Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-05-05
2002-03-19
Schwartzman, Robert A. (Department: 1632)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S054000
Reexamination Certificate
active
06358933
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is related to the field of medicine, particularly to the development of new immunoenhancing formulations allowing an increase of the amount and quality of the immune response to vaccine antigens.
The technical aim of the proposed invention is the development of formulations that are capable of increasing the levels of the immune response to the nucleic acid-based vaccine.
The successful use of adjuvants to enhance this new kind of vaccines is not obvious. Recently, new compounds capable of enhancing the nucleic acid-based vaccines have been found. Inclusive, one of the first findings in the field of DNA immunization was the impossibility of alum to enhance this kind of vaccine, and this is the most generally used adjuvant in vaccines in the market.
The use of the direct immunization with DNA began in 1990. Nowadays the research is developed in the field of preventive vaccines as well as in the genetic therapies of somatic cells to treat cancers, infections and metabolic diseases. DNA vaccines have some advantages compared to the other vaccine strategies. As the attenuated or recombinant viruses, the plasmidic vectors activates T-CD8+ cytotoxic cells (Wang, B. et al. 1993 Proc. Natl. Acad. Sci. U.S.A. 90, 4156-4160), (Xiang, Z. Q. et al. 1994 Virology 199, 132-140).
Once inoculated, DNA is capable of continually expressing their constitutive genes for months (Wolff, J. A. et al. 1990 Science 247: 1465) and it doesn't seem to be pathologic or mutagenic to the target cell, because the majority of plasmids exist in a circular and non-replicative and non-integrative form (Wolff, J. A. et al. 1990 Science 247: 1465).
There's no induction of anti DNA antibodies (Xiang, Z. Q., et al. 1995 Virology 209: 569) neither serious inflammatory reactions or other complications in the site of the inoculation. Furthermore, the plasmidic DNA can be easily manipulated and it is relatively cheap in big quantities with high levels of purity (Tsuji, T. et al. 1997 Eur. J. Immunol. 27: 782-787).
Although the mechanisms involved in the induction and the maintenance of the immune response are not clear yet, the strategy of coinoculation of plasmids coding for cytokines and costimulatory factors has been successfully used. It is known that there are some other factors involved in the response, i.e. the own characteristics of the vector which could affect the rate of transcription (Davis et al. 1993 Hum. Gene ther., 4, 151-159).
Nowadays it is known that myocytes are able to present antigens associated to the Major Histocompatability System (MHC) Class I (Pardoll, D. M. and Beckerrieg, A. M. 1995 Immunity 3: 165)(Cohen, J. 1993 Science. 259: 1745), but these cells express MHC class I and II molecules poorly. For an efficient antigenic presentation, a costimulatory signal or antigen-independent second signal for the activation and proliferation of T cells after the antigen-specific interaction of the T cell receptor (TCR) and the MHC is essential (Bluestone, J. A., 1995 Immunity 2: 555).
With the use of plasmids coding for the costimulatory molecules B7-1 and B7-2, an increased co-stimulatory signal can be expressed in the myocytes (Hohlfeld, R. y Engel, A. G., 1994 Immunol Today, 15, 269) inducing higher levels of proliferation and activation of specific T cells for the introduced antigen. Applied to the tumor immunology, it has been probed that the poor immunogenicity of some tumors is due to the lack of costimulatory molecules. The transduction of DNA coding for B7-1 or B7-2 molecules in tumor cells greatly enhanced the antitumoral immunity (Townsend, S. E. y Allison, J. P. 1993 Science, 259: 368) Gajewski, T. F.,1996 J. Immunol. 156: 465)(Yang, G., et al. 1995 J. Immunol. 154: 2794).
Recently it has been reported that the inoculation in the same adenovirus of genes coding for the hepatitis B surface antigen (HBsAg) and the B7-1 molecule induced a higher cytotoxic response specific for the HBsAg compared with the gene of the viral antigen alone (He, X. S. et al. 1996 Proc. Natl. Acad. Sci., U.S.A. 93: 7274). It has also been demonstrated that the co-inoculation of plasmidic DNA coding for B7-1 with the vaccinal DNA of HIV-1 increased the specific cellular response for HIV-1 compared to the inoculation of HIV-1 plasmidic DNA alone. It could be demonstrated that the increase in cellular immunity with B7-2 depended on &ggr;IFN. (Tsuji, T. et al. 1997 Eur. J. Immunol. 27: 782-787). In this article, any enhancing effect related to the coinoculation of B7-1 couldn't be demonstrated. This phenomena can be explained taking into consideration that the B7-2 are more rapidly induced by the antigen presenting cells (APC) than the B7-1 molecules (Hathcock, K. S. et al. 1994 J. Exp. Med. 180: 631) that's why B7-2 are preferred for the initial antigenic presentation. Similar results have been obtained by other authors, demonstrating the enhanced response of CD8+ cytotoxic lymphocytes (Kim, J. J. et al. 1997 Nature Biotechnology 15: 641-646). The &ggr;-IFN is a pleiotropic cytokine capable of enhancing T-cell mediated responses, upregulating the expression of the MHC determinants. The treatment of myoblasts in culture with &ggr;-IFN increased the susceptibility to cytolysis by T cells and also provided signals for T cell lines proliferation. However, it has been found that the coinoculation of a plasmid coding for the G protein of Rabia Virus and the plasmid coding for &ggr;-IFN did not increase the antiviral immune response (Xiang, Z. et al. 1995 Immunity 2, 129-135).
Recent studies have shown that the effect of the &ggr;-IFN depends on the promotor used (Xiang, Z. et al. 1997 Vaccine Vol. 15(8) 896-898). The colony Stimulating Factor of Granulocytes and Macrophages (GMCSF) has also been coinoculated as a plasmid (Xiang, Z. et al. 1995 Immunity 2, 129-135). Primary immune responses can be induced with this cytokine (Tao, M. H. et al. 1994 Nature 362, 755-758) by activation or recruiting of professional antigen presenting cells (Heufler, C. et al 1988 J. Exp. Med. 167, 700-705).
In 1995, Xiang and cols evidenced that the enhancing effect of the plasmid coding for GM-CSF over the humoral immune response against the G protein of Rabbia Virus after the co-inoculation of the two plasmids. Both plasmids coinoculated separately in the time (hours) did not generate any effect in the antibody response to the Rabbia Virus. It suggests that cotransfection of individual APC cells or the proximity of the APC to the secreting cell are important factors, showing the local activity of the cytokine (Xiang, Z. et al. 1995 Immunity 2, 129-135).
The increase of the antibody response observed by coinoculation with the plasmid expressing GM-CSF shows that the primary effect of GM-CSF over the Th cell response, resulting in an increase in the activation of specific antigen B cells. In experiments using cytokine depending cell lines, the lack of response to IL4 indicates that DNA vaccines induce principally Th cells, as previously shown and that the cytokine GM-CSF enhance this pattern of response (Xiang, Z. et al 1995 Immunity 2, 129-135).
IL-12 is a very important immunomodulatory cytokine. It has been demonstrated that the expression plasmid coinoculated along with a plasmid coding for HIV-1 protein, enhanced the HIV-1 specific cell mediated immunity. Although the mechanisms involved in the induction and maintaining of the immune response are not clear, this kind of strategy could be successful (Takashi, T. et al. 1997 J. Immunol. 158: 4008-4013).
In addition to their adjuvant properties, the treatment of HIV-1 positive patients with IL-12 retarded the progression to AIDS. (Clerici, M. et al. 1993 Science 262: 1721). It also normalizes some parameters, for example, the cytotoxic activity mediated by natural killer cells (NK) (Chehimi, J. et al. 1992 J. Exp. Med. 175: 789). IL-12 also inhibits apoptosis of CD4+ cells (Randrizzani, M. et al. Cell Immunol. 161: 14).
In coadministration studies of plasmids coding for IL-6 and haemaglutinin inoculated using t
Aguilar Rubido Julio César
Crombet Menedez Lissere
Guillen Nieto Gerardo Enrique
Herrera Buch Antonieta
Iglesias Perez Enrique
Centro de Ingenieria Genetica Y Biotechologia
Hoffmann & Baron , LLP
Li Q Janice
Schwartzman Robert A.
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