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-2Ralpha) and a 75 kD (IL-2Rbeta) protein. 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 leukemia (ATL). Using unmodified anti-Tac monoclonal antibody that reacts with IL-2Ralpha, 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-determining 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. A clinical trial with this antibody has been initiated in patients with IL-2 receptor-expressing leukemias and lymphomas as well as individuals with corticosteroid-resistant graft versus host disease. 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 10 of the 15 patients with ATL underwent a 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.
