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[SANET-MG] Antibodies in Hybrid Tobacco Plants in Kentucky comments due by next friday



Comments on the EA for synthetic antibodies grown in tobacco plants in Kentucky are due by next Friday. Even though APHIS seems to automatically ignore comments criticizing field test releases of GM crops it is worthwhile to keep commenting. I urge others to make , even brief, comments on this important subject. Monocl;onal antibodies have been prepared and tested in a number of food crops including corn and rice. APHIS seems to be promoting release of such potential pollutants of the food supply so it is unwise to fail to comment at the time comments are sought, even though such comments are ignored by the regulators.
29 June 2007
Professor Joe Cummins
University of western Ontario and
Institute of Science in Society
Comments on the Environmental Assessment of the Environmental Release to Produce
Antibodies in Hybrid Tobacco Plants in Kentucky
USDA/APHIS Environmental Assessment In response to the Planet Biotechnology permit application 05-354-03r for an environmental release to produce antibodies in genetically engineered N. tabacum X N. glauca hybrid plants U.S. Department of Agriculture Animal and Plant Health Inspection Service Biotechnology Regulatory Services APHIS-2007-0029 Planet Biotechnology, Inc.; Availability of an Environmental Assessment for a Field Release of Nicotiana Hybrids Genetically Engineered To Produce Antibodies Comments due by 07/13/2007 http://www.regulations.gov/fdmspublic/component/main The Animal and Plant Health Inspection Service (APHIS) of the United States Department of Agriculture, has prepared an environmental assessment (EA) in response to a request for a permit (APHIS Number 05-354-03r) submitted by Planet Biotechnology for environmental release of a genetically engineered Nicotiana interspecies hybrid. Plant Biotechnology crossed a genetically engineered Nicotiana tabacum that produces an antimicrobial antibody which binds to a bacterium (Streptococcus mutans) associated with tooth decay in humans, with N. glauca (N. tabacum X N. glauca) to generate an interspecific Nicotiana hybrid line, 06PBCarHG1 On December 21, 2005, APHIS received a permit application (05-354-03r) from Planet Biotechnology of Hayward, CA. The application requests permission to release a genetically engineered N. tabacum X N. glauca hybrid line, 06PBCarHG1, into the environment in a confined field trial. The purpose of the environmental release is to grow the genetically engineered Nicotiana hybrid line, 06PBCarHG1, which produces an antibody, designated by Planet Biotechnology as CaroRx™. The environmental release 100 acres ,in Daviess County, Kentucky, will begin in June 2007 and will conclude in the fall of 2007. Following harvest of the Nicotiana hybrid leaves, the permittee will extract and purify the CaroRx™ antibody. Application of CaroRx™ to human teeth is intended to prevent tooth decay . In the United States, CaroRx™ is an Investigational New Drug (BB-IND # 7526) and in the European Union, it is a registered Medical Device (1). The Caro RX antibody in Genetically Modified Tobacco is used for passive immunisation Plant Biotechnology generated the transformed Nicotiana interspecies hybrid line, 06PBCarHG1, by first cloning and expressing the CaroRxTM gene in N. tabacum line H8-105 and then crossing H8-105 with N. glauca. The Nicotiana hybrid line, 06PBCarHG1,is genetically engineered with the constituent parts of the secretory CaroRxTM antibody (light chain from mouse, heavy chain from mouse, J chain from mouse, and secretory component from rabbit), all driven by the cauliflower mosaic virus (CaMV) promoter. These constituent parts were cloned and expressed in tobacco by independent transformation events. The events were combined into a single line by classical breeding methods (Ma 1995). Hybrid line 06PBCarHG1 contains two additional protein products that are expressed under the control of a plant recognized NOS promoter (one of very few bacterial promoters known to be expressed in plants). These proteins are NPTII (from E.coli), an enzyme that confers resistance to kanamycin, which is used as a selectable marker, and NOS (from A. tumefaciens), an enzyme that forms nopaline from the amino acid arginine and alpha-ketoglutaric acid. NOS, although present in the plasmid vector used in the production 06PBCarHG1, was not utilized as a selectable marker in the construction of 06PBCarHG1. Line 06PBCarHG1 also contains trfA (from E. coli) that encodes for a DNA-binding protein important for plasmid DNA replication and add3 (from E. coli) that encodes for resistance to the antibiotic streptomycin/spectinomycin. However, because trfA and add3 are driven by bacterial promoters that are not recognized by plants, these genes are not expressed in 06PBCarHG1. Additional noncoding sequences (sequences contained in the transformed plant, but not converted into protein products) present in 06PBCarHG1 are ColEI and RK2 origin of replication sequences (from E. coli) and the nos terminator from A. Tumefaciens (1). The monoclonal antibody produced in genetically modified (GM) tobacco is is a synthetic mixture of gene sequences of mouse and rabbit. The application of the synthetic antibody leads to passive immunity to the bacterium, Streptococcus mutans, in humans treated with the antibody. Active immunity to Streptococcus mutans has also been developed and that alternative will be discussed below. A planet Biotechnology patent US Patent 6,303,341 deals with the production of protective immune globulins in plants (2) US Patent 6,995014 transgenic plants expressing monoclonal antibodies (3). The fundamental publications began with the assembly of monoclonal antibodies in transgenic tobacco plants (4) followed by generation of secretary antibodies in plants (5). Recombinant plant monoclonal antibodies were tested on human subjects for preventive immunotherapy to prevent caries (6). That small clinical study proved the concept but was not sufficient to establish the that the treatment was safe for a large heterogeneous population. The EA for Caro RX antibody in Genetically Modified Tobacco presumes that the recombinant antibody will be contained on the 100 acre test site because there will be little or no pollen produced by the hybrid tobacco plants. There is a good chance that the dust and debris from decaying plant pars will lead to surface and ground water contamination with the GM antibody and the surface and groundwater surrounding the test acreage should be monitored. Since the genes and proteins produced in the GM tobacco are synthetic approximations of natural antibodies the product should not be presumed safe for wild and protected animals o consume but rather laboratory studies should be conducted on the safety of the GM antibody prior o the field tests. It is worth mentioning that GM antibodies may not be required for passive immunization to prevent dental caries. A mouth rinse of egg yolk from chickens immunized against Streptococcus mutans to produce antibodies that effectively controlled colonization of the bacteria in human (7). In contrast, use of transgenic probiotic bacteria is riskier than GM tobacco antibodies. Lactobacili modified to contain single chain antibodies against Streptococcus mutans provide continous release of recombinant antibody into the oral cavity is considered therapeutically superior to the mouth wash procedure I8). However, such GM bacteria may create untoward side effects.
DNA Vaccines for Active Immunization
Passive immunity is not the only approach to immunological control of Streptococcus mutans. Antigens from the bacterium causing dental caries is delivered using oral or nasal applications. The preferred delivery of the antigen is through an anti-caries DNA plasmid Inter nasal application of the plasmid significantly reduce3d dental caries in rats (9). Genetic adjuvants such as gens for interleukin 5 or the cholera toxin gene enhanced protection against caries in mice (10). Internasal immunization of rabbits and monkeys with an anti-caries vaccine proved effective in preventing dental caries (11). An anti-caries DNA found to produce extended immunity in mice was approved for human trials by the United States Food and Drug Administration (12). Active immunization may be inherently superior to passive immunization and the use of DNA vaccines will likely avoid potential environmental pollution associated with the production of passive vaccines in crop plants.
Conclusion
Considering the large field test release of GM tobacco modified with a mouse-rabbit hybrid antibody destined for passive immunization of human to prevent dental caries it can be asked “is this release really necessary?”. The environmental risks of the field release of the may exceed the benefits of the release. First, it was not proved that the benefits of the GM tobacco for passive immunization was superior to the use of egg yolk from chickens immunized with the bacteria causing dental caries. Second, active immunization against the pathogen causing dental caries may prove to provide long term protection against disease using DNA vaccines without posing the environmental risks associated with production of passive vaccines in crop plants.
References
1. U.S. Department of Agriculture Animal and Plant Health Inspection Service Biotechnology Regulatory Services USDA/APHIS Environmental Assessment In response to the Planet Biotechnology permit application 05-354-03r for an environmental release to produce antibodies in genetically engineered N. tabacum X N. glauca hybrid plants 2007 http://www.regulations.gov/fdmspublic/component/main 2. Hiatt,A,Ma,J,Lehner,T and Mostov,K. Method for producing imunoglobulins containing protection proteins in plants and their use 2004 United States Patent 6,303,341 3. Hein,M,Hiatt,A and Ma,J. Transgenic crops expressing assembled secretory antibodies 2006 Units States Patent 6,995,014 4. Ma JK, Lehner T, Stabila P, Fux CI and Hiatt A. Assembly of monoclonal antibodies with IgG1 and IgA heavy chain domains in transgenic tobacco plants. Eur J Immunol. 1994 Jan;24(1):131-8. 5. Ma JK, Hiatt A, Hein M, Vine ND, Wang F, Stabila P, van Dolleweerd C, Mostov K and Lehner T. Generation and assembly of secretory antibodies in plants. Science. 1995 May 5;268(5211):716-9. 6. Ma JK, Hikmat BY, Wycoff K, Vine ND, Chargelegue D, Yu L, Hein MB and Lehner T. Characterization of a recombinant plant monoclonal secretory antibody and preventive immunotherapy in humans. Nat Med. 1998 May;4(5):601-6. 7. Hatta H, Tsuda K, Ozeki M, Kim M, Yamamoto T, Otake S, Hirasawa M, Katz J, Childers NK and Michalek SM. Passive immunization against dental plaque formation in humans: effect of a mouth rinse containing egg yolk antibodies (IgY) specific to Streptococcus mutans. Caries Res. 1997;31(4):268-74. 8. Kruger C, Hultberg A, van Dollenweerd C, Marcotte H and Hammarstrom L. Passive immunization by lactobacilli expressing single-chain antibodies against Streptococcus mutans. Mol Biotechnol. 2005 Nov;31(3):221-31. 9. Xu QA, Yu F, Fan MW, Bian Z, Chen Z, Peng B, Jia R and Guo JH. Protective efficacy of a targeted anti-caries DNA plasmid against cariogenic bacteria infections. Vaccine. 2007 Jan 26;25(7):1191-5 10. Han TK and Dao ML. Enhancement of salivary IgA response to a DNA vaccine against Streptococcus mutans wall-associated protein A in mice by plasmid-based adjuvants. J Med Microbiol. 2007 May;56(Pt 5):675-80. 11. Jia R, Guo JH, Fan MW, Bian Z, Chen Z, Fan B, Yu F and Xu QA. Immunogenicity of CTLA4 fusion anti-caries DNA vaccine in rabbits and monkeys. Vaccine. 2006 Jun 12;24(24):5192-200. 12. Xu QA, Yu F, Fan MW, Bian Z, Chen Z, Fan B, Jia R and Guo JH. Immunogenicity and persistence of a targeted anti-caries DNA vaccine. J Dent Res. 2006 Oct;85(10):915-8

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