Il-12 formulations for enhancing hematopoiesis

Abstract

Provided are formulations for proteins to be injected into mammals. Specifically, formulations for recombinant IL-12 in mice and primates.

1 - 47 . (canceled) 
     
     
         48 . A method of treating a mammal for an immune system deficiency, comprising: administering one or more therapeutically effective dose(s) of a composition as needed to ameliorate the deficiency, wherein the composition comprises:
 (a) about 15 μg/ml up to about 30 μg/ml of human IL-12 or an IL-12 variant thereof having hematopoietic activity;   (b) about 50 mM up to about 300 mM of at least one stabilizer, wherein the at least one stabilizer is a salt;   (c) about 0.01% up to about 0.2% of at least one surfactant, wherein the at least one surfactant is a poloxamer; and   (d) water,   wherein the IL-12 or IL-12 variant is solubilized and the composition has a pH of about 4.5 to about 7.5.   
     
     
         49 . The method of  claim 48 , wherein the mammal is a human. 
     
     
         50 . The method of  claim 48 , wherein the immune system deficiency is a deficiency in hematopoiesis. 
     
     
         51 . The method of  claim 50 , wherein;
 (a) the deficiency in hematopoiesis is the result of a treatment having an associated hematopoietic toxicity;   (b) the treatment is administered to the mammal to treat a disease state;   (c) the one or more therapeutically effective dose(s) of the composition are administered near the time of administration of the treatment; and   (d) the administration of the composition to the mammal reduces the hematopoietic toxicity of the treatment.   
     
     
         52 . The method of  claim 51 , wherein the treatment comprises chemotherapy, radiation therapy, or a combination thereof. 
     
     
         53 . The method of  claim 51 , wherein:
 (a) the treatment comprises one or more high dose treatment modalities;   (b) the treatment is administered in a dose dense treatment regimen;   (c) the treatment comprises one or more high dose treatment modalities and the high dose treatment modality comprises administration of radiation therapy;   (d) the treatment comprises one or more high dose treatment modalities and the dose dense treatment regimen comprises administration of radiation therapy;   (e) administration of the composition results in protection of bone marrow cells from the associated hematopoietic toxicity of the treatment;   (f) administration of the composition results in chemoprotection of bone marrow cells;   (g) the bone marrow cells comprise hematopoietic repopulating cells, hematopoietic stem cells, hematopoietic progenitor cells, or any combination thereof; or   (h) any combination thereof.   
     
     
         54 . The method of  claim 51 , wherein:
 (a) the treatment is targeted to treating one or more solid tumors;   (b) the treatment is targeted to treating one or more hematopoietic cell disorders;   (c) the treatment is targeted to treating virus infection;   (d) the treatment is targeted to treating one or more solid tumors and the method results in an increased remission of the one or more solid tumors, as compared with the treatment intended to target the disease state alone;   (e) the treatment is targeted to treating one or more hematopoietic cell disorders, and the method results in an increased remission of the one or more hematopoietic cell disorders, as compared with the treatment intended to target the disease state alone; or   (f) the treatment is targeted to treating virus infection and:
 (i) the method results in a decrease in the virus infection or its associated symptoms; 
 (ii) the white blood cell count of the mammal is increased; 
 (iii) the T-cell count of the mammal is increased; or 
 (iv) any combination thereof. 
   
     
     
         55 . The method of  claim 51 , wherein:
 (a) the treatment comprises chemotherapy and:
 (i) the chemotherapy leads to a deficiency in one or more hematopoietic cell types or lineages and the administration of the composition ameliorates the deficiency; 
 (ii) the chemotherapy treatment comprises administration of more than one chemotherapy; 
 (iii) the composition is administered before the chemotherapy; 
 (iv) the composition is administered after the chemotherapy; 
 (v) the composition is administered before or after the chemotherapy; 
 (vi) the composition is administered before and after chemotherapy; or 
 (vii) any combination thereof; or 
   (b) the treatment comprises radiation therapy and:
 (i) administration of the composition results in radioprotection of bone marrow cells; 
 (ii) administration of the composition results in radioprotection of bone marrow cells and the bone marrow cells comprise hematopoietic repopulating cells, hematopoietic stem cells hematopoietic progenitor cells, or any combination thereof; 
 (iii) the radiation therapy comprises a near-lethal dose of radiation; 
 (iv) the radiation therapy comprises a sub-lethal dose of radiation; 
 (v) the radiation therapy is administered in a dose dense treatment regimen; 
 (vi) the composition is administered before the radiation therapy; 
 (vii) the composition is administered after the radiation therapy; 
 (viii) the composition is administered before or after the radiation therapy; 
 (ix) the composition is administered before and after the radiation therapy; 
 (x) the radiation therapy leads to a deficiency in one or more hematopoietic cell types or lineages and the administration of the composition ameliorates the deficiency; or 
 (xi) any combination thereof. 
   
     
     
         56 . The method of  claim 51 , wherein one or more therapeutically effective dose(s) of the composition is administered at various time intervals before, before and after, or after the administration of the treatment. 
     
     
         57 . The method of  claim 51 , wherein the deficiency in hematopoiesis comprises:
 (a) a deficiency in one or more hematopoietic cell types or lineages;   (b) is substantially the result of a disease state;   (c) comprises a lymphopenia;   (d) comprises a myelopenia;   (e) comprises a leucopenia;   (f) comprises a leukopenia which is neutropenia;   (g) comprises erythropenia;   (h) comprises megakaryopenia;   (i) comprises a deficiency in platelets;   (j) comprises a deficiency in lymphocytes;   (k) comprises a deficiency in erythrocytes;   (l) comprises a deficiency in monocytes;   (m) comprises a deficiency in neutrophils;   (n) comprises a deficiency in T cells;   (o) comprises a deficiency in granulocytes;   (p) comprises a deficiency in dendritic cells;   
       or
 (q) any combination thereof. 
 
     
     
         58 . The method of  claim 48 , wherein the deficiency:
 (a) is ameliorated by the IL-12 or IL-12 variant facilitated proliferation of one or more types of bone marrow cells;   (b) is ameliorated by the IL-12 or IL-12 variant facilitated proliferation of hematopoietic repopulating cells, hematopoietic stem cells, hematopoietic progenitor cells, or any combination thereof;   (c) is exacerbated by chemotherapy, radiation therapy, or a combination thereof; or   (d) any combination thereof.   
     
     
         59 . The method of  claim 48 , wherein the immune system deficiency is due to a hematopoietic malignancy. 
     
     
         60 . The method of  claim 48 , wherein the immune system deficiency is due to an infectious disorder causing primary or secondary immunodeficiency. 
     
     
         61 . The method of  claim 48 , wherein the immune system deficiency is due to a congenital disorder. 
     
     
         62 . The method of  claim 48 , wherein the at least one stabilizer is present in the composition in an amount selected from: less than about 250 mM, less than about 225 mM, less than about 200 mM, less than about 175 mM, less than about 170 mM, less than about 160 mM, less than about 155 mM, less than about 150 mM, less than about 145 mM, less than about 140 mM, less than about 135 mM, less than about 130 mM, less than about 120 mM, and less than about 100 mM. 
     
     
         63 . The method of  claim 48 , wherein the at least one stabilizer is sodium chloride. 
     
     
         64 . The method of  claim 48 , wherein the composition does not comprise trehalose. 
     
     
         65 . The method of  claim 48 , wherein the composition has a pharmaceutically acceptable EC50 for expression of interferon gamma when peripheral blood mononuclear cells are exposed to the composition. 
     
     
         66 . The method of  claim 48 , wherein the wherein the composition is stable for at least 4 weeks of storage at 25° C. 
     
     
         67 . The method of  claim 48 , wherein the composition comprises:
 (a) about 150 mM sodium chloride; and   (b) about 0.1% poloxamer 188,   wherein the composition has a pH of at least 5.5 and less than 6.5.