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Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 [R. P. J., T. A. W.], and Protein Design Labs, Palo Alto, California 94304 [N. F. L., N. M. A., W. P. S., C. Q.]
The Mr 55,000 interleukin 2 receptor peptide (Tac; CD25) is not expressed by normal resting T-cells but is markedly up-regulated in adult T-cell leukemia and other malignancies, as well as on T-cells activated in normal immune, autoimmune, allograft, and graft-versus-host settings. Anti-Tac is a mouse monoclonal antibody directed against the Tac peptide. Our prior attempts to use this antibody in humans for antitumor therapy and immune regulation have been limited by weak recruitment of effector functions and neutralization by antibodies to mouse immunoglobulins. To circumvent these difficulties, we prepared several chimeric "humanized" anti-Tac antibodies by genetic engineering, including one "hyperchimeric" antibody (anti-Tac-H) in which the molecule is human except for the small hypervariable segments of the complementarity-determining regions retained from the mouse antibody. These constructs maintain high affinities for antigen and abilities to block T-cell activation and demonstrate new capabilities to perform antibody-dependent cell-mediated cytotoxicity, absent in the mouse anti-Tac. Hence, humanized antibodies have been developed to a tumor-associated antigen and activated T-cell marker with significant features that offer new therapeutic possibilities for select neoplastic and immune disorders.
1 To whom requests for reprint should be addressed.
Received 8/17/89. Revised 11/16/89. Accepted 11/27/89.
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