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  Apoptin-associating proteinUSPTO Application #: 20080103099Title: Apoptin-associating protein Abstract: The invention relates to the field of apoptosis. The invention provides novel therapies, for example, novel combinatorial therapies or novel therapeutic compounds that can work alone, sequentially to, or jointly with Apoptin, especially in those cases wherein p53 is completely or partially non-functional. (end of abstract) Agent: Trask Britt - Salt Lake City, UT, US Inventors: Mathieu Hubertus, M. Noteborn, Astrid Adriana, A.M. Danen-van Oorschot, Jennifer Leigh Rohn, Bertram Weiss, Luisella Toschi USPTO Applicaton #: 20080103099 - Class: 514012000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 25 Or More Peptide Repeating Units In Known Peptide Chain Structure The Patent Description & Claims data below is from USPTO Patent Application 20080103099. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATION [0001] This application is a divisional of co-pending U.S. patent application Ser. No. 11/879,370 filed Jul. 16, 2007, U.S. Pat. No. ______, which is a divisional of Ser. No. 09/733,416, filed Dec. 8, 2000, U.S. Pat. No. 7,256,274, which itself claims priority from European Patent Office application 00250119.5 filed Apr. 7, 2000, and European Patent Office application 99204242.4 filed Dec. 10, 1999, the contents of the entirety of each of which are incorporated by this reference. TECHNICAL FIELD [0002] The invention relates generally to biotechnology, and, more particularly, to the field of apoptosis. BACKGROUND [0003] Apoptosis is an active and programmed physiological process for eliminating superfluous, altered or malignant cells (Earnshaw, 1995; Duke et al., 1996). Apoptosis is characterized by shrinkage of cells, segmentation of the nucleus, condensation and cleavage of DNA into domain-sized fragments, in most cells followed by internucleosomal degradation. The apoptotic cells fragment into membrane-enclosed apoptotic bodies. Finally, neighboring cells and/or macrophages will rapidly phagocytose these dying cells (Wyllie et al., 1980; White, 1996). Cells grown under tissue-culture conditions and cells from tissue material can be analyzed for being apoptotic with agents staining DNA, as, e.g., DAPI, which stains normal DNA strongly and regularly, whereas apoptotic DNA is stained weakly and/or irregularly (Noteborn et al., 1994; Telford et al., 1992). [0004] The apoptotic process can be initiated by a variety of regulatory stimuli (Wyllie, 1995; White, 1996; Levine, 1997). Changes in the cell survival rate play an important role in human pathogenesis of diseases, e.g., in cancer development and auto-immune diseases, where enhanced proliferation or decreased cell death (Kerr et al., 1994; Paulovich, 1997) is observed. A variety of chemotherapeutic compounds and radiation have been demonstrated to induce apoptosis in tumor cells, in many instances via wild-type p53 protein (Thompson, 1995; Bellamy et al., 1995; Steller, 1995; McDonell et al., 1995). [0005] Many tumors, however, acquire a mutation in p53 during their development, often correlating with poor response to cancer therapy. Certain transforming genes of tumorigenic DNA viruses can inactivate p53 by directly binding to it (Teodoro, 1997). An example of such an agent is the large T antigen of the tumor DNA virus SV40. For several (leukemic) tumors, a high expression level of the proto-oncogene Bcl-2 or Bcr-abl is associated with a strong resistance to various apoptosis-inducing chemotherapeutic agents (Hockenberry 1994; Sachs and Lotem, 1997). [0006] For such tumors lacking functional p53 (representing more than half of the tumors), alternative anti-tumor therapies are under development based on induction of apoptosis independent of p53 (Thompson 1995; Paulovich et al., 1997). One has to search for the factors involved in induction of apoptosis, which do not need p53 and/or cannot be blocked by anti-apoptotic activities, such as Bcl-2 or Bcr-abl-like ones. These factors might be part of a distinct apoptosis pathway or might be (far) downstream of the apoptosis-inhibiting compounds. [0007] Apoptin is a small protein derived from chicken anemia virus (CAV; Noteborn and De Boer, 1995; Noteborn et al., 1991; Noteborn et al., 1994; 1998a), which can induce apoptosis in human malignant and transformed cell lines, but not in untransformed human cell cultures. In vitro, Apoptin fails to induce programmed cell death in normal lymphoid, dermal, epidermal, endothelial and smooth-muscle cells. However, when normal cells are transformed, they become susceptible to apoptosis by Apoptin. Long-term expression of Apoptin in normal human fibroblasts revealed that Apoptin has no toxic or transforming activity in these cells (Danen-van Oorschot, 1997; and Noteborn, 1996). [0008] In normal cells, Apoptin was found predominantly in the cytoplasm, whereas in transformed or malignant cells, i.e., characterized by hyperplasia, metaplasia ordysplasia, it was located in the nucleus, suggesting that the localization of Apoptin is related to its activity (Danen-van Oorschot et al. 1997). [0009] Apoptin-induced apoptosis occurs in the absence of functional p53 (Zhuang et al., 1995a), and cannot be blocked by Bcl-2, Bcr-abl (Zhuang et al., 1995), or the Bcl-2-associating protein BAG-1 (Danen-Van Oorschot, 1997a; Noteborn, 1996). [0010] Therefore, Apoptin is a therapeutic compound for the selective destruction of tumor cells, or other hyperplasia, metaplasia or dysplasia, especially for those tumor cells that have become resistant to (chemo)-therapeutic induction of apoptosis, due to the lack of functional p53 and (over)-expression of Bcl-2 and other apoptosis-inhibiting agents (Noteborn and Pietersen, 1998). It appears that even pre-malignant, minimally transformed cells, are sensitive to the death-inducing effect of Apoptin. In addition, Noteborn and Zhang (1998) have shown that Apoptin-induced apoptosis can be used as diagnosis of cancer-prone cells and treatment of cancer-prone cells. [0011] The fact that Apoptin does not induce apoptosis in normal human cells, at least not in vitro, shows that a toxic effect of Apoptin treatment in vivo will be very low. Noteborn and Pietersen (1998) and Pietersen et al. (1999) have provided evidence that adenovirus-expressed Apoptin does not have an acute toxic effect in vivo. In addition, in nude mice it was shown that Apoptin has a strong anti-tumor activity. [0012] However, to further enlarge the array of therapeutic anti-cancer or anti-auto-immune-disease compounds available in the art, additional therapeutic compounds are desired that are designed to work alone, sequentially to, or jointly with Apoptin, especially in those cases wherein p53 is (partly) non-functional. [0013] The invention provides, for example, novel combinatorial therapies or novel therapeutic compounds that can work alone, sequentially to, or jointly with Apoptin, especially in those cases wherein p53 is non-functional or partially non-functional. BRIEF DESCRIPTION OF THE DRAWINGS [0014] FIG. 1 shows the partial sequence (SEQ ID NO:10) of vector pMT2SM-AAP-4. The DNA sequence of the AAP-4 cDNA starts at position 12 of the DNA sequence and is indicated as "start AAP4 cDNA." [0015] FIG. 2 shows the amino acid sequence (SEQ ID NO:12) of the analyzed region of the Apoptin-associating clone AAP-4 (bold). In addition, the three C-terminal amino acids H-E-G of the multiple cloning site of pACT are given to illustrate that the AAP-4 amino acid sequence is in frame with the GAL4-activation domain. This feature proves that the AAP-4 region is indeed synthesized in yeast cells. [0016] FIG. 3 shows the apoptotic activity of AAP-4 protein and/or Apoptin in human osteosarcoma-derived Saos-2 cells and in human osteosarcoma U2OS cells. (-): no apoptotic activity; (++): strong apoptotic activity; (+++): very strong apoptotic activity. In total, three independent experiments have been carried out for both cell types. [0017] FIG. 4 shows a schematic representation of the nuclear "circular" apoptotic structures containing AAP-4 protein, which are visible in human tumor cells undergoing apoptosis. [0018] FIG. 5 shows the nucleic acid sequence (SEQ ID NO:13) of full-length AAP-4. [0019] FIG. 6 shows the amino acid sequence (SEQ ID NO:14) deduced from the nucleic acid sequence of FIG. 5. [0020] FIG. 7 shows the SET domain (SEQ ID NO:14) of the AAP-4 protein. Continue reading... Full patent description for Apoptin-associating protein Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Apoptin-associating protein patent application. Patent Applications in related categories: 20080103098 - Recombinant expression of proteins in a disulfide-bridged, two-chain form - Polypeptides or proteins are produced as a disulfide bridged dichain by recombinant expression in E. coli host cells and exert biologic activity as such a dichain. A C-terminal amino acid of the first chain is Arg or Lys. The second chain has N-terminally 1 to 20 amino acid residues and ... ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Apoptin-associating protein or other areas of interest. ### Previous Patent Application: Targeted delivery of drugs for the treatment of viral infections Next Patent Application: Recombinant expression of proteins in a disulfide-bridged, two-chain form Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the Apoptin-associating protein patent info. IP-related news and info Results in 0.27111 seconds Other interesting Feshpatents.com categories: Novartis , Pfizer , Philips , Polaroid , Procter & Gamble , |
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