Anti-IL-2 receptor monoclonal antibody (anti-Tac) treatment of T-cell lymphoma.
The abnormal and activated T cells in certain neoplasms of mononuclear cells, select autoimmune disorders, and organ allograft rejection express the IL-2R alpha subunit identified by the anti-Tac monoclonal antibody. In contrast, normal resting cells do not express this inducible receptor. Patients with ATL were treated with different forms of IL-2R-directed therapy to exploit the difference in IL-2R expression between normal and malignant cells. Using the unmodified anti-Tac monoclonal antibody, 7 of 19 patients with ATL treated have undergone a remission (2 cases complete), with no toxicity observed. Unmodified murine monoclonal antibodies are limited by their immunogenicity and poor effector functions. Genetic engineering was used to produce humanized anti-Tac that contains the complementarity-determining regions from the mouse with the remainder of the molecule derived from human IgG1-kappa. This antibody is less immunogenic than the murine version, has improved pharmacokinetics, and, in contrast with the parent antibody, manifests ADCC 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 at the doses used (5, 10, and 15 microCi), 11 of the 17 patients with ATL underwent a partial or sustained a complete remission. Thus, the clinical application of IL-2R-directed therapy represents a new perspective for the treatment of T-cell lymphomas, including HTLV-I-associated ATL.
Waldmann
T A
TA
Metabolism Branch, National Cancer Institute, Bethesda, Maryland.
D036002:ADP Ribose Transferases; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D000918:Antibody Specificity; D000920:Antibody-Dependent Cell Cytotoxicity; D001427:Bacterial Toxins; D001729:Bismuth / Q000008:administration & dosage / Q000627:therapeutic use; D005098:Exotoxins / Q000008:administration & dosage / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D015490:HTLV-I Infections / Q000235:genetics; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000209:etiology; D000922:Immunotoxins / Q000627:therapeutic use; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015202:Protein Engineering; D011868:Radioisotopes / Q000008:administration & dosage / Q000627:therapeutic use; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D037521:Virulence Factors; D015021:Yttrium Radioisotopes / Q000008:administration & dosage / Q000627:therapeutic use; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D001427:Bacterial Toxins; D001729:Bismuth; D005098:Exotoxins; D000922:Immunotoxins; D009363:Neoplasm Proteins; D011868:Radioisotopes; D015375:Receptors, Interleukin-2; D037521:Virulence Factors; D015021:Yttrium Radioisotopes; D000097668:Pseudomonas aeruginosa Exotoxin A