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(12) United States Patent (10) Patent No.: US 9.498,544 B2 Ennis Et Al

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USOO949854.4B2 (12) United States Patent (10) Patent No.: US 9.498,544 B2 Ennis et al. (45) Date of Patent: Nov. 22, 2016 (54) GENETICALLY MODIFIED HUMAN (56) References Cited UMIBILICAL CORD PERVASCULAR CELLS FOR PROPHYLAXIS AGAINST OR U.S. PATENT DOCUMENTS TREATMENT OF BIOLOGICAL, OR 5,158,867 A 10/1992 McNally et al. CHEMICAL AGENTS 5,919,702 A 7/1999 Purchio et al. 6,132,724 A 10/2000 Blum (71) Applicant: Tissue Regeneration Therapeutics 7,122,178 B1 10/2006 Simmons et al. 7,547,546 B2 6/2009 Davies et al. Inc., Toronto (CA) 2003.0161818 A1 8, 2003 Weiss et al. 2004/O136967 A1 7/2004 Weiss et al. 2004/O137612 A1 7/2004 Baksh et al. (72) Inventors: Jane Elizabeth Ennis, Oakville (CA); 2005/OO 19911 A1 1/2005 Gronthos et al. Jeffrey Donald Turner, 2005, 0148074 A1 7/2005 Davies et al. Chute-a-Blondeau (CA); John Edward 2005/O158289 A1 7/2005 Simmons et al. Davies, Toronto (CA) 2005/0281790 A1 12/2005 Simmons et al. 2006, OOO8452 A1 1/2006 Simmons et al. 2006, O193840 A1 8, 2006 Gronthos et al. (73) Assignee: Tissue Regeneration Therapeutics 2006, O199263 A1 9/2006 Auger et al. Inc., Toronto (CA) 2006/0286O77 A1 12/2006 Gronthos et al. 2007/0134205 A1 6/2007 Rosenberg 2008.0020459 A1 1/2008 Baksh et al. (*) Notice: Subject to any disclaimer, the term of this 2008.0113434 A1 5/2008 Davies et al. patent is extended or adjusted under 35 2009/0047277 A1 2/2009 Reed et al. U.S.C. 154(b) by 0 days. 2009,0269318 A1 10/2009 Davies et al. 2009/0275127 A1 11/2009 Ennis et al. 2009,0285842 A1 11/2009 Davies et al. (21) Appl. No.: 14/657,102 FOREIGN PATENT DOCUMENTS (22) Filed: Mar. 13, 2015 WO WO-01 (11011 A2 2, 2001 WO WO-02/086.104 A1 10, 2002 (65) Prior Publication Data WO WO-2004/072273 A1 8, 2004 WO WO-2004/094599 A2 11/2004 US 2015/O182636 A1 Jul. 2, 2015 WO WO-2005/001076 A2 1, 2005 WO WO-2005/027633 A2 3, 2005 WO WO-2005/038O12 A2 4/2005 WO WO-2005/085428 A1 9, 2005 Related U.S. Application Data WO WO-2006/OO2627 A2 1, 2006 WO WO-2006/O12404 A2 2, 2006 (63) Continuation of application No. 12/988,909, filed as WO WO-2006/O19357 A1 2, 2006 application No. PCT/CA2009/000528 on Apr. 20, WO WO-2007/071048 A1 6, 2007 2009, now Pat. No. 9,005,599. WO WO-2007/099534 A2 9, 2007 (60) Provisional application No. 61/046,630, filed on Apr. WO WO-2007/128115 A1 11, 2007 21, 2008. OTHER PUBLICATIONS (51) Int. Cl. Hu et al. (Vaccine 25, 2007: published online Jan. 22, 2007 A6 IK 4.8/00 (2006.01) 3210-3214).* CI2N 5/073 (2010.01) Aggarwal et al., “Human mesenchymal stem cells modulate C07K 6/10 (2006.01) allogeneic immune cell responses.” Blood 105(4): 1815-1822 A6 IK 35/44 (2015.01) (2005). A6 IK 39/2 (2006.01) Aubin, “Bone stem cells,” J Cell Biochem Suppl. 30-31:73-82 C07K I4/56 (2006.01) (1998). CI2N 5/0775 (2010.01) (Continued) A61 K 35/12 (2015.01) A61 K 39/00 (2006.01) (52) U.S. Cl. Primary Examiner — Scott Long CPC ........... A61K 48/0008 (2013.01); A61K 35/44 (74) Attorney, Agent, or Firm — Clark & Elbing LLP (2013.01); A61K 39/12 (2013.01); C07K 14/56 (2013.01); C07K 16/1081 (2013.01); C12N 5/0605 (2013.01); C12N 5/0668 (2013.01); (57) ABSTRACT A61 K 2035/124 (2013.01); A6 IK 2039/505 The invention provides methods of preventing or treating (2013.01); A61 K 2039/5156 (2013.01); C07K diseases or disorders caused by biological agents or chemi 2317/14 (2013.01); C12N 2510/00 (2013.01); cal agents in a subject (e.g., a mammal. Such as a human) by CI2N 2760/14134 (2013.01); C12N administering genetically modified human umbilical cord 2770/36134 (2013.01) perivascular cells. (58) Field of Classification Search CPC ....... A61K 48/00; C12N 5/073; C07K 16/10 See application file for complete search history. 20 Claims, No Drawings US 9.498.544 B2 Page 2 (56) References Cited Geyer et al., “Plant-derived human butyrylcholinesterase, but not an organophosphorous-compound hydrolyzing variant thereof, pro tects rodents against nerve agents.” Proc Natl Acad Sci U S A. OTHER PUBLICATIONS 107(47):20251-6 (2010). Gronthos et al., “Postnatal human dental pulp stem cells (DPSCs) in Baksh et al., "Comparison of proliferative and multilineage differ vitro and in vivo,” Proc. Natl. Acad. Sci. USA97(25): 13625-13630 entiation potential of human mesenchymal stem cells derived from (2000). umbilical cord and bone marrow,” Stem Cells. 25(6): 1384-1392 Hamada et al., “Mesenchymal stem cells (MSC) as therapeutic (2007). cytoreagents for gene therapy,” Cancer Sci. 96(3):149-156 (2005). Beckstead et al., “Enzyme histochemistry and Haynesworth et al., “Cell-based tissue engineering therapies: the immunohistochemistry on biopsy specimens of pathologic human influence of whole body physiology.” Adv Drug Deliv Rev. 33(1- bone marrow,” Blood. 57(6):1088-98 (1981). 2):3-14 (1998). Beckstead et al., “Enzyme histochemistry on bone marrow biopsies: Hendrickx et al., “Innate immunity to adenovirus.” Hum Gene Ther. reactions useful in the differential diagnosis of leukemia and lym 25(4):265-84 (2014). phoma applied to 2-micron plastic sections.” Blood. 55(3):386-394 Horwitz et al., “Transplantability and therapeutic effects of bone (1980). marrow-derived mesenchymal cells in children with osteogenesis Bianco et al., “Uno, neSSuno e centomila: Searching for the identity imperfecta,” Nat Med. 5(3):309-313 (1999). of mesodermal progenitors.” Exp Cell Res. 251(2):257-63 (1999). Hu et al., “Abundant Progenitor Cells in the Adventitia Contribute Bieback et al., “Critical parameters for the isolation of to Atherosclerosis of Vein Graffs in ApoE-Deficient Mice,” J. Clin. mesenchymal stem cells from umbilical cord blood.” Stem Cells. Invest. 113: 1258-1265 (2004). 22(4):625-634 (2004). Huang et al., “Recombinant human butyrylcholinesterase from milk Blong et al., “Tetramerization domain of human of transgenic animals to protect against organophosphate poison butyrylcholinesterase is at the C-terminus,” Biochem J. 327(Pt ing.” Proc Natl Acad Sci U S A. 104(34): 13603-8 (2007). 3):747-57 (1997). Ilyushin et al., "Chemical polysialylation of human recombinant Brazzolotto et al., “Human butyrylcholinesterase produced in insect butyrylcholinesterase delivers a long-acting bioscavenger for nerve cells: huprine-based affinity purification and crystal structure.” agents in vivo..” Proc Natl Acad Sci U S A. 110(4): 1243-8 (2013). FEBS J. 279(16): 2905-16 (2012). Ilyushin et al., “Recombinant human butyrylcholinesterase as a Can et al., “Concise Review: Human Umbilical Cord Stroma with new-age bioscavenger drug: development of the expression sys Regard to the Source of Fetus-Derived Stem Cells,” Stem Cells tem.” Acta Naturae. 5(1):73-84 (2013). 25:2886-2895 (2007). International Preliminary Report on Patentability and Written Opin Canfield et al., “Osteogenic Potential of Vascular Pericytes' Bone ion of the International Searching Authority for International Appli Engineering, JE Davies, Toronto, EM Squared 143-151 (2000). cation No. PCT/CA2006/002092 issued Jun. 24, 2008 (7 pages). Capasso et al., “The evolution of adenoviral vectors through genetic International Preliminary Report on Patentability and Written Opin and chemical surface modifications,” Viruses. 6(2): 832-55 (2014). ion of the International Searching Authority for International Appli Caplan, "Mesenchymal Stem Cells,” J. Orthop. Res. 9:641-650 cation No. PCT/CA2007/00781 Issued Nov. 11, 2008 (8 pages). (1991). International Preliminary Report on Patentability and Written Opin Chacko and Reynolds, “Architecture of Distended and ion of the International Searching Authority for International Appli Nondistended Human Umbilical Cord Tissues, with Special Refer cation No. PCT/CA2009/000528 issued Oct. 26, 2010 (7 pages). ence to the Arteries and Veins.” Carnegie Institute of Washington, International Search Report for International Application No. PCT/ Contributions to Embryology 237:137-150 (1954). CA2007/00781 mailed Jul. 31, 2007 (5 pages). Chilukuri et al., “Adenovirus-transduced human International Search Report for International Application No. PCT/ butyrylcholinesterase in mouse blood functions as a bioscavenger of CA2009/000528 mailed Jul. 28, 2009 (5 pages). chemical warfare nerve agents.” Mol Pharmacol. 76(3):612-7 Karahuseyinoglu et al., “Functional structure of adipocytes differ (2009). entiated from human umbilical cord stroma-derived stem cells,” Chilukuri et al., “Polyethylene glycosylation prolongs the circula Stem Cells. 26(3):682-691 (2008). tory stability of recombinant human butyrylcholinesterase.” Chem Kogler et al., “A new human Somatic stem cell from placental cord Biol Interact. 157-8:115-21 (2005). blood with intrinsic pluripotent differentiation potential.” J Exp Conget and Minguell, “Phenotypical and Functional Properties of Med. 200(2): 123-135 (2004). Human Bone Marrow Mesenchymal Progenitor Cells,” J. Cell Kronman et al., "Hierarchy of post-translational modifications Physiol. 181:67-73 (1999). involved in the circulatory longevity of glycoproteins. Demonstra Corcione et al., “Human Mesenchymal StemCells Modulate B-Cell tion of concerted contributions of glycan sialylation and Subunit Functions.” Blood 107:367-372 (2006). assembly to the pharmacokinetic behavior of bovine Di Nicola et al., “Human bone marrow stromal cells suppress acetylcholinesterase.” J Biol Chem. 275(38): 29488-502 (2000). T-lymphocyte proliferation induced by cellular or nonspecific Kulkarni et al., “Absence of Wharton's jelly around the umbilical mitogenic stimuli.” Blood. 99(10):3838-3843 (2002). arteries.” Indian J Pediatr. 74(8):787-89 (2007). Djouad et al., “Immunosuppressive Effect of Mesenchymal Stem Li et al., “High-level expression of functional recombinant human Cells Favors Tumor Growth in Allogenic Animals.” Blood butyrylcholinesterase in silkworm larvae by Bac-to-Bac system.” 102:3837-3844 (2003).
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    THETWO TONTTI USTUDIUL 20170267753A1 LUI HI HA UNIT ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2017 /0267753 A1 Ehrenpreis (43 ) Pub . Date : Sep . 21 , 2017 ( 54 ) COMBINATION THERAPY FOR (52 ) U .S . CI. CO - ADMINISTRATION OF MONOCLONAL CPC .. .. CO7K 16 / 241 ( 2013 .01 ) ; A61K 39 / 3955 ANTIBODIES ( 2013 .01 ) ; A61K 31 /4706 ( 2013 .01 ) ; A61K 31 / 165 ( 2013 .01 ) ; CO7K 2317 /21 (2013 . 01 ) ; (71 ) Applicant: Eli D Ehrenpreis , Skokie , IL (US ) CO7K 2317/ 24 ( 2013. 01 ) ; A61K 2039/ 505 ( 2013 .01 ) (72 ) Inventor : Eli D Ehrenpreis, Skokie , IL (US ) (57 ) ABSTRACT Disclosed are methods for enhancing the efficacy of mono (21 ) Appl. No. : 15 /605 ,212 clonal antibody therapy , which entails co - administering a therapeutic monoclonal antibody , or a functional fragment (22 ) Filed : May 25 , 2017 thereof, and an effective amount of colchicine or hydroxy chloroquine , or a combination thereof, to a patient in need Related U . S . Application Data thereof . Also disclosed are methods of prolonging or increasing the time a monoclonal antibody remains in the (63 ) Continuation - in - part of application No . 14 / 947 , 193 , circulation of a patient, which entails co - administering a filed on Nov. 20 , 2015 . therapeutic monoclonal antibody , or a functional fragment ( 60 ) Provisional application No . 62/ 082, 682 , filed on Nov . of the monoclonal antibody , and an effective amount of 21 , 2014 . colchicine or hydroxychloroquine , or a combination thereof, to a patient in need thereof, wherein the time themonoclonal antibody remains in the circulation ( e . g . , blood serum ) of the Publication Classification patient is increased relative to the same regimen of admin (51 ) Int .
  • Selectively Targeting TGF-Β with Trabedersen/OT-101 in Treatment of Evolving and Mild ARDS in COVID-19

    Selectively Targeting TGF-Β with Trabedersen/OT-101 in Treatment of Evolving and Mild ARDS in COVID-19

    Review Article CLINICAL INVESTIGATION Selectively targeting TGF-β with Trabedersen/OT-101 in treatment of evolving and mild ARDS in COVID-19 Abstract Fatih M Uckun1,2*, Based on the role of TGF- β in the immunopathology of ARDS, we and others have proposed the use of Larn Hwang1, Vuong Trieu1 TGF-β inhibitors for the treatment of COVID-19 pneumonia and ARDS. TGF-targeting is employed as a strategy to stimulate the immune system of advanced-stage cancer patients in an attempt to overcome the 1Immuno-Oncology Program, Oncotelic immunosuppression and T-cell exhaustion within the tumor microenvironment. Nevertheless, we do not Inc., Agoura Hills, CA 91301, USA anticipate any worsening of existing ARDS or Cytokine Storm/Cytokine Release Syndrome (CRS) of COVID-19 patients as a treatment-emergent complication with our contemplated use of the anti-TGF-β RNA therapeutic 2COVID-19 Task Force, Worldwide Clinical OT-101. That is because (i) inhibitors of TGF-β signaling are not associated with ARDS, Cytokine Storm/CRS, Trials, Wayne, PA 19087, USA or systemic capillary leak, (ii) OT-101 did not cause any pulmonary toxicity, non-infectious pneumonitis, CRS, systemic or pulmonary capillary leak or ARDS in any of the 61 patients with advanced solid tumors enrolled *Author for correspondence: in Phase I/II study (ClinicalTrials.gov identifier: NCT00844064) who received much longer periods of OT-101 [email protected] therapy, and (iii) OT-101 did not cause in human subjects an elevation of TNF-α, IL-6 or IL-10 levels associated with CRS and ARDS in COVID-19 patients-likewise, OT-101 did not induce production of these inflammatory cytokines in cultures of human white blood cells.
  • WO 2016/176089 Al 3 November 2016 (03.11.2016) P O P C T

    WO 2016/176089 Al 3 November 2016 (03.11.2016) P O P C T

    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/176089 Al 3 November 2016 (03.11.2016) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A01N 43/00 (2006.01) A61K 31/33 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/US2016/028383 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 20 April 2016 (20.04.2016) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 62/154,426 29 April 2015 (29.04.2015) US TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: KARDIATONOS, INC. [US/US]; 4909 DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Lapeer Road, Metamora, Michigan 48455 (US).