Therapy for Argentine hemorrhagic fever in nonhuman primates with a humanized monoclonal antibody

Zeitlin, Larry; Cross, Robert W.; Geisbert, Joan B.; Borisevich, Viktoriya; Agans, Krystle N.; Prasad, Abhishek N.; Enterlein, Sven; Aman, M. Javad; Bornholdt, Zachary A.; Brennan, Miles B.; Campbell, Lioudmila; Kim, Do; Mlakar, Neil; Moyer, Crystal L.; Pauly, Michael; Shestowsky, William S.; Whaley, Kevin J.; Fenton, Karla A.

doi:10.1073/pnas.2023332118

Cited by 11 publications

(7 citation statements)

References 21 publications

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“…The generation of NAbs has been shown to be effective for the prevention and treatment of HF arenaviral infection ( 6 , 7 , 30 ). Here, we utilized a mouse model of MACV and JUNV live-attenuated immunization combined with antigen-specific B cell sorting to isolate a NAb specific to MACV GP1 (termed MAC1) and seven NAbs specific to JUNV GP1 (termed JUN1 to -7), which recognize an overlapping epitope.…”

Section: Introductionmentioning

confidence: 99%

Contrasting Modes of New World Arenavirus Neutralization by Immunization-Elicited Monoclonal Antibodies

Mehmet

Krumm

et al. 2022

mBio

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The GP1 subcomponent of the New World arenavirus GP is a primary target of the neutralizing antibody response, which has been shown to be effective in the prevention and treatment of infection. Here, we characterize the structural basis of the antibody-mediated immune response that arises from immunization of mice against Junín virus and Machupo virus, two rodent-borne zoonotic New World arenaviruses.

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Section: Introductionmentioning

confidence: 99%

Contrasting Modes of New World Arenavirus Neutralization by Immunization-Elicited Monoclonal Antibodies

Mehmet

Krumm

et al. 2022

mBio

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“…These findings revealed that targeting anti-glycoprotein antibodies is sufficient for protection. Our work was subsequently supported by data showing that neutralizing monoclonal antibodies targeting GP1 alone are sufficient to protect guinea pigs and non-human primates against JUNV infection [22,23]. Here, we investigated the protective efficacy of neutralizing polyclonal antibodies targeting MACV strain Carvallo GPc against an otherwise lethal infection with the MACV strain Chicava.…”

Section: Introductionmentioning

confidence: 94%

Glycoprotein-Specific Polyclonal Antibodies Targeting Machupo Virus Protect Guinea Pigs against Lethal Infection

Golden,

Kwilas,

Hooper

2024

Vaccines

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Convalescent plasma has been shown to be effective at protecting humans against severe diseases caused by New World (NW) arenaviruses, including Junin virus (JUNV) and Machupo virus (MACV). This plasma contains antibodies against the full complement of structural proteins including the nucleocapsid and envelope glycoproteins (GPcs) consisting of GP1 and GP2. To gain insights into the protective and cross-protective properties of anti-GPc-specific polyclonal antibodies, we evaluated the ability of a DNA vaccine-produced anti-GPc rabbit antisera targeting MACV strain Carvallo to provide heterologous protection against another MACV strain termed Chicava in the Hartley guinea pig model. The neutralizing activity of the rabbit antisera against the heterologous MACV strains Chicava and Mallale was found to be 54-fold and 23-fold lower, respectively, compared to the titer against the homologous MACV strain Carvallo in the PRNT50 assay. Despite lower neutralizing activity against the strain Chicava, the rabbit antisera protected 100% of the guinea pigs from this strain when administered up to four days post-infection, whereas all the control animals succumbed to the disease. Using vesicular stomatitis virus (VSV) particles pseudotyped with MACV GPc, we identified a single amino acid difference at position 122 between the strains Chicava and Carvallo GPc that significantly influenced the neutralization activity of the rabbit antisera. These findings indicate that polyclonal antibodies targeting the MACV glycoproteins can protect against lethal infection in a post-challenge setting. These data will help guide future antibody-based therapeutics development against NW arenaviruses.

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“…Neutralizing mAbs to Junín virus have also been identified that protect guinea pigs and nonhuman primates from infection ( Zeitlin et al, 2016 , 2021 ). Immunization-elicited antibodies against NWAs that block binding of their GPs to human TfR1 (hTfR1) have also been isolated and could be used therapeutically ( Amanat et al, 2020 ; Ng et al, 2022 ).…”

Section: Antibodiesmentioning

confidence: 99%

Entry inhibitors as arenavirus antivirals

Iyer,

Yan,

Ross

2024

Front. Microbiol.

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Arenaviruses belonging to the Arenaviridae family, genus mammarenavirus, are enveloped, single-stranded RNA viruses primarily found in rodent species, that cause severe hemorrhagic fever in humans. With high mortality rates and limited treatment options, the search for effective antivirals is imperative. Current treatments, notably ribavirin and other nucleoside inhibitors, are only partially effective and have significant side effects. The high lethality and lack of treatment, coupled with the absence of vaccines for all but Junín virus, has led to the classification of these viruses as Category A pathogens by the Centers for Disease Control (CDC). This review focuses on entry inhibitors as potential therapeutics against mammarenaviruses, which include both New World and Old World arenaviruses. Various entry inhibition strategies, including small molecule inhibitors and neutralizing antibodies, have been explored through high throughput screening, genome-wide studies, and drug repurposing. Notable progress has been made in identifying molecules that target receptor binding, internalization, or fusion steps. Despite promising preclinical results, the translation of entry inhibitors to approved human therapeutics has faced challenges. Many have only been tested in in vitro or animal models, and a number of candidates showed efficacy only against specific arenaviruses, limiting their broader applicability. The widespread existence of arenaviruses in various rodent species and their potential for their zoonotic transmission also underscores the need for rapid development and deployment of successful pan-arenavirus therapeutics. The diverse pool of candidate molecules in the pipeline provides hope for the eventual discovery of a broadly effective arenavirus antiviral.

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Therapy for Argentine hemorrhagic fever in nonhuman primates with a humanized monoclonal antibody

Cited by 11 publications

References 21 publications

Contrasting Modes of New World Arenavirus Neutralization by Immunization-Elicited Monoclonal Antibodies

Contrasting Modes of New World Arenavirus Neutralization by Immunization-Elicited Monoclonal Antibodies

Glycoprotein-Specific Polyclonal Antibodies Targeting Machupo Virus Protect Guinea Pigs against Lethal Infection

Entry inhibitors as arenavirus antivirals

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