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(12) United States Patent (10) Patent No.: US 6,592,865 B2 Parry Et Al

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(12) United States Patent (10) Patent No.: US 6,592,865 B2 Parry Et Al USOO6592865B2 (12) United States Patent (10) Patent No.: US 6,592,865 B2 Parry et al. (45) Date of Patent: Jul. 15, 2003 (54) METHODS AND COMPOSITIONS FOR Drummer et al., Effects of Chronic Enalapril Treatment on MODULATING ACE-2 ACTIVITY Enzymes Resposible for the Catabolism of Angiotensin I and Formation of Angiotensin II, Biochemical Pharmacol (75) Inventors: Tom J. Parry, Walkersville, MD (US); ogy, 39(3):513–518 (1990). Les Sekut, Ijamsville, MD (US) Ito et al., “Pharmacological profile of depressor response elicited by Sarthran in rat ventrolateral medulla, Am. J. (73) Assignee: Human Genome Sciences, Inc., Physiol. Heart Circ. Physiol., 279:H2961-H2966 (2000). Rockville, MD (US) Johnson et al., “Radioimmunoassay for Immunoreactive (*) Notice: Subject to any disclaimer, the term of this des-Leu'HAngiotensin I," Peptides, 10:489–492 (1989). patent is extended or adjusted under 35 Lembeck et al., “Demonstration of extrapulmonary activity U.S.C. 154(b) by 0 days. of angiotensin converting enzyme in intact tissue prepara tions.” Br. J. Pharmacol., 100:49-54 (1990). (21) Appl. No.: 10/158,847 Miano et al., “Different modulation of aromatase activity in frog testis in vitro by ACE and ANG II,” Am. J. Physiol., 277 (22) Filed: Jun. 3, 2002 (Regulatory Integrative Comp. Physiol. 46):R1261-R1267 (65) Prior Publication Data (1999). Oparil et al., “Mechanism of Pulmonary Conversion of US 2003/009 1557 A1 May 15, 2003 Angiotensin I to Angiotensin II in the Dog,” Circ. Res., Related U.S. Application Data 29:682-690 (Dec. 1971). (60) Provisional application No. 60/295,004, filed on Jun. 4, Sibinga et al., “A Pair of ACES for Openers’?,’ Circ. Res., 2001. 87:523-525 (2000). Snyder et al., “Inhibition of angiotensin-converting enzyme (51) Int. Cl." ......................... A61K 38/00; A61K 38/08 (52) U.S. Cl. ................................ 424/94, 514/2; 514/15 by des-Leu"-angiotensin I: a potential mechanism of (58) Field of Search ........................................ 514/2, 15 endogenous angiotensin-converting enzyme regulation,” Biochimica et Biophysica Acta, 871:1–5 (1996). (56) References Cited Tipnis et al., “A Human Homolog of Angiotensin-convert ing Enzyme,” J. Biol. Chem., 275(43):33238–33243 (Oct. U.S. PATENT DOCUMENTS 27, 2000). 5,444,067 A 8/1995 Kivlighn et al. Turner et al., “The angiotensin-converting enzyme gene 5,508.266 A 4/1996 Fink family: genomics and pharmacology,” TiPS, 23(4): 177-183 6,194,556 B1 2/2001 Acton et al. (Apr. 2002). FOREIGN PATENT DOCUMENTS Turner et al., “ACEH/ACE2 is a novel mammalian metal WO WO 99/52540 A1 10/1999 locarboxypeptidase and a homologue of angiotensin-con WO WO OO/18899 A2 4/2000 verting enzyme insensitive to ACE inhibitors,” Can. J. WO WOOO/O66104 A9 11/2000 Physiol. Pharmacol., 80:346–353 (2002). WO WO O2/12471 A2 2/2002 Vickers et al., “Hydrolysis of Biological Peptides by Human WO WO O2/39997 A2 5/2002 Angiotensin-converting Enzyme-related Carboxypepti OTHER PUBLICATIONS dase,” J. Biol. Chem., 277(17): 14838–14843 (Apr. 26, 2002). Bramucci et al., “Bradykinin is not involved in angiotensin converting enzyme modulation of ovarian Steroidogenesis and prostaglandin production in frog Rana eSculenta, "Acta. Primary Examiner Rebecca E. Prouty Physiol. Scand., 175:123-128 (2002). Assistant Examiner. Sheridan L. Swope Bramucci et al., “Different modulation of Steroidogenesis (74) Attorney, Agent, or Firm-Human Genome Sciences, and prostaglandin production in frog ovary in vitro by ACE Inc. and ANG II,” Am. J. Physiol., 273 (Regulatory Integrative (57) ABSTRACT Comp. Physiol. 42:R2089–R2096 (1997). Dasarathy et al., “Calcium ionophore A23.187 elevates The invention relates to the use of angiotensin II in combi angiotensin-converting enzyme in cultured bovine endothe nation with angiotesin 1-9 to potentiate angiotensin II activ lial cells,” Biochinica et Biophysica Acta, 1010:16-19 ity. The invention also relates to the use of combinations of (1989). angiotensin II and angiotensin 1-9 to increase vasoconstric Donoghue, et al., “A Novel Angiotensin-Covnerting tion and to treat disorders associated with low blood pres Enzyme-Related Carboxypeptidase (ADE2) Converts SUC. Angiotensin I to Angiotensin 1-9, Circ. Res., 87:e1-e9 (2000). 5 Claims, 4 Drawing Sheets U.S. Patent Jul. 15, 2003 Sheet 1 of 4 US 6,592,865 B2 Figure 1 All Effect (experimental) A All + A1-9 Combination All + A1-9 additivity (predicted regr, line) 20 A Combination Regression Line 15 10 O 0.5 1 15 log Peptide Concentration (nM) U.S. Patent Jul. 15, 2003 Sheet 2 of 4 US 6,592,865 B2 Figure 2 1SO 140 120 100 (ôHuuuu)dVIN A1-9 All U.S. Patent Jul. 15, 2003 Sheet 3 of 4 US 6,592,865 B2 Figure 3 -O- A 1-9 160 -- A & A 1-9 1ug -0- A a. 150 s C E 140 5 a 30 d 120 ; : . Vehicle 110 1. 10 1OO 1000 Angiotensin Il Dose (ng/kg/min) U.S. Patent Jul. 15, 2003 Sheet 4 of 4 US 6,592,865 B2 Figure 4 180 160 140 120 100 -O- inactive Peptide -- ACE2 inhibitor peptide - (0- - Peptide vehicle/inactive cohort 80 A Peptide vehicle/ACE2 inhib. cohort V ACE2 Control for Inactive Cohort 60 O 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Peptide Dose (mg/kg) US 6,592,865 B2 1 2 METHODS AND COMPOSITIONS FOR (1985); Snyder et al., Biochemica et Biophysica Acta MODULATING ACE-2 ACTIVITY 871:1–5 (1986)). Circulating A1-9 has been detected in vivo at levels twice that of angiotensin II (Oparil et al., Circula This application claims benefit under 35 U.S.C. S119(e) tion Research 29 682-690 (1971); Johnson et al., Peptides of U.S. Patent Application No. 60/295,004, filed Jun. 4, 10:489–492) (1989)). In the case of ACE-2, the above 2001, which is hereby incorporated by reference in its reaction is not blocked by captopril, lisinopril or enalaprilat entirety. (Donoghue et al., Circulation Research 87:e1-e9 (2000); Tipinis et al., The Journal of Biological Chemistry FIELD OF THE INVENTION 275:33238-33243 (2000)). The unique expression profile of The present invention relates to polypeptides that regulate ACE-2, Spectum of its enzymatic activity and inhibitory production of Angiotensin 1-9 via Such mechanisms as, for effects of its product A1-9 on ACE have led to the specu example, inhibition of ACE-2. Such polypeptides have uses lation that ACE-2 functions to affect circulatory homeostasis for example, in the detection, isolation, and/or purification by promoting vasodilation (Donoghue et al., Circulation of ACE-2 and/or Angiotensin 1-9. The invention also relates Research 87:e 1-e9 (2000); Snyder et al., The Journal of 15 Biological Chemistry 260:7857-7860 (1985)). However, to nucleic acid molecules encoding these ACE-2 binding A1-9 has been shown to be a weak vasoconstrictor in polypeptides, vectors and host cells containing these nucleic isolated rat aorta and have weak pressor activity in anesthe acids, and methods for producing the Same. The present tized rats and dogs (Oparil et al., Circulation Research invention also relates to methods and compositions for 29:682-690 (1971)). Therefore, we hypothesized that one of detecting, diagnosing, or prognosing a disease or disorder the physiologic roles of ACE-2 is to increase arterial pres asSociated with aberrant ACE-2 or Angiotensin 1-9 expres Sure through the actions of its catabolic product, A1-9. AS Sion or inappropriate function of ACE-2.or Angiotensin 1-9, Such, ACE-2 might be a valid target for drug development in comprising ACE-2 binding polypeptides or fragments or hypertension. variants thereof, that specifically regulate ACE-2 action. The present invention further relates to methods and composi Accordingly, molecules that specifically bind ACE-2 tions for preventing, treating or ameliorating a disease or 25 would find a variety of uses in the Study of ACE-2, angio disorder associated with aberrant ACE-2 or Angiotensin 1-9 tensin 1-9) (SEQ ID NO:145), and angiotensin, as well as expression or inappropriate ACE-2 function or Angiotensin ACE, and its known substrates: Angiotensin II (SEQ ID 1-9 function, comprising administering to an animal, pref NO: 144), Angiotensin 1-7, des-Asp, bradykinin, erably a human, an effective amount of one or more ACE-2 neurotensin, and Substance P. Further, molecules that Spe binding polypeptides or fragments or variants thereof, that cifically bind ACE-2 would also find a variety of uses in the Specifically regulate ACE-2. manufacture and purification of ACE-2, ACE, angiotensin, angiotensin II, and/or Angiotensin 1-9 in commercial and BACKGROUND OF THE INVENTION medically pure quantities, and in the development new therapeutic or diagnostic reagents. ACE-2 binding polypep The renin-angiotensin System (RAS) plays an important 35 tides may also find medical utility in, for example, the role in circulatory homeostasis at both Systemic and local treatment of cardiovascular disorders (e.g., hypertension, levels. Angiotensin converting enzyme (ACE), a 175 kD chronic heart failure, left ventricular failure, Stroke, cerebral protein known to be widely distributed throughout the vasospasm after Subarachnoid injury, atherOSclerotic heart cardiovascular System, has been long recognized as the key disease, and retinal hemorrhage), renal disorders (e.g., renal enzyme in the generation of angiotensin II, a peptide that 40 vein thrombosis, kidney infarction, renal artery embolism, regulates fluid balance, blood pressure and local blood flow renal artery Stenosis, myocardial hypertrophy, hypertrophy in a number of tissues (Peach, M. J. Physiological Reviews and/or hyperplasia of conduit and/or resistance vessels, 57:313-370 (1997)). As part of an ongoing strategy to myocyte hypertrophy, and fibroblast proliferative diseases), establish genes associated with cardiovascular function via inflammatory diseases (e.g., SIRS (systemic Inflammatory high throughput cDNA sequencing, we identified a member 45 Response Syndromes), Sepsis, polytrauma, inflammatory of the RAS family of enzymes, ACE-2, from human kidney.
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