Engineered bispecific antibodies achieve broad and potent protection against multiple ebolavirus species

Ebolaviruses, including EBOV, SUDV, and BDBV, cause severe hemorrhagic fever, yet currently licensed monoclonal antibody (mAb) therapies against EBOV lack cross-species efficacy. While mAbs offer high specificity, favourable safety profiles, and durable serum persistence, their susceptibility to viral escape highlights the need for broader, more resilient antibody strategies. Bispecific antibodies (bsAbs), which concurrently target non-overlapping epitopes, have the potential to enhance neutralization potency, expand strain coverage, and mitigate mutation-driven resistance. In this study, we engineered three bsAb formats-CrossMab®, DVD-IgG, and IgG-ScFv-directed against distinct ebolavirus epitopes and systematically characterized their antiviral activities. All bsAbs exhibited potent neutralizing activity and conferred substantial protection in mouse challenge models. Notably, the IgG-ScFv format demonstrated the greatest improvements in neutralization potency and in vivo efficacy. These findings provide a framework for rational bsAb design and underscore their promise as next-generation immunotherapeutics capable of broad and durable protection against diverse ebolaviruses.