Alpha tumor necrosis factor (TNF) was discovered in 1975. Since 1984, the recombinant TNF was transferred for clinical studies, which were stopped in three years due to high toxic potential and low efficiency of TNF under systemic administration.

However, outstanding clinical results were obtained laterfrom the use of TNF in combination with chemotherapeutic agent melphalan and IFN-gamma. They were administeredas isolated regional perfusion to patients with limb sarcomas and melanomas and as isolated organ perfusion to patients with liver cancer. The end result was TNF authorization in Europe in 2006.

The scientists of the whole world searched for TNF derivative (mutant) molecules with lowered systemic toxicity. A revolutionary medical product was created in Russia in 1990. It was a recombinant drug of Tumor Necrosis Factor fused with thymosin alpha-1 (TNF-T) on a genetic level. The drug had low systemic toxicity, but it retained the antitumor activity of natural TNF and obtained new immune stimulating properties.

The fused protein ?-tumor necrosis factor thymosin alpha-1 (TNF-T) that we have constructed has specific cytotoxicity on the L-929 fibrosarcoma cells, which is 2.000.000 units per 1 mg of the protein, and it shows significant immune stimulating influence. In terms of range and power of cytotoxic and cytostatic activity on the tumor cells, TNF-Tis not inferior to human TNF, and is even superior to it in some tumors. Furthermore, the overall toxic potential of the TNF-T is more than 100 times lower than that of TNF, which was proved by clinical trials in the Nikolai Blokhin Russian Cancer Research Center (Moscow) and N.N. Petrov Research and Development Establishment of Oncology (Saint-Petersburg).

For the first time the clinic has confirmed, that the addition of thymosine-a1 to the C-end of the TNF has lowered its overall toxic potential and gave it new properties.

In 2009, Refnot-pharm, LLC obtained Manufacturing and Marketing License for TND-T substance and for the first andthe only patented and officially registered Russian medical product REFNOT in the pharmaceutical form of lyophilisate for preparation of solution for subcutaneous injection.

REFNOT (TNF-T) has passed III phases of clinical trials. It was registered on 27.03.2009 as an antitumor drug. It is authorizedfor usein breast cancer treatment combined with chemotherapeutic agents and as an immunomodulator indisseminated melanoma.

Clinical studies of the drug are still ongoing, and the proposed indications will extend in accordance with the data from clinical studies.