Matrix with immunomodulating activity

Details Matrix with immunomodulating activity Matrix with immunomodulating activity

1991-05-21

1997-10-21

Woodward, Michael P.

Drug, bio-affecting and body treating compositions

Nonspecific immunoeffector, per se ; or nonspecific...

514 25, A61K 4708, A61K 4500

Patent

active

056793545

DESCRIPTION:

BRIEF SUMMARY
The present invention concerns an iscom matrix comprising at least one lipid and at least one saponin with immunomodulating effect, a process for preparing the matrix, a vaccine and a kit comprising the same and new saponins for incorporation in the matrix and a process for preparing the new saponins.
Many microbial and vital antigens can be produced by modern techniques today. Their full promise in vaccines will however not be realized unless they are administered along with an effective adjuvant, an agent that increases antibody and/or cell-mediated immune responses.
The only adjuvants currently authorized for human use in most countries are aluminum hydroxide and aluminum phosphate which have been used for many years to increase antibody responses to e.g. diphtheria and tetanus toxoids. Although these adjuvants are sufficient for many vaccines, studies have shown that other adjuvants, e.g. Freund's complete adjuvant (FCA), and Quil A often are more efficacious in eliciting antibody response and cell-mediated immunity in experimental animals. In fact, they are frequently required for protection. However. FCA produces granulomas at injection sites, which makes them unacceptable for human and veterinary vaccines. In fact, even aluminum hydroxide may give rise to reactions in form of granuloma at the injection site. For these reasons, many attempts are made to develop adjuvants with the efficacy of FCA but without undesirable side effects.
In Morein's EPC Patent Applications Nos. 83850273.0 and 85850326.1, there are described immunogenic complexes between antigenic determinants with hydrophobic regions and glycosides, among them triterpensaponins and especially Quil A, so called iscom complexes. In such an iscom, the amount of Quil A can be about 10-100 times lower and produce the same antigenic effect as when Quil A in free form is mixed with the antigen.
European Patent Application 87200035.1 indicates that the presence of antigen is not necessary for formation of the basic iscom structure, this being possible to form from a sterol, such as cholesterol, a phospholipid, such as phosphatidylethanolamine, and a glycoside such as Quil A.
It has now been discovered that a phospholipid is not needed for the preparation of the basic iscom structure including no antigen. Instead a sterol, such as cholesterol in conjunction with a glycoside such as Quil A are the essential structural components assembled into a complex resembling the typical cage-like iscom structure, so called matrix. It has also turned out that the matrix has immunomodulating effects such as adjuvant or immunosuppressive effect.
The present invention concerns a complex between at least one lipid such as a sterol, preferably cholesterol, and one or more saponins, such as triterpensaponins, especially Quil A or subcomponents thereof which is not a lipid vesicle without any intentional antigens or antigenic determinants for use as an immunomodulating agent. Thus, there is not integrated any antigenic component as is done in an iscom. This matrix has adjuvant effect and can be used mixed together with one or more antigens preferably in multimeric form.
In this iscom matrix there is also possible to integrate other adjuvants with hydrophobic regions. Addition of other lipids may be required to facilitate the inclusion of other adjuvants. Thus the present invention also concerns a complex containing lipids and adjuvants, other than cholesterol and saponins. Such complexes contains the matrix consisting of cholesterol and saponin, preferably Quil A or subcomponents thereof, one or more other adjuvants and one or more lipids other than cholesterol. These are preferably not lipid vesicles or liposomes and have a very special structure in electron microscopy.
Liposomes have been described in the literature and their general structure is well known to biological research workers. Liposomes are vesicles comprising one or more series of lipid layers forming onion-like structures spaced one from another by aqueous material.
The matrix can be injected in an an

REFERENCES:
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"The Requirement of Lipids for the Formation of Immunostimulating Complexes (Iscoms)", Biotechnology and Applied Biochemistry, vol. 10, 1988, By K. Lovgren et al., pp. 161-172.
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"Triterpenoid Saponins as Antiulcer Agents", Chemical Abstracts vol. 108, No. 20, May 1988, By Y. Muto et al., p. 398.

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