Durable Immunity to Ricin Toxin Elicited by Intranasally Administered Monoclonal Antibody–Based Immune Complexes

Tolman, Lindsey; Yates, Jennifer L.; Rong, Yinghui; Reynolds-Peterson, Claire; Ehrbar, Dylan; Torres-Vélez, Fernando J.; Mantis, Nicholas J.

doi:10.4049/immunohorizons.2100105

Cited by 4 publications

(13 citation statements)

References 59 publications

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“…The necessity of T cell help is particularly interesting, as previous work reported endogenous IgG generation within roughly 7 days of i.n. RICs administration [3]. This rapid timeline for a T-dependent adaptive response is unusual, as T cell activation alone can take 24 h [14], and germinal centers (GCs) typically do not begin forming until approximately 4 days after initial antigen exposure [15], with full formation about 7-10 days after antigen encounter [16].…”

Section: Discussionmentioning

confidence: 99%

“…For collection of BALF, 1mL of 0.6mM EDTA in PBS was used to flush the lungs intratracheally before recollection of fluid and storage at -80°C until use. Blood was procured from the submandibular vein and serum isolated as described previously [3]. prior to RICs immunization.…”

Section: Mouse Studiesmentioning

confidence: 99%

“…96-well high-binding microtiter plates (ThermoFisher Scientific) were coated overnight with ricin toxin (0.1 μg/well in PBS) at 4°C. The plates were then washed and blocked as previously described [3] before the addition of mouse sera or mAbs. Sera and mAbs were diluted in ELISA block solution (5% goat serum in 0.1% PBS-Tween).…”

Section: Cd4 + T Cellmentioning

confidence: 99%

“…immunization. We recently reported that intranasal administration of RICs to mice induces a rapid and durable serum anti-RT IgG response within 10-14 days without a detectable IgM phase [3]. To ascertain whether CD4 + T cells are involved in this response, groups of adult BALB/c mice were treated with anti-CD4 antibodies (400 μg by intraperitoneal injection) before and after intranasal RICs administration on study day 0.…”

Section: Role Of Cd4 + T Cells In Stimulating De Novo Rt-specific Igg...mentioning

confidence: 99%

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Inflammatory Profiles Induced following Intranasal Vaccination with Ricin Toxin-Immune Complexes

Tolman,

Mantis

2023

Preprint

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Ricin toxin (RT), a ribosome-inactivating protein derived from castor beans (Ricinus communis), is lethal in extremely small doses via inhalation, due in part to pulmonary inflammation triggeredby the toxin. While no licensed countermeasures for RT exists, a myriad of toxin-neutralizing monoclonal antibodies (mAbs) against RT’s enzymatic (RTA) and binding (RTB) subunits have been described, including PB10 (anti-RTA) and SylH3 (anti-RTB). We recently demonstrated that a single administration of PB10 and SylH3 as an RT immune complex (RIC) to mice by the intranasal route functions as a potent immunogen, stimulating the rapid onset of high titer toxin-neutralizing antibodies that persist for months. In this report, we demonstrate that the de novo antibody response following RICs exposure is wholly dependent on CD4+T cell help, as treatment of mice with an anti-CD4 monoclonal antibody abrogated the onset of RT-specific antibodies. To investigate other immunological factors associated with RICs, we examined the early local and systemic inflammatory cytokine and chemokine responses associated with intranasal RT and RIC administration. We report that RICs stimulate an inflammatory profile in the bronchoalveolar lavage fluids (BALF) and serum similar to that elicited by RT itself, but markedly reduced in magnitude. Of the 32 analytes examined, the most pronounced were IL-6, KC (CXCL1), G-CSF, and GM-CSF. To evaluate the role of IL-6 in driving the de novo onset of RT antibodies, groups of mice were treated (or not) with an IL-6 neutralizing monoclonal antibody prior to intranasal RICs challenge. While the monoclonal antibody treatment successfully depleted circulating IL-6 to levels below detection, it had no impact on the kinetics or magnitude of RICs-induced RT-specific antibody response. Thus, our results suggest that other cytokines/chemokines triggered by RICs are involved in influencing long lasting durable antibody responses to RT.

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Section: Discussionmentioning

confidence: 99%

Section: Mouse Studiesmentioning

confidence: 99%

Section: Cd4 + T Cellmentioning

confidence: 99%

Section: Role Of Cd4 + T Cells In Stimulating De Novo Rt-specific Igg...mentioning

confidence: 99%

See 2 more Smart Citations

Inflammatory Profiles Induced following Intranasal Vaccination with Ricin Toxin-Immune Complexes

Tolman,

Mantis

2023

Preprint

Self Cite

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“…In addition, it was confirmed that intranasal RIC administration was more effective than i.p. delivery in inducing immunity against intranasal RT exposure [ 99 ].…”

Section: Current Therapeutic Antibodiesmentioning

confidence: 99%

Medical Countermeasures against Ricin Intoxication

Rasetti-Escargueil

Avril²

2023

Toxins

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Ricin toxin is a disulfide-linked glycoprotein (AB toxin) comprising one enzymatic A chain (RTA) and one cell-binding B chain (RTB) contained in the castor bean, a Ricinus species. Ricin inhibits peptide chain elongation via disruption of the binding between elongation factors and ribosomes, resulting in apoptosis, inflammation, oxidative stress, and DNA damage, in addition to the classically known rRNA damage. Ricin has been used in traditional medicine throughout the world since prehistoric times. Because ricin toxin is highly toxic and can be readily extracted from beans, it could be used as a bioweapon (CDC B-list). Due to its extreme lethality and potential use as a biological weapon, ricin toxin remains a global public health concern requiring specific countermeasures. Currently, no specific treatment for ricin intoxication is available. This review focuses on the drugs under development. In particular, some examples are reviewed to demonstrate the proof of concept of antibody-based therapy. Chemical inhibitors, small proteins, and vaccines can serve as alternatives to antibodies or may be used in combination with antibodies.

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A Monoclonal Antibody with a High Affinity for Ricin Isoforms D and E Provides Strong Protection against Ricin Poisoning

Lequesne,

Dano,

Rouaix

et al. 2024

Toxins

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Ricin is a highly potent toxin that has been used in various attempts at bioterrorism worldwide. Although a vaccine for preventing ricin poisoning (RiVax™) is in clinical development, there are currently no commercially available prophylaxis or treatments for ricin intoxication. Numerous studies have highlighted the potential of passive immunotherapy using anti-ricin monoclonal antibodies (mAbs) and have shown promising results in preclinical models. In this article, we describe the neutralizing and protective efficacy of a new generation of high-affinity anti-ricin mAbs, which bind and neutralize very efficiently both ricin isoforms D and E in vitro through cytotoxicity cell assays. In vivo, protection assay revealed that one of these mAbs (RicE5) conferred over 90% survival in a murine model challenged intranasally with a 5 LD50 of ricin and treated by intravenous administration of the mAbs 6 h post-intoxication. Notably, a 35% survival rate was observed even when treatment was administered 24 h post-exposure. Moreover, all surviving mice exhibited long-term immunity to high ricin doses. These findings offer promising results for the clinical development of a therapeutic candidate against ricin intoxication and may also pave the way for novel vaccination strategies against ricin or other toxins.

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Durable Immunity to Ricin Toxin Elicited by Intranasally Administered Monoclonal Antibody–Based Immune Complexes

Cited by 4 publications

References 59 publications

Inflammatory Profiles Induced following Intranasal Vaccination with Ricin Toxin-Immune Complexes

Inflammatory Profiles Induced following Intranasal Vaccination with Ricin Toxin-Immune Complexes

Medical Countermeasures against Ricin Intoxication

A Monoclonal Antibody with a High Affinity for Ricin Isoforms D and E Provides Strong Protection against Ricin Poisoning

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