MECHANISMS OF CELLULAR CYTOTOXICITY MEDIATED BY A RECOMBINANT ANTIBODY IL2 FUSION PROTEIN AGAINST HUMAN-MELANOMA CELLS

Functional characteristics were established for a genetically engineer ed fusion protein between human IL2 and mouse/human chimeric mAb 225 d irected against human epidermal growth factor receptor (EGFR), aberran tly expressed on human melanoma cells. The emphasis of these studies w as on the mechanism(s) of action by which the ch225-IL2 fusion protein mediated cytotoxic killing of human melanoma cells by different human immune effector cells. Ch225-IL2 fusion protein bound to human EGFR w ith the high affinity of the parental antibody, and was as active as t he equivalent amount of rhIL2. Ch225-IL2 enhanced cellular cytotoxicit y mediated by freshly separated PBMC, isolated natural killer (NK) cel ls and activated T cells against melanoma cell lines. NK cells, which constitutively express both Fc gamma RIII and IL2R, interacted with ch 225-IL2, mainly through Fc gamma RIII, while the involvement of IL2R w as secondary. However, the effect of ch225-IL2 on activated T cells wa s most likely mediated through IL2R. These results suggest that the ge netically engineered ch225-IL2 fusion protein may become a potent immu notherapeutic agent capable of stimulating various immune effector pop ulations to effectively kill human melanoma cells.