Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Reexamination Certificate
2000-06-23
2002-10-29
Caputa, Anthony C. (Department: 1642)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
C530S350000, C530S380000, C530S385000, C530S387100, C530S387700, C530S388100, C530S388200, C530S388400, C424S133100, C424S134100
Reexamination Certificate
active
06472511
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to methods for inducing humoral and cellular immune responses against tumor cells and infectious agents. In particular, this invention is directed to methods for stimulating an immune response using an antibody that binds with an epitope of an antigen that is associated with a tumor or an infectious agent, and that contains at least one &agr;-galactosyl epitope. The present invention also is directed to mutated antibodies that contain at least one &agr;-galactosyl epitope in an engineered glycosylation site located in the constant region of the heavy chain.
2. Related Art
Transplants performed between phylogenetically disparate species are known to be susceptible to hyperacute rejection which is initiated by binding of xenoreactive natural antibodies to endothelium in the donor organ. Binding of these antibodies activates complement, leading to tissue injury and destruction of the graft. For example, porcine organs transplanted into primates are nearly always rejected within hours. Fukushima et al.,
Transplantation
57:923 (1994); Pruitt et al., Transplantation 57:363 (1994).
The major xenoantigen responsible for such rejection has recently been identified as a single carbohydrate structure, the &agr;-galactosyl epitope (Gal&agr;1-3Gal&bgr;1-4GlcNAc-R). Galili et al.,
J. Exp. Med.
162:573 (1985); Galili et al.,
Proc. Nat'l Acad. Sci. USA
84:2369 (1987); Galili et al.,
J. Biol. Chem.
263:17755 (1988). The &agr;-galactosyl epitope is a glycosidic moiety that is expressed on the surface of cells from most mammalian species excluding humans and other old World primates (catarrhine primates). Expression of the &agr;-galactosyl epitope is mediated by the &agr;1,3galactosyl transferase, an enzyme which is absent in old World primates and humans. In humans, as much as 1% of the total serum IgG is specific for the &agr;-galactosyl epitope. Galili et al.,
J. Exp. Med.
160:1519 (1984); Avila et al.,
J. Immunol.
142:2828 (1989). Significant levels of anti-&agr;-galactosyl (“anti-Gal”) IgM and IgA have also been reported.
Recently, LaTemple et al.,
Cancer Res.
56:3069 (1996), reported their studies on conferring xenograft characteristics to human cells by ex vivo treatment of tumor cells with neuraminidase and recombinant &agr;1,3galactosyl transferase. The reaction converts the sialylated N-acetyllactosamine found on the human cell surface carbohydrate moieties into the &agr;-galactosyl epitope. Tumor cells armed with this epitope were reintroduced to the patients. The results indicated that anti-Gal antibodies help opsonize the tumor cells for phagocytosis by professional antigen presenting cells. LaTemple et al. hypothesized that the antigen presenting cells, after ingesting the “armed” tumor cells (tumor vaccines), would present the appropriate tumor-associated antigens (TAAs) to T cells, and that the patient would eventually develop a tumor-specific immunity. The exploitation of the hyperacute rejection mediated by anti-Gal activated complement, however, will require all tumor cells to be “induced” with the &agr;-galactosyl epitope, and was not and could not be addressed by this approach. Moreover, the vaccines of LaTemple et al. require removal of a patient's tumor cells, in vitro treatment with enzymes to produce the &agr;-galactosyl epitope, washing and lethal irradiation.
Galili et al., international publication No. WO 95/24924, describe a more general method for enhancing the immune response to an antigen by positioning an &agr;-galactosyl epitope either on or juxtaposed to the target antigen. According to this method, such a mixture stimulates opsonization by binding anti-Gal to &agr;-galactosyl epitopes which increases phagocytosis and subsequent processing of the target antigen by the macrophages. This general approach, however, also requires numerous ex vivo steps.
Therefore, the &agr;-galactosyl epitope has potential as a means to enhance the immune response to a target antigen, but a need exists for a method that does not depend upon extensive in vitro manipulation.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a method for enhancing the immune response to a tumor cell or infectious agent by using antibodies that contain the &agr;-galactosyl epitope to induce a patient's immune system to target an antigen associated with the tumor cell or infectious agent.
Another object of this invention is to provide mutated antibodies that contain at least one engineered glycosylation site with a carbohydrate moiety comprising at least one &agr;-galactosyl epitope.
These and other objects are achieved, in accordance with one embodiment of the present invention by the provision of a method for stimulating humoral and cellular immune responses in a mammal against a tumor that expresses a tumor associated antigen (TAA) or against a disease caused by an infectious agent, comprising the step of:
(a) administering an &agr;-Gal antibody to the mammal, wherein the &agr;-Gal antibody comprises:
(i) an antibody component that binds with a specified target epitope, wherein the target epitope is an epitope of a TAA or an epitope of an antigen associated with an infectious agent, and
(ii) at least one &agr;-galactosyl epitope,
wherein the &agr;-Gal antibody can form a complex with cells that express said target epitope and antibodies that bind the &agr;-galactosyl epitope.
REFERENCES:
patent: 95/24924 (1995-09-01), None
patent: 97/23637 (1997-07-01), None
Borrebaeck et al., “Does endogenous glycosylation prevent the use of mouse . . . cancer therapeutics?”, Immunology Today, vol. 14:10, pp. 477-479, 1993.
Thall et al., “Distribution of Gal&agr;l→3Ga1&bgr;1→4G1cNAc Residues on Secreted Mammalian . . . Radioimmuno-Assay”, Biochemistry, 29, pp. 3959-3965, 1990.
Latemple et al., “Cancer Research”, Synthesis of &agr;-Galactosy1 Epitopes by Recombinant . . . Anti-Galactose, vol. 56, pp. 3069-3076, Jul., 1996.
Leung et al., “The Journal of Immunology”, Engineering a Unique Glycosylation Site for Site-Specific Conjugation of Haptens to Antibody Fragments1, vol. 154, pp. 5919-5926, (1995).
Leung et al., “Int. J. Cancer”, Effect of VK Framework-1 Glycosylation on the Binding Affinity of . . . Potential Use as a Novel Conjugation Site,60, pp. 534-538, 1995.
Galili, “Immunology Today”, Interaction of the natural anti-Gal antibody with &agr;-galactosyl epitopes: a major obstacle for xenotransplantation in humans, vol. 14, No. 10, pp. 480-482, (1993).
Qu et al., “Glycobiology”, Structure determination of N-linked oligosaccharides engineered at the CH1domain of humanized LL2, vol. 7, No. 6, pp. 803-809, (1997).
U. Galili et al., A Unique Natural Human IgG Antibody with Anti-&agr;-Galactosyl Specificity J. Exp. Med. vol. 160, 11/84, pp. 1519-1531.
J.L. Avila et al., “Immunogenic Gal&agr;l→3Gal Carbohydrate Epitopes are Present on Pathogenic American Trypanosoma and Leishmania”, J. of Immun., vol. 142, No. 8, (1989) pp. 2828-2834.
U. Galili et al., “&agr;-Galactosyl (Gal&agr;;=3Gal&bgr;1-4GlcNac-R) epitopes on human cells: synthesis of the epitope on human red cells by recombinant primate”, Glycobiology, vol. 5, No. 8, pp. 775-782, (1995).
U. Galili et al., “Human Natural Anti-&agr;-Galactosyl IgG”, J. Exp. Med., vol. 162, (8/85), pp. 573-582.
U. Galili et al., “Evolutionary relationship between the natural anti-Gal antibody and the Gal&agr;l→Epitope in primates” Proc. Natl. Acad. Sci., vol. 84, pp. 1369-1373, (1987).
U. Galili et al., “Man, Apes, and Old World Monkeys Differ from Other Mammals in the Expression of &agr;-Galactosyl Epitopes on Nucleated Cells”, J. Biol. Chem., vol. 263, pp. 17755-17762, (1988).
U. Galili et al., “A Unique Natural Human IgG Antibody with Anti-&agr;-Galactosyl Specificity”, J. Exp. Med. vol. 160, pp. 1519-1531, (1984).
D. C. LaTemple, Synthesis of &agr;-Galactosyl Epitopes by Recombinant &agr;1,3Galactosyltransferase for Opsonization of Human Tumor Cell Vaccines by Anti-Galactose, Cancer Res. vol.
Leung Shui-on
Qu Zhengxing
Caputa Anthony C.
Harris Alana M.
Immunomedics Inc.
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