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(12) United States Patent (10) Patent No.: US 8,679,472 B1 Reichert Et Al

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(12) United States Patent (10) Patent No.: US 8,679,472 B1 Reichert Et Al USOO8679472B1 (12) United States Patent (10) Patent No.: US 8,679,472 B1 Reichert et al. (45) Date of Patent: Mar. 25, 2014 (54) CRYSTAL OF HUMAN INTERFERON ALPHA 6,180,096 B1 1/2001 Kline 2B IN COMPLEX WITH ZINC 6,250,469 B1 6/2001 Kline 6,482.613 B1 1 1/2002 Goeddelet al. 6,524,570 B1 2/2003 Glue et al. (75) Inventors: Paul Reichert, Montville, NJ (US); 6,610,830 B1 8, 2003 Goeddeletal. Marianna Marshall Long, 2008/0201 123 A1* 8/2008 Cosgrove ........................ TO3/11 Birmingham, AL (US); Alan W. Hruza, Hackettstown, NJ (US); Peter Orth, OTHER PUBLICATIONS New York, NY (US); Tattanahalli L. Ramagopal et al., Acta Crystallographica Section D. Biological Crys Nagabhushan, Parsippany, NJ (US) tallography D59:868-875, 2003.* Kitago et al., Acta Crystallographica Section D. Biological Crystal (73) Assignee: Merck, Sharp & Dohme Corp., lography D61: 1013-1021, 2005.* Rahway, NJ (US) Radhakrishnan et al., Zinc mediated dimer of human interferon-C2b revealed by X-ray crystallography. Structure (1996) 4(12): 1453 (*) Notice: Subject to any disclaimer, the term of this 1463. patent is extended or adjusted under 35 Physicians Desk Reference(R) Electronic Library-Rebetron(R), U.S.C. 154(b) by 210 days. RebetolR, Intron RA (last accessed Oct. 2007). Physicians Desk Reference(R). Electronic Library-Pegasys(R (last (21) Appl. No.: 11/973,362 accessed Oct. 2007). Physicians Desk Reference R. Electronic Library-ActimmuneR (last Filed: Oct. 5, 2007 accessed Oct. 2007). (22) Physicians Desk Reference(R). Electronic Library-Betaseron(R) (last accessed Oct. 2007). Related U.S. Application Data Physicians Desk Reference(R). Electronic Library-Pegintron(R) (last (60) Provisional application No. 60/849,520, filed on Oct. accessed Oct. 2007). 5, 2006. Physicians Desk Reference R. Electronic Library-Infergen R (last accessed Oct. 2007). (51) Int. C. Physicians Desk Reference(R). Electronic Library-Alferon N injec A6 IK38/2I (2006.01) tion(R) (last accessed Oct. 2007). Physicians Desk Reference(R). Electronic Library-Rebifr) (last A6M5/00 (2006.01) accessed Oct. 2007). (52) U.S. C. Intron R A Product Information: www.IntronA.com (last accessed USPC ............. 424/85.7: 514/1.1 : 514/4.3; 604/187 Oct. 2007). (58) Field of Classification Search In “Preparation and analysis of protein crystals” By Alexander None McPherson, Robert E. Krieger Publishing Co. Krieger Drive, See application file for complete search history. Malabar, Florida 1989, p. 174-180. (56) References Cited * cited by examiner U.S. PATENT DOCUMENTS Primary Examiner — David J Steadman 5,441,734 A 8, 1995 Reichert et al. (57) ABSTRACT 5,460,956 A 10, 1995 Reichert et al. 5,908,621 A 6, 1999 Glue et al. This application covers a novel PEGylated interferon and a 5,935,566 A 8, 1999 Yuen et al. novel crystalline form of interferon which are useful, inter 5,951,974 A 9, 1999 Gilbert et al. alia, for detailed structural analysis of interferon as well as 5,972,331 A 10, 1999 Reichert et al. 6,004,549 A * 12/1999 Reichert et al. .............. 424,85.7 treatment and prevention of viral infections and hyperprolif 6,027,565 A 2/2000 Bugg erative diseases such as leukemia. 6,042,822 A 3, 2000 Gilbert et al. 6,177,074 B1 1/2001 Glue et al. 12 Claims, 2 Drawing Sheets U.S. Patent Mar. 25, 2014 Sheet 1 of 2 US 8,679,472 B1 Figure 1 U.S. Patent Mar. 25, 2014 Sheet 2 of 2 US 8,679,472 B1 Figure 2 US 8,679,472 B1 1. 2 CRYSTAL OF HUMAN INTERFERON ALPHA are on His34. In an embodiment of the invention, about 0% of 2B IN COMPLEX WITH ZINC said moieties are on His 34. In an embodiment of the inven tion, more than 50% of said moieties are on Lys 49, Lys 121, This application claims the benefit of U.S. provisional Lys 31. His 7 and Cys 1. In an embodiment of the invention patent application No. 60/849,520, filed Oct. 5, 2006; which 5 about 100% of said moieties are on Lys 49, Lys 121, Lys 31, is herein incorporated by reference in its entirety. His 7 and Cys 1. In an embodiment of the invention, said interferon is interferon alpha2b (e.g., SEQID NO:1). In an FIELD OF THE INVENTION embodiment of the invention, the complex is crystalline (e.g., which belongs to space group C2 or space group P2). In an The present application relates to interferon polypeptide 10 embodiment of the invention, the crystal diffracts X-rays to compositions about 2 A resolution. In an embodiment of the invention, the crystal belongs to BACKGROUND OF THE INVENTION space group P2, and diffracts X-rays to about 1.95 A resolu tion. The human interferon alphas are a family of proteins com 15 The present invention provides a crystalline composition prising at least 24 subspecies, Zoon K. C. Interferon 9:1-12 comprising comprising a complex of interferon-a2b-Zn"- (1987), Gresser I., ed. Academic Press, New York. They were interferon-a2b or a structural homologue thereof, wherein the originally described as agents capable of inducing an anti complex three dimensional structure is characterized by viral state in cells but are known as pleitropic lymphokines structural coordinates comprising a root mean square devia affecting many functions of the immune system, Opdenakker, tion of common residue backbone atoms or alpha carbon et al., Expermentia 45: 513-520 (1989). Apart from their in atoms of less than about 1.5A when Superimposed on back vitro biological activities, the human interferon alphas are bone atoms or alpha carbon atoms described by structural currently used for several indications, e.g., hairy cell leuke coordinates of Table 3 or 4. In an embodiment of the inven mia, Kaposi Sarcoma, Venereal warts, hepatitis B and hepa tion, the composition comprises an interferon alpha2b dimer titis C. 25 complexed with Zn" wherein said crystal belongs to C2 Presently, interferon is administered to patients by injec space group. In an embodiment of the invention, the crystal tion. Injection Suffers from several drawbacks including pain diffracts X-rays to a 2A resolution. and poor patient compliance. An alternative mode of admin The present invention provides, a crystalline composition istration of interferon or PEG-interferon would be beneficial. comprising an interferon alpha 2b dimer complexed with Macromolecules have limited modes of administration. 30 Zn" wherein said crystal belongs to P2 space group and Transdermal or oral delivery is difficult because of their sheer diffracts X-rays to about 1.95 A resolution. In an embodiment size which usually has a molecular weight greater than 7,000 of the invention, the crystal belongs to space group P2 com KDa, and instability in the gastrointestinal environment. In prising unit cell parameters a=62.2 A, b=75.3 A, c=149.2 A general, protein drugs are administered either by Subcutane and B=91.4. In an embodiment of the invention, the crystal ous or intravenous injection usually in hospital or clinical 35 belongs to space group C2 comprising unit cell parameters settings. Proteins having a molecular weight less than 30,000 a=114.7 A, b=98.4 A, c=62.4 A and B=93.9°. In an embodi have serum half-lives duration of hours when injected subcu ment of the invention, said crystal comprises a particle diam taneously or intravenously and characteristically show a eter of from about 1 um to about 70 Lum or from about 0.5um "burst’ (rapid blood serum clearance rate) profile when blood to about 7 um. levels are measured over time. There is increasing awareness 40 The present invention also provides a pharmaceutical com that drug release patterns (continuous versus pulsatile) sig position (e.g., Sustained release formulation or a composition nificantly affect therapeutic responses. Suitable for pulmonary delivery such as a dry powder) com Pulmonary delivery of a crystalline interferon alpha has prising any of the foregoing compositions and a pharmaceu been described previously (U.S. Pat. No. 5,972,331). The tically acceptable carrier. Also provided is an injectable patent describes a method for preparing a crystalline inter 45 device comprising the pharmaceutical composition. The feron alpha suitable for aerosol formulation either for sys present invention also provides a pharmaceutical composi temic or topical (inhaled) drug delivery. tion of the invention in an inhaler. There remains a need in the art for high quality, highly The present invention also provides a method for produc ordered interferon crystals that are particularly useful for ing a complex comprising an interferon alpha 2 dimer bound pulmonary delivery or delivery in a Sustained release formu 50 to a divalent cation wherein said interferon is chemically lation. A Zn" mediated interferon alpha2b dimeric crystal modified with a half-life extending moiety wherein less than was produced previously (see Radhakrishnan et al., Structure. 50% of said moieties are on His 34 comprising 4(12): 1453-63 (1996); see also U.S. Pat. No. 5,441,734 to (1) expressing the interferon polypeptide in a bacterial cell; Reichert et al.); however, interferon structural data gained (2) isolating a soluble fraction comprising the polypeptide from the prior art crystals, was only to a 2.7 A or 2.9 A 55 from said cell; resolution. (3) chromatographically purifying said polypeptide from Due to the ongoing strong scientific interest in understand said soluble fraction by cation exchange chromatogra ing interferon and its properties, there is also an interest in phy, weak anion exchange chromatography and ciba obtaining crystals which are of Superior quality and particu cron Blue 3G chromatography; larly useful for interferon structural determination.
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