Abstract
Multiple agents in the family Filoviridae (filoviruses) are associated with sporadic human outbreaks of highly lethal disease, while others, including several recently identified agents, possess strong zoonotic potential. Although viral glycoprotein (GP)-specific monoclonal antibodies have demonstrated therapeutic utility against filovirus disease, currently FDA-approved molecules lack antiviral breadth. The development of broadly neutralizing antibodies has been challenged by the high sequence divergence among filovirus GPs and the complex GP proteolytic cleavage cascade that accompanies filovirus entry. Despite this variability in the antigenic surface of GP, all filoviruses share a site of vulnerability—the binding site for the universal filovirus entry receptor, Niemann-Pick C1 (NPC1). Unfortunately, this site is shielded in extracellular GP and only uncovered by proteolytic cleavage by host proteases in late endosomes and lysosomes, which are generally inaccessible to antibodies. To overcome this obstacle, we previously developed a ‘Trojan horse’ therapeutic approach in which engineered bispecific antibodies (bsAbs) coopt viral particles to deliver GP:NPC1 interaction-blocking antibodies to their endo/lysosomal sites of action. This approach afforded broad protection against members of the genus Ebolavirus but could not neutralize more divergent filoviruses. Here, we describe next-generation Trojan horse bsAbs that target the endo/lysosomal GP:NPC1 interface with pan-filovirus breadth by exploiting the conserved and widely expressed host cation-independent mannose-6-phosphate receptor for intracellular delivery. Our work highlights a new avenue for the development of single therapeutics protecting against all known and newly emerging filoviruses.
Highlights
Several members of the family Filoviridae of enveloped viruses, including Ebola virus (EBOV), Bundibugyo virus (BDBV), Sudan virus (SUDV) and Marburg virus (MARV), cause outbreaks of highly lethal disease in humans [1]
We explored a multifunctional cell-surface receptor, the cationindependent mannose-6-phosphate receptor/insulin-like growth factor 2 receptor, as an alternative endo/ lysosomal delivery strategy for monoclonal antibody (mAb) targeting the filovirus GPCL:Niemann-Pick C1 (NPC1) interaction
Bornholdt, and co-workers screened a large panel of human mAbs to identify broadly neutralizing antibodies targeting conserved ebolavirus GP epitopes outside the RBS and developed them into a cocktail, MBP134, with pan-ebolavirus breadth and protective efficacy against EBOV, BDBV, and SUDV in nonhuman primates [14, 15, 40]
Summary
Several members of the family Filoviridae of enveloped viruses (filoviruses), including Ebola virus (EBOV), Bundibugyo virus (BDBV), Sudan virus (SUDV) and Marburg virus (MARV), cause outbreaks of highly lethal disease in humans [1]. Monoclonal antibody (mAb) therapeutics, such as ZMappTM, REGN-EB3 (InmazebTM), and mAb114 (EbangaTM), have shown promise in human outbreaks, with the latter two having received FDA approval, they lack antiviral breadth [7,8,9,10]. These EBOV therapeutics cannot recognize and block infection by any other filovirus [7, 8, 11,12,13]. No mAb-based therapeutics with true pan-filovirus breadth have been identified to date, concordant with the limited conservation in the antigenic surface of the viral entry glycoprotein (GP) across filovirus species and differences in viral epitope shielding due to species-specific variations in GP glycosylation [16]
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