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(10) Patent No.: US 8853358 B2 US008853358B2 (12) United States Patent (10) Patent No.: US 8,853,358 B2 Cerami et al. (45) Date of Patent: Oct. 7, 2014 (54) TISSUE PROTECTIVE PEPTIDES AND WO WO95/21919 8, 1995 PEPTIDE ANALOGS FOR PREVENTING AND WO WOOOf 61164 10, 2000 TREATING DISEASES AND DISORDERS W8 w88: 86% R38. ASSOCATED WITH TISSUE DAMAGE WO WO 2004/004656 1, 2004 WO WO 2004/096.148 11, 2004 (75) Inventors: Anthony Cerami, Ossining, NY (US); WO WO 2005/025606 3, 2005 Michael Brines, Woodbridge, CT (US) WO WO 2005/032467 4/2005 WO WO 2006/091727 A2 8, 2006 (73) Assignee: Araim Pharmaceuticals, Inc., W. W. 3. 26 A 29. Tarrytown, NY (US) WO WO 2007/O10552. A 1, 2007 WO WO 2007/O19545. A 2, 2007 (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 479 days. Barlow, "Chapter 10: Peptide Drug Design”: Introduction to the (21) Appl. No.: 12/863,973 Principles of Drug Design and Action, 4th edition, 2006; pp. 327 354. (22) PCT Filed: Jan. 22, 2009 ISA/EPPCT International Search Report and Written Opinion dated (86). PCT No.: PCT/US2O09/OOO424 6. 2009, for International Application No. PCT/US2009/ S371 (c)(1), IPEA/EP, PCT International Preliminary Report on Patentability (2), (4) Date: Jul. 21, 2010 dated May 18, 2010 for International Application No. PCT/US2009/ OO424. (87) PCT Pub. No.: WO2009/094172 Brines et al., “Nonerythropoietin, tissue-protective peptides derived from the tertiary structure of erythropoietin.” Aug. 2008, Proceedings PCT Pub. Date: Jul. 30, 2009 of the NEN of E.the this States E. O O vol. 105, No. 31, pp. 10925-10930. (65) Prior Publication Data Konstantinopoulos et al., “Selective modulation of the erythropoietic US 2011 FO263504 A1 Oct. 27, 2011 and tissue-protective effects of erythropoietin: Time to reach the full therapeutic potential of erythropoietin.” Aug. 29, 2007, BBA — Related U.S. Application Data Reviews on Cancer, vol. 1776, No. 1, pp. 1-9. Leist et al., “Derivatives of Erythropoietin that are Tissue protective (60) Provisional application No. 61/062,012, filed on Jan. but not Erythropoietic.” Science, American Association for the 22, 2008, provisional application No. 61/062,022, Advancement of Science, Jul. 9, 2004, vol. 305, No. 5681, pp. 239 filed on Jan. 22, 2008, provisional application No. 243. 61/062,045, filed on Jan. 22, 2008, provisional Noli, N., 1997, “Design, Synthesis and Conformational Analysis of application No. 61/133,912, filed on Jul. 3, 2008, hCM-CSF(13-31)-Gly-Pro-Gly-(103-116). Journal of Peptide Sci provisional application No. 61/203,890, filed on Dec. ence, vol. 3:323-335. 30, 2008. Sun, et al., 1999, "Redox Regulation of Cell Signaling by Selenocysteine in Mammalian Thioredoxin Reductases,” J. Biol. (51) Int. Cl. Chem. VI. 274, No. 35, pp. 24522-24530. A6 IK38/04 (2006.01) Wolfert, M.A., 1998, "Chloroquine and Amphipathic Peptide Helices A6 IK38/08 (2006.01) Show Synergistic Transfection in Vitro.” Gene Therapy, vol. 5:409 C07K I4/505 (2006.01) 411. (52) U.S. Cl. Congote, BBRC, 324(2):673-678 (2004). CPC .................................... C07K 14/505 (2013.01) USPC .......................................... 530/327: 514/21.6 (Continued) (58) Field of Classification Search None Primary Examiner — Karlheinz, R Skowronek See application file for complete search history. Assistant Examiner — Lianko Garyu (56) References Cited (74) Attorney, Agent, or Firm — Jones Day U.S. PATENT DOCUMENTS (57) ABSTRACT 5,700,909 A 12, 1997 O'Brien 8,071,544 B2 12/2011 Cerami et al. The present invention provides peptides and peptide analogs 8,071,554 B2 12/2011 Cerami et al. that have tissue protective activities while having little or no potentially undesirable hematopoietic effects. The peptides FOREIGN PATENT DOCUMENTS and peptide analogs are useful in preventing and treating a EP O 116446 8, 1984 variety of diseases and disorders associated with tissue dam EP 0410246 B1 7, 1990 age. EP 0.116446 B1 8, 1990 EP O 410246 A 1, 1991 EP 1736 481 12/2006 6 Claims, 22 Drawing Sheets US 8,853.358 B2 Page 2 (56) References Cited Kaiser et al., “Recombinant human erythropoietin prevents the death of mice during cerebral malaria.” J. Infectious Diseases, 193(7):987 OTHER PUBLICATIONS 995 (2006). Park et al., “Identification of functionally important residues of human thrombopoietin.” J. Biol. Chem., 273(1):256-261 (1998). Elliott et al., “Mapping of the Active Site of Recombinant Human Peggion et al., “Design, synthesis, and conformational strudies of the Erythropoietin”. Blood, American Society of Hematology, US, 493 hCM-CSF derived peptide (13-27)-Gly-(75-87).” Biopolymers, 502 (1997). 50(5):545-554 (1999). Elliott et al., “Structural requirements for additional N-linked carbo Takashi et al., “Protein characteristics of thrombopoietin.” Stem hydrate on recombinant human erythropoietin, Journal of Biological Cells, 14(S1): 139-147 (1996). Chemistry”, 279(16): 16854-16862 (2004). Tahara et al., “Neutralization of biological activity and inhibition of Elliottet al., “Fine-Structure Epitope Mapping of Antierythropoletin receptor binding by antibodies against humanthrombopoietin. Stem Monoclonal Antibodies Reveals a Model of Recombinant Human Cells 16(1):54-60 (1998). Erythropoietin Structure”. Blood, American Society of Hematology, Von Feldt et al., “Development of GM-CSF antagonist peptides.” US, 2702-2713 (1996). Peptide Res., 8(1):20-27, 30-32 (1995). Skelton, et al., J. Mol. Biol.,316(5):1111-1125 (2002). Abstract only. Website: http://www.merckmanuals.com/professional/neurologic ISR dated Jul. 28, 2008 for PCT/US06/031061. disorders/peripheral nervous system and motor unit disor ISR dated Jun. 22, 2009 for European Application No. 06801051.1. ders overview of peripheral nervous system disorders.html. 8 Beffy et al., “An immunodominant epitope in a functional domain pages, retrieved on Mar. 7, 2013. near the N-terminus of human granulocyte-macrophage colony Website: http://www.nlm.nih.gov/medlineplus/ stimulating factor identified by cross-reaction of synthetic peptides peripheralnervesdisorders.html. 4 pages, retrieved on Mar. 7, 2013. with neutralizing anti-protein and anti-peptide antibodies.” Wen et al., “Erythropoietin structure-function relationships.” J. Biol. Hybridoma, 13(6):457-468 (1994). Chem., 269(36):22839-22846 (1994). Brines et al., “Erythropoietin mediates tissue protection through an Yu et al., “Investigation of n-terminal glutamate cyclization of recom erythropoietin and common B-subunit heteroreceptor.” Proc. Natl. binant monoclonal antibody informulation development.” J. Pharm. Acad. Sci. U.S.A., 101(41): 14907-14912 (2004). Biomed. Anal., 42(4):455-463, (2006). Ghezzi et al., "Erythropoietin as an antiapoptotic, tissue protective cytokine.” Cell Death & Differentiation, 11(S1):S37-S44 (2004). * cited by examiner U.S. Patent Oct. 7, 2014 Sheet 1 of 22 US 8,853,358 B2 0. 6 EPO 0. 5 0. 4. O 3 0. 2 0. 1 peptide ID 0. O o-o-o-o- -T-I-T-I-T- 0.1 10 100 1000 10000 100000 pM FIG. 1 U.S. Patent Oct. 7, 2014 Sheet 2 of 22 US 8,853,358 B2 15 O-O-O- O 10 N 9 O 5 O O 200 400 600 peptide D plg/kg) FIG.2 U.S. Patent Oct. 7, 2014 Sheet 3 of 22 US 8,853,358 B2 Z 50O "E: ug kg peptidepeptide ID ID N 90 ug/ kg peptide ID D 500 ug/ kg peptide ID Ñ N`S ZZZZZZZZZZZZZZZ ZZZZZZZZZZZZZZZ FG.3A 0 peptide ID 30 peptide ID 10H N 90 peptide ID S```` S`N ZZZZZZZZZZZZZZ ZZZZZZZZZZ D 300 peptide ID FIG.3B O peptide ID 3 0 peptide ID NIZ 9 0 peptide ID ZZZZZZZZ ZZZZZZZZZ ); O 300 peptide ID FIG.3C U.S. Patent Oct. 7, 2014 Sheet 4 of 22 120 5 .2 100 OS. c. c. c. c. -St S. S. S. 5 o O O d vess S S5 S5 O) -- -He an9. s e od so C. o n m n O O (D l 9. also o Ol FIG.4 U.S. Patent Oct. 7, 2014 Sheet 5 of 22 US 8,853,358 B2 350 A peptide IDIX S3(n=6 5C) 250 D 3 200 H S. 150 O 2 4. 6 8 10 De Ryck score FIG.5 U.S. Patent Oct. 7, 2014 Sheet 6 of 22 US 8,853,358 B2 (p/6u) FG.6A 300 200 R Control Vehicle NN O .1 pug/kg peptide ID 1. 0 ug /kg peptide ID 00 1 0 ug / kg peptide ID 00 (/d) nroCD © O Shom Vehicle Control Vehicle 0.1 pug/kg peptide ID 1.0 pig / kg peptide ID 10 pig / kg peptide ID U.S. Patent Oct. 7, 2014 Sheet 7 of 22 US 8,853,358 B2 1.5 Shom Vehicle 1.0 Control Vehicle Z.NN ug/kg peptide ID 1 min ZZ 0.5 ug/kg peptide D 30 min E.E. ug/kg peptide D6 h 0.0 FIG.7A 300 Shom Vehicle 200 Control Vehicle w Y pug/kg peptide ID 1 min s 1 pug/kg peptide ID 30 min 100 1 ug/kg peptide ID 6 h O FIG.7B 400 S BS 300 O Shom Vehicle 3 Control Vehicle 35 200 1 ug/kg peptide ID 1 min 2 3 1 ug/kg peptide ID 50 min Ét 100 1 ug/kg peptide ID 6 h E o U.S. Patent Oct. 7, 2014 Sheet 8 of 22 US 8,853,358 B2 12 --O-- PBS h o-peptide ID 9 E. 6 O s S 3 U.S. Patent Oct. 7, 2014 Sheet 10 of 22 US 8,853,358 B2 55 p<0.01 H--- as S 45 O E 5 S.
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