SDF-1 Binding Nucleic Acids and the use Thereof in Cancer Treatment

Abstract

The present invention is related to a nucleic acid molecule capable of binding to SDF-1, preferably capable of inhibiting SDF-1, whereby the nucleic acid molecule is for use in a method for the treatment and/or prevention of a disease or disorder, for use in a method for the treatment of a subject suffering from a disease or disorder or being at risk of developing a disease or disorder as an adjunct therapy, or for use as a medicament for the treatment and/or prevention of a disease or disorder, whereby the disease or disorder is cancer.

1 - 10 . (canceled) 
     
     
         107 . A nucleic acid molecule capable of binding to SDF-1, preferably capable of inhibiting SDF-1, whereby the nucleic acid molecule is for use in a method for the treatment and/or prevention of a disease or disorder, for use in a method for the treatment of a subject suffering from a disease or disorder or being at risk of developing a disease or disorder as an adjunct therapy, or for use as a medicament for the treatment and/or prevention of a disease or disorder, whereby the disease or disorder is cancer. 
     
     
         108 . The nucleic acid molecule according to  claim 107 , hereby the cancer is a cancer selected from the group of hematological cancer and solid tumors, whereby preferably the hematological cancer is selected from the group comprising leukemia and myeloma and the solid tumors are selected from the group comprising glioblastoma, colorectal cancer, breast cancer, lymphoma, prostate cancer, pancreatic cancer, renal cancer, ovarian cancer and lung cancer. 
     
     
         109 . The nucleic acid molecule according to  claim 107  or  108 , whereby the adjunct therapy sensitizes the subject, wherein the sensitized subject is more responsive to a therapy for the treatment and/or prevention of the disease or disorder. 
     
     
         110 . The nucleic acid according, to  claim 109 , whereby the therapy for the treatment and/or prevention of the disease or disorder comprises the administration of a further pharmaceutically active agent and/or irradiating the subject and/or surgery and/or cellular therapy. 
     
     
         111 . The nucleic acid molecule according to  claim 110 , whereby the further pharmaceutically active agent is selected from the group comprising of an antibody, an alkylating agent, an anti-metabolite, a plant alkaloid, a plant terpenoid, a topoisomerase inhibitor, Leucovorin, Methotrexate, Tamoxifen, Sorafenib, Lenalidomide, Bortezomib, Dexamethasone, Fluorouracil, and Prednisone. 
     
     
         112 . The nucleic acid molecule according to  claim 107 , whereby the nucleic acid molecule is capable of blocking the interaction between SDF-1 and an SDF-1 receptor, whereby the SDF-1 receptor is selected from the group comprising CXCR4 and CXCR7. 
     
     
         113 . The nucleic acid molecule according to  claim 107 , whereby the treatment or prevention of the disease or disorder is caused by the nucleic acid molecule inhibiting the interaction between SDF-1 and an SDF-1 receptor. 
     
     
         114 . The nucleic acid according to  claim 107 , comprising in 5′→3′ direction a first terminal stretch of nucleotides, a central stretch of nucleotides, and a second terminal stretch of nucleotides, or a second terminal stretch of nucleotides, the central stretch of nucleotides, and a first terminal stretch of nucleotides,
 whereby the nucleic acid molecule is selected from the group comprising an SDF-1 binding nucleic acid molecule of type B, an SDF-1 binding nucleic acid molecule of type C, an SDF-1 binding nucleic acid molecule of type A and an SDF-1 binding nucleic acid molecule of type D; 
 whereby the central stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type B comprises the nucleotide sequence: 5′ GUGUGAUCUAGAUGUADWGGCUGWUCCUAGUYAGG 3′ (SEQ ID NO:52), and whereby the first terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type B comprises a nucleotide sequence of 5′ X 1 X 2 SVNS 3′ and the second terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type B comprises a nucleotide sequence of 5′ BVBSX 3 X 4  3′, whereby X 1  is either absent or is A, X 2  is G, X 3  is C and X 4  is either absent or is U; or X 1  is absent, X 2  is either absent or is G, X 3  is either absent or is C and X 4  is absent; 
 whereby the central stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type C comprises the following nucleotide sequence: GGUYAGGGCUHRXAAGUCGG (SEQ ID NO:108), whereby XA is either absent or is A, and whereby the first terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type C comprises a nucleotide sequence of 5′ RKSBUSNVGR 3′ (SEQ ID NO:138) and the second stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type C comprises a nucleotide sequence of 5′ YYNRCASSMY 3′ (SEQ. ID. NO:139); or 
 whereby the first terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type C comprises a nucleotide sequence of 5′ XSSSSV 3′ and the second terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type C comprises a nucleotide sequence of 5 BSSSXS 3′, whereby XS is either absent or is S, or 
 whereby the first terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type C comprises a nucleotide sequence of 5′ CGUGCGCUUGAGAUAGG 3′ (SEQ ID NO:220) and the second terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type C comprises a nucleotide sequence of 5′ CUGAUUCUCACG 3′ (SEQ ID NO:221); or 
 the first terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type C′ comprises a nucleotide sequence of 5′ UGAGAUAGG 3′ and the second terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type C comprises a nucleotide sequence of 5′ CUGAUUCUCA 3′ (SEQ ID NO:222); or 
 the first terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type C comprises a nucleotide sequence of 5′ GAGAUAGG 3′ and the second terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type C comprises a nucleotide sequence of 5′ CUGAUUCUC 3′; 
 whereby the central stretch of nucleotides of SDF-1 binding nucleic acid molecule of type A, comprises a nucleotide sequence of 5′ AAAGYRACAHGUMAAXAUGAAAGGUARC 3′ (SEQ ID NO:74), whereby XA is either absent or is A, and whereby the first terminal stretch of nucleotides SDF-1 binding nucleic acid molecule of type A comprises a nucleotide sequence of 5′ X 1 X 2 NNBV 3′ and the second terminal stretch of nucleotides SDF-1 binding nucleic acid molecule of type A comprises a nucleotide sequence of 5′ BNBNX 3 X 4  3′ whereby X 1  is either absent or R, X 2  is S, X 3  is S and X 4  is either absent or Y, or X 1  is absent, X 2  is either absent or S, X 3  is either absent or S and X 4  is absent; and 
 whereby the SDF-1 binding nucleic acid molecule of type D comprises a nucleotide sequence according to any one of SEQ ID NO:142 to SEQ ID NO: 144. 
 
     
     
         115 . The nucleic acid molecule according: to  claim 114 , whereby the central stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type B comprises the following nucleotide sequence: 5′ GUGUGAUCUAGAUGUADUGGCUGAUCCUAGUCAGG 3′ (SEQ ID NO:53). 
     
     
         116 . The nucleic acid molecule according to  claim 113  or  114 , whereby the first terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type B comprises a nucleotide sequence of 5′ X 1 X 2 SSBS 3′ and the second terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type B comprises a nucleotide sequence of 5′ BVSSX 3 X 4  3′, whereby X 1  is absent, X 2  is either absent or G, X 3  is either absent or C, and X 4  is absent, preferably the first terminal stretch of nucleotides comprises a nucleotide sequence of 5′ GCGUG 3′ and the second terminal stretch of nucleotides comprises a nucleotide sequence of 5′ UACGC 3′. 
     
     
         117 . The nucleic acid molecule according, to  claim 116 , whereby the SDF-1 binding nucleic acid molecule of type B comprises a nucleotide sequence according to any one of SEQ ID NO:5 to SEQ ID NO:20 and SEQ ID NO:22 to SEQ ID NO:28, preferably any one of SEQ ID NO:5 to SEQ ID NO:7, SEQ ID NO:16, SEQ ID NO:22 and SEQ ID NO:28, more preferably any one of SEQ ID NO:22 and SEQ ID NO:28. 
     
     
         118 . The nucleic acid molecule according to  claim 114 , whereby the central stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type C comprises a nucleotide sequence of 5′ GGUYAGGGCUHRAAGUCGG 3′ (SEQ ID NO:109), 5′ GGUYAGGGCUHRAGUCGG 3′ (SEQ ID NO:110) or 5′ GGUUAGGGCUHGAAGUCGG 3′ (SEQ ID NO:111), preferably 5′ GGUUAGGGCUHGAAGUCGG 3′ (SEQ ID NO:111). 
     
     
         119 . The nucleic acid molecule according to  claim 114  or  118 , whereby the first terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type C comprises a nucleotide sequence of 5′ RKSBUGSVGR 3′ (SEQ ID NO:140) and the second terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type C comprises a nucleotide sequence of 5′ YCNRCASSMY 3′ (SEQ ID NO:141). 
     
     
         120 . The nucleic acid molecule according to  claim 114  or  118 , whereby the first terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type C comprises a nucleotide sequence of 5′ SGGSR 3′ and the second terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type C comprises a nucleotide sequence of 5′ YSCCS 3′. 
     
     
         121 . The nucleic acid molecule according to  claim 120 , whereby the SDF-1 binding nucleic acid molecule of type C comprises a nucleotide sequence according to any one of SEQ ID NO:95 to SEQ ID NO:107, SEQ ID NO: 112 to SEQ ID NO:137, SEQ ID NO:223 and SEQ ID NO:224, preferably any one of SEQ NO:120, SEQ NO:128, SEQ ID NO:129, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:223 and SEQ ID NO:224. 
     
     
         122 . The nucleic acid molecule according to  claim 114 , whereby the central stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type A comprises a nucleotide sequence of 5′ AAAGYRACAHGUMAAUGAAAGGUARC 3′ (SEQ ID NO:75), or 5′ AAAGYRACAHGUMAAAUGAAAGGUARC 3′ (SEQ ID NO:76), or 5′ AAAGYAACAHGUCAAUGAAAGGUARC 3′ (SEQ ID NO:77), preferably the central stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type A comprises a nucleotide sequence of 5′ AAAGYAACAHGUCAAUGAAAGGUARC 3′ (SEQ ID NO: 77). 
     
     
         123 . The nucleic acid molecule according to  claim 114  or  122 , whereby the first terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type A comprises a nucleotide sequence of 5′ X 2 BBBS 3′ and the second terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type A comprises a nucleotide sequence of 5′ SBBVX 3  3′, whereby X 2  is either absent or is S and X 3  is either absent or is S; preferably the first terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type A comprises a nucleotide sequence of 5′ CUGUG 3′ and the second terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type A comprises a nucleotide sequence of 5′ CGCAG 3′; or the first terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type A comprises a nucleotide sequence of 5′ GCGUG 3′ and the second terminal stretch of nucleotides of the SDF-1 binding nucleic acid molecule of type A comprises a nucleotide sequence of 5′ CGCGC 3′. 
     
     
         124 . The nucleic acid molecule according to  claim 123 , whereby the SDF-1 binding nucleic acid molecule of type A comprises a nucleotide sequence according to any one of SEQ ID NO:60 to SEQ ID NO:73, SEQ ID NO:78 to SEQ ID NO:82, SEQ ID NO:84 to SEQ ID NO:87, SEQ 11D NO:89 to SEQ ID NO:94, and SEQ ID NO:145, preferably any one of SEQ ID NO:60, SEQ ID NO:63, SEQ ID NO:66, SEQ ID NO:78, SEQ ID NO:84, and SEQ ID NO:146, more preferably any one of SEQ ID NO:84 and SEQ ID NO:146. 
     
     
         125 . The nucleic acid molecule according to  claim 107 , whereby the nucleic acid molecule comprises a modification, whereby the modification is preferably a high molecular weight moiety and/or whereby the modification preferably allows to modify the characteristics of the nucleic acid molecule in terms of residence time in the animal or human body, preferably the human body. 
     
     
         126 . The nucleic acid molecule according to  claim 107 , whereby the nucleic acid molecule is an L-nucleic acid molecule. 
     
     
         127 . A pharmaceutical composition comprising as a first pharmaceutically active agent the nucleic acid molecule according to  claim 107  and optionally a further constituent, whereby the further constituent is selected from the group comprising a pharmaceutically acceptable excipient, a pharmaceutically acceptable carrier and a further pharmaceutically active agent, and whereby the pharmaceutical composition is for use in a method for the treatment and/or prevention of a disease or disorder, or for use in a method for the treatment of a subject suffering from a disease or disorder or being at risk of developing a disease or a disorder as an adjunct therapy, or for the treatment and/or prevention of a disease or disorder, whereby the disease or disorder is cancer. 
     
     
         128 . The pharmaceutical composition according to  claim 127 , whereby the adjunct therapy sensitizes the subject, wherein the sensitized subject is more responsive to a therapy for the treatment and/or prevention of the disease or disorder. 
     
     
         129 . The pharmaceutical composition according to  claim 128 , whereby the therapy for the treatment and/or prevention of the diseases or disorder comprises the administration of a further pharmaceutically active agent and/or irradiating the subject and/or surgery and/or cellular therapy. 
     
     
         130 . The pharmaceutical composition according to any one of  claims 127  to  129 , whereby the further pharmaceutically active agent is a pharmaceutically active agent selected from the group comprising an antibody, an alkylating agent, an anti-metabolite, a plant alkaloid, preferably vincristine, a plant terpenoid, a topoisomerase inhibitor, Leucovorin, Methotrexate, Tamoxifen, Sorafenib, Lenalidomide, Bortezomib, Dexamethasone, Flurouracil, and Prednisone. 
     
     
         131 . The pharmaceutical composition according to  claim 130 , whereby the cancer is a cancer selected from the group of hematological cancer and solid tumors, whereby preferably the hematological cancer is selected from the group of leukemia and myeloma and the solid tumors are selected from the group comprising glioblastoma, colorectal cancer, breast cancer, lymphoma, prostate cancer, pancreatic cancer, renal cancer, ovarian cancer and lung cancer. 
     
     
         132 . A medicament comprising one or several dosage units of at least a first pharmaceutically active agent, wherein the first pharmaceutically active agent is a nucleic acid molecule capable of binding to SDF-1 as defined in  claim 107 , whereby the medicament is for use in a method for the treatment and/or prevention of a disease or disorder, or for use in a method for the treatment of a subject suffering from a disease or disorder or being at risk of developing a disease or a disorder as an adjunct therapy, or for the treatment and/or prevention of a disease or disorder, whereby the disease or disorder is cancer. 
     
     
         133 . The medicament according to  claim 132 , whereby the adjunct therapy sensitizes the subject, wherein the sensitized subject is more responsive to a therapy for the treatment and/or prevention of the disease or disorder. 
     
     
         134 . The medicament according to  claim 133 , whereby the therapy for the treatment and/or prevention of the diseases or disorder comprises the administration of a further pharmaceutically active agent and/or irradiating the subject and/or surgery and/or cellular therapy. 
     
     
         135 . The medicament according to any of  claims 132  to  134 , wherein the medicament comprises a further pharmaceutically active agent, preferably one or several dosage units of a further pharmaceutically active agent, whereby the further pharmaceutically active agent is selected from the group comprising an antibody, an alkylating agent, an anti-metabolite, a plant alkaloid, preferably vincristine, a plant terpenoid, a topoisomerase inhibitor, Leucovorin, Methotrexate, Tamoxifen, Sorafenib, Lenalidomide, Bortezomib, Dexamethasone, Fluorouracil, and Prednisone. 
     
     
         136 . The medicament according to  claim 135 , wherein the cancer is a cancer selected from the group of hematological cancer and solid tumors, whereby preferably the hematological cancer is selected from the group comprising leukemia and myeloma and the solid tumors are selected from the group comprising glioblastoma, colorectal cancer, breast cancer, lymphoma, prostate cancer, pancreatic cancer, renal cancer, ovarian cancer and lung cancer. 
     
     
         137 . A method for the treatment of as subject suffering from or being at risk of developing cancer, whereby the method comprises
 a) administering to the subject a pharmaceutically effective amount of a nucleic acid molecule capable of binding, to SDF-1 as defined in  claim 107 .   
     
     
         138 . The method according to  claim 137 , whereby the method further comprises
 b) irradiating the subject and/or surgery and/or cellular therapy and/or administering a pharmaceutically effective amount of a further pharmaceutically active agent to the subject, whereby the further pharmaceutically active agent is a pharmaceutically active agent selected from the group comprising an antibody, an alkylating agent, an anti-metabolite, a plant alkaloid, preferably vincristine, a plant terpenoid, a topoisomerase inhibitor, Leucovorin, Methotrexate, Tamoxifen, Sorafenib, Lenalidomide, Bortezomib, Dexamethasone, Flurouracil, and Prednisone.   
     
     
         139 . The method according to  claim 138 , wherein the pharmaceutically effective amount of a nucleic acid molecule capable of binding to SDF-1 is administered as an adjunct therapy or part of an adjunct therapy. 
     
     
         140 . The method according to  claim 139 , whereby the adjunct therapy sensitizes the subject, wherein the sensitized subject is more responsive to a therapy for the treatment and/or prevention of the disease or disorder. 
     
     
         141 . The method according to  claim 140 , whereby the therapy for the treatment and/or prevention of the disease or disorder comprises the administration of a further pharmaceutically active agent and/or irradiating the subject and/or surgery and/or cellular therapy as performed in step b). 
     
     
         142 . The method according to any one of  claims 137  to  141 , whereby the cancer is a cancer selected from the group of hematological cancer and solid tumors, whereby preferably the hematological cancer is selected from the group comprising leukemia and myeloma and the solid tumors are selected from the group comprising glioblastoma, colorectal cancer, breast cancer, lymphoma, prostate cancer, pancreatic cancer, renal cancer, ovarian cancer and lung cancer.