Tumor therapy with high affinity laminin receptor-targeted vectors and compounds

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 that expresses 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 vector selected from the group consisting of an adenovirus-based vector, an adeno-associated virus-based vector, a retrovirus-based vector, a lentiviral-based vector, a herpes virus-based vector, a vaccinia virus-based vector, a Baculovirus-based vector, and a papilloma virus-based vector, the vector also containing at least one anti-tumor gene, and a Sindbis virus E2 HALR binding domain. 
     
     
         2 . The method according to  claim 1 , wherein the vector is administered systemically. 
     
     
         3 . The method according to  claim 1 , wherein the vector is replication defective. 
     
     
         4 . The method according to  claim 1 , wherein the vector is replication competent. 
     
     
         5 . The method according to  claim 1 , wherein the vector is modified to carry at least one anti-tumor gene. 
     
     
         6 . The method according to  claim 1 , wherein the anti-tumor gene is 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. 
     
     
         7 . The method according to  claim 6 , wherein the anti-tumor gene is an apoptosis-inducing gene. 
     
     
         8 . The method according to  claim 6 , wherein the anti-tumor gene is a cytokine-encoding gene. 
     
     
         9 . The method according to  claim 6 , 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. 
     
     
         10 . The method according to  claim 1 , wherein the mammal has at least a partially functional immune system. 
     
     
         11 . The method according to  claim 1 , wherein the mammal is a human. 
     
     
         12 . The method according to  claim 1 , wherein the tumor is a solid tumor. 
     
     
         13 . The method according to  claim 12 , 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. 
     
     
         14 . The method according to  claim 12 , 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 
     
     
         15 . The method according to  claim 1 , wherein the tumor is a member selected from the group consisting of leukemia, lymphoma, myeloma, and plasmacytoma. 
     
     
         16 . The method according to  claim 1 , which comprises administering the vector parenterally. 
     
     
         17 . The method according to  claim 1 , which comprises administering the vector orally. 
     
     
         18 . The method according to  claim 1 , which comprises administering the vector by aerosol delivery. 
     
     
         19 . A pharmaceutical composition for treating a mammal suffering from a tumor that expresses more High Affinity Laminin Receptors (HALRs) than normal cells of the same lineage, which composition comprises a vector selected from the group consisting of an adenovirus-based vector, an adeno-associated virus-based vector, a retrovirus-based vector, a lentiviral-based vector, a herpes virus-based vector, a vaccinia virus-based vector, a Baculovirus-based vector, and a papilloma virus-based vector, the vector also containing at least one anti-tumor gene, and a Sindbis virus E2 HALR binding domain, and wherein the composition further comprises a pharmaceutically acceptable carrier or diluent. 
     
     
         20 . The pharmaceutical composition according to  claim 19 , wherein the vector is replication defective. 
     
     
         21 . The pharmaceutical composition according to  claim 19 , wherein the vector is replication competent. 
     
     
         22 . The pharmaceutical composition according to  claim 19 , 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. 
     
     
         23 . The pharmaceutical composition according to  claim 22 , wherein the anti-tumor gene is an apoptosis-inducing gene. 
     
     
         24 . The pharmaceutical composition according to  claim 22 , wherein the anti-tumor gene is a cytokine-encoding gene. 
     
     
         25 . The pharmaceutical composition according to  claim 22 , 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. 
     
     
         26 . The pharmaceutical composition according to  claim 19 , wherein the mammal has at least a partially functional immune system. 
     
     
         27 . The pharmaceutical composition according to  claim 19 , wherein the mammal is a human. 
     
     
         28 . The pharmaceutical composition according to  claim 19 , wherein the tumor is a solid tumor. 
     
     
         29 . The pharmaceutical composition according to  claim 28 , 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. 
     
     
         30 . The pharmaceutical composition according to  claim 28 , 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. 
     
     
         31 . The pharmaceutical composition according to  claim 28 , wherein the tumor is a member selected from the group consisting of leukemia, lymphoma, myeloma, and plasmacytoma. 
     
     
         32 . A vector selected from the group consisting of an adenovirus-based vector, an adeno-associated virus-based vector, a retrovirus-based vector, a lentiviral-based vector, a herpes virus-based vector, a vaccinia virus-based vector, a Baculovirus-based vector, and a papilloma virus-based vector, the vector also comprising at least one anti-tumor gene, and a Sindbis virus E2 HALR binding domain. 
     
     
         33 . The vector according to  claim 32 , wherein the vector is replication defective. 
     
     
         34 . The vector according to  claim 32 , wherein the vector is replication competent. 
     
     
         35 . The vector according to  claim 32 , 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. 
     
     
         36 . The vector according to  claim 35 , wherein the anti-tumor gene is an apoptosis-inducing gene. 
     
     
         37 . The vector according to  claim 35 , wherein the anti-tumor gene is a cytokine-encoding gene. 
     
     
         38 . The vector according to  claim 35 , 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.