Lymphokine receptors: a target for immunotherapy of lymphomas

Lymphoma cells often express lymphokine receptors that provide a target for therapy. For example, malignant cells of patients with HTLV-1-associated adult T-cell leukemia/lymphoma (ATL) express IL-2 receptors. In contrast, normal resting cells do not express the IL-2 receptors identified by the anti-Tac monoclonal antibody. Using the unmodified anti-Tac monoclonal antibody, one-third of the 19 patients treated with ATL have undergone a remission. However, unmodified murine monoclonal antibodies are limited by their immunogenicity and their poor effector functions. To address these issues, we used genetic engineering to produce humanized anti-Tac that contains the complementarity-determining regions from the mouse with the remainder of the antibody derived from human IgG1-kappa. Humanized anti-Tac is dramatically less immunogenic than the murine versions and, in contrast to the parent antibody, manifests antibody-dependent cellular cytotoxicity with human mononuclear cells. To enhance its effector function, anti-Tac was armed with toxins or with alpha- and beta-emitting radionuclides. In a clinical trial with 90Y-anti-Tac, 11 of the 17 patients with ATL underwent a partial or sustained complete remission. Thus, the clinical application of lymphokine-receptor-directed therapy provides a new perspective for treatment of certain lymphomas, including HTLV-1-associated ATL.