Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy
Identifieur interne : 000759 ( Ncbi/Merge ); précédent : 000758; suivant : 000760Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy
Auteurs : Yan Zhang [États-Unis] ; Xuexiang Du [États-Unis] ; Mingyue Liu [États-Unis] ; Fei Tang [États-Unis] ; Peng Zhang [États-Unis] ; Chunxia Ai [États-Unis] ; James K. Fields [États-Unis] ; Eric J. Sundberg [États-Unis] ; Olga S. Latinovic [États-Unis] ; Martin Devenport [États-Unis] ; Pan Zheng [États-Unis] ; Yang Liu [États-Unis]Source :
- Cell Research [ 1001-0602 ] ; 2019.
Abstract
It remains unclear why the clinically used anti-CTLA-4 antibodies, popularly called checkpoint inhibitors, have severe immunotherapy-related adverse effects (irAEs) and yet suboptimal cancer immunotherapeutic effects (CITE). Here we report that while irAE-prone Ipilimumab and TremeIgG1 rapidly direct cell surface CTLA-4 for lysosomal degradation, the non-irAE-prone antibodies we generated, HL12 or HL32, dissociate from CTLA-4 after endocytosis and allow CTLA-4 recycling to cell surface by the LRBA-dependent mechanism. Disrupting CTLA-4 recycling results in robust CTLA-4 downregulation by all anti-CTLA-4 antibodies and confers toxicity to a non-irAE-prone anti-CTLA-4 mAb. Conversely, increasing the pH sensitivity of TremeIgG1 by introducing designed tyrosine-to-histidine mutations prevents antibody-triggered lysosomal CTLA-4 downregulation and dramatically attenuates irAE. Surprisingly, by avoiding CTLA-4 downregulation and due to their increased bioavailability, pH-sensitive anti-CTLA-4 antibodies are more effective in intratumor regulatory T-cell depletion and rejection of large established tumors. Our data establish a new paradigm for cancer research that allows for abrogating irAE while increasing CITE of anti-CTLA-4 antibodies.
Url:
DOI: 10.1038/s41422-019-0184-1
PubMed: 31267017
PubMed Central: 6796842
Links toward previous steps (curation, corpus...)
- to stream Pmc, to step Corpus: 000089
- to stream Pmc, to step Curation: 000089
- to stream Pmc, to step Checkpoint: 000719
Links to Exploration step
PMC:6796842Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy</title><author><name sortKey="Zhang, Yan" sort="Zhang, Yan" uniqKey="Zhang Y" first="Yan" last="Zhang">Yan Zhang</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Immunotherapy,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Du, Xuexiang" sort="Du, Xuexiang" uniqKey="Du X" first="Xuexiang" last="Du">Xuexiang Du</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Immunotherapy,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Liu, Mingyue" sort="Liu, Mingyue" uniqKey="Liu M" first="Mingyue" last="Liu">Mingyue Liu</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Immunotherapy,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Tang, Fei" sort="Tang, Fei" uniqKey="Tang F" first="Fei" last="Tang">Fei Tang</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Immunotherapy,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Zhang, Peng" sort="Zhang, Peng" uniqKey="Zhang P" first="Peng" last="Zhang">Peng Zhang</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Immunotherapy,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Ai, Chunxia" sort="Ai, Chunxia" uniqKey="Ai C" first="Chunxia" last="Ai">Chunxia Ai</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Immunotherapy,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Fields, James K" sort="Fields, James K" uniqKey="Fields J" first="James K." last="Fields">James K. Fields</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Basic Science Division, Institute of Human Virology,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Graduate Program in Molecular Microbiology and Immunology,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Sundberg, Eric J" sort="Sundberg, Eric J" uniqKey="Sundberg E" first="Eric J." last="Sundberg">Eric J. Sundberg</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Basic Science Division, Institute of Human Virology,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Department of Microbiology and Immunology,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Latinovic, Olga S" sort="Latinovic, Olga S" uniqKey="Latinovic O" first="Olga S." last="Latinovic">Olga S. Latinovic</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Basic Science Division, Institute of Human Virology,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Department of Microbiology and Immunology,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Devenport, Martin" sort="Devenport, Martin" uniqKey="Devenport M" first="Martin" last="Devenport">Martin Devenport</name><affiliation wicri:level="2"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="GRID">grid.417460.0</institution-id><institution>OncoImmune, Inc,</institution></institution-wrap>Rockville, MD 20850 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Rockville</wicri:cityArea></affiliation></author><author><name sortKey="Zheng, Pan" sort="Zheng, Pan" uniqKey="Zheng P" first="Pan" last="Zheng">Pan Zheng</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Immunotherapy,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="GRID">grid.417460.0</institution-id><institution>OncoImmune, Inc,</institution></institution-wrap>Rockville, MD 20850 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Rockville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Department of Surgery,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Liu, Yang" sort="Liu, Yang" uniqKey="Liu Y" first="Yang" last="Liu">Yang Liu</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Immunotherapy,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="GRID">grid.417460.0</institution-id><institution>OncoImmune, Inc,</institution></institution-wrap>Rockville, MD 20850 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Rockville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Department of Surgery,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31267017</idno><idno type="pmc">6796842</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796842</idno><idno type="RBID">PMC:6796842</idno><idno type="doi">10.1038/s41422-019-0184-1</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000089</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000089</idno><idno type="wicri:Area/Pmc/Curation">000089</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000089</idno><idno type="wicri:Area/Pmc/Checkpoint">000719</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000719</idno><idno type="wicri:Area/Ncbi/Merge">000759</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy</title><author><name sortKey="Zhang, Yan" sort="Zhang, Yan" uniqKey="Zhang Y" first="Yan" last="Zhang">Yan Zhang</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Immunotherapy,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Du, Xuexiang" sort="Du, Xuexiang" uniqKey="Du X" first="Xuexiang" last="Du">Xuexiang Du</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Immunotherapy,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Liu, Mingyue" sort="Liu, Mingyue" uniqKey="Liu M" first="Mingyue" last="Liu">Mingyue Liu</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Immunotherapy,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Tang, Fei" sort="Tang, Fei" uniqKey="Tang F" first="Fei" last="Tang">Fei Tang</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Immunotherapy,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Zhang, Peng" sort="Zhang, Peng" uniqKey="Zhang P" first="Peng" last="Zhang">Peng Zhang</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Immunotherapy,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Ai, Chunxia" sort="Ai, Chunxia" uniqKey="Ai C" first="Chunxia" last="Ai">Chunxia Ai</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Immunotherapy,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Fields, James K" sort="Fields, James K" uniqKey="Fields J" first="James K." last="Fields">James K. Fields</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Basic Science Division, Institute of Human Virology,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Graduate Program in Molecular Microbiology and Immunology,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Sundberg, Eric J" sort="Sundberg, Eric J" uniqKey="Sundberg E" first="Eric J." last="Sundberg">Eric J. Sundberg</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Basic Science Division, Institute of Human Virology,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Department of Microbiology and Immunology,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Latinovic, Olga S" sort="Latinovic, Olga S" uniqKey="Latinovic O" first="Olga S." last="Latinovic">Olga S. Latinovic</name><affiliation wicri:level="2"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Basic Science Division, Institute of Human Virology,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Department of Microbiology and Immunology,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Devenport, Martin" sort="Devenport, Martin" uniqKey="Devenport M" first="Martin" last="Devenport">Martin Devenport</name><affiliation wicri:level="2"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="GRID">grid.417460.0</institution-id><institution>OncoImmune, Inc,</institution></institution-wrap>Rockville, MD 20850 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Rockville</wicri:cityArea></affiliation></author><author><name sortKey="Zheng, Pan" sort="Zheng, Pan" uniqKey="Zheng P" first="Pan" last="Zheng">Pan Zheng</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Immunotherapy,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="GRID">grid.417460.0</institution-id><institution>OncoImmune, Inc,</institution></institution-wrap>Rockville, MD 20850 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Rockville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Department of Surgery,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author><author><name sortKey="Liu, Yang" sort="Liu, Yang" uniqKey="Liu Y" first="Yang" last="Liu">Yang Liu</name><affiliation wicri:level="2"><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Immunotherapy,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="GRID">grid.417460.0</institution-id><institution>OncoImmune, Inc,</institution></institution-wrap>Rockville, MD 20850 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Rockville</wicri:cityArea></affiliation><affiliation wicri:level="2"><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Department of Surgery,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</nlm:aff><country xml:lang="fr">États-Unis</country><placeName><region type="state">Maryland</region></placeName><wicri:cityArea>Baltimore</wicri:cityArea></affiliation></author></analytic><series><title level="j">Cell Research</title><idno type="ISSN">1001-0602</idno><idno type="eISSN">1748-7838</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">It remains unclear why the clinically used anti-CTLA-4 antibodies, popularly called checkpoint inhibitors, have severe immunotherapy-related adverse effects (irAEs) and yet suboptimal cancer immunotherapeutic effects (CITE). Here we report that while irAE-prone Ipilimumab and TremeIgG1 rapidly direct cell surface CTLA-4 for lysosomal degradation, the non-irAE-prone antibodies we generated, HL12 or HL32, dissociate from CTLA-4 after endocytosis and allow CTLA-4 recycling to cell surface by the LRBA-dependent mechanism. Disrupting CTLA-4 recycling results in robust CTLA-4 downregulation by all anti-CTLA-4 antibodies and confers toxicity to a non-irAE-prone anti-CTLA-4 mAb. Conversely, increasing the pH sensitivity of TremeIgG1 by introducing designed tyrosine-to-histidine mutations prevents antibody-triggered lysosomal CTLA-4 downregulation and dramatically attenuates irAE. Surprisingly, by avoiding CTLA-4 downregulation and due to their increased bioavailability, pH-sensitive anti-CTLA-4 antibodies are more effective in intratumor regulatory T-cell depletion and rejection of large established tumors. Our data establish a new paradigm for cancer research that allows for abrogating irAE while increasing CITE of anti-CTLA-4 antibodies.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Linsley, Ps" uniqKey="Linsley P">PS Linsley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Freeman, Gj" uniqKey="Freeman G">GJ Freeman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wu, Y" uniqKey="Wu Y">Y Wu</name></author><author><name sortKey="Guo, Y" uniqKey="Guo Y">Y Guo</name></author><author><name sortKey="Liu, Y" uniqKey="Liu Y">Y Liu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wing, K" uniqKey="Wing K">K Wing</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kuehn, Hs" uniqKey="Kuehn H">HS Kuehn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tivol, Ea" uniqKey="Tivol E">EA Tivol</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Waterhouse, P" uniqKey="Waterhouse P">P Waterhouse</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hou, Tz" uniqKey="Hou T">TZ Hou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Leach, Dr" uniqKey="Leach D">DR Leach</name></author><author><name sortKey="Krummel, Mf" uniqKey="Krummel M">MF Krummel</name></author><author><name sortKey="Allison, Jp" uniqKey="Allison J">JP Allison</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kocak, E" uniqKey="Kocak E">E Kocak</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mokyr, Mb" uniqKey="Mokyr M">MB Mokyr</name></author><author><name sortKey="Kalinichenko, T" uniqKey="Kalinichenko T">T Kalinichenko</name></author><author><name sortKey="Gorelik, L" uniqKey="Gorelik L">L Gorelik</name></author><author><name sortKey="Bluestone, Ja" uniqKey="Bluestone J">JA Bluestone</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hodi, Fs" uniqKey="Hodi F">FS Hodi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Phan, Gq" uniqKey="Phan G">GQ Phan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wolchok, Jd" uniqKey="Wolchok J">JD Wolchok</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Larkin, J" uniqKey="Larkin J">J Larkin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Postow, Ma" uniqKey="Postow M">MA Postow</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Weber, J" uniqKey="Weber J">J Weber</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sanmamed, Mf" uniqKey="Sanmamed M">MF Sanmamed</name></author><author><name sortKey="Chen, L" uniqKey="Chen L">L Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Calabrese, Lh" uniqKey="Calabrese L">LH Calabrese</name></author><author><name sortKey="Calabrese, C" uniqKey="Calabrese C">C Calabrese</name></author><author><name sortKey="Cappelli, Lc" uniqKey="Cappelli L">LC Cappelli</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Blank, Cu" uniqKey="Blank C">CU Blank</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Amaria, Rn" uniqKey="Amaria R">RN Amaria</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tawbi, Ha" uniqKey="Tawbi H">HA Tawbi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hellmann, Md" uniqKey="Hellmann M">MD Hellmann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Motzer, Rj" uniqKey="Motzer R">RJ Motzer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Maio, M" uniqKey="Maio M">M Maio</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Schadendorf, D" uniqKey="Schadendorf D">D Schadendorf</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wei, Sc" uniqKey="Wei S">SC Wei</name></author><author><name sortKey="Duffy, Cr" uniqKey="Duffy C">CR Duffy</name></author><author><name sortKey="Allison, Jp" uniqKey="Allison J">JP Allison</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Korman, Aj" uniqKey="Korman A">AJ Korman</name></author><author><name sortKey="Peggs, Ks" uniqKey="Peggs K">KS Peggs</name></author><author><name sortKey="Allison, Jp" uniqKey="Allison J">JP Allison</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Du, X" uniqKey="Du X">X Du</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Selby, Mj" uniqKey="Selby M">MJ Selby</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Simpson, Tr" uniqKey="Simpson T">TR Simpson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bulliard, Y" uniqKey="Bulliard Y">Y Bulliard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Du, X" uniqKey="Du X">X Du</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Linsley, Ps" uniqKey="Linsley P">PS Linsley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lo, B" uniqKey="Lo B">B Lo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ribas, A" uniqKey="Ribas A">A Ribas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Burr, Ml" uniqKey="Burr M">ML Burr</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Igawa, T" uniqKey="Igawa T">T Igawa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Arce Vargas, F" uniqKey="Arce Vargas F">F Arce Vargas</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Romano, E" uniqKey="Romano E">E Romano</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tarhini, Aa" uniqKey="Tarhini A">AA Tarhini</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Eggermont, Am" uniqKey="Eggermont A">AM Eggermont</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chuang, E" uniqKey="Chuang E">E Chuang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zou, W" uniqKey="Zou W">W Zou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pyzik, M" uniqKey="Pyzik M">M Pyzik</name></author><author><name sortKey="Rath, T" uniqKey="Rath T">T Rath</name></author><author><name sortKey="Lencer, Wi" uniqKey="Lencer W">WI Lencer</name></author><author><name sortKey="Baker, K" uniqKey="Baker K">K Baker</name></author><author><name sortKey="Blumberg, Rs" uniqKey="Blumberg R">RS Blumberg</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Liu, H" uniqKey="Liu H">H Liu</name></author><author><name sortKey="Saxena, A" uniqKey="Saxena A">A Saxena</name></author><author><name sortKey="Sidhu, Ss" uniqKey="Sidhu S">SS Sidhu</name></author><author><name sortKey="Wu, D" uniqKey="Wu D">D Wu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Anderson, M" uniqKey="Anderson M">M Anderson</name></author><author><name sortKey="Moshnikova, A" uniqKey="Moshnikova A">A Moshnikova</name></author><author><name sortKey="Engelman, Dm" uniqKey="Engelman D">DM Engelman</name></author><author><name sortKey="Reshetnyak, Yk" uniqKey="Reshetnyak Y">YK Reshetnyak</name></author><author><name sortKey="Andreev, Oa" uniqKey="Andreev O">OA Andreev</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Cell Res</journal-id><journal-id journal-id-type="iso-abbrev">Cell Res</journal-id><journal-title-group><journal-title>Cell Research</journal-title></journal-title-group><issn pub-type="ppub">1001-0602</issn><issn pub-type="epub">1748-7838</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31267017</article-id><article-id pub-id-type="pmc">6796842</article-id><article-id pub-id-type="publisher-id">184</article-id><article-id pub-id-type="doi">10.1038/s41422-019-0184-1</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes" equal-contrib="yes"><name><surname>Zhang</surname><given-names>Yan</given-names></name><address><email>yzhang@ihv.umaryland.edu</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Du</surname><given-names>Xuexiang</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Liu</surname><given-names>Mingyue</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Tang</surname><given-names>Fei</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Peng</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Ai</surname><given-names>Chunxia</given-names></name><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Fields</surname><given-names>James K.</given-names></name><xref ref-type="aff" rid="Aff2">2</xref><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Sundberg</surname><given-names>Eric J.</given-names></name><xref ref-type="aff" rid="Aff2">2</xref><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Latinovic</surname><given-names>Olga S.</given-names></name><xref ref-type="aff" rid="Aff2">2</xref><xref ref-type="aff" rid="Aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Devenport</surname><given-names>Martin</given-names></name><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Zheng</surname><given-names>Pan</given-names></name><address><email>pzheng@ihv.umaryland.edu</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff5">5</xref><xref ref-type="aff" rid="Aff6">6</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Liu</surname><given-names>Yang</given-names></name><address><email>yaliu@ihv.umaryland.edu</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff5">5</xref><xref ref-type="aff" rid="Aff6">6</xref></contrib><aff id="Aff1"><label>1</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Immunotherapy,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Divisions of Basic Science Division, Institute of Human Virology,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</aff><aff id="Aff3"><label>3</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Graduate Program in Molecular Microbiology and Immunology,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Department of Microbiology and Immunology,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</aff><aff id="Aff5"><label>5</label><institution-wrap><institution-id institution-id-type="GRID">grid.417460.0</institution-id><institution>OncoImmune, Inc,</institution></institution-wrap>Rockville, MD 20850 USA</aff><aff id="Aff6"><label>6</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 2175 4264</institution-id><institution-id institution-id-type="GRID">grid.411024.2</institution-id><institution>Department of Surgery,</institution><institution>University of Maryland Baltimore School of Medicine,</institution></institution-wrap>Baltimore, MD 21201 USA</aff></contrib-group><pub-date pub-type="epub"><day>2</day><month>7</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>2</day><month>7</month><year>2019</year></pub-date><pub-date pub-type="ppub"><month>8</month><year>2019</year></pub-date><volume>29</volume><issue>8</issue><fpage>609</fpage><lpage>627</lpage><history><date date-type="received"><day>18</day><month>3</month><year>2019</year></date><date date-type="accepted"><day>14</day><month>5</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s) 2019</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">It remains unclear why the clinically used anti-CTLA-4 antibodies, popularly called checkpoint inhibitors, have severe immunotherapy-related adverse effects (irAEs) and yet suboptimal cancer immunotherapeutic effects (CITE). Here we report that while irAE-prone Ipilimumab and TremeIgG1 rapidly direct cell surface CTLA-4 for lysosomal degradation, the non-irAE-prone antibodies we generated, HL12 or HL32, dissociate from CTLA-4 after endocytosis and allow CTLA-4 recycling to cell surface by the LRBA-dependent mechanism. Disrupting CTLA-4 recycling results in robust CTLA-4 downregulation by all anti-CTLA-4 antibodies and confers toxicity to a non-irAE-prone anti-CTLA-4 mAb. Conversely, increasing the pH sensitivity of TremeIgG1 by introducing designed tyrosine-to-histidine mutations prevents antibody-triggered lysosomal CTLA-4 downregulation and dramatically attenuates irAE. Surprisingly, by avoiding CTLA-4 downregulation and due to their increased bioavailability, pH-sensitive anti-CTLA-4 antibodies are more effective in intratumor regulatory T-cell depletion and rejection of large established tumors. Our data establish a new paradigm for cancer research that allows for abrogating irAE while increasing CITE of anti-CTLA-4 antibodies.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Tumour immunology</kwd><kwd>Cancer immunotherapy</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/100000060</institution-id><institution>U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)</institution></institution-wrap></funding-source><award-id>AI64350</award-id><principal-award-recipient><name><surname>Liu</surname><given-names>Mingyue</given-names></name></principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© IBCB, SIBS, CAS 2019</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc><affiliations><list><country><li>États-Unis</li></country><region><li>Maryland</li></region></list><tree><country name="États-Unis"><region name="Maryland"><name sortKey="Zhang, Yan" sort="Zhang, Yan" uniqKey="Zhang Y" first="Yan" last="Zhang">Yan Zhang</name></region><name sortKey="Ai, Chunxia" sort="Ai, Chunxia" uniqKey="Ai C" first="Chunxia" last="Ai">Chunxia Ai</name><name sortKey="Devenport, Martin" sort="Devenport, Martin" uniqKey="Devenport M" first="Martin" last="Devenport">Martin Devenport</name><name sortKey="Du, Xuexiang" sort="Du, Xuexiang" uniqKey="Du X" first="Xuexiang" last="Du">Xuexiang Du</name><name sortKey="Fields, James K" sort="Fields, James K" uniqKey="Fields J" first="James K." last="Fields">James K. Fields</name><name sortKey="Fields, James K" sort="Fields, James K" uniqKey="Fields J" first="James K." last="Fields">James K. Fields</name><name sortKey="Latinovic, Olga S" sort="Latinovic, Olga S" uniqKey="Latinovic O" first="Olga S." last="Latinovic">Olga S. Latinovic</name><name sortKey="Latinovic, Olga S" sort="Latinovic, Olga S" uniqKey="Latinovic O" first="Olga S." last="Latinovic">Olga S. Latinovic</name><name sortKey="Liu, Mingyue" sort="Liu, Mingyue" uniqKey="Liu M" first="Mingyue" last="Liu">Mingyue Liu</name><name sortKey="Liu, Yang" sort="Liu, Yang" uniqKey="Liu Y" first="Yang" last="Liu">Yang Liu</name><name sortKey="Liu, Yang" sort="Liu, Yang" uniqKey="Liu Y" first="Yang" last="Liu">Yang Liu</name><name sortKey="Liu, Yang" sort="Liu, Yang" uniqKey="Liu Y" first="Yang" last="Liu">Yang Liu</name><name sortKey="Sundberg, Eric J" sort="Sundberg, Eric J" uniqKey="Sundberg E" first="Eric J." last="Sundberg">Eric J. Sundberg</name><name sortKey="Sundberg, Eric J" sort="Sundberg, Eric J" uniqKey="Sundberg E" first="Eric J." last="Sundberg">Eric J. Sundberg</name><name sortKey="Tang, Fei" sort="Tang, Fei" uniqKey="Tang F" first="Fei" last="Tang">Fei Tang</name><name sortKey="Zhang, Peng" sort="Zhang, Peng" uniqKey="Zhang P" first="Peng" last="Zhang">Peng Zhang</name><name sortKey="Zheng, Pan" sort="Zheng, Pan" uniqKey="Zheng P" first="Pan" last="Zheng">Pan Zheng</name><name sortKey="Zheng, Pan" sort="Zheng, Pan" uniqKey="Zheng P" first="Pan" last="Zheng">Pan Zheng</name><name sortKey="Zheng, Pan" sort="Zheng, Pan" uniqKey="Zheng P" first="Pan" last="Zheng">Pan Zheng</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/ChloroquineV1/Data/Ncbi/Merge
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000759 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Ncbi/Merge/biblio.hfd -nk 000759 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= ChloroquineV1
|flux= Ncbi
|étape= Merge
|type= RBID
|clé= PMC:6796842
|texte= Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Ncbi/Merge/RBID.i -Sk "pubmed:31267017" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Ncbi/Merge/biblio.hfd \
| NlmPubMed2Wicri -a ChloroquineV1
| This area was generated with Dilib version V0.6.33. |  |