Title: Antibodies to meningococcal polysaccharide
United States Patent: 6,350,449
Inventors: Jennings; Harold J. (Gloucester, CA); Pon; Robert
(Aylmer, CA); Lussier; Michele (St. Augustin-des-Maures, CA); Michon;
Francis (Laurel, MD)
Assignee: Baxter International Inc. (Deerfield, IL)
Appl. No.: 357491
Filed: July 20, 1999
The invention relates to chemically-modified group B polysaccharides of
Neisseria meningitidis. The invention also provides vaccines in which the
respective modified polysaccharides are conjugated to a protein carrier,
and the like, as well as antibodies to these conjugate vaccines. More
specifically, the present invention provides novel group B meningococcal
unsaturated N-acyl derivative polysaccharides, novel conjugates of the
group B meningococcal unsaturated N-acyl derivative polysaccharides,
pharmaceutical compositions comprising conjugate molecules of group B
meningococcal unsaturated N-acyl derivative polysaccharide fragments
covalently bound to proteins, and the use of these compositions as
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 (C2)
groups replaced by an unsaturated C3-5 acyl group.
In another aspect, there is provided an antigenic conjugate comprising
unsaturated C3-5 N-acyl derivative polysaccharides conjugated
to an immunologically suitable protein, having enhanced immunogenicity
compared to native polysaccharides with reduced inducement of
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 parenterally 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
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.
Claim 1 of 12 Claims
What is claimed is:
1. An immune composition comprising antibodies raised in a mammal
immunized with a conjugate molecule comprising at least one polysaccharide
having a structure of a modified group B meningococcal polysaccharide
wherein the modification comprises substitution of N-acetyl groups of the
group B meningococcal polysaccharide with unsaturated acyl groups of
wherein R2 is an unsaturated C2-4 group and the
polysaccharide is covalently bound to a protein.
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