How can we use nature’s poisons to our benefit?
Ricin is a protein toxin that is extracted from the castor bean. Photo: Agricultural Reasearch Service, USDA.
Vitetta: Most people know that ricin is a potential biological weapon, but it can also be harnessed for biomedicine. My research involves using a portion of the ricin toxin to develop a new class of therapeutics, called “immunotoxins.” Over the past few decades, immunotoxins have been taken from discovery to clinical trials in patients with a variety of cancers. In addition, emerging from this medical work was the development of a new and effective vaccine against ricin, which completed its first successful clinical trial in 2005. The vaccine was safe and induced antibody production in human volunteers.
Ricin, a natural toxin, is a byproduct of castor oil production. Ricin is very easy to obtain, with an estimated 50,000 tons available in the world today. Castor beans grow wild everywhere, and you don’t really need a whole lot of expertise to purify it. In fact, you don’t even need to purify it. If you mash up castor beans you basically get a crude toxin powder that is very stable. Ricin can be used to contaminate food, water, or air and in high enough levels is fatal when ingested or breathed in. Anyone can pull up information on the Internet about ricin production—sad but true. The fact that it is easy to get, easy to work with, and so toxic makes it very worrisome. It is quite different from something like anthrax, where you must have the scientific know-how to make it.
Immunotoxins are made by linking a tumor-seeking antibody to a portion of the ricin toxin. [An antibody is a protein molecule that defends the body against germs or harmful compounds; some antibodies are synthetic]. Once bound to the cancer cell, it is internalized and kills it, but because the antibody targets only cancer cells, it spares normal cells. When you think of the damaging side effects of current cancer therapies and other therapies for viral disease, such as HIV, immunotoxins offer a promising alternative. They are the “magic bullet” immunologist Paul Ehrlich envisioned in the 1900s, where a therapeutic agent could be delivered directly to abnormal cells without much effect on healthy cells.
We can find sources for immunotoxins in nature. In addition to the castor bean, there are other plants, such as pokeweed. Bacterial toxins are also known. Our lab chose ricin, not only because it’s easy to obtain, but also because the structure is easy to work with. We knew we could separate the A and B chains of the protein to get a very toxic subunit A chain that we could manipulate to attach to an antibody and create a specific delivery system.
Have any of your experiments proven successful?
Vitetta: They have been very successful, in mice and in humans. We can cure mice with tumors by using the appropriate dose and dose regimen of immunotoxins. Clinical studies in human cancer patients are ongoing and encouraging. But it will take time to realize the full potential of immunotoxins and get them FDA approved.
The immunotoxins developed by our team are completing several Phase I and II trials in adult patients with Hodgkin’s and non-Hodgkin’s lymphoma prior to entering larger Phase II/III trials. I am also working collaboratively with Larry Herrera on the preclinical studies for a clinical trial in pediatric pre-B-cell acute lymphocytic leukemia. Immunotoxins are also under development to prevent graft-versus-host disease (GVHD), a complication of bone marrow transplants.
Do any hurdles remain before we can treat cancer using ricin?
Vitetta: There is one. We discovered in our trials that some patients given the experimental therapy developed vascular leak syndrome. This syndrome affects blood vessels. So we genetically modified the toxin’s A chain to avoid this problem. This new version doesn’t have vascular-leak-syndrome-inducing abilities in mice, and we hope it proves to be the case with patients. We hope it will kill tumor cells without causing this side effect. Then we will have to do so more dose findings in humans. At that point I think, if the results are all good, then we’ll let a company take this forward into very large trials because that is something our university lab doesn’t have the money or the wherewithal to do.
How did you apply your medical research to biodefense research?
Vitetta: What we are doing is very simple. Based on the knowledge of the structure of ricin A chain acquired in developing cancer treatments, we knew we could engineer the molecule so that we can make a safe and effective vaccine. And that is what we have done. We have eliminated the parts of the molecule that cause problems and toxicities and retained the parts that are necessary to immunize, and so we have been able to create a very good vaccine that has no side effects. The vaccine we developed helps the immune system recognize ricin and produce ricin-neutralizing antibodies.
If you go to the website of our lab at the Cancer Immunobiology Center, you will get an update on our work. To date, the lab has engineered a vaccine using an inactivated subunit that protects mice from 10 lethal doses of ricin. The vaccine is safe at doses up to 100-fold higher than intended for human use. A clinical trial has shown excellent safety and immunogenicity in human volunteers. Further studies in mice are being carried out using oral and aerosol ricin in a special biosafety lab at the center.
What do you foresee for this ricin vaccine?
Vitetta: The vaccine has been licensed to a company. My guess is that they will market it to the armed forces of many countries, including the United States and many countries in Europe. It may perhaps be used to vaccinate soldiers, I don’t know, but it could certainly be stockpiled as a deterrent to anyone using ricin as a biological weapon. When it was obvious a vaccine was needed, it was clear to me we knew exactly how to make it because of all the work we have done on cancer. It was really just another year or year and a half to create the vaccine. The clinical trials, however, were both expensive and labor-intensive since they were carried out entirely in our medical school.
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