Molecular design of hybrid tumour necrosis factor α with polyethylene glycol increases its anti-tumour potency
Y. Tsutsumi, T. Kihira, S. Tsunoda, T. Kanamori, S. Nakagawa and T. MayumiBritish Journal of Cancer (1995), Vol. 71 pages 963-968
This study was conducted to increase the anti-tumour potency and reduce the toxic side-effects of tumour necrosis factor α (TNF-α). Natural human TNF-α was chemically conjugated with monomethoxy polyethylene glycol (PEG) using succinimidyl coupling of lysine amino groups of TNF-α. The number-average molecular weight of PEG-modified TNF-α (PEG-TNF-α) increased with an increase in the reaction time and the initial molar ratio of PEG relative to TNF-α. The resulting modified TNF-α was separated into fractions of various molecular weights. The specific activity of separated PEG-TNF-αs relative to that of native TNF-α gradually decreased with an increase in the degree of PEG modification, but the plasma half-life was drastically increased with the increase in molecular weight of modified TNF-α. PEG-TNF-αs, in which 29% and 56% of lysine residues were coupled to PEG, had anti-tumour activity approximately 4 and 100 times greater than unmodified TNF-α in the murine Meth-A fibrosarcoma model. Extensive PEG modification did not increase its in vivo activity. A high dose of unmodified TNF-α induced toxic side-effects, but these were not observed with the modified TNF-αs. Optimal PEG modification of TNF-α markedly increased its bioavailability and may facilitate its potential anti-tumour therapeutic use.