Tumor therapy with non-viral-based high affinitiy laminin receptor-targeted vectors

Abstract

The present invention relates to methods and compositions for treating tumors using vectors that preferentially target tumor cells. In particular, the invention relates to alphavirus-based, preferably Sindbis virus-based, vectors and to non-alphavirus-based vectors, which have a preferential affinity for high affinity laminin receptors (HALR). These vectors are efficiently targeted to tumors and have the ability to cause tumor necrosis.

1 . A method for treating a mammal suffering from a tumor wherein the tumor cells express more High Affinity Laminin Receptors (HALRs) than normal cells of the same lineage, which comprises administering to the mammal in need of such treatment an effective amount for treating the tumor of a non-viral vector that contains at least one anti-tumor gene, has a Sindbis virus E2 HALR binding domain, and contains an agent selected from the group consisting of a liposome, a microsphere, and a protein matrix. 
     
     
         2 . The method according to  claim 1 , wherein the vector is administered systemically. 
     
     
         3 . The method according to  claim 1 , wherein the non-viral vector is modified to carry at least one anti-tumor gene. 
     
     
         4 . The method according to  claim 1 , wherein the anti-tumor gene is a member selected from the group consisting of a suicide gene, an apoptosis-inducing gene, a tumor suppressor gene, an oncogene antagonist gene, an immunostimulatory gene, a tumor suppressor effector gene, an antisense oligonucleotide-encoding sequence, a ribozyme-encoding sequence, and an immunogenic peptide-encoding sequence. 
     
     
         5 . The method according to  claim 4 , wherein the anti-tumor gene is an apoptosis-inducing gene. 
     
     
         6 . The method according to  claim 4 , wherein the anti-tumor gene is a cytokine-encoding gene. 
     
     
         7 . The method according to  claim 4 , wherein the anti-tumor gene encodes a protein selected from the group consisting of p53, RB, anti-Ras antibodies, anti-Raf antibodies, a herpes simplex virus thymidine kinase [HSV-tk], varicella zoster virus thymidine kinase [VZV-tk], a bacterial cytosine deaminase, flt-3 ligand, GM-CSF, IL-2, IL-7, IL-12, and IL-13. 
     
     
         8 . The method according to  claim 1 , wherein the mammal has at least a partially functional immune system. 
     
     
         9 . The method according to  claim 1 , wherein the mammal is a human. 
     
     
         10 . The method according to  claim 1 , wherein the tumor is a solid tumor. 
     
     
         11 . The method according to  claim 10 , wherein the solid tumor is a member selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, and leiomyosarcoma, rhabdomyosarcoma. 
     
     
         12 . The method according to  claim 10 , wherein the solid tumor is a member selected from the group consisting of colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, epidermoid carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, neuroglioma, and retinoblastoma 
     
     
         13 . The method according to  claim 10 , wherein the tumor is a member selected from the group consisting of leukemia, lymphoma, myeloma, and plasmacytoma. 
     
     
         14 . The method according to  claim 1 , wherein the non-viral vector is administered parenterally, 
     
     
         15 . The method according to  claim 1 , wherein the non-viral vector is administered orally. 
     
     
         16 . The method according to  claim 1 , wherein the non-viral vector is administered by aerosol delivery. 
     
     
         17 . A pharmaceutical composition for treating a mammal suffering from a tumor wherein the tumor cells express more High Affinity Laminin Receptors (HALRs) than normal cells of the same lineage, which composition comprises a non-viral vector that contains at least one anti-tumor gene, and a Sindbis virus E2 HALR binding domain, the vector also comprising an agent selected from the group consisting of a liposome, a microsphere, and a protein matrix, and wherein the composition further comprises a pharmaceutically acceptable carrier or diluent. 
     
     
         18 . The pharmaceutical composition according to  claim 15 , wherein the anti-tumor gene is a member selected from the group consisting of a suicide gene, an apoptosis-inducing gene, a tumor suppressor gene, an oncogene antagonist gene, an immunostimulatory gene, a tumor suppressor effector gene, an antisense oligonucleotide-encoding sequence, a ribozyme-encoding sequence, and an immunogenic peptide-encoding sequence. 
     
     
         19 . The pharmaceutical composition according to  claim 18 , wherein the anti-tumor gene is an apoptosis-inducing gene. 
     
     
         20 . The pharmaceutical composition according to  claim 18 , wherein the anti-tumor gene is a cytokine-encoding gene. 
     
     
         21 . The pharmaceutical composition according to  claim 18 , wherein the anti-tumor gene encodes a protein selected from the group consisting of p53, RB, anti-Ras antibodies, anti-Raf antibodies, herpes simplex virus thymidine kinase [HSV-tk], varicella zoster virus thymidine kinase [VZV-tk], bacterial cytosine deaminase, flt-3 ligand, GM-CSF, IL-2, IL-7, IL-12, and IL-13. 
     
     
         22 . The pharmaceutical composition according to  claim 18 , wherein the mammal has at least a partially functional immune system. 
     
     
         23 . The pharmaceutical composition according to  claim 18 , wherein the mammal is a human. 
     
     
         24 . The pharmaceutical composition according to  claim 18 , wherein the tumor is a solid tumor. 
     
     
         25 . The pharmaceutical composition according to  claim 24 , wherein the solid tumor is a member selected from the group consisting of fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, and leiomyosarcoma, rhabdomyosarcoma. 
     
     
         26 . The pharmaceutical composition according to  claim 22 , wherein the solid tumor is a member selected from the group consisting of colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, epidermoid carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, neuroglioma, and retinoblastoma. 
     
     
         27 . The pharmaceutical composition according to  claim 24 , wherein the tumor is selected from the group consisting of leukemia, lymphoma, myeloma, and plasmacytoma. 
     
     
         28 . A non-viral vector comprising at least one anti-tumor gene, and a Sindbis virus E2 HALR binding domain, the vector also comprising an agent selected from the group consisting of a liposome, a microsphere, and a protein matrix. 
     
     
         29 . The non-viral vector according to  claim 28 , wherein the anti-tumor gene is a member selected from the group consisting of a suicide gene, an apoptosis-inducing gene, a tumor suppressor gene, an oncogene antagonist gene, an immunostimulatory gene, a tumor suppressor effector gene, an antisense oligonucleotide-encoding sequence, a ribozyme-encoding sequence, and an immunogenic peptide-encoding sequence. 
     
     
         30 . The non-viral vector according to  claim 28 , wherein the anti-tumor gene is an apoptosis-inducing gene. 
     
     
         31 . The non-viral vector according to  claim 28 , wherein the anti-tumor gene is a cytokine-encoding gene. 
     
     
         32 . The non-viral vector according to  claim 28 , wherein the anti-tumor gene encodes a protein selected from the group consisting of p53, RB, anti-Ras antibodies, anti-Raf antibodies, herpes simplex virus thymidine kinase [HSV-tk], varicella zoster virus thymidine kinase [VZV-tk], bacterial cytosine deaminase, flt-3 ligand, GM-CSF, IL-2, IL-7, IL-12, and IL-13.