Safety Evaluation and Pharmacokinetics of a Novel Human Tumor Necrosis Factor-alpha Exhibited a Higher Antitumor Activity and a Lower Systemic Toxicity

Overview

Journal Anticancer Drugs

Specialty Oncology

Date 2010 Feb 19

PMID 20166241

Citations 4

Authors

Meng Li

Xin Qin

Xiaochang Xue

Cun Zhang

Zhen Yan

Wei Han

Chris Komarck

Thomas D Wang

Yingqi Zhang

Affiliations

Soon will be listed here.

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].

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