Compositions and methods for regulating erythropoiesis

Abstract

The present application discloses a previously unknown function of CD24 expressed on a subset of dendritic cells. The invention encompasses regulating CD24 on these cells to regulate erythropoiesis, induce EPO production and levels, increase RBC levels, and to treat, for example, stress-mediated erythropoiesis. The compositions and methods of the invention are useful, for example, in treating anemia.

1 - 37 . (canceled) 
     
     
         38 . A method of treating a disease, disorder, or condition associated with a decrease in erythrocyte production, said method comprising administering to a subject in need thereof a pharmaceutical composition comprising a pharmaceutically-acceptable carrier, an effective amount of at least one agonist of CD24, and optionally at least one additional therapeutic agent, thereby treating a disease, disorder, or condition associated with a decrease in erythrocyte production. 
     
     
         39 - 42 . (canceled) 
     
     
         43 . The method of  claim 38 , wherein said agonist is a monoclonal antibody selected from the group consisting of M1/69, 91, 30-F1, J11d, eBioSN3, and ML5, or biologically active fragments or homologs thereof. 
     
     
         44 - 55 . (canceled) 
     
     
         56 . The method of  claim 38 , wherein said subject has a disease, disorder, or condition associated with a decrease in erythrocyte production. 
     
     
         57 . The method of  claim 56 , wherein said disease, disorder, or condition is selected from the group consisting of aplastic anemia, hypoplastic anemia, chronic renal failure, end-stage renal disease, transplantation, renal transplantation, cancer, acquired immune deficiency syndrome, chemotherapy, radiotherapy, bone marrow transplantation, sepsis, rheumatoid arthritis, chronic persistent infection such as HIV, tuberculosis, hepatitis B, hepatitis C, chronic hepatitis, and chronic anemia in the elderly. 
     
     
         58 . The method of  claim 57 , wherein said disease, disorder, or condition is anemia. 
     
     
         59 . The method of  claim 58 , wherein said anemia is associated with hypoxic stress. 
     
     
         60 - 74 . (canceled) 
     
     
         75 . The method of  claim 38 , wherein said additional therapeutic agent is selected from the group consisting of G-CSF, IL-4, SCF, Flt3L, EPO, BMP4, anti-microbial agents, and host-derived danger associated-pattern molecules. 
     
     
         76 . The method of  claim 75 , wherein said host-derived danger associated-pattern molecule is HMGB1 or Hsp70. 
     
     
         77 . A method of stimulating stem cell factor synthesis, said method comprising contacting a CD24 +  dendritic cell with an effective amount of an agonist of CD24 and optionally an additional agent. 
     
     
         78 . The method of  claim 77 , wherein said dendritic cell is BDCA3 + . 
     
     
         79 . The method of  claim 77 , wherein said additional agent is a host-derived danger associated-pattern molecule. 
     
     
         80 . The method of  claim 77 , wherein said agonist is an antibody, or a biologically active fragment or homolog thereof, directed against CD24. 
     
     
         81 . The method of  claim 80 , wherein said antibody is selected from the group consisting of a polyclonal antibody, a monoclonal antibody, a chimeric antibody, a single-chain antibody, a synthetic antibody, and a humanized antibody. 
     
     
         82 . The method of  claim 81 , wherein said monoclonal antibody is selected from the group consisting of M1/69, 91, 30-F1, J11d, eBioSN3, and ML5, or biologically active fragments or homologs thereof. 
     
     
         83 . The method of  claim 82 , wherein said fragment is an F(ab)2 fragment. 
     
     
         84 . The method of  claim 77 , where said method stimulates said dendritic cell. 
     
     
         85 . The method of  claim 77 , wherein said CD24 has the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:4, or homologs thereof. 
     
     
         86 . The method of  claim 81 , wherein said antibody is directed against a CD24 peptide having the sequence of SEQ ID NO:2 or SEQ ID NO:4, or homologs or fragments thereof. 
     
     
         87 - 93 . (canceled) 
     
     
         94 . A method of identifying of an agonist of CD24 useful for stimulating erythropoiesis, said method comprising contacting a dendritic cell expressing CD24 with a test compound, measuring the stem cell factor level in said cell following said contact, wherein an increase in stem cell factor in said cell relative to a control cell not contacted with said test compound, is an indication that said test compound is an agonist of CD24, thereby identifying of an agonist of CD24 useful for stimulating erythropoiesis. 
     
     
         95 . The method of  claim 94 , wherein said test compound is a small molecule, drug, prodrug, or an antibody directed against CD24. 
     
     
         96 - 101 . (canceled)