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United States Patent (10) Patent No.: US 9,587,016 B2 Lipson (45) Date of Patent: Mar

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United States Patent (10) Patent No.: US 9,587,016 B2 Lipson (45) Date of Patent: Mar USOO9587016B2 (12) United States Patent (10) Patent No.: US 9,587,016 B2 Lipson (45) Date of Patent: Mar. 7, 2017 (54) TREATMENT METHOD FOR LUNG WO WO O3,053,340 A1 T 2003 REMODELING DSEASES WO WO 2008/070117 * 6, 2008 WO WO 2009,026428 A1 2, 2009 (71) Applicant: FibroGen, Inc., San Francisco, CA WO WO 2011/056234 A1 5, 2011 (US) OTHER PUBLICATIONS (72) Inventor: Kenneth E. Lipson, San Mateo, CA Ahmed, M.S., et al., “Induction of Pulmonary Connective Tissue (US) Growth Factor in Heart Failure is Associated With Pulmonary Assignee: FIBROGEN, INC., San Francisco, CA Parenchymal and Vascular Remodeling.” Cardio. Res. (2007) (73) T4:323,333. (US) Bhatt, N., et al., “Promising Pharmacologic Innovations in Treating (*) Notice: Subject to any disclaimer, the term of this Pulmonary Fibrosis,” Current Opin in Pharm. (2006) 6:284-292. patent is extended or adjusted under 35 Guha, M., “Specific Down-Regulation of Connective Tissue U.S.C. 154(b) by 0 days. Growth Factor Attenuates Progression of Nephropathy in Mouse Models of Type 1 and Type 2 Diabetes.” FASEB Jour. (2007) 21:1-14. (21) Appl. No.: 14/741,747 Kondo, S., et al., “Characterization of a Mouse tgf3'-UTR Segment That Mediates Repressive Regulation of Gene Expression.” Biochem. & Biophys, Res. Comm. (2000) 278: 119-124. (22) Filed: Jun. 17, 2015 Kothapalli. D., “Transforming Growth Factor B Induces Anchor age-Independent Gwoth of NRK Fibroblasts via a Connective Tissue Growth Factor-Dependent Signaling Pathway,” Cell (65) Prior Publication Data Growth & Differ. (1997), vol. 8:61-68. Lai, T.-C., et al., “Small Interfering RNAs (siRNAs) Targeting US 2015/037627O A1 Dec. 31, 2015 TGF-B1 mRNA Suppress Asbestos-Induced Expression of TGF-B1 and CTGF in Fibroblasts,” J. Environ. Path. (2009) 28(2):109-119. Related U.S. Application Data Li, C., et al., “Role of Connective Tissue Growth Factor (IGFBP-8) in Radiation-Induced Lung Fibrosis (RILF).” Inter. Jour. Rad. (63) Continuation of application No. 13/883,521, filed as Oncol. (2008) vol. 72, No. 1 (Abstract). application No. PCT/US2011/059589 on Nov. 7, Ostrau, C., et al., "Lovastatin Attenuates Ionizing Radiation-In 2011, now abandoned. duced Normal Tissue Damage In Vivo.” Radio, & Oncol. (2009) (60) Provisional application No. 61/456,370, filed on Nov. 92:492-499. 5, 2010. Ponticos, M., et al., “Pivotal Role of Connective Tissue Growth Factor in Lung Fibrosis.” Arthritis & Rheumat. (2009) vol. 60, (7):2142-2155. (51) Int. C. Shimo, T., “Inhibition of Endogenous Expression of Connective A 6LX 39/395 (2006.01) Tissue Growth Factor by Its Antisense Oligonucleotide and Anti C07K 6/22 (2006.01) sense RNA Suppresses Proliferation and Migration of Vascular A6 IK 45/06 (2006.01) Endothelial Cells,” J. Biochem (1998) 124:130-140. A61 K 39/00 (2006.01) Thannickal, V., et al., “Idiopathic Pulmonary Fibrosis: Emerging (52) U.S. C. Concepts on Pharmacotherapy.” Expert Opin. Pharmacosher. (2004) CPC .......... C07K 16/22 (2013.01); A61K 39/3955 5(8): 1671-1686. (2013.01); A61K 45/06 (2013.01); A61 K Uchio, K., et al., “Down-Regulation of Connective Tissue Growth 2039/505 (2013.01); C07K 2317/24 (2013.01); Factor and Type 1 Collagen mRNA Expression by Connective C07K 2317/76 (2013.01) Tissue Growth Factor Antisense Olignocleotide During Experimen (58) Field of Classification Search tal Liver Fibrosis' Woudn Repair Regen (2004) : 60-66. None (Continued) See application file for complete search history. Primary Examiner — Marianne P Allen (56) References Cited (74) Attorney, Agent, or Firm — FibroGen, Inc.: Leanne U.S. PATENT DOCUMENTS C. Price; Paul Borchardt 6,492,129 B1 12/2002 Grotendorst 7,115,390 B1 10/2006 Grotendorst et al. (57) ABSTRACT 7,405,274 B2 7/2008 Lin et al. 7,871,617 B2 * 1/2011 Lin ........................ CO7K 16/22 The present invention relates to methods and medicaments 424,133.1 useful for pre-treatment, treatment, or amelioration of lung 8,642,034 B2 * 2/2014 Streisand ................... 424,133.1 remodeling disease. Methods and medicaments for reduc 2003/011381.6 A1 6, 2003 Weitz et al. ing, preventing, or reversing increased lung density, improv ing lung function, and increasing Survivability in Subjects FOREIGN PATENT DOCUMENTS having lung remodeling disease are also provided. WO WO 96.38172 A1 12, 1996 WO WOOO,35936 A1 6, 2000 4 Claims, 11 Drawing Sheets US 9,587,016 B2 Page 2 (56) References Cited Bickelhaupt, S., et al., “Attenuation and Reversal of Radiation OTHER PUBLICATIONS Induced Pulmonary Fibrosis in a Murine Model by an Anti-CTGF Monoclonal Antibody.” Int. J. Radiat. Oncol. (2010) 78:Suppl. Williams, J.A., et al., “Effect of Administration of Lovastatin on the (Abstract). Development of Late Pulmonary Effects after Whole-Lung Irradia tion in a Murine Model.” Rad. Res. (2004) 151:560-567 * cited by examiner U.S. Patent Mar. 7, 2017 Sheet 1 of 11 US 9,587,016 B2 CN 3ris88c: . TW at { ringikjor 8 w88ks 2 d c. 12 As w8w axe 28 a PX ea as as y y - d Hi4 & 8 OS 2. & 6 S. 20 22 23, 28 t 6-2 ine weeks) G. A. wS- control --&- irradiated 4 2 4 8 12 16 20 24 26 ine (weeks) Fig. 18 U.S. Patent Mar. 7, 2017 Sheet 2 of 11 US 9,587,016 B2 r:- edera -s fibrosis g J. s {:} (s S. s m t G8 (f FE, C -)- control -Sirradiated -30) ai S -400 $ 35 8g S3 - o 8 -600 ------,Y Ys C -78 |-t-t-t- line (weeks) U.S. Patent Mar. 7, 2017 Sheet 4 of 11 US 9,587,016 B2 (). w can R aw v. & w:- R. C. Ni 8-2 -233 -&- R. C.81; d-3 - C.K 8 -383 E D *x is 400 s i -30 -68 ra-era-Ma-M O 23 300 a;08 Days F.G. 3A U.S. Patent Mar. 7, 2017 Sheet S of 11 US 9,587,016 B2 as no R -$- R, CN; d-2} -200 - {k: ge -800 K gy -4CO Rg c i -508 -60 O 1(O 23 30 a. iDays FG 33 res are r war K.C.Ligg+1 i2. -2}O -300 s 92 400 s c -8. U.S. Patent Mar. 7, 2017 Sheet 6 of 11 US 9,587,016 B2 Week 30 G. &A U.S. Patent Mar. 7, 2017 Sheet 7 of 11 US 9,587,016 B2 Week 30 & oxygen saiutation ung density (ii) ormat saturatics range, & . s- a sea -- so as was --- a ra- ass- Wa Ni w SOO -N S. ..., & Y.: W s &OO O K: & S. s 3CO e 3. 3. h C 8 r &O ga 9. , 2 st2. *G 43 U.S. Patent Mar. 7, 2017 Sheet 9 of 11 US 9,587,016 B2 OC M. CN s e -- R; CLNi; di-2 80- ex a R {f} g 60 . 83 3. AO st ke on kee as or oo & wool o ox w 5G 10) 53 200 253 303 Days U.S. Patent Mar. 7, 2017 Sheet 10 of 11 US 9,587,016 B2 35?). T-cir-corror--oncor-coor-o- ...) -I.aa. s: 90 . - T - S{ . | | | | f | | | | 8 3 - 8. --- - || | | |: | Notoxia iyperoxia korrix}xia hiyperoxia awasawaawaaaaXow -- igg - 3 FA G. S. U.S. Patent Mar. 7, 2017 Sheet 11 of 11 US 9,587,016 B2 2% SO% 28 93% -G, US 9,587,016 B2 1. 2 TREATMENT METHOD FOR LUNG SUMMARY OF THE INVENTION REMODELING DSEASES In one embodiment, the present invention provides a This application is a continuation of U.S. application Ser. method of treating a lung remodeling disease in a Subject, No. 13/883,521 filed 29 Jan. 2014, which claims benefit of 5 the method comprising administering to the Subject an International Application No. PCT/US2011/059589 filed 7 anti-connective tissue growth factor (anti-CTGF) agent, Nov. 2011, which claims the benefit of U.S. Provisional thereby treating the lung remodeling disease. In another embodiment, the present invention provides a method for Application Ser. No. 61/456,370, filed on 5 Nov. 2010, pre-treating a subject at increased probability of being which are hereby incorporated by reference in their entirety. 10 afflicted with a lung remodeling disease to prevent or reduce FIELD OF THE INVENTION a resulting pathological feature of the lung remodeling disease, the method comprising administering to the Subject The present invention relates to methods and medica an anti-CTGF agent, thereby preventing or reducing a result ments useful for treatment of lung remodeling diseases. ing pathological feature of lung remodeling disease. In some 15 embodiments, the anti-CTGF agent is selected from the Methods and medicaments for improving lung function, group consisting of antibodies, antibody fragments, anti reducing lung inflammation, and increasing Survivability in body mimetics, antisense oligonucleotides, siRNA, miRNA, Subjects having a lung remodeling disease are also provided. ribozymes, aptamers and Small molecules. In a preferred embodiment, the anti-CTGF agent for use in these methods BACKGROUND 2O is an antibody that binds specifically to connective tissue growth factor (CTGF). In particular embodiments, the anti Lung remodeling diseases (LRD) are a group of disorders CTGF agent is an antibody that has the same amino acid that lead to progressive loss of function in the alveoli. sequence as the antibody produced by the cell line identified Although the disease typically involves an initial acute by ATCC Accession No. PTA-6006, or is an antibody that inflammatory response, many patients do not seek treatment 25 binds to CTGF competitively with an antibody produced by until the disease has progressed to a more advanced chronic the cell line identified by ATCC Accession No.
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