Spatial organization of mAbs in complex with the virus glycoprotein determines the success of intravenous rabies therapy

Abstract Rabies is a complex disease that has defied efforts to develop an effective treatment. Although it can be successfully prevented through vector control or pre- or post-exposure prophylaxis, no therapeutic options exist for symptomatic rabies, and the disease is still responsible for about 59 000 human deaths each year. Following our successful attempts to use the human monoclonal antibodies RVC20 and RVC58 for intracerebroventricular treatment of rabies, we report here on the effects of these mAbs when administered intravenously to symptomatic rabid mice. Only a small proportion of mAbs was detected to cross the blood-brain barrier, yet this limited amount sufficiently cleared the viral infection and was enough to cure the infected animals. Remarkably, these mAbs were more effective at preventing rabies-related death when used individually rather than when used as a cocktail. RVC58 achieved an 80% survival rate, likely due to its distinct binding topography, potent viral neutralization, and enhanced FcγR engagement in the presence of virions. The significance of this work is that the use of a single mAb could substantially lower the costs and improve treatment accessibility in under-resourced settings, potentially contributing to improved equity of global health. These findings establish intravenous mAb therapy as a promising therapeutic approach for symptomatic rabies and provide a foundation for clinical development of an accessible treatment option. Highlights Intravenous injected RVC58 clears rabies virus from infected brains in vivo RVC58 modulates immune response and restore clinical health in rabid mice Therapeutical effects of RVC58 relies on mAb binding topography, viral neutralization, and FcγR engagement RVC58 is a breakthrough for treating human clinical rabies Competing Interest Statement S.K., H.B., and G.D.M. have received funding through sponsored research awards from Vir Biotechnology Inc. related to the work described in this paper. F.B and D.C. are employees of Vir Biotechnology Inc. and may hold shares in Vir Biotechnology Inc. D.C., H.B., and G.D.M. hold a patent for the mAbs used in this study (PCT/EP2019/078439). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.