Rescue of rhesus macaques from the lethality of aerosolized ricin toxin

Roy, Chad J.; Ehrbar, Dylan; Bohorova, Natasha; Bohorov, Ognian; Kim, Do; Pauly, Michael; Whaley, Kevin J.; Rong, Yinghui; Torres-Vélez, Fernando J.; Vitetta, Ellen S.; Didier, Peter J.; Doyle-Meyers, Lara A.; Zeitlin, Larry; Mantis, Nicholas J.

doi:10.1172/jci.insight.124771

Cited by 29 publications

(44 citation statements)

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“…AMs are hypersensitive to the effects of ricin, possibly due to high levels of MR expression . The success of PB10 + SylH3 in that study and the current study has prompted us to generate a humanized version of SyH3 with the goal of testing it in combination with humanized PB10 in the Rhesus macaque model …”

Section: Discussionmentioning

confidence: 88%

“…For example, we recently demonstrated that i.v. delivery of a single MAb, PB10, directed against RTA was able to rescue Rhesus macaques from lethal dose aerosol challenge if administered within a 4 h window . In that model, ricin intoxication is largely restricted to the lung with little systemic involvement .…”

Section: Introductionmentioning

confidence: 98%

“…In this report, we sought to revisit the sensitivity of KCs and LSECs to ricin in light of efforts to develop MAb‐based therapies and prophylactics for ricin exposure . For example, we recently demonstrated that i.v.…”

Section: Introductionmentioning

confidence: 99%

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Sensitivity of Kupffer cells and liver sinusoidal endothelial cells to ricin toxin and ricin toxin–Ab complexes

Mooney

Torres-Vélez

Doering

et al. 2019

Journal of Leukocyte Biology

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Ricin toxin is a plant‐derived, ribosome‐inactivating protein that is rapidly cleared from circulation by Kupffer cells (KCs) and liver sinusoidal endothelial cells (LSECs)—with fatal consequences. Rather than being inactivated, ricin evades normal degradative pathways and kills both KCs and LSECs with remarkable efficiency. Uptake of ricin by these 2 specialized cell types in the liver occurs by 2 parallel routes: a “lactose‐sensitive” pathway mediated by ricin's galactose/N‐acetylgalactosamine‐specific lectin subunit (RTB), and a “mannose‐sensitive” pathway mediated by the mannose receptor (MR; CD206) or other C‐type lectins capable of recognizing the mannose‐side chains displayed on ricin's A (RTA) and B subunits. In this report, we investigated the capacity of a collection of ricin‐specific mouse MAb and camelid single‐domain (VHH) antibodies to protect KCs and LSECs from ricin‐induced killing. In the case of KCs, individual MAbs against RTA or RTB afforded near complete protection against ricin in ex vivo and in vivo challenge studies. In contrast, individual MAbs or VHHs afforded little (<40%) or even no protection to LSECs against ricin‐induced death. Complete protection of LSECs was only achieved with MAb or VHH cocktails, with the most effective mixtures targeting RTA and RTB simultaneously. Although the exact mechanisms of protection of LSECs remain unknown, evidence indicates that the Ab cocktails exert their effects on the mannose‐sensitive uptake pathway without the need for Fcγ receptor involvement. In addition to advancing our understanding of how toxins and small immune complexes are processed by KCs and LSECs, our study has important implications for the development of Ab‐based therapies designed to prevent or treat ricin exposure should the toxin be weaponized.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 98%

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Sensitivity of Kupffer cells and liver sinusoidal endothelial cells to ricin toxin and ricin toxin–Ab complexes

Mooney

Torres-Vélez

Doering

et al. 2019

Journal of Leukocyte Biology

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“…The benefit of the PB10/SylH3 MAb cocktail over PB10 alone in the PrEP model incentivized us to produce a humanized variant of SylH3 that could be paired with huPB10 for eventual testing in NHPs [12]. The chimeric mouse Fv-human IgG1 Fc variant of SylH3 constructed several years ago was used as the starting material [22].…”

Section: Resultsmentioning

confidence: 99%

“…Intervention studies with toxin-neutralizing monoclonal antibodies (MAbs) in mice and NHPs have demonstrated the intoxication process can be reversed, but only if MAbs are administered within a short window after RT exposure [12]. In a recent study conducted in Rhesus macaques, the five animals that received a single intravenous fusion of a humanized MAb, huPB10, within 4 h after 3 x LD 50 RT aerosol exposure survived toxin challenge, whereas only a single animal that received huPB10 at 12 h survived RT intoxication [12]. These results largely mimicked what had been previously reported in mouse studies with the murine version of PB10, demonstrating a degree of congruence between the two animal models.…”

Section: Introductionmentioning

confidence: 99%

A Humanized Monoclonal Antibody Cocktail to Prevent Pulmonary Ricin Intoxication

Rong

Pauly

Guthals

et al. 2020

Toxins

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PB10 IgG1, a monoclonal antibody (MAb) directed against an immunodominant epitope on the enzymatic subunit (RTA) of ricin toxin (RT), has been shown to passively protect mice and non-human primates from an aerosolized lethal-dose RT challenge. However, it was recently demonstrated that the therapeutic efficacy of PB10 IgG1 is significantly improved when co-administered with a second MAb, SylH3, targeting RT’s binding subunit (RTB). Here we report that the PB10/SylH3 cocktail is also superior to PB10 alone when used as a pre-exposure prophylactic (PrEP) in a mouse model of intranasal RT challenge. The benefit of the PB10/SylH3 cocktail prompted us to engineer a humanized IgG1 version of SylH3 (huSylH3). The huPB10/huSylH3 cocktail proved highly efficacious in the mouse model, thereby opening the door to future testing in non-human primates.

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