Recent successes in therapeutics for Ebola virus disease: no time for complacency

Iversen, Patrick L.; Kane, Christopher D.; Zeng, Xiankun; Panchal, Rekha G.; Warren, Travis K.; Radoshitzky, Sheli R.; Kuhn, Jens H.; Mudhasani, Rajini; Cooper, Christopher L.; Shurtleff, Amy C.; Nasar, Farooq; Sunay, Melek M.E.; Duplantier, Allen J.; Eaton, Brett; Zumbrun, Elizabeth E.; Bixler, Sandra L.; Martin, S De; Meinig, J. Matthew; Chiang, Chih-Yuan; Sánchez-Lockhart, Mariano; Palacios, Gustavo; Kugelman, Jeffrey R.; Martins, Karen; Pitt, M. Louise M.; Crozier, Ian; Saunders, David

doi:10.1016/s1473-3099(20)30282-6

Cited by 51 publications

(39 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Emerging viruses are a constant and unpredictable threat to human health. In the past two decades alone, the world has seen outbreaks of Ebola virus, 22 SARS, 23 Middle East Respiratory Syndrome (MERS), 24 2009 H1N1 swine flu, 25 Zika Virus, 26 and SARS CoV-2, 27 among others. Prophylactic vaccines often require long development timelines, for example, the recently approved Ebola virus vaccine required over 15 years of pre-clinical and clinical development before showing efficacy.…”

Section: Resultsmentioning

confidence: 99%

“…Prophylactic vaccines often require long development timelines, for example, the recently approved Ebola virus vaccine required over 15 years of pre-clinical and clinical development before showing efficacy. 28 Development of broadly neutralizing monoclonal antibodies is confounded by the difficulty of identifying broadly neutralizing epitopes, 22 which often requires years of research. Because of such issues, convalescent COVID-19 plasma has emerged as a promising approach to address the COVID-19 pandemic.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Capturing and Recreating Diverse Antibody Repertoires as Multivalent Recombinant Polyclonal Antibody Drugs

Keating

Mizrahi

Ms³

et al. 2020

Preprint

View full text Add to dashboard Cite

Plasma-derived polyclonal antibodies are polyvalent drugs used for many important clinical indications that require modulation of multiple drug targets simultaneously, including emerging infectious disease and transplantation. However, plasma-derived drugs suffer many problems, including low potency, impurities, constraints on supply, and batch-to-batch variation. In this study, we demonstrated proofs-of-concept for a technology that uses microfluidics and molecular genomics to capture diverse mammalian antibody repertoires as multivalent recombinant drugs. These “recombinant hyperimmune” drugs comprised thousands to tens of thousands of antibodies and were derived from convalescent human donors, or vaccinated human donors or immunized mice. Here we used our technology to build a highly potent recombinant hyperimmune for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) in less than three months. We also validated a recombinant hyperimmune for Zika virus disease that abrogates antibody-dependent enhancement (ADE) through Fc engineering. For patients with primary immune deficiency (PID), we built high potency polyvalent recombinant hyperimmunes against pathogens that commonly cause serious lung infections. Finally, to address the limitations of rabbit-derived anti-thymocyte globulin (ATG), we generated a recombinant human version and demonstrated in vivo function against graft-versus-host disease (GVHD). Recombinant hyperimmunes are a novel class of drugs that could be used to target a wide variety of other clinical applications, including cancer and autoimmunity.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Capturing and Recreating Diverse Antibody Repertoires as Multivalent Recombinant Polyclonal Antibody Drugs

Keating

Mizrahi

Ms³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Hence, mAbs and RITs could only be used therapeutically to address acute EVD. However, in combination with EBOV-specific small-molecule antivirals that cross such barriers, acute and persistent EBOV infection in immune-privileged sites of EVD survivors [ 52 ] could be addressed simultaneously and synergistically [ 53 ]. In addition, recent studies suggest that RITs could be modified to enhance entry in privileged sites [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

An immunotoxin targeting Ebola virus glycoprotein inhibits Ebola virus production from infected cells

et al. 2021

View full text Add to dashboard Cite

Ebola virus (EBOV), a member of the mononegaviral family Filoviridae, causes severe disease associated with high lethality in humans. Despite enormous progress in development of EBOV medical countermeasures, no anti-EBOV treatment has been approved. We designed an immunotoxin in which a single-chain variable region fragment of the EBOV glycoprotein-specific monoclonal antibody 6D8 was fused to the effector domains of Pseudomonas aeruginosa exotoxin A (PE38). This immunotoxin, 6D8-PE38, bound specifically to cells expressing EBOV glycoproteins. Importantly, 6D8-PE38 targeted EBOV-infected cells, as evidenced by inhibition of infectious EBOV production from infected cells, including primary human macrophages. The data presented here provide a proof of concept for immunotoxin-based targeted killing of infected cells as a potential antiviral intervention for Ebola virus disease.

show abstract

“…A variety of mAbs and mAb cocktails have been developed and initially evaluated in rodent and nonhuman primate (NHP) models ( 24 ), with Mab114 (a single antibody) ( 25 ) and REGN-EB3 (a cocktail of three antibodies) ( 26 ) shown to have superior efficacy in humans in a recent clinical trial conducted during the North Kivu/Ituri outbreak ( 27 ). Intriguingly, some cases of EVD recrudescence, such as those described above, have been associated with the use of EBOV-specific countermeasures, including mAb therapeutics and convalescent plasma ( 28 ). However, whether antibody-based therapeutics are directly linked to the development of EBOV persistence, recrudescence, or other clinical sequelae is a critical, but so far unanswered, question.…”

Section: Introductionmentioning

confidence: 99%

Atypical Ebola Virus Disease in a Nonhuman Primate following Monoclonal Antibody Treatment Is Associated with Glycoprotein Mutations within the Fusion Loop

Banadyga

Zhu

Kailasan

et al. 2021

mBio

View full text Add to dashboard Cite

Ebola virus (EBOV) is responsible for numerous devastating outbreaks throughout Africa, including the 2013–2016 West African outbreak as well as the two recent outbreaks in the Democratic Republic of the Congo (DRC), one of which is ongoing. Although EBOV disease (EVD) has typically been considered a highly lethal acute infection, increasing evidence suggests that the virus can persist in certain immune-privileged sites and occasionally lead to EVD recrudescence. Little is understood about the processes that contribute to EBOV persistence and recrudescence, in part because of the rarity of these phenomena but also because of the absence of an animal model that recapitulates them. Here, we describe a case of EBOV persistence associated with atypical EVD in a nonhuman primate (NHP) following inoculation with EBOV and treatment with an experimental monoclonal antibody cocktail. Although this animal exhibited only mild signs of acute EVD, it developed severe disease 2 weeks later and succumbed shortly thereafter. Viremia was undetectable at the time of death, despite abundant levels of viral RNA in most tissues, each of which appeared to harbor a distinct viral quasispecies. Remarkably, sequence analysis identified a single mutation in glycoprotein (GP) that not only resisted antibody-mediated neutralization but also increased viral growth kinetics and virulence. Overall, this report represents the most thoroughly characterized case of atypical EVD in an NHP described thus far, and it provides valuable insight into factors that may contribute to EBOV persistence and recrudescent disease. IMPORTANCE Ebola virus remains a global threat to public health and biosecurity, yet we still know relatively little about its pathogenesis and the complications that arise following recovery. With nearly 20,000 survivors from the 2013–2016 West African outbreak, as well as over 1,000 survivors of the recent outbreak in the DRC, we must consider the consequences of virus persistence and recrudescent disease, even if they are rare. In this study, we describe a case of atypical Ebola virus disease in a nonhuman primate after treatment with a monoclonal antibody. Not only does this study underscore the potential for atypical disease presentations, but it also emphasizes the importance of considering how medical countermeasures might relate to these phenomena, especially as antibodies are incorporated into the standard of care. The results presented herein provide a foundation from which we can continue to investigate these facets of Ebola virus disease.

show abstract

Recent successes in therapeutics for Ebola virus disease: no time for complacency

Cited by 51 publications

References 63 publications

Capturing and Recreating Diverse Antibody Repertoires as Multivalent Recombinant Polyclonal Antibody Drugs

Capturing and Recreating Diverse Antibody Repertoires as Multivalent Recombinant Polyclonal Antibody Drugs

An immunotoxin targeting Ebola virus glycoprotein inhibits Ebola virus production from infected cells

Atypical Ebola Virus Disease in a Nonhuman Primate following Monoclonal Antibody Treatment Is Associated with Glycoprotein Mutations within the Fusion Loop

Contact Info

Product

Resources

About