CD70-restricted specific activation of TRAILR1 or TRAILR2 using scFv-targeted TRAIL mutants.
To combine the CD27 stimulation inhibitory effect of blocking CD70 antibodies with an antibody-dependent cellular cytotoxicity (ADCC)-independent, cell death-inducing activity for targeting of CD70-expressing tumors, we evaluated here fusion proteins of the apoptosis-inducing TNF family member TRAIL and a single-chain variable fragment (scFv) derived from a high-affinity llama-derived anti-human CD70 antibody (lαhCD70). A fusion protein of scFv:lαhCD70 with TNC-TRAIL, a stabilized form of TRAIL, showed strongly enhanced apoptosis induction upon CD70 binding and furthermore efficiently interfered with CD70-CD27 interaction. Noteworthy, introduction of recently identified mutations that discriminate between TRAILR1 and TRAILR2 binding into the TRAIL part of scFv:lαhCD70-TNC-TRAIL resulted in TRAIL death receptor-specific fusion proteins with CD70-restricted activity.
Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Röntgenring 11, Würzburg, Germany.
J
J
Trebing
1] Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Röntgenring 11, Würzburg, Germany [2] Faculty of Pharmacy, Department of Biochemistry, Mansoura University, El-Gomhoria Street, Mansoura, Egypt.
M
M
El-Mesery
Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Röntgenring 11, Würzburg, Germany.
V
V
Schäfer
Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Röntgenring 11, Würzburg, Germany.
D
D
Weisenberger
Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Röntgenring 11, Würzburg, Germany.
D
D
Siegmund
arGEN-X BVBA, Technologiepark 30, Zwijnaarde, Belgium.
K
K
Silence
Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Röntgenring 11, Würzburg, Germany.
H
H
Wajant
D017209:Apoptosis / Q000187:drug effects; D053282:CD27 Ligand / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000276:immunology*; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D013045:Species Specificity; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics / Q000276:immunology
D053282:CD27 Ligand; C505771:CD70 protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D057127:Single-Chain Antibodies; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7