| Methods and compositions using cellular asialodeterminants and glycoconjugates for targeting cells to tissues and organs -> Monitor Keywords |
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Methods and compositions using cellular asialodeterminants and glycoconjugates for targeting cells to tissues and organsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Whole Live Micro-organism, Cell, Or Virus Containing, Genetically Modified Micro-organism, Cell, Or Virus (e.g., Transformed, Fused, Hybrid, Etc.), Eukaryotic CellMethods and compositions using cellular asialodeterminants and glycoconjugates for targeting cells to tissues and organs description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070110734, Methods and compositions using cellular asialodeterminants and glycoconjugates for targeting cells to tissues and organs. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims the benefit of U.S. Provisional Patent Application No. 60/364,498, filed Mar. 15, 2002, the entirety of which is incorporated by reference herein for all purposes. FIELD OF THE INVENTION [0002] The present invention is in the field of clinical medicine and therapy. The invention relates to methods and compositions for targeting cells to an organ of interest, using sialo- or asialodeterminants, particularly neoasialodeterminants, on cell surfaces and/or on free glycoconjugates. BACKGROUND OF THE INVENTION [0003] Morell et al. determined that when a sialyl group of ceruloplasmin is removed by neuraminidase, this plasma protein rapidly disappears from serum. They disclosed that this phenomenon is due to the uptake by the asialoglycoprotein (ASGP) receptor present in liver cells (J. Biol. Chem., 243:155 (1968)). Thereafter, it was reported that the ASGP receptor is present only in liver cells (Adv. Enzymol., 41:99, (1974)). Such specific uptake by liver cells has been identified from the fact that when asialoceruloplasmin or asialoorosomucoid, which is experimentally labeled with tritium, is injected into the living body, the isotope is selectively detected only in liver cells. Scheinberg, I. H., et al., Hepatic removal of circulating proteins, in Davidson C. S., ed. Problems in Liver Diseases, pp. 279-285, New York, Stratton Company, (1979). In addition, it was also disclosed that this receptor specifically recognizes and absorbs glycoproteins having D-galactose or N-acetylgalactosamine as the terminal sugar group (Ann. Rev. Biochem. 51:531, (1982)). [0004] The cell membrane of liver cells comprises a cell structure which combines with asialoglycoprotein terminated with galactose. This cell structure was first named hepato-binding protein (HBP) but is presently called asialoglycoprotein (ASGP) receptor. Further, it has been observed that among various desialylated glycoproteins, the desialylated alpha(1)-acid glycoprotein, asialoorosomucoid, most rapidly disappears from the serum after injection. Therefore, it has been determined that asialo-alpha(1)-acid glycoprotein is both specifically and well taken up by liver cells (J. Biol. Chem., 245:4397 (1970)). The ASGP receptor is constituted with a single polypeptide having a molecular weight of about 40,000 and can recognize a glycoprotein having a galactose residue at the nonreductive terminal position of the saccharide chain (i.e., asialoglycoprotein). [0005] While the physiological functions of an ASGP receptor are still uncertain, it is believed that an ASGP receptor participates in the metabolism of glycoproteins. In fact, the increase of the blood level of an ASGP is observed in case of hepatic diseases such as chronic hepatitis, liver cirrhosis and hepatic cancer. Further, the decrease of the quantity of an ASGP receptor is observed in an experimental model of hepatic disorder induced by administration of chemicals. [0006] In view of these phenomena, it may be possible to diagnose hepatic diseases through assessment of the quantity and quality of an ASGP receptor determined by the use of an ASGP-like substance, i.e., an ASGP receptor-directing compound. In fact, asialoglycoconjugates have been covalently linked to other agents as a means of targeting chemical (immunosuppressive drugs) and biological agents (antibodies) to be taken up by the liver for therapeutic and diagnostic purposes (see, e.g., U.S. Pat. Nos. 5,346,696, 5,679,323, and 5,089,604). [0007] Adoptive cellular immunotherapy in general is a treatment that employs biological reagents to effect an immune-mediated response. Currently, most adoptive immunotherapies are autolymphocyte therapies (ALT) directed to treatments using the patient's own immune cells which have been processed to either enhance the immune cell mediated response or to recognize specific antigens or foreign substances in the body, including cancer cells. The treatments are accomplished by removing the patient's lymphocytes and exposing these cells in vitro to biologics and drugs to activate the immune function of the cells. Once the autologous cells are activated, these ex vivo activated cells are reinfused into the patient to enhance the immune system to treat various forms of cancer, infectious diseases, autoimmune diseases or immune deficiency diseases. [0008] Adoptive immunotherapies may utilize, for instance, natural killer (NK) cells activated with interleukin-2 (IL-2), lymphokine-activated killer (LAK) cells and/or tumor-infiltrating lymphocytes (TILs) and/or cytotoxic lymphocytes (CTLs). LAK therapy involves the in vitro generation of LAK cells by culturing autologous peripheral blood leukocytes in high concentrations of IL-2. The LAK cells are then reinfused into the cancer patient in a treatment that may also involves infusion of IL-2. Rosenberg, et al., "Cancer immunotherapy using interleukin-2 and interleukin-2 activated lymphocytes," Annual Review of Immunology 4:681-709 (1986). TIL therapy involves the generation of LAK cells from mononuclear cells originally derived from the inflammatory infiltrating cells present in and around solid tumors, obtained from surgical resection specimens. Rosenberg, et al., "A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes," Science 233:1318-1321 (1986). Many further variations of adoptive immunotherapy have been developed in recent years. See, e.g., U.S. Pat. No. 6,406,699, issued Jun. 18, 2002 to Wood, disclosing and claiming a composition and method of cancer antigen immunotherapy, and methods in references disclosed and cited therein. [0009] In addition to cancer immunotherapies, adoptive immunotherapy has applications for deficiency or dysfunction of T cells associated with several diseases and conditions, including recurrent infections by viruses such as herpesvirus (HSV, VZV, CMV), hepatitis B virus, and papillomavirus. See, e.g., Spiegel, R. J., "The alpha interferons: Clinical overview", Seminars in Oncology 14:1 (1987). ALT is also being evaluated in the treatment of patients infected with HIV. O. Martinez-Maza, "HIV-Induced Immune Dysfunction and AIDS-Associated Neoplasms," in Biological Approaches to Cancer Treatment: Biomodulation, M. Mitchell, Editor, McGraw-Hill, Inc., Chapter 9, pages 181-204 (1993). [0010] A stem cell is a special kind of cell that has a unique capacity to renew itself and to give rise to specialized cell types. Although most cells of the body such as heart cells or skin cells, are committed to conduct a specific function, a stem cell is uncommitted and remains uncommitted until it receives a signal to develop into a specialized cell. In 1998, stem cells from early human embryos were first isolated and grown in culture. It is recognized that these stem cells are, indeed, capable of becoming almost all of the specialized cells of the body. In recent years, stem cells present in adults also have been shown to have the potential to generate replacement cells for a broad array of tissues and organs, such as the heart, the liver, the pancreas, and the nervous system. Thus, this class of adult human stem cell holds the promise of being able to repair or replace cells or tissues that are damaged or destroyed by many devastating diseases and disabilities. It is highly useful to effect such therapies by targeting stem cells to particular organs of the body. [0011] In the prior art, lymphocytes and stem cells generally have been presented to the desired organs either by injection into the tissue or by infusion into the local circulation. However, localization of normal bone marrow stem cells and lymphocytes to the liver has been demonstrated upon injection of such cells into mice. Samlowski et al., Immunol. 88:309-322 (1984); Samlowski et al., Proc. Natl. Acad. Sci. 82:2508-2512 (1985). [0012] It is also known that a large proportion of cells infused into mammals adhere to the lung endothelium, independent of cell type or physiological homing properties. It has been observed that stem cells accumulate in the lungs when they are administered. Morrison et al., Nature Medicine 2:1281-1282 (1996); Martino et al., Eur. J. Immunol. 23:1023-1028 (1993); Pereira et al., Proc. Natl. Acad. Sci. USA 92:4857-4861 (1993); and Gao et al., Cells Tissues Organs 169:12-20 (2001). [0013] Orosomucoid, asialo-orosomucoid and agalacto/asialo-orosomucoid have been shown to inhibit neutrophil activation, superoxide anion generation, and platelet activation. Costello et al., Clin Exp Immunol 55:465-472 (1984); and Costello et al., Nature 281:677-678 (1979). These proteins also induced transient immunosuppression and protected against TNF challenge. Bennett, et al., Proc. Natl. Acad. Sci. USA 77:6109-6113 (1980) and Libert, et al., J. Exp. Med. 180:1571-1575 (1994). Orosomucoid demonstrated specific binding to pulmonary endothelial cells, which appeared to be independent of carbohydrate recognition sites. Schnitzer, et al., Am. J. Physiol 263:H48-H55 (1992). Moreover, orosomucoid was shown to bind to skin capillary endothelial cells in a dose dependent manner, thereby maintaining normal capillary permeability in the face of inflammatory agonists that caused leakage in control animals. Muchitsch, et al., Arch Int Pharmacodyn 331:313-321 (1996). Similarly, infused orosomucoid bound to kidney capillaries and restored the permselectivity of glomerular filtration. Muchitsch, et al., Nephron 81:194-199 (1999). [0014] Entrapment of neuraminidase-treated lymphocytes in the liver also has been reported, including autoimmune reactions against liver cells by syngeneic neuraminidase-treated lymphocytes, in mice intravenously injected with lymphocytes isolated from spleen or thymus. Kolb-Bachofen, V., et al., Immunol. 123:2830-2834 (1979). Studies on interactions between neuraminidase-treated rat lymphocytes and liver cells in culture have demonstrated adhesion between cells is due to stereo-specific interactions between a mammalian hepatic membrane lectin (i.e., the ASGP receptor) and galactosyl residues which are exposed on the lymphocyte surface after removal of sialic acid residues. Kolb, H., et al., Adv. Exp. Med. Biol. 114:219-222 (1979). [0015] In view of the above, a need exists to develop methods for delivery of lymphocytes and stem cells through the circulation to specific organs. Such methods would provide a means to target non-invasively solid organs such as the liver, heart, lungs and kidneys. In addition, very diffuse tissues, such as the lung, which are not amenable to dosage by injection could be targeted. Such methods would be useful in adoptive immunotherapies and regenerative stem cell therapies involving such organs as the liver, heart, lungs and kidneys. [0016] The present invention addresses these and other needs. BRIEF SUMMARY OF THE INVENTION [0017] The present invention features a method for delivering a cell to a target tissue in a mammal comprising the steps of administering a carbohydrate presenting molecule (e.g., a glycoconjugate) to a mammal and then administering the cell to the mammal. [0018] As used herein, the term "administering" refers to any method of inducing an increased concentration of the cell in the circulation of the mammal, whether by infusion from an extraneous source or by mobilizing the cell into the circulation from a depot within the mammal, such as the marrow. Means for mobilizing stem cells, for instance, using GM-CSF and GCSF, for example, are well known in the art. See, e.g., Simmons et al., The mobilization of primitive hemopoietic progenitors into the peripheral blood. Stem Cells, 12 Suppl 1:187-201 (1994). [0019] The methods according to the present invention are especially applicable to stem cells, such as those derived from the bone marrow, peripheral blood, umbilical cord or from mesenchymal stem cells expanded in culture. The stem cells within the scope of the invention include any cell capable of differentiating into a desired target tissue. Such cells include pluripotent stem cells, embryonic stem cells, multipotent adult stem cells, and progenitor or precursor cells. [0020] The methods according to the present invention also are especially applicable to immune system cells, such as natural killer (NK) cells activated with interleukin-2 (IL-2), lymphokine-activated killer (LAK) cells and/or activated lymphocytes including but not limited to tumor-infiltrating lymphocytes (TILs). [0021] The methods of the present invention allow cells such as normal stem or immune cells to be targeted to such target tissues as the heart, the liver, the kidneys and the lungs, among others. In some embodiments wherein the cell is targeted to the heart, the methods feature administering an orosomucoid (O) or administering an asialoorosomucoid (ASO), and administering the cell to the mammal. In embodiments wherein the cell is targeted to the lungs, the methods feature administering the cell to the mammal in a saline or a serum albumin-saline solution or cell culture media without protein/albumin. In embodiments wherein the cell is targeted to the liver, the methods feature administering an orosomucoid or an asialoorosomucoid and administering the cell to the mammal. In some embodiments, the orosomucoid is administered concurrently or prior to administering the cell to the mammal. The methods according to the present invention are also useful for either inhibiting or enhancing sequestration of a stem cell or immune cell in the liver of a mammal even in the absence of targeting the cell to a target organ. Continue reading about Methods and compositions using cellular asialodeterminants and glycoconjugates for targeting cells to tissues and organs... 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