Recombinant Human Albumin-Human Granulocyte Colony Stimulating Factor for the Prevention of Neutropenia

Abstract

Disclosed are compositions and methods for treating, preventing and ameliorating conditions and diseases characterized by a lowered white blood cell count. The methods and compositions described herein include a fusion polypeptide formed from human serum albumin protein (“HSA”) and human granulocyte-colony stimulating factor (“G-CSF”).

What is claimed is: 
     
         1 . A method of treating or preventing neutropenia in a human subject comprising administering to a human subject exhibiting neutropenia or at risk of developing neutropenia, recombinant human albumin-human granulocyte colony stimulating factor in an amount effective to treat the subject. 
     
     
         2 . A method of treating or preventing leukopenia in a human subject comprising administering to a human subject exhibiting leukopenia or at risk of developing leukopenia, recombinant human albumin-human granulocyte colony stimulating factor in an amount effective to treat the subject. 
     
     
         3 . The method according to  claim 1  wherein the human subject is suffering from a non-myeloid malignancy and is receiving at least one myelosuppressive anti-cancer drug associated with a clinically significant incidence of febrile neutropenia. 
     
     
         4 . A method of decreasing the incidence of infection, as manifested by febrile neutropenia, in a human subject with non-myeloid malignancies and receiving at least one myelosuppressive anti-cancer drug associated with a clinically significant incidence of febrile neutropenia, comprising administering to the subject recombinant human albumin-human granulocyte colony stimulating factor in an amount effective to treat the subject. 
     
     
         5 . The method of  claim 1 , wherein:
 (a) grade 4 neutropenia in the subject is eliminated;   (b) grade 4 neutropenia in the subject is reduced;   (c) the duration of severe neutropenia is reduced in the subject;   (d) the duration of grade 4 neutropenia in the subject is less than 5 days;   (e) the duration of grade 3 neutropenia in the subject is eliminated;   (f) the duration of grade 3 neutropenia in the subject is decreased; or   (g) any combination thereof.   
     
     
         6 . The method of  claim 1 , wherein administering recombinant human albumin-human granulocyte colony stimulating factor induces a rise in white blood cells (WBC). 
     
     
         7 . The method according to  claim 1 , wherein:
 (a) the number of neutrophils is increased in the subject;   (b) a decrease in the number of neutrophils is inhibited in the subject;   (c) the nadir absolute neutrophil count (ANC) is increased in the subject;   (d) the recovery ANC is increased in the subject;   (e) the time to ANC recovery is reduced in the subject; or   (f) any combination thereof.   
     
     
         8 . The method according to  claim 1 , wherein the amount of recombinant human albumin-human granulocyte colony stimulating factor administered to the subject is selected from the group consisting of:
 (a) from about 50 μg/kg to about 450 μg/kg;   (b) about 50 μg/kg;   (c) about 150 μg/kg;   (d) about 300 μg/kg;   (e) about 450 μg/kg;   (f) from about 30 mg to about 60 mg;   (g) about 30 mg;   (h) about 40 mg;   (i) about 50 mg;   (j) about 60 mg; or   (k) any combination thereof.   
     
     
         9 . The method of  claim 1 , wherein neutropenia is selected from the group consisting of primary neutropenia, acute neutropenia, severe chronic neutropenia (SCN), severe congenital neutropenia (Kostmann's syndrome), severe infantile genetic agranulocytosis, benign neutropenia, cyclic neutropenia, chronic idiopathic neutropenia, secondary neutropenia, syndrome associated neutropenia, and immune-mediated neutropenia. 
     
     
         10 . The method of  claim 1  wherein neutropenia is caused or associated with radiation, alcoholism, drugs, allergic disorders, aplastic anemia, autoimmune disease, T-γ lymphoproliferative disease LPD), myelodysplasia, myelofibrosis, dysgammaglobulinemia, paroxysmal nocturnal hemoglobinuria, cancer, vitamin B 12  deficiency, folate deficiency, viral infection, bacterial infection, spleen disorder, hemodialysis, or transplantation, leukemia, myeloma, lymphoma, metastatic solid tumors which infiltrate and replace the bone marrow, toxins, bone marrow failure, Schwachman-Diamond syndrome, cartilage-hair hypoplasia, dyskeratosis congenita, glycogen storage disease type IB, splenomegaly of any cause, intrinsic defects in myeloid cells or their precursors. 
     
     
         11 . The method of  claim 3 , wherein recombinant human albumin-human granulocyte colony stimulating factor is administered at a time selected from the group consisting of:
 (a) at least 12 hours after administration of the myelosuppressive anti-cancer drug;   (b) at least 18 hours after administration of the myelo suppressive anti-cancer drug;   (c) at least 24 hours after administration of the myelosuppressive anti-cancer drug.   
     
     
         12 . The method of  claim 11  wherein administering recombinant human albumin-human granulocyte colony stimulating factor prior to the myelosuppressive anti-cancer drug induces a rise in WBC. 
     
     
         13 . The method of  claim 11  wherein administering recombinant human albumin-human granulocyte colony stimulating factor prior to chemotherapy induces a rise in ANC. 
     
     
         14 . The method of  claim 3  wherein the non-myeloid malignancy comprises breast cancer. 
     
     
         15 . The method of  claim 3  wherein the myelosuppressive anticancer drugs comprise doxorubicin and docetaxel. 
     
     
         16 . The method of  claim 15  wherein about 50 mg/m 2  doxorubicin and about 75 mg/m 2  docetaxel are administered sequentially by intravenous infusion on the same day for at least one treatment cycle. 
     
     
         17 . The method of  claim 15  wherein about 60 mg/m 2  doxorubicin and about 75 mg/m 2  docetaxel are administered sequentially by intravenous infusion on the same day for at least one treatment cycle. 
     
     
         18 . The method of  claim 3 , wherein ANC and WBC return to normal at a time period selected from the group consisting of:
 (a) by day 10 after chemotherapy;   (b) by day 11 after chemotherapy;   (c) by day 12 after chemotherapy;   (d) by day 13 after chemotherapy:   (e) by day 14 after chemotherapy; or   (f) by day 15 after chemotherapy.   
     
     
         19 . The method of  claim 3 , wherein on day 14 after chemotherapy administration the rise in ANC in patients treated with recombinant human albumin-human granulocyte colony stimulating factor is lower than the rise in ANC in patients treated with an equivalent dose of pegfilgrastim. 
     
     
         20 . The method according to  claim 1  wherein administering recombinant human albumin-human granulocyte colony stimulating factor induces a rise in lymphocytes, monocytes, eosinophils, basophils, or any combination thereof. 
     
     
         21 . The method according to  claim 1  wherein the number of lymphocytes, monocytes, eosinophils, basophils or any combination thereof is increased in the subject. 
     
     
         22 . The method according to  claim 1 , wherein a decrease in the number of lymphocytes, monocytes, eosinophils, or basophils is inhibited in the subject.