R24, IgG3 mouse monoclonal antibody (mAb) raised against a human melanoma, (ATCC Accession No. HB 8445) recognizes the GD3 ganglioside. The GD3 ganglioside is abundantly expressed on most melanomas, however, expression of the GD3 ganglioside on normal tissue is selective and occurs at low concentrations (1). Gangliosides are a subset of glycosphinogolipids which in turn are a subset of glycolipids. Glycolipids, as their name implies, are sugar-containing lipids.
R24 comprises a known mixture of three variant antibody species (FIG. 11) designated V1-V24, V2-R24, and R24. The V1-R24 and V2-R24 variants comprise one and two irrelevant antibody light chains, respectively; in contrast. R24 comprises relevant light chains. Generally, light and heavy antibody chains in combination effect specific antibody-antigen binding. However, antibodies comprising irrelevant antibody light chains, unlike antibodies comprising relevant antibody light chains, do not specifically bind an antigen.
In order to avoid confusion, the R24 variant from hereinafter will be referred to as xe2x80x9cR24xe2x80x9d and R24 comprising the three variant species will be referred to as the xe2x80x9cR24 composition.xe2x80x9d Each variant exhibits differences which imply that the GD3-binding region (also termed xe2x80x9cparatopexe2x80x9d) of V1-R24, V2-R24, and R24 are altered.
Anti-idiotypic monoclonal antibodies which mimic and possess the internal image of a saccharidic epitope have been developed (2). The saccharidic epitope is a tumor associated globoside, i.e. a glycolipid. However, these anti-idiotypic monoclonal antibodies do not specifically mimic a glycosphingolipid, a ganglioside, or more particularly the GD3 ganglioside. Additionally, these anti-idiotypic monoclonal antibodies are not directed against R24 or any antibodies which specifically bind a glycosphingolipid or a ganglioside, let alone the GD3 ganglioside.
Mice have been primed against capsular antigens of pathogenic bacteria by administration of monoclonal anti-idiotypic antibodies which mimic the polysaccharide capsule of E. coli (a gram negative bacteria) (3). It is generally known that lipopolysaccharides (LPS) is a major component of the outer membrane of gram negative bacteria and is released when bacteria are lysed. LPS consists of a heteropolysaccharide chain linked coavlently to a glycolipid. It is important to point out that although these monoclonal anti-idiotypic antibodies were used as a means to prime a subject against a LPS, there is no suggestion of generating monoclonal anti-idiotypic antibodies against R24 or any antibodies which would specifically bind glycosphingolipids or gangliosides, in particular the GD3 ganglioside.
The GD3 ganglioside is poorly immunogenic (1). Accordingly, the GD3 ganglioside is an appealing target for cancer immunotherapy because of the commercial utility of designing molecules which would structurally mimic GD3 and possess dramatically significant immunogenic properties.
The present invention also provides an anti-idiotypic monoclonal antibody which specifically induces an immune response against a glycosphingolipid and more specifically against a ganglioside. Additionally, this invention provides a composition of matter comprising an effective amount of a cytokine and a melanoma ganglioside-specific antibody attached to a carrier. Finally, this invention provides a method of generating the previously-identified anti-idiotypic antibody which comprises: (a) preparing an antibody; (b) purifying the antibody; (c) attaching the antibody onto a carrier so as to produce an immunogen; (d) combining the immunogen with a cytokine so as to produce a novel immunogen-cytokine combination; and (e) injecting the novel immunogen-cytokine combination into a mammal thereby producing the anti-idiotypic antibody.
USPTO Backgrounds
USPTO Backgrounds