Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Patent
1996-11-25
1999-02-09
Cunningham, Thomas M.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
4241971, 4242571, 4241841, 4241851, 4241901, 4241941, 4242821, 530326, 530348, 530350, 530402, 530403, 514 12, A61K 39385, A61K 39112, A61K 3909
Patent
active
058690581
DESCRIPTION:
BRIEF SUMMARY
This is a continuation of Application No. PCT/US95/06575 filed May 24, 1995, which claims priority benefits of Israel Application No. 109790 filed May 25, 1994.
FIELD OF THE INVENTION
A synthetic peptide, is described having an amino acid sequence corresponding to that of a T cell epitope of the heat shock protein 65 of E. coli (hereinafter GroEL) and its analogs able to be recognized in association with a range of mouse major histocompatibility complex (MHC) molecules. Said peptide or its analogs can be used as synthetic carriers in the preparation of immunogenic conjugates consisting of said peptides and a natural or synthetic hapten derived from a pathogenic agent of interest.
BACKGROUND OF THE INVENTION
Immunization against infection caused by pathogenic microorganism (bacteria, viruses and parasites) is generally achieved by inoculating an individual with the natural antigen (attenuated or killed microorganism) or parts of said infectious agent (for example detoxified microbial products) in order to stimulate a protective immune response able to neutralize the pathogenic microbe or its deleterious effects.
Limited availability of the natural antigenic substance, risks involved in handling pathogenic material as well as storage problems stimulated the interest in the development of subunit vaccines. Isolated protective epitopes nevertheless are often characterized by their poor immunogenicity. The carbohydrate capsules of bacteria are an example of such coats: They are not easily recognized by T cells and therefore the immune response to these antigens is deprived of T cell help, T cell memory, IgG class switch, and affinity maturation. Such an immune response is inefficient and resistance to infection with bacteria encoated with carbohydrate capsules is not easily obtained by vaccination, with bacterial carbohydrates. Peptide epitopes too may be poorly immunogenic, the absence of a T cell epitope and the genetically restricted immune response being the reason.
It is now well established that most antigens require T cell help to induce B cells to produce antibodies. Conjugating a "helper" or T cell determinant to a B cell-specific antigen was shown to induce humoral immune responses to the coupled B cell epitope. The discovery by Avery & Goebel (1929) that coupling of polysaccharides to protein carriers increases immunogenicity has recently been used for the preparation of vaccines for human use. Both in humans and in rodents these conjugates behave like T cell dependent antigens by exhibition of immunological memory. There are similarities between conjugate polysaccharide vaccines and protein carrier-hapten systems. Thus the capsular polysaccharide (CPS) conjugates are able to induce protective levels of CPS antibodies in infants, while CPS alone is not. It is possible that the superior immunogenicity of conjugates compared to that of pure polysaccharides is due to the help by carrier-specific T cells, as has been demonstrated in the carrier-hapten system in rodents.
In most cases, T cell independent (T-ind) antigens have been coupled to large immunogenic carrier proteins such as tetanus toxoid, cholera toxin or diphtheria toxoid. Nevertheless, besides dosage limitations and the risk of sensitization to the carrier itself, as reported for tetanus toxoid, the immunological response to high molecular weight carrier molecules harboring stimulatory as well as suppressive T cell epitopes is not very predictable. It has been shown that the antibody response to a hapten coupled to a carrier protein can also be inhibited when the recipient has been previously immunized with the unmodified protein. This phenomenon has been termed carrier-induced epitope suppression and was recently demonstrated to occur with a number of hapten-protein conjugates (Herzenberg & Tokuhisa, 1982). Since the development of more potent conjugate vaccines against a large number of extremely infectious organisms is still important, efforts are being made to search for more appropriate carrier molecules providing the needed T cell
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Bianco, A.E., et al. , 1986, A
Cohen Irun R.
Fridkin Matityahu
Konen-Waisman Stephanie
Cunningham Thomas M.
Lubet Martha
Yeda Research and Development Co. Ltd.
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