Methods and compositions for inhibiting the growth of hematopoietic malignant cells

Abstract

Disclosed herein are compositions and methods for reducing the growth of hematopoietic malignant cells (e.g., B-cell leukemia cells). The methods involve reducing the growth of hematopoietic malignant cells by contacting hematopoietic malignant cells with GP88 antagonists. GP88 is an 88 KDa autocrine growth factor that promotes the growth of hematopoictic malignant cells. Antagonists to GP88 are provided which inhibit its expression or biological activity. The antagonists include antisense oligonucleotides and antibodies. Also provided are methods for determining if a patient is responding or is responsive to anti-cancer therapy (e.g., glucocorticoid therapy). Increased levels of GP88 in hematopoietic cells indicates a patient is not responding or responsive to anti-cancer therapy.

I claim:  
     
         1 . A method of inhibiting the growth or viability of hematopoietic malignant cells comprising contacting hematopoietic malignant cells with a GP88 antagonist wherein said antagonist inhibits the growth or viability of said hematopoietic malignant cells.  
     
     
         2 . The method of  claim 1 , wherein said hematopoietic malignant cells are leukemia cells of B cell lineage.  
     
     
         3 . The method of  claim 1 , wherein said hematopoietic malignant cells are multiple myeloma cells.  
     
     
         4 . The method of  claim 1 , wherein said GP88 antagonist is an anti-GP88 antibody.  
     
     
         5 . The method of  claim 1 , wherein said GP88 antagonist is a humanized anti-GP88 antibody.  
     
     
         6 . The method of  claim 1 , wherein said GP88 antagonist is a neutralizing anti-GP88 antibody.  
     
     
         7 . The method of  claim 1 , wherein said GP88 antagonist is an anti-GP88 antibody comprising a plurality of portions wherein at least one portion is derived from a human.  
     
     
         8 . The method of  claim 1 , wherein said GP88 antagonist is an anti-GP88 nucleic acid.  
     
     
         9 . The method of  claim 8 , wherein said anti-GP88 nucleic acid is selected from the group consisting of antisense nucleic acid and RNAi.  
     
     
         10 . The method of  claim 8 , wherein said GP88 antagonist inhibits the growth of said hematopoietic malignant cells by at least about 50%.  
     
     
         11 . The method of  claim 8 , wherein said GP88 antagonist inhibits the phophorylation activity of MAPK in said hematopoietic malignant cells.  
     
     
         12 . The method of  claim 8 , wherein said GP88 antagonist inhibits the activity of PI3 kinase in said hematopoictic malignant cells.  
     
     
         13 . A composition for inhibiting the growth of hematopoietic malignant cells, comprising a carrier and an GP88 antagonist in an amount sufficient to inhibit the growth of said hematopoietic malignant cells.  
     
     
         14 . The composition of  claim 13 , wherein said hematopoictic malignant cells are multiple myeloma cells.  
     
     
         15 . The composition of  claim 13 , wherein said GP88 antagonist is an anti-GP88 antibody.  
     
     
         16 . The composition of  claim 13 , wherein said GP88 antagonist is a neutralizing anti-GP88 antibody.  
     
     
         17 . A composition of  claim 13 , wherein said GP88 antagonist is an anti-GP88 antibody comprising a plurality of portions wherein at least one portion is derived from a human.  
     
     
         18 . A composition according to  claim 13 , wherein said GP88 antagonist is an anti-GP88 antibody capable of reducing the proliferation of lymphoma cells by at least about 50%.  
     
     
         19 . A composition according to  claim 13 , wherein said GP88 antagonist is an anti-GP88 nucleic acid.  
     
     
         20 . A composition according to  claim 19  wherein said GP88 nucleic acid is selected from the group consisting of antisense nucleic acid and RNAi.  
     
     
         21 . A method for diagnosing B-cell leukemia comprising determining whether GP88 is present in a tissue sample containing B cells, wherein the presence of GP88 in said tissue sample indicates B-cell leukemia.  
     
     
         22 . The method of  claim 21 , wherein said B-cell leukemia is multiple myeloma.  
     
     
         23 . The method of  claim 21 , wherein said tissue comprises a material selected from the group consisting of blood, bone marrow, lymph, spleen, and liver.  
     
     
         24 . The method of  claim 21 , wherein said GP88 is GP88 protein.  
     
     
         25 . The method of  claim 21 , wherein said GP88 is GP88 nucleic acid.  
     
     
         26 . The method of  claim 24 , wherein said GP88 protein is detected with an anti-GP88 antibody.  
     
     
         27 . The method of  claim 24 , wherein said GP88 protein is detected with a humanized anti-GP88 antibody.  
     
     
         28 . The method of  claim 24 , wherein said GP88 protein is detected with an anti-GP88 antibody, wherein said anti-GP88 antibody is derived from an animal immunized with a material comprising the peptide of SEQ ID NO: 3.  
     
     
         29 . The method of  claim 24 , wherein said GP88 protein is detected with an anti-GP88 antibody, wherein said anti-GP88 antibody is derived from an animal immunized with a material comprising the peptide of SEQ ID NO: 4.  
     
     
         30 . The method of  claim 24 , wherein said GP88 protein is detected with an anti-GP88 antibody, wherein said anti-GP88 antibody is derived from an animal immunized with a material comprising the peptide of SEQ ID NO: 5.  
     
     
         31 . The method of  claim 24 , wherein said GP88 protein is detected with an anti-GP88 antibody, wherein said anti-GP88 antibody is derived from an animal immunized with a material comprising the peptide of SEQ ID NO: 6.  
     
     
         32 . The method of  claim 24 , wherein said GP88 protein is detected with an anti-GP88 antibody, wherein said anti-GP88 antibody is derived from an animal immunized with a material comprising the peptide of SEQ ID NO: 7.  
     
     
         33 . The method of  claim 24 , wherein said GP88 protein is detected by Western blot analysis.  
     
     
         34 . The method of  claim 24 , wherein said GP88 protein is by immunoassay.  
     
     
         35 . A method for diagnosing B-cell leukemia, comprising determining whether GP88 is present in a sample containing B-cells, wherein the presence of GP88 in said B-cells indicates B-cell leukemia.  
     
     
         36 . The method of  claim 35 , wherein said B-cell leukemia is multiple myeloma.  
     
     
         37 . A method for diagnosing multiple myeloma, comprising determining whether GP88 is present in bone marrow tissue, wherein the presence of GP88 in said bone marrow tissue indicates multiple myeloma.  
     
     
         38 . The method of  claim 37 , wherein the presence of GP88 in said bone marrow tissue is detected with an anti-GP88 antibody.  
     
     
         39 . The method of  claim 37 , wherein the presence of GP88 in said bone marrow tissue is detected by immunoassay.  
     
     
         40 . A method of determining whether a patient having a hematopoictic malignancy is responding or responsive to anti-cancer agents, comprising: 
 measuring a first level GP88 in a tissue sample containing hematopoictic cells obtained from said patient at a first time;    measuring the level of GP88 in a tissue sample containing hematopoietic cells obtained from said patient at a second time;    comparing said first level of GP88 with said second level of GP88; and    determining that a patient is not responding or responsive to anti-cancer agents if the second level of GP88 is higher than the first level of GP88.    
     
     
         41 . The method of  claim 40 , wherein said anti-cancer agent is a glucocorticoid or glucocorticoid analog.  
     
     
         42 . The method of  claim 41 , wherein said glucocorticoid or glucocorticoid analog is selected from the group consisting of dexamethasone, prednisolone, methylprednisolone, hydrocortisone, betamethasone, prednisone, fludrocortisone, cortisone, corticosterone, triamcinolone, and paramethasone.  
     
     
         43 . The method of  claim 40 , wherein said GP88 is detected with an anti-GP88 antibody or antibody fragment.  
     
     
         44 . The method of  claim 40 , wherein said GP88 is detected with an anti-GP88 nucleic acid.  
     
     
         45 . The method of  claim 40 , wherein said tissue sample is selected from group consisting of blood, bone marrow, lymph, spleen, and liver.  
     
     
         46 . The method of  claim 40 , wherein said hemapoietic cells are B-cell leukemia cells.  
     
     
         47 . The method of  claim 40 , wherein said hemapoietic cells are multiple mycloma cells.  
     
     
         48 . A method of treating hematopoietic malignancies with an anti-cancer agent in a patient comprising: 
 determining a first level of GP88 present in a tissue sample containing hematopoietic cells obtained from said patient at a first time;    determining a second level of GP88 present in a tissue sample containing hematopoietic cells obtained from said patient at a second time;    comparing the first level of GP88 with the second level of GP88; and    administering an anti-cancer agent to said patient in an amount sufficient to treat or prevent hemapoietic malignancies if the second level of GP88 is the same as or lower than the first level of GP88.    
     
     
         49 . The method of  claim 48 , wherein said anti-cancer agent is a glucocorticoid.  
     
     
         50 . The method of  claim 48 , wherein said anti-cancer agent is a glucocorticoid or glucocorticoid analog selected from the group consisting of dexamethasone, prednisolone, methylprednisolone, hydrocortisone, betamethasone, prednisone, fludrocortisone, cortisone, corticosterone, triamcinolone, and paramethasone.  
     
     
         51 . The method of  claim 48 , wherein said hematopoictic malignancy is B-cell leukemia.  
     
     
         52 . A method of determining whether a patient is responding or responsive to the anti-tumorigenic effects of anti-cancer therapy comprising: 
 determining a first level of GP88 in hematopoeitic cells obtained from said patient at a first time;    determining a second level of GP88 in hematopoeitic cells obtained from said patient at a second time;    comparing said first level of GP88 with said second level of GP88; and    determining that a patient is resistant to the anti-tumorigenic effects of anti-cancer therapy if the second level of GP88 is higher than the first level of GP88.    
     
     
         53 . The method of  claim 52 , wherein said anti-cancer therapy is glucocorticoid therapy.  
     
     
         54 . The method of  claim 52 , wherein said anti-cancer therapy comprises administering dexamethasone to a patient.  
     
     
         55 . A method of determining whether a patient is responding or responsive to the anti-tumorigenic effects of glucocorticoids or glucocorticoid analogs comprising: 
 determining a first level of GP88 in a tissue sample containing B-cells obtained from said patient at a first time;    determining a second level of GP88 in a tissue sample containing B-cells obtained from said patient at a second time;    comparing the first level of GP88 with the second level of GP88; and    determining that a patient is resistant to the anti-tumorigenic effects of glucocorticoids if the second level of GP88 is higher that the first level of GP88.    
     
     
         56 . The method of  claim 55 , wherein said GP88 is detected with an anti-GP88 antibody or antibody fragment.  
     
     
         57 . The method of  claim 55 , wherein said GP88 is detected with an anti-GP88 nucleic acid.  
     
     
         58 . The method of  claim 55 , wherein said glucocorticoids or glucocorticoid analogs are selected from the group consisting of dexamethasone, dexamethasone, prednisolone, methylprednisolone, hydrocortisone, betamethasone, prednisone, fludrocortisone, cortisone, corticosterone, triamcinolone, and paramethasone.  
     
     
         59 . The method of  claim 55 , wherein said tissue sample is selected from the group consisting of blood, bone marrow, lymph node, spleen, and liver.