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United States Patent 19 11 Patent Number: 5,656,725 Chittenden Et Al

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United States Patent 19 11 Patent Number: 5,656,725 Chittenden Et Al US005656725A United States Patent 19 11 Patent Number: 5,656,725 Chittenden et al. 45) Date of Patent: Aug. 12, 1997 54 PEPTIDES AND COMPOSITIONS WHICH Reed, et al., Antisense-Mediated Inhibition of BCL2 Pro MODULATE APOPTOSIS tooncogene Expression And Leukemic Cell Growth Sur vival: Comparisons of Phosphodiester And Phosphorothio 75 Inventors: Thomas D. Chittenden, Brookline; ate Oligodeoxynucleotides. Cancer Research 50:6565-6570 Robert J. Lutz, Wayland, both of (1990). Mass. Yin, et al., BH1 And BH2 Domains Of Bcl-2 Are Required For Inhibition Of Apoptosis And Heterodimerization With 73) Assignee: Apoptosis Technology, Inc., Bax, Nature 369:321-323 (1994). Cambridge, Mass. Williams, Programmed Cell Death: Apoptosis And Onco genesis, Cell 65:1097-1098 (1991). 21 Appl. No.: 440,391 Lin, et al., Characterization Of A1, A Novel Hempoietic 22) Filed: May 12, 1995 Specific Early-Response Gene With Sequence Similarity To Bcl-2, The Journal of Immunology 151:1979-1988 (1993). 51 Int. CI. ... C07K 7/06; C07K 7/08; Neilan, et al. An African Swine Fever Virus Gene With C07K 14/47 Similarity To The Proto-Oncogene Bcl-2 And The Epstein (52) U.S. Cl. .......................... 530/324;530/325; 530/326; Barr Virus Gene BHRF1, Journal of Virology 67:4391-4394 530/327: 530/328; 530/329; 530/330 (1993). 58) Field of Search ..................................... 530/324, 325, Campos, et al., Effects Of BC1-2 Antisenses Oligodeoxy 530/326,327,328,329, 330; 514/12, 13, nucleotides On. In Vitro Proliferation And Survival Of Nor 14, 15, 16, 17 mal Marrow Progenitors And Leukemic Cells, Blood 84:595-600 (1994). 56 References Cited Williams, et al., Molecular Regulation Of Apoptosis: U.S. PATENT DOCUMENTS Genetic Controls On Cell Death, Cell 74:777-779 (1993). Fanidi, et al., Coperative Interaction Between C-myc And 5,015,568 5/1991 Tsujimoto ................................... 435/5 Bcl-2 Proto-Oncogenes. Nature 359:554-556 (1992). 5202,429 4/1993 Tsujimoto ....... ... 536/23.5 Hengartner, et al., C. Elegans Cell Survival Gene Ced-9 5,283,173 2/1994 Fields et al. ................................ 436/6 Encodes AFunctional Homolog Of The Mammalian Proto OTHER PUBLICATIONS Oncogene Bcl-2. Cell 76:665-676 (1994). Vaux, et al., Prevention Of Programmed Cell Death In Chittenden, et al., Nature 374.733-736 (20 Apr. 1995). Caenorhabditis Elegans By Human Bcl-2, Science Chittenden, et al., EMBO J. 14(22):5589-5596 (1995). 258:1955-1957 (1992). Haigh, et al., Nature 344: 257-259 (1990). Hockenbery, et al., Bcl-2 Is An Inner Mitochondrial Mem Bitterman, et al., Repair. After Acute Lung Injury, Chest brane Protein That Blocks Programmed Cell Death, Nature 105(3):P 118S-121S (1994). 348:334-336 (1990). Boise, et al., Bcl-X, A Bcl-2-Related Gene That Functions Evan, et al., Induction Of Apoptosis. In Fibroblasts. By As A Dominant Regulator of Apoptotic Cell Death, Cell C-myc Protein, Cell 69:119-128 (1992). 74:597-608 (1993). Harrington, et al., C-Myc-Induced Apoptosis. In Fibroblasts Henderson, et al., Epstein-Barr Virus-Coded BHRF1 Pro Is Inhibited by Specific Cytokines, The EMBO Journal tein, A Viral Homologue of BC1-2, Protects Human B Cells 13:3286-3295 (1994). From Programmed Cell Death, Proc. Natl. Acad. Sci. USA Casey, Protein Lipidation in Cell Signaling, Sci 90:8479-8483 (1993). ence:268-221-225 (1995). Hengartner, et al., Caenorhabditis Elegans Gene Ced-9 (List continued on next page.) Protects Celis From Programmed Cell Death, Nature 356:494-499 (1992). Primary Examiner-Mindy Fleisher Hibner, et al., Signaling Of Programmed Cell Death Induc Assistant Examiner Terry A. McKelvey tion. In WEHI-231 B Lymphoma Cells, Eur: J. Immunol. Attorney, Agent, or Firm-Hale and Dorr 23(11):2821-2825 (1993). 57 ABSTRACT Hockenbery, et al., BCL2 Protein Is Topographically Restricted. In Tissues Characterized By Apoptotic Cell The present invention is directed to novel peptides and Death, Proc. Natl. Acad. Sci. USA 88:6961-6965 (1991). compositions capable of modulating apoptosis in cells, and Korsmeyer, et al. BC1-2/Bax: A RheostatThat Regulates An to methods of modulating apoptosis employing the novel Anti-Oxidant Pathway And Cell Death, Cancer Biology peptides and compositions of the invention. In one aspect, 4:327-332 (1993). the invention is directed to a novel peptide designated the Kozopas, et al., MCL1, A Gene Expressed In Programmed "GD domain,” which is essential both to Bak's interaction Myeloid Cell Differentiation, Has Sequence Similarity To with Bcl-X and to Bak's cell killing function. Methods of BCL2, Proc. Natl. Acad. Sci. USA 90:3516-3520 (1993). identifying agonists or antagonists of GD domain function Oltvai et al., Bcl-2-Heterodimerizes in Vivo With A Con are provided. The GD domain is responsible for mediating served Homolog, Bax. That Accelerates Programed Cell key protein/protein interactions of significance to the actions Death, Cell 74:609-619 (1993). of multiple cell death regulatory molecules. Carson, et al., Apoptosis And Disease, The Lancet, 341:1251-1254 (1993). 2 Claims, 10 Drawing Sheets 5,656,725 Page 2 OTHER PUBLICATIONS Tanaka, et al., Cellular Commitment To Oncogene-Induced Transformation Or Apoptosis Is Dependent On The Tran Guarente, Strategies for the identification of interacting scription Factor RF-1, Cell 77:829-839 (1994). proteins Proc. Natl. Acad. Sci: 90:1639-1641 (1993). Rao, et al., The Adenovirus E1A Proteins Induce Apoptosis, Germino, et al., Screening for in vivo protein-protein inter Which Is Inhibited By The E1B 19-kDa And Bcl-2 Pro actions Proc. Natl. Acad. Sci.: 90:933-937 (1993). teins, Proc. Natl. Acad. Sci. USA 89:7742-7746 (1992). Reed, Bcl-2 And The Regulation Of Programmed Cell Wu, et al., P53 And E2F-1 Cooperate To Mediate Apoptosis, Death, J. Celi. Biol. 124:1-6 (1994). Proc. Natl. Acad. Sci. USA 91:3602-3606 (1994). U.S. Patent Aug. 12, 1997 Sheet 1 of 10 5,656,725 450 90 400 80 (M 350 70 300 60 250 50 200 40 150 30 Z 100 20 50 10 O O E. VECTOR HA-BAK VECTOR HA-BAK CO-TRANSFECTED PLASMID CO-TRANSFECTED PLASMID FIG. 1A FIG.1B HEA 400 250 350 BT549 200 5 250300 ODEAD 200 O DEAD 100 LME (r. 150 LME g 100 O - s VECTOR HA-BAK VECTOR HA-BAK CO-TRANSFECTED PLASMID CO-TRANSFECTED PLASMID FIG.1C FIG.1D U.S. Patent Aug. 12, 1997 Sheet 2 of 10 5,656,725 (SEQ.ID NO:11) (SEQ.D NO:1 KIIS IN AAPADPEMVTLPLQ CDDINRRYDSEFQ HYDROPHOBIC 8-gal Bcl-2 HONOLOGY DOMAINS ASSAY 211 BAK WT RESIDUES DELETED 2-40 AN 19-21 AC 124-139 A 162-77 All 140-61 ASPACER 13:39 O A +ll 3,924-139 O AN---- 53-66 O AAA 82-94 A GD 67-81 APS 95-123 ATM 4-52 O EZOOE, AYR 140-21 A Af 102-21 ORs 2. APst 73 123 QVG 75 123 187 21 OWG+C 58 103 PEM 58 103 187 21 ZZ PEM+C FIG.2 U.S. Patent Aug. 12, 1997 Sheet 3 of 10 5,656,725 interactics. Bakwit. GST-E-X, if vitro S. input Bcl-X GST FG3A iisatist. Bakx. Bix, is S. rix-ak FG, 3B U.S. Patent Aug. 12, 1997 Sheet 4 of 10 5,656,725 (SEQ.ID NO:11) (SEQID NO:1) AAPADPEMVTLPLQ GDDINRRYDSEFQ Hoopoeic is |- HOMOLOGY DONIANS ASSAY Bcl-X. II 21 BAK WT -- + RESIDUES DELETED 2-40 AN - - 91-21 AC +/- + 124-139 A -- - 162-177 All -- - 140-16 ASPACER + + 3:33 O A + + + 1912-139 O A N++ + - 53-66 O AAA + + 82-94 A CD e 67-8 APS +/- -/+ 95-23 ATM -- -- 41-52 O GOZZOOE, AYR -- - 40-2 s A Af ND -- 102-21 CES ZT A Pst ND -- 73 25 OVG +/- -- 73 123 87 21 OVG+C - ND 58 103 ZZ PEM - 58 103 87 2 TZ PEM+C -- ND FIG.4 U.S. Patent Aug. 12, 1997 Sheet 5 of 10 5,656,725 e - i Cy Cy s a.a c s na2 C f 8 i. 2. g i 3. U.S. Patent Aug. 12, 1997 Sheet 6 of 10 5,656,725 TX-108 GOWD?dig XDg 097XO8 D?dig U.S. Patent Aug. 12, 1997 Sheet 7 of 10 5,656,725 Y 3. input PEM GST 5,656,725 1. 2 PEPTIDES AND COMPOSITIONS WHCH A., et al., Nature 359:554-556 (1992); Hockenbery, D. M., MODULATE APOPTOSIS et al., Cell 75: 241-251 (1993)). There is also conservation of Bcl-2 function across species. For example, the ced-9 FIELD OF THE INVENTION gene of the nematode C. elegans appears to be a structural The present invention relates generally to the field of cell 5 and functional homolog of bcl-2 (Hengartner, M. O., et al., physiology, and more particularly, to programmed cell Cell 76: 665–676 (1994)) and bcl-2 can complement ced-9 death, or apoptosis. The novel peptides and compositions of mutations in transgenic animals (Vaux, D. L., et al., Science 258: 1955-1957 (1991)). These observations suggest that the invention are useful for modulating apoptosis in cells. Bcl-2 is intimately connected with an evolutionarily con BACKGROUND OF THE INVENTION 10 served cell death program. It is known that bcl-2 is a member of a family of related The phenomenon of programmed cell death, or genes, at least some of which also modulate apoptosis. Of "apoptosis,” is known to be involved in and important to the these, bcl-X bears the highest degree of homology to bcl-2, normal course of a wide variety of developmental processes, and is differentially spliced to produce a long form, termed including immune and nervous system maturation.
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