Intravenous Administration of Polyethylene Glycol‐modified Tumor Necrosis Factor‐α Completely Regressed Solid Tumor in Meth‐A Murine Sarcoma Model

Complete regression of solid tumors was achieved by plural intravenous (i.v.) administrations of polyethylene glycol (PEG)‐modified tumor necrosis factor‐a (TNF‐α), prepared by covalently modifying natural human TNF‐α with N‐succinimidyl succinate PEG. The anti‐tumor efficacy of PEG‐modifled TNF‐α (MPEG‐TNF‐α), in which 56% of the TNF‐α‐lysine residues were coupled with PEG, was compared with that of native TNF‐α in the Meth‐A murine fibrosarcoma model. MPEG‐TNF‐α and native TNF‐α were given as i.v. injections twice a week for 2 weeks. The anti‐tumor activity of MPEG‐TNF‐α was dose‐dependent and was far superior to that of native TNF‐α. Complete regression was observed in 3 of the 8 mice administered native TNF‐α at the dose of 10,000 JRU (Japan reference unit), but 4 of the 5 remaining mice died during the therapeutic period. At 5,000 JRU of native TNF‐α, no case of complete regression was observed. By contrast, complete regression was obtained in all 10 mice given 200 JRU of MPEG‐TNF‐α. No side‐effects were observed at the dose of 500 JRU of MPEG‐TNF‐α, which was 2.5 times the minimal dose (200 JRU) of MPEG‐TNF‐α required for complete regression in all treated mice. MPEG‐TNF‐α appears to have potential as a candidate anti‐tumor therapeutic agent.