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Mutants of lymphotoxin-α with augmented cytotoxic activity via TNFR1 for use in cancer therapy.

Abstract
The cytokine lymphotoxin-α (LTα) is a promising candidate for use in cancer therapy. However, the instability of LTαin vivo and the insufficient levels of tumor necrosis factor receptor 1 (TNFR1)-mediated bioactivity of LTα limit its therapeutic potential. Here, we created LTα mutants with increased TNFR1-mediated bioactivity by using a phage display technique. We constructed a phage library displaying lysine-deficient structural variants of LTα with randomized amino acid residues. After affinity panning, we screened three clones of lysine-deficient LTα mutant, and identified a LTα mutant with TNFR1-mediated bioactivity that was 32 times that of the wild-type LTα (wtLTα). When compared with wtLTα, the selected clone showed augmented affinity to TNFR1 due to slow dissociation rather than rapid association. In contrast, the mutant showed only 4 times the TNFR2-mediated activity of wtLTα. In addition, the LTα mutant strongly and rapidly activated caspases that induce TNFR1-mediated cell death, whereas the mutant and wtLTα activated nuclear factor-kappa B to a similar extent. Our data suggest that the kinetics of LTα binding to TNFR1 play an important role in signal transduction patterns, and a TNFR1-selective LTα mutant with augmented bioactivity would be a superior candidate for cancer therapy.
AuthorsTomohiro Morishige, Yasuo Yoshioka, Shogo Narimatsu, Shinji Ikemizu, Shin-ichi Tsunoda, Yasuo Tsutsumi, Yohei Mukai, Naoki Okada, Shinsaku Nakagawa
JournalCytokine (Cytokine) Vol. 61 Issue 2 Pg. 578-84 (Feb 2013) ISSN: 1096-0023 [Electronic] England
PMID23246116 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Ltd. All rights reserved.
Chemical References
  • Lymphotoxin-alpha
  • Mutant Proteins
  • NF-kappa B
  • Receptors, Tumor Necrosis Factor, Type I
  • Caspases
Topics
  • Amino Acid Sequence
  • Caspases (metabolism)
  • Cell Death (drug effects)
  • Cell Line, Tumor
  • Electron Spin Resonance Spectroscopy
  • Enzyme Activation (drug effects)
  • Humans
  • Isoelectric Point
  • Kinetics
  • Lymphotoxin-alpha (chemistry, pharmacology, therapeutic use)
  • Models, Molecular
  • Molecular Sequence Data
  • Mutant Proteins (chemistry, pharmacology, therapeutic use)
  • NF-kappa B (metabolism)
  • Neoplasms (drug therapy, enzymology, pathology)
  • Protein Binding (drug effects)
  • Receptors, Tumor Necrosis Factor, Type I (chemistry, metabolism)

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