Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Binds specifically-identified oligosaccharide structure
Reexamination Certificate
2001-05-17
2004-01-13
Devi, S. (Department: 1645)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Binds specifically-identified oligosaccharide structure
C424S150100, C424S135100, C424S165100, C530S387300, C530S387500, C530S388400, C530S300000
Reexamination Certificate
active
06676938
ABSTRACT:
The present invention relates to compounds that are capable of eliciting a protective immune response against the capsular polysaccharide of group B Streptococcus (GBS), particularly type III GBS. Such compounds are useful in the development of vaccines that are effective against diseases caused by these pathogens.
Group B streptococci (GBS) are recognised as a major cause of sepsis and meningitis in neonates and in susceptible adult patients such as those suffering from diabetes, cirrhosis and solid tumours. Although the use of antibiotics has had a dramatic impact on case fatality rate, the attack rates for infection have changed little. Indeed, even in industrialised countries, the incidence of mortality and permanent disability remains high in spite of appropriate therapy being applied.
GBS are classified into serotypes based on specific type of capsular polysaccharides (CHO) possessed by the organism. The capsular polysaccharide has anti-phagocytic properties and is considered to be the main virulence factor of GBS (Baker et al., 1995; Rubens et al., 1987). Capsular type III GBS are responsible for the majority of neonatal infection and for approximately 90% of meningitis cases (Baker et al., 1995).
Immunisation of fertile women with a combination of type-antigens has been proposed as a strategy for the prevention of neonatal disease, with the rationale that specific antibodies passing through the placental barrier can prevent neonatal infection (Baker et al., 1981). Indeed, a significant correlation has been shown between GBS infection in neonates and low levels of maternal antibodies to the type-specific CHO (Baker et al., 1981; Baker et al., 1976).
Polysaccharide vaccines have been developed in an attempt to control the incidence of diseases caused by GBS. The major problem with the capsular polysaccharide vaccines is their poor immunogenicity. This is believed to derive from the T-cell independent (TI) type of immune reaction that is the only antibody response used by the body against polysaccharide antigens. This type of response does not involve MHC Class II restriction molecules for antigen presentation to T-cells; as a consequence, T-cell help is prevented.
A widely accepted method to potentiate the immunogenicity of polysaccharide antigens is by their conjugation with proteins. To a large extent, this approach has been successful in the prevention of
Haemophilus influenzae
type b infections (Ala'Aldeen and Hormaeche, 1995). Type CHOs conjugated with tetanus toxoid (Paoletti et al., 1994; Kasper et al., 1996; Baker et al., 1996) or GBS proteins (Madoff et al., 1992; Larsonn et al., 1996) are currently being evaluated as potential vaccines for the prevention of GBS disease.
An alternative strategy to obtain effective and boostable antibody responses against carbohydrate antigens involves the development of protein molecules mimicking the conformation of relevant carbohydrate epitopes. The advantage of this approach is that, by their chemical nature, proteins have an intrinsic ability to stimulate T cell help in an antigen-specific way. This strategy resulted in the development of a monoclonal antiidiotypic antibody (mAb) coupled to a carrier protein that was successfully used as a surrogate vaccine to immunoprotect BALB/c mice against lethal
Streptococcus pneumoniae
infection (McNamara et al., 1984). Monoclonal antibodies mimicking the K13
Escherichia coli
(Stein et al., 1984) and the group C
Neisseria meningitidis
(Westerink et al., 1988) capsular antigens have also been described.
However, although these reports illustrate the concept that compounds can be generated that to some extent mimic the antigenic determinants of capsular polysaccharides, it is widely-appreciated in the art that the specific compounds developed so far (mouse monoclonal antibodies) are unlikely human vaccine candidates and are often ineffective in conferring long-lasting protective immunity. Furthermore, no such compounds have to date been generated that are effective against GBS.
There thus remains a great need for the development of new, improved vaccine strategies that are effective in combating diseases caused by GBS and in particular for a compound that is capable of eliciting a protective immune response against GBS when used as a vaccine.
SUMMARY OF THE INVENTION
According to the present invention there is provided a peptide, oligopeptide or polypeptide compound that is capable of eliciting a protective immune response against the capsular polysaccharide of group B Streptococcus. Such compounds are useful as immunogenic compounds and may in turn be useful as components of vaccines that are protective against diseases caused by GBS.
Preferably, the compounds are capable of eliciting a protective immune response against the type III capsular polysaccharide of group B Streptococcus, which is widely recognised as being the major virulence determinant of GBS. Neonatal protection can be obtained by immunising mothers with these compounds.
By the term “protective immune response” is meant the development of a beneficial humoral response and/or a cellular response that is directed against the compound of the invention in an animal or human patient. A humoral response is antibody-mediated and involves the generation of antibodies with affinity for the compounds of the invention. This means that upon GBS invasion of an individual who has been immunised with a compound according to the invention, the individual's immune system will possess an immunologic memory of the compound and will be therefore able to mount an immediate humoral attack against the GBS organisms.
A cellular response is elicited by the presentation of antigenic epitopes in association with Class I or Class II molecules of the major histocompatibility complex (MHC). This activates antigen-specific CD4+ T helper cells or CD8+ cytotoxic T lymphocyte cells.
Species in which the compounds of the present invention may be effective in eliciting an immune response include all mammals, especially humans. In most cases, it will be preferred that the compounds are active eliciting an immune response in humans. The population of humans that are in greatest need of protection from disease caused by GBS are neonates. However, various sectors of the adult population are also at risk, particularly those who are suffering from debilitating chronic disease such as diabetes, cirrhosis or who carry a solid tumour.
An effective strategy to protect neonates involves the elicitation, in mothers, of antibodies that are capable of crossing the placental barrier. Such antibodies belong to the IgG class and are produced only in response to antigens capable of stimulating both B and T lymphocytes (T-dependent antigens). The compounds provided according to the present invention have the ability to stimulate the production of specific IgG. Moreover, maternal immunisation with these compounds is effective to protect neonates from GBS disease.
By peptide is meant a compound of between 3 and 10 amino acids covalently coupled together. An oligopeptide will comprise between 10 and 30 linked amino acids, whilst a polypeptide will contain greater than 30 amino acids.
The structure of the peptide, oligopeptide or polypeptide compounds according to the invention will be such as to contain in the folded three-dimensional structure an epitope that mimics an immunological determinant group of the capsular polysaccharide of group B Streptococcus. Preferably, this epitope mimics an immunological determinant group of the type III capsular polysaccharide of group B Streptococcus.
Peptides and oligopeptides are ideal candidates for use as immunogenic compounds due to their small size; these molecules are sufficiently large to mimic antigenic epitopes (that are typically determined by between 5 and 12 amino acids), yet are small enough to possess pharmacokinetic properties that are advantageous over those of more bulky molecules such as immunoglobulins. By their chemical nature, these molecules possess an intrinsic ability to stimulate T cell
Polonelli Luciano
Teti Giuseppe
Blackburn Robert P.
Chiron S.r.L.
Devi S.
Hale Rebecca M.
Robins Roberta L.
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