Treatment of disturbances of iron distribution
AssigneeHoffmann-La Roche Inc.
InventorsPaul Lehmann, Ralf Roeddiger, Ruth Walter-Matsui
Life of this patent
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Abstract
A method of, and pharmaceutical composition for, treating disturbances of iron distribution in diabetes using erythropoietin are disclosed.
Claims20
A method of treating disturbances in iron distribution in a patient suffering from non-insulin dependent diabetes mellitus comprising administering to a patient suffering from non-insulin dependent diabetes and disturbances in iron distribution, a therapeutically effective amount of human erythropoietin protein having the amino acid sequence of SEQ ID NO:1 sufficient to treat said disturbances in iron distribution without administering iron.
A method of treating disturbances in iron distribution in a patient suffering from non insulin dependent diabetes mellitus comprising administering a therapeutically effective amount of human erythropoietin protein having the amino acid sequence of SEQ ID NO:1 modified by the addition of up to 3 glycosylation sites, wherein the modification is selected from the group consisting of:
- Asn30Thr32;
- Asn51Thr53;
- Asn57Thr59;
- Asn69;
- Asn69Thr71;
- Ser68Asn69Thr71;
- Val87Asn88Thr90;
- Ser87Asn88Thr90;
- Ser87Asn88Gly89Thr90;
- (SEQ ID NO:
- 2);
- Ser87Asn88Thr90Thr92;
- Ser87Asn88Thr90Ala162;
- Asn69Thr71Ser87Asn88Thr90;
- Asn30Thr32Val87Asn88Thr90;
- Asn89Ile90Thr91;
- Ser87Asn89Ile90Thr91;
- Asn136Thr138;
- Asn138Thr140;
- Thr125;
- and
- Pro124Thr125.
A method of treating disturbances in iron distribution in a patient suffering from non insulin dependent diabetes mellitus comprising administering a therapeutically effective amount of human erythropoietin protein, without administering iron, wherein the protein (EPO) is an analog of SEQ ID NO:1, said analog is selected from the group consisting of:
- (a) human erythropoietin protein having the amino acid sequence, Ser Ser Ser Ser Lys Ala Pro Pro Pro Ser Leu Pro Ser Pro Ser Arg Leu Pro Gly Pro Ser Asp Thr Pro Ile Leu Pro Gln (SEQ ID NO:
- 3), extending from the cathoxy terminus;
- (b) the analog in (a) further comprising Ser87 Asn88 Thr90 EPO;
- (c) the analog in (a) further comprising Asn30 Thr32 Val87 Asn88 Thr90 EPO;
- (d) the analog in (a) further comprising Gln24 Ser87 Thr88 Thr90 EPO;
- (e) the analog in (a) further comprising Gln38 Ser87 Asn88 Thr90 EPQ;
- (f) the analog in (a) further comprising Gln83 Ser87 Asn88 Thr90 EPO and (g) darbepoetin alfa.
A method of treating disturbances m iron distribution in a patient suffering from non-insulin dependent diabetes mellitus comprising administering a conjugate of human erythropoietin protein of SEQ ID NO:1, wherein said conjugate comprising the erythropoietin protein of SEQ ID NO:1 having one to three free amino groups covalently linked to n poly(ethylene glycol) groups of the formula —CO—(CH2)x—(OCH2CH2)m—OR with the —CO of each poly(ethylene glycol) group forming an amide bond with one of said amino groups;
- wherein R is a lower-alkyl;
- x is 2 or 3;
- in is from about 450 to about 900;
- n is from 1 to 3;
- and n and in are chosen so that the molecular weight of the conjugate minus the erythropoietin protein is from 20 kilodaltons to 100 kilodaltons.
A method of treating disturbances in iron distribution in a patient suffering from non-insulin dependent diabetes mellitus comprising administering a conjugate of human erythropoietin of SEQ ID NO:1 wherein, said conjugate comprises the erythropoietin protein of SEQ ID NO:1 having one to three free amino groups covalently linked to the erythropoietin protein via a linker of the formula —C(O)—X—S—Y—with the C(O) of the linker forming an amide bond with one of said amino groups, X is —(CH2)k— or CH2(O—CH2—CH2)k—, k is from 1 to 10, Y is
- the average molecular weight of each poly(ethylene glycol) moiety is from about 20 kilodaltons to about 40 kilodaltons, and the molecular weight of the conjugate is from about 51 kilodaltons to about 175 kilodaltons.
A composition for the treatment of disturbances in iron distribution comprising from about 25 to about 2,500 μg/ml of erythropoietin protein, from about 10 to about 200 mmol/l sulfate, a pharmaceutically acceptable carrier, wherein said composition has a pH of from about 6.0 to about 7.0.
A method of treating disturbances in iron distribution in a patient suffering from diabetes comprising administering a therapeutically effective amount of a composition of human erythropoietin protein of SEQ ID NO:1, wherein the composition comprises from about 25 to about 2,500 μg/ml of erythropoietin protein, from about 10 to about 200 mmol/l sulfate and having a pH of from about 6.0 to about 7.0.
A method of treating disturbances in non distribution in a patient suffering from diabetes comprising administering a therapeutically effective amount of a composition of human erythropoietin protein of SEQ ID NO:1 modified by the addition of up to 3 glycosylation sites, wherein the composition comprises from about 25 to about 2,500 μg/ml of erythropoietin protein, from about 10 to about 200 mmol/l sulfate and having a pH of from about 6.0 to about 7.0.
A method of treating disturbances in iron distribution in a patient suffering from diabetes comprising administering a composition of a conjugate of human erythropoietin protein of SEQ ID NO:1, wherein said conjugate comprises the erythropoietin protein of SEQ ID NO:1, having one to three free amino groups being covalently linked to n poly(ethylene glycol) groups of the formula —O—(CH2)x—(OCH2CH2)m—OR with the —CO of each poly(ethylene glycol) group forming an amide bond with cine of said amino groups;
- wherein R is a lower-alkyl;
- x is 2 or 3;
- m is from about 450 to about 900;
- n is from, 1 to 3;
- and n and m are chosen so that the molecular weight of the conjugate minus the erythropoietin protein is from 20 kilodaltons to 100 kilodaltons, wherein said composition comprises from about 25 to about 2500 ug/ml of erythropoietin protein, from about 10 to about 200 mmol/l sulphate and having a pH of from about 6.0 to about 7.0.
A method of treating disturbances in iron distribution in a patient suffering from diabetes comprising administering a composition of a conjugate of human erythropoietin protein of SEQ ID NO:1, wherein said conjugate the erythropoietin protein of SEQ ID NO:1 having one to three free amino groups covalently linked to from one to three lower-alkoxy poly(ethylene glycol) groups, each poly(ethylene glycol) group being covalently linked to the eryhropoietin protein via a linker of the formula—C(O)—X—S—Y—with the C(O) of the linker forming ah amide bond with one of said amino groups, X is —(CH2)k— or —CH2(O—CH2—CH2)k—, k is from 1 to 10, Y is
- wherein the average molecular weight of each poly(ethylene glycol) moiety is from about 20 kilodaltons to about 40 kilodaltons, and the molecular weight of the conjugate is from about 51 kilodaltons to about 175 kilodaltons wherein said composition comprises from about 25 to about 2500 ug/ml of erythropoietin protein, from about 10 to about 200 mold sulfate and having a pH of from about 6.0 to about 7.0.
Dependencies are inferred from the claim text.