US2009142334A1PendingUtilityA1

DETECTION AND MODULATION OF IAPs AND NAIP FOR THE DIAGNOSIS AND TREATMENT OF PROLIFERATIVE DISEASE

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Assignee: AEGERA THERPEUTICS INCPriority: Feb 13, 1997Filed: Apr 28, 2008Published: Jun 4, 2009
Est. expiryFeb 13, 2017(expired)· nominal 20-yr term from priority
Inventors:Robert G. KornelukAlexander E. MackenziePeter ListonStephen BairdBenjamin K. TsangChristine Pratt
G01N 33/5011C12N 2310/11A01K 2217/05C12Q 1/6886C12N 15/1135A61K 38/1709C12Q 2600/106C07K 14/4703C12N 2799/022A61K 48/00A61P 35/00C12Q 2600/136C12N 15/113G01N 33/57595
59
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Claims

Abstract

Disclosed are diagnostic and prognostic kits for the detection and treatment of proliferative diseases such as ovarian cancer, breast cancer, and lymphoma. Also disclosed are cancer therapeutics utilizing IAP antisense nucleic acids, IAP fragments, and antibodies which specifically bind IAP polypeptides.

Claims

exact text as granted — not AI-modified
1 . A method for enhancing apoptosis in a cell from a mammal with a proliferative disease, the method comprising: administering to the cell a compound that inhibits the biological activity of an IAP polypeptide, the compound being administered to the cell in an amount sufficient to enhance apoptosis in the cell. 
     
     
         2 . The method of  claim 1 , wherein the cell is proliferating in the proliferative disease. 
     
     
         3 . The method of  claim 1 , wherein the biological activity is the level of expression of the polypeptide. 
     
     
         4 . The method, according to  claim 1 , wherein the biological activity is the level of expression of an mRNA molecule encoding the IAP polypeptide. 
     
     
         5 . The method, according to  claim 1 , wherein the biological activity is an apoptosis inhibiting activity. 
     
     
         6 . The method of  claim 3 , wherein the level of expression is measured by assaying the amount of the IAP polypeptide present in the cell. 
     
     
         7 . The method of  claim 1 , wherein the IAP polypeptide is selected from the group consisting of: HIAP-1, m-HIAP-1, HIAP-2, m-HIAP-2, XIAP, and m-XIAP. 
     
     
         8 . The method of  claim 1 , wherein the IAP polypeptide is XIAP. 
     
     
         9 . The method of  claim 1 , wherein the IAP polypeptide is HIAP-1. 
     
     
         10 . The method of  claim 1 , wherein the IAP polypeptide is HIAP-2. 
     
     
         11 . The method of  claim 1 , wherein the compound is a negative regulator of an IAP-dependent anti-apoptotic pathway. 
     
     
         12 . The method of  claim 1 , wherein the compound is a fragment of the IAP polypeptide, said fragment comprising at least one BIR domain and a ring zinc finger domain. 
     
     
         13 . The method of  claim 1 , wherein the compound is a compound that prevents enhances cleavage of the IAP polypeptide. 
     
     
         14 . The method of  claim 1 , wherein the compound is a purified antibody or a fragment thereof that specifically binds to the IAP polypeptide. 
     
     
         15 . The method of  claim 1 , wherein the compound is a ribozyme. 
     
     
         16 . The method of  claim 1 , wherein the compound is an antisense nucleic acid molecule have a nucleic acid sequence that is complementary to the coding strand of a nucleic acid sequence encoding the IAP polypeptide. 
     
     
         17 . The method of  claim 13 , wherein the cleavage is decreased by at least 20% in the cell. 
     
     
         18 . The method of  claim 14 , wherein the antibody binds to a BIR domain of the IAP polypeptide. 
     
     
         19 . The method of  claim 16 , wherein the nucleic acid sequence encoding the IAP polypeptide has about 50% or greater identity with the nucleotide sequence of SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, or SEQ ID NO: 13. 
     
     
         20 . The method of  claim 16 , wherein the antisense nucleic acid molecule decreases the level of the nucleic acid sequence encoding the IAP polypeptide by at least 20%, the level being measured in the cytoplasm of the cell. 
     
     
         21 . The method of  claim 16 , wherein the antisense nucleic acid molecule is encoded by a virus vector. 
     
     
         22 . The method of  claim 16 , wherein the antisense nucleic acid molecule is encoded by a transgene. 
     
     
         23 . The method of  claim 1 , wherein the mammal is a human or a mouse. 
     
     
         24 . The method of  claim 1 , wherein the proliferative disease is cancer. 
     
     
         25 . The method of  claim 24 , wherein the cancer is in a tissue selected from the group consisting of: ovary, breast, pancreas, lymph node, skin, blood, lung, brain, kidney, liver, nasopharyngeal cavity, thyroid, central nervous system, prostate, colon, rectum, cervix, endometrium, and lung. 
     
     
         26 . A method of inducing apoptosis in a cell in a mammal diagnosed as having a proliferative disorder, the method comprising: administering to the mammal an antisense nucleic acid which inhibits the biological activity of an inhibitor apoptosis (IAP), wherein the antisense is complimentary to a mammalian IAP nucleic acid sequence encoding an IAP polypeptide selected from the group consisting of: a human XIAP-1 (SEQ ID 3), XIAP-1 (SEQ ID 5), XIAP-2 (SEQ ID 7) m-XIAP-1(SEQ ID 9), HIAP-1 (SEQ ID 11), and HIAP-2 (SEQ ID 13). 
     
     
         27 . The method of  claim 26 , in which the mammal is a human. 
     
     
         28 . The method of  claim 26 , in which the proliferative disease is cancer. 
     
     
         29 . The method of  claim 28 , in which the cancer is ovarian cancer, adinocarcenoma, lymphoma or pancreatic cancer. 
     
     
         30 . The method of  claim 26 , in which the biological activity is inhibition of apoptosis. 
     
     
         31 . The method of  claim 26  in which the IAP biological activity is inhibited by at least 25%. 
     
     
         32 . The method of  claim 26  in which the IAP is HIAP-1. 
     
     
         33 . The method of  claim 26  in which the IAP is HIAP-2. 
     
     
         34 . The method of  claim 26  in which the IAP is XIAP. 
     
     
         35 . The method of  claim 26  in which the mammal is a human. 
     
     
         36 . The method of  claim 26  in which the cell is proliferating in the proliferative disease. 
     
     
         37 . A method of treating a patient diagnosed as having a proliferative disease, the method comprising: administering to the patient: an administering to the patient an antisense nucleic acid which inhibits the biological activity of an inhibitor apoptosis (IAP), wherein the antisense is complimentary to a mammalian IAP nucleic acid sequence encoding an IAP polypeptide selected from the group consisting of: a human XIAP-1 (SEQ ID 3), XIAP-1 (SEQ ID 5), XIAP-2 (SEQ ID 7) m-XIAP-1(SEQ ID 9), HIAP-1 (SEQ ID 11), and HIAP-2 (SEQ ID 13). 
     
     
         38 . The method of  claim 37 , wherein the mammal is a human. 
     
     
         39 . The method of  claim 37 , wherein the proliferative disease is cancer. 
     
     
         40 . The method of  claim 39 , wherein the cancer is ovarian cancer, adenocarcinoma, lymphoma, or pancreatic cancer.

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