Immuno-RNA-constructs
Subject of the invention is a compound, consisting of a targeting moiety which specifically binds to a disease related cell surface marker, a nucleic acid which specifically induces cell death and a linker, wherein the linker covalently links the targeting moiety to the nucleic acid. Subject of the invention are also medicaments comprising the compound and their use as a medicament for the treatment of diseases, including proliferative diseases.
1. A compound comprising:
a targeting moiety, which specifically binds to a disease related cell surface marker,
a nucleic acid moiety which specifically induces cell death or down-regulates a specific key element of a regulatory pathway of the target cell and
a linker, which covalently links the targeting moiety to the nucleic acid moiety
wherein the nucleic acid moiety knocks-down expression of eukaryotic elongation factor 2 (eEF-2), homologues of eEF-2 or analogues of eEF-2.
2. The compound of claim 1 , wherein the linker is a disulfide bond, a phosphodiester bond, a phosphothioate bond, an amide bond, an amine bond, a thioether bond, an ether bond, an ester bond or a carbon-carbon bond.
3. The compound of claim 1 , wherein the targeting moiety is a nucleic acid or a polypeptide.
4. The compound of claim 1 , wherein the targeting moiety is a binding ligand for a cell surface receptor.
5. The compound of claim 1 , wherein the targeting moiety is at least one aptamer, an antibody, a diabody or a derivative or fragment of an antibody.
6. The compound of claim 5 , wherein the targeting moiety is represented by at least two aptamers.
7. The compound of claim 1 , wherein the targeting moiety is selected from the group consisting of carbohydrates, lipids, vitamins, small receptor ligands, nucleic acids, cell surface carbohydrate binding proteins and their ligands, lectins, r-type lectins, galectins, ligands to the cluster of differentiation (CD) antigens, CD30, CD40, cytokines, chemokines, colony stimulating factors, type-1 cytokines, type-2 cytokines, interferons, interleukins, lymphokines, monokines, mutants, derivatives and/or combinations of any of the above.
8. The compound of claim 1 , wherein the disease related cell surface marker is selected from the group consisting of CD antigens, cytokine receptors, hormone receptors, growth factor receptors, ion pumps, channel-forming proteins, multimeric extracellular matrix proteins, metallo proteases, Her3 or PSMA.
9. The compound of claim 1 , wherein the targeting moiety binds to a cell surface receptor of a target cell and mediates subsequent translocation of the compound into the cytosol of the target cell.
10. The compound of claim 9 , wherein after translocation of the compound into the target cell the nucleic acid moiety induces cell death of the target cell.
11. The compound of claim 1 , wherein the nucleic acid moiety is a siRNA, a shRNA an antisense DNA or RNA, a dsRNA or a miRNA.
12. The compound of claim 1 , wherein the nucleic acid moiety comprises 10 to 40 nucleic acid base pairs or nucleic acid bases.
13. The compound of claim 1 , wherein the nucleic acid moiety is specifically inhibitory to activity of apoptosis inhibitors.
14. The compound of claim 1 comprising an aptamer and the nucleic acid moiety linked by a phosphodiester or by a phosphothioate bond.
15. The compound of claim 1 comprising an antibody and a RNA linked by a disulfide bond.
16. The compound of claim 14 consisting of an RNA.
17. A DNA coding for the RNA of claim 16 .
18. A cell, an organ or a non-human animal transfected with a RNA or DNA encoding a compound comprising:
a targeting moiety, which specifically binds to a disease related cell surface marker,
a nucleic acid moiety which specifically induces cell death or down-regulates a specific key element of a regulatory pathway of the target cell and
a linker, which covalently links the targeting moiety to the nucleic acid moiety
wherein the nucleic acid moiety knocks-down expression of eukaryotic elongation factor 2 (eEF-2), homologues of eEF-2 or analogues of eEF-2.
19. The compound of 1 further comprising a moiety, which enables purification and/or detection of the compound, facilitates translocation of the compound into the target cell and/or intracellular separation therein, and/or activates the nucleic acid.