Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-04-22
2004-08-17
Reynolds, Deborah J. (Department: 1632)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C435S069300, C435S419000, C435S468000
Reexamination Certificate
active
06777546
ABSTRACT:
FIELD OF THE INVENTION
The present invention generally relates to edible vaccines produced in plants, useful for the treatment of autoimmune disease.
BACKGROUND
Systemic immunosuppressive therapy in autoimmune disease and transplantation is associated with increased rates of infection, malignancy and numerous side effects. The induction of antigen-specific hyporesponsiveness without drugs is therefore desirable. Immune responses to orally administered proteins is intrinsically modulated and may induce a state of systemic hyporesponsiveness termed oral tolerance (Kay et al., (1989), Immunology, vol. 66, pp. 416-421; Peng et al., (1990), Clin. exp. Immunol., vol. 81, pp. 510-515; Lamont et al., (1989), Immunology, vol. 66, pp. 595-599). Although many factors have been implicated in this phenomenon, including soluble mediators and suppressor T cells, it is apparent that antigen processing by mucosal tissue is critical for this effect.
Various studies have reported oral administration of antigens, thought to be associated with autoimmune diseases, in an effort to induce oral tolerance and prevent or reduce autoimmune disease.
In International Patent Application Publication No. WO 92/07581, and in Weiner et al., (1992), Proc. Natl. Acad. Sci. USA, vol. 89, pp. 7762-7766, Wiener et al. describe suppression of the mammalian response to allografts by oral administration of splenocytes or splenocyte preparations from tissue donors, or oral administration of short synthesized peptides corresponding to fragments of class II Major Histocompatibility Complex (MHC) proteins.
There are, however, several problems associated with the approach of oral tolerance. First, the complexity of foreign peptide presentation in transplantation makes it difficult to identify peptide sequences suitable for induction of tolerance.
Second, the induction of oral tolerance to antigens is dose dependent and an insufficient level of an oral antigen may prime gut lymphocytes and cause the opposite and undesired effect of sensitization. It is therefore necessary to be able to obtain and deliver the antigens in a sufficient quantity to induce oral tolerance.
Third, the nature of the peptide itself may stimulate rather than reduce immune responsiveness.
If the entire amino acid sequence of an antigen protein is used to induce oral tolerance, then a greater array of potentially tolerance-inducing peptides will be presented to the immune system. If complex antigens such as MHC proteins or other transplantation antigens are to be used as intact proteins, however, it is difficult to obtain these proteins in sufficient quantities by in vitro synthesis. It may also be difficult to deliver a sufficient quantity of these protein antigens to induce oral tolerance.
Transgenic plants have been used to express a variety of single chain heterologous polypeptides with considerable success (Trudel et al., (1992), Plant Science, v. 87, pp. 55-67). More complex multi-chain proteins such as antibodies have also been expressed in plants but with less consistent results (Swain, W. F. (1991), Tibtech, v. 9. p. 107).
It has been proposed that viral antigens expressed in plants may provide an “edible vaccine”, whereby ingestion of plants containing the viral antigen by a human would stimulate an increased immune response and provide immunization against the virus (Mason et al., (1992), Proc. Natl. Acad. Sci. USA, vol. 89, pp. 11745-11749).
The high cost of production and purification of synthetic peptides manufactured by chemical or fermentation based processes may prevent their broad scale use as oral vaccines. The production of immunogenic proteins in transgenic plants, on the other hand, offers an economical alternative. Attempts have been made to produce transgenic plants that express bacterial antigens of
E. coli
and Streptococcus mutants. For instance, Curtiss et al. (WO 90/0248) report the transformation of sunflower with the
E. coli
LT-B gene. Also, the expression of LT-B and its assembly into G
M1
-binding pentamers in tobacco and potato plants has been reported (Haq et al. 1995). Additionally, Arntzen et al. (WO 96/12801) disclose vectors for the independent and coordinate expression of LT-A and LT-B, which optionally contain a SEKDEL microsomal retention signal. The transformation of tobacco and potato plants with these genes is also described.
It has been shown that the inclusion of KDEL amino acid sequences at the carboxy terminus of a protein can enhance the recognition for that protein by the plant ER retention machinery (see, e.g., Munro and Pelham 1987). However, such modifications can be problematic because other factors, such as protein conformation or protein folding in the transformed cells, may interfere with the accessability of this carboxy terminal signal to the plant ER retention machinery. Retention of key biological properties in the recombinant proteins produced in plants, specifically ligand binding and the presentation of antigenic epitopes, is of considerable importance to the successful production of edible vaccines in transgenic plants.
Oral vaccines derived from transgenic plants are potentially an effective and inexpensive means for inducing oral tolerance, and secretory immune responses to enterotoxins, in mammals including humans. Recently, plants have been used for the production of vaccine antigens such as viral capsid proteins and bacterial enterotoxins (Haq, T. A., Mason, H. S., Clements, J. D., and Arntzen, C. J., 1995
, Science
268:714-716; Mason, H. S., Ball, J. M., Shi, J. -J., Jiang, X., Estes, M. K., and Arntzen, C. J. 1996
, Proc. Natl. Acad. Sci. USA
93:5335-5340; Arakawa, T., Chong, D. K. X., and Langridge, W. H. R. 1998
, Nat. Biotechnol.
16:292-297; Arakawa, T., Chong, D. K. X., Merritt, J. L., and Langridge, W. H. R. 1997
, Transgenic Res.
6:403-413). Production of autoantigens in food plants for the induction of oral tolerance offers the following advantages. Plants can synthesize proteins at low cost and protein intake can be achieved through direct consumption of the edible plant tissues.
Cholera toxin (CT) is a potent mucosal immunogen that has strong mucosal adjuvant qualities (Clements et al., 1988; Holmgren et al., 1993). Thus, immune responses against other antigens can be enhanced by co-presentation with low doses of CT.
The nontoxic cholera toxin B subunit (CTB) has been used to increase the tolerogenic nature of orally administered antigens based on the affinity of CTB for G
M1
-ganglioside, a cell surface receptor located on the M cells in gut-associated lymphoid tissues (GALT) and enterocytes in the intestinal villi (Sun, J. -B., Holmgren, J., and Czerkinsky, C., 1994
, Proc. Natl. Acad. Sci. USA
91:10795-10799; Weiner, H. L., 1994
, Proc. Natl. Acad. Sci. USA
91:10762-10765). This application of CTB has proven useful in the prevention and treatment of autoimmune diseases in animals (Sun, J. -B., Rask, C., Olsson, T., Holmgren, J., and Czerkinsky, C., 1996
, Proc. Natl. Acad. Sci. USA
93:7196-7201; Bergerot, I., Ploix, C., Petersen, J., Moulin, V., Rask, C., Fabien, N., Lindblad, M., Mayer, A., Czerkinsky, C., Holmgren, J., and Thivolet, C. 1997
, Proc. Natl. Acad. Sci. USA
94:4610-4614).
There is a need in the art for a vaccine that is capable of delivering the entire amino acid sequence of a complex autoantigen for the induction of oral tolerance.
There is also a need in the art for a vaccine that is capable of delivering sufficient quantities of the entire amino acid sequence of a complex autoantigen for the induction of oral tolerance.
There is also a need in the art for an economical method for producing safe vaccines.
There is also a need in the art for an economical method for producing safe, edible vaccines.
There is also a need in the art for an economical method for producing safe, edible vaccines in plants.
There is also a need in the art for an edible vaccine that can facilitate efficient, site-specific delivery of a concentration of an autoantigen sufficient to induce oral tolerance.
There is also a need in the art for an edible vaccine that can f
Arakawa Takeshi
Langridge William H. R.
Farah David A.
Loma Linda University
Reynolds Deborah J.
Sheldon & Mak PC
Woitach Joseph
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