Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Patent
1996-12-06
1998-10-06
Woodward, Michael P.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
4242251, 514 251, 514 261, 514 331, 514 351, 536 41, 536 63, A61K 3900, A61K 3929, C07G 300, C07H 1524
Patent
active
058173145
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a novel saponin component and a vaccine formulation comprising same as an immune adjuvant. More specifically, it pertains to a novel saponin component having a molecular weight of about 956 daltons, a process for isolating the saponin component from the bark of Quillaja saponaria Molina, a vaccine formulation comprising the saponin component as an immune adjuvant, a method for increasing the immune response to an antigen by employing an adjuvant composition comprising the saponin component and a second adjuvant.
BACKGROUND OF THE INVENTION
Bioengineering technologies have made significant contributions to the development of vaccines which contain recombinant antigens derived from various viral coat proteins. However, vaccines effective in preventing such threatening diseases as those caused by HIV(Human Immunodeficiency Virus) and HCV(Hepatitis C Virus) have not yet become available due partly to the lack of adjuvants effective in boosting the relatively weak antigenicity of the recombinant antigens. Therefore, extensive studies have been carried out to develop adjuvants suitable for use in such vaccines.
Currently, aluminum hydroxide(alum) is the only available adjuvant approved for human use because of its low toxicity. However, alum has been known to be ineffective when used with antigens for diseases caused by HIV, HCV, HSV(Herpes Simplex Virus) as well as schistosomiasis, whooping cough and typhoid(Sanchez-Pescador et al., J. Immunol., 141, 1720-1727(1988); James, S. L., et al., ibid., 140, 2753-2759(1988); Edelman R., Rev. Infect. Dis., 2, 370-383(1980)). A need to develop new adjuvants has thus been recognized, and in response to this need, there have been proposed a number of adjuvants, e.g., saponins, oil emulsions, monophosphoryl lipid A and Freund's adjuvants. However, each of these adjuvants has been found to have the problem of unsatisfactory adjuvant activity, high toxicity and/or undesirable adverse effects. Freund's adjuvant, for example, may cause granulomatous inflammation, while saponins described in the prior art tend to suffer from the toxicity problem as described below.
Saponins are plant glycosides which have many commercial uses such as foaming agents in beverages, detergents in the textile industries and others. It has been recently shown that a mixture of Quillaja saponins obtained by extracting the bark of the South American tree, Quillaja saponaria Molina, exhibits humoral and cellular immune responses(Espinet R. G., Gac. Vet., 13, 268-273 (1951); Dalsgaard K., Arch. Gesamte Virus Forsch., 44, 243-254(1974); Morein B., Nature, 322, 287-288(1988)). A purified form of Quillaja saponins is commercially available under the name, "Quil-A"(Iscotec AB, Sweden; and Superfos Biosector a/s, Frydenlundsvej 30, DK-Vedbaek, Denmark).
Quil-A is, however, a mixture of a large number of homologous glycosides which may be represented by the general chemical structure wherein triterpenoid quillaic acid, the aglycone, is bonded to a sugar moiety of various type and length through a glycosidic linkage. It is also known that each of these glycosidic components displays widely varying adjuvant activity and toxicity, and therefore, Quil-A is not safe for use in pharmaceutical formulations for man(Kersten et al., Infect. Immun., 56, 432-438(1988)). Accordingly, there have been attempts to identify only the safe and effective Quillaja saponin components and to develop a method for preparing thereof.
Kensil et al. subjected the methanol soluble fraction of a crude Quillaja bark extract to reversed phase high pressure liquid chromatography("RP-HPLC") using a 40 mM acetic acid solution in methanol/water(58:42(v/v)) and obtained several purified saponin components. Among those, a component designated QS-18 was found to show a high hemolytic activity, i.e., highly toxic. Another component having the QS-21 designation, on the other hand, had a low toxicity while showing a high adjuvant activity. Also reported to posses adjuvant effects are component
REFERENCES:
patent: 5057540 (1991-10-01), Kensil et al.
Kensil et al. 1991 J Immunol. 146 (2) 431-437, Jan. 15, 1991.
Newman et al. 1992 AIDS Res. Hum Retrovir. 8 (8) 1413-1418, Aug. 1, 1992.
Ronnberg et al. 1995 Vaccine 13 (14) 1375-1382, Jul. 1, 1995.
Cho Joong-Myung
Kwon Young-Sun
So Hong-Seob
Yoon Hye-Sung
LG Chemical Ltd.
Woodward Michael P.
Zeman Mary K.
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