Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Reexamination Certificate
1998-10-15
2002-03-26
Minnifield, Nita (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
C424S218100, C424S816000, C424S278100, C424S156100, C424S155100, C424S277100, C530S387100
Reexamination Certificate
active
06361775
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to cancer and viral vaccines.
BACKGROUND OF THE INVENTION
The basic rationale for immune therapy against tumors is the induction of an effective immune response against tumor-associated antigens (TAA), which in turn results in immune-mediated destruction of proliferating tumor cells expressing these antigens. For an immune response to be effective against TAAs comprising protein, these antigens must first be endocytosed by macrophages. Within macrophages, TAAs are degraded in the lysosomal compartment and the resulting peptides are expressed on the surface of the macrophage cell membrane in association with MHC Class II molecules. This expression mediates recognition by specific CD4
+
helper T cells and subsequent activation of these cells to effect the immune response (Stevenson, 1991, FASEB J. 5:2250; Lanzavecchia, 1993, Science 260:937; Pardoll, 1993, Immunol. Today 14:310). The majority of human TAA molecules have not been defined in molecular terms and as a consequence, no generic version of these molecules is available for exploitation as a potential anti-tumor vaccine. Attempts to modify autologous tumor cells in each individual patient as a means of eliciting an immune response to TAAs have met with little success. In order for autologous TAA-expressing tumor cells to function as effective vaccines, they must be opsonized in some manner so that their phagocytosis by macrophages is enhanced.
To date, available viral vaccines comprise either infectious, attenuated live virus, non-infectious killed virus or subunits thereof. While live attenuated virus is a more efficacious vaccine than killed virus, vaccines of this type are often genetically unstable and thus, have the potential to revert to a wild type, virulent phenotype. In addition, administration of live attenuated vaccines is contraindicated in immunocompromised individuals and in pregnant women. Non-infectious, killed virus vaccines and vaccines comprising viral subunits also have disadvantages in that they have insufficient immunogenic properties and must be administered in high concentrations at frequent intervals.
Anti-Gal, a naturally occurring antibody present in all humans, specifically interacts with the carbohydrate epitope Gal&agr;1-3Gal&bgr;1-4GlcNAc-R (&agr;-galactosyl epitope). This antibody does not interact with any other known carbohydrate epitope produced by mammalian cells (Galili, 1993, Springer Seminar Immunopathology 15:153). Anti-Gal constitutes approximately 1% of circulating IgG (Galili et al., 1984, J. Exp. Med. 160:1519) and is also found in the form of IgA and IgM (Davine et al., 1987, Kidney Int. 31:1132; Sandrin et al., 1993, Proc. Natl. Acad. Sci. USA 90:11391). It is produced by 1% of circulating B lymphocytes (Galili et al., 1993, Blood 82:2485).
Both anti-Gal and &agr;-galactosyl epitope exhibit a unique distribution pattern in mammals. Anti-Gal is produced abundantly in humans, apes and Old World monkeys, but is absent in New World monkeys, prosimians and non-primate mammals (Galili et al., 1987, Proc. Natl. Acad. Sci. USA 84:1369). In contrast, the &agr;-galacyosyl epitope is found as part of the terminal carbohydrate structure on glycolipids and on carbohydrate chains of glycoproteins, in particular on asparagine (N)-linked carbohydrate chains, in non-primate mammals, prosimians and New World monkeys, but is absent in Old World monkeys, apes and humans (Galili et al., 1987, Proc. Natl. Acad. Sci. USA 84:1369; Galili et al., 1988, J. Biol. Chem. 263:17755).
Asparagine (N)-linked carbohydrate chains similar to those present on mammalian cells, are found attached to envelope glycoproteins of viruses which bud from vertebrate cells (Klenk, 1990, p. 25-37. In: Regenmortel and Neurath (ed.). Immunochemistry of Viruses, II. The Basis for Serodiagnosis and Vaccines. Elsevier Publishers B.V., N.Y.). These carbohydrate chains most often are of the simple high-mannose type containing mannose and N-acetylglucosamine only or of the complex type wherein they contain additional carbohydrates such as galactose, N-acetylglucosamine, fucose and sialic acid. Oligosaccharide chains on viral glycoproteins are synthesized in large part by host cell glycosylation enzymes (Kornfeld et al., 1985, Ann. Rev. Biochem. 54:631; Schlesinger et al., 1986, p. 121-148. In: Schlesinger and Schlesinger (ed.), The Togaviridae and Flaviviridae, Plenum Press, N.Y.; Rademacher et al., 1988, Ann. Rev. Biochem. 57:785)).
Sialylated N-linked complex carbohydrate chains are common on viral glycoproteins and on cell surface glycoproteins since sialyltransferases, which are prevalent in the Golgi apparatus of all mammalian cells, “cap” N-acetyllactosaminyl residues of viral carbohydrate chains with sialic acid (Klenk et al., 1980, Curr. Topics Microbiol. Immunol. 90:19-48; Kornfeld et al., 1985, Ann. Rev. Biochem,. 54:631; Rademacher et al., 1988, Ann. Rev. Biochem. 57:785). Geyer et al. (1984, Biochemistry 23:5628) report &agr;-galactosyl epitopes as a major carbohydrate structure on Friend murine leukemia virus.
SUMMARY OF THE INVENTION
The invention encompasses compositions and methods for enhancing an immune response to an antigen in an anti-Gal synthesizing animal. In order to elicit an effective, protective immune response to a vaccine, the vaccinating antigen must be processed in vivo by antigen-presenting cells or macrophages. Processing includes uptake of antigen by macrophages, fragmentation of antigen within the lysosomal compartment of these cells and ultimately, presentation of the fragmented peptide on the membrane of the macrophage in association with class II major histocompatibility (MHC) molecules. According to the methods and compositions of the invention, an immune response to an antigen is enhanced by positioning &agr;-galactosyl epitopes either on or juxtaposed to the antigen. When an antigen so treated is administered to an anti-Gal synthesizing animal, opsonization of the antigen is effected by binding of anti-Gal to the &agr;-galactosyl epitopes thereby enhancing phagocytosis and subsequent processing of the antigen by macrophages.
In one aspect, the invention features a method of inducing an immune response to an antigen in an anti-Gal synthesizing animal comprising providing an &agr;-galactosyl epitope containing complex, which complex includes the antigen and a lipid bilayer, and administering an immunizing effective amount of the complex to the animal.
In another aspect, the invention features a method of opsonizing an antigen in an anti-gal synthesizing animal comprising providing an &agr;-galactosyl epitope containing complex, which complex includes the antigen and a lipid bilayer, and administering an immunizing effective amount of the complex to the animal.
In both aspects, the antigen is preferably positioned so that it is juxtaposed to the lipid bilayer. More preferably, the antigen is either inserted in or encapsulated by the lipid bilayer.
In yet another aspect, the invention features a method of opsonizing an antigen in an anti-Gal synthesizing animal comprising encapsulating the antigen in a lipid bilayer to form a complex, incubating the complex in the presence of &agr;-galactosyl epitope containing glycosphingolipids to effect insertion of the &agr;-galactosyl epitopes into the lipid bilayer, and administering the complex so incubated to the animal.
In another aspect, the invention features a method of opsonizing a tumor cell in an anti-Gal synthesizing animal having a tumor comprising obtaining the tumor cell from the animal, incubating the cell in the presence of a preparation of &agr;-galactosyl containing glycosphingolipids to effect insertion of the &agr;-galactosyl epitopes into the membrane of the cell, irradiating the cell so treated and then administering the cell to the animal.
In yet another aspect, the invention features a method of opsonizing a tumor associated antigen in an anti-Gal synthesizing animal having a tumor comprising obtaining a tumor associated antigen containing cell from the animal, extracting the cell me
Galili Uri
Repik Patricia M.
Drinker Biddle & Reath LLP
Medical College of Pennsylvania
Minnifield Nita
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