H. Shikama et al., NOVEL MUTEIN OF TUMOR-NECROSIS-FACTOR-ALPHA (F4614) WITH REDUCED HYPOTENSIVE EFFECT, Journal of interferon & cytokine research, 15(8), 1995, pp. 677-684
To eliminate systemic toxicity, including the hypotension associated w
ith human tumor necrosis factor cy (TNF-(alpha), we constructed mutant
proteins (muteins) by mean of genetic engineering. A novel mutein, F4
614, containing mutations of (5)Thr --> Gly and (6)Pro --> Asp, which
resulted in the introduction of cell-adhesive Arg-Gly-Asp and (29)Arg
--> Val, had remarkably reduced hypotensive effects and lower lethalit
y, We present evidence that the Arg --> Val mutation at position 29 is
largely responsible for the reduced hypotensive effect. This effect o
f F3614 was thought to be closely correlated with its low inducibility
of nitric oxide and prostaglandin E(2) in vivo. In addition, the ther
apeutically effective dose of F46P4 to MethA fibrosarcoma-transplanted
mice was increased compared with that of TNF-alpha. Indicating a wide
therapeutic index. These results indicated that F4614 has several adv
antages as a systemic therapeutic drug in the treatment of cancer.