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(12) United States Patent (10) Patent No.: US 6,822,071 B1 Stephens Et Al

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(12) United States Patent (10) Patent No.: US 6,822,071 B1 Stephens Et Al USOO6822071B1 (12) United States Patent (10) Patent No.: US 6,822,071 B1 Stephens et al. (45) Date of Patent: Nov. 23, 2004 (54) POLYPEPTIDES FROM CHLAMYDIA (56) References Cited PNEUMONIAE AND THEIR USE IN THE DIAGNOSIS, PREVENTION AND FOREIGN PATENT DOCUMENTS TREATMENT OF DISEASE WO 99/27105 * 6/1999 (75) Inventors: Richard S. Stephens, Orinda, CA (US); OTHER PUBLICATIONS Wayne Mitchell, San Francsico, CA Gerhold et al-BioEssays 18(12):973-981, 1996.* (US); Sue S. Kalman, Saratoga, CA Wells et al Journal of Leukocyte Biology 61(5):545-550, (US); Ronald Davis, Palo Alto, CA 1997.* (US) Russell et al Journal of Molecular Biology 244:33-350, 1994.* (73) Assignee: The Regents of the University of Rudinger et al., in “Peptide Hormones' Parsons, TA ets, California, Oakland, CA (US) University Park Press pp. 1–6, 1976.* Burgess et al, The Journal of Cell Biology, 111:2129-2138, Notice: Subject to any disclaimer, the term of this 1990.* patent is extended or adjusted under 35 Lazar et al, Molecular and Cellular Biology U.S.C. 154(b) by 0 days. 8(3):1247–1252, 1988.* Jobling et al, Mol-Microbiol. 5(7): 1755–67, 1991.* (21) Appl. No.: 09/438,185 Pir-68 Database Accession No. E72002 Kalmar et al. Apr. (22) Filed: Nov. 11, 1999 23, 1999.* (Under 37 CFR 1.47) * cited by examiner Primary Examiner Patricia A. Duffy Related U.S. Application Data (74) Attorney, Agent, or Firm Townsend and Townsend (60) Provisional application No. 60/128,606, filed on Apr. 8, and Crew 1999, and provisional application No. 60/108.279, filed on Nov. 12, 1998. (57) ABSTRACT Int. Cl.......................... A61K 3800; C07K 14/00 (51) Chlamydia pneumoniae polypeptides are provided. The C. (52) U.S. C. .... ... 530/300; 530/350, 530/402; pneumoniae polypeptides can be used to prepare pharma 530/810; 530/811; 530/812; 530/813; 530/814; ceutical compositions for the treatment or prevention of 530/820; 530/825 disease. In addition, the proteins can be used in methods for (58) Field of Search ................................. 435/183, 184; the diagnosis of C. pneumoniae infection. 514/2; 424/185.1, 190.1, 192.1, 193.1, 234.1, 263.1 6 Claims, No Drawings US 6,822,071 B1 1 2 POLYPEPTIDES FROM CHLAMYDIA C. pneumoniae is related to other Chlamydia Species, but PNEUMONIAE AND THEIR USE IN THE the level of sequence similarity is relatively low. Very little DIAGNOSIS, PREVENTION AND is known about the biology of this organism, although it TREATMENT OF DISEASE appears to be an important human pathogen. Allelic diver sity and Structural relationships between Specific genes of CROSS-REFERENCES TO RELATED Chlamydia species is described in Kaltenboeck et al. (1993) APPLICATIONS J Bacteriol 175(2):487–502; Gaydos et al. (1992) Infect The present application is related to No. 60/128,606, filed Immun 60(12):5319-5323; Everett et al. (1997) Int J Syst Apr. 8, 1999 and No. 60/108,279, filed Nov. 12, 1998, which Bacteriol 47(2):461–473; and Pudjiatmoko et al. (1997) Int are incorporated herein by reference. J Syst Bacteriol 47(2):425-431. A number of studies have been published describing STATEMENT AS TO RIGHTS TO INVENTIONS methods for detection of C. pneumoniae, and for distin MADE UNDER FEDERALLY SPONSORED guishing between Chlamydia Species. Such methods include RESEARCH AND DEVELOPMENT PCR detection (Rasmussen et al. (1992) Mol Cell Probes 15 6(5):389–394; Holland et al. (1990) J Infect Dis 162(4): 1. Field of the Invention 984-987); a simplified polymerase chain reaction-enzyme This invention relates to nucleic acids and polypeptides immunoassay (Wilson et al. (1996) J Appl Bacteriol 80(4): from Chlamydia pneumoniae and to their use in the 431–438); Sequence determination and restriction endonu diagnosis, prevention and treatment of diseases associated clease cleavage (Herrmann et al. (1996) J Clin Microbiol with C. pneumoniae. 34(8): 1897–1902). 2. Background of the Invention Antigenic and molecular analyses of different C. pneu Chlamydiaceae is a family of obligate intracellular para moniae strains is described in Jantos et al. (1997) Clin Site with a tropism for epithelial cells lining the mucus Microbiol 35(3):620–623. Some genes of C. pneumoniae membranes. The bacteria have two morphologically distinct have been isolated and Sequenced. These include the Gro E forms, “elementary body” and “reticulate body”. The 25 operon (Kikuta et al. (1991) Infect Immun 59(12): elementary body is the infectious form, and has a rigid cell 4665-4669); the major outer membrane protein Perez et al. wall, primarily of croSS-linked outer membrane proteins. (1991) Infect Immun 59(6):2195-2199; the DnaK protein The reticulate body is the intracellular, metabolically active homolog (Komak et al. (1991) Infect Immun 59(2): form. A unique developmental cycle between these two 721-725); as well as a number of ribosomal and other genes. forms characterizes Chlamydia growth. C. pneumoniae is a human respiratory pathogen that SUMMARY OF THE INVENTION causes acute respiratory disease, and approximately 10% of This invention provides the genomic Sequence of Chlamy community-acquired pneumonia Antibody prevalence Stud dia pneumoniae. The Sequence information is useful for a ies have shown that virtually everyone is infected with C. 35 variety of diagnostic and analytical methods. The genomic pneumoniae at Some time, and that reinfection is common. Sequence may be embodied in a variety of media, including In addition to respiratory disease, Studies have shown an computer readable forms, or as a nucleic acid comprising a asSociation of this organism with coronary artery disease. It Selected fragment of the Sequence. Such fragments generally has been demonstrated in atherOSclerotic lesions of the aorta consist of an open reading frame, transcriptional or transla and coronary arteries by immunocytochemistry and by poly 40 tional control elements, or fragments derived therefrom. merase chain reaction (Kuo et al. (1993) J Infect Dis Proteins encoded by the open reading frames are useful for 167(4):841–849). diagnostic purposes, as well as for their enzymatic or Recent reports have further demonstrated the presence of Structural activity. C. pneumoniae in the walls of abdominal aortic aneurysms (Juvonen et al. (1997).J. Vasc Surg. 25(3):499-505). Abdomi 45 DEFINITIONS nal aortic aneurysms are frequently associated with atherosclerosis, and inflammation may be an important The term "amino acid” refers to naturally occurring and factor in aneurysmal dilatation. C. pneumoniae may play a Synthetic amino acids, as well as amino acid analogs and role in maintaining an inflammation and triggering the amino acid mimetics that function in a manner Similar to the development of aortic aneurysms. 50 naturally occurring amino acids. Naturally occurring amino Muhlestein et al. (1996) JACC 27:1555–61, reported a acids are those encoded by the genetic code, as well as those differential incidence of Chlamydia species within the coro amino acids that are later modified, e.g., hydroxyproline, nary artery wall of patients with atherosclerosis verSuS those Y-carboxyglutamate, and O-phosphoSerine. Amino acid ana with other forms of cardiovascular disease. The extremely logs refers to compounds that have the Same basic chemical high rate of possible infection in patients with Symptomatic 55 Structure as a naturally occurring amino acid, i.e., an O. atherosclerotic disease compared to the very low rate in carbon that is bound to a hydrogen, a carboxyl group, an patients with normal coronary arteries or coronary artery amino group, and an R group., e.g., homoserine, norleucine, disease from chronic transplant rejection provides evidence methionine Sulfoxide, methionine methyl sulfonium Such for a direct link between the atherosclerotic process and analogs have modified R groups (e.g., norleucine) or modi Chlamydia infection. Because a history of chlamydial infec 60 fied peptide backbones, but retain the same basic chemical tion is So prevalent in the population, the issue of causality Structure as a naturally occurring amino acid. Amino acid remains. On a physiologic and pathologic level, abnormal mimetics refers to chemical compounds that have a structure interactions among endothelial cells, platelets, macrophages that is different from the general chemical Structure of an and lymphocytes may lead to a cascade of events resulting amino acid, but that functions in a manner Similar to a in acute endothelial damage, thrombosis and repair, chroni 65 naturally occurring amino acid. cally leading to the development of atheroma in blood Amino acids may be referred to herein by either their vessels. commonly known three letter symbols or by the one-letter US 6,822,071 B1 3 4 symbols recommended by the IUPAC-IUB Biochemical can be modified to yield a functionally identical molecule. Nomenclature Commission. Nucleotides, likewise, may be Accordingly, each Silen: Variation of a nucleic acid which referred to by their commonly accepted Single-letter codes. encodes a polypeptide is implicit in each described "Amplification' primers are oligonucleotides comprising Sequence. either natural or analogue nucleotides that can Serve as the AS to amino acid Sequences, one of skill will recognize basis for the amplification of a Select nucleic acid Sequence. that individual Substitutions, deletions or additions to a They include, e.g., polymerase chain reaction primerS and nucleic acid, peptide, polypeptide, or protein Sequence ligase chain reaction oligonucleotides. which alters, adds or deletes a Single amino acid or a Small “Antibody” refers to an immunoglobulin molecule able to percentage of amino acids in the encoded Sequence is a bind to a specific epitope on an antigen. Antibodies can be “conservatively modified variant” where the alteration a polyclonal mixture or monoclonal. Antibodies can be results in the Substitution of an amino acid with a chemically intact immunoglobulins derived from natural Sources or Similar amino acid.
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