Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific... – Synthetic or structurally-modified peptidoglycan or...
Reissue Patent
2000-08-25
2003-03-25
Stucker, Jeffrey (Department: 1648)
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
Synthetic or structurally-modified peptidoglycan or...
C424S093710, C424S184100, C530S395000
Reissue Patent
active
RE038046
ABSTRACT:
BACKGROUND OF THE INVENTION
Vertebrates have two basic immune responses: humoral or cellular. Humoral immunity is provided by the special class of cells produced by B lymphocytes. These cells produce antibodies which circulate in the blood and lymphatic fluid. On the other hand, cell mediated immunity is provided by the T cells of the lymphatic system.
The cellular immune response is particularly effective against fungi, parasites, intracellular viral infections, cancer cells and foreign matter, whereas the humoral response primarily defends against the extracellular phases of bacterial and viral infections.
Containment of antigen at its point of entry is accomplished by walling off the area by local inflammation. Acute inflammation is characterized by the influx of plasma proteins and polymorphonuclear leukocytes. Chronic inflammation is characterized by the infiltration of T-lymphocytes and macrophages. When acute (antibody induced) and, chronic (T-cell induced) inflammations occur in the skin, they are called immediate and delayed type hypersensitivity reactions respectively.
Epiglycanin (epi) is the major cell surface glycoprotein produced by the mammary adenocarcinoma transplantable cell line TA3Ha. Friberg, Jr., J.N.C.I., 48:1463 (1972); Codington, et al., Cancer Res. 43:4373 (1983). The TA3Ha carcinoma cells are covered by a mucin-like glycocalix composed mainly of epiglycanin. Codington, et al., J.N.C.I., 60:811 (1978); Miller, et al., J.N.C.I., 68:981 (1982). Epi is mainly carbohydrate in composition, and expresses multiple T and Tn determinants T and Tn are general carcinoma autoantigens. Springer, Science, 224:1198 (1984).
Synthetic T and Tn antigens have been prepared, and used in DTH diagnostics. Lemieuax, EP Appl. 44,188. However, their therapeutic or prophylactic use has not been disclosed.
Bretscher, Eur. J. Immunol., 9:311-316 (1979) cultured DTH-Effector cells in vitro and injected them with the sensitizing antigen (burro erythrocytes) into the foot pads of mice. We have used cancer-associated, well characterized carbohydrate antigens to sensitize effector cells and have taught a therapeutic use for them.
It is known that tumors may be treated with a mixture of IL-2 and IL-2-activated killer cells. See Fortune, pages 16-21 (Nov. 25, 1985), reporting on the work of Steven Rosenberg. The IL-2 induces a general immune response. It thus places a heavy burden on the immune system, diverting resources from the desired cellular response. High, possibly toxic levels of IL-2 are required to induce a cellular response. At these levels, it may unintentionally induce an autoimmune response. Our procedure induces a response which is specific, because the cells recognize a cancer-associated carbohydrates markers. Only a low level of our inducer is required to stimulate the cellular immune system.
SUMMARY OF THE INVENTION
We have found that the cell-mediated immune response to cancer cells is enhanced by parenteral administration of natural and synthetic cancer-associated carbohydrate antigens or by parenteral administration of DTH effector cells primed by such antigens. This enhancement is likely to be advantageous for both therapy and prophylaxis when the body's primary defense against a challenge is a cellular immune response, e.g., against tumors. The use of other specific carbohydrate antigens, including polysaccharides, glycolipids and glycoproteins, may be useful in protecting a subject against other threats controlled by T cells. It is known that parasites, viruses, bacteria and fungi bear surface carbohydrate determinants.
While we do not favor the use of lymphokines (e.g., IL-2) alone to induce a general cellular immune response, lymphokines may be used in conjunction with the specific antigens or primed DTH-Effector cells of this invention to enhance the specific CMI response.
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Codington, JF et al., “Further Studies on the Relationship Between Large Glycoprotein Molecules and Allotransplantability in the TA3 Tumor of the Mouse: Studies on Segregating TA3-Ha Hybrids”, J. Natl. Cancer Inst.6(4):811-818 (Apr. 1978).*
Codington, JF et al., “Cell Surface Characteristics of an Allotransplantable TA3 Ascites Subline Resulting from a Process of Immunoselection”, Cancer Research 43:4373-4381 (Sep. 1983).*
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Bretscher, PA, “In vitro Induction of delayed-type hypersensitivity”, Eur. J. Immunol. 9:311-316 (1979).
Henningsson Carina
Longenecker B. Michael
Biomira, Inc.
Cooper Iver P.
Stucker Jeffrey
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