Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy
Identifieur interne : 000777 ( Main/Exploration ); 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
Affiliations:
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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" 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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><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)
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