A cocktail of engineered chimeric antibodies targeting the central nervous system produces a broad-spectrum therapeutic effect for symptomatic rabies

Rabies is a lethal disease caused by rabies virus (RABV), and once symptoms appear, the fatality rate is nearly 100%. RABV is a neurotropic virus, and the presence of the blood-brain barrier (BBB) prevents peripheral neutralizing antibodies and immune cells from entering the central nervous system (CNS) to eliminate the virus. However, currently reported symptomatic treatments for rabies lack broad target coverage and may cause some degree of neuron damage. Here, we constructed four chimeric human-mouse antibodies with high neutralizing activity and affinity against RABV, further identifying their targeted antigenic epitopes as I, II, and IV. Meanwhile, we screened a highly efficient brain-shuttle peptide: SynB1, and fused it with antibodies to achieve targeted delivery of antibodies into the brain following intravenous injection. More importantly, our results showed that combined treatment of RABV-infected mice with three SynB1-antibodies targeting different epitopes could reduce their clinical symptoms and increase their survival ratio to 80%. Collectively, the non-invasive brain delivery method based on hybrid antibody-conjugated cell-penetrating peptides offers a promising strategy for the effective treatment of a broad-spectrum symptomatic rabies.