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US 2012/0231019 A1 YONEYAMA Et Al US 20120231 019A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0231019 A1 YONEYAMA et al. (43) Pub. Date: Sep. 13, 2012 (54) FIBROSIS INHIBITOR (30) Foreign Application Priority Data (75) Inventors: HIROYUKIYONEYAMA, Jun. 7, 2007 (JP) ................................. 2007-151164 Minato-ku (JP); Yoshiro Kai. Kashihara-shi (JP); Hideki Publication Classification Tagashira, Minato-ku (JP); Jun (51) Int. Cl. Koyama, Minato-ku (JP) A 6LX 39/395 (2006.01) (73) Assignee: Stelic Institute of Regenerative A6IP 29/00 (2006.01) Medicine, Stelic Institute & Co. CI2P 2L/02 (2006.01) C07K 6/8 (2006.01) (21) Appl. No.: 13/474,048 (52) U.S. Cl. ................... 424/172.1; 530/389.1; 435/70.4 (22) Filed: May 17, 2012 (57) ABSTRACT Related U.S. Application Data An objective of the present invention is to provide methods (63) Continuation of application No. 12/663,420, filed on for treating or preventing fibrotic diseases, which are based on Mar. 5, 2010, filed as application No. PCT/JP2008/ the novel finding that fibrosis is Suppressed by administering 060455 on Jun. 6, 2008. ER-TR7 to a subject. Patent Application Publication Sep. 13, 2012 Sheet 1 of 13 US 2012/0231019 A1 ER-R-REAE RO R. R. REA R §§ §§ x 100 Patent Application Publication Sep. 13, 2012 Sheet 2 of 13 US 2012/0231019 A1 }|-galvanimš! Narºga 3| * Patent Application Publication Sep. 13, 2012 Sheet 3 of 13 US 2012/0231019 A1 sesses &E:::: R UNTREATED ER-TR7 FIG. 3 Patent Application Publication Sep. 13, 2012 Sheet 4 of 13 US 2012/0231019 A1 8x38: 8x.333 8: 2s 8x8.83. …(¿? ·§§§§§§§§§ ******** #####~$$$$$$$$$$$$$$ × ****** Patent Application Publication Sep. 13, 2012 Sheet 5 of 13 US 2012/0231019 A1 DC CES S CERA 0 g/ml 10 g/ml Patent Application Publication Sep. 13, 2012 Sheet 6 of 13 US 2012/0231019 A1 s ESERN 8 SAN BO 75 kD ER-RT SO kD 50 kD a ANGEN S S S S &x Patent Application Publication Sep. 13, 2012 Sheet 7 of 13 US 2012/0231019 A1 NORA. OUSE FBROSS-ODE OUSE Patent Application Publication Sep. 13, 2012 Sheet 8 of 13 US 2012/0231019 A1 NORA. OUSE F BROSS-ODE OUSE Fig. 8 Patent Application Publication Sep. 13, 2012 Sheet 9 of 13 US 2012/0231019 A1 NORA. OSE F BROSS-ODE. OSE Fig. 9 Patent Application Publication Sep. 13, 2012 Sheet 10 of 13 US 2012/0231019 A1 ?? Q* **** 100) Patent Application Publication Sep. 13, 2012 Sheet 11 of 13 US 2012/0231019 A1 NORA. OUSE F BROSS-ODE OUSE (x00 Patent Application Publication Sep. 13, 2012 Sheet 12 of 13 US 2012/0231019 A1 FIG. 12 Patent Application Publication Sep. 13, 2012 Sheet 13 of 13 US 2012/0231019 A1 FIG. 13 US 2012/0231 019 A1 Sep. 13, 2012 FIBROSIS INHIBITOR Japan Society for Dialysis Therapy in 2004. The number of dialysis patients was 35,000, up 3.2% from the previous year, TECHNICAL FIELD and increasing each year. 0006. At present, there is no radical therapeutic method for 0001. The present invention relates to agents for treating completely curing fibrotic diseases. The reason is that the or preventing fibrotic diseases, and uses thereof. cause and pathogenesis is not understood. Presently, the pur pose of treatment is to improve patients’ quality of life (QOL) BACKGROUND ART through maintaining relief from Symptoms by controlling the 0002 Fibrosis is an uncontrolled wound healing response. activeness of the disease. The ultimate form of treatment is An injured tissue is repaired by replacing damaged cells with dialysis or organ transplantation. However, these therapeutic cells of the same type, but occasionally, parenchymal tissues methods significantly impair patients QOL, and many cases are replaced by connective tissues. In Such cases, fibroblasts show complications and recurrence of fibrosis in a trans become activated and differentiate into myoblasts, leading to planted organ. Pathologically, fibrotic diseases are character synthesis, deposition, formulation, and remodeling of the ized by overaccumulation of extracellular matrix Such as extracellular matrix. This results in fibrosis. Chronic fibrotic collagen. The overactivation of fibroblasts is recently disease is a general term for the terminal stage of chronic assumed to be the major cause of the overaccumulation. Thus, inflammatory conditions that can develop in various organs, fibroblasts are drawing attention as a therapeutic target. and is accompanied by excessive tissue fibrosis. Chronic 0007 Currently, as candidate therapeutic agents for fibrotic disease includes, for example, cirrhosis of the liver fibrotic diseases, hope is placed on adrenal cortical steroids, and sclerosis of the kidney. Furthermore, these fibrotic dis colchicine, IL-10, and the like, which Suppress chronic eases progress into organ failure or cancer (Non-patent Docu inflammation: TGF-B inhibitors, HGF (suppressing the activ ment 1). ity of TGF-B), endothelin inhibitors, angiotensin inhibitors, 0003. A colonic disease known to involve fibrosis is and such, which activate fibroblasts; matrix metalloprotein Crohn's disease, which has been designated as a specified ase (MMP) which degrades collagen, etc. However, none has disease by the Ministry of Health, Labor, and Welfare of lead to an established therapeutic method. Japan. Crohn's disease has been defined as “a disease of 0008 ER-TR7 is a rat monoclonal antibody against non uncertain etiology mostly seen in young Subjects, which lymphocytic cells of mouse thymus, which was produced by involves granulomatous inflammatory focus with fibrosis and Van Vliet et al. in 1984 (Non-patent Document 2). ER-TR7 ulcers, can affect any part of the gastrointestinal tract from the has been reported as an antibody that recognizes reticular oral cavity to anus, and may also affect areas other than the fibroblasts (Non-patent Document 3), and is commercially gastrointestinal tract (specifically skin). Most lesion areas available from several Suppliers as a connective tissue marker have longitudinal ulcers, cobblestone appearances, or aphtha for various organs. However, the antigen is yet unidentified. in the Small or large intestine, or both. Crohn's disease is Recently, it was reported that, when contacted with lympho categorized into disease types such as longitudinal ulcer type cytes, lymph node fibroblastic reticular cells contribute to the and cobblestone appearance type, or Small intestine type, immunological function by secreting ER-TR7 antigen as an Small/large intestine type, and large intestine type according extracellular matrix to make a reticular meshwork (Non to the location of Stenosis. Common symptoms include patent Document 4). abdominal pain, diarrhea, weight loss, fever, and anal lesions. 0009. Non-patent Document 1 Wynn T. A. J. Clin. Occasionally, the disease may show symptoms similar to Invest., (2007) 117: 524-529 those of appendicitis, ileus, intestinal perforation, or massive 0010 Non-patent Document 2 Van Vliet E. et al., Eur. J. bleeding. Alternatively, the disease may develop with anal Immunol., (1984) 14:524-529 lesions or fever, without abdominal symptoms. Extragas 0011 Non-patent Document 3 Van Vliet E. et al., J. His trointestinal complications include anemia, hypoproteine tochem. Cytochem., (1986) 34: 883-890 mia, ankylosing spondylitis, aphthous stomatitis, erythema 0012 Non-patent Document 4 Katakai T. et al., J. Exp. nodosum, pyoderma gangrenosum, iritis, and growth disor Med., (2004) 200: 783-795 ders. 0004. In Japan, the former Ministry of Health and Welfare DISCLOSURE OF THE INVENTION set up a study group in 1975, defined diagnostic criteria for Crohn's disease, and implemented a nationwide Survey. The Problems to be Solved by the Invention number of patients has been increasing every year since the 0013 An objective of the present invention is to provide start of the survey. The number of Medical Care Certificates agents that can Suppress tissue fibrosis, which are useful in issued was 128 in 1976, but was increased to 24,396 in 2007. treating or preventing fibrotic diseases. The most common age at onset ranges from 20 to 24 in men, and 15 to 19 in women. The male-to-female ratio is about 2:1. Means for Solving the Problems Thus, Crohn's disease is more common in men. 0005. As for other chronic fibrotic diseases, carriers of 0014. The present inventors suspected that ER-TR7, a hepatitis virus, which is a major cause of progression to monoclonal antibody that has been used as a fibrosis marker, cirrhosis, are estimated to be 1,200,000 to 1,400,000 for type may neutralize fibrosis-enhancing Substances and thus have B and 1,000,000 to 2,000,000 for type C, according to blue the effect of Suppressing fibrosis. The present inventors car ribbon panel report on hepatitis countermeasures presented in ried out research based on this assumption and as a result, 2001. Furthermore, the number of patients who undergo discovered that ER-TR7 can suppress fibrosis. Thus, the dialysis due to chronic renal failure caused by kidney fibrosis present invention was completed. ER-TR7 and functionally was approximately 250,000 according to the fundamental equivalent Substances are effective fibrosis-Suppressing Survey on chronically-dialyzed patients conducted by the agents treating or preventing fibrosis. US 2012/0231 019 A1 Sep. 13, 2012 0015 The present invention relates to agents for suppress of intestinal length measurement in a control group, and ing fibrosis and therapeutic agents for fibrotic diseases com ulcerative colitis model groups (untreated and ER-TR7 prising the agents as an active ingredient, more specifically, treated). provides the following: 0032 FIG. 4 shows the suppression of fibrosis marker 001 6 1 a fibrosis-suppressing agent comprising gene expression as a result of ER-TR7 administration in ER-TR7 or a functionally equivalent substance as an active ulcerative colitis model mice. (1) to (3) show alterations in the ingredient; expression levels of C-SMA, TNFC., and type 1 collagen, 0017 2 the agent of 1, wherein the substance has an respectively, determined by qPCR.
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