A Humanized Monoclonal Antibody Cocktail to Prevent Pulmonary Ricin Intoxication

Rong, Yinghui; Pauly, Michael; Guthals, Adrian; Pham, Henry; Ehrbar, Dylan; Zeitlin, Larry; Mantis, Nicholas J.

doi:10.3390/toxins12040215

Cited by 16 publications

(9 citation statements)

References 51 publications

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“…Moreover, they have a long half-life and can be used for prophylactic or therapeutic purposes [ 37 , 38 ]. Several studies have evaluated the protective capacity of different mAbs directed against RTA or RTB, and different strategies have been proposed to extend the therapeutic window or the efficacy, such as a combination of Abs targeting different epitopes of the different ricin subunits [ 24 , 39 , 40 ] or a combination with other agents such as doxycycline to reduce inflammation [ 41 ]. Depending on the origin of the ricin beans, the ricin amounts and composition might vary, due to differences in ricin D or E proportions, and/or posttranslational modifications, which might affect their toxicity and their recognition by Abs [ 4 , 19 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Ricin Antibodies’ Neutralizing Capacity against Different Ricin Isoforms and Cultivars

Delgado

Avril²,

Prigent

et al. 2021

Toxins

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Ricin, a highly toxic protein from Ricinus communis, is considered a potential biowarfare agent. Despite the many data available, no specific treatment has yet been approved. Due to their ability to provide immediate protection, antibodies (Abs) are an approach of choice. However, their high specificity might compromise their capacity to protect against the different ricin isoforms (D and E) found in the different cultivars. In previous work, we have shown the neutralizing potential of different Abs (43RCA-G1 (anti ricin A-chain) and RB34 and RB37 (anti ricin B-chain)) against ricin D. In this study, we evaluated their protective capacity against both ricin isoforms. We show that: (i) RB34 and RB37 recognize exclusively ricin D, whereas 43RCA-G1 recognizes both isoforms, (ii) their neutralizing capacity in vitro varies depending on the cultivar, and (iii) there is a synergistic effect when combining RB34 and 43RCA-G1. This effect is also demonstrated in vivo in a mouse model of intranasal intoxication with ricin D/E (1:1), where approximately 60% and 40% of mice treated 0 and 6 h after intoxication, respectively, are protected. Our results highlight the importance of evaluating the effectiveness of the Abs against different ricin isoforms to identify the treatment with the broadest spectrum neutralizing effect.

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Section: Discussionmentioning

confidence: 99%

Ricin Antibodies’ Neutralizing Capacity against Different Ricin Isoforms and Cultivars

Delgado

Avril²,

Prigent

et al. 2021

Toxins

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show abstract

“…The suggestion that there is a cryptic CRD in subdomain 1β is not entirely dismissible [ 41 ], but, at best, it contributes only a small fraction to cell attachment and even fully obstructing this element would not account for SylH3’s toxin-neutralizing activity. Irrespective of the mechanism of SylH3 action, the mAb has proven to have value prophylactically and therapeutically alone and when combined with an RTA-specific mAb, PB10, and used in mouse models of pulmonary ricin intoxication [ 39 , 42 ].…”

Section: Discussionmentioning

confidence: 99%

Sites of vulnerability on ricin B chain revealed through epitope mapping of toxin-neutralizing monoclonal antibodies

2020

Self Cite

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Ricin toxin’s B subunit (RTB) is a multifunctional galactose (Gal)-/N-acetylgalactosamine (GalNac)-specific lectin that promotes uptake and intracellular trafficking of ricin’s ribosome-inactivating subunit (RTA) into mammalian cells. Structurally, RTB consists of two globular domains (RTB-D1, RTB-D2), each divided into three homologous sub-domains (α, β, γ). The two carbohydrate recognition domains (CRDs) are situated on opposite sides of RTB (sub-domains 1α and 2γ) and function non-cooperatively. Previous studies have revealed two distinct classes of toxin-neutralizing, anti-RTB monoclonal antibodies (mAbs). Type I mAbs, exemplified by SylH3, inhibit (~90%) toxin attachment to cell surfaces, while type II mAbs, epitomized by 24B11, interfere with intracellular toxin transport between the plasma membrane and the trans-Golgi network (TGN). Localizing the epitopes recognized by these two classes of mAbs has proven difficult, in part because of RTB’s duplicative structure. To circumvent this problem, RTB-D1 and RTB-D2 were expressed as pIII fusion proteins on the surface of filamentous phage M13 and subsequently used as “bait” in mAb capture assays. We found that SylH3 captured RTB-D1 (but not RTB-D2) in a dose-dependent manner, while 24B11 captured RTB-D2 (but not RTB-D1) in a dose-dependent manner. We confirmed these domain assignments by competition studies with an additional 8 RTB-specific mAbs along with a dozen a single chain antibodies (VHHs). Collectively, these results demonstrate that type I and type II mAbs segregate on the basis of domain specificity and suggest that RTB’s two domains may contribute to distinct steps in the intoxication pathway.

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“…The suggestion that there is a cryptic CRD in subdomain 1β is not entirely dismissible [39], but, at best, it contributes only a small fraction to cell attachment and even fully obstructing this element would not account for SylH3’s toxin-neutralizing activity. Irrespective of the mechanism of SylH3 action, the mAb has proven to have value prophylactically and therapeutically alone and when combined with an RTA-specific mAb, PB10, and used in mouse models of pulmonary ricin intoxication [37, 40].…”

Section: Discussionmentioning

confidence: 99%

Sites of Vulnerability on Ricin B Chain Revealed through Epitope Mapping of Toxin-Neutralizing Monoclonal Antibodies

Vance

Poon

Mantis

2020

Preprint

Self Cite

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Ricin toxin’s B subunit (RTB) is a multifunctional galactose (Gal)-/N-acetylgalactosamine (GalNac)-specific lectin that promotes efficient uptake and intracellular trafficking of ricin’s ribosome-inactivating subunit (RTA) into mammalian cells. Structurally, RTB consists of two globular domains (RTB-D1, RTB-D2), each divided into three homologous sub-domains (α, β, γ). The two carbohydrate recognition domains (CRDs) are situated on opposite sides of RTB (sub-domains 1α and 2γ) and function non-cooperatively. Previous studies have revealed two distinct classes of toxin-neutralizing, anti-RTB monoclonal antibodies (mAbs). Type I mAbs, exemplified by SylH3, inhibit (∼90%) toxin attachment to cell surfaces, while type II mAbs, epitomized by 24B11, interfere with intracellular toxin transport between the plasma membrane and the trans-Golgi network (TGN). Localizing the epitopes recognized by these two classes of mAbs has proven difficult, in part because of RTB’s duplicative structure. To circumvent this problem, full-length RTB or the two individual domains, RTB-D1 and RTB-D2, were expressed as pIII fusion proteins on the surface of filamentous phage M13 and subsequently used as “bait” in mAb capture assays. The results indicated that SylH3 captured RTB-D1, while 24B11 captured RTB-D2. Analysis of additional toxin-neutralizing and non-neutralizing mAbs along with single chain antibodies (VHHs) known to compete with SylH3 or 24B11 confirmed these domain assignments. These results not only indicate that so-called type I and type II mAbs segregate on the basis of domain specificity, but suggest that RTB’s two domains may contribute to distinct steps in the intoxication pathway.

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A Humanized Monoclonal Antibody Cocktail to Prevent Pulmonary Ricin Intoxication

Cited by 16 publications

References 51 publications

Ricin Antibodies’ Neutralizing Capacity against Different Ricin Isoforms and Cultivars

Ricin Antibodies’ Neutralizing Capacity against Different Ricin Isoforms and Cultivars

Sites of vulnerability on ricin B chain revealed through epitope mapping of toxin-neutralizing monoclonal antibodies

Sites of Vulnerability on Ricin B Chain Revealed through Epitope Mapping of Toxin-Neutralizing Monoclonal Antibodies

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