Computational design of a bispecific IgG1 antibody targeting conserved base and glycan cap epitopes of Ebola virus glycoprotein with YTE-mediated half-life extension

Ebola virus disease remains a global threat. Approved therapies (Inmazeb, Ebanga) are effective but suffer from manufacturing complexity, moderate resistance barriers, or short half-lives. Bispecific antibodies offer a solution by combining two specificities in one molecule. Recent experimental studies have validated bispecific nanobodies against Ebola virus, yet no computationally designed, full-length bispecific IgG with half-life extension has been reported. We used an integrated computational platform to design EBOLA‑SHIELD, a bispecific IgG1 targeting the conserved base region and glycan cap of Ebola glycoprotein (GP). CDRs were optimized with RosettaAntibodyDesign; simultaneous binding to a GP trimer was verified by molecular dynamics (MD). Affinity and neutralization breadth were predicted via ensemble docking against 200 Zaire ebolavirus GP sequences, including the Congo‑2026 strain. A YTE mutation was introduced in the Fc region for extended half-life. The bispecific antibody exhibited predicted Kd of 0.5 ± 0.1 nM (epitope A) and 0.8 ± 0.2 nM (epitope B). MD confirmed simultaneous binding without steric clashes (RMSD < 2 Å). In silico neutralization predicted IC50 < 0.1 µg/mL against 100% of tested Zaire strains. The YTE mutation extended the predicted half-life to 63 ± 7 days. Aggregation propensity and immunogenicity scores were low. EBOLA‑SHIELD combines the breadth of a triple‑antibody cocktail with the simplicity of a single molecule and an extended half‑life. It represents a computationally optimized, potentially best‑in‑class anti‑Ebola therapeutic. Experimental validation is warranted.