A human-derived two-antibody cocktail confers prophylactic and therapeutic protection against authentic Mpox virus

With sustained human-to-human transmission worldwide, Mpox virus remains a significant global health burden. However, there are no licensed therapeutics against Mpox, with clinical management limited to supportive care and pain management. Given the virus complex life cycles, effective treatments require the inhibition of both mature intracellular virions (MV) and extracellular virions (EV). Here, we describe the isolation of human monoclonal antibodies (mAbs) from antigen specific memory B cell using flow cytometry-based cell sorting. We also characterize the therapeutic potential of 2-mAb cocktails targeting both MV and EV using an in vitro neutralization assay and a mouse challenge model. Several developed human 2-mAb cocktails neutralized authentic Mpox in vitro . When administered 24 hours before or after Mpox challenge, the lead 2-mAb cocktail inhibited viral loads in mouse tissues, with the exception of the testes. Overall, our study identifies several human 2-mAb cocktails with therapeutic potential for controlling Mpox disease.

Mpox virus, which has emerged as a significant public health threat, is now endemic to several countries worldwide. Existing Mpox vaccines offer only partial protection, and the primary antiviral, tecovirimat, has demonstrated no clinical benefits, highlighting an urgent need for novel therapeutics. Recognizing the limitations of animal-derived antibodies for therapeutic use, we isolated human antibodies and demonstrated the therapeutic potential of two-antibody cocktails using an in vitro neutralization assay and a mouse challenge model. Importantly, the two antibodies within our lead cocktail were predicted to bind to conserved epitopes on their Mpox targets. Overall, this study documents the development of a human two-antibody cocktail with both prophylactic and therapeutic potential against Mpox, offering a promising new avenue for clinical intervention.