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(19) TZZ _¥_T (11) EP 2 984 163 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C12N 5/071 (2010.01) C12N 5/078 (2010.01) 01.02.2017 Bulletin 2017/05 (86) International application number: (21) Application number: 15729886.0 PCT/GB2015/051673 (22) Date of filing: 09.06.2015 (87) International publication number: WO 2015/189587 (17.12.2015 Gazette 2015/50) (54) IMMUNO-MODULATORY PROGENITOR (IMP) CELL IMMUNMODULATORISCHE VORLÄUFERZELLE CELLULE PROGÉNITRICE IMMUNO-MODULATRICE (IMP) (84) Designated Contracting States: (56) References cited: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB • ABDI REZA ET AL: "Immunomodulation by GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO mesenchymal stem cells: a potential therapeutic PL PT RO RS SE SI SK SM TR strategy for type 1 diabetes", DIABETES, Designated Extension States: AMERICAN DIABETES ASSOCIATION, US, vol. BA ME 57, no. 7, 1 July 2008 (2008-07-01), pages Designated Validation States: 1759-1767, XP008098188, ISSN: 0012-1797, DOI: MA 10.2337/DB08-0180 • HEBA ABDELRAZIK ET AL: "Mesenchymal stem (30) Priority: 12.06.2014 GB 201410504 cells expanded in human platelet lysate display a decreased inhibitory capacity on T- and NK-cell (43) Date of publication of application: proliferation and function", EUROPEAN 17.02.2016 Bulletin 2016/07 JOURNAL OF IMMUNOLOGY, vol. 41, no. 11, 1 November 2011 (2011-11-01), pages 3281-3290, (73) Proprietor: Cell Therapy Limited XP55053525, ISSN: 0014-2980, DOI: Swansea SA2 8PP (GB) 10.1002/eji.201141542 • CAPELLI C ET AL: "Human platelet lysate allows (72) Inventors: expansion and clinical grade production of • REGINALD, Ajan mesenchymal stromal cells from small samples Swansea of bone marrow aspirates or marrow filter West Glamorgan SA2 8PP (GB) washouts", BONE MARROW • EVANS, Martin John TRANSPLANTATION, NATURE PUBLISHING Swansea GROUP, GB, vol. 40, no. 8, 1 October 2007 West Glamorgan SA2 8PP (GB) (2007-10-01), pages785-791, XP002545732, ISSN: • SULTAN, Sabena 0268-3369, DOI: 10.1038/SJ.BMT.1705798 Swansea [retrieved on 2007-08-06] cited in the application West Glamorgan SA2 8PP (GB) • KARUSSIS ET AL: "Immunomodulation and neuroprotectionwith mesenchymal bone marrow (74) Representative: Wilkinson, Marc George stem cells (MSCs): A proposed treatment for J A Kemp multiple sclerosis and other 14 South Square neuroimmunological/neurodegenerative Gray’s Inn diseases", JOURNAL OF NEUROLOGICAL London WC1R 5JJ (GB) SCIENCES, ELSEVIER SCIENTIFIC PUBLISHING CO, AMSTERDAM, NL, vol. 265, no. 1-2, 11 January 2008 (2008-01-11), pages 131-135, XP022419440, ISSN: 0022-510X Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 984 163 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 984 163 B1 • YOO K H ET AL: "Comparison of • "ESGCT and FSGT Collaborative Congress immunomodulatory properties of mesenchymal Helsinki, Finland September 17-20, 2015 stem cells derived from adult human tissues", Abstracts", HUMAN GENE THERAPY, 17 CELLULAR IMMUNOLOGY, ACADEMIC PRESS, September 2015 (2015-09-17), XP055215257, SAN DIEGO, CA, US, vol. 259, no. 2, 1 January ISSN: 1043-0342, DOI: 2009 (2009-01-01), pages 150-156, XP026614283, 10.1089/hum.2015.29008.abstracts ISSN: 0008-8749, DOI: 10.1016/J.CELLIMM.2009.06.010 [retrieved on 2009-06-23] • KAREN ENGLISH: "Mechanisms of mesenchymal stromal cell immunomodulation", IMMUNOLOGY AND CELL BIOLOGY, vol. 91, no. 1, 23 October 2012 (2012-10-23), pages 19-26, XP55208784, ISSN: 0818-9641, DOI: 10.1038/icb.2012.56 • ALMA J NAUTA AND WILLEM E FIBBE: "Hnmunomodulatoryproperties of mesenchymal stromal cells", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 110, no. 10, 1 November 2007 (2007-11-01), pages 3499-3506, XP007913721, ISSN: 0006-4971, DOI: 10.1182/BLOOD-2007-02-069716 [retrieved on 2007-07-30] 2 EP 2 984 163 B1 Description Field of the Invention 5 [0001] The invention relates to immuno-modulatory progenitor (IMP) cells and their use in therapy. Background to the Invention [0002] Mesodermal cells are derived from a number of tissues and act as the supportive structure for other cell types. 10 Bone marrow for instance is made of both haematopoietic and mesenchymal derived cells. Two principle mesenchymal cell types have been previously described and characterized, namely (i) mesenchymal stem cells (MSCs) and their precursors and (ii) mesenchymal precursor cells (MPCs) found in the bone marrow. Mesenchymal stem cells (MSCs) are multipotent, adult stem cells. MSCs differentiate to form the different specialised cells found in the skeletal tissues. For example, they can differentiate into cartilage cells (chondrocytes), bone cells (osteoblasts) and fat cells (adipocytes). 15 [0003] MSCs are used in a variety of therapies, such as the treatment of Age-related Macular Degeneration (AMD) and myocardial infarct. Once administered to the patient, the MSCs typically migrate (or home) to the damaged tissue and exert their therapeutic effects through paracrine signaling and by promoting survival, repair and regeneration of the neighbouring cells in the damaged tissue. [0004] Current therapies typically involve the infusion of a mixture of MSC subtypes some of which do not migrate 20 efficiently to the tissue of interest. This necessitates the use of a high cell-dose which can lead to off-target side effects and volume-related side effects. MSCs are typically obtained from bone marrow and so it is difficult to obtain large amounts. Summary of the Invention 25 [0005] This invention relates to a novel cell type that has not been previously identified or isolated, the immuno- modulatory progenitor cell. This IMP cell is quite distinct and different to both MSCs and MPCs in its composition, function and characteristics which impart an enhanced immuno-modulatory capacity. [0006] The inventors have surprisingly identified a new immuno-modulatory progenitor (IMP) cell having a specific 30 marker expression pattern. In particular, the IMP cell expresses on its surface MIC A/B, CD304 (Neuropilin 1), CD178 (FAS ligand), CD289 (Toll-like receptor 9), CD363 (Sphingosine-1-phosphate receptor 1), CD99, CD181 (C-X-C chem- okine receptor type 1; CXCR1), epidermal growth factor receptor (EGF-R), CXCR2 and CD126, The IMP cell expresses significantly greater amounts of these markers on its surface than a mesenchymal stem cell (MSC). The IMP cells of the invention can be isolated from mononuclear cells (MCs), such as peripheral blood MCs. The IMP cells are capable 35 of efficiently migrating to and repairing damaged tissues. In particular, they are capable of homing, adherence, trans- migration, proliferation, angiogenic effects and paracrine signalling. Accordingly, the invention provides an immuno- modulatory progenitor (IMP) cell, wherein the cell expresses on it surface detectable levels of MIC A/B, CD304 (Neuropilin 1), CD178 (FAS ligand), CD289 (Toll-like receptor 9), CD363 (Sphingosine-1-phosphate receptor 1), CD99, CD181 (C- X-C chemokine receptor type 1; CXCR1), epidermal growth factor receptor (EGF-R), CXCR2 and CD126. 40 [0007] The invention also provides: - a population of two or more IMP cells of the invention; - a population of immuno-modulatory progenitor (IMP) cells, wherein 45 (i) at least 90% of the cells in the population express on their surfaces detectable levels of MIC A/B, (ii) at least 60% of the cells in the population express on their surfaces detectable levels of CD304 (Neuropilin 1), (iii) at least 45% of the cells in the population express on their surfaces detectable levels of CD178 (FAS ligand), (iv) at least 10% of the cells in the population express on their surfaces detectable levels of CD289 (Toll-like receptor 9), 50 (v) atleast 15%of the population express on their surfaces detectable levels of CD363 (Sphingosine-1-phosphate receptor 1), (vi) at least 20% of the cells in the population express on their surfaces detectable levels of CD99, (vii) at least 80% of the cells in the population express on their surfaces detectable levels of CD181 (C-X-C chemokine receptor type 1; CXCR1), 55 (viii) at least 30% of the cells in the population express on their surfaces detectable levels of epidermal growth factor receptor (EGF-R), (xi) at least 60% of the cells in the population express on their surfaces detectable levels of CXCR2 and (x) at least 5% of the cells in the population express on their surfaces detectable levels of CD126; 3 EP 2 984 163 B1 - a pharmaceutical composition comprising (a) an IMP cell of the invention or a population of the invention and (b) a pharmaceutically acceptable carrier or diluent, one or more liposomes and/or one or more microbubbles; - a method of producing a population of IMP cells of the invention, comprising (a) culturing mononuclear cells (MCs) for from 15 to 25 days in a medium comprising platelet lysate, at less than 20% oxygen (O 2) and under conditions 5 which allow the IMP cells to adhere to induce the MCs to differentiate into IMP cells and (b) harvesting and culturing those IMP cells which have an expression pattern as defined above and thereby producing a population of the invention; - a population of the invention or a pharmaceutical composition of the invention for use in a method of repairing a damaged tissue in a patient; and 10 - a population of the invention or a pharmaceutical composition of the invention for use in a method of treating a cardiac, bone, cartilage, tendon, ligament, liver, kidney or lung injury or disease in a patient.
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    Code lists Page 1 Code lists AESEV Page 2 AESEV Codelist Name: Severity/Intensity Scale for Adverse Events Description: A scale that defines the degree or state of disease existing in a patient as a result of the occurrence of an adverse event. (NCI) C41338,1; Grade 1 C41339,2; Grade 2 C41340,3; Grade 3 AGEU Page 3 AGEU Codelist Name: Age Unit Description: Those units of time that are routinely used to express the age of a subject. C25301,Days C25529,Hours; h; hr C29846,Month C29844,Week C29848,Year CMDOSFRM Page 4 CMDOSFRM Codelist Name: Concomitant Medication Dose Form Description: A terminology subset of the CDISC SDTM Pharmaceutical Dosage Form codelist created for CDASH Concomitant Medication Dose Form codelist. (NCI) C42887,AEROSOL; aer C25158,CAPSULE; cap C28944,CREAM; C42933,GAS; C42934,GEL; C42966,OINTMENT; oint C42968,PATCH; C42972,POWDER; C42989,SPRAY; C42993,SUPPOSITORY; supp C42994,SUSPENSION; susp C42998,TABLET; tab CMDOSFRQ Page 5 CMDOSFRQ Codelist Name: Concomitant Medication Dosing Frequency per Interval Description: A terminology subset of the CDISC SDTM Frequency codelist created for CDASH Concomitant Medication Dosing Frequency per Interval codelist. (NCI) C64496,BID; BD; Twice per day C64499,PRN; As needed C25473,QD; Daily C64530,QID; 4 times per day C64498,QM; Every Month; Per Month C64525,QOD; Every other day C64527,TID; 3 times per day C17998,UNKNOWN; U; UNK; Unknown CMDOSU Page 6 CMDOSU Codelist Name: Concomitant Medication Dose Units Description: A terminology subset of the CDISC SDTM Unit codelist created for CDASH Concomitant Medication Dose Units codelist. (NCI) C48480,CAPSULE; Capsule Dosing Unit; cap C48155,g; Gram C48579,IU; IE; International Unit C28253,mg; Milligram C28254,mL; Milliliter; cm3 C65060,PUFF; Puff Dosing Unit C48542,TABLET; Tablet Dosing Unit; tab C48152,ug; Microgram; mcg CMROUTE Page 7 CMROUTE Codelist Name: Concomitant Medication Route of Administration Description: A terminology subset of the CDISC SDTM Route codelist created for CDASH Concomitant Medication Route of Administration codelist.
  • Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease

    Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients with Stable Coronary Heart Disease

    Supplementary Online Content Ganz P, Heidecker B, Hveem K, et al. Development and validation of a protein-based risk score for cardiovascular outcomes among patients with stable coronary heart disease. JAMA. doi: 10.1001/jama.2016.5951 eTable 1. List of 1130 Proteins Measured by Somalogic’s Modified Aptamer-Based Proteomic Assay eTable 2. Coefficients for Weibull Recalibration Model Applied to 9-Protein Model eFigure 1. Median Protein Levels in Derivation and Validation Cohort eTable 3. Coefficients for the Recalibration Model Applied to Refit Framingham eFigure 2. Calibration Plots for the Refit Framingham Model eTable 4. List of 200 Proteins Associated With the Risk of MI, Stroke, Heart Failure, and Death eFigure 3. Hazard Ratios of Lasso Selected Proteins for Primary End Point of MI, Stroke, Heart Failure, and Death eFigure 4. 9-Protein Prognostic Model Hazard Ratios Adjusted for Framingham Variables eFigure 5. 9-Protein Risk Scores by Event Type This supplementary material has been provided by the authors to give readers additional information about their work. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Supplemental Material Table of Contents 1 Study Design and Data Processing ......................................................................................................... 3 2 Table of 1130 Proteins Measured .......................................................................................................... 4 3 Variable Selection and Statistical Modeling ........................................................................................