Research Article: The Need for Continued Development of Ricin Countermeasures

Date Published: March 26, 2012

Publisher: Hindawi Publishing Corporation

Author(s): Ronald B. Reisler, Leonard A. Smith.

http://doi.org/10.1155/2012/149737

Abstract

Ricin toxin, an extremely potent and heat-stable toxin produced from the bean of the ubiquitous Ricinus communis (castor bean plant), has been categorized by the US Centers for Disease Control and Prevention (CDC) as a category B biothreat agent that is moderately easy to disseminate. Ricin has the potential to be used as an agent of biological warfare and bioterrorism. Therefore, there is a critical need for continued development of ricin countermeasures. A safe and effective prophylactic vaccine against ricin that was FDA approved for “at risk” individuals would be an important first step in assuring the availability of medical countermeasures against ricin.

Partial Text

In the aftermath of September 11, 2001, it has become increasingly clear that there is a need to enhance readiness against attack from both state sponsors and nonstate sponsors of bioterrorism. Ricin toxin, an extremely potent and heat-stable toxin produced from the bean of the Ricinus communis (castor bean plant) [1], has been categorized by the US Centers for Disease Control and Prevention (CDC) as a category B biothreat agent for biological warfare and bioterrorism [2]. In fact, according to Cookson and Nottingham, ricin was code named compound W and considered for weaponization during the US offensive Biological Warfare Program [3]. The US intelligence community believes that ricin was a component of the biowarfare program of the former Soviet Union, Iraq, and possibly other countries as well [4, 5].

Ricin is a 65 kilodalton (kDa) polypeptide toxin comprised of two dissimilar polypeptide chains (an A-chain and a B-chain) held together by a disulfide bond [1, 4, 5]. The A-chain, ~32 kDa, targets the ribosome and is therefore a potent inhibitor of protein synthesis [4, 5]. Consequently, the A-chain has been classified as a ribosome-inactivating protein (RIP) [4, 5]. The B-chain, ~34 kDa, is a galactose or an N-acetylgalactosamine-binding lectin that attaches to cell-surface receptors [4, 5]. After binding and subsequent endocytosis, the holotoxin travels through the Golgi apparatus to the endoplasmic reticulum where the disulfide bond linking the A and B chains is reduced. Once the disulfide bond is broken, the A-chain molecule is transported to the cytosol where it inactivates the ribosome. In fact, just one ricin molecule per cell may be sufficient to permanently inhibit that cell from performing essential cellular protein synthesis [6].

Initially, as early as the 1890s, Paul Ehrlich vaccinated mice with oral doses of ricin and then subsequently challenged the mice with subcutaneous lethal doses of ricin [10]. Later, in the 1940s, a formalin-inactivated holotoxin vaccine was developed by the US Army that enhanced survival in animals [11]. This vaccine candidate did not progress past preclinical testing. Pretreating animals with passive transfer of either IgG polyclonal antibody [12–14] or monoclonal directed against RTA, appeared to effectively protect them from lethal parenteral challenge to ricin [15–17]. Protection against a lethal dose of aerosolized ricin with passive transfer of either IgG polyclonal or monoclonal antibody directed against RTA has proved to be more difficult to achieve.

Neal et al. reported that passive prophylactic administration (intraperitoneal {IP} injection) of GD12 (a murine IgG1 monoclonal antibody (Mab)—anti-RTA) when administered 24 h prior to challenge was sufficient to protect mice against intraperitoneal ricin challenge of 5 LD50 [37]. Neal et al. further demonstrated that GD12 protected mice utilizing a backpack tumor delivery system after intragastric ricin challenge of 5 mg/kg. Neal et al. did not test GD12 in the setting of post-exposure prophylaxis. In a follow-up study, Neal et al. demonstrated similar protection in mice when two other monoclonal antibodies, R70 (anti-RTA) and 24B11 (anti-RTB), were passively administered using the so-called backpack tumor model [38]. The mice then survived challenge with intragastric ricin 5 mg/kg 12–24 h. In addition, R70 Mab protected mice after it was administered IP, 12–24 h before intragastric ricin challenge of 5 mg/kg.

Stechmann et al. have recently reported on the successful identification of a selective small molecule inhibitor, Retro-2, that protected mice in a ricin nasal challenge model, when Retro-2 was administered IP one hour prior to challenge [40]. This small molecule inhibitor is attractive in that it does not act on the toxin itself, but rather it blocks retrograde transport of the toxin, a host-toxin interaction. Stechmann et al. argue that since Retro-2 blocks retrograde transport and does not act on the toxin or the host cell itself, there is a decreased likelihood that significant drug resistance will develop to Retro-2. Moreover, Retro-2 appears to be nontoxic to HeLa cells. Small molecules inhibitors offer another promising potential avenue for the development of effective prophylaxis against ricin toxin exposure [41].

Schep et al. have recently argued somewhat simplistically that although ricin is toxic, it does not deserve to be a priority in biological countermeasure development [9]. They maintain that bioterrorists do not possess the technical and logistical skills necessary to formulate and mill ricin powder. St. Georgiev similarly maintained that ricin is more compatible with a tool of assassination instead of a weapon of mass destruction [42]. However, Radosavljevic and Belojevic have recently formulated a much more compelling and comprehensive approach to biodefense prioritization and risk assessment [8]. Their approach incorporates all of the potential biothreat agents on the CDC biothreat agent list. Furthermore, their model considers quantitative and qualitative parameters in assessing risk and has four main components: perpetrators (government institutions/organizations, terrorist groups, individuals); agent (CDC categories A, B, and C); means and media of delivery (air, food, water, fomites); target (direct and indirect) [8].

While small molecule inhibitors and Mabs for post-exposure treatment are still being evaluated in a pre-clinical setting, RiVax has been studied in two phase I clinical trials, and RVEc is currently in a phase I human trials. A safe and effective prophylactic vaccine against ricin that is FDA approved for “at risk” individuals should be an important first step in countering this 120-year-old threat.

 

Source:

http://doi.org/10.1155/2012/149737

 

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