Methods for dosing an actriib antagonist and monitoring of treated patients

Abstract

In certain aspects, the present invention provides methods for dosing a patient with an ActRIIb antagonist and methods for managing patients treated with an ActRIIb anatagonist. In certain aspects, the methods involve measuring one or more hematologic parameters in a patient.

1 - 45 . (canceled) 
     
     
         46 . A method for treating a disorder in a subject, comprising:
 (i) administering to the subject one or more doses of an ActRIIb polypeptide comprising an amino acid sequence that is at least 90% identical to any one of SEQ ID NOs: 2, 3 or 8, wherein the polypeptide binds to GDF11 and/or activin;   (ii) monitoring in the subject one or more hematologic parameters selected from blood pressure, red blood cell levels, hemoglobin levels, iron stores, transferrin saturation, ferritin level, and hematocrit level;   (iii) determining whether the subject has:   a) blood pressure elevated above baseline or hypertension;   b) a red blood cell level greater than the normal range for subjects of similar age and sex;   c) a hemoglobin level of greater than the normal range for subjects of similar age and sex;   d) iron stores that are lower than the normal range for subjects of similar age and sex;   e) a transferrin saturation of less than 20%;   f) a ferritin level of less than 100 ng/ml; or   g) a hematocrit level greater than the normal range for subjects of similar age and sex; and   (iv) reducing the number of doses and/or delaying administration of a further dose administered to the subject if a determination in step (iii) is affirmative.   
     
     
         47 . The method of  claim 46 , wherein step (iv) comprises reducing the number of doses administered to the subject if a determination in step (iii) is affirmative. 
     
     
         48 . The method of  claim 46 , wherein step (iv) comprises delaying administration of a further dose of the ActRIIb polypeptide to the subject if a determination in step (iii) is affirmative. 
     
     
         49 . The method of  claim 46 , wherein the subject is determined in step (iii) to have a blood pressure elevated above baseline or is determined to be hypertensive. 
     
     
         50 . The method of  claim 46 , wherein the subject is determined in step (iii) to have a red blood cell level greater than the normal range for subjects of similar age and sex. 
     
     
         51 . The method of  claim 46 , wherein the subject is determined in step (iii) to have a hemoglobin level of greater than the normal range for subjects of similar age and sex. 
     
     
         52 . The method of  claim 46 , wherein the subject is determined in step (iii) to have iron stores that are lower than the normal range for subjects of similar age and sex. 
     
     
         53 . The method of  claim 46 , wherein the subject is determined in step (iii) to have a transferrin saturation of less than 20%. 
     
     
         54 . The method of  claim 46 , wherein the subject is determined in step (iii) to have a ferritin level of less than 100 ng/ml. 
     
     
         55 . The method of  claim 46 , wherein the subject is determined in step (iii) to have a hematocrit level greater than the normal range for subjects of similar age and sex. 
     
     
         56 . The method of  claim 46 , wherein if the subject is determined in step (iii) to have a blood pressure elevated above baseline or is determined to be hypertensive, the method further comprises administering a blood pressure lowering agent to the subject until the subject's blood pressure is not elevated above baseline or until the subject is not hypertensive. 
     
     
         57 . The method of  claim 46 , wherein the disorder is anemia. 
     
     
         58 . The method of  claim 57 , wherein the anemia is associated with a myelodysplastic syndrome. 
     
     
         59 . The method of  claim 57 , wherein the anemia is associated with a hemoglobinopathy. 
     
     
         60 . The method of  claim 57 , wherein the anemia is associated with a thalassemia. 
     
     
         61 . The method of  claim 57 , wherein the anemia is associated with sickle cell disease. 
     
     
         62 . The method of  claim 57 , wherein the anemia is associated with chronic renal disease or failure. 
     
     
         63 . The method of  claim 57 , wherein the anemia is associated with acute renal disease or failure. 
     
     
         64 . The method of  claim 46 , wherein the disorder is cancer. 
     
     
         65 . The method of  claim 64 , wherein the cancer is breast cancer. 
     
     
         66 . The method of  claim 46 , wherein the disorder is a disorder associated with muscle loss or insufficient muscle growth. 
     
     
         67 . The method of  claim 46 , wherein the disorder is muscular dystrophy. 
     
     
         68 . The method of  claim 67 , wherein the muscular dystrophy is Duchenne Muscular Dystrophy. 
     
     
         69 . The method of  claim 67 , wherein the muscular dystrophy is Becker Muscular Dystrophy. 
     
     
         70 . The method of  claim 67 , wherein the muscular dystrophy is Facioscapulohumeral Muscular Dystrophy. 
     
     
         71 . The method of  claim 66 , wherein the disorder is cachexia. 
     
     
         72 . The method of  claim 66 , wherein the disorder is sarcopenia. 
     
     
         73 . The method of  claim 46 , wherein the ActRIIb polypeptide comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 3. 
     
     
         74 . The method of  claim 46 , wherein the ActRIIb polypeptide comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 3. 
     
     
         75 . The method of  claim 46 , wherein the ActRIIb polypeptide comprises the amino acid sequence of SEQ ID NO: 3. 
     
     
         76 . The method of  claim 46 , wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 2. 
     
     
         77 . The method of  claim 46 , wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 2. 
     
     
         78 . The method of  claim 46 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 2. 
     
     
         79 . The method of  claim 46 , wherein the ActRIIb polypeptide is a fusion protein comprising an immunoglobulin Fc domain. 
     
     
         80 . The method of  claim 46 , wherein the ActRIIb polypeptide comprises one or more amino acid modifications selected from the group consisting of: a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, and an amino acid conjugated to a lipid moiety. 
     
     
         81 . The method of  claim 46 , wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 8. 
     
     
         82 . The method of  claim 46 , wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 8. 
     
     
         83 . The method of  claim 46 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 8. 
     
     
         84 . The method of  claim 46 , wherein the ActRIIb polypeptide binds to activin. 
     
     
         85 . The method of  claim 46 , wherein the ActRIIb polypeptide binds activin A. 
     
     
         86 . The method of  claim 46 , wherein the ActRIIb polypeptide binds to activin B 
     
     
         87 . The method of  claim 46 , wherein the ActRIIb polypeptide binds to GDF11. 
     
     
         88 . The method of  claim 46 , wherein the ActRIIb polypeptide binds activin B and GDF11. 
     
     
         89 . The method of  claim 46 , wherein the ActRIIb polypeptide inhibits signaling by GDF11. 
     
     
         90 . The method of  claim 46 , wherein the ActRIIb polypeptide inhibits signaling by activin. 
     
     
         91 . The method of  claim 90 , wherein the ActRIIb polypeptide inhibits signaling by activin A. 
     
     
         92 . The method of  claim 90 , wherein the ActRIIb polypeptide inhibits signaling by activin B.