We have prepared and characterized a humanized chimeric (""""""""hyperchimeric"""""""") antibody (""""""""anti-Tac-H) against the interleukin 2 receptor (""""""""Tac"""""""") in which only the small antigen binding domains are retained from the mouse; this antibody is more than 90% human in origin. This is the second hyperchimeric antibody to be produced against a human antigen and the first that was approved for clinical trial in this country. Tac is not expressed on normal resting T cells but is markedly up-regulated in adult T cell leukemia and other lymphoid and myeloid malignancies and with activation of cytotoxic T lymphocytes in allograft and graft-versus-host settings. Unlike the murine antibody, anti-Tac-H performs ADCC with human effectors against human targets. Anti-Tac-H has prolonged in vivo survival and reduced immunogenicity in humans relative to the murine antibody, and has shown increased effectiveness in suppressing allograft rejection in primates and in graft-versus-host responses in phase I human studies. Most studies of murine anti-Tac in malignancy were in adult T cell leukemia; the present pilot clinical trial seeks to extend this modality to a wider range of more common Tac-expressing disorders to which anti-IL2 receptor antibody may be fruitfully applied. For this study, we will employ a multidose therapeutic program in small numbers of patients with Hodgkin's disease, non-Hodgkin's lymphoma, acute myelogenous leukemia and chronic myelogenous leukemia. The proposal contains three principal aims: 1. To confirm and extend information on toxicity, pharmacokinetics, immunogenicity and pharmacodynamics developed in phase I studies; 2. To suggest those Tac-expressing malignancies that may be responsive to anti-Tac-H therapy; and 3. To investigate mechanisms of response or non-response under this treatment. This therapeutic application in leukemias and lymphomas is the culmination of five years of development and preclinical testing of an agent whose conception and design contained many original features. The trial of anti-Tac-H in therapy in man will be a major test of the validity of these concepts, whose goal is to improve the therapeutic profile of monoclonal antibodies in human malignant disease.
