Gram-positive encapsulated bacterium Streptococcus pneumoniae (pneumococcus) is a major cause of morbidity and mortality worldwide. They colonize the upper respiratory tract and cause invasive pneumococcal diseases such as meningitis, bacteremia and bactermic pneumonia, and non-invasive pneumococcal diseases including acute otis media and pneumonia. These diseases are prevalent in young children, the elderly and immunocompromised individuals of all ages. In developing countries Streptococcus pneumoniae related diseases cause an estimated 1.2 million deaths annually of young children.
Structurally, three distinguished layers can be seen on the bacterial surface: plasma membrane, cell wall and capsule. The cell wall consists of a peptidoglycan backbone anchoring the cell wall polysaccharide (C-polysaccharide) and the capsular polysaccharide (CPS). The C-polysaccharide is a structure common to all the pneumococcal serotypes, whereas CPS is specific to each of the 90 know serotypes and is the main virulence factor.
Out of the 90 serotypes the most common and prevalent serotypes found in the world are shown in FIG. 1. This distribution varies also based on geography and age difference. Thus, a vaccine comprising glycoconjugates containing an immunogenic carrier and saccharide structures derived from the capsular polysaccharide of the most common and prevalent Streptococcus pneumoniae serotypes would provide immunization against a high percentage of the diseases caused by this class of Gram-positive bacteria.
Several poly-valent pneumococcal vaccines were manufactured up to present. The commercially available 23-valent pneumococcal polysaccharide vaccine (PPV), contains purified capsular polysaccharide (CPS) antigens of 23 serotypes. However, this vaccine is not effective in the case of infants and young children. The currently marketed pneumococcal conjugate vaccine (PCV), PCV-7 (Prevnar™) contains saccharides of capsular antigens of serotype 4, 6B, 9V, 14, 18C, 19F and 23F individually conjugated to diphtheria CRM197 and is effective in infants.
The currently marketed vaccines are effective in North America and Europe for individuals of a particular age. The manufacturing process for these vaccines is complex and results in a higher price. Therefore, the vaccine is unaffordable in most developing countries. It is the object of the present invention to provide affordable synthetic saccharide vaccines that contain most of the prevalent serotypes of the developing world.
Streptococcus pneumoniae type 1 (SP1) is one of the most prevalent S. pneumoniae serotypes. Streptococcus pneumoniae type 1 capsular polysaccharide is a linear polymer having as a repeating unit: [→3)-α-2,4,6-trideoxy-4-amino-D-GalNAc-(1→4)-α-D-GalAp-(1→3)-α-D-GalAp-(1→].
Synthetic saccharide structures derived from [→3)-α-2,4,6-trideoxy-4-amino-D-GalNAc-(14)-α-D-GalAp-(1→3)-α-D-GalAp-(1→] trisaccharide repeating unit of Streptococcus pneumoniae type 1 capsular polysaccharide were already reported. However, the method developed by Bundle (Chem. Eur. J. 2010, 16, 3476.) provides α-methoxy saccharides, which are not suitable for conjugation to an immunogenic carrier.
It is the objective of the present invention to provide an improved synthetic route to access saccharide structures functionalized with a linker, said saccharide structures being derived from [→3)-α-2,4,6-trideoxy-4-amino-D-GalNAc-(1→4)-α-D-GalAp-(1→3)-α-D-GalAp-(1→] trisaccharide repeating unit of Streptococcus pneumoniae type 1 capsular polysaccharide. Said saccharide structures have the advantage of being functionalized with a linker thus, being suitable to be conjugated to an immunogenic carrier. Therefore, it is an objective of the present invention to provide glycoconjugates and pharmaceutical compositions containing said glycoconjugates for immunization against diseases associated with bacteria containing in their capsular polysaccharide one of the following structures: α-2,4,6-trideoxy-4-amino-D-GalNAc-(1→4)-α-D-GalAp-(1→3)-α-D-GalAp; α-2,4,6-trideoxy-4-amino-D-GalNAc-(1→4)-α-D-GalAp; α-D-GalAp-(1→3)-α-D-GalAp; α-D-GalAp; α-2,4,6-trideoxy-4-amino-D-GalNAc; α-D-GalAp-(1→3)-α-D-GalAp-(1→3)-α-2,4,6-trideoxy-4-amino-D-GalNAc; α-D-GalAp-(1→3)-α-2,4,6-trideoxy-4-amino-D-GalNAc; α-D-GalAp-(1→3)-α-2,4,6-trideoxy-4-amino-D-GalNAc-(1→4)-α-D-GalAp. The pharmaceutical compositions comprising the saccharides of general formula (I) and/or the intermediates of general formula (II) and/or the glycoconjugates according to the present invention are for use in immunization against diseases associated with bacteria, and especially associated with Streptococcus pneumoniae, said diseases including pneumonia, meningitis, otitis media, bacteremia and acute exacerbation of chronic bronchitis, sinusitis, arthritis and conjunctivitis
The objective of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the figures, and the examples of the present application.
USPTO Backgrounds
USPTO Backgrounds