Two distinct mechanisms of antitumor activity mediated by the combination of interleukin 2 and monoclonal antibodies.

Previously we described a human B-lymphoma xenotransplantation model in which the immunotherapeutic activity of monoclonal antibodies (mAbs), directed against human B-cell antigens, can be studied. An anti-CD19 mAb of IgG2a subclass was therapeutically active by itself in this model, and its efficacy was increased by simultaneous administration of recombinant interleukin 2 (rIL-2). Immunotherapy with IgG1 or IgG2b isotype variants of an anti-CD19 mAb was ineffective if given alone. We now show that the combination of these ineffective isotype variants with rIL-2 results in significant antitumor effects, although IgG2a anti-CD19 mAb in combination with rIL-2 was therapeutically more active. In vitro studies of the effector mechanisms possibly involved in these treatment modalities indicate that the antitumor activity of IgG1 or IgG2b anti-CD19 mAbs in combination with rIL-2 may be mediated by rIL-2-induced antibody-dependent cellular cytotoxic activity of lymphocytes. The antitumor effect of IgG2a anti-CD19 mAb in combination with rIL-2 may be mediated not only by rIL-2-induced antibody-dependent cellular cytotoxic activity of lymphocytes but also by IgG2a-restricted antitumor activity of monocytes/macrophages. These results may explain the greater in vivo efficacy of treatment with rIL-2 and IgG2a subclass mAb versus treatment with rIL-2 and IgG1 or IgG2b subclass mAbs.