Claims
- 1. A method of modulating the megalin-receptor mediated binding and/or uptake of a radiodiagnostic and/or radiotherapeutic or a pharmaceutically acceptable salt thereof into cells of the kidney in a patient in need thereof, comprising
administering to said patient an effective amount of a radiodiagnostic and/or radiotherapeutic or a pharmaceutically acceptable salt thereof, and administering to said patient an effective amount of a modulator of the megalin-receptor mediated uptake of said radiodiagnostic and/or radiotherapeutic into cells of the kidney, or a pharmaceutical salt thereof, a prodrug thereof, or a metabolite thereof.
- 2. A method according to claim 1 wherein said modulator is administered before, simultaneously together with and/or after said radiodiagnostic and/or radiotherapeutic.
- 3. A method according to claim 1 wherein said modulator is a modulator of the expression of the megalin receptor in kidney cells.
- 4. A method according to claim 1 wherein said modulator is an inhibitor of the megalin-receptor mediated uptake of said radiodiagnostic and/or radiotherapeutic into cells of the kidney.
- 5. A method according to claim 1 wherein said modulator is administered as an injection (intraperitoneally and/or intravenously), an infusion, a bolus dose and/or as an oral dosage.
- 6. A method according to claim 1 wherein said modulator is a compound selected from the group of compounds comprising modified cubilin, vitamin-binding proteins, carrier proteins, lipoproteins, apolipoproteins (such as apo E, and apo B, clusterin), LPO-antagonists (such as probucol), RAP and derivatives thereof, Ca2+, Ca2+-scavengers, lipids, cytochrome C, antimegalin IgG, anti-cubilin IgG, anti-poly alpha2,8 KDN antibody, aminoglycosides (such as gentamicin), hormones and precursors thereof, drugs and toxins, enzymes and inhibitors thereof, and immune- and stress-response related proteins, maleate, dextran-based conjugates, aristolochic acid, cadmium chloride, and L-camithine.
- 7. A method according to claim 1 wherein said modulator exhibits an affinity to megalin and/or cubilin of 50-500 nM, preferably of less than 50 nM.
- 8. A method according to claim 1 wherein said modulator can pass through the filtration barrier of the glomerulus.
- 9. A method according to claim 1 wherein said modulator reduces the uptake of said radiotherapeutic into cells of the kidney by more than about 60%.
- 10. A method according to claim 1 wherein said modulator does not significantly (p<0.05) reduce the uptake (% ID/g) of said radiodiagnostic and/or radiotherapeutic into tumour cells.
- 11. A method according to claim 1 wherein the administration is performed during the prevention, diagnosis, monitoring and/or therapy of cancer and other diseases, like Parkinson disease, Alzheimer syndrome, coronary diseases, arteriosclerosis, and restenosis.
- 12. A method according to claim 11 wherein said cancer is selected from the group comprising prostate cancer, breast cancer, leukaemia, pancreatic cancer, lung cancer, colon cancer, sarcoma, glioblastoma, melanoma, ovarian cancer, head and neck carcinomas, and lymphoma.
- 13. A method according to claim 1 wherein said radiodiagnostic and/or radiotherapeutic is selected from the group of compounds comprising radiolabeled antibodies, radiolabeled peptides, radiolabeled enzymes, radiolabeled nucleic acids, comprising radiometals selected from the group of Fluorine-18, Chromium-51, Cobalt-58, Gallium-67, Copper-67, Molybdenum-99, Technetium-99, Indium-111, Iodine-123, Iodine-125, Iodine-131, Yttrium-90, Gold Au-198 colloid, Xenon-133, Thallium-201, Rhenium-188, Strontium-189, Actinium-225, Astatine-211, Bismuth-212/213, Rhenium-186, Holmium-166, Samarium-153, and Lutetium-177.
- 14. A method according to claim 1 wherein said modulator is administered together with a cofactor selected from the group of compounds comprising modified cubilin, vitamin-binding proteins, carrier proteins, lipoproteins, apolipoproteins (such as apo E, and apo B, clustering, LPO-antagonists (such as probucol), RAP and derivatives thereof, Ca2+, Ca2+-scavengers, lipids, cytochrome C, antimegalin IgG, anti-cubilin IgG, anti-poly alpha2,8 KDN antibody, aminoglycosides (such as gentamicin), hormones and precursors thereof, drugs and toxins, enzymes and inhibitors thereof, and immune- and stress-response related proteins, maleate, dextran-based conjugates, aristolochic acid, cadmium chloride, and L-carnithine.
- 15. A method according to claim 1 wherein the administration is performed during the prevention of damages of the kidney of a patient during a radiotherapy.
- 16. A method of treatment of a cancerous or other disease in a patient in need thereof, comprising
administering to said patient an effective amount of a radiotherapeutic or a pharmaceutically acceptable salt thereof, and administering to said patient an effective amount of a modulator of the megalin-receptor mediated uptake of said radiotherapeutic into cells of the kidney, or a pharmaceutical salt thereof, a prodrug thereof, or a metabolite thereof.
- 17. A method according to claim 16 wherein said modulator is administered before, simultaneously together with and/or after said radiotherapeutic.
- 18. A method according to claim 16 wherein said modulator is a modulator of the expression of the megalin receptor in kidney cells.
- 19. A method according to claim 16 wherein said modulator is an inhibitor of the megalin-receptor mediated uptake of said radiotherapeutic into cells of the kidney.
- 20. A method according to claim 16 wherein said modulator is administered as an injection (intraperitoneally and/or intravenously), an infusion, a bolus dose and/or as an oral dosage.
- 21. A method according to claim 16 wherein said modulator is a compound selected from the group of compounds comprising modified cubilin, vitamin-binding proteins, carrier proteins, lipoproteins, apolipoproteins (such as apo E, and apo B, clustering, LPO-antagonists (such as probucol), RAP and derivatives thereof, Ca2+, Ca2+-scavengers, lipids, cytochrome C, antimegalin IgG, anti-cubilin IgG, anti-poly alpha2,8 KDN antibody, aminoglycosides (such as gentamicin), hormones and precursors thereof, drugs and toxins, enzymes and inhibitors thereof, and immune- and stress-response related proteins, maleate, dextran-based conjugates, aristolochic acid, cadmium chloride, and L-carnithine.
- 22. A method according to claim 16 wherein said modulator exhibits an affinity to megalin and/or cubilin of 50-500 nM, preferably of less than 50 nM.
- 23. A method according to claim 16 wherein said modulator can pass through the filtration barrier of the glomerulus.
- 24. A method according to claim 16 wherein said modulator reduces the uptake of said radiotherapeutic into cells of the kidney by more than about 60%.
- 25. A method according to claim 16 wherein said modulator does not significantly (p<0.05) reduce the uptake (% ID/g) of said radiotherapeutic into cancerous or other diseased cells to be treated.
- 26. A method according to claim 25 wherein said cancer is selected from the group comprising prostate cancer, breast cancer, leukaemia, pancreatic cancer, lung cancer, colon cancer, sarcoma, glioblastoma, melanoma, ovarian cancer, head and neck carcinomas, and lymphoma.
- 27. A method according to claim 16 wherein said radiotherapeutic is selected from the group of compounds comprising radiolabeled antibodies, radiolabeled peptides, radiolabeled enzymes, radiolabeled nucleic acids, comprising radiometals selected from the group of Fluorine-18, Chromium-51, Cobalt-58, Gallium-67, Copper-67, Molybdenum-99, Technetium-99, Indium-111, Iodine-123, Iodine-125, Iodine-131, Yttrium-90, Gold Au-198 colloid, Xenon-133, Thallium-201, Rhenium-188, Strontium-189,- Actinium-225, Astatine-211, Bismuth-212/213, Rhenium-186, Holmium-166, Samarium-153, Lutetium-177.
- 28. A method according to claim 16 wherein said modulator is administered together with a cofactor selected from the group of compounds comprising modified cubilin, vitamin-binding proteins, carrier proteins, lipoproteins, apolipoproteins (such as apo E, and apo B, clusterin), LPO-antagonists (such as probucol), RAP and derivatives thereof, Ca2+, Ca2+-scavengers, lipids, cytochrome C, antimegalin IgG, anti-cubilin IgG, anti-poly alpha2,8 KDN antibody, aminoglycosides (such as gentamicin), hormones and precursors thereof, drugs and toxins, enzymes and inhibitors thereof, and immune- and stress-response related proteins, maleate, dextran-based conjugates, aristolochic acid, cadmium chloride, and L-carnithine.
- 29. A method of screening for modulator compounds of the megalin-receptor mediated binding and/or uptake of radiotherapeutics and/or radiodiagnostics into cells of the kidney, comprising:
providing an assay for measuring the megalin-receptor mediated binding and/or uptake of radiotherapeutics and/or radiodiagnostics, adding at least one radiotherapeutic and/or radiodiagnostic and/or a suitably labelled precursor thereof to the assay; adding a candidate compound to be tested to the assay; and determining if the amount of radiotherapeutics and/or radiodiagnostics bound to or taken up by the megalin-receptor-mediated binding and/or uptake is altered as compared to binding or uptake in the absence of the candidate compound to be tested, wherein a difference in binding or uptake mediated by the megalin-receptor identifies a compound which is a modulator of the megalin-receptor mediated binding and/or uptake of radiotherapeutics and/or radiodiagnostics into cells of the kidney.
- 30. A method according to claim 29 wherein said candidate compound is added before, simultaneously together with and/or after said radiotherapeutic and/or radiodiagnostic.
- 31. A method according to claim 29 wherein said determining if the amount of the radiotherapeutic and/or radiodiagnostics bound to or taken up by the megalin-receptor-mediated binding and/or uptake is altered as compared to binding or uptake in the absence of the candidate compound to be tested comprises measuring the expression of the megalin receptor in cells of the kidney.
- 32. A method according to claim 31, further comprising measuring the expression of cubilin in the cells of the kidney.
- 33. A method according to claim 29 wherein said candidate compound is added together with a cofactor selected from the group of compounds comprising modified cubilin, vitamin-binding proteins, carrier proteins, lipoproteins, apolipoproteins (such as apo E, and apo B, clusterin), LPO-antagonists (such as probucol), RAP and derivatives thereof, Ca2+, Ca2+-scavengers, lipids, cytochrome C, antimegalin IgG, anti-cubilin IgG, anti-poly alpha2,8 KDN antibody, aminoglycosides (such as gentamicin), hormones and precursors thereof, drugs and toxins, enzymes and inhibitors thereof, and immune- and stress-response related proteins, maleate, dextran-based conjugates, aristolochic acid, cadmium chloride, and L-carnithine.
- 34. The method of claim 29 wherein the assay is performed in vitro.
- 35. The method of claim 29 wherein the assay is performed in a mammalian cell culture.
- 36. The method of claim 35 wherein said mammalian cell culture comprises kidney cells, such as LLC-PK1 (ATCC CL-101); LLC-RK1 (ATCC CC1-106); A6 (ATCC CCL-102); OK (ATCC CRL-1840); MDCK (ATCC CCL-34); HK-2 (ATCC CRL-2190); HaK (ATCC CCL-15); and LLC-MK2 (ATCC CCL-7).
- 37. The method of claim 35 wherein said mammalian cell is transformed with a plasmid containing a DNA sequence encoding the megalin-receptor.
- 38. The method of claim 35 wherein said cell mammalian cell is further transformed with a plasmid containing a DNA sequence encoding cubilin.
- 39. The method of claim 35 wherein said mammalian cell is a human cell.
- 40. The method of claim 35 wherein said mammalian cell is a mouse cell or rat cell.
- 41. The method of claim 29 wherein the assay is performed in vivo.
- 42. The method of claim 41 wherein the assay is performed in a mouse or rat.
- 43. The method of claim 31 wherein the assay includes a cell expressing the megalin-receptor protein and the compound is a nucleic acid sequence which potentially alters expression of the megalin-receptor protein.
- 44. The method of claim 29 wherein said radiotherapeutic is selected from the group of compounds comprising radiolabeled antibodies, radiolabeled enzymes, radiolabeled peptides, radiolabeled nucleic acids, comprising radiometals selected from the group of Fluorine-18, Chromium-51, Cobalt-58, Gallium-67, Copper-67, Molybdenum-99, Technetium-99, Indium-111, Iodine-123, Iodine-125, Iodine-131, Yttrium-90, Gold Au-198 colloid, Xenon-133, Thallium-201, Rhenium-188, Strontium-189, Actinium-225, Astatine-211, Bismuth-212/213, Rhenium-186, Holmium-166, Samarium-153, and Lutetium-177.
- 45. The method of claim 29 wherein the candidate compound is selected from a library of naturally occurring or synthetic compounds which are randomly tested for alteration of binding.
- 46. The method of claim 29 wherein said candidate compound is selected from the group of megalin-binding compounds comprising modified cubilin, vitamin-binding proteins, carrier proteins, lipoproteins, apolipoproteins, like apo E and apo B, clusterin, LPO-antagonists, like probucol, RAP and derivatives thereof, Ca2+, Ca2+-scavengers, lipids, cytochrome C, antimegalin IgG, anti-cubilin IgG, anti-poly alpha2,8 KDN antibody, amino-glycosides, like gentamicin, hormones and precursors thereof, drugs and toxins, enzymes and inhibitors thereof, and immune- and stress-response related proteins, maleate, dextran-based conjugates, aristolochic acid, cadmium chloride, and L-carnithine.
- 47. The method of claim 29 wherein the assay is selected from the group comprising a two-hybrid assay, a biochemical pull-down assay, a high-throughput screening, in vitro fluorescent polarisation assay, an in vitro fluorescent binding assay, a conformational sensor-solid-phase chemiluminescence assay, a surface plasmon resonance assay, a filter binding assay, a sepharose chromatography, and a scintillation proximity assay.
- 48. The method of claim 29 wherein the assay is a cell expressing both the megalin receptor and the cofactor.
- 49. The method of claim 29 wherein the assay is an in vitro, cell-free mixture comprising a pre-determined amount of the megalin receptor and the cofactor.
- 50. Modulator of the megalin-receptor mediated binding and/or uptake of radiotherapeutics into cells of the kidney, identified according to a method according to claim 29.
- 51. Modulator of the megalin-receptor mediated binding and/or uptake of radiotherapeutics into cells of the kidney according to claim 50, which is an inhibitor.
- 52. Modulator of the megalin-receptor mediated binding and/or uptake of radiotherapeutics into cells of the kidney according to claim 50, which has an affinity to megalin and/or cubilin of 50-500 nM, preferably of less than 50 nM.
- 53. Modulator of the megalin-receptor mediated binding and/or uptake of radiotherapeutics into cells of the kidney according to claim 50, which can pass through the filtration barrier of the glomerulus.
- 54. Modulator of the megalin-receptor mediated binding and/or uptake of radiotherapeutics into cells of the kidney according to claim 50, which reduces the uptake of said radiotherapeutic into cells of the kidney by more than about 60%.
- 55. Modulator of the megalin-receptor mediated binding and/or uptake of radiotherapeutics into cells of the kidney according to claim 50, wherein said modulator does not significantly (p<0.05) reduce the uptake (% ID/g) of a radiotherapeutic into tumour cells.
- 56. Modulator of the megalin-receptor mediated binding and/or uptake of radiotherapeutics into cells of the kidney according to claim 50, wherein the compound competitively inhibits binding of the radiotherapeutic to the megalin-receptor protein.
- 57. Modulator of the megalin-receptor mediated binding and/or uptake of radiotherapeutics into cells of the kidney according to claim 50, wherein the compound sterically inhibits binding of the radiotherapeutic to the megalin-receptor protein.
- 58. Modulator of the megalin-receptor mediated binding and/or uptake of radiotherapeutics into cells of the kidney according to claim 50, wherein said compound is selected from the group of megalin-binding compounds comprising modified cubilin, vitamin-binding proteins, carrier proteins, lipoproteins, apolipoproteins (such as apo E, and apo B, clusterin), LPO-antagonists (such as probucol), RAP and derivatives thereof, Ca2+, Ca2+-scavengers, lipids, cytochrome C, antimegalin IgG, anti-cubilin IgG, anti-poly alpha2,8 KDN antibody, aminoglycosides (such as gentamicin), hormones and precursors thereof, drugs and toxins, enzymes and inhibitors thereof, and immune- and stress-response related proteins, maleate, dextran-based conjugates, aristolochic acid, cadmium chloride, and L-carnithine.
- 59. A method for producing a pharmaceutical composition for the treatment of cancer, comprising
screening for a modulator compound of the megalin-receptor mediated binding and/or up-take of radiotherapeutics into cells of the kidney according to claim 18, and mixing of said modulator compound thus identified with a pharmaceutically suitable carrier and/or diluent.
- 60. A pharmaceutical composition, produced according to claim 59.
- 61. A pharmaceutical composition according to claim 60 further comprising a safe and effective amount of a chemotherapeutic agent.
- 62. A pharmaceutical composition according to claim 61 wherein said chemotherapeutic agent is selected from the group consisting of a DNA-interactive agent, alkylating agent, antimetabolite, tubulin-interactive agent, and a hormonal agent.
- 63. A pharmaceutical composition according to claim 61 wherein said chemotherapeutic agent is selected from the group consisting of Methotrexate, Fluorouracil, Fluorodeoxyuridin, CB3717, Azacitidine, Floxuridine, Mercapyopurine, 6-Thioguanine, Pentostatin, Cytarabine, and Fludarabine.
- 64. Use of a modulator of the megalin-receptor mediated binding and/or uptake of radiotherapeutics into cells of the kidney according to claim 59 for the prevention, diagnosis, monitoring and/or therapy of cancer.
Priority Claims (1)
Number |
Date |
Country |
Kind |
03006592.4 |
Mar 2003 |
EP |
|
Parent Case Info
[0001] This application claims the benefit of the filing date of U.S. Provisional Application Serial No. 60/457,999 filed Mar. 28, 2003.
Provisional Applications (1)
|
Number |
Date |
Country |
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60457999 |
Mar 2003 |
US |