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  • 1
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    Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-11-28
    Description: Human tumours typically harbour a remarkable number of somatic mutations. If presented on major histocompatibility complex class I molecules (MHCI), peptides containing these mutations could potentially be immunogenic as they should be recognized as 'non-self' neo-antigens by the adaptive immune system. Recent work has confirmed that mutant peptides can serve as T-cell epitopes. However, few mutant epitopes have been described because their discovery required the laborious screening of patient tumour-infiltrating lymphocytes for their ability to recognize antigen libraries constructed following tumour exome sequencing. We sought to simplify the discovery of immunogenic mutant peptides by characterizing their general properties. We developed an approach that combines whole-exome and transcriptome sequencing analysis with mass spectrometry to identify neo-epitopes in two widely used murine tumour models. Of the 〉1,300 amino acid changes identified, approximately 13% were predicted to bind MHCI, a small fraction of which were confirmed by mass spectrometry. The peptides were then structurally modelled bound to MHCI. Mutations that were solvent-exposed and therefore accessible to T-cell antigen receptors were predicted to be immunogenic. Vaccination of mice confirmed the approach, with each predicted immunogenic peptide yielding therapeutically active T-cell responses. The predictions also enabled the generation of peptide-MHCI dextramers that could be used to monitor the kinetics and distribution of the anti-tumour T-cell response before and after vaccination. These findings indicate that a suitable prediction algorithm may provide an approach for the pharmacodynamic monitoring of T-cell responses as well as for the development of personalized vaccines in cancer patients.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yadav, Mahesh -- Jhunjhunwala, Suchit -- Phung, Qui T -- Lupardus, Patrick -- Tanguay, Joshua -- Bumbaca, Stephanie -- Franci, Christian -- Cheung, Tommy K -- Fritsche, Jens -- Weinschenk, Toni -- Modrusan, Zora -- Mellman, Ira -- Lill, Jennie R -- Delamarre, Lelia -- England -- Nature. 2014 Nov 27;515(7528):572-6. doi: 10.1038/nature14001.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genentech, South San Francisco, California 94080, USA. ; Immatics Biotechnologies GmbH, 72076 Tubingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25428506" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CD8-Positive T-Lymphocytes/immunology ; Cancer Vaccines/immunology ; Cell Line, Tumor ; Exome/*genetics ; Female ; Gene Expression Profiling ; Immunity, Cellular/immunology ; Immunogenetic Phenomena/*genetics ; Immunoprecipitation ; *Mass Spectrometry ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; *Mutation ; Neoplasms/*genetics/immunology ; Peptides/genetics ; Protein Structure, Tertiary
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Novel antibody-antibiotic conjugate eliminates intracellular S. aureus (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-11-05
    Description: Staphylococcus aureus is considered to be an extracellular pathogen. However, survival of S. aureus within host cells may provide a reservoir relatively protected from antibiotics, thus enabling long-term colonization of the host and explaining clinical failures and relapses after antibiotic therapy. Here we confirm that intracellular reservoirs of S. aureus in mice comprise a virulent subset of bacteria that can establish infection even in the presence of vancomycin, and we introduce a novel therapeutic that effectively kills intracellular S. aureus. This antibody-antibiotic conjugate consists of an anti-S. aureus antibody conjugated to a highly efficacious antibiotic that is activated only after it is released in the proteolytic environment of the phagolysosome. The antibody-antibiotic conjugate is superior to vancomycin for treatment of bacteraemia and provides direct evidence that intracellular S. aureus represents an important component of invasive infections.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lehar, Sophie M -- Pillow, Thomas -- Xu, Min -- Staben, Leanna -- Kajihara, Kimberly K -- Vandlen, Richard -- DePalatis, Laura -- Raab, Helga -- Hazenbos, Wouter L -- Morisaki, J Hiroshi -- Kim, Janice -- Park, Summer -- Darwish, Martine -- Lee, Byoung-Chul -- Hernandez, Hilda -- Loyet, Kelly M -- Lupardus, Patrick -- Fong, Rina -- Yan, Donghong -- Chalouni, Cecile -- Luis, Elizabeth -- Khalfin, Yana -- Plise, Emile -- Cheong, Jonathan -- Lyssikatos, Joseph P -- Strandh, Magnus -- Koefoed, Klaus -- Andersen, Peter S -- Flygare, John A -- Wah Tan, Man -- Brown, Eric J -- Mariathasan, Sanjeev -- England -- Nature. 2015 Nov 19;527(7578):323-8. doi: 10.1038/nature16057. Epub 2015 Nov 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Infectious Diseases Department, Genentech Inc., South San Francisco, California 94080, USA. ; Medicinal Chemistry Department, Genentech Inc., South San Francisco, California 94080, USA. ; Translational Immunology Department, Genentech Inc., South San Francisco, California 94080, USA. ; Protein Chemistry Department, Genentech Inc., South San Francisco, California 94080, USA. ; Biochemical and Cellular Pharmacology Department, Genentech Inc., South San Francisco, California 94080, USA. ; Structural Biology Department, Genentech Inc., South San Francisco, California 94080, USA. ; Pathology Department, Genentech Inc., South San Francisco, California 94080, USA. ; Drug metabolism and Pharmacokinetics Department, Genentech Inc., South San Francisco, California 94080, USA. ; Symphogen A/S, Pederstrupvej 93, DK-2750 Ballerup, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26536114" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Bacterial Agents/*pharmacology/therapeutic use ; *Bacteremia/drug therapy/microbiology ; Carrier State/drug therapy/microbiology ; Drug Design ; Female ; Immunoconjugates/chemistry/*pharmacology/*therapeutic use ; Intracellular Space/drug effects/*microbiology ; Methicillin-Resistant Staphylococcus aureus/drug effects/pathogenicity ; Mice ; Microbial Sensitivity Tests ; Phagosomes/drug effects/metabolism/microbiology ; Staphylococcal Infections/drug therapy/*microbiology/pathology ; Staphylococcus aureus/*drug effects/pathogenicity ; Vancomycin/*pharmacology/therapeutic use
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Structure of the pseudokinase-kinase domains from protein kinase TYK2 reveals a mechanism for Janus kinase (JAK) autoinhibition (2014)
    National Academy of Sciences
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    Publication Date: 2014-05-19
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    Structure of TYK2 pseudokinase-kinase [Biochemistry] (2014)
    National Academy of Sciences
    Details
    Publication Date: 2014-06-04
    Description: Janus kinases (JAKs) are receptor-associated multidomain tyrosine kinases that act downstream of many cytokines and interferons. JAK kinase activity is regulated by the adjacent pseudokinase domain via an unknown mechanism. Here, we report the 2.8-Å structure of the two-domain pseudokinase–kinase module from the JAK family member TYK2 in its autoinhibited...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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