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Phase I evaluation of humanized OKT3: toxicity and immunomodulatory effects of hOKT3gamma4
1The Division of Hematology/Oncology, Lutheran General Hospital, Park Ridge, Illinois 60068, USA.
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 (hOKT3gamma4) 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 hOKT3gamma4 in a Phase I clinical trial. hOKT3gamma4 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 microg/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-microg dose level, which defined 800 microg 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 microg). Persistent CD3 modulation occurred after administration of 1600 microg of hOKT3gamma4. 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. hOKT3gamma4 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. hOKT3gamma4 at a dose of 800 microg should be further evaluated.
Insights
A humanized anti-CD3 antibody (hOKT3gamma4) effectively activates T-lymphocytes in cancer patients. This humanized antibody shows reduced immunogenicity compared to its murine counterpart, permitting repeated administration and demonstrating therapeutic potential for cancer treatment.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Murine anti-CD3 (OKT3) is a T-lymphocyte mitogen but causes immune responses limiting its use.
- A humanized anti-CD3 antibody, hOKT3gamma4, was developed to reduce immunogenicity while retaining T-cell activation.
- Previous trials with OKT3 showed potential but were hampered by immune neutralization.
Purpose of the Study:
- To evaluate the safety and activity of the humanized anti-CD3 antibody, hOKT3gamma4, in a Phase I clinical trial.
- To determine the maximally tolerated dose (MTD) of hOKT3gamma4.
- To assess T-lymphocyte activation and immunogenicity of hOKT3gamma4 in cancer patients.
Main Methods:
- Phase I clinical trial administering hOKT3gamma4 via i.v. infusion every 2 weeks for three injections.
- Six dose levels (50 to 1600 microg/injection) were evaluated.
- Safety, T-lymphocyte activation, CD3 modulation, and anti-idiotypic antibody responses were monitored.
Main Results:
- Headache and fever were common transient toxicities; rigors and dyspnea at 1600 microg defined the MTD at 800 microg.
- Dose-dependent in vivo T-lymphocyte activation was observed, most pronounced at 800 and 1600 microg.
- Persistent CD3 modulation occurred at 1600 microg; anti-idiotypic antibodies were detected in a minority of patients without attenuating T-cell activation.
- Malignant ascites resolved in three patients with peritoneal mesothelioma, pancreatic, and ovarian adenocarcinomas.
Conclusions:
- hOKT3gamma4 can induce T-lymphocyte activation in cancer patients.
- The humanized antibody demonstrates reduced immunogenicity, allowing for repetitive i.v. administration.
- Biweekly i.v. administration of hOKT3gamma4 at 800 microg warrants further therapeutic evaluation.