Diagnosis and treatment of malignant neoplasms

Abstract

The invention features a method for diagnosing and inhibiting growth of a malignant neoplasm in a mammal by contacting a cell or a bodily fluid of the mammal with an antibody which binds to an human aspartyl (asparaginyl) beta-hydroxylase (HAAH) polypeptide. Methods of immunization to generate an HAAH-specific immune response are also within the invention.

1 . A method of inhibiting tumor growth in a mammal comprising administering to said mammal a compound which inhibits expression of HAAH.  
     
     
         2 . The method of  claim 1 , wherein said compound is a HAAH antisense nucleic acid.  
     
     
         3 . The method of  claim 2 , wherein said HAAH antisense nucleic acid is 10-50 nucleotides in length.  
     
     
         4 . The method of  claim 2 , wherein said the sequence of said HAAH antisense nucleic acid is complementary to a nucleic acid sequence is the 5′ untranslated region of a HAAH gene.  
     
     
         5 . The method of  claim 2 , wherein the sequence of said HAAH antisense nucleic acid comprises 5′CAT TCT TAC GCT GGG CCA TT 3′ (SEQ ID NO:10).  
     
     
         6 . The method of  claim 2 , wherein the sequence of said HAAH antisense nucleic acid comprises 5′ TTA CGC TGG GCC ATT GCA CG 3′ (SEQ ID NO:11)  
     
     
         7 . The method of  claim 2 , wherein the sequence of said HAAH antisense nucleic acid comprises 5′ CTG GGC CAT TGC ACG GTC CG 3′ (SEQ ID NO:12).  
     
     
         8 . The method of  claim 1 , wherein said compound is a ribozyme.  
     
     
         9 . The method of  claim 1 , wherein said tumor is derived from endodermal tissue.  
     
     
         10 . The method of  claim 1 , wherein said tumor is selected from the group consisting of colon cancer, breast cancer, pancreatic cancer, liver cancer, and cancer of the bile ducts.  
     
     
         11 . The method of  claim 10 , wherein said tumor is a CNS tumor.  
     
     
         12 . An HAAH antisense nucleic acid, wherein said nucleic acid comprises a sequence which is complementary to a sequence of a HAAH gene.  
     
     
         13 . An HAAH antisense nucleic acid, wherein said nucleic acid comprises a sequence which is complementary to a noncoding sequence of a HAAH gene.  
     
     
         14 . An HAAH antisense nucleic acid, wherein said nucleic acid comprises a sequence which is complementary to a sequence in the 5′ untranslated region of a HAAH gene.  
     
     
         15 . The nucleic acid of  claim 14 , wherein the sequence of said HAAH antisense nucleic acid comprises 5′CAT TCT TAC GCT GGG CCA TT 3′ (SEQ ID NO:10).  
     
     
         16 . The nucleic acid of claim,  14 , wherein the sequence of said HAAH antisense nucleic acid comprises 5′ TTA CGC TGG GCC ATT GCA CG 3′ (SEQ ID NO:11)  
     
     
         17 . The nucleic acid of claim,  14 , wherein the sequence of said HAAH antisense nucleic acid comprises 5′ CTG GGC CAT TGC ACG GTC CG 3′ (SEQ ID NO:12).  
     
     
         18 . A method of confering an immune response to a tumor cell in a mammal, comprising administering to said mammal an antibody which binds to aspartyl (asparaginyl) beta hydroxylase (HAAH).  
     
     
         19 . The method of  claim 18 , wherein said tumor cell is a brain tumor cell.  
     
     
         20 . The method of  claim 19 , wherein said brain tumor cell is selected from the group consisting of a glioma, a glioblastoma, an astrocytoma, and a hemangioma.  
     
     
         21 . The method of  claim 18 , wherein said tumor cell is a pancreatic carcinoma cell.  
     
     
         22 . The method of  claim 18 , wherein said antibody binds to an extracellular domain of HAAH.  
     
     
         23 . The method of  claim 18 , wherein said antibody binds to a catalytic domain of HAAH.  
     
     
         24 . The method of  claim 23 , wherein said catalytic domain comprises amino acids 660-700 of SEQ ID NO:2.  
     
     
         25 . The method of  claim 18 , wherein said antibody is FB50 or a fragment thereof.  
     
     
         26 . The method of  claim 18 , wherein said antibody is selected from the group consisting of FB50, 86A, 5C7 and 19B.  
     
     
         27 . The method of  claim 18  wherein said antibody is a mixture of one or more antibodies selected from the group consisting of FB50, 86A, 5C7 and 19B.  
     
     
         28 . The method of  claim 18 , wherein said antibody is a high affinity single chain antibody.  
     
     
         29 . A method of inhibiting tumor growth in a mammal, comprising administering to said mammal an HAAH-binding antibody conjugated to a cytotoxic agent.  
     
     
         30 . A method of inducing an HAAH-specific immune response in a mammal, comprising administering to said mammal an HAAH polypeptide.  
     
     
         31 . The method of  claim 30 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO:2.  
     
     
         32 . The method of  claim 30 , wherein said polypeptide comprises an extracellular domain of HAAH and lacks an intracellular domain of HAAH.  
     
     
         33 . The method of  claim 30 , wherein said polypeptide comprises a catalytic domain of HAAH.  
     
     
         34 . The method of  claim 33 , wherein said polypeptide comprises amino acids 650-700 of SEQ ID NO:2.  
     
     
         35 . The method of  claim 30 , further comprising administering an adjuvant composition.  
     
     
         36 . A method of inducing an HAAH-specific immune response in a mammal, comprising administering to said mammal a polynucleotide composition encoding an HAAH polypeptide, or a degenerate variant of said polynucleotide.  
     
     
         37 . The method of  claim 36 , wherein said composition comprises a transfection-enhancing agent.  
     
     
         38 . The method of  claim 36 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO:2.  
     
     
         39 . The method of  claim 36 , wherein said polypeptide comprises an extracellular domain of HAAH and lacks an intracellular domain of HAAH.  
     
     
         40 . The method of  claim 36 , wherein said polypeptide comprises a catalytic domain of HAAH.  
     
     
         41 . The method of  claim 40 , wherein said polypeptide comprises amino acids 650-700 of SEQ ID NO:2.  
     
     
         42 . A method for diagnosing a neoplasm in a mammal, comprising contacting a tissue of said mammal with a detectably-labeled antibody which binds to HAAH, wherein an increase in the level of antibody binding at a tissue site compared to the level of binding to a normal nonneoplastic tissue indicates the presence of a neoplasm at said tissue site.  
     
     
         43 . The method of  claim 42 , wherein said antibody is labeled with a radioactive compound.  
     
     
         44 . The method of  claim 43 , wherein said radioactive compound is selected from the group consisting of  125 I,  99 Tc.  
     
     
         45 . The method of  claim 42 , wherein said antibody is labeled with Gd +++  or Fe ++ .  
     
     
         46 . The method of  claim 42 , wherein said antibody is labeled with a colorimetric agent.  
     
     
         47 . The method of  claim 42 , wherein said tissue is a lymphoid tissue.  
     
     
         48 . A fragment of HAAH comprising an extracellular domain and lacking a cytoplasmic domain of said HAAH.  
     
     
         49 . A fragment of HAAH, wherein said fragment lacks residues 660-758 of SEQ ID NO:2.  
     
     
         50 . A fragment of HAAH, wherein said fragment lacks residues 679-697 of SEQ ID NO:2.  
     
     
         51 . A fragment of HAAH, wherein said fragment lacks at least one residue of SEQ ID NO:2, wherein said residue is selected from the group consisting of residue 661, 662, 663, 670, 671, 672, and 673.  
     
     
         52 . A fragment of HAAH, wherein said fragment lacks enzymatic activity.  
     
     
         53 . A fragment of HAAH, wherein said fragment lacks an alpha-ketoglutarate binding domain and an EGF-like domain.