Abstract
The Centers for Disease Control and Prevention have listed the potential bioweapon ricin as a Category B Agent. Ricin is a so-called A/B toxin produced by plants and is one of the deadliest molecules known. It is easy to prepare and no curative treatment is available. An immunotherapeutic approach could be of interest to attenuate or neutralise the effects of the toxin. We sought to characterise neutralising monoclonal antibodies against ricin and to develop an effective therapy. For this purpose, mouse monoclonal antibodies (mAbs) were produced against the two chains of ricin toxin (RTA and RTB). Seven mAbs were selected for their capacity to neutralise the cytotoxic effects of ricin in vitro. Three of these, two anti-RTB (RB34 and RB37) and one anti-RTA (RA36), when used in combination improved neutralising capacity in vitro with an IC50 of 31 ng/ml. Passive administration of association of these three mixed mAbs (4.7 µg) protected mice from intranasal challenges with ricin (5 LD50). Among those three antibodies, anti-RTB antibodies protected mice more efficiently than the anti-RTA antibody. The combination of the three antibodies protected mice up to 7.5 hours after ricin challenge. The strong in vivo neutralising capacity of this three mAbs combination makes it potentially useful for immunotherapeutic purposes in the case of ricin poisoning or possibly for prevention.
Highlights
Ricin is a 60–64 kDa glycoprotein of the A–B toxin family, found in the castor bean plant Ricinus communis [25]
Initial immunisation using 12.5 mg of r30">30]. The A-chain (RTA) led to death of the mice, which explains the lower doses of RTA as compared with RTB
Among a total of 1063 hybridomas from six fusions of spleen cells of mice immunised with RTA, 44 were found to secrete anti-RTA antibodies, and the best 11 clones were selected
Summary
Ricin is a 60–64 kDa glycoprotein of the A–B toxin family, found in the castor bean plant Ricinus communis [25]. The B-chain (RTB) is a galactose-specific lectin which folds into two globular domains, each binding a galactose or N-acetyl galactosamine residue present on glycoproteins and glycolipids at the cell surface [29]. This binding allows ricin to be internalised by endocytosis and retrograde transported to the endoplasmic reticulum where the interchain disulfide bonds are reduced [30]. The A-chain (RTA) is translocated to the cytosol, where its strong N-glycosidase activity depurinates an adenine residue of the 28 S ribosomal RNA loop contained within the 60 S subunit [10] This irreversible process inactivates elongation of polypeptides and leads to cell death
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