Dr. Waldmann developed IL-2 receptor directed therapy for patients with leukemia. The scientific basis for this approach is provided by his observation that resting T cells do not express IL-2 receptors but receptors are expressed by the abnormal T cells of patients with lymphoma/leukemia, those with select forms of autoimmune disease, and individuals rejecting allografts. Dr. Waldmann proposed a multichain model for the high affinity IL-2 receptor involving two IL-2 binding proteins: a 55 kD (IL-2R-alpha) Mik-beta1. To exploit the difference in IL-2 receptor expression between normal and malignant cells, he has initiated IL-2 receptor directed therapy in patients with human lymphotropic virus I (HTLV-I), associated adult T-cell (ATL). Using unmodified anti-Tac monoclonal antibody one-third of the patients with ATL treated have undergone a remission. There was no toxicity observed; however, unmodified monoclonal antibodies are limited by their immunogenicity and their poor effector functions. To address these issues """"""""humanized"""""""" anti-Tac was produced that retains the complementarity regions from the mouse with the remainder of the molecule derived from human IgG1. This antibody is dramatically less immunogenic than the murine version, and, in contrast to the parent antibody, manifests antibody-dependent cellular cytotoxicity. To enhance its effector function anti-Tac was armed with toxins and alpha- and beta-emitting radionuclides. In a clinical trial of 90Y anti-Tac in ATL patients, at the doses used (5 and 10 mCi 90Y anti-Tac per patient) no toxicity was observed in 5 of the 6 patients with ATL studied. Five of the six patients with ATL underwent a sustained partial or complete remission. Thus the clinical application of IL-2 receptor directed therapy represents a new perspective for the treatment of certain neoplastic diseases, autoimmune disorders and for the prevention of allograft rejection.
