Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Patent
1995-02-22
1998-04-07
Woodward, Michael P.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
4241841, 4241851, 4241901, 4241931, 4241941, 42419711, 4242581, 4242781, A61K 39385, A61K 3909, A61K 39112
Patent
active
057361460
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to conjugates of enhanced immunogenicity based on synthetic peptide carriers constituting T cell epitopes, to their preparation and to vaccines suitable for immunization comprising said conjugates.
BACKGROUND OF THE INVENTION
Antibody responses have been subclassified into two main types on the basis of their requirement for T cells. The primary humoral immune response to T cell-dependent (T-dep) antigens is characterized by B and T cell activation and proliferation leading on one hand to the differentiation of plasma cells and immunoglobulin secretion, and on the other hand to the formation of germinal centers and immunological memory. Upon restimulation by antigen, these memory cells play the leading part in the secondary antibody response. The cardinal characteristics of the secondary response to T-dep antigens are rapidity of antibody production, greater magnitude of response as compared to the primary response, and an immunoglobulin class switch from IgM to IgG.
There are, however, a small number of antigens capable of activating B cells independently from T cell help referred to as T cell-independent (T-ind) antigens. They include among others bacterial capsular polysaccharides, like the capsular polysaccharide of Streptococcus pneumoniae, polymerized Salmonella flagellin, poly-D-amino acids and the E. coli lipopolysaccharide. T-ind antigens are characteristically of high molecular weight, with a repeating structure, and in most instances, are slowly degraded. They persist for long periods on the surface of specialized macrophages and can bind to antigen-specific B cells with great avidity through their multivalent attachment to the complementary immunoglobulin receptors which they crosslink. At high enough concentration, they have the ability to polyclonally activate a substantial proportion of the B cell pool, i.e. without reference to the antigen specificity of the surface receptor hypervariable region. In general, the T-ind antigens give rise to predominantly IgM responses, some IgG3 in the mouse, and relatively poor, if any, memory.
Capsulated bacteria such as Haemophillus influenza type b, Streptococcus pneumoniae, Neisseria meningitidis, group B Streptococci, and E. coli type K1, cause serious invasive diseases in humans, especially in infants and in immunocompromised individuals. Plasma anti-polysaccharide antibodies have been shown to be protective against invasive diseases caused by most of these pathogens and vaccines consisting of purified capsular polysaccharides (CPS) have been developed to induce such antibodies in the individuals at risk. Polysaccharides are, however, poor immunogens in infants, and their use as vaccines is seriously hampered by this fact. The reason for their poor immunogenicity is believed to be related to their belonging to the group of T-ind antigens.
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-dep antigens by exhibiting induction of immunological memory. There are similarities between conjugate polysaccharide vaccines and protein carrier-hapten systems. Thus the 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-ind antigens have been coupled to large immunogenic proteins such as tetanus toxoid, cholera toxin or diptheria toxoid. Nevertheless, the immunological response to high molecular weight carrier molecules harboring stimulatory as well as suppressive T cell epitopes are 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 h
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Hindersson,
Cohen Irun R.
Fridkin Matityahu
Konen-Waisman Stephanie
Woodward Michael P.
Yeda Research and Development Co. Ltd.
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