A novel human tumor necrosis factor alpha mutant showed potent antitumor activity and reduced toxicity in vivo
Abstract
Aim: To study the antitumor activity and systemic toxicity of human tumor necrosis factor alpha (hTNFalpha) mutant M2 (R2K-N30S-R32W-L157F-hTNFalpha).
Methods: Mouse sarcoma S180 tumors and hepatoma HAC tumors were implanted into mice, and human urocyst carcinoma CP-3 tumors were implanted into nude mice. The xenografted mice were injected with wild-type hTNFalpha and its mutant M2 at different doses. After 7 d (mice) or 10 d (nude mice) of injection, the tumor weight was measured to calculate the inhibition rate of hTNFalpha and M2. Systemic toxicity experiments were done on Rhesus monkeys by injecting them with wild-type hTNFalpha and mutant M2 respectively for 10 consecutive d. Observations were made on the monkeys both before and after the injection.
Results: For mice implanted with sarcoma S180 and hepatoma HAC tumors, the inhibition rate of M2 was similar to that of wild-type hTNFalpha at the dose of 0.025 mg/kg, while for nude mice implanted with human urocyst carcinoma CP-3, the inhibition rate of M2 (45.5 %) was much higher than that of wild-type hTNFalpha (15.5 %). When the dose came to 0.25 and 2.5 mg/kg respectively, however, the inhibition rate of M2 greatly increased (the highest was 75.9 %). The tests of systemic toxicity of hTNFalpha and its mutant M2 in monkeys proved that M2 presented lower toxicity than wild-type hTNFalpha did.
Conclusion: hTNFalpha mutant M2 not only presented higher antitumor activity than wild-type hTNFalpha did on mouse tumor (S180 and HAC)- and human tumor (CP-3)-implanted mice, but also showed lower systemic toxicity in the Rhesus monkey.
Keywords:
Methods: Mouse sarcoma S180 tumors and hepatoma HAC tumors were implanted into mice, and human urocyst carcinoma CP-3 tumors were implanted into nude mice. The xenografted mice were injected with wild-type hTNFalpha and its mutant M2 at different doses. After 7 d (mice) or 10 d (nude mice) of injection, the tumor weight was measured to calculate the inhibition rate of hTNFalpha and M2. Systemic toxicity experiments were done on Rhesus monkeys by injecting them with wild-type hTNFalpha and mutant M2 respectively for 10 consecutive d. Observations were made on the monkeys both before and after the injection.
Results: For mice implanted with sarcoma S180 and hepatoma HAC tumors, the inhibition rate of M2 was similar to that of wild-type hTNFalpha at the dose of 0.025 mg/kg, while for nude mice implanted with human urocyst carcinoma CP-3, the inhibition rate of M2 (45.5 %) was much higher than that of wild-type hTNFalpha (15.5 %). When the dose came to 0.25 and 2.5 mg/kg respectively, however, the inhibition rate of M2 greatly increased (the highest was 75.9 %). The tests of systemic toxicity of hTNFalpha and its mutant M2 in monkeys proved that M2 presented lower toxicity than wild-type hTNFalpha did.
Conclusion: hTNFalpha mutant M2 not only presented higher antitumor activity than wild-type hTNFalpha did on mouse tumor (S180 and HAC)- and human tumor (CP-3)-implanted mice, but also showed lower systemic toxicity in the Rhesus monkey.