DOCSLIB.ORG

WO 2018/156617 A2 30 August 2018 (30.08.2018) W !P O PCT

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
WO 2018/156617 A2 30 August 2018 (30.08.2018) W !P O PCT (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 2018/156617 A2 30 August 2018 (30.08.2018) W !P O PCT (51) International Patent Classification: MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, A61K 47/59 (2017.01) A61K 38/18 (2006.01) TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (21) International Application Number: PCT/US20 18/0 19003 Published: (22) International Filing Date: — without international search report and to be republished 2 1 February 2018 (21 .02.2018) upon receipt of that report (Rule 48.2(g)) (25) Filing Language: English (26) Publication Langi English (30) Priority Data: 62/462,079 22 February 2017 (22.02.2017) US (71) Applicant: THE REGENTS OF THE UNIVERSITY OF MICHIGAN [US/US]; Office of Technology Tran s fer, 1600 Huron Parkway, 2nd Floor, Ann Arbor, Michigan 48109-2590 (US). (72) Inventors: MOON, James J.; c/o The Regents of the University of Michigan, Office of Technology Transfer, 1600 Huron Parkway, 2nd Floor, Ann Arbor, Michigan 48109-2590 (US). FAN, Yuchen; c/o The Regents of the University of Michigan, Office of Technology Transfer, 1600 Huron Parkway, 2nd Floor, Ann Arbor, Michigan 48109-2590 (US). NAM, Jutaek; c/o The Regents of the University of Michigan, Office of Technology Transfer, 1600 Huron Parkway, 2nd Floor, Ann Arbor, Michigan 48109-2590 (US). (74) Agent: GOETZ, Robert A.; Casimir Jones, S.C., 2275 Deming Way, Ste 310, Middleton, Wisconsin 53562 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 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. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, < EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (54) Title: COMPOSITIONS AND METHODS FOR DELIVERY OF POLYMER / BIOMACROMOLECULE CONJUGATES (57) Abstract: The present invention relates to polymers associated with (e.g., complexed, conjugated, encapsulated, absorbed, ad sorbed, admixed) bio macromolecule agents (e.g., peptides, neo-antigens, adjuvant molecules, nucleic acids, etc.) configured for treat 00 ing, preventing or ameliorating various types of disorders, and methods of synthesizing the same. In particular, the present invention is o directed to compositions comprising polymer moieties (e.g., poly(L-glutamic acid moieties)) associated with biomacromolecule agents, methods for synthesizing such polymer conjugates, as well as systems and methods utilizing such polymer conjugates. COMPOSITIONS AND METHODS FOR DELIVERY OF POLYMER / BIOMACROMOLECULE CONJUGATES CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application Number 62/462,079, filed February 22, 201 7, which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was supported by NIH grant EB022563 and Army/MRMC grant W81XWH-1 6-1-0369. The government has certain rights in the invention. FIELD OF THE INVENTION The present invention relates to polymers associated with (e.g., complexed, conjugated, encapsulated, absorbed, adsorbed, admixed) biomacromolecule agents (e.g., peptides, neo-antigens, adjuvant molecules, nucleic acids, etc.) configured for treating, preventing or ameliorating various types of disorders, and methods of synthesizing the same. In particular, the present invention is directed to compositions comprising polymer moieties (e.g., poly(L-glutamic acid moieties)) associated with biomacromolecule agents, methods for synthesizing such polymer conjugates, as well as systems and methods utilizing such polymer conjugates. BACKGROUND OF THE INVENTION Subunit vaccines composed of molecularly defined antigens such as peptides, proteins, or nucleotides can relieve reactogenicity and toxicity often induced by live- attenuated whole-cell or whole-virus vaccines, thus offering a promising approach for vaccine development. However, subunit antigens suffer from low immunogenicity in vivo. Hence, subunit vaccines require additional adjuvants as well as delivery strategies to improve vaccine efficacy. Specifically, oligopeptide antigens are subjected to low draining efficiency to lymphoid tissues from injection sites, while peptide sequences of low aqueous solubility further limit lymphoid draining and raise formulation concerns. To address these challenges, subunit antigens have been encapsulated into nanoparticulate delivery systems or conjugated to biopolymers, resulting in enhanced lymphoid draining due to their high molecular weight and water solubility. However, clinical translation of such approaches have been very limited due to (1) manufacturing challenges of scale-up production of nanoparticles and biopolymers in a reproducible manner; (2) difficulty of reliably synthesizing vaccine platforms incorporated with a wide range of oligopeptide antigens, including personalized cancer neo- antigens; and (3) limited in vivo efficacy to generate cellular and humoral immune responses. Accordingly, there is an unmet medical need for a new generalizable strategy for improving efficacy of oligopeptide antigens. SUMMARY Experiments conducted during the course of developing embodiments for the present invention demonstrated that poly(L-glutamic acid) (PGA) can be readily coupled with antigen (Ag) peptides, including neo-antigens, and adjuvants, producing stable PGA-antigen conjugates that markedly improve Ag/adjuvant co-delivery to lymphoid organs and achieve sustained Ag presentation on dendritic cells. Moreover, it was shown that the PGA platform can be easily adapted to neoantigens, generating potent anti-tumor immunity (see, Example I). Experiments conducted during the course of developing embodiments for the present invention further demonstrated the therapeutic efficacy of a neo-antigen vaccine (peptide antigens and tumor neo-antigens conjugated on PGA polypeptides) tested on a MC38 tumor model (see, Example II). Experiments conducted during the course of developing embodiments for the present invention further demonstrated cancer immunotherapy with PEI- neo-antigen peptide conjugates (see, Example III). Accordingly, the present invention relates to polymers associated with (e.g., complexed, conjugated, encapsulated, absorbed, adsorbed, admixed) biomacromolecule agents (e.g., peptides, neo-antigens, adjuvant molecules, nucleic acids, etc.) configured for treating, preventing or ameliorating various types of disorders, and methods of synthesizing the same. In particular, the present invention is directed to compositions comprising polymer moieties (e.g., poly(L-glutamic acid moieties)) associated with biomacromolecule agents, methods for synthesizing such polymer conjugates, as well as systems and methods utilizing such polymer conjugates. In certain embodiments, the present invention provides compositions comprising a polymer moiety comprising a polymer associated with (e.g., complexed, conjugated, encapsulated, absorbed, adsorbed, admixed) any kind of biomacromolecule agent (e.g., nucleic acid, peptides, glycolipids, etc.). Such embodiments are not limited to a specific type of polymer comprised within the polymer moiety. Indeed, any type or kind of polymer would find use within various embodiments of the present invention. Examples of such polymer moieties include, but are not limited to, poly(L-glutamic acid (PGA), polyethyleneimine (PEI), p ly ga a g amic acid), polygly colic acid, polygly colic acid trimethyl-carbonates, polygly colic acidtrimethyl- carbonates, polygly colides, copolymers of the polylactides and polygly colides, polylactic acid (PLLA), poly(lactic-co-gly colic acid) po y(D L act c-co-g co de) (PLGA), PLGA derivatives, polyacrylic acid, polyethylene glycol (PEG), PEG derivatives, methoxy polyethylene glycol (mPEG), poly(D,L-iactide)-block- o polyethylene glycol (diblock), polyethyleneoxide-propyleneoxide, polyethylene oxide (PEO), polyether esters (e.g., polyethyleneoxide, polyalkeneoxalates, polyorthoesters as well as their copolymers), poly-L-lysine, chitosan, hyaluronic acid, fatty acids, fatty acyls, polyamine, polyvinyl alcohol, polyvinylalcoholes, pol vinyl pyrrolidinone acrylic acid ethylene co-polymer, poly(po ypropy aery acid) (PPAA), polyacrylic acid, methoxy polyethylene, albumin, human serum albumin, cellulose derivatives, cyc dex r s and their derivatives (e.g., including polytryptophan, poiytyrosine, polypropyleneoxide), folate linked cyclodextrin, folate linked cyclodextran, β-cyclodextrines, alginate, carrageenan, pectin, dextran, collagen, collagen-N-hydroxysuccinimide, polyaniline, polyalanine, polytryptophan, poiytyrosine, polyamino acids, amino sugars, glycerolipid, glycerophospholipid, sphinglipid, sterol lipid, prenoi lipid saccarolipid,
Load more

Recommended publications
  • WHO Drug Information Vol. 12, No. 3, 1998
    WHO DRUG INFORMATION VOLUME 12 NUMBER 3 • 1998 RECOMMENDED INN LIST 40 INTERNATIONAL NONPROPRIETARY NAMES FOR PHARMACEUTICAL SUBSTANCES WORLD HEALTH ORGANIZATION • GENEVA Volume 12, Number 3, 1998 World Health Organization, Geneva WHO Drug Information Contents Seratrodast and hepatic dysfunction 146 Meloxicam safety similar to other NSAIDs 147 Proxibarbal withdrawn from the market 147 General Policy Issues Cholestin an unapproved drug 147 Vigabatrin and visual defects 147 Starting materials for pharmaceutical products: safety concerns 129 Glycerol contaminated with diethylene glycol 129 ATC/DDD Classification (final) 148 Pharmaceutical excipients: certificates of analysis and vendor qualification 130 ATC/DDD Classification Quality assurance and supply of starting (temporary) 150 materials 132 Implementation of vendor certification 134 Control and safe trade in starting materials Essential Drugs for pharmaceuticals: recommendations 134 WHO Model Formulary: Immunosuppressives, antineoplastics and drugs used in palliative care Reports on Individual Drugs Immunosuppresive drugs 153 Tamoxifen in the prevention and treatment Azathioprine 153 of breast cancer 136 Ciclosporin 154 Selective serotonin re-uptake inhibitors and Cytotoxic drugs 154 withdrawal reactions 136 Asparaginase 157 Triclabendazole and fascioliasis 138 Bleomycin 157 Calcium folinate 157 Chlormethine 158 Current Topics Cisplatin 158 Reverse transcriptase activity in vaccines 140 Cyclophosphamide 158 Consumer protection and herbal remedies 141 Cytarabine 159 Indiscriminate antibiotic
    [Show full text]
  • The Activation of the Glucagon-Like Peptide-1 (GLP-1) Receptor by Peptide and Non-Peptide Ligands
    The Activation of the Glucagon-Like Peptide-1 (GLP-1) Receptor by Peptide and Non-Peptide Ligands Clare Louise Wishart Submitted in accordance with the requirements for the degree of Doctor of Philosophy of Science University of Leeds School of Biomedical Sciences Faculty of Biological Sciences September 2013 I Intellectual Property and Publication Statements The candidate confirms that the work submitted is her own and that appropriate credit has been given where reference has been made to the work of others. This copy has been supplied on the understanding that it is copyright material and that no quotation from the thesis may be published without proper acknowledgement. The right of Clare Louise Wishart to be identified as Author of this work has been asserted by her in accordance with the Copyright, Designs and Patents Act 1988. © 2013 The University of Leeds and Clare Louise Wishart. II Acknowledgments Firstly I would like to offer my sincerest thanks and gratitude to my supervisor, Dr. Dan Donnelly, who has been nothing but encouraging and engaging from day one. I have thoroughly enjoyed every moment of working alongside him and learning from his guidance and wisdom. My thanks go to my academic assessor Professor Paul Milner whom I have known for several years, and during my time at the University of Leeds he has offered me invaluable advice and inspiration. Additionally I would like to thank my academic project advisor Dr. Michael Harrison for his friendship, help and advice. I would like to thank Dr. Rosalind Mann and Dr. Elsayed Nasr for welcoming me into the lab as a new PhD student and sharing their experimental techniques with me, these techniques have helped me no end in my time as a research student.
    [Show full text]
  • The National Drugs List
    ^ ^ ^ ^ ^[ ^ The National Drugs List Of Syrian Arab Republic Sexth Edition 2006 ! " # "$ % &'() " # * +$, -. / & 0 /+12 3 4" 5 "$ . "$ 67"5,) 0 " /! !2 4? @ % 88 9 3: " # "$ ;+<=2 – G# H H2 I) – 6( – 65 : A B C "5 : , D )* . J!* HK"3 H"$ T ) 4 B K<) +$ LMA N O 3 4P<B &Q / RS ) H< C4VH /430 / 1988 V W* < C A GQ ") 4V / 1000 / C4VH /820 / 2001 V XX K<# C ,V /500 / 1992 V "!X V /946 / 2004 V Z < C V /914 / 2003 V ) < ] +$, [2 / ,) @# @ S%Q2 J"= [ &<\ @ +$ LMA 1 O \ . S X '( ^ & M_ `AB @ &' 3 4" + @ V= 4 )\ " : N " # "$ 6 ) G" 3Q + a C G /<"B d3: C K7 e , fM 4 Q b"$ " < $\ c"7: 5) G . HHH3Q J # Hg ' V"h 6< G* H5 !" # $%" & $' ,* ( )* + 2 ا اوا ادو +% 5 j 2 i1 6 B J' 6<X " 6"[ i2 "$ "< * i3 10 6 i4 11 6! ^ i5 13 6<X "!# * i6 15 7 G!, 6 - k 24"$d dl ?K V *4V h 63[46 ' i8 19 Adl 20 "( 2 i9 20 G Q) 6 i10 20 a 6 m[, 6 i11 21 ?K V $n i12 21 "% * i13 23 b+ 6 i14 23 oe C * i15 24 !, 2 6\ i16 25 C V pq * i17 26 ( S 6) 1, ++ &"r i19 3 +% 27 G 6 ""% i19 28 ^ Ks 2 i20 31 % Ks 2 i21 32 s * i22 35 " " * i23 37 "$ * i24 38 6" i25 39 V t h Gu* v!* 2 i26 39 ( 2 i27 40 B w< Ks 2 i28 40 d C &"r i29 42 "' 6 i30 42 " * i31 42 ":< * i32 5 ./ 0" -33 4 : ANAESTHETICS $ 1 2 -1 :GENERAL ANAESTHETICS AND OXYGEN 4 $1 2 2- ATRACURIUM BESYLATE DROPERIDOL ETHER FENTANYL HALOTHANE ISOFLURANE KETAMINE HCL NITROUS OXIDE OXYGEN PROPOFOL REMIFENTANIL SEVOFLURANE SUFENTANIL THIOPENTAL :LOCAL ANAESTHETICS !67$1 2 -5 AMYLEINE HCL=AMYLOCAINE ARTICAINE BENZOCAINE BUPIVACAINE CINCHOCAINE LIDOCAINE MEPIVACAINE OXETHAZAINE PRAMOXINE PRILOCAINE PREOPERATIVE MEDICATION & SEDATION FOR 9*: ;< " 2 -8 : : SHORT -TERM PROCEDURES ATROPINE DIAZEPAM INJ.
    [Show full text]
  • List of Approved Ndas for Biological Products That Were Deemed to Be Blas on March 23, 2020
    List of Approved NDAs for Biological Products That Were Deemed to be BLAs on March 23, 2020 On March 23, 2020, an approved application for a biological product under section 505 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) was deemed to be a license for the biological product under section 351 of the Public Health Service Act (PHS Act) (see section 7002(e)(4)(A) of the Biologics Price Competition and Innovation Act of 2009). To enhance transparency and facilitate planning for the March 23, 2020, transition date, FDA compiled a preliminary list of approved applications for biological products under the FD&C Act that were listed in FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (the Orange Book) and that would be affected by this transition provision. FDA posted this list on the FDA website in December 2018, and periodically updated this list before the March 23, 2020, transition date. The September 2019 update to this preliminary list added certain administratively closed applications related to approved applications for biological products that were on the December 2018 version of this list. The January 2020 update to the preliminary list reflected a change to the definition of “biological product” made by the Further Consolidated Appropriations Act, 2020, which was enacted on December 20, 2019. Section 605 of this Act further amended the definition of a “biological product” in section 351(i) of the PHS Act to remove the parenthetical “(except any chemically synthesized polypeptide)” from the statutory category of “protein.” FDA has provided below a list of each approved application for a biological product under the FD&C Act that was deemed to be a license (i.e., an approved biologics license application (BLA)) for the biological product on March 23, 2020.
    [Show full text]
  • Corticorelin Acetate, a Synthetic Corticotropin-Releasing Factor with Preclinical Antitumor Activity, Alone and with Bevacizumab, Against Human Brain Tumor Models
    ANTICANCER RESEARCH 30: 5037-5042 (2010) Corticorelin Acetate, a Synthetic Corticotropin-releasing Factor with Preclinical Antitumor Activity, alone and with Bevacizumab, against Human Brain Tumor Models IDOIA GAMEZ1, ROBERT P. RYAN1 and STEPHEN T. KEIR2 1Celtic Pharmaceutical Development Services America, Inc., New York, NY 10022, U.S.A.; 2The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC 27710, U.S.A. Abstract. Background: Corticorelin acetate (CrA) is a brain tumors. The cause of PBE is believed to result in part synthetic form of corticotropin-releasing factor that is from the leakage of edematous brain tumor fluid from currently undergoing clinical trials in the treatment of abnormal tumor vasculature into the surrounding tissue (1, peritumoral brain edema (PBE). This study preclinically 2). The mechanism(s) of action by which CrA exerts its investigated its potential as an antitumor agent against beneficial effect in the therapy of PBE has not been human brain tumor xenografts. Materials and Methods: The elucidated, but two factors appear to be relevant: decreased in vivo efficacy of CrA as a single agent and in combination vascular leakage and preserved integrity of the endothelial with the antiangiogenic agent, bevacizumab, was examined cells, which ultimately helps to maintain the blood-brain in three different patient-derived human brain tumor barrier (3, 4). xenografts implanted orthotopically (intracranially) or CrA appears to mediate its activity through two subtypes subcutaneously in athymic mice. Results: CrA significantly of G-protein coupled receptors: CRF receptor-1 (CRFR1) increased the lifespan of mice implanted orthotopically with and CRF receptor-2 (CRFR2) (5). These CRFRs are widely two different pediatric brain tumor xenograft models.
    [Show full text]
  • 1. Two Components, Two Sets of Lecturers
    Conditions 1. Two components, two sets of lecturers. 2. Lectures 1-5 Prof. F. Hudecz Lectures 6-9 Dr. Gy. Domány Lectures 10-12 Dr. P. Buzder-Lantos 3. Examination: two parts determined by the lecturers and one mark. - option A: written test - option B: presentation based on literature - option C: oral examination 4. Participation at lectures > 70 % [email protected] Some Approved Peptide Pharmaceuticals and their Methods of Manufacture First generatioin Second generation New generation Oxytocin (L) Carbetocin (S) Abarelix (GnRH) (L) ACTH (1-24) & (1-39) (L,S) Terlipressin (L,S) Cetrorelix (GnRH) (L) Vasopressin (L,S) Felypressin (L,S) Ganirelix (GnRH) (L) Insulin (E,SS, R) Buserelin (L,S) Eptifibatide Glucagon (E,S,R) Deslorelin (L,S) Bivalirudin (L) Calcitonins (L,S,R) Goserelin (L) Copaxone (L) TRH (L) Histrelin (L) Techtide P-289(S) Gonadorelin (L,S) Leuprolide (L,S) Cubicin (F) Somatostatin (L,S) Nafarelin (S) Fuzeon (antiHIV (H) GHRH (1-29) & (1-44) (S) Tryptorelin (L,S) Ziconotide (pain) (S) CRF (Human & Ovine) (S) Lecirelin (S) Pramlintide (diabetes) (S) Cyclosporin (F) Lanreotide (S) Exenatide (diabetes) (S) Thymopentin (L) Octreotide (L,S) Icatibant (brady-rec) Thymosin Alpha-1 (S) Atosiban (L) Romiplostim (hormon) Secretins (Human & Porcine) (E,S) Desmopressin (L,S) Degarelix (GnRH) Parathyroid Hormone (1-34) & (1-84)(S) Lypressin (L) Mifamurtide (rák, adj.) Vasoactive Intestinal Polypeptide (S) Ornipressin Ecallantide (ödéma) Brain Natriuretic Peptide (R) Pitressin (L) Liraglutide (diabetes) Cholecystokinin (L) ACE Inhibitors (Enalapril, Lisinopril) (L) Tesamorelin Tetragastrin (L) HIV Protease Inhibitors (L) Surfaxin Pentagastrin (L) Peginesatide Eledoisin (L) Carfilzomib Linaclotide (enz.inh) L = in solution; S = on solid phase; E = extraction; F = fermentation; H = hybrid synthesis; R = recombinant; SS = semi-synthesis.
    [Show full text]
  • Origin, Adaptation and Evolutionary Pathways of Fungal Viruses
    Virus Genes 16:1, 119±131, 1998 # 1998 Kluwer Academic Publishers, Boston. Manufactured in The Netherlands. Origin, Adaptation and Evolutionary Pathways of Fungal Viruses SAID A. GHABRIAL Department of Plant Pathology, University of Kentucky, Lexington, KY, USA Abstract. Fungal viruses or mycoviruses are widespread in fungi and are believed to be of ancient origin. They have evolved in concert with their hosts and are usually associated with symptomless infections. Mycoviruses are transmitted intracellularly during cell division, sporogenesis and cell fusion, and they lack an extracellular phase to their life cycles. Their natural host ranges are limited to individuals within the same or closely related vegetative compatibility groups. Typically, fungal viruses are isometric particles 25±50 nm in diameter, and possess dsRNA genomes. The best characterized of these belong to the family Totiviridae whose members have simple undivided dsRNA genomes comprised of a coat protein (CP) gene and an RNA dependent RNA polymerase (RDRP) gene. A recently characterized totivirus infecting a ®lamentous fungus was found to be more closely related to protozoan totiviruses than to yeast totiviruses suggesting these viruses existed prior to the divergence of fungi and protozoa. Although the dsRNA viruses at large are polyphyletic, based on RDRP sequence comparisons, the totiviruses are monophyletic. The theory of a cellular self-replicating mRNA as the origin of totiviruses is attractive because of their apparent ancient origin, the close relationships among their RDRPs, genome simplicity and the ability to use host proteins ef®ciently. Mycoviruses with bipartite genomes ( partitiviruses), like the totiviruses, have simple genomes, but the CP and RDRP genes are on separate dsRNA segments.
    [Show full text]
  • The Double Stranded RNA Analog Poly-IC Elicits Both Robust IFN-Λ Production and Oncolytic Activity in Human Gastrointestinal Cancer Cells
    www.oncotarget.com Oncotarget, 2018, Vol. 9, (No. 77), pp: 34471-34484 Research Paper The double stranded RNA analog poly-IC elicits both robust IFN-λ production and oncolytic activity in human gastrointestinal cancer cells Chantal Bou-Hanna1,*, Anne Jarry1,2,*, Jean-François Mosnier1,3, Céline Bossard1,2,3 and Christian L. Laboisse1,3 1University of Nantes, EA4273 Biometadys, Nantes, France 2Current address: CRCINA, INSERM, Université d’Angers, Université de Nantes, Nantes, France 3Pathology Department, Nantes University Hospital, Nantes, France *Equal co-authors Correspondence to: Christian L. Laboisse, email: [email protected]; [email protected] Keywords: dsRNA/poly-IC; IFN-λ; immunoadjuvant; oncolysis; human gastrointestinal cancer Received: February 09, 2018 Accepted: September 06, 2018 Published: October 02, 2018 Copyright: Bou-Hanna et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Purpose: Type III IFN (IFN-λ) is the dominant frontline response over type I IFN in human normal intestinal epithelial cells upon viral infection, this response being mimicked by the dsRNA analog poly-IC. Poly-IC also induces cell death in murine intestinal crypts ex vivo. Here we examined whether these innate defense functions of normal intestinal epithelial cells are recapitulated in gastrointestinal carcinoma cells so that they could be harnessed to exert both immunoadjuvant and oncolytic functions, an unknown issue yet. Experimental design: Four human gastrointestinal carcinoma cell lines versus the Jurkat lymphoma cell line were used to assess the effects of intracellular poly-IC on i) IFN-λ secretion and cell proliferation and ii) role of NFκB signaling using the NFκB inhibitory peptide SN50 as a screening probe and a siRNA approach.
    [Show full text]
  • List of Union Reference Dates A
    Active substance name (INN) EU DLP BfArM / BAH DLP yearly PSUR 6-month-PSUR yearly PSUR bis DLP (List of Union PSUR Submission Reference Dates and Frequency (List of Union Frequency of Reference Dates and submission of Periodic Frequency of submission of Safety Update Reports, Periodic Safety Update 30 Nov. 2012) Reports, 30 Nov.
    [Show full text]
  • Patient Resource Free
    PATIENT RESOURCE FREE Third Edition CancerUnderstanding Immunotherapy Published in partnership with CONTENT REVIEWED BY A DISTINGUISHED PRP MEDICAL PATIENT ADVISORY RESOURCE BOARD PUBLISHING® Understanding TABLE OF CONTENTS Cancer Immunotherapy Third Edition IN THIS GUIDE 1 Immunotherapy Today 2 The Immune System 4 Immunotherapy Strategies 6 Melanoma Survivor Story: Jane McNee Chief Executive Officer Mark A. Uhlig I didn’t look sick, so I didn’t want to act sick. Publisher Linette Atwood Having and treating cancer is only one part of your life. Co-Editor-in-Chief Charles M. Balch, MD, FACS Jane McNee, melanoma survivor Co-Editor-in-Chief Howard L. Kaufman, MD, FACS Senior Vice President Debby Easum 7 The Road to Immunotherapy Vice President, Operations Leann Sandifar 8 Cancer Types Managing Editor Lori Alexander, MTPW, ELS, MWC™ 14 Side Effects Senior Editors Dana Campbell Colleen Scherer 15 Glossary Graphic Designer Michael St. George 16 About Clinical Trials Medical Illustrator Todd Smith 16 Cancer Immunotherapy Clinical Trials by Disease Production Manager Jennifer Hiltunen 35 Support & Financial Resources Vice Presidents, Amy Galey Business Development Kathy Hungerford 37 Notes Stephanie Myers Kenney Account Executive Melissa Amaya Office Address 8455 Lenexa Drive CO-EDITORS-IN-CHIEF Overland Park, KS 66214 For Additional Information [email protected] Charles M. Balch, MD, FACS Advisory Board Visit our website at Professor of Surgery, The University of Texas PatientResource.com to read bios of MD Anderson Cancer Center our Medical and Patient Advisory Board. Editor-in-Chief, Patient Resource LLC Editor-in-Chief, Annals of Surgical Oncology Past President, Society of Surgical Oncology For Additional Copies: To order additional copies of Patient Resource Cancer Guide: Understanding Cancer Immunotherapy, Howard L.
    [Show full text]
  • Gastric Secretory and Plasma Hormonal Responses to Sham-Feeding of Varying Duration in Patients with Duodenal Ulcer
    Gut: first published as 10.1136/gut.22.12.1003 on 1 December 1981. Downloaded from Gut, 1981, 22,1003-1010 Gastric secretory and plasma hormonal responses to sham-feeding of varying duration in patients with duodenal ulcer S J KONTUREK,* J SWIERCZEK, N KWIECIEN, W OBTUTOWICZ, M DOBRZANSKA, B KOPP, AND J OLEKSY From the Institute ofPhysiology, Medica, Academy, Krakow, and District Hospital, Krakow, Poland SUMMARY Gastric acid and serum gastrin, pancreatic polypeptide, and insulin responses to cephalic vagal stimulation were studied in eight patients with duodenal ulcer using modified sham- feeding for periods varying from four to 30 minutes. In addition, the maximal acid response to sham-feeding was compared with that induced by pentagastrin in 10 healthy subjects and 14 patients with duodenal ulcer. It was found that the gastric acid response to modified sham-feeding reached the maximal value after 15 minutes of sham-feeding and amounted to about 68% of the pentagastrin maximum. The serum pancreatic polypeptide response was also increased after modified sham-feeding and depended on the duration of this procedure, whereas gastrin and insulin responses were not significantly affected by modified sham-feeding. When the peak acid output induced by modified sham-feeding was normalised as percentage of the peak response to pentagastrin, it was similar in healthy subjects and in patients with duodenal ulcer; this indicates that the increased peak acid response to modified sham-feeding observed in patients with duodenal ulcer corresponded with
    [Show full text]
  • Classification Decisions Taken by the Harmonized System Committee from the 47Th to 60Th Sessions (2011
    CLASSIFICATION DECISIONS TAKEN BY THE HARMONIZED SYSTEM COMMITTEE FROM THE 47TH TO 60TH SESSIONS (2011 - 2018) WORLD CUSTOMS ORGANIZATION Rue du Marché 30 B-1210 Brussels Belgium November 2011 Copyright © 2011 World Customs Organization. All rights reserved. Requests and inquiries concerning translation, reproduction and adaptation rights should be addressed to [email protected]. D/2011/0448/25 The following list contains the classification decisions (other than those subject to a reservation) taken by the Harmonized System Committee ( 47th Session – March 2011) on specific products, together with their related Harmonized System code numbers and, in certain cases, the classification rationale. Advice Parties seeking to import or export merchandise covered by a decision are advised to verify the implementation of the decision by the importing or exporting country, as the case may be. HS codes Classification No Product description Classification considered rationale 1. Preparation, in the form of a powder, consisting of 92 % sugar, 6 % 2106.90 GRIs 1 and 6 black currant powder, anticaking agent, citric acid and black currant flavouring, put up for retail sale in 32-gram sachets, intended to be consumed as a beverage after mixing with hot water. 2. Vanutide cridificar (INN List 100). 3002.20 3. Certain INN products. Chapters 28, 29 (See “INN List 101” at the end of this publication.) and 30 4. Certain INN products. Chapters 13, 29 (See “INN List 102” at the end of this publication.) and 30 5. Certain INN products. Chapters 28, 29, (See “INN List 103” at the end of this publication.) 30, 35 and 39 6. Re-classification of INN products.
    [Show full text]