Molecular design of hybrid tumour necrosis factor alpha with polyethylene glycol increases its anti-tumour potency
Open Access
- 1 May 1995
- journal article
- research article
- Published by Springer Nature in British Journal of Cancer
- Vol. 71 (5) , 963-968
- https://doi.org/10.1038/bjc.1995.186
Abstract
This study was conducted to increase the anti-tumour potency and reduce the toxic side-effects of tumour necrosis factor alpha (TNF-alpha). Natural human TNF-alpha was chemically conjugated with monomethoxy polyethylene glycol (PEG) using succinimidyl coupling of lysine amino groups of TNF-alpha. The number-average molecular weight of PEG-modified TNF-alpha (PEG-TNF-alpha) increased with an increase in the reaction time and the initial molar ratio of PEG relative to TNF-alpha. The resulting modified TNF-alpha was separated into fractions of various molecular weights. The specific activity of separated PEG-TNF-alpha s relative to that of native TNF-alpha 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-alpha. PEG-TNF-alpha s, 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-alpha in the murine Meth-A fibrosarcoma model. Extensive PEG modification did not increase its in vivo activity. A high dose of unmodified TNF-alpha induced toxic side-effects, but these were not observed with the modified TNF-alpha s. Optimal PEG modification of TNF-alpha markedly increased its bioavailability and may facilitate its potential anti-tumour therapeutic use.Keywords
This publication has 29 references indexed in Scilit:
- Antitumor Activity of a Novel Chimera Tumor Necrosis Factor (TNF-STH) Constructed by Connecting rTNF-S with Thymosin β4 Against Murine Syngeneic TumorsJournal of Immunotherapy, 1991
- Site-Directed Pegylation of Recombinant Interleukin-2 at its Glycosylation SiteNature Biotechnology, 1990
- Phase I study of intratumoral application of recombinant human tumor necrosis factorEuropean Journal of Cancer and Clinical Oncology, 1989
- Evaluation of recombinant human tumor necrosis factor by scheduled intratumoral administration in mice bearing transplantable tumors.The Tohoku Journal of Experimental Medicine, 1989
- A Progress Report on the Treatment of 157 Patients with Advanced Cancer Using Lymphokine-Activated Killer Cells and Interleukin-2 or High-Dose Interleukin-2 AloneNew England Journal of Medicine, 1987
- Phase I study of recombinant human tumor necrosis factorCancer Chemotherapy and Pharmacology, 1987
- Antitumor activity of murine tumor necrosis factor (TNF) against transplanted murine tumors and heterotransplanted human tumors in nude miceInternational Journal of Cancer, 1984
- Biological Activity of Recombinant Human Interleukin-2 Produced in Escherichia coliScience, 1984
- A pharmacokinetic analysis program (multi) for microcomputer.Journal of Pharmacobio-Dynamics, 1981
- Renal filtration, transport, and metabolism of low-molecular-weight proteins: A reviewKidney International, 1979