Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
2001-07-20
2003-07-22
Devi, S. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S197110, C424S193100, C424S184100, C424S203100, C424S257100, C424S831000, C436S123000
Reexamination Certificate
active
06596283
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to chemically-modified group B polysaccharides of
Neisseria meningitidis
. This invention also provides vaccines in which the respective modified polysaccharides are conjugated to a protein carrier, and the like.
BACKGROUND OF THE INVENTION
Meningitis caused by group B
N. meningitidis
and
E. coli
K1 remain major world health problems. Group B meningitis occurs in both endemic and epidemic situations and accounts for approximately half of all recorded cases of meningococcal meningitis, while K1-positive
E. coli
are the leading cause of meningitis in neonates. Currently there is no vaccine commercially available against disease caused by group B meningococci and
E. coli
K1. This is in large part due to the fact that the group B meningococcal polysaccharide (GBMP) is only poorly immunogenic in humans. This poor immunogenicity of native GBMP and resulting immune tolerance has been postulated to be due to the presence of a common epitope in human and animal tissue. There are some recently reported candidate vaccines based on complexes of the GBMP with outer membrane proteins, but, as yet, there is no clear evidence of their efficacy in humans.
Recently, a new concept of a vaccine based on a synthetic chemically modified (N-propionylated) group B polysaccharide-protein (N-Pr-GBMP-protein) conjugate has been developed. The vaccine induces in mice high titers of IgG antibodies which are not only protective, but also cross-react with unmodified GBMP (i.e. N-acetyl-GBMP). This concept is described and claimed in U.S. Pat. No. 4,727,136, issued Feb. 23, 1988 to Harold J. Jennings, et al.
It has been inferred that a vaccine which raises cross-reactive antibodies, such as that described in U.S. Pat. No. 4,727,136, could only be successful at the expense of breaking immune tolerance. This hypothesis is legitimized by the identification of a common epitope consisting of a chain of &agr;-(2-8)-linked sialic acid residues (with a minimum requirement of ten residues) in both the native N-Ac-GBMP and in human and animal tissue (Jennings,
Contrib. Microbiol. Immunol
. Basel, Karger, 1989, Vol. 10, 151-165). These polysialosyl chains function as developmental antigens and have for the most part been associated with the fetal state in embryonic neural cell adhesion (Finne et al,
Biochem. Biophys. Res. Commun.,
1983, 112, 482). During post-natal maturation, this antigen is down-regulated (Friedlander et al,
J. Cell Biol.
1985, 101, 412) but is expressed in mature humans during the regeneration of diseased muscles (Cashman et al,
Ann. Neuron.,
1987, 21, 481) in tumor cells (Roth et al,
Proc. Natl. Acad. Sci.,
1988, 85, 299) and in natural killer (NK) and CD3
+
T cells (Husmann et al,
Eur. J. Immunol.,
1989, 19, 1761. Although the consequences of breaking tolerance to these fetal antigens have not yet been established, it is desirable to develop vaccines which have reduced immunogenicity for human epitopes.
Therefore, an object of the present invention is to develop modified group B meningococcal polysaccharides which are immunogenic yet induce antibodies which have reduced cross-reactivity with native epitopes of the host. It is another object to provide polysaccharide-protein conjugates which comprise these modified polysaccharides. Another object of this invention is to provide vaccines having immunogenic properties which exhibits substantially reduced cross-reactivity with GBMP.
SUMMARY OF THE INVENTION
The present invention generally provides chemically-modified group B polysaccharides of
Neisseria meningitidis
. The present invention also provides for vaccines in which the respective modified polysaccharides are conjugated to a protein carrier.
Specifically, this invention provides for unsaturated group B N-acyl derivative polysaccharides of
N. meningitidis
, conjugates of the unsaturated N-acyl derivative polysaccharide covalently bound to proteins, pharmaceutical compositions comprising conjugate molecules of
N. meningitidis
unsaturated N-acyl derivative polysaccharides, and the use of these compositions as vaccines.
In one aspect of the invention, there is provided a modified B polysaccharide of
N. meningitidis
having sialic acid residue N-acetyl (C
2
) groups replaced by an unsaturated C
3-5
acyl group.
In another aspect, there is provided an antigenic conjugate comprising unsaturated C
3-5
N-acyl derivative polysaccharides conjugated to an immunologically suitable protein, having enhanced immunogenicity compared to native polysaccharides with reduced inducement of cross-reactive antibodies.
In a further aspect, there is provided a vaccine comprising the unsaturated N-acyl derivative polysaccharide-protein conjugate in association with a suitable carrier or diluent. The vaccines of the invention may also comprise a therapeutically effective amount of an adjuvant suitable for human use, for example aluminum phosphate, aluminum hydroxide or stearyl tyrosine.
In a yet further aspect, there is provided a method of immunizing mammals against
N. meningitidis
and
E. coli
K1 infections, which method comprises administering parentally to mammals subject to such infections, including humans, an immunologically effective amount of the vaccine of the invention. The vaccine is typically administered in an amount of about 1 to 50 micrograms per kilogram body weight, for example 5 to 25, micrograms per kilogram body weight.
In yet another aspect, the invention provides serum and a gamma globulin fraction capable of protection against meningitis caused by group B
N. meningitidis
and
E. coli
K1. The fraction is produced by immunizing a mammal with a vaccine of the invention and preferably separating the gamma globulin fraction from the immune serum. The fraction is then administered to an individual to provide protection against or to treat on-going infection caused by the above organisms. From this, it will be appreciated that the immunogenic vaccine conjugates of the invention will be a source of therapeutic antiserum in light of their favorable immunogenicity with minimal inducement of GBMP cross-reactive antibodies. The conjugates of the invention will also be useful for raising monoclonal antibodies and, possibly, antiidiotype antibodies.
We have found that most of the bactericidal and protective antibodies induced by the N-Pr-GBMP-protein conjugate described in the above-referred to Jennings et al U.S. Pat. No. 4,727,136 are not associated with the GBMP cross-reactive antibodies. In fact, most of the protective activity is contained in an N-Pr-GBMP-specific antibody population which does not cross-react with GBMP. In light of this, it is believed that the N-Pr-GBMP mimics a unique bactericidal epitope on the surface of group B meningococci.
The present invention is based on the discovery that it is possible to synthesize chemically modified GBMP's which mimic the bactericidal epitope and which, in their conjugated form, not only exhibit enhanced immunogenicity but also avoid substantially the inducement of antibodies that do cross-react with GBMP.
In arriving at the present invention, different chemically modified GBMP's have been synthesized and conjugated individually to protein, followed by injection of the conjugates into mice and the effects compared to those produced by the N-Pr-GBMP protein conjugate. Surprisingly, it has now been found that the presence of an unsaturated bond in the N-acyl results in particularly immunogenic conjugates
These and other features of the invention will be better understood through a study of the following detailed description of a specific embodiment of the invention. The scope of the invention is limited only through the claims appended hereto.
DETAILED DESCRIPTION OF THE INVENTION
This invention generally provides novel group B Neisseria meningitidis unsaturated N-acyl derivative polysaccharides, novel conjugates of the group B unsaturated N-acyl derivatives, pharmaceutical compositions comprising conjugate molecules of group B
Neisseria meningitidis
unsaturated N-
Jennings Harold J.
Lussier Michele
Michon Francis
Pon Robert
Devi S.
Morgan & Finnegan , LLP
National Research Council of Canada
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