Ricin clinical trials

Clinically, monoclonal antibodies are also proposed as drug delivery vehicles in certain tumors where specific tumor-associated antigens are expressed. In this context, investigators have found that by conjugating toxins such as the A chain polypeptide of the plant protein ricin or the bacterial toxin from Corynebacterium diphtheriae to monoclonal antibodies specific for certain tumor type, as few as one or two molecules of antibody-toxin conjugate can destroy a tumor cell in vitro. Some success has also been obtained in clinical trials with monoclonal antibody-toxin conjugates. 

The lethal dose of ricin by injection for humans is unknown, but it has been estimated to be in the range of 1-10 pg/kg bodyweight based on analogy with NHP studies and from extrapolation of human clinical trials (see below). 

Consistent with animal studies comparing RTA and ricin, humans tolerate much higher levels of RTA than ricin. In Phase I/II clinical trials of two experimental IgTs containing dgRTA administered (i.v.) to Hodgkins lymphoma patients, for example, dose-limiting toxicity was observed at levels of approximately 15 mg/m (about 0.5 mg/kg) (Schnell et al., 2003). 

By comparing the maximum sublethal doses for laboratory mice with the maximum tolerated doses (MTDs) obtained from human clinical trials, and assuming a similar LD50/MTD ratio for the two species, an estimate of the LD50 of ricin or abrin for humans would be about 0.6-1 pg/kg (i.v.)... 

The aerosol toxicity of ricin has been documented in several laboratory animals, including rhesus (Wilhelmsen and Pitt, 1996) and African green monkeys, but it remains unclear which, if any, of these effectively model the human response to ricin. Is it necessary to conduct animal trials with medical countermeasures for ricin in an NHP aerosol model, or will other animal models suffice to predict the human response The unexpected appearance of VLS in human clinical trials underscores the difficulty in extrapolating from animal models. Data addressing these questions will be critical in devising practical and effective strategies for coping with ricin as a toxin weapon. 

Schnell, R., Vitetta, E., Schindler, J., Barth, S., Winkler, U., Borchmann, P., Hansmann, M.L., Diehl, V., Ghetie, V. and Engert, A. (1998) Clinical trials with an anti-CD25 ricin A-chain experimental and immunotoxin (RFT5-SMPT-dgA) in Hodgkin s lymphoma. Leuk Lymphoma, 30, 525-537. 

Vitetta, E.S., Smallshaw, J.E., Coleman, E., Jafri, H., Eoster, C., Munford, R. and Schindler, J. (2006) A pilot clinical trial of a recombinant ricin vaccine in normal humans. Proc Natl Acad Sci USA, 103, 2268-2273. 

Schindler J, Sausville E, Messmann R et al. (2001). The toxicity of deglycosylated ricin A-chain-containing immunotoxins in patients with non-Hodgkin s lymphoma is exacerbated by prior radiotherapy a retrospective analysis of patients in five clinical trials. Clin Cancer Res, 7, 255-258. 

In one large clinical trial,40 low doses (18-20 pg/ m2) of intravenous ricin administered to cancer patients were well tolerated. Flulike symptoms with fatigue—in some cases very pronounced fatigue— and muscular pain were common, and sometimes nausea and vomiting occurred. The symptoms began 4 to 6 hours after administration and lasted for 1 to 2 days. Two toxic deaths were reported in Phase I clinical trails of the closely related protein toxin, abrin these patients had general seizures and other signs of central nervous system toxicity. 

The exact cause of death is unknown and probably varies with route of intoxication. Results of ricin A-chain immunotoxin clinical trial studies demonstrated that ricin A-chain caused a vascular leak syndrome characterized by hypoalbuminemia and edema subsequent in vitro studies with human umbilical vein endothelial cells showed that ricin damaged endothelial cells.45 In mice, rats, and primates, high doses via inhalation appear to produce severe enough pulmonary damage to cause death,... 

Ricin, a type II RIP found in the bean of the castor plant, has been extensively used for targeted tumor therapies replacing the lectin B chain, which binds to almost all mammalian cells, with peptides, antibodies, or proteins targeting cancer cells leads to selective target toxicity [105]. Several clinical trials by this approach have been conducted (see Section 7). 

---