Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Recombinant or stably-transformed bacterium encoding one or...
Patent
1992-09-30
1995-11-28
Nucker, Christine M.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Recombinant or stably-transformed bacterium encoding one or...
4241841, 4241851, 4242341, 4241921, 4241941, 4241971, 4242001, 4242031, 4242411, 4242821, 435 693, 4351723, 530350, 530825, 530403, 530812, 536 234, 536 237, 514 2, A61K 3902, A61K 39108, C07K 14195, C07K, C07K
Patent
active
054705738
DESCRIPTION:
BRIEF SUMMARY
The invention concerns carrier-bound recombinant proteins, a process for their production and their use, in particular as immunogens and vaccines.
The main purpose of the immunological system in humans and animals is to resist and avoid pathological damages which arise as a result of degenerate cells of infectious viruses, bacteria, fungi or protozoa. A special characteristic of the immunological system is that an increasingly stronger resistance occurs after repeated infections with pathogens. The aim of immunization is to build up the power of the immunological system against particular pathogens without causing corresponding diseases.
Antibodies and cellular T and B lymphocytes are responsible for the specific resistance to pathogens. An essential prerequisite for this is the recognition of foreign structures such as e.g. those which occur on a bacterial cell. Depending on the stimulation of the immunological system a temporary or a lifelong immunity to pathogens can be built up in this process after immunization.
It is important for the quality of monoclonal and polyclonal antibodies as well as for the effectiveness of vaccines that the immunological response to the antigen occurs to a sufficient extent. However, viral antigens or recombinant human proteins often show a poor immunological response or none at all if they are used without further modification. For this reason these antigens are often linked to carriers (preferably to proteins) in order to amplify the immunological response. However, the antigens can be changed at or near the antigenic determinants by the binding of the antigens to the carrier. As a result the immunological response can be substantially weakened.
In order to improve the immunological response it is advantageous to incorporate such antigens into the outer membrane of bacteria and to use these complexes as immunogens (J. Immunol. 139 (1987) 1658-1664, Bacterial Vaccines and Local Immunity--Ann. Sclavor 1986, n. 1-2, pp. 19-22, Proceedings of Sclavo International Conference, Siena, Italy, 17-19 November 1986). Attenuated or dead pathogens (bacteria or viruses), treated partial components of pathogens (membrane proteins of bacteria, structural proteins of viruses) or recombinant live vaccines (viruses or bacteria) are also used.
A disadvantage of using live bacteria or viruses as immunogens for the immunization is that an undesired pathogenic spread of the germs cannot be excluded.
However, the antigenic determinant can be altered by killing or fragmenting the bacteria and viruses before their use as an immunogen or vaccine which can substantially reduce the immunological response.
The object of the present invention is therefore to provide immunogens and vaccines which do not have these disadvantages.
This object is achieved via a carrier bound, recombinant protein. This carrier bound, recombinant protein is obtained by expressing a first gene coding for a fusion protein and a second gene, hereinafter referred to as "lysis gene", which codes for one of: (a) a lytically-active, bacteriophage membrane protein, (b) a lytically-active, toxin release gene, or (c) a lytically active, partial sequence of one of these. The fusion protein comprises at least one hydrophobic, non-lytically active protein domain capable of membrane integration and a recombinant protein carrier bound, recombinant protein is then isolated from the culture broth.
The expression of the fusion protein gene and the lysis gene is preferably controlled by two different promoters (FIG. 1). The expression of the lysis gene is preferably delayed with respect to the expression of the fusion protein.
With this type of expression of fusion protein gene and lysis gene one obtains at first the integration of a multitude of fusion proteins into the membrane of the gram-negative bacteria used as the host organism and subsequently lysis of these bacteria takes place. The usually impermeable cell wall complex of the bacteria is made so permeable by this that the cytoplasmic components of the bacteria are released (Eur. J.
REFERENCES:
patent: 4839293 (1989-06-01), Cantor et al.
patent: 5075223 (1991-12-01), Lubitz et al.
Maratea, D et al. Gene 40: 39-46 (1985).
Harkness, R. E. et al. FEMS Microbiol. Lett. 48: 19-24 (1987).
Szostak, M. et al. Res. Microbiol. 141: 1005-1007.
Lubitz Werner
Szostak Michael P.
Boehringer Mannheim GmbH
Nucker Christine M.
Tuscan Michael
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