro Trent P, Khromykh Alexander A, Reading Patrick C, Young Paul R, Chappell Keith J, Shi Yi, Bailey Dalan, Marsh Glenn A, Chiu Sandra, Rojas-Fernandez Alejandro, Watterson Daniel
School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia.
Australian Infectious Disease Research Centre, Global Virus Network Centre of Excellence, Brisbane, Queensland, Australia.
Nat Struct Mol Biol. 2025 Jul 8. doi: 10.1038/s41594-025-01598-2.
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.
尼帕病毒（NiV）和亨德拉病毒（HeV）是高致病性亨尼帕病毒，目前尚无获批的人类疫苗或治疗方法。在此，我们报告了一种高效双特异性疗法，该疗法将抗融合糖蛋白纳米抗体与抗受体结合糖蛋白（RBP）抗体相结合，以提供一种对病毒逃逸具有抗性的双靶点生物制剂。我们表明，纳米抗体DS90作用于NiV和HeV融合糖蛋白内一个独特的保守位点，并提供中和作用以及对NiV疾病的完全保护。与领先的单价方法相比，DS90与抗RBP单克隆抗体m102.4的双特异性工程改造可实现中和、消除病毒逃逸并提供对NiV疾病的卓越保护。这些发现对开发限制亨尼帕病毒逃逸突变体出现的交叉中和免疫疗法具有启示意义。
