NEW TNF-ALPHA ANALOGS - A POWERFUL BUT LESS TOXIC BIOLOGICAL TOOL AGAINST TUMORS

Our approach to the modification of recombinant human tumour necrosis factor alpha (rhTNF-alpha) comprised changes in flexible loop regions on the surface of the TNF molecule. Using this approach, two different rhTNF-alpha analogues LK 801 and LK 805 were synthesized and tested f or their ability to affect the growth of Sa-1 tumour cells. Results ob tained in vitro indicate that neither rhTNF-alpha nor its analogues ha ve a direct cytotoxic effect. In vivo experiments were performed on su bcutaneous Sa-1 tumours in A/J mice, where the antitumour effect and t he toxic side effects of the cytokines were followed. There was no sig nificant difference between growth delay of tumours in animals treated with native rhTNF-alpha and in animals treated with one of the analog ues. On the contrary, the LD50 for rhTNF-alpha was 29.1 mu g, for LK 8 01 59.3 mu g, and for LK 805 even 66.1 mu g, indicating that LK 801 an d especially LK 805 were significantly better tolerated. The results c onfirm that the rhTNF-alpha molecule has been successfully modified re sulting in two new analogues with a potent antitumor activity and much lower systemic toxicity. A particularly low systemic toxicity and a s trong antitumor effect were observed after treatment with LK 805 sugge sting that this analogue merits further investigation in pre-clinical and clinical trials. (C) 1997 Academic Press Limited.