DOCSLIB.ORG

(12) United States Patent (10) Patent N0.: US 8470342 B2

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) United States Patent (10) Patent N0.: US 8470342 B2 US008470342B2 (12) United States Patent (10) Patent N0.: US 8,470,342 B2 Klinman et a]. (45) Date of Patent: Jun. 25, 2013 (54) METHODS OF ALTERING AN IMMUNE OTHER PUBLICATIONS RESPONSE INDUCED BY CPG H d t 1 “Th D. t . l.k M t 11 t . ADAMIO OLIGODEOXYNUCLEOTIDES I un ausene a ., ‘e I1s1n egnn- 1 e e a opro einase I is Involved in Constitutive Cleavage of CX3CLl (fractalkine) and (75) Inventors: Dennis M_ Klinman’ Potomac, MD Regulates CXBCLl-mediated Cell-CellAdhesion,”Blood 10211186 (US); Mayda Gursel, Ankara (TR); 1195 (2003) Ihsan Gursel’ Ankara (TR) Wuttge et al., “CXCLl6/SR-PSOX Is an Interferon-y-Regulated Chemokine and Scavenger Receptor Expressed in Atherosclerotic (73) Assigneez The United states OfAmeriCa, as Lesions,” A(rterio)sclerosis, Thrombosis, and Vascular Biology Represented by the Secretary of the 24:750'755 2004 ~ _ _ _ Department of Health and Human Abel et al., The Transmembrane CXC-Chemokine Ligand 16 1s services Washington DC (Us) Induced by IFN-yand TNF-otand Shed by the Activity of the ’ ’ Disintergrin-Like Metalloproteinase ADAMlO,” Journal of Immu * N t- . S b- u d~ 1 - th t fthi nology 172(10):6362-6372 (May 15, 2004). ( ) 0 Ice :teJITtC isoeilgn 2x11251115; de ilnllioer 3 2 Gijbeles et al., “Reversal of Experimental Autoimmune % S C 154(1)) b 214 da JS Encephalomyelitis With a Hydroxamate Inhibitor of Matrix Metal ' ' ' y y ' loproteases,”Journal of Clinical Investigation 94:2177-2182 (1994). _ Gough et al., “A Disintegrin and Metalloproteinase lO-Mediated (21) Appl' NO" 13/005’488 Cleavage and Shedding Regulates the Cell Surface Expression of (22) Flled.. _ Jan. 12, 2011 CXC Chemokine Ligand 16,” Journal ofImmunology 17213678 3685 (2004). Gursel et al., “CXCLl6 In?uences the Nature and Speci?cally of (65) Pnor Pubhcatlon Data CpG-Induced Immune Activation,” Journal of Immunology US 2011/0110883 A1 May 12, 2011 l77(3):l575-l580 (Aug. 3, 2006). International Search report from PCT Application No. PCT/US2006/ Related US. Application Data 033774, dated Feb. 5, 2007. _ _ _ _ _ Tobata et al., “Distribution and Kinetics of SR-PSOX/CXCL16 and (62) Dlvlsloll of apphcanon NO‘ 12/065’085’ ?led as CXCR6 Expression on Human Dendritic cell Subsets and CD4+ T apphcanon NO‘ PCT/US2006/033774 on Aug‘ 28’ Cells,” Journal ofLeukocyte Biology 77:777-786 (2005). 2006’ HOW Pat' NO' 7>892>569~ Verthelyi et al., “Human Peripheral Blood Cells Differentially Rec (60) Provisional application NO‘ 60/713 547 ?led on Aug‘ ogniZe and Respond to Two Distinct CPG Motifs,”Journal ofImmu 31 2005 ’ ’ nology 166(4):2372-2377 (Feb. 15, 2001). (51) Int_ CL Primary Examiner * Patricia A Duffy A61]; 45/00 (200601) (74) Attorney, Agent, or Firm * Klarquist Sparkman, LLP A61K 39/12 (2006.01) A61K 39/02 (2006.01) (57) ABSTRACT (52) U-S- Cl- It is disclosed herein that agents that affect the activity and/or . .. expression of can be used to alter the uptake of 424/2341; 424/2741 D-type CpG oligodeoxynucleotides (D ODNs). Methods of (58) Field of Classi?cation Search inducing an immune response are disclosed that include None _ _ _ administering agents that increase the activity and/or expres See aPPhCaUOn ?le for Complete Search hlstory- sion of CXCL16 and a D ODN. Methods of decreasing an _ immune response to a CpG ODN are also disclosed. These (56) References Clted methods include administering an agent that decreases the FOREIGN PATENT DOCUMENTS activity and/or expression of CXCL1 6. Compositions includ JP 2 138868 5/1990 ing one or more D-type ODNs and an agent that modulates W0 W0 9556755 11/1999 that activity and/ or expression of CXCL1 6 are provided. W0 W0 00/61 151 10/2000 W0 WO 01/22990 4/2001 17 Claims, 7 Drawing Sheets US. Patent Jun. 25, 2013 Sheet 1 of7 US 8,470,342 B2 NCIO G NCIO >1 NGO Cl 0 O .M ow wo/ ,..... w. o L8 N r 2.u W03 mON 00.?omdowdovd :23cozgcmucoo200 6 U M m. w m0?@E8 4;.0E 00 cu LO O "I m. ‘ omd- v0.0- o o 0 (W 9017) GO US. Patent Jun. 25, 2013 Sheet 2 of7 US 8,470,342 B2 G NUumO 0O Q 8 n,}a)G n 9OGMW GM w,Wd.3mNi ...................N OMO GWm.m mm,é >3nuH amé, numiaoM ,. wm. QNGE Mx w d 2»$6,,mg»,, 869.3 am m .. .. w;~.N21.2, mw , ._, , m . ZOOZQO“cacaomxmm.GE mw zmomo2on750xQ8 n, <mt®¢ . a @8011! US. Patent Jun. 25, 2013 Sheet 4 of7 US 8,470,342 B2 QFIOXO ‘m @0502._. .GEmw US. Patent Jun. 25,2013 Sheet 5 of7 US 8,470,342 B2 ZOOQ v333 £2, HGM mm.P m»... 5“ “NAMES 33 US. Patent Jun. 25, 2013 Sheet 6 of7 US 8,470,342 B2 (2) NCIO (1 (L) NGOCI NCIO )1 @.UE IOJlUOO-G mum->1 Lumpew 0 O O om? om? CD (.0 00 (SHOHIHH) ma US. Patent Jun. 25,2013 Sheet 7 of7 US 8,470,342 B2 5282682023S9a. m5839a68% .v\w?EH55o\‘ Qowd.M EHmw§mmawér&mU»,‘musam‘. W,w?E a o., mvNF %m962w2 gEitIt.. ‘U‘U‘Uwa.U o l @mw .oZSE5 .2.‘mm..wn\ UK{K . o0 750! a wN .W..r wzoomO2‘ mKGE QSQ M8 owB w.3 .3..................................... US 8,470,342 B2 1 2 METHODS OF ALTERING AN IMMUNE Methods to alter the uptake and subsequent immune activa RESPONSE INDUCED BY CPG tion triggered by CpG ODN are disclosed herein. OLIGODEOXYNUCLEOTIDES SUMMARY PRIORITY CLAIM, It is disclosed herein that agents that affect the activity CROSS REFERENCE TO RELATED and/or expression of CXCL16 can be used to alter the uptake APPLICATIONS of CpG oligodeoxynucleotides (ODN), speci?cally D-type CpG oligodeoxynucleotides (D ODN). Thus, agents that This application is a divisional of US. patent application affect the activity and/ or expression of CXCL1 6 can be used Ser. No. 12/065,085, ?led Feb. 27, 2008 now US. Pat. No. to alter an immune response induced by D ODN. In one 7,892,569, Which is the US. National Stage of International example, the agent increases the activity and/or expression of CXCL16, thereby increasing the uptake of D ODN. Agents Application No. PCT/US2006/033774, ?led Aug. 28, 2006, that increase the activity and/or expression of CXCL1 6 can be Which Was published in English under PCT Article 21(2), used to increase an immune response induced by a D ODN. Which in turn claims the bene?t of US. Provisional Applica Agents that decrease the activity and/or expression of tion No. 60/713,547, ?led Aug. 31, 2005. The prior applica CXCL16 can be used to decrease an immune response tions are incorporated herein by reference in their entirety. induced by D ODN. Speci?c compositions including one or more D-type FIELD 20 ODNs and an agent that modulates that activity and/or expression of CXCL1 6 are provided herein. These composi This application relates to the ?eld of immunology, spe tions are of use to induce an immune response, such as to a ci?cally to agents that can be used to alter the uptake of speci?c antigen. immunostimulatory oligodeoxynucleotides (ODNs). The foregoing and other features and advantages Will 25 become more apparent from the folloWing detailed descrip BACKGROUND tion of several embodiments, Which proceeds With reference to the accompanying ?gures. DNA is a complex macromolecule Whose activities are in?uenced by its base composition and base modi?cation, as BRIEF DESCRIPTION OF THE FIGURES Well as helical orientation. Bacterial DNA, as Well as certain 30 synthetic oligodeoxynucleotides (ODNs) containing unm FIGS. 1A-1C are graphs and digital images illustrating that ethylated CpG sequences, can induce proliferation and CXCL16 selectively recognizes D ODN. FIG. 1A is a line immunoglobulin production by murine B cells. Unmethy graph shoWing CpG ODN binding to recombinant CXCL16. lated CpG dinucleotides are more frequent in the genomes of 96-Well ?at bottom ELISA plates Were coated With 0.4 ug/ml bacteria and viruses than vertebrates. Studies have suggested 35 anti-CXCL16 antibody and then incubated Without (dotted that immune recognition of these motifs may contribute to the lines) or With 200 ng/ml of recombinant CXCL1 6 (full lines). host’s innate immune response. (Klinman et al., Proc. Natl. FolloWing Washing, 1, 0.2 or 0.04 uM biotin-conjugated K or D oligodeoxynucleotide (ODN) Were added. After Washing, Acad. Sci. USA 9312879, 1996;Y1 et al., .I. Immun. 15715394, ODN binding Was detected colorimetrically using phos 1996; Liang et al., J. Clin. Invest. II 9:89, 1996; Krieg et al., 40 phatase-conjugated avidin folloWed by a phosphatase spe Nature 3741546, 1995). ci?c colorimetric substrate. Results are presented as A CpG oligodeoxynucleotide (ODN) is an oligodeoxy averagezstandard deviation (SD) of three independent read nucleotide including a CpG motif, Wherein the pyrimidine ings. FIG. 1B is a set of digital images and plots shoWing that ring of the cytosine is unmethylated. Three types of CpG D but not K ODN colocaliZe With CXCL16 and its uptake is ODNs have been identi?ed1 C-type, K-type and D-type 45 enhanced in transfected HEK293 cells. CXCL16 transfected ODNs. Generally, CpG ODNs range from about 8 to 30 bases HEK293 cells Were incubated With 3 uM of FITC conjugated in siZe. D- and K-type nucleic acid sequences have been CpG ODN at 37° C. for 20 minutes. Cells Were stained for described in the published PCT Publication No. W0 CXCL16 expression (left) and colocaliZation (bright cells, 98/ 18810A1 (K-type) and published PCT Publication No.
Load more

Recommended publications
  • United States Patent (10) Patent No.: US 7,935,351 B2 Klinman Et Al
    US007935351B2 (12) United States Patent (10) Patent No.: US 7,935,351 B2 Klinman et al. (45) Date of Patent: *May 3, 2011 (54) USE OF CPG OLIGODEOXYNUCLEOTIDES 35. A 3. 2. RS:udolph s et alal. TO INDUCE ANGOGENESIS 5,288,509 A 2f1994 Potman et al. 5.488,039 A 1, 1996 M tal. (75) Inventors: Dennis M. Klinman, Potomac, MD 5.492.899 A 2, 1996 NE al. (US); Mei Zheng, Augusta, GA (US); 5,585,479 A 12/1996 Hoke et al. Barry T. Rouse, Knoxville, TN (US) 5,602,1095,591,721 A 2/19971/1997 MasorAgrawal et etal. al. 5,612,060 A 3, 1997 A1 d (73) Assignees: The United States of America as 5,614,191 A 3, 1997 al represented by the Department of 5,650,156 A 7/1997 Grinstaffet al. Health and Human Services, 5,663,153 A 9, 1997 Hutcerson et al. Washington, DC (US); University of 3. A RE SEE, Tennessee Research Foundation, 5,700,590 A 12/1997 Masoretal Knoxville, TN (US) 5,712.256 A 1/1998 Kulkarni et al. 5,723,335 A 3, 1998 Hutcerson et al. (*) Notice: Subject to any disclaimer, the term of this 3. 2. A 38. El cal patent is extended or adjusted under 35 5.840,705 A 11/1998 Tsukuda U.S.C. 154(b) by 761 days. 5,849,719 A 12, 1998 Carson et al. This patent is Subject to a terminal dis- 33: A 23: SEE claimer. 5,922,766 A 7/1999 Acosta et al.
    [Show full text]
  • Human Naive B Cells Cells by Cpg Oligodeoxynucleotide-Primed T+
    Presentation of Soluble Antigens to CD8+ T Cells by CpG Oligodeoxynucleotide-Primed Human Naive B Cells This information is current as Wei Jiang, Michael M. Lederman, Clifford V. Harding and of September 27, 2021. Scott F. Sieg J Immunol 2011; 186:2080-2086; Prepublished online 14 January 2011; doi: 10.4049/jimmunol.1001869 http://www.jimmunol.org/content/186/4/2080 Downloaded from References This article cites 36 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/186/4/2080.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 27, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2011 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Presentation of Soluble Antigens to CD8+ T Cells by CpG Oligodeoxynucleotide-Primed Human Naive B Cells Wei Jiang,*,† Michael M. Lederman,*,† Clifford V. Harding,†,‡ and Scott F. Sieg*,† Naive B lymphocytes are generally thought to be poor APCs, and there is limited knowledge of their role in activation of CD8+ T cells.
    [Show full text]
  • Toll-Like Receptor 9 and 21 Have Different Ligand Recognition Profiles
    Toll-like receptor 9 and 21 have different ligand recognition profiles and cooperatively mediate activity of CpG-oligodeoxynucleotides in zebrafish Da-Wei Yeha,b,1, Yi-Ling Liua,1, Yin-Chiu Loc, Chiou-Hwa Yuhd, Guann-Yi Yuc, Jeng-Fan Loe, Yunping Luof, Rong Xiangg, and Tsung-Hsien Chuanga,h,2 aImmunology Research Center, National Health Research Institutes, Miaoli 35053, Taiwan; bInstitute of Molecular Medicine, National Tsing-Hua University, HsinChu 30013, Taiwan; cNational Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli 35053, Taiwan; dInstitute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli 35053, Taiwan; eInstitute of Oral Biology, National Yang-Ming University, Taipei 11221, Taiwan; fDepartment of Immunology, School of Basic Medicine, Peking Union Medical College, Beijing 100005, People’s Republic of China; gSchool of Medicine, University of Nankai, Tianjin 300071, People’s Republic of China; and hProgram in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan Edited by Ken J. Ishii, National Institute of Biomedical Innovation, Ibaraki, Japan, and accepted by the Editorial Board October 29, 2013 (received for review March 21, 2013) CpG-oligodeoxynucleotides (CpG-ODNs) are potent immune stim- containing a GTCGTT motif. In contrast, the GTCGTT motif uli currently under investigation as antimicrobial agents for containing CpG-ODN generates stronger immune responses in different species. Toll-like receptor (TLR) 9 and TLR21 are the humans and various domestic animals (8, 9). cellular receptors of CpG-ODN in mammals and chickens, respec- Toll-like receptors (TLRs) are pattern recognition recep- tively. The avian genomes lack TLR9, whereas mammalian tors that play crucial roles in the initiation of host defense genomes lack TLR21.
    [Show full text]
  • Oligodeoxynucleotide in Murine Asthma Anti-Inflammatory Effects Of
    In Vivo Role of p38 Mitogen-Activated Protein Kinase in Mediating the Anti-inflammatory Effects of CpG Oligodeoxynucleotide in Murine Asthma This information is current as of September 23, 2021. Barun K. Choudhury, James S. Wild, Rafeul Alam, Dennis M. Klinman, Istvan Boldogh, Nilesh Dharajiya, William J. Mileski and Sanjiv Sur J Immunol 2002; 169:5955-5961; ; doi: 10.4049/jimmunol.169.10.5955 Downloaded from http://www.jimmunol.org/content/169/10/5955 References This article cites 37 articles, 21 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/169/10/5955.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 23, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2002 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology In Vivo Role of p38 Mitogen-Activated Protein Kinase in Mediating the Anti-inflammatory Effects of CpG Oligodeoxynucleotide in Murine Asthma1 Barun K.
    [Show full text]
  • P020210615609549638679.Pdf
    The Journal of Immunology SCARB2/LIMP-2 Regulates IFN Production of Plasmacytoid Dendritic Cells by Mediating Endosomal Translocation of TLR9 and Nuclear Translocation of IRF7 Hao Guo,*,† Jialong Zhang,* Xuyuan Zhang,*,† Yanbing Wang,* Haisheng Yu,*,† Xiangyun Yin,*,† Jingyun Li,*,† Peishuang Du,* Joel Plumas,‡ Laurence Chaperot,‡ ,x,{ ,‖,# , Jianzhu Chen,* Lishan Su,* Yongjun Liu,* ** and Liguo Zhang* Downloaded from Scavenger receptor class B, member 2 (SCARB2) is essential for endosome biogenesis and reorganization and serves as a receptor for both b-glucocerebrosidase and enterovirus 71. However, little is known about its function in innate immune cells. In this study, we show that, among human peripheral blood cells, SCARB2 is most highly expressed in plasmacytoid dendritic cells (pDCs), and its expression is further upregulated by CpG oligodeoxynucleotide stimulation. Knockdown of SCARB2 in pDC cell line GEN2.2 dramatically reduces CpG-induced type I IFN production. Detailed studies reveal that SCARB2 localizes in late endosome/ http://www.jimmunol.org/ lysosome of pDCs, and knockdown of SCARB2 does not affect CpG oligodeoxynucleotide uptake but results in the retention of TLR9 in the endoplasmic reticulum and an impaired nuclear translocation of IFN regulatory factor 7. The IFN-I production by TLR7 ligand stimulation is also impaired by SCARB2 knockdown. However, SCARB2 is not essential for influenza virus or HSV-induced IFN-I production. These findings suggest that SCARB2 regulates TLR9-dependent IFN-I production of pDCs by mediating endosomal translocation of TLR9 and nuclear translocation of IFN regulatory factor 7. The Journal of Immunology, 2015, 194: 4737–4749. ysosomes are ubiquitous acid membrane-bound organelles which also includes scavenger receptor class B, member 1 involved in the degradation of molecules, complexes, and (SCARB1), and CD36 (5).
    [Show full text]
  • Screening of Novel Immunostimulatory Cpg Odns and Their Anti-Leukemic Effects As Immunoadjuvants of Tumor Vaccines in Murine Acute Lymphoblastic Leukemia
    519-529.qxd 20/12/2010 01:05 ÌÌ ™ÂÏ›‰·519 ONCOLOGY REPORTS 25: 519-529, 2011 519 Screening of novel immunostimulatory CpG ODNs and their anti-leukemic effects as immunoadjuvants of tumor vaccines in murine acute lymphoblastic leukemia JIN WANG, WANGGANG ZHANG, AILI HE, WANHONG ZHAO and XINGMEI CAO Department of Hematology, Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an 710004, Shaanxi Province, P.R. China Received July 29, 2010; Accepted October 11, 2010 DOI: 10.3892/or.2010.1093 Abstract. Acute lymphoblastic leukemia (ALL) is a common Additional therapeutic strategies are required in order to malignant disease and a major cause of mortality due to further prolong remission duration and eradicate minimal recurrent disease. Immunotherapy is a promising strategy for residual disease, ideally with less toxicity than conventional eradicating minimal residual disease and thus preventing the chemotherapy. One of the these approaches is active immuno- relapse of leukemia. Apart from stem cell transplantation, therapy with novel vaccination regimens. We previously CpG oligodeoxynucleotides (ODNs) are excellent candidates launched a phase-I clinical trial and evaluated the efficacy for the immunotherapy of leukemia. However, the number of and toxicity of vaccination in patients with relapsed or usable CpG ODNs is limited. In this study, we tested a panel refractory acute leukemia, which proved to be a feasible, of CpG ODNs and obtained three CpG ODN sequences with safe, and capable way of eliciting anti-leukemic responses strong immunostimulatory activity by comparing their in vivo (1). capacity to activate lymphocytes. The data revealed that the As tumor cells are considered to be poorly immunogenic, flanking bases, the spacing of individual CpG motifs and poly- it is difficult to elicit an effective specific anti-tumor activity guanosine ends, contribute to the immunostimulatory activity from these cells alone.
    [Show full text]
  • Oligodeoxynucleotide Dendritic Cells to the TLR9 Agonist Cpg Distinct
    Distinct Responses of Lung and Spleen Dendritic Cells to the TLR9 Agonist CpG Oligodeoxynucleotide This information is current as Li Chen, Meenakshi Arora, Manohar Yarlagadda, Timothy of September 24, 2021. B. Oriss, Nandini Krishnamoorthy, Anuradha Ray and Prabir Ray J Immunol 2006; 177:2373-2383; ; doi: 10.4049/jimmunol.177.4.2373 http://www.jimmunol.org/content/177/4/2373 Downloaded from References This article cites 62 articles, 32 of which you can access for free at: http://www.jimmunol.org/content/177/4/2373.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Distinct Responses of Lung and Spleen Dendritic Cells to the TLR9 Agonist CpG Oligodeoxynucleotide1 Li Chen,* Meenakshi Arora,* Manohar Yarlagadda,* Timothy B. Oriss,* Nandini Krishnamoorthy,* Anuradha Ray,*† and Prabir Ray2*† Dendritic cells (DCs) sense various components of invading pathogens via pattern recognition receptors such as TLRs.
    [Show full text]
  • Oligonucleotide-Ficoll Conjugate Nanoparticle Adjuvant for Enhanced Immunogenicity of Anthrax Protective Antigen † † † † † † Bob Milley,*, Radwan Kiwan, Gary S
    This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Article pubs.acs.org/bc Optimization, Production, and Characterization of a CpG- Oligonucleotide-Ficoll Conjugate Nanoparticle Adjuvant for Enhanced Immunogenicity of Anthrax Protective Antigen † † † † † † Bob Milley,*, Radwan Kiwan, Gary S. Ott, Carlo Calacsan, Melissa Kachura, John D. Campbell, ‡ † Holger Kanzler, and Robert L. Coffman † Dynavax Technologies Corporation, 2929 Seventh Street, Suite 100, Berkeley, California 94710, United States ‡ MedImmune LLC, One MedImmune Way, Gaithersburg, Maryland 20878, United States ABSTRACT: We have synthesized and characterized a novel phosphorothioate CpG oligodeoxynucleotide (CpG ODN)-Ficoll conjugated nanoparticulate adjuvant, termed DV230-Ficoll. This adjuvant was constructed from an amine-functionalized-Ficoll, a heterobifunctional linker (succinimidyl-[(N-maleimidopropionamido)- hexaethylene glycol] ester) and the CpG-ODN DV230. Herein, we describe the evaluation of the purity and reactivity of linkers of different lengths for CpG-ODN-Ficoll conjugation, optimization of linker coupling, and conjugation of thiol-functionalized CpG to maleimide- functionalized Ficoll and process scale-up. Physicochemical character- ization of independently produced lots of DV230-Ficoll reveal a bioconjugate with a particle size of approximately 50 nm and covalent attachment of more than 100 molecules of CpG per Ficoll. Solutions of purified DV230-Ficoll were stable for at least 12 months at frozen and refrigerated temperatures and stability was further enhanced in lyophilized form. Compared to nonconjugated monomeric DV230, the DV230-Ficoll conjugate demonstrated improved in vitro potency for induction of IFN-α from human peripheral blood mononuclear cells and induced higher titer neutralizing antibody responses against coadministered anthrax recombinant protective antigen in mice.
    [Show full text]
  • Oligodeoxynucleotide Dendritic Cells to the TLR9 Agonist Cpg Distinct
    Distinct Responses of Lung and Spleen Dendritic Cells to the TLR9 Agonist CpG Oligodeoxynucleotide This information is current as Li Chen, Meenakshi Arora, Manohar Yarlagadda, Timothy of September 23, 2021. B. Oriss, Nandini Krishnamoorthy, Anuradha Ray and Prabir Ray J Immunol 2006; 177:2373-2383; ; doi: 10.4049/jimmunol.177.4.2373 http://www.jimmunol.org/content/177/4/2373 Downloaded from References This article cites 62 articles, 32 of which you can access for free at: http://www.jimmunol.org/content/177/4/2373.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 23, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Distinct Responses of Lung and Spleen Dendritic Cells to the TLR9 Agonist CpG Oligodeoxynucleotide1 Li Chen,* Meenakshi Arora,* Manohar Yarlagadda,* Timothy B. Oriss,* Nandini Krishnamoorthy,* Anuradha Ray,*† and Prabir Ray2*† Dendritic cells (DCs) sense various components of invading pathogens via pattern recognition receptors such as TLRs.
    [Show full text]
  • Toll-Like Receptors As Potential Therapeutic Targets for Multiple Diseases
    REVIEWS TOLL-LIKE RECEPTORS AS POTENTIAL THERAPEUTIC TARGETS FOR MULTIPLE DISEASES Claudia Zuany-Amorim, John Hastewell and Christoph Walker The family of Toll-like receptors (TLRs) is receiving considerable attention as potential regulators and controllers of the immune response through their ability to recognize pathogen-associated molecular patterns. The discovery that endogenous ligands, as well as microbial components, are recognized by TLRs, and that small-molecular-mass synthetic compounds activate TLRs, raised interest in these receptors as potential targets for the development of new therapies for multiple diseases. In this review, we discuss the current and future use of TLR agonists or antagonists in chronic inflammatory diseases and highlight potential problems that are associated with such approaches. 2 INNATE IMMUNITY The immune system has been divided traditionally into PAMPs . The first report of a mammalian TLR and its The early response of a host to an INNATE and ADAPTIVE component, each of which has involvement in host defence — TLR-4 as a receptor for infections by pathogens, such as different roles and functions in defending the organism LIPOPOLYSACCHARIDE (LPS)3 — was followed rapidly by the bacteria and viruses, before the against foreign agents, such as bacteria or viruses. The discovery that the human genome contains several antigen-specific, adaptive innate immune system has developed a series of con- TLRs — ten have been found so far, TLR-1–TLR-10. immune response is induced. served receptors, known as pattern-recognition recep- Members of the TLR family share characteristic extra- ADAPTIVE IMMUNITY tors (PRRs), that recognize specific pathogen-associated cellular and cytoplasmic domains.
    [Show full text]
  • Toll-Like Receptors and Their Potential Roles in Kidney Disease
    J Am Soc Nephrol 15: 854–867, 2004 Signaling Danger: Toll-Like Receptors and their Potential Roles in Kidney Disease HANS-JOACHIM ANDERS,* BERNHARD BANAS,† and DETLEF SCHLO¨ NDORFF* *Nephrological Center, Medizinische Poliklinik, Klinikum der Universität München-Junenstadt, Germany; and †Klinik u. Poliklinik f. Innere Medizin II, Universität Regensburg, Germany. Abstract. Toll-like receptors (TLR) are an emerging family of cells are among the non-immune cells that express TLR1, -2, receptors that recognize pathogen-associated molecular pat- -3, -4, and -6, suggesting that these TLR might contribute to terns and promote the activation of leukocytes and intrinsic the activation of immune responses in tubulointerstitial injury renal cells. Ligands of the TLR include exogenous microbial (e.g., bacterial pyelonephritis, sepsis, and transplant nephrop- components such as LPS (TLR4), lipoproteins and peptidogly- athy). In addition, TLR9 has been shown to be involved in cans (TLR1, -2, -6), viral RNA (TLR3), bacterial and viral antigen-induced immune complex glomerulonephritis and lu- unmethylated cytosin-guanosin dinucleotide (CpG)-DNA pus nephritis by regulating humoral and cellular immune re- (TLR9), and endogenous molecules including heat-shock pro- sponses. TLR are evolutionary conserved regulators of innnate teins and extracellular matrix molecules. Upon stimulation, and adaptive immune reponses. It is likely that TLR are in- TLR induce expression of inflammatory cytokines or costimu- volved in many if not all types of renal inflammation. Here the latory molecules via the MyD88-dependent and MyD88-inde- authors provide an overview on the biology of TLR, summa- pendent signaling pathways shared with the interleukin-1 re- rize the present data on their expression in the kidney, and ceptors.
    [Show full text]
  • Therapeutic Administration of a Synthetic Cpg Oligodeoxynucleotide Triggers Formation of Anti-Cpg Antibodies
    Published OnlineFirst June 27, 2012; DOI: 10.1158/0008-5472.CAN-12-0257 Cancer Priority Report Research Therapeutic Administration of a Synthetic CpG Oligodeoxynucleotide Triggers Formation of Anti-CpG Antibodies Julia Karbach1, Antje Neumann1, Claudia Wahle1, Kathrin Brand1, Sacha Gnjatic2, and Elke Jager€ 1 Abstract The synthetic oligodeoxynucleotide CpG 7909, which contains unmethylated cytosine/guanine (CpG) motifs, has potent immunostimulatory effects when coadministered with NY-ESO-1 peptides or recombinant NY-ESO-1 protein, resulting in an enhanced cellular and humoral immune response against the vaccine antigen. In this study, we report the development of anti-CpG-ODN antibodies in 21 of 37 patients who received CpG 7909 either alone or as a vaccine adjuvant. Specific anti-CpG immunoglobulin G (IgG) antibody titers ranged from 1:400 to 1:100,000. The anti-CpG antibodies cross-reacted with other synthetic CpG-ODNs but not with the DNA of mixed bacterial vaccine and were shown to be phosphorothioate backbone specific. Vaccine-related severe side effects observed in some patients were most likely not related to the development of anti-CpG antibodies. In addition, anti-CpG antibodies did not have negative effects on the vaccine immune response. These results show that anti- CpG antibodies develop in humans against short unmethylated CpG dinucleotide sequences after administration of CpG 7909. Our data therefore substantiate the potency of CpG 7909 to directly stimulate human B-cells and suggest that anti-CpG antibody monitoring should be a part of ongoing and planned clinical trials with CpG- ODNs. Cancer Res; 72(17); 4304–10. Ó2012 AACR. Introduction act on B-cell and monocyte activation.
    [Show full text]