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39000:2039),46KA61M 1/3472 (2013.01); Too A61M (2939), I/3486 Phagocytosise., and Killingcee of Staphylococcus EN USO09567568B2 (12) United States Patent (10) Patent No.: US 9,567,568 B2 MeVOrach (45) Date of Patent: Feb. 14, 2017 (54) METHOD OF PREPARING APOPTOTIC 4,801,531 A 1/1989 Frossard MONOCYTES 4,838,852 A 6, 1989 Edelson et al. 4,879,219 A 11/1989 Wands et al. 5,011,771 A 4, 1991 Bellet et al. (71) Applicant: Enlivex Therapeutics Ltd., Jerusalem 5, 192,659 A 3, 1993 Simons (IL) 5,272,057. A 12/1993 Smulson et al. 5,281.521 A 1/1994 Trojanowski et al. (72) Inventor: Dror Mevorach, Jerusalem (IL) 5,591.457 A 1, 1997 Bolton 5,951,509 A 9, 1999 Morris (73) Assignee: ENTYES THERAPEUTICS LTD., 6,219,5845,985,914 B1A 11/19994/2001 ZeldLee is et al. Jerusalem (IL) 6,354.297 B1 3/2002 Eiseman 6,607,722 B2 8, 2003 Edelson et al. (*) Notice: Subject to any disclaimer, the term of this 7,109,031 B2 9, 2006 Edelson et al. patent is extended or adjusted under 35 7,989,203 B2 * 8/2011 Albert ................ A61K 39,0008 U.S.C. 154(b) by 0 days. 435,347 2005, OO31618 A1 2/2005 Mevorach (21) Appl. No.: 14/499,279 2005/0202098 A1 9, 2005 Mevorach (22) Filed: Sep. 29, 2014 FOREIGN PATENT DOCUMENTS O O WO WO 97,387O7 10, 1997 (65) Prior Publication Data WO WO 99.35493 7, 1999 WO WO O2/060376 8, 2002 US 2015/OO56678 A1 Feb. 26, 2015 WO WO 2006/117786 11 2006 Related U.S. Application Data OTHER PUBLICATIONS (62) Division of application No. 11/121,048, filed on May ck 4, 2005, now abandoned. Rs."eldenreich, S., et al. J. "No..... ImmunOl. ;159: (51) Int. Cl Bohnenkamp, H.R., et al. J. Immunol. Methods 2004:294:67-80.* we Abboud CN, et al. (2000) In: Hoffman ea, ed. Hemotology, Basic CI2N 5/0786 (2010.01) Principles and Practice London: Churchill Livingstone, 22-244. A6 IK 35/5 (2015.01) Accorsi et al. (2001) "Large Volume Leukapheresis With AMICUS A6 IK 35/26 (2015.01) Cell Separator in Peripheral Blood Stem Cell Autologous Trans A6 IK 39/00 (2006.01) plant'. Transfusion and Apheresis Science, 24:79-83. Albert ML, et al. (1998) Dendritic cells acquire antigen from A6M I/34 (2006.01) apoptotic cells and induce class I-restricted CTLS. Nature; 392 A6 IK 4I/00 (2006.01) (6671):86-9. CI2N I3/00 (2006.01) Andrade et al., (2000) Apoptosis in Systemic lupus erythematosus. A61 M 1/36 (2006.01) Clinical implications. Rheum Dis Clin North Am 26 (2): 215-27. (52) U.S. Cl. Andreietal. (1999) “The Secretory Route of the Leaderless Protein CPC ............. CI2N 5/0645 (2013.01); A61K 35/15 Interleukin 1 p Involves Exocytosis of Endolysosome-Related (2013.01); A61K 35/26 (2013.01); A61 K Vesicles'. Molecular Biology of the Cell, 10:1463-1475. 39000:2039),46KA61M 1/3472 (2013.01); too A61M (2939), I/3486 phagocytosisE., and killingCEE of Staphylococcus EN"E" aureus'. Infect Immun; (2014.02): CI2N 13/00 (2013.01); A61 K 69 (3): 1287-97. 2039/515 (2013.01); A61M 1/3681 (2013.01): Bergmann MW, et al. (2001) “The proteosome inhibitor, P.S.-341 CI2N 2500/90 (2013.01) inhibits growth, induces apoptosis and overcomes drug resistance in (58) Field of Classification Search humah multiple myeloma cells”. Cancer Research; 61:3071-6. None Beyth et al. (2005) “Human Mesenchymal Stem Cells Alter Anti See application file for complete search history. E. st Mayon and Induce T-Cell Unresponsive neSS, Slood, : (56) References Cited (Continued) U.S. PATENT DOCUMENTS Primary Examiner — Gerald R Ewoldt 3,791932 A 2f1974 Schuurs et al. 3.74). Att ZC. , i.Agent, Sara,or Firm —LP Marka S. Cohen;Ole PearlEa 3,839,153 A 10, 1974 Schuurs et al. s 3,850,578 A 11/1974 McConnell 3,850,752. A 1 1/1974 Schuurs et al. (57) ABSTRACT 332; A 13: Ply A method of isolating monocyte populations of cells and 3,879,262 A 4, 1975 Schuurs et al. inducing apoptos1s 1n these populations without production 3,901,654 A 8, 1975 Gross of pro-inflammatory mediators is disclosed. The method 3,935,074 A 1/1976 Rubenstein et al. comprises isolating the monocytes and, Subjecting them to E. A g 2. f:A 1 Substrate-adherence and serum deprivation conditions. 4034,074 A 7, 1977 an et al. Apoptotic monocytes as prepared are useful for treating 4,098,876 A 7, 1978 Piasio et al. inflammation-associated diseases. 4,666,828. A 5/1987 Gusella 4,683.202 A 7, 1987 Mullis 2 Claims, 12 Drawing Sheets US 9,567,568 B2 Page 2 (56) References Cited Lauber et al., (2003) “Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal.” Cell 113 (6): 717-30. OTHER PUBLICATIONS Licht et al. (2004) “Decreased Phagocytosis of Apoptosis of Burgstaler et al. (2004) “Hematopoietic Progenitor Cell Large Apoptotic Cells in Diseased SLE Mice'. Journal of Autoimmunity, Volume Leukapheresis (LVL) on the Fenwal Amicus Blood Sepa 22: 139-145. rator'. Journal of Clinical Apheresis, 19:103-111. Liu et al. (2002) “Immune Tolerance After Delivery of Dying Cells Caricchio et al., (2003) “Ultraviolet B Radiation-Induced Cell to Dendritic Cells In Situ”, J Exp Med, 196: 1091-1097. Death: Critical Role of Ultraviolet Dose in Inflammation and Lupus Autoantigen Redistribution'. The Journal of Immunology 171: Mackenzie A.et al. (2001) “Rapid secretion of interleukin-1beta by 5778-5786. microvesicle shedding.” Immunity; 15 (5):825-35. Chang et al. (2001) "Mammalian MAP Kinase Signalling Cas Mangan et al. (1991) “Differential Regulation of Human Monocyte cades', Nature, 410:37-40. Programmed Cell Death (Apoptosis) by Chemotactic Factors and Chen et al., (2001) "TGF-beta released by apoptotic T cells con Pro-Inflammatory Cytokines'. 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(1998) “Interleukin-1, interleukin-1 receptors and system: Bcl-2, BH3—only proteins and more.” Annu Rev Immunol interleukin-1 receptor antagonist.” Int Rev Immunol; 16 (5-6):457 21:71-105. 99. Matthew et al. (1998) “Dendritic Cells Acquire Antigen From Elhalel et al.(2003) “CTLA-4. FasL Induces Alloantigen-Specific Apoptotic Cells and Induce Class IRestricted CTLs”. Nature, Hyporesponsiveness'. The Journal of Immunology, 170: 5842 392:86-89. 5850. Fadok et al. (1992) “Exposure of Phosphatidylserine on the Surface Mevorach (1999) “The Immune Response to Apoptotic Cells'. of Apoptotic Lymphocytes TriggerS Specific Recognition and Annals of the N.Y. Academy of Sciences, 887: 191-198. Abstract. Removal by Macrophages'. The Journal of Immunology, Mevorach (2000) "Opsonization of Apoptotic Cells. Implications 148(7):2207-2216. for Uptake and Autoimmunity”. Annals of the N.Y. Academy of Fadok et al. (1998)"Macrophages That Have Ingested Apoptotic Sciences, 926: 226-235. Abstract. Cells in Vitro Inhibit Proinflammatory Cytokine Production Zanke BWet al. (1996) “The stress-activated protein kinase path Through Autocrine/Paracrine Mechanisms Involving TGF-p, PGE2. way mediates cell death following injury induced by cis-platinum, and PAF'. Journal of Clinical Investigation, 101(4):890-898. UV irradiation or heat.” Curr Biol; 6 (5):606-13. Fahy RJ, et al. (1999) “Spontaneous human monocyte apoptosis Mevorach et al. (1998) "Systemic Exposure to Irradiated Apoptotic utilizes a caspase-3-dependent pathway that is blocked by endotoxin Cells Induces Autoantibody Production”, J Exp Med, 188(2): 387 and is independent of caspase-1.” J Immunol; 163 (4): 1755-62. 392. 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