Speciifcally, in 2012, the use of purified polyclonal antibodies from the sera of vaccinated NHPs against the EBOV GP (treatment initiated 2 days post-challenge with EBOV) resulted in 100% survival from EBOV disease [2]

Speciifcally, in 2012, the use of purified polyclonal antibodies from the sera of vaccinated NHPs against the EBOV GP (treatment initiated 2 days post-challenge with EBOV) resulted in 100% survival from EBOV disease [2]. Emergence of EBOV Monoclonal Immunotherapy Before the 2012 polyclonal antibody report, the monoclonal antibody (mAb) KZ52, which binds to and neutralizes the EBOV GP, was identified from an EBOV survivor [3]. number of cases in the 1976 and 1995 EBOV outbreaks. Clinical trials using convalescent blood-based products were initiated in Sierra Leone, Liberia, and Guinea, where the results of one of the trials showed no benefit of convalescent plasma; similar results have been observed in NHP studies, suggesting that putative protection with this resource does not constitute an effective immunotherapy against EBOV [1]. Although these and other data have suggested that efficacious passive immunotherapy against EBOV was not achievable, the field Ca2+ channel agonist 1 continued to pursue this therapy from various angles, resulting in the first report of a successful passive immunotherapy (polyclonal or monoclonal) against EBOV in NHPs [2]. Speciifcally, in 2012, the use of purified polyclonal antibodies from the sera of vaccinated NHPs against the EBOV GP (treatment initiated 2 days post-challenge with EBOV) resulted in 100% survival from EBOV disease [2]. Emergence of EBOV Monoclonal Immunotherapy Before the 2012 polyclonal antibody report, the monoclonal antibody (mAb) KZ52, which binds to and neutralizes the EBOV GP, was identified from an EBOV survivor [3]. KZ52 was observed to neutralize EBOV infection in cell cultures and in a guinea pig-adapted EBOV model but unfortunately was not efficacious in a NHP model of EBOV infection [3]. The KZ52 mAb immunotherapy failure in the gold-standard NHP model was discouraging; however, as polyclonal immunotherapy continued to Ca2+ channel agonist 1 be examined, so was mAb immunotherapy. In 2012 two different laboratories identified mAb combinations directed against the EBOV GP that were efficacious against EBOV challenge in the NHP model. These mAb combinations were designated ZMab (2G4, 4G7, and 1H3) [4] and MB-003 (6D8, 13F6, and 13C6) [5]. Through subsequent collaborations, three of the mAbs (2G4, 4G7, and 13F6) were combined to form ZMapp, which completely protected NHPs from lethal EBOV challenge even when administered as late as 5 days following virus exposure [6]. While impressive, this cocktail is specific only for the EBOV GP and not the GPs of other ebolavirus species. However, these successful NHP studies led to a clearer picture of the sites on the EBOV GP that were vulnerable to mAbs and that might also confer protection in humans [7]. The anti-EBOV Ca2+ channel agonist 1 GP mAbs discussed to this point are not an exhaustive list, but represent the state of the art in anti-EBOV GP mAbs at a time when polyclonal or mAb immunotherapy against EBOV was only Pax1 an afterthought, especially when considering immunotherapies against other ebolavirus species (Figure 1). Open in a separate window Figure 1 Ebolavirus Glycoprotein (GP) and Neutralizing Antibodies. Top panel: Cartoon of an ebolavirus GP trimer showing the putative mucin-like domains that theoretically block the more conserved (amino acid) receptor binding sites, rendering binding to the fusion loop region of the GP less accessible. After proteolytic cleavage (GPCL), these sites become accessible during entry into the host cell; the monoclonal antibodies (mAbs) CA45 and ADI-15878/15742 both bind the GPs depicted but also bind to GPCL with higher affinity. Bottom panel: mAb-binding sites and antibody-binding angles for KZ52 (blue), 2G4 (purple), 4G7 (yellow), 13C6 (green), CA45 (orange), and ADI-15878/15472 (rainbow). Note that KZ52, 2G4, 4G7, CA45, and ADI-15878/15472 all bind in areas in close proximity to one another; however, the regions where CA45 and ADI-15878/15472 bind are conserved at the amino acid level between EBOV, SUDV, and BDBV, leading to improved affinity and therapeutic efficacy against all three GPs in small animal models (EBOV: mouse, guinea pig; SUDV: mouse, guinea pig; BDBV: ferret). More Than One Ebolavirus Threat From late 2013 through 2016, the world was concerned about media reports of the EBOV outbreak turned epidemic occurring in West Africa. One point that may not have been apparent from these reports is that this epidemic was caused by only one of a number of different species of ebolavirus. Of the five known ebolavirus species, EBOV, SUDV, and BDBV have resulted in lethal outbreaks in humans. Before 2013, the vast majority of ebolavirus outbreaks occurred in Central Africa. Of particular interest, outbreaks of EBOV, SUDV, and BDBV occurred in the Democratic Republic of Congo (DRC) or on the borders of the Ca2+ channel agonist 1 DRC in South.