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Phase I Evaluation of Humanized OKT3

Toxicity and Immunomodulatory Effects of hOKT3₄

The Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60637 [J. A., D. P., A. K., J. A. B.]; The Division of Hematology/Oncology, Lutheran General Hospital, Park Ridge, Illinois 60068 [J. R., D. G., J. M.]; and R.W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey 08869 [T. H., R. Z., L. J.]

Murine anti-CD3 (OKT3, Muromonab-CD3) is a potent human T-lymphocyte mitogen. A previous clinical Phase I trial examined OKT3 as an immunomodulator for the treatment of cancer. However, the murine monoclonal antibody triggered a potent humoral response that neutralized the antibody activity during subsequent administration. Thus, a "humanized" form of OKT3 (hOKT3₄) was developed to minimize immunogenicity. The genetically engineered human anti-CD3 retained its binding activity and effectively activated T cells in vitro. Therefore, we evaluated the safety and activity of hOKT3₄ in a Phase I clinical trial. hOKT3₄ was administered as a 10-min i.v. infusion every 2 weeks for three injections (one course of therapy). Six dose levels ranging from 50 to 1600 µg/injection were evaluated. Headache and fever were common, transient toxicities but were not dose limiting. The dose-limiting toxicities were rigors and dyspnea at the 1600-µg dose level, which defined 800 µg as the maximally tolerated dose in this trial. A dose-dependent in vivo T-lymphocyte activation was produced by this treatment, and the most significant T-lymphocyte activation occurred in patients treated at the two highest dose levels (800 and 1600 µg). Persistent CD3 modulation occurred after administration of 1600 µg of hOKT3₄. Anti-idiotypic antibodies were detected in only 6 of 24 patients after multiple injections and were not associated with attenuation of T-lymphocyte activation. Malignant ascites resolved in three patients, one each with peritoneal mesothelioma, pancreatic adenocarcinoma, and ovarian adenocarcinoma. hOKT3₄ can induce T-lymphocyte activation in patients with cancer, and the immunogenicity of the "humanized" antibody is sufficiently reduced relative to its murine "parent" to permit immunostimulation by repetitive i.v. administration. The therapeutic potential of biweekly i.v. hOKT3₄ at a dose of 800 µg should be further evaluated.