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(12) United States Patent (10) Patent No.: US 9,034,312 B2 Naughton Et Al

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(12) United States Patent (10) Patent No.: US 9,034,312 B2 Naughton Et Al USOO9034312B2 (12) United States Patent (10) Patent No.: US 9,034,312 B2 Naughton et al. (45) Date of Patent: *May 19, 2015 (54) EXTRACELLULAR MATRIX JP 2006-249.031 A 9, 2006 COMPOSITIONS FOR THE TREATMENT OF RU 231 1892 C2 12/2007 CANCER WO 90,02796 A1 3, 1990 WO 95.33821 A1 12/1995 WO 96.39101 A1 12, 1996 (75) Inventors: Gail K. Naughton, San Diego, CA (US); WO O3,073998 A2 9, 2003 Emmett Pinney, San Diego, CA (US) WO 2006/026652 A2 3, 2006 WO 2006/055981 A2 5, 2006 (73) Assignee: Histogen, Inc., San Diego, CA (US) WO WO 2010/0563782006/067633 A2 6,5, 20062010 (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 OTHER PUBLICATIONS U.S.C. 154(b) by 0 days. Chemical Encyclopedia, vol. 2, Editorship Soviet Encyclopedia, M. This patent is Subject to a terminal dis 1990, pp. 432-433 (English Translation). claimer. Barker C.R. et al.; The topoisomerase II-Hsp90 complex. a new chemotherapeutic target?: Int J Cancer, Jun. 1, 2006, 118(11); p. (21) Appl. No.: 12/822,126 2685-2693 (Abstract). Moiseenko, MD VM. “Modern tactics treatment of patients with (22) Filed: Jun. 23, 2010 malignant neoplasms of bone metastases”; (Manual for physicians); Oncology Institute, Petrova RU, Dec. 21, 2012, 8 pages: (translation). (65) Prior Publication Data Falanga et al.: “Low Oxygen Stimulates Proliferation of Fibroblasts Seeded as Single Cells'; J. Cell. Physiol., 1993, vol. 154, p. 506-510. US 2011 FOO974O3 A1 Apr. 28, 2011 Falanga et al.: “Low Oxygen Tension Stimulates Collagen Synthesis and COLIAI Transcription Through the Action of TGF-13 I'; J. Cell. (51) Int. Cl. Physiol., 2002, vol. 191, p. 42-50. A6 IK35/12 (2006.01) CI2N5/09 (2010.01) * cited by examiner (52) U.S. Cl. CPC .............. A6IK35/12 (2013.01); C12N5/0693 (2013.01) Primary Examiner – Marcia S Noble (58) Field of Classification Search (74) Attorney, Agent, or Firm — DLA Piper LLP (US) CPC .............................. C12N5/0693: A61K35/12 See application file for complete search history. (57) ABSTRACT (56) References Cited The present invention is directed to methods of inhibiting U.S. PATENT DOCUMENTS cancer cell growth or proliferation by contacting the cancer cell with an extracellular matrix (ECM) composition. Also 5,980,946 A 11/1999 Jones et al. provided are methods of delivering a chemotherapeutic agent 2007/0077232 A1 4/2007 Naughton et al. to a cancer cell by contacting a cancer cell with an extracel 2008, 0220466 A1 9/2008 Fulga et al. lular matrix composition containing a chemotherapeutic agent. Also provided are compositions containing ECM and a FOREIGN PATENT DOCUMENTS chemotherapeutic agent. CA WO95/30423 * 11, 1995 ......... A61K 31,725 JP A 2002-530069 5, 2000 JP A 2007-528252 5, 2006 33 Claims, 18 Drawing Sheets U.S. Patent May 19, 2015 Sheet 1 of 18 US 9,034,312 B2 F.G. 1 O. 0.05 - No treatment treated with ECM U.S. Patent May 19, 2015 Sheet 2 of 18 US 9,034.312 B2 F.G.. 2 0, 5 O S. 9. 0. 4. O 2 C o d S O, 3. O s E O. 2 O untreated U.S. Patent May 19, 2015 Sheet 3 of 18 US 9,034,312 B2 F.G. 3 B 16/CAM 1Sa 0.5 0.4 SD 0.3 E 0.2 % 1 no treatment mixed With On ECM ECM U.S. Patent May 19, 2015 Sheet 4 of 18 US 9,034,312 B2 FIG. 4 C6TUMCAM1 3. O O 5t 250 s B 2 O O 1 5 O 100 5 O to treatent ECM ECM + cjs Cisplatin U.S. Patent May 19, 2015 Sheet 5 of 18 US 9,034,312 B2 F.G. 5 C6 TUMCAM.2 250 - 200 - e 150 - s : 2 100 - : Nott ECM ECMcis cisplatin U.S. Patent May 19, 2015 Sheet 6 of 18 US 9,034,312 B2 F.G. 6A U.S. Patent May 19, 2015 Sheet 7 of 18 US 9,034,312 B2 F.G. 6B U.S. Patent May 19, 2015 Sheet 8 of 18 US 9,034,312 B2 FIG. 7 0.3OO . 0.250 0.200 0.150 : 0.100 0.050 . O.OOO ... Nott ECM ECM+cis Cis U.S. Patent May 19, 2015 Sheet 9 of 18 US 9,034,312 B2 FG 8 FIG s 9 U.S. Patent May 19, 2015 Sheet 10 of 18 US 9,034,312 B2 FIG ... 10 FG ... 11 U.S. Patent May 19, 2015 Sheet 11 of 18 US 9,034,312 B2 F.G. 12 C6 Glioma 1800 600 1400 1. 2 O O 10 OO anOn Notxt an ECM 800 see ECM-CS 600 an CIS 400 200 O |low-on-on day 9 day 15 day 18 U.S. Patent May 19, 2015 Sheet 12 of 18 US 9,034,312 B2 F.G. 13A F.G. 13B U.S. Patent May 19, 2015 Sheet 13 of 18 US 9,034,312 B2 FG 13C FG 13D U.S. Patent May 19, 2015 Sheet 14 of 18 US 9,034,312 B2 F.G. 14 MDA435 Cels 300 250 sa r S 200 8 e amnenO Tct ad s 150 at ECM t E terre ECM-Cis has 100 agoCS day11 day18 day 21 day 25 U.S. Patent May 19, 2015 Sheet 15 of 18 US 9,034,312 B2 F.G. 15 U.S. Patent May 19, 2015 Sheet 16 of 18 US 9,034,312 B2 F.G. 16 BioNeusis treated B16 tumcam 0.9 10mg/mLBNeu B162-3e6/egg 100uL/dose 0.7 0.6 0.5 - O.4 0.3 0.2 0.1 NOTXT BNtt Single dose U.S. Patent May 19, 2015 Sheet 17 of 18 US 9,034,312 B2 F.G. 17 Dose Curve (B16 tumor CAM) O. 8 OO 0.000 No Treatment 1mg/mL. 10mg/ml 100mg/mL U.S. Patent May 19, 2015 Sheet 18 of 18 US 9,034.312 B2 F.G. 18 Tumor inhibition Activity by Molecular Weight 70 50 40 : 30 20 10 : >100K Molecular Weight Fractions of concentrated BN US 9,034,312 B2 1. 2 EXTRACELLULAR MATRIX Accordingly, new materials are needed for soft tissue COMPOSITIONS FOR THE TREATMENT OF repair and augmentation that overcome the deficiencies of CANCER prior materials. The need exists to provide a safe, injectable, long lasting, bioabsorbable, Soft tissue repair and augmenta CROSS REFERENCE TO RELATED tion material. APPLICATION(S) In vitro cultured ECM compositions can additionally be used to treat damaged tissue. Such as, damaged cardiac This application is a continuation-in-part and claims the muscle and related tissue. The compositions are useful as benefit of priority under 35 U.S.C. S 120 of U.S. patent appli implants or biological coatings on implantable devices. Such cation Ser. No. 12/363,479, filed Jan. 30, 2009, and claims the 10 as, Stents or vascular prosthesis to promote vascularization in benefit of priority under 35 U.S.C. S 119(e) of U.S. Ser. No. organs, such as the heart and related tissue. 61/114,966, filed Nov. 14, 2008, the entire content of which is Coronary heart disease (CHD), also called coronary artery incorporated by reference in the disclosure of this application. disease (CAD), ischaemic heart disease, and atherosclerotic heart disease, is characterized by a narrowing of the Small BACKGROUND OF THE INVENTION 15 blood vessels that Supply blood and oxygen to the heart. Coronary heart disease is usually caused by a condition called 1. Field of the Invention atherosclerosis, which occurs when fatty material and plaque The present invention relates generally to use of extracel builds up on the walls of arteries causing the arteries to lular matrix compositions and more specifically, the use of narrow. As the coronary arteries narrow, blood flow to the extracellular matrix compositions to inhibit cell proliferation. heart can slow down or stop, causing chest pain (stable 2. Background Information angina), shortness of breath, heart attack, and other symp The extracellular matrix (ECM) is a complex structural tOmS. entity Surrounding and Supporting cells that are found in vivo Coronary heart disease (CHD) is the leading cause of death within mammalian tissues. The ECM is often referred to as in the United States for men and women. According to the the connective tissue. The ECM is primarily composed of 25 American Heart Association, more than 15 million people three major classes of biomolecules including structural pro have some form of the condition. While the symptoms and teins such as collagens and elastins, specialized proteins such signs of coronary heart disease are evident in the advanced as fibrillins, fibronectins, and laminins, and proteoglycans. state of the disease, most individuals with coronary heart Growth of ECM compositions in vitro and their use in a disease show no evidence of disease for decades as the disease variety of therapeutic and medical applications have been 30 progresses before a Sudden heart attack occurs. The disease is described in the art. One therapeutic application of such ECM the most common cause of Sudden death, and is also the most compositions includes treatment and repair of soft tissue and common reason for death of men and women over 20 years of skin defects such as wrinkles and Scars. age. According to present trends in the United States, half of The repair or augmentation of soft tissue defects caused by healthy 40-year-old males will develop CHD in the future, as defects.
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