Novel Mutein of Tumor Necrosis Factor α (F4614) with Reduced Hypotensive Effect

  title={Novel Mutein of Tumor Necrosis Factor $\alpha$ (F4614) with Reduced Hypotensive Effect},
  author={Hiroshi Shikama and Keizo Miyata and Nahoko Sakae and Yachiyo Mitsuishi and Koji Nishimura and Kensei Kuroda and Masanari Kato},
  journal={Journal of Interferon and Cytokine Research},
To eliminate systemic toxicity, including the hypotension associated with human tumor necrosis factor α (TNF-α), we constructed mutant proteins (muteins) by mean of genetic engineering. A novel mutein, F4614, containing mutations of 5Thr → Gly and 6Pro → Asp, which resulted in the introduction of cell-adhesive Arg-Gly-Asp and 29Arg → Val, had remarkably reduced hypotensive effects and lower lethality. We present evidence that the Arg → Val mutation at position 29 is largely responsible for the… Expand
A novel human tumor necrosis factor alfa mutein, F4614, inhibits in vitro and in vivo growth of murine and human hepatoma: Implication for immunotherapy of human hepatocellular carcinoma
Immunohistochemical analysis of the tumors treated by F4614 revealed that tumors were surrounded with a large number of Mac‐1+ cells and a small number of CD4+ and CD8+ T cells; that suggests that intratumoral injection of F 4614 elicited host immunoreactions, suggesting that F46 14 may be a new strategy for immunotherapy of HCC. Expand
Improvement of potential therapeutic value of tumor necrosis-α (TNF-α) by charge modulation in the tip region
Examination of structural models of TNF bound to soluble TNF receptor 1 (TNFR1) indicates that simple mutations in the tip region most probably cannot interact with receptor binding sites, and therefore do not directly modulate cytotoxicity. Expand
Human tumor necrosis factor-alpha mutant RGD-V29 (F4614) shows potent antitumor activity and reduced toxicity against human tumor xenografted nude mice.
RGD-V29 appears to be a low-toxicity mutant of rhTNF that shows preferential activity towards tumors, and therefore merits further investigation in pre-clinical and clinical studies. Expand
RGD-FasL Induces Apoptosis in Hepatocellular Carcinoma
RGD-FasL appears to be a low-toxicity selective inducer of tumor cell death, which merits further investigation in preclinical and clinical studies and offers a versatile technology for complexing target ligands with therapeutic recombinant proteins. Expand
Proinflammatory cytokines block growth of breast cancer cells by impairing signals from a growth factor receptor.
Evidence is provided to link both neutralization of endogenous growth factors and administration of exogenous bioactive cytokines as an integrative approach to cancer therapy and support the novel idea that the major inhibitory properties of proinflammatory cytokines on growth of breast cancer cells are manifested prominently in the presence of growth factors. Expand
Preferential Activity of Wild‐type and Mutant Tumor Necrosis Factor‐α against Tumor‐derived Endothelial‐like Cells
Tumor‐derived endothelial‐like cells (tEC) are prepared by culturing human umbilical vein endothelial cells (HUVEC) in the presence of HT1080 human fibrosarcoma‐conditioned medium and acquire physiological properties of tumor‐associated vasculature, and may be a useful model system for the study of the mechanisms of TNF antitumor action. Expand
A rat extremity soft tissue sarcoma model for the study of systemic treatment with Stealth® liposome-encapsulated tumor necrosis factor-α and cytotoxic agents
The possible use of liposome-encapsulated TNF-α and cytotoxic agents and Liposomes used are so-called Stealth® or long circulating liposomes which have a prolonged blood residence time and tend to localize in high percentages in tumors. Expand
Identification of the heparin-binding domain of TNF-alpha and its use for efficient TNF-alpha purification by heparin-Sepharose affinity chromatography.
The N-terminus of the trimeric TNF-alpha molecule comprises two basic arginines within the short amino-acid sequence VRSSSR, which is here shown to be essential for binding of TNF-alpha toExpand
Integrin Targeted Delivery of Radiotherapeutics
Integrin αvβ3 is highly expressed on activated endothelial cells, new-born vessels as well as some tumor cells, but is not present in resting endothelial Cells and most normal organ systems, making it a suitable target for anti-tumor therapy. Expand
RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature.
This review will summarize the structural requirements for RGD-peptides andRGD-mimetics as ligands for alphavbeta3 and show how they have been introduced in the various types of constructs by chemical and recombinant techniques. Expand


A novel Mutein of TNFα Containing the Arg-Gly-Asp Sequence Shows Reduced Toxicity in Intestine
The results suggest that the Arg-Gly-Asp sequence introduced into the TNFα molecule abrogates the side effect of this cytokine such as tissue injury or shock, and that F4168 could be useful for systemic therapy. Expand
A YIGSR-containing novel mutein without the detrimental effect of human TNF-α of enhancing experimental pulmonary metastasis
The injection of B16F10 melanoma cells with recombinant human tumor necrosis factor alpha (TNF-α) into the tail vein of C57BL/6 mice resulted in 2- to 25-fold more metastatic foci in the lungs thanExpand
A human tumor necrosis factor (TNF) alpha mutant that binds exclusively to the p55 TNF receptor produces toxicity in the baboon
It is concluded that selective p55 TNF receptor activation is associated with early hemodynamic changes and the autocrine release of endogenous TNF alpha, but the role of the p75 T NF receptor in systemic TNF toxicity requires further study. Expand
Identity of tumour necrosis factor and the macrophage-secreted factor cachectin
It is suggested that the ‘cachectin’ and ‘TNF’ activities of murine macrophage conditioned medium are attributable to a single protein, which modulates the metabolic activities of normal as well as neoplastic cells through interaction with specific high-affinity receptors. Expand
NG-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide.
  • R. Kilbourn, S. Gross, +4 authors R. Lodato
  • Chemistry, Medicine
  • Proceedings of the National Academy of Sciences of the United States of America
  • 1990
It is suggested that excessive nitric oxide production mediates the hypotensive effect of TNF, a potent vasodilator initially characterized as endothelium-derived relaxing factor. Expand
Phase I study of recombinant tumor necrosis factor in cancer patients.
RTNF was well tolerated clinically in this dose range, and there was evidence of antitumor effect, and the clearance of rTNF in the serum was described by a monoexponential equation with a half-life calculated to be 14-18 min. Expand
Shock and tissue injury induced by recombinant human cachectin.
It appears that a single protein mediator (cachectin) is capable of inducing many of the deleterious effects of endotoxin. Expand
Endothelial cell production of nitrogen oxides in response to interferon gamma in combination with tumor necrosis factor, interleukin-1, or endotoxin.
It is suggested that endothelial cell-derived nitric oxide plays a role in the development of hypotension in patients treated with tumor necrosis factor or interleukins and that administration of substrate analogues such as L-NMMA may favorably alter the toxicity associated with these immunomodulators and result in a higher maximum tolerated dose, with subsequent improvement in the antitumor activity. Expand
An endotoxin-induced serum factor that causes necrosis of tumors.
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. Expand
Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro.
The observations indicate that the effects of rTNF-alpha on cell growth are not limited to tumor cells, but rather that this protein may have a broad spectrum of activities in vivo. Expand