Phase I evaluation of humanized OKT3: Toxicity and immunomodulatory effects of hOKT3 gamma(4)

Murine anti-CDS (OKT3, Muromonab-CD3) is a potent human T-lymphocyte mitoge n, A previous clinical Phase I trial examined OKT3 as an immunomodulator fo r the treatment of cancer. However, the murine monoclonal antibody triggere d a potent humoral response that neutralized the antibody activity during s ubsequent administration. Thus, a "humanized" form of OKT3 (hOKT3 gamma(4)) was developed to minimize immunogenicity, The genetically engineered human anti-CD3 retained its binding activity and effectively activated T cells i n vitro. Therefore, we evaluated the safety and activity of hOKT3 gamma(4) in a Phase I clinical trial. hOKT3 gamma(4), was administered as a 10-min i .v. infusion every 2 weeks for three injections (one course of therapy). Si x dose levels ranging from 50 to 1600 mu g/injection were evaluated. Headac he and fever were common, transient toxicities but were not dose Limiting. The dose-limiting toxicities were rigors and dyspnea at the 1600-mu g dose level, which defined 800 pg as the maximally tolerated dose in this trial. A dose-dependent in vivo T-lymphocyte activation was produced by this treat ment, and the most significant T-lymphocyte activation occurred in patients treated at the two highest dose levels (800 and 1600 mu g). Persistent CD3 modulation occurred after administration of 1600 mu g of hOKT3 gamma(4) An ti-idiotypic antibodies were detected in only 6 of 24 patients after multip le injections and were not associated with attenuation of T-lymphocyte acti vation. Malignant ascites resolved in three patients, one each with periton eal mesothelioma, pancreatic adenocarcinoma, and ovarian adenocarcinoma, hO KT3 gamma(4) can induce T-lymphocyte activation in patients with cancer, an d the immunogenicity of the "humanized" antibody is sufficiently reduced re lative to its murine "parent" to permit immunostimulation by repetitive i.v . administration. The therapeutic potential of biweekly i.v. hOKT3 gamma(4) at a dose of 800 mu g should be further evaluated.