March 18, 2006

Prof. Joe Cummins

A drug trial catastrophe reflects upon the secretive open field testing of pharm crops

This week saw the report of a drug trial that led to catastrophic injury to human volunteers. Six volunteers were injured , one of whom, may face up to a year or more of coma. The drug being tested (TGN 1412) was a recombinant humanized monoclonal antibody being developed to treat diseases including leukemia and arthritis. The tests of the drug were being undertaken in Britain by a German biotechnology company (TeGenero).. The six young men participating in the drug trial were healthy volunteers paid a small fee to participate in the experiment (1,2,3,4). The Mab and its properties were described in a paper published in 2003, The drug is described as a superagonist (a super activator) of T-cells. The drug is expected to lead to development of T-cell stimulatory drugs (5). T-cells are - a small lymphocyte developed in the thymus; they orchestrate the immune system's response to infected or malignant cells. The drug trial went wrong after a single relatively high dose led to over stimulation of the immune system leading to inflammation and organ destruction.

Presently 18 Mab drugs have been approved by the US FDA. There are over 355 Mab drugs in clinical development. The drugs approved currently are mainly for cancer treatment and control of the immune system with a single anti-viral Mab. The approvals have been received by both traditional pharmaceutical corporations and by biotechnology companies of relatively recent origin (6). Problems associated with the development of Mab drugs are widely recognized. A drug approved for treating multiple sclerosis (MS) was associated with several deaths from brain infections. The drug was believed to block immune cell migration to the brain allowing virus infection. That drug has been voluntarily suspended for further study. The problem associated with up-regulating the immune system include inflammation of the eye, skin, gut, pituitary gland along with cases of hepatitis and loss of skin pigmentation(7). A humanized Mab used to treat colon cancer caused 17% of the cancer patients to experience adverse immune events . However, the initiation of adverse events could be detected by preliminary low level treatment and those patients could be removed from further treatment prior to the onset of severe adverse events(8). In the German human study in Britain a single high dose of Mab was reportedly used leading to adverse immune response (inflammation and organ failure) in all of those treated. In that experiment animal studies had been done but those experiments alone are not sufficient to pinpoint all of the many problems associated with Mabs drug therapy. Adverse effects of the drug at low levels in one or two human subjects should have been studied before the whole group was exposed to high levels of the drug.

Currently the Mab drugs approved have mainly been prepared from cell cultures. The cost to the patients would be $20,000 t0 50,000 per year, the colon cancer drug Erbitux costs $17,000 per month(7). Very wealthy people alone may benefit from such drugs. However, producing the drugs in transgenic farm animals or in crop plants promises to greatly reduce the cost of Mab drugs. Mice have been modified toproduce human antibodies and there are efforts to create farm animals producing human antibodies (9).Human monoclonal antibodies have been produced in chicken eggs at relatively high levels in the egg (10). Humanized Mabs have been produced using the yeast Pichia pastoris. The yeast has been glycoengineered to express human patterns of glycosylation so that the immunological problems arising from non-human glycosylation will be avoided (11).

Plant based production of recombinant antibodies has been discussed extensively. A review published in 2003 reported that six plant derived antibodies have been developed as human therapeutics. One the drug Avicidin developed by NeoRx and Monsanto , the drug had some anticancer effect on colon cancer it caused severe diarrhea and for that reason was withdrawn. Another plant derived antibody CaroRx produced in tobacco reduces teeth decay by preventing adhesion of the bacterium Streptococcus mutans. A Mab targeting cancer antigen CEA has been produced in tobacco, pea, rice and wheat. A humanized Mab recognizing herpes simples virus 2 has been produced in soybean. Antibodies targeting non-hodgkin’s lymphoma were produced using a virus vector in tobacco. Finally, Mab produced in tobacco targeted human chorionic gonadotropin , that Mab was planned to be used in contraception, pregnancy detection and therapy of tumors (12).Plant based production of prophylactic antibodies for rabies and for other disease conditions have been described (13). The hazards associated with producing genetically modified crops to produce vaccines and therapeutic antibodies was reviewed. The main threat is the genetic pollution of major food crops leading to food that is toxic (14). Humanized Mabs structured to attack Herpes virus or produces proteins that regulate the human immune system were to be produced by the green alga Chlamydomonas in large plastic tubes near a beach. Chlamydomonas is a common soil microbe so that the nature and location of the production facility invited environmental spread of the alga and as well the human genes they contained to soil microbes. Direct human exposure to such microbes is likely to lead to untoward consequences(15). Molecular pharming (producing pharmaceuticals in transgenic crops) is turning into a new battlefront in the imposition of recombinant crops. Large governments appear to be prepared siding with corporations against the many people who do not wish to see the food supply contaminated with un-prescribed drugs (16).

At least 29 field test releases of genetically modified (GM) crops acknowledged to be production of antibody but actual genes have been deemed confidential business information (CBI). The crops modified have been maize and soybean and the testers included Prodigene , Monsanto and Agracetus. The field releases have been done in Hawaii, Nebraska, Wisconsin, Iowa, Indiana Minnesota, Puerto Rico, Texas and other states (17). Of course other crops and Mabs may have been tested as well but designated pharmaceutical products CBI. The actual locations of such tests are deemed CBI and no effort has been made to notify by-standers and neighbors of the tests. People may be exposed to Mabs from modified crops by pollen, dust debris from leaves, stems and flowers along with polluted surface and groundwater. Once the Mab genes escape to fertilize neighboring crops they will likely be fixed in that population and persist in a Hardy-Wienberg equilibrium within the food crop.

Mab and humanized Mab production can be achieved without endangering the public by using plant cell culture. Exposure of humans without their knowledge or consent in secretive open field trials threatens the health , even the life, of those people. Such secretive field trials should not be allowed. The location and nature of current and previous field trials should be revealed to the public. Such revelations may explain an array of mysterious maladies for which there has been no previous explanation. There is something disturbing about serious injury of young six volunteers who were paid a mere pittance to risk their lives for those producing drugs that are so costly that they can benefit the very rich alone. The secretive exposure of bystanders and neighbors to very hazardous recombinant plants to benefit corporations is equally disturbing.

References

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15.Cummins,J. and Ho,M. GM Pharmaceuticals from common green alga Science in Society 2005, 27,6-7

16. Ho,MW Molecular Pharming-the new battlefield over GM crops Science in Society 2005,27,4

17. Information Systems for Biotechnology Environmental field test release database:antibody released 2006 http://www.isb.vt.edu/cfdocs/fieldtests3.cfm