Abstract
Ricin toxin’s binding subunit (RTB) is a galactose-/N-acetylgalactosamine (Gal/GalNac)-specific lectin that mediates uptake and intracellular trafficking of ricin within mammalian cells. Structurally, RTB consists of two globular domains, each divided into three homologous sub-domains (α, β, γ). In this report, we describe five new murine IgG monoclonal antibodies (mAbs) against RTB: MH3, 8A1, 8B3, LF1, and LC5. The mAbs have similar binding affinities (KD) for ricin holotoxin, but displayed a wide range of in vitro toxin-neutralizing activities. Competition ELISAs indicate that the two most potent toxin-neutralizing mAbs (MH3, 8A1), as well as one of the moderate toxin-neutralizing mAbs (LF1), recognize distinct epitopes near the low affinity Gal recognition domain in RTB subdomain 1α. Evaluated in a mouse model of systemic ricin challenge, all five mAbs afforded some benefit against intoxication, but only MH3 was protective. However, neither MH3 nor 24B11, another well-characterized mAb against RTB subdomain 1α, could passively protect mice against a mucosal (intranasal) ricin challenge. This is in contrast to SylH3, a previously characterized mAb directed against an epitope near RTB’s high affinity Gal/GalNac recognition element in sub-domain 2γ, which protected animals against systemic and mucosal ricin exposure. SylH3 was significantly more effective than MH3 and 24B11 at blocking ricin attachment to host cell receptors, suggesting that mucosal immunity to ricin is best imparted by antibodies that target RTB’s high affinity Gal/GalNac recognition element in subdomain 2γ, not the low affinity Gal recognition domain in subdomain 1α.
Highlights
Ricin toxin exposure by injection or inhalation triggers immediate severe local and systemic inflammatory responses that are accompanied by widespread necrosis and fibrosis [1, 2]
We report the production and characterization of five new Ricin toxin’s binding subunit (RTB)-specific murine IgG monoclonal antibodies (mAbs): MH3, 8A1, 8B3, LF1, and LC5
In an effort to isolate additional RTB-specific mAbs against RTB, groups of BALB/c mice were immunized as described in the Materials and Methods
Summary
Ricin toxin exposure by injection or inhalation triggers immediate severe local and systemic inflammatory responses that are accompanied by widespread necrosis and fibrosis [1, 2]. Uptake of ricin into mammalian cells, including lung epithelial cells, is mediated by ricin’s binding subunit (RTB), a galactose- and N-acetylgalactosamine (Gal/GalNAc)-specific lectin. B cell epitopes on RTB collection and analysis, decision to publish, or preparation of the manuscript
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