Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy
Identifieur interne : 000777 ( Main/Curation ); précédent : 000776; suivant : 000778Hijacking 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
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PMC:6796842Le document en format XML
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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>
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