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Membrane-proximal TRAIL species are incapable of inducing short circuit apoptosis signaling: Implications for drug development and basic cytokine biology.

TRAIL continues to garner substantial interest as a recombinant cancer therapeutic while the native cytokine itself serves important tumor surveillance functions when expressed in membrane-anchored form on activated immune effector cells. We have recently developed the genetically stabilized TRAIL p... Full description

Journal Title: Scientific reports March 3, 2016, Vol.6, p.22661
Main Author: Tatzel, Katharina
Other Authors: Kuroki, Lindsay , Dmitriev, Igor , Kashentseva, Elena , Curiel, David T , Goedegebuure, S Peter , Powell, Matthew A , Mutch, David G , Hawkins, William G , Spitzer, Dirk
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 2045-2322 ; DOI: 10.1038/srep22661
Link: http://search.proquest.com/docview/1770861444/?pq-origsite=primo
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title: Membrane-proximal TRAIL species are incapable of inducing short circuit apoptosis signaling: Implications for drug development and basic cytokine biology.
format: Article
creator:
  • Tatzel, Katharina
  • Kuroki, Lindsay
  • Dmitriev, Igor
  • Kashentseva, Elena
  • Curiel, David T
  • Goedegebuure, S Peter
  • Powell, Matthew A
  • Mutch, David G
  • Hawkins, William G
  • Spitzer, Dirk
subjects:
  • Animals–Pharmacology
  • Antibodies, Neoplasm–Drug Effects
  • Apoptosis–Genetics
  • Cho Cells–Metabolism
  • Cricetinae–Methods
  • Cricetulus–Drug Therapy
  • Cytokines–Genetics
  • Drug Screening Assays, Antitumor–Metabolism
  • Hek293 Cells–Pharmacology
  • Humans–Antagonists & Inhibitors
  • Jurkat Cells–Genetics
  • Mice–Metabolism
  • Neoplasms–Metabolism
  • Single-Chain Antibodies–Metabolism
  • Tnf-Related Apoptosis-Inducing Ligand–Metabolism
  • Antibodies, Neoplasm
  • Cytokines
  • Single-Chain Antibodies
  • Tnf-Related Apoptosis-Inducing Ligand
  • Tnfsf10 Protein, Human
  • Tnfsf10 Protein, Mouse
ispartof: Scientific reports, March 3, 2016, Vol.6, p.22661
description: TRAIL continues to garner substantial interest as a recombinant cancer therapeutic while the native cytokine itself serves important tumor surveillance functions when expressed in membrane-anchored form on activated immune effector cells. We have recently developed the genetically stabilized TRAIL platform TR3 in efforts to improve the limitations associated with currently available drug variants. While in the process of characterizing mesothelin-targeted TR3 variants using a single chain antibody (scFv) delivery format (SS-TR3), we discovered that the membrane-tethered cytokine had a substantially increased activity profile compared to non-targeted TR3. However, cell death proceeded exclusively via a bystander mechanism and protected the mesothelin-positive targets from apoptosis rather than leading to their elimination. Incorporation of a spacer-into the mesothelin surface antigen or the cancer drug itself-converted SS-TR3 into a cis-acting phenotype. Further experiments with membrane-anchored TR3 variants and the native cytokine confirmed our hypothesis that membrane-proximal TRAIL species lack the capacity to physically engage their cognate receptors coexpressed on the same cell membrane. Our findings not only provide an explanation for the "peaceful" coexistence of ligand and receptor of a representative member of the TNF superfamily but give us vital clues for the design of activity-enhanced TR3-based cancer therapeutics.
language: eng
source:
identifier: E-ISSN: 2045-2322 ; DOI: 10.1038/srep22661
fulltext: fulltext
issn:
  • 20452322
  • 2045-2322
url: Link


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titleMembrane-proximal TRAIL species are incapable of inducing short circuit apoptosis signaling: Implications for drug development and basic cytokine biology.
creatorTatzel, Katharina ; Kuroki, Lindsay ; Dmitriev, Igor ; Kashentseva, Elena ; Curiel, David T ; Goedegebuure, S Peter ; Powell, Matthew A ; Mutch, David G ; Hawkins, William G ; Spitzer, Dirk
contributorTatzel, Katharina (correspondence author) ; Tatzel, Katharina (record owner)
ispartofScientific reports, March 3, 2016, Vol.6, p.22661
identifierE-ISSN: 2045-2322 ; DOI: 10.1038/srep22661
subjectAnimals–Pharmacology ; Antibodies, Neoplasm–Drug Effects ; Apoptosis–Genetics ; Cho Cells–Metabolism ; Cricetinae–Methods ; Cricetulus–Drug Therapy ; Cytokines–Genetics ; Drug Screening Assays, Antitumor–Metabolism ; Hek293 Cells–Pharmacology ; Humans–Antagonists & Inhibitors ; Jurkat Cells–Genetics ; Mice–Metabolism ; Neoplasms–Metabolism ; Single-Chain Antibodies–Metabolism ; Tnf-Related Apoptosis-Inducing Ligand–Metabolism ; Antibodies, Neoplasm ; Cytokines ; Single-Chain Antibodies ; Tnf-Related Apoptosis-Inducing Ligand ; Tnfsf10 Protein, Human ; Tnfsf10 Protein, Mouse
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descriptionTRAIL continues to garner substantial interest as a recombinant cancer therapeutic while the native cytokine itself serves important tumor surveillance functions when expressed in membrane-anchored form on activated immune effector cells. We have recently developed the genetically stabilized TRAIL platform TR3 in efforts to improve the limitations associated with currently available drug variants. While in the process of characterizing mesothelin-targeted TR3 variants using a single chain antibody (scFv) delivery format (SS-TR3), we discovered that the membrane-tethered cytokine had a substantially increased activity profile compared to non-targeted TR3. However, cell death proceeded exclusively via a bystander mechanism and protected the mesothelin-positive targets from apoptosis rather than leading to their elimination. Incorporation of a spacer-into the mesothelin surface antigen or the cancer drug itself-converted SS-TR3 into a cis-acting phenotype. Further experiments with membrane-anchored TR3 variants and the native cytokine confirmed our hypothesis that membrane-proximal TRAIL species lack the capacity to physically engage their cognate receptors coexpressed on the same cell membrane. Our findings not only provide an explanation for the "peaceful" coexistence of ligand and receptor of a representative member of the TNF superfamily but give us vital clues for the design of activity-enhanced TR3-based cancer therapeutics.
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titleMembrane-proximal TRAIL species are incapable of inducing short circuit apoptosis signaling: Implications for drug development and basic cytokine biology.
authorTatzel, Katharina ; Kuroki, Lindsay ; Dmitriev, Igor ; Kashentseva, Elena ; Curiel, David T ; Goedegebuure, S Peter ; Powell, Matthew A ; Mutch, David G ; Hawkins, William G ; Spitzer, Dirk
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