Human lymphotoxin mutein lacks hypotensive activity but has higher in vivo antitumor activity than lymphotoxin or tumor necrosis factor.

@article{Taniyama1997HumanLM,
  title={Human lymphotoxin mutein lacks hypotensive activity but has higher in vivo antitumor activity than lymphotoxin or tumor necrosis factor.},
  author={M Taniyama and T Morita and Yukiko Yamagishi and Akihisa Kato and Christopher David Bando and Noriyuki Okawa and Akira Kaji},
  journal={Proceedings of the National Academy of Sciences of the United States of America},
  year={1997},
  volume={94 7},
  pages={
          3324-9
        }
}
  • M. Taniyama, T. Morita, A. Kaji
  • Published 1 April 1997
  • Chemistry, Medicine, Biology
  • Proceedings of the National Academy of Sciences of the United States of America
A serious drawback of tumor necrosis factor alpha (TNF) as a clinical antitumor agent is that it also has hypotensive activity. To overcome this problem, derivatives of its sister cytokine lymphotoxin (TNF-beta or LT) were prepared. One of them, mutein 2 (Mut2) has a deletion of amino acids 1-7 but contains substituted amino acids, Met-Phe-Pro at positions 8-10 of the mature human LT. This mutein has no hypotensive activity at the maximum dose (10 mg/kg) tested on rats. In contrast, a much… 
1 Citations
High Resolution Crystal Structure of a Human Tumor Necrosis Factor-α Mutant with Low Systemic Toxicity*
TLDR
The L29S mutation causes substantial restructuring of the loop containing residues 29–36 into a rigid segment as a consequence of induced formation of intra- and intersubunit interactions, explaining the altered receptor binding affinity and thermal stability of M3S.

References

SHOWING 1-10 OF 46 REFERENCES
Biological effects of recombinant human tumor necrosis factor and its novel muteins on tumor and normal cell lines.
TLDR
The data suggest that rhTNF and its muteins represent potentially useful anticancer agents; however, adequate dosing and prolonged exposure may be critical in demonstrating cytotoxicity/cytostasis.
Structure-activity studies of human tumour necrosis factors.
The mechanism by which tumour necrosis factors (TNF and lymphotoxin, also called TNF alpha and TNF beta respectively) exert their cytotoxic activity on many malignant cells, remains largely unknown.
Studies on the anti-tumor efficacy of systemically administered recombinant tumor necrosis factor against several murine tumors in vivo.
The anti-tumor activity of recombinant human tumor necrosis factor (rHTNF) was examined against four newly induced murine sarcomas (MCA-101, -102, -105, and -106) and a murine adenocarcinoma (MCA-38)
Recombinant human alpha lymphotoxin (tumor necrosis factor-beta) induces peripheral neutrophilia and lymphopenia in the rat.
TLDR
RLT-induced neutrophilia and lymphopenia suggested that the changes in circulating leukocyte subsets were not attributable to hemodynamic changes nor to the hemodynamic-change-related release of adrenal hormones, which suggested that rLT does not mediate its hematologic effects on peripheral blood leukocytes via the release of cortisol.
A novel recombinant tumor necrosis factor‐alpha mutant with increased anti‐tumor activity and lower toxicity
We prepared a novel recombinant tumor necrosis factor‐α (TNF) mutant (mutant 471), in which 7 N‐terminal aminoacids were deleted and Pro8Ser9Asp10 was replaced by ArgLysArg, and compared its
An endotoxin-induced serum factor that causes necrosis of tumors.
TLDR
It is proposed that TNF mediates endotoxin-induced tumor necrosis, and that it may be responsible for the suppression of transformed cells by activated macrophages.
Evidence that tumor necrosis factor has an important role in antibacterial resistance.
TLDR
Evidence that TNF plays an important role in antibacterial defenses was obtained by showing that administration of pure murine rTNF protects mice against a normally lethal Listeria challenge given 1 to 24 h later.
...
...