title: Safety evaluation and pharmacokinetics of a novel human tumor necrosis factor-alpha exhibited a higher antitumor activity and a lower systemic toxicity.
abstract: We had prepared earlier a prokaryotic-expressed tumor necrosis factor-alpha (TNF-[alpha]) mutant that exhibited a higher antitumor activity and a lower systemic toxicity compared with that of wild-type TNF-[alpha] in both syngeneic murine tumor models and human tumor xenografts models. For its clinical use as an antitumor agent, we evaluated repeated-dose toxicity, anaphylaxis, genetic toxicity, pharmacokinetic, and metabolism in different animals according to the criteria of the biological investigational new drug application. It was found to be safe at a dose of 4x10(6) IU/kg/day for 60 days after administration in rhesus monkeys, but the TNF-[alpha] antibody level and liver toxicity needed to be monitored. No systemic anaphylaxis or genetic toxicity was found and the pharmacokinetic characteristics of the recombinant mutated human TNF-[alpha] (rmhTNF-[alpha]) were suited for clinical use. More than 96.3% of rmhTNF-[alpha] could be reclaimed from the urine and feces in 24 h after administration, which indicated the main excretion route. The results proved that the characteristics of this rmhTNF-[alpha] satisfied clinical trial requirements. The related positive clinical trial results will be reported in future. This study of novel rmhTNF-[alpha] is of considerable importance, not only given the proven usefulness of TNF-[alpha] local application therapies under isolated limp perfusion and isolated hepatic perfusion conditions for selected indications, but also implicated for systemic application of TNF-[alpha].
authors.affiliation: Biotechnology Center, Department of Pharmacy, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Qin
authors.forename: Xiaochang
authors.initials: X
authors.lastname: Xue
authors.forename: Cun
authors.initials: C
authors.lastname: Zhang
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Chris
authors.initials: C
authors.lastname: Komarck
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Wang
authors.forename: Yingqi
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics*; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D011817:Rabbits; D051381:Rats; D011994:Recombinant Proteins / Q000009:adverse effects / Q000235:genetics / Q000493:pharmacokinetics; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects* / Q000235:genetics / Q000493:pharmacokinetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha