1992 Stohlman Memorial Lecture: targeting the IL-2 receptor.
Patients with human T-cell lymphotropic virus I (HTLV-I)-associated leukemia/lymphoma were treated with different forms of IL-2 receptor (IL-2R)-directed therapy that exploit the difference in IL-2R expression between normal and malignant cells. Using unmodified anti-Tac monoclonal antibody, one-third of the patients with adult T-cell leukemia (ATL) treated have undergone a remission, in two cases complete. There was little 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 contains the complementarity-determining regions from the mouse with the remainder of the molecule derived from human IgG1 kappa. This antibody is dramatically less immunogenic than the murine version, has improved pharmacokinetics, and, in contrast to the parent antibody, manifests antibody-dependent cellular cytotoxicity (ADCC). 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, 10, and 15 mCi 90Y-anti-Tac per patient), 10 of the 15 patients with ATL treated to date underwent sustained partial or complete remission. Thus, the clinical application of IL-2R-directed therapy represents a new perspective for the prevention of allograft rejection and for the treatment of graft-versus-host disease, select autoimmune disorders, and leukemia/lymphoma.
Waldmann
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Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D000922:Immunotoxins / Q000627:therapeutic use; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000532:radiotherapy / Q000628:therapy*; D008213:Lymphocyte Activation; D015375:Receptors, Interleukin-2 / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D015375:Receptors, Interleukin-2