Phase I evaluation of humanized OKT3: Toxicity and immunomodulatory effects of hOKT3γ4

Jon Richards, Julie Auger, Donna Peace, Danielle Gale, Judy Michel, Ann Koons, Tom Haverty, Robert Zivin, Linda Jolliffe, Jeffrey A. Bluestone

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

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 (hOKT3γ4) 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 hOKT3γ4 in a Phase I clinical trial. hOKT3γ4 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 hOKT3γ4. 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. hOKT3γ4 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. hOKT3γ4 at a dose of 800 μg should be further evaluated.

Original languageEnglish (US)
Pages (from-to)2096-2101
Number of pages6
JournalCancer Research
Volume59
Issue number9
StatePublished - May 1 1999

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Richards, J., Auger, J., Peace, D., Gale, D., Michel, J., Koons, A., Haverty, T., Zivin, R., Jolliffe, L., & Bluestone, J. A. (1999). Phase I evaluation of humanized OKT3: Toxicity and immunomodulatory effects of hOKT3γ4. Cancer Research, 59(9), 2096-2101.