Interleukin-2 enhancement of monoclonal antibody-mediated cellular cytotoxicity against human melanoma

Abstract

Disialoganglioside GD2 is present on human neuroblastoma and melanoma cells. 3F8 is a murine IgG3 monoclonal antibody specific for GD2, which has shown antitumor effects in patients in preliminary clinical studies. Since antibody mediated cellular cytotoxicity (ADCC) was one of the likely mechanisms producing these observed tumor regressions, the current study was carried out to investigate the activation of ADCC by interleukin-2 (IL-2). ADCC (against human neuroblastoma and melanoma cell lines in vitro) mediated by normal human peripheral blood lymphocytes was increased 100 to 330% after preincubation with IL-2. At limiting concentrations of 3F8 antibody (10 to 100 times less than the amount required by unactivated peripheral blood lymphocytes), activated peripheral blood lymphocytes still mediated efficient ADCC. Activation of ADCC was detected earlier than lymphokine activated killer cell (LAK) activity, required less IL-2 for optimum induction (50 versus 1000 units/ml), and was of equal or greater absolute magnitude (+10 to +200%) against the cell lines tested. ADCC and LAK were independent and additive when measured against the same cell line. The precursor cells for both LAK and activated ADCC bore IgG Fc receptors, but by day 4 of culture with IL-2 much of the LAK activity resided in the Fc negative, Leu11 negative population, and did not mediate ADCC. IL-2 activated ADCC may be of value alone or in conjunction with LAK cells in the therapy of tumors which bind the antibody 3F8.