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Title:  Antibodies to meningococcal polysaccharide conjugate vaccines

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

Abstract

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 vaccines.

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 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 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 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.

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 Formula (II), 

   

wherein R2 is an unsaturated C2-4 group and the polysaccharide is covalently bound to a protein.


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If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

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