Methods and compositions using GDF15 polypeptides for increasing red blood cells
In certain aspects, the present invention provides compositions and methods for increasing red blood cell and/or hemoglobin levels in vertebrates, including rodents and primates, and particularly in humans.
1. A method of treating anemia associated with stress erythropoiesis in a human patient, the method comprising administering to a patient in need thereof an effective amount of a GDF15 polypeptide and an erythropoietin receptor activator, wherein the GDF15 polypeptide comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 8; wherein the GDF15 polypeptide is capable of binding to ALK5; and wherein the erythropoietin receptor activator is selected from the group consisting of epoetin alfa, epoetin beta, epoetin delta, epoetin omega, darbepoetin alfa and methoxy-polyethylene-glycol epoetin beta.
2. The method of claim 1 , wherein the GDF15 polypeptide comprises an amino acid sequence selected from the group consisting of:
a) a polypeptide comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1,
b) a polypeptide comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 2,
c) a polypeptide comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 3,
d) a polypeptide comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 4,
e) a polypeptide comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5,
f) a polypeptide comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 6, and
g) a polypeptide comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 7.
3. The method of claim 1 , wherein the GDF15 polypeptide is administered in a pharmaceutical preparation.
4. The method of claim 3 , wherein the pharmaceutical preparation comprises a GDF15 prodomain polypeptide.
5. The method of claim 4 , wherein the GDF15 prodomain polypeptide comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the sequence of amino acids 30-196 of SEQ ID NO: 1.
6. The method of claim 4 , wherein the pharmaceutical preparation comprises a GDF15 polypeptide noncovalently associated with the GDF15 prodomain polypeptide.
7. The method of claim 1 , wherein the GDF15 polypeptide is administered to the patient simultaneously with the erythropoietin receptor activator.
8. The method of claim 1 , wherein the GDF15 polypeptide and erythropoietin receptor activator are administered to the patient sequentially.
9. The method of claim 1 , wherein the GDF15 polypeptide comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 8.
10. The method of claim 1 , wherein the GDF15 polypeptide comprises the amino acid sequence of SEQ ID NO: 8.
11. The method of claim 1 , wherein the stress erythropoiesis is caused by hypoxia.
12. The method of claim 1 , wherein the stress erythropoiesis is caused by hemorrhaging.