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- Nachgewiesen in: USPTO Patent Applications
- Sprachen: English
- Document Number: 20110274691
- Publication Date: November 10, 2011
- Appl. No: 12/863737
- Application Filed: January 23, 2009
- Claim: 1. An isolated antibody that binds to an extracellular domain of ferroportin (SEQ ID NO: 16) and that preserves ferroportin activity.
- Claim: 2. The antibody of claim 1, wherein said antibody preserves ferroportin activity in the presence of hepcidin.
- Claim: 3. The antibody of claim 1, wherein said antibody decreases the level of ferritin expression as determined by a ferritin assay at an EC50 of about 10−6 M or less.
- Claim: 4. The antibody of claim 1, wherein said antibody decreases the intracellular iron level in a subject at an EC50 of about 1×10−6 M or less.
- Claim: 5. The antibody of claim 1, wherein said antibody increases circulating iron level or Tsat in a subject.
- Claim: 6. The antibody of claim 1, wherein said antibody increases the level in a subject of one of at least hemoglobin or hematocrit, or both.
- Claim: 7. The antibody of claim 1, wherein said antibody increases in a subject one of at least the red blood cell count, the red blood cell hemoglobin content or the red blood cell mean cell volume of red blood cell count, or any combinations thereof.
- Claim: 8. The antibody of claim 1, wherein said antibody increases in a subject one of at least the reticulocyte count, the reticulocyte hemoglobin content or the reticulocyte mean cell volume of reticulocyte count, or any combinations thereof.
- Claim: 9. The antibody of claim 1, wherein said antibody inhibits internalization of ferroportin.
- Claim: 10. The antibody of claim 1, wherein said antibody inhibits degradation of ferroportin.
- Claim: 11. The antibody of claim 9 wherein the antibody inhibits hepcidin-mediated internalization or degradation of ferroportin.
- Claim: 12. The antibody of claim 1, wherein the extracellular domain of ferroportin comprises an amino acid sequence selected from the group consisting of amino acids 46-60, 116-126, 204-205, 325-342, 394-449, 513-517, 35-57, 116-124, 332-340, 393-449 and 515-518 of SEQ ID NO: 16 and fragments thereof at least 4 amino acids in length.
- Claim: 13. The antibody of claim 1, wherein the antibody is a monoclonal antibody.
- Claim: 14. The isolated antibody of claim 13, that comprises at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 5-10, SEQ ID NOs: 29-34, SEQ ID NOs: 39-44, SEQ ID NOs: 49-54, SEQ ID NOs: 59-64, SEQ ID NOs: 69-74, SEQ ID NOs: 79-84, SEQ ID NOs: 89-94, SEQ ID NOs: 99-104, and SEQ ID NOs: 109-114.
- Claim: 15. An isolated monoclonal antibody which binds to an extracellular domain of ferroportin (SEQ ID NO: 16) with a Kd of 10−6 M or less.
- Claim: 16. An isolated monoclonal antibody that binds to an extracellular domain of human ferroportin (SEQ ID NO: 16) and that inhibits cellular iron retention.
- Claim: 17. An isolated monoclonal antibody that binds to an extracellular domain of human ferroportin (SEQ ID NO: 16) and that reduces internalization and/or degradation of ferroportin.
- Claim: 18. An isolated antibody that binds to an extracellular domain of ferroportin (SEQ ID NO: 16), wherein said antibody comprises an amino acid sequence at least 90% identical to SEQ ID NOs: 2 or 4, said amino acid sequence comprising at least one CDR selected from the group consisting of SEQ ID NOs: 5-10 and any CDRs comprising at least one amino acid change to any of SEQ ID NOs: 5-10.
- Claim: 19. An isolated antibody that binds to an extracellular domain of ferroportin (SEQ ID NO: 16), wherein said antibody comprises an amino acid sequence at least 90% identical to SEQ ID NOs: 26 or 28, said amino acid sequence comprising at least one CDR selected from the group consisting of SEQ ID NOs: 29-34 and any CDRs comprising at least one amino acid change to any of SEQ ID NOs: 29-34.
- Claim: 20. An isolated antibody that binds to an extracellular domain of ferroportin (SEQ ID NO: 16), wherein said antibody comprises an amino acid sequence at least 90% identical to SEQ ID NOs: 36 or 38, said amino acid sequence comprising at least one CDR selected from the group consisting of SEQ ID NOs: 39-44 and any CDRs comprising at least one amino acid change to any of SEQ ID NOs: 39-44.
- Claim: 21. An isolated antibody that binds to an extracellular domain of ferroportin (SEQ ID NO: 16), wherein said antibody comprises an amino acid sequence at least 90% identical to SEQ ID NOs: 46 or 48, said amino acid sequence comprising at least one CDR selected from the group consisting of SEQ ID NOs: 49-54 and any CDRs comprising at least one amino acid change to any of SEQ ID NOs: 49-54.
- Claim: 22. An isolated antibody that binds to an extracellular domain of ferroportin (SEQ ID NO: 16), wherein said antibody comprises an amino acid sequence at least 90% identical to SEQ ID NOs: 56 or 58, said amino acid sequence comprising at least one CDR selected from the group consisting of SEQ ID NOs: 59-64 and any CDRs comprising at least one amino acid change to any of SEQ ID NOs: 59-64.
- Claim: 23. An isolated antibody that binds to an extracellular domain of ferroportin (SEQ ID NO: 16), wherein said antibody comprises an amino acid sequence at least 90% identical to SEQ ID NOs: 66 or 68, said amino acid sequence comprising at least one CDR selected from the group consisting of SEQ ID NOs: 69-74 and any CDRs comprising at least one amino acid change to any of SEQ ID NOs: 69-74.
- Claim: 24. An isolated antibody that binds to an extracellular domain of ferroportin (SEQ ID NO: 16), wherein said antibody comprises an amino acid sequence at least 90% identical to SEQ ID NOs: 76 or 78, said amino acid sequence comprising at least one CDR selected from the group consisting of SEQ ID NOs: 79-84 and any CDRs comprising at least one amino acid change to any of SEQ ID NOs: 79-84.
- Claim: 25. An isolated antibody that binds to an extracellular domain of ferroportin (SEQ ID NO: 16), wherein said antibody comprises an amino acid sequence at least 90% identical to SEQ ID NOs: 86 or 88, said amino acid sequence comprising at least one CDR selected from the group consisting of SEQ ID NOs: 89-94 and any CDRs comprising at least one amino acid change to any of SEQ ID NOs: 89-94.
- Claim: 26. An isolated antibody that binds to an extracellular domain of ferroportin (SEQ ID NO: 16), wherein said antibody comprises an amino acid sequence at least 90% identical to SEQ ID NOs: 96 or 98, said amino acid sequence comprising at least CDR selected from the group consisting of SEQ ID NOs: 99-104 and any CDRs comprising at least one amino acid change to any of SEQ ID NOs: 99-104.
- Claim: 27. An isolated antibody that binds to an extracellular domain of ferroportin (SEQ ID NO: 16), wherein said antibody comprises an amino acid sequence at least 90% identical to SEQ ID NOs: 106 or 108, said amino acid sequence comprising at least one CDR selected from the group consisting of SEQ ID NOs: 109-114 and any CDRs comprising at least one amino acid change to any of SEQ ID NOs: 109-114.
- Claim: 28. An isolated monoclonal antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises amino acids 18-466 of SEQ ID NO: 14 and the light chain comprises amino acids 21-239 of SEQ ID NO: 12.
- Claim: 29. An isolated antibody that binds to an extracellular domain of ferroportin (SEQ ID NO: 16), wherein the antibody comprises an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 26, SEQ ID NO: 36, SEQ ID NO: 46, SEQ ID NO: 56, SEQ ID NO: 66, SEQ ID NO: 76, SEQ ID NO: 86, SEQ ID NO: 96 and SEQ ID NO: 106.
- Claim: 30. An isolated antibody that binds to an extracellular domain of ferroportin (SEQ ID NO: 16), wherein the antibody comprises an amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 28, SEQ ID NO: 38, SEQ ID NO: 48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO: 98 and SEQ ID NO: 108.
- Claim: 31. An isolated antibody that binds to an extracellular domain of ferroportin (SEQ ID NO: 16), wherein the antibody comprises a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 26, SEQ ID NO: 36, SEQ ID NO: 46, SEQ ID NO: 56, SEQ ID NO: 66, SEQ ID NO: 76, SEQ ID NO: 86, SEQ ID NO: 96 and SEQ ID NO: 106.
- Claim: 32. An isolated antibody that binds to an extracellular domain of ferroportin (SEQ ID NO: 16), wherein the antibody comprises a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 28, SEQ ID NO: 38, SEQ ID NO: 48, SEQ ID NO:58, SEQ ID NO:68, SEQ ID NO:78, SEQ ID NO:88, SEQ ID NO: 98 and SEQ ID NO: 108.
- Claim: 33. The isolated antibody of claim 1, wherein the antibody binds to a fragment of said human ferroportin that comprises at least one, two, three, four, five or more amino acids located within amino acids 393-449 of SEQ ID NO: 16, or that binds to an epitope of human ferroportin comprising one or more amino acids of said fragment.
- Claim: 34. The isolated antibody of claim 33, wherein the antibody binds to a fragment of said human ferroportin that comprises at least ten or more amino acids located within amino acids 393-449 of SEQ ID NO: 16, or an epitope within or of said fragment.
- Claim: 35. The isolated antibody of claim 34, wherein the antibody binds to a fragment of said human ferroportin that comprises at least one, two, three, four, five or more amino acids located within amino acids 439-449 of SEQ ID NO: 16 or that binds to an epitope of human ferroportin comprising one or more amino acids of said fragment.
- Claim: 36. The isolated antibody of claim 1, wherein the antibody binds to a fragment of said human ferroportin that consists of amino acids ANIVPETSPES (amino acids 439-449 of SEQ ID NO: 16) or that binds to an epitope of human ferroportin comprising one or more amino acids of said fragment.
- Claim: 37. The isolated antibody of claim 1, wherein the antibody binds to a fragment of said human ferroportin that is selected from the group consisting of amino acids IVPETSPESV (amino acids 441-450 of SEQ ID NO: 16), amino acids NIVPETSPES (amino acids 440-449 of SEQ ID NO: 16), amino acids VPETSPSV (amino acids 442-451 of SEQ ID NO: 16), amino acids PETSPESVPI (amino acids 443-452 of SEQ ID NO: 16), amino acids TSPESVPIIS (amino acids 445-454 of SEQ ID NO: 16), amino acids ANIVPETSP (amino acids 439-447 of SEQ ID NO: 16), amino acids IVPETSPES (amino acids 441-449 of SEQ ID NO: 16), amino acids ANIVPETS (amino acids 439-446 of SEQ ID NO: 16), amino acids IVPETSPE (amino acids 441-448 of SEQ ID NO: 16), amino acids IVPETSP (amino acids 441-447 of SEQ ID NO: 16), and amino acids PETSPES (amino acids 443-449 of SEQ ID NO: 16), or that binds to an epitope of human ferroportin comprising one or more amino acids of said fragment.
- Claim: 38. The isolated antibody of claim 1, wherein the antibody binds to a fragment of said human ferroportin that is selected from the group consisting of amino acids LVELYGNSLL (amino acids 50-69 of SEQ ID NO: 16); amino acids FLVELYGNSL (amino acids 49-68 of SEQ ID NO: 16), amino acids VELYGNSLLL (amino acids 51-70 of SEQ ID NO: 16), amino acids ELYGNSLLLT (amino acids 52-71 of SEQ ID NO: 16), amino acids LYGNSLLLTA (amino acids 53-72 of SEQ ID NO: 16), amino acids LAFLYMTVLG (amino acids 314-323 of SEQ ID NO: 16), amino acids AFLYMTVLGF (amino acids 315-324 of SEQ ID NO: 16), amino acids FLYMTVLGFD (amino acids 316-325 of SEQ ID NO: 16), amino acids IQGESITPTKIPEIT (amino acids 413-427 of SEQ ID NO: 16); amino acids IQGESITPTK (amino acids 413-422 of SEQ ID NO: 16), amino acids QGESITPTKI (amino acids 414-423 of SEQ ID NO: 16), amino acids GESITPTKIP (amino acids 415-424 of SEQ ID NO: 16), amino acids ESITPTKIPE (amino acids 416-425 of SEQ ID NO: 16), amino acids SITPTKIPEI (amino acids 417-426 of SEQ ID NO: 16), amino acids ITPTKIPEIT (amino acids 418-427 of SEQ ID NO: 16), amino acids DGWVSYYNQP (amino acids 297-306 of SEQ ID NO: 16), amino acids ITTEIYMSNGSNS (amino acids 426-438 of SEQ ID NO: 16), amino acids TEIYMSNGSNSA (amino acids 428-439 of SEQ ID NO: 16), amino acids ITTEIYMSNG (amino acids 426-435 of SEQ ID NO: 16), amino acids TTEIYMSNGS (amino acids 427-436 of SEQ ID NO: 16), amino acids TEIYMSNGSN (amino acids 428-437 of SEQ ID NO: 16), amino acids EIYMSNGSNS (amino acids 429-438 of SEQ ID NO: 16), amino acids IYMSNGSNSA (amino acids 430-439 of SEQ ID NO: 16), amino acids YHGWVLTSCY (amino acids 124-133 of SEQ ID NO: 16), amino acids RDGWVSYYNQ (amino acids 296-305 of SEQ ID NO: 16), amino acids EIYMSNG (amino acids 429-435 of SEQ ID NO; 16), amino acids IYMSNGSN (amino acids 430-437 of SEQ ID NO: 16), amino acids ITPTK (amino acids 418-422 of SEQ ID NO: 16), amino acids SITPTKIPEI (amino acids 417-426 of SEQ ID NO: 16) and amino acids EIYMSNGSNS (amino acids 429-438 of SEQ ID NO: 16) or that binds to an epitope of human ferroportin comprising one or more amino acids of said fragment.
- Claim: 39. The isolated antibody of claim 1, wherein said antibody is a chimerized, humanized, or fully human antibody.
- Claim: 40. The isolated antibody of claim 39, wherein said antibody is a chimerized antibody.
- Claim: 41. The isolated antibody of claim 39, wherein the antibody is a humanized antibody.
- Claim: 42. The isolated monoclonal antibody of claim 13, wherein the monoclonal antibody is a single chain Fv antibody fragment.
- Claim: 43. The isolated monoclonal antibody of claim 13, wherein the antibody is an Fab fragment, F(ab′)2 fragment, an Fd, a domain antibody (dAb), a diabody, a maxibody or a nanobody.
- Claim: 44. The isolated monoclonal antibody of claim 13, wherein the antibody is a fully human antibody.
- Claim: 45. The isolated monoclonal antibody of claim 13, comprising a framework amino acid sequence that is a human consensus antibody sequence, a human germline antibody sequence, or human germline consensus antibody sequence.
- Claim: 46. The isolated monoclonal antibody of claim 13, wherein the antibody is of an IgA, IgG, IgE, IgD or IgM isotype.
- Claim: 47. The isolated monoclonal antibody of claim 13, wherein the antibody is of an IgG1, IgG2, IgG3 or IgG4 isotype.
- Claim: 48. The isolated monoclonal antibody of claim 1, wherein the antibody is an IgG antibody.
- Claim: 49. The isolated monoclonal antibody of claim 48, wherein the antibody comprises two heavy chains and two light chains.
- Claim: 50. A nucleic acid encoding the antibody of claim 1.
- Claim: 51. A vector comprising the nucleic acid of claim 50.
- Claim: 52. A host cell comprising the vector of claim 51 or the nucleic acid of claim 50.
- Claim: 53. A method for producing an antibody of claim 1 comprising (a) administering to a mammal a nucleic acid encoding ferroportin (SEQ ID NO: 16), optionally (b) administering to said mammal the same or a different nucleic acid nucleic acid encoding ferroportin (SEQ ID NO: 16), optionally (c) administering to said mammal a composition comprising cell membrane expressing ferroportin, and (d) obtaining cells expressing antibody from said mammal.
- Claim: 54. A method of producing an antibody of claim 1 comprising culturing the host cell of claim 52 such that the nucleic acid is expressed to produce the antibody.
- Claim: 55. The method of claim 54, further comprising recovering the antibody from the host cell culture.
- Claim: 56. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically-acceptable carrier, excipient or diluent.
- Claim: 57. A method for detecting the presence of ferroportin in a sample comprising incubating the sample with the monoclonal antibody of claim 13 under conditions that allow binding of the monoclonal antibody to ferroportin; and detecting the bound monoclonal antibody or the bound ferroportin.
- Claim: 58. The method of claim 57, wherein the monoclonal antibody binds to the same epitope as antibody 31A5 or competes with antibody 31A5 for binding to ferroportin by about 75%.
- Claim: 59. The method of claim 57, wherein the monoclonal antibody binds to the same epitope as antibody 37A2 or competes with antibody 37A2 for binding to ferroportin by about 75%.
- Claim: 60. The method of claim 57, wherein the monoclonal antibody binds to the same epitope as antibody 37B9 or competes with antibody 37B9 for binding to ferroportin by about 75%.
- Claim: 61. The method of claim 57, wherein the monoclonal antibody binds to the same epitope as antibody 37C8 or competes with antibody 37C8 for binding to ferroportin by about 75%.
- Claim: 62. The method of claim 57, wherein the monoclonal antibody binds to the same epitope as antibody 37G8 or competes with antibody 37G8 for binding to ferroportin by about 75%.
- Claim: 63. The method of claim 57, wherein the monoclonal antibody binds to the same epitope as antibody 38A4 or competes with antibody 38A4 for binding to ferroportin by about 75%.
- Claim: 64. The method of claim 57, wherein the monoclonal antibody binds to the same epitope as antibody 38C8 or competes with antibody 38C8 for binding to ferroportin by about 75%.
- Claim: 65. The method of claim 57, wherein the monoclonal antibody binds to the same epitope as antibody 38D2 or competes with antibody 38D2 for binding to ferroportin by about 75%.
- Claim: 66. The method of claim 57, wherein the monoclonal antibody binds to the same epitope as antibody 38E3 or competes with antibody 38E3 for binding to ferroportin by about 75%.
- Claim: 67. The method of claim 57, wherein the monoclonal antibody binds to the same epitope as antibody 38G6 or competes with antibody 38G6 for binding to ferroportin by about 75%.
- Claim: 68. The method of claim 57, further comprising incubating the sample with a polyclonal antibody that binds ferroportin.
- Claim: 69. The method of claim 68, wherein the monoclonal antibody is immobilized on a solid support.
- Claim: 70. The method of claim 68, wherein the polyclonal antibody is labeled.
- Claim: 71. The method of claim 68, wherein the polyclonal antibody is immobilized on a solid support.
- Claim: 72. The method of claim 69, wherein the monoclonal antibody is labeled.
- Claim: 73. The method of claim 57, wherein the antibody is immobilized on a solid support, and further comprising contacting the ferroportin with a second antibody of claim 1.
- Claim: 74. The method of claim 57, wherein the biological sample is isolated from a human.
- Claim: 75. The method of claim 74, wherein the biological sample is selected from the group consisting of tissue, and blood cells.
- Claim: 76. The method of claim 73, wherein the second antibody recognizes an epitope that is distinct from that recognized by the antibody immobilized on the solid support.
- Claim: 77. The method of claim 73 wherein the second antibody is labeled.
- Claim: 78. The method of claim 73, comprising incubating a purified ferroportin standard of a known amount with said antibody.
- Claim: 79. A method of treating a subject having a disorder of iron homeostasis comprising administering to said subject a therapeutically-effective amount of the antibody of claim 1.
- Claim: 80. The method of claim 79, wherein the disorder of iron homeostasis is selected from the group consisting of anemia, sepsis, anemia of inflammation, anemia of cancer, chemotherapy induced anemia, chronic inflammatory anemia, congestive heart failure, end stage renal disorder, chronic kidney disease (stage I, II, II, IV or V), iron deficiency anemia, ferroportin disease, hemochromatosis, diabetes, inflammation, rheumatoid arthritis, arteriosclerosis, tumors, vasculitis, systemic lupus, erythematosus, hemoglobinopathies, and red blood cell disorders.
- Claim: 81. The method of claim 79, further comprising administering an erythropoiesis stimulator to said subject.
- Claim: 82. The method of claim 81, wherein the erythropoiesis stimulator is selected from the group consisting of erythropoietin, erythropoietin variants and antibodies that bind to erythropoietin.
- Claim: 83. A method of selecting a treatment regimen for a subject in need of treatment comprising: (a) screening a subject for a decreased level of circulating iron; (b) prescribing to said subject an antibody of claim 1.
- Claim: 84. The method of claim 83, wherein the screening comprises obtaining a biological sample and determining the level of iron in said sample.
- Claim: 85. The method of claim 83, further comprising prescribing an erythropoiesis stimulator to said subject.
- Claim: 86. The method of claim 83, further comprising prescribing iron to said subject.
- Claim: 87. A combination therapy for the treatment of a disorder of iron homeostasis comprising administering to a subject in need of treatment an antibody of claim 1 and an erythropoiesis stimulator in therapeutically-effective amounts.
- Claim: 88. The combination therapy of claim 87, wherein the antibody and the erythropoiesis stimulator are formulated into one composition.
- Claim: 89. The combination therapy of claim 87, wherein the antibody and the erythropoiesis stimulator are formulated into separate compositions.
- Claim: 90. A combination therapy for the treatment of a disorder of iron homeostasis comprising administering to a subject in need thereof an antibody of claim 1 and an anti-hepcidin antibody in therapeutically-effective amounts.
- Claim: 91. The combination therapy of claim 90, wherein the antibody and the anti-hepcidin antibody are formulated into one composition.
- Claim: 92. The combination therapy of claim 90, wherein the antibody and the anti-hepcidin antibody are formulated in separate compositions.
- Claim: 93. A method of treating a subject that is hypo-responsive to therapy with an erythropoietin stimulator, comprising administering to said subject an antibody of claim 1.
- Claim: 94. The method of claim 93, further comprising administering an erythropoiesis stimulator to said subject.
- Claim: 95. The method of claim 93, wherein the subject is suffering from a condition selected from the group consisting of anemia, sepsis, anemia of inflammation, anemia of cancer, chemotherapy induced anemia, chronic inflammatory anemia, congestive heart failure, end stage renal disorder, chronic kidney disease (stage I, II, II, IV or V), iron deficiency anemia, ferroportin disease, hemochromatosis, diabetes, inflammation, rheumatoid arthritis, arteriosclerosis, tumors, vasculitis, systemic lupus, erythematosus, hemoglobinopathies, red blood cell disorders and kidney failure.
- Claim: 96. The method of claim 93, wherein the subject is suffering from anemia.
- Claim: 97. The method of claim 93, wherein the subject is human.
- Claim: 98. The method of claim 94, wherein the erythropoiesis stimulator is human erythropoietin of SEQ ID NO: 21.
- Claim: 99. The method of claim 94, wherein the erythropoiesis stimulator is darbepoietin alfa of SEQ ID NO: 22.
- Claim: 100. The method of claim 94, further comprising phlebotomizing the subject.
- Claim: 101. A combination therapy for the treatment of iron overload comprising administering to a subject in need of treatment an antibody of claim 1 and an iron chelator in therapeutically-effective amounts.
- Current U.S. Class: 4241/391
- Current International Class: 61; 07; 12; 12; 12; 12; 12; 12; 01; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 07
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