DOCSLIB.ORG

Mai Muuttunut Hiu Li Huwuluhan

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mai Muuttunut Hiu Li Huwuluhan MAIMUUTTUNUT US009809653B2 HIU LI HUWULUHAN (12 ) United States Patent ( 10 ) Patent No. : US 9 ,809 ,653 B2 Baudat et al. (45 ) Date of Patent: Nov . 7 , 2017 (54 ) ANTI- LAMP1 ANTIBODIES AND ANTIBODY ( 58) Field of Classification Search DRUG CONJUGATES , AND USES THEREOF None See application file for complete search history . ( 71 ) Applicant: SANOFI, Paris (FR ) (72 ) Inventors: Yves Baudat, Paris (FR ) ; Francis ( 56 ) References Cited Blanche, Paris ( FR ) ; Béatrice Cameron , Paris (FR ) ; Tarik Dabdoubi, U . S . PATENT DOCUMENTS Le Coudray Montceaux (FR ) ; 4 , 179 , 337 A 12 / 1979 Davis et al. Anne -Marie LeFebvre , Le Plessis Pâté 4 ,256 ,746 A 3 / 1981 Miyashita et al . ( FR ) ; Magali Mathieu , Choisy le Roi 4 , 294 , 757 A 10 / 1981 Asai 4 , 301 , 144 A 11/ 1981 Iwashita et al. (FR ) ; Ana Merino - Trigo , Paris (FR ) ; 4 , 307 ,016 A 12 / 1981 Asai et al. Manoel Nunes, Paris (FR ) 4 ,313 ,946 A 2 / 1982 Powell et al . 4 , 315 , 929 A 2 / 1982 Freedman et al. 4 ,322 , 348 A 3 / 1982 Asai et al. ( 73 ) Assignee : SANOFI, Paris ( FR ) 4 ,331 , 598 A 5 / 1982 Hasegawa et al. 4 , 361, 650 A 11/ 1982 Asai et al . ( * ) Notice : Subject to any disclaimer, the term of this 4 , 362 ,663 A 12 / 1982 Kida et al. patent is extended or adjusted under 35 4 , 364 , 866 A 12 / 1982 Asai et al. U . S . C . 154 ( b ) by 0 days . 4 ,371 , 533 A 2 / 1983 Akimoto et al . 4 ,424 ,219 A 1 / 1984 Hashimoto et al. 4 ,450 , 254 A 5 / 1984 Isley et al. (21 ) Appl. No. : 14/ 751 ,598 4 ,496 ,689 A 1 / 1985 Mitra 4 ,640 ,835 A 2 / 1987 Shimizu et al. ( 22 ) Filed : Jun . 26 , 2015 (Continued ) (65 ) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2016 / 0280793 A1 Sep . 29, 2016 EP 0125023 Al 11/ 1984 EP 0173494 A2 3 /1986 Related U .S . Application Data ( Continued ) (63 ) Continuation of application No . PCT/ EP2013 / 078017 , filed on Dec. 26 , 2013 . OTHER PUBLICATIONS George et al. (Circulation . 1998 ; 97 : 900 -906 ). * ( 30 ) Foreign Application Priority Data (Continued ) Dec . 27 , 2012 ( EP ) . 12306691 Dec. 27 , 2012 (EP ) .. .. 12306694 Primary Examiner — Sheela J Huff (51 ) Int . Ci. ( 74 ) Attorney , Agent, or Firm — Sandra A . Brockman -Lee A61K 39 / 395 (2006 .01 ) CO7K 16 / 28 ( 2006 . 01 ) A61K 47 / 48 ( 2006 .01 ) (57 ) ABSTRACT GOIN 33 /574 ( 2006 .01 ) Antibodies are provided which specifically bind human and COOK 16 / 30 ( 2006 .01 ) C120 1 / 68 ( 2006 . 01 ) Macaca fascicularis lysosomal- associated membrane pro A61K 39/ 00 ( 2006 .01 ) tein 1 (LAMP1 ) proteins and immunoconjugates comprising ( 52 ) U . S . CI. said antibodies conjugated or linked to a growth inhibitory CPC . .. CO7K 16 /2896 ( 2013 .01 ) ; A61K 47/ 48384 agent . Pharmaceutical compositions comprising antibodies (2013 .01 ) ; A61K 47 /48561 ( 2013 . 01 ) ; A61K or immunoconjugates of the invention and use of the anti 47 /48569 (2013 .01 ) ; A61K 47 / 48584 bodies or immunoconjugates for the treatment of cancer are ( 2013 .01 ) ; A61K 47/ 48592 (2013 .01 ) ; A6IK also provided , as well as LAMP1 antibodies , isolated 47/ 48615 ( 2013 .01 ) ; CO7K 16 / 30 (2013 .01 ) ; nucleic acids, vectors and host cells comprising a sequence CO7K 16 / 3023 ( 2013 .01 ) ; C07K 16 / 3046 encoding said antibodies and the use of said antibody as a ( 2013 . 01 ) ; CO7K 16 /3069 (2013 .01 ) ; C120 diagnostic tool. The application further provides for the 1 /6886 ( 2013 .01 ) ; GOIN 33 /574 ( 2013 .01 ) ; detection of LAMP1 gene amplification or gain in cancer A61K 2039 / 505 ( 2013 .01 ) ; COZK 2317 / 24 cells leading to the determination if patients with cancer are ( 2013 . 01 ) ; CO7K 2317 / 33 ( 2013 .01 ) ; COOK likely to respond to anti -LAMP1 therapy. Anti- LAMP1 2317 /34 ( 2013 . 01 ) ; COZK 2317 /41 ( 2013 .01 ) ; therapeutic agent for use for treating cancer in a patient CO7K 2317/ 565 ( 2013 .01 ) ; CO7K 2317 / 73 harboring LAMP1 gene copy number gain in cancer cells is (2013 .01 ) ; CO7K 2317 / 732 ( 2013 .01 ) ; COOK further provided . 2317 / 77 ( 2013 .01 ) ; CO7K 2317 / 92 ( 2013 .01 ) ; C12Q 2600 /106 ( 2013. 01 ) ; C12Q 2600/ 156 (2013 .01 ) 17 Claims, 47 Drawing Sheets US 9 ,809 , 653 B2 Page 2 (56 ) References Cited Anonymous, Anti LAMP1 Human MaxPab (H00003916 -B01P ) , tebu -bio , retrieved from http : / /www .tebu -bio .com /Product / U . S . PATENT DOCUMENTS 157H00003916 - 1301P on Jul. 11, 2014 . Anonymous, APC anti -human CD107a (LAMP - 1 ) Product Data 4 ,670 ,417 A 6 / 1987 Iwasaki et al. 4 , 791 , 192 A 12 / 1988 Nakagawa et al. Sheet , retrieved from http :/ /www .biolegend . com /apc -anti -human 4 ,816 , 567 A 3 / 1989 Cabilly et al. cd107a -lamp - 1 - antibody - 5428 .html on Oct. 8 , 2013 . 4 , 861, 719 A 8 / 1989 Miller Anonymous, LAMP1 antibody H00003916 - B01P Product 4 , 975 , 278 A 12 / 1990 Senter et al. Datasheet , Novusbio , retrieved from http : // www .novusbio .com / 5 , 202 , 238 A 4 / 1993 Fell , Jr . et al . PDFs/ H00003916 - B01P. pdf on Jul. 11 , 2014 . 5 ,204 , 244 A 4 / 1993 Fell et al. Baskar J . F . , et al. , “ The Enhancer Domain of the Human 5 , 208 , 020 A 5 / 1993 Chari et al. Cytomegalovirus Major Immediate -Early Promoter Determines 5 ,225 ,539 A 7 / 1993 Winter 5 , 278 , 056 A 1 / 1994 Bank et al . Cell Type- Specific Expression in Transgenic Mice ,” Journal of 5 , 475 , 092 A 12 / 1995 Chari et al. Virology , 1996 , vol . 70 ( 5 ) , pp . 3207 - 3214 . uuu5 , 500 , 362 A 3 / 1996 Robinson et al. Berman H . M ., et al. , “ The Protein Data Bank ,” Nucleic Acids 5 , 530 , 101 A 6 / 1996 Queen et al. Research , 2000 , vol. 28 ( 1 ) , pp . 235 - 242 . 5 , 565 , 332 A 10 / 1996 Hoogenboom et al . Beroukhim R . , et al. , “ Assessing the Significance of Chromosomal 5 , 585 , 089 A 12 / 1996 Queen et al. Aberrations in Cancer : Methodology and Application to Glioma, " 5 ,585 ,499 A 12 / 1996 Chari et al. Proceedings of the National Academy of Sciences of the United 5 , 821 , 337 A 10 / 1998 Carter et al . 5 , 846 , 545 A 12 / 1998 Chari et al. States of America , 2007 , vol. 104 (50 ) , pp . 20007 - 20012 . 5 , 859 , 205 A 1 / 1999 Adair et al . Beroukhim R ., et al . , “ The Landscape of Somatic Copy -Number 5 , 882 ,877 A 3 / 1999 Gregory et al. Alteration Across Human Cancers ,” Nature , 2010 , vol . 463 (7283 ) , 5 , 994 , 524 A 11/ 1999 Matsushima et al . pp . 899 - 905 . 6 ,013 , 516 A 1 / 2000 Verma et al. Brady G . , et al. , “ New Cosmid Vectors Developed for Eukaryotic 6 ,018 ,032 A 1 / 2000 Koike et al . DNA Cloning, ” Gene, 1984 , vol . 27 ( 2 ) , pp . 223 - 232 . 6 , 127 , 175 A 10 / 2000 Vigne et al. Cancer Genome Atlas Research Network . , “ Comprehensive 6 , 180, 349 B1 1 / 2001 Ginzinger et al. genomic characterization defines human glioblastoma genes and 6 , 333 , 410 B1 12 / 2001 Chari et al . core pathways, ” Nature , 2008 , vol. 455 (7216 ) , pp . 1061 - 1068 . 6 ,464 ,998 B110 / 2002 Beuzard et al . Carlsson S . R . , et al. , “ The Polylactosaminoglycans of Human 2005 / 0003403 A11 / 2005 Rossi et al . Lysosomal Membrane Glycoproteins Lamp - 1 and Lamp - 2 . Local 2011/ 0123554 AL 5 /2011 Osterroth et al. ization on the Peptide Backbones , " The Journal of Biological Chemistry , 1990 , vol. 265 (33 ) , pp . 20488 - 20495. FOREIGN PATENT DOCUMENTS Caron P . C . , et al ., “ Engineered Humanized Dimeric Forms of IgG are More Effective Antibodies, ” The Journal of Experimental Medi EP 0239400 B1 . 8 / 1994 EP 0592106 B1 11 / 2004 cine, 1992 , vol. 176 ( 4 ) , pp . 1191 - 1195 . EP 0519596 B1 2 / 2005 Cook N . R ., et al ., “ Lysosome Associated Membrane Protein 1 EP 2050764 A1 4 / 2009 (LAMP1 ) Traffics Directly from the Tgn to Early Endosomes , " W0 8101145 A1 4 / 1981 Traffic ( Copenhagen , Denmark ) , 2004 , vol . 5 ( 9 ) , pp . 685 -699 . WO 8702671 A1 5 / 1987 Corbett T . H . , et al. , “ Evaluation of Single Agents and Combinations WO 8705330 A1 9 / 1987 of Chemotherapeutic Agents in Mouse Colon Carcinomas, ” Cancer, WO 8807378 A1 10 / 1988 1977 , vol. 40 ( 5 suppl) , pp . 2660 -2680 . WO 9109967 A1 7 / 1991 Cromwell M . E . , et al. , “ Protein Aggregation and Bioprocessing ," WO 9411026 A2 5 / 1994 The Aaps Journal, 2006 , vol. 8 ( 3 ) , pp . E572 - E579 . WO 9419478 A1 9 / 1994 Database UniProt [Online ] 11 RecName: Full = Lysosome- associ WO 9514785 A1 6 / 1995 ated membrane glycoprotein 1 ; Short = LAMP- 1 ; Short = Lysosome WO 9602576 A1 2 / 1996 WO 9622378 A1 7 / 1996 associated membrane proteinl ; AltName: Full = CD107 antigen - like WO 9710354 A1 3 / 1997 family member A ; AltName: CD antigen = CD107a ; Flags : Precur WO 9845322 A2 10 / 1998 sor, XP002714306 , Jul . 1 , 1989 , Database accession No . P11279 . WO 2004016801 A2 2 / 2004 Database UniProt [Online ] , 11 SubName: Full = Lysosome -associ WO 2004048537 A2 6 / 2004 ated membrane glycoprotein 1 , Flags : Fragment , XP002714307 , WO 2004091668 A1 10 / 2004 Jan . 25, 2012 , Database accession No. G7PVS1 . WO 2005012912 A2 2 / 2005 Denis N . , et al. , “ Quantitative Proteomic Analysis of Pcsko Gain of WO 2008010101 A2 1 / 2008 Function in Human Hepatic Huh7 Cells ,” Journal of Proteome W0 2009032661 Al 3 / 2009 Research , 2011, vol. 10 ( 4 ) , pp . 2011 - 2026 . WO 2012078688 A2 6 / 2012 Edge A . S ., et al. , “ Deglycosylation of Glycoproteins by WO 2012087336 A1 6 / 2012 Trifluoromethanesulfonic Acid , ” Analytical Biochemistry , 1981, WO 2012088254 Al 6 / 2012 vol. 118 ( 1 ) , pp . 131 - 137 . Enns C . A . , et al ., “ The Transferrin Receptor, ” Biomembranes , 1996 , OTHER PUBLICATIONS vol. 4 , pp . 255 -287 . Foote J. , et al ., “ Antibody Framework Residues Affecting the Abba M . C . , et al.
Load more

Recommended publications
  • Single-Cell RNA Sequencing Demonstrates the Molecular and Cellular Reprogramming of Metastatic Lung Adenocarcinoma
    ARTICLE https://doi.org/10.1038/s41467-020-16164-1 OPEN Single-cell RNA sequencing demonstrates the molecular and cellular reprogramming of metastatic lung adenocarcinoma Nayoung Kim 1,2,3,13, Hong Kwan Kim4,13, Kyungjong Lee 5,13, Yourae Hong 1,6, Jong Ho Cho4, Jung Won Choi7, Jung-Il Lee7, Yeon-Lim Suh8,BoMiKu9, Hye Hyeon Eum 1,2,3, Soyean Choi 1, Yoon-La Choi6,10,11, Je-Gun Joung1, Woong-Yang Park 1,2,6, Hyun Ae Jung12, Jong-Mu Sun12, Se-Hoon Lee12, ✉ ✉ Jin Seok Ahn12, Keunchil Park12, Myung-Ju Ahn 12 & Hae-Ock Lee 1,2,3,6 1234567890():,; Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell tran- scriptome profiling of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions. 1 Samsung Genome Institute, Samsung Medical Center, Seoul 06351, Korea.
    [Show full text]
  • Cell Communication and Signaling Biomed Central
    Cell Communication and Signaling BioMed Central Review Open Access Extravasation of leukocytes in comparison to tumor cells Carina Strell and Frank Entschladen* Address: Institute of Immunology, Witten/Herdecke University, Stockumer Str. 10, 58448 Witten, Germany Email: Carina Strell - [email protected]; Frank Entschladen* - [email protected] * Corresponding author Published: 4 December 2008 Received: 18 November 2008 Accepted: 4 December 2008 Cell Communication and Signaling 2008, 6:10 doi:10.1186/1478-811X-6-10 This article is available from: http://www.biosignaling.com/content/6/1/10 © 2008 Strell and Entschladen; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract The multi-step process of the emigration of cells from the blood stream through the vascular endothelium into the tissue has been termed extravasation. The extravasation of leukocytes is fairly well characterized down to the molecular level, and has been reviewed in several aspects. Comparatively little is known about the extravasation of tumor cells, which is part of the hematogenic metastasis formation. Although the steps of the process are basically the same in leukocytes and tumor cells, i.e. rolling, adhesion, transmigration (diapedesis), the molecules that are involved are different. A further important difference is that leukocyte interaction with the endothelium changes the endothelial integrity only temporarily, whereas tumor cell interaction leads to an irreversible damage of the endothelial architecture. Moreover, tumor cells utilize leukocytes for their extravasation as linkers to the endothelium.
    [Show full text]
  • Lysosomal Membrane Glycoproteins Bind Cholesterol and Contribute to Lysosomal Cholesterol Export
    1 Lysosomal membrane glycoproteins bind cholesterol and 2 contribute to lysosomal cholesterol export 3 4 Jian Li and Suzanne R. Pfeffer* 5 Department of Biochemistry, Stanford University School of Medicine 6 Stanford, CA USA 94305-5307 7 8 *Correspondence to: [email protected]. 9 10 Abstract: LAMP1 and LAMP2 proteins are highly abundant, ubiquitous, mammalian proteins 11 that line the lysosome limiting membrane, and protect it from lysosomal hydrolase action. 12 LAMP2 deficiency causes Danon’s disease, an X-linked hypertrophic cardiomyopathy. LAMP2 13 is needed for chaperone-mediated autophagy, and its expression improves tissue function in 14 models of aging. We show here that LAMP1 and LAMP2 bind cholesterol in a manner that 15 buries the cholesterol 3β-hydroxyl group; they also bind tightly to NPC1 and NPC2 proteins that 16 export cholesterol from lysosomes. Quantitation of cellular LAMP2 and NPC1 protein levels 17 suggest that LAMP proteins represent a significant cholesterol binding site at the lysosome 18 limiting membrane, and may signal cholesterol availability. Functional rescue experiments show 19 that the ability of LAMP2 to facilitate cholesterol export from lysosomes relies on its ability to 20 bind cholesterol directly. 21 22 23 Introduction 24 Eukaryotic lysosomes are acidic, membrane-bound organelles that contain proteases, lipases and 25 nucleases and degrade cellular components to regenerate catabolic precursors for cellular use (1- 26 3). Lysosomes are crucial for the degradation of substrates from the cytoplasm, as well as 27 membrane bound compartments derived from the secretory, endocytic, autophagic and 28 phagocytic pathways. The limiting membrane of lysosomes is lined with so-called lysosomal 29 membrane glycoproteins (LAMPs) that are comprised of a short cytoplasmic domain, a single 30 transmembrane span, and a highly, N- and O-glycosylated lumenal domain (4-6).
    [Show full text]
  • Sensitization to the Lysosomal Cell Death Pathway by Oncogene- Induced Down-Regulation of Lysosome-Associated Membrane Proteins 1 and 2
    Research Article Sensitization to the Lysosomal Cell Death Pathway by Oncogene- Induced Down-regulation of Lysosome-Associated Membrane Proteins 1 and 2 Nicole Fehrenbacher,1 Lone Bastholm,2 Thomas Kirkegaard-Sørensen,1 Bo Rafn,1 Trine Bøttzauw,1 Christina Nielsen,1 Ekkehard Weber,3 Senji Shirasawa,4 Tuula Kallunki,1 and Marja Ja¨a¨ttela¨1 1Apoptosis Department and Centre for Genotoxic Stress Response, Institute for Cancer Biology, Danish Cancer Society; 2Institute of Molecular Pathology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark; 3Institute of Physiological Chemistry, Medical Faculty, Martin-Luther-University Halle-Wittenberg, Halle, Germany; and 4Department of Cell Biology, School of Medicine, Fukuoka University, Fukuoka, Japan Abstract molecules of the cell to breakdown products available for Expression and activity of lysosomal cysteine cathepsins metabolic reuse (3, 4). Cathepsin proteases are among the best- correlate with the metastatic capacity and aggressiveness of studied lysosomal hydrolases. They are maximally active at the tumors. Here, we show that transformation of murine acidic pH of lysosomes (pH 4–5). However, many of them can be Y527F embryonic fibroblasts with v-H-ras or c-src changes the active at the neutral pH outside lysosomes, albeit with a decreased distribution, density, and ultrastructure of the lysosomes, efficacy and/or altered specificity (5). For example, transformation and tumor environment enhance the expression of lysosomal decreases the levels of lysosome-associated membrane pro- teins (LAMP-1 and LAMP-2) in an extracellular signal- cysteine cathepsins and increase their secretion into the extracel- regulated kinase (ERK)- and cathepsin-dependent manner, lular space (6). Once outside the tumor cells, cathepsins stimulate and sensitizes the cells to lysosomal cell death pathways angiogenesis, tumor growth, and invasion in murine cancer induced by various anticancer drugs (i.e., cisplatin, etoposide, models, thereby enhancing cancer progression (7, 8).
    [Show full text]
  • Dipeptidase Aminodipeptidase, Quiescent Cell Proline of a Novel
    Vesicular Localization and Characterization of a Novel Post-Proline-Cleaving Aminodipeptidase, Quiescent Cell Proline Dipeptidase This information is current as of September 26, 2021. Murali Chiravuri, Fernando Agarraberes, Suzanne L. Mathieu, Henry Lee and Brigitte T. Huber J Immunol 2000; 165:5695-5702; ; doi: 10.4049/jimmunol.165.10.5695 http://www.jimmunol.org/content/165/10/5695 Downloaded from References This article cites 28 articles, 18 of which you can access for free at: http://www.jimmunol.org/content/165/10/5695.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 26, 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 © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Vesicular Localization and Characterization of a Novel Post-Proline-Cleaving Aminodipeptidase, Quiescent Cell Proline Dipeptidase1 Murali Chiravuri,* Fernando Agarraberes,† Suzanne L. Mathieu,* Henry Lee,* and Brigitte T. Huber2* A large number of chemokines, cytokines, and signal peptides share a highly conserved X-Pro motif on the N-terminus.
    [Show full text]
  • Fluid Biomarkers in Frontotemporal Dementia: Past, Present and Future
    Neurodegeneration J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2020-323520 on 13 November 2020. Downloaded from Review Fluid biomarkers in frontotemporal dementia: past, present and future Imogen Joanna Swift ,1 Aitana Sogorb- Esteve,1,2 Carolin Heller ,1 Matthis Synofzik,3,4 Markus Otto ,5 Caroline Graff,6,7 Daniela Galimberti ,8,9 Emily Todd,2 Amanda J Heslegrave,1 Emma Louise van der Ende ,10 John Cornelis Van Swieten ,10 Henrik Zetterberg,1,11 Jonathan Daniel Rohrer 2 ► Additional material is ABSTRACT into a behavioural form (behavioural variant fron- published online only. To view, The frontotemporal dementia (FTD) spectrum of totemporal dementia (bvFTD)), a language variant please visit the journal online (primary progressive aphasia (PPA)) and a motor (http:// dx. doi. org/ 10. 1136/ neurodegenerative disorders includes a heterogeneous jnnp- 2020- 323520). group of conditions. However, following on from a series presentation (either FTD with amyotrophic lateral of important molecular studies in the early 2000s, major sclerosis (FTD- ALS) or an atypical parkinsonian For numbered affiliations see advances have now been made in the understanding disorder). Neuroanatomically, the FTD spectrum end of article. of the pathological and genetic underpinnings of the is characteristically associated with dysfunction and disease. In turn, alongside the development of novel neuronal loss in the frontal and temporal lobes, but Correspondence to more widespread cortical, subcortical, cerebellar Dr Jonathan Daniel Rohrer, methodologies for measuring proteins and other Dementia Research molecules in biological fluids, the last 10 years have and brainstem involvement is now recognised. Centre, Department of seen a huge increase in biomarker studies within FTD.
    [Show full text]
  • An Underappreciated Yet Critical Hurdle for Successful Cancer Immunotherapy Robert Sackstein1,2,3,4, Tobias Schatton1,3,5,6 and Steven R Barthel1,3,5
    Laboratory Investigation (2017) 97, 669–697 © 2017 USCAP, Inc All rights reserved 0023-6837/17 $32.00 PATHOBIOLOGY IN FOCUS T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy Robert Sackstein1,2,3,4, Tobias Schatton1,3,5,6 and Steven R Barthel1,3,5 Advances in cancer immunotherapy have offered new hope for patients with metastatic disease. This unfolding success story has been exemplified by a growing arsenal of novel immunotherapeutics, including blocking antibodies targeting immune checkpoint pathways, cancer vaccines, and adoptive cell therapy (ACT). Nonetheless, clinical benefit remains highly variable and patient-specific, in part, because all immunotherapeutic regimens vitally hinge on the capacity of endogenous and/or adoptively transferred T-effector (Teff) cells, including chimeric antigen receptor (CAR) T cells, to home efficiently into tumor target tissue. Thus, defects intrinsic to the multi-step T-cell homing cascade have become an obvious, though significantly underappreciated contributor to immunotherapy resistance. Conspicuous have been low intralesional frequencies of tumor-infiltrating T-lymphocytes (TILs) below clinically beneficial threshold levels, and peripheral rather than deep lesional TIL infiltration. Therefore, a Teff cell ‘homing deficit’ may arguably represent a dominant factor responsible for ineffective immunotherapeutic outcomes, as tumors resistant to immune-targeted killing thrive in such permissive, immune-vacuous microenvironments. Fortunately, emerging
    [Show full text]
  • Protein Composition of the Hepatitis a Virus Quasi-Envelope
    Protein composition of the hepatitis A virus quasi-envelope Kevin L. McKnighta,b,c, Ling Xiec,d, Olga González-Lópeza,b,c, Efraín E. Rivera-Serranoa,b,c, Xian Chenc,d, and Stanley M. Lemona,b,c,1 aDepartment of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7292; bDepartment of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7292; cLineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295; and dDepartment of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7260 Edited by Mary K. Estes, Baylor College of Medicine, Houston, TX, and approved April 12, 2017 (received for review November 27, 2016) The Picornaviridae are a diverse family of RNA viruses including many within extracellular vesicles before cell lysis, often with many pathogens of medical and veterinary importance. Classically consid- capsids packaged within a single vesicle (4–6). The cellular egress ered “nonenveloped,” recent studies show that some picornaviruses, of these classically nonenveloped viruses in membrane-bound notably hepatitis A virus (HAV; genus Hepatovirus) and some mem- vesicles has blurred the distinction between enveloped and bers of the Enterovirus genus, are released from cells nonlytically in nonenveloped viruses and has important implications for path- membranous vesicles. To better understand the biogenesis of quasi- ogenesis (2). enveloped HAV (eHAV) virions, we conducted a quantitative proteo- Several lines of evidence indicate that the biogenesis of quasi- mics analysis of eHAV purified from cell-culture supernatant fluids by enveloped eHAV virions is dependent upon components of the isopycnic ultracentrifugation.
    [Show full text]
  • Glycosylation Inhibition Reduces Cholesterol Accumulation in NPC1 Protein-Deficient Cells
    Glycosylation inhibition reduces cholesterol accumulation in NPC1 protein-deficient cells Jian Li1, Maika S. Deffieu1, Peter L. Lee1, Piyali Saha, and Suzanne R. Pfeffer2 Department of Biochemistry, Stanford University School of Medicine, Stanford, CA 94305-5307 Edited by Stuart A. Kornfeld, Washington University School of Medicine, St. Louis, MO, and approved October 28, 2015 (received for review October 16, 2015) Lysosomes are lined with a glycocalyx that protects the limiting In this paper, we have used two approaches to modify the gly- membrane from the action of degradative enzymes. We tested the cocalyx. Alteration of glycosylation decreases lysosomal cholesterol hypothesis that Niemann-Pick type C 1 (NPC1) protein aids the transfer levels in NPC1-deficient Chinese hamster ovary (CHO) and human of low density lipoprotein-derived cholesterol across this glycocalyx. A cells. These experiments support a model in which NPC1 protein prediction of this model is that cells will be less dependent upon NPC1 functions to help cholesterol traverse the glycocalyx that lines the if their glycocalyx is decreased in density. Lysosome cholesterol content interior of lysosome limiting membranes. was significantly lower after treatment of NPC1-deficient human fibroblasts with benzyl-2-acetamido-2-deoxy-α-D-galactopyrano- Results and Discussion side, an inhibitor of O-linked glycosylation. Direct biochemical LAMP1 and LAMP2 proteins represent the major glycoproteins measurement of cholesterol showed that lysosomes purified from of the lysosome membrane (12). These proteins are glycosylated NPC1-deficient fibroblasts contained at least 30% less cholesterol on both asparagine residues (N linked) and serine or threonine when O-linked glycosylation was blocked.
    [Show full text]
  • Supplemental Materials 1 SUPPLEMENTAL METHODS CSC
    BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) J Immunother Cancer Identification of MM immunotherapy targets by MS – Supplemental materials 1 SUPPLEMENTAL METHODS 2 CSC-technology 3 Approximately 100 million cells from each biological replicate (n=3-6) were taken 4 through the CSC-Technology workflow as previously described in detail.(1-3) Cells were 5 washed with PBS and oxidized by treatment with 1 mM sodium meta-periodate (Pierce, 6 Rockford, IL) in PBS pH 7.6 for 15 min at 4°C followed by 2.5 mg/ml biocytin hydrazide 7 (Biotium, Hayward, CA) in PBS pH 6.5 for 1 hour at 4°C. Cells were then collected and 8 homogenized in 10mM Tris pH 7.5, 0.5 mM MgCl2 and the resulting cell lysate was centrifuged 9 at 800 x g for 10 min at 4°C. The supernatant was centrifuged at 210,000 x g for 16 hours at 4°C 10 to collect the membranes. The supernatant was removed and the membrane protein pellet was 11 washed with 25 mM Na2CO3 to disrupt peripheral protein interactions. To the resulting 12 membrane pellet, 300µl 100 mM NH4HCO3, 5 mM Tris(2-carboxyethyl) phosphine (Sigma, St. 13 Louis, MO), and 0.1% (v/v) Rapigest (Waters, Milford, MA) were added and placed on a 14 Thermomixer (750 rpm) to continuously vortex. Proteins were allowed to reduce for 10 min at 15 25°C followed by alklylation with 10 mM iodoacetamide for 30 min.
    [Show full text]
  • Lamp2s and Chaperone-Mediated Autophagy 4443 of Trichloroacetic Acid to a final Concentration of 10%
    Journal of Cell Science 113, 4441-4450 (2000) 4441 Printed in Great Britain © The Company of Biologists Limited 2000 JCS1804 Unique properties of lamp2a compared to other lamp2 isoforms A. M. Cuervo* and J. F. Dice Department of Physiology, Tufts University School of Medicine, Boston, MA, USA *Author for correspondence (e-mail: [email protected]) Accepted 28 September; published on WWW 16 November 2000 SUMMARY Lamp2a acts as a receptor in the lysosomal membrane for other lamp2s. Four positively-charged amino acids substrate proteins of chaperone-mediated autophagy. uniquely present in the cytosolic tail of lamp2a are required Using antibodies specific for the cytosolic tail of lamp2a and for the binding of substrate proteins. Lamp2a also others recognizing all lamp2 isoforms, we found that in rat distributes to an unique subpopulation of perinuclear liver lamp2a represents 25% of lamp2s in the lysosome. We lysosomes in cultured fibroblasts in response to serum show that lamp2a levels in the lysosomal membrane in withdrawal, and lamp2a, more than other lamp2s, tends to rat liver and fibroblasts in culture directly correlate with multimerize. These characteristics may be important for rates of chaperone-mediated autophagy in a variety lamp2a to act as a receptor for chaperone-mediated of physiological and pathological conditions. The autophagy. concentration of other lamp2s in the lysosomal membrane show no correlation under the same conditions. Key words: Lysosome, Protein degradation, Membrane receptor, Furthermore, substrate proteins bind to lamp2a but not to Chaperone, Rat liver INTRODUCTION Part of this matrix form of lamp2 reversibly aggregates with other lysosomal enzymes in a pH-dependent manner (Jadot et Lysosome-associated membrane proteins (lamps) are a al., 1997).
    [Show full text]
  • Integrin Binding and Mechanical Tension Induce Movement of Mrna and Ribosomes to Focal Adhesions Marina E
    letters to nature costimulates primary allogeneic proliferative responses and cytotoxicity mediated by small, resting T lymphocytes. J. Exp. Med. 175, 353–360 (1992). 22. Kagi, D. et al. Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity. Science 265, 528–530 (1994). 23. Brunner, T. et al. Cell-autonomous Fas (CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T-cell hybridomas. Nature 373, 441–444 (1995). 24. Dhein, J., Walczak, H., Baumler, C., Debatin, K.-M. & Krammer, P. H. Autocrine T-cell suicide mediated by APO-1/(Fas/CD95). Nature 373, 438–441 (1995). 25. Ju, S.-T. et al. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 373, 444-448 (1995). 26. Ja¨a¨ttela, M., Benedict, M., Tewari, M., Shayman, J. A. & Dixit, V. M. Bcl-x and Bcl-2 inhibit TNF and Fas-induced apoptosis and activation of phospholipase A2 in breast carcinoma cells. Oncogene 10, 2297–2305 (1995). + 8 27. Subramanian, T., Kuppuswamy, M., Mak, S. & Chinnadurai, G. Adenovirus cyt locus, which controls cell transformation and tumorigenicity, is an allele of lp+ locus, which codes for a 19-kilodalton tumor antigen. J. Virol. 52, 336–343 (1984). 28. Babiss, L. E., Fisher, P. B. & Ginsberg, H. S. Effect on transformation of mutations in the early region 1b-encoded 21- and 55-kilodalton proteins of adenovirus 5. J. Virol. 52, 389–395 (1984). 29. Ranheim, T. S. et al. Characterization of mutants within the gene for the adenovirus E3 14.7- kilodalton protein which prevents cytolysis by tumor necrosis factor.
    [Show full text]