Phase I Evaluation of an Anti-Breast Carcinoma Monoclonal Antibody 260F9- Recombinant Ricin A Chain Immunoconjugate1

Four women with metastatic breast cancer were treated with monoclo nal antibody 260K9-recombinant ricin A chain, a ricin A chain immuno conjugate (1C) which targets a M, 55,000 antigen expressed by human mammary carcinomas. Patients were treated by daily, 1-h i.v. injections for 6 to 8 consecutive days. Two patients were treated with 10 MR/kg daily and the two others were treated with 50 «ig/kg daily. The trial was suspended after four patients had been treated because patients treated with a continuous infusion schedule with this 1C had developed significant neurological toxicity at doses similar to those used in this study. The half-life of the 1C showed a t.,a of approximately 1.8 h, a t.,/3 of approximately 8.3 h, and a peak concentration of about 200 ng/ml, at the lower dose level, and showed a f.,or of approximately 2.5 h, t, p of about 10.4 h, and a peak concentration of 500 and 850 ng/ml for the two patients at the higher dose level. All four patients developed evidence of a human anticonjugate antibody response within 16 days of the onset of therapy. The treatment was associated with significant toxicity, mani fested by a syndrome consisting of weight gain, edema, hypoalbuminemia, and dyspnea. Similar symptoms were observed in patients treated by continuous infusions of the 1C. This clinical syndrome, seen at doses of 1C which were insufficient to saturate antigen-expressing malignant tumor deposits in this trial, has been seen in other 1C therapy trials and in clinical trials using the cytokine interleukin 2. To investigate a possible mechanism responsible for this toxicity, human monocytes were incu bated with varying concentrations of 1C. There was detectable binding of 1C to human monocytes at 1C concentrations which were achieved clini cally in this trial. Furthermore, the binding appeared to be abrogated by preincubation of the monocytes with pooled human immunoglobulin, thus suggesting that binding occurs via Fey receptor-mediated mechanisms. Binding was not affected if different linkers between recombinant ricin A chain and the antibody were used or if a different antibody moiety was used in the 1C preparation. Chemically linked dimers of MOPC-21 bound to human monocytes at least as well as the ICs; this binding was not abrogated by preincubation with pooled human immunoglobulin. Since the 1C preparations used in this clinical trial contained small percentages of dimers and/or multimers, the clinical toxicity syndromes which we observed may be related to this series of observations. A more complete understanding of the relationship of this previously unreported mecha nism of 1C binding to human cells expressing Fc*yreceptors with the clinical manifestations of the capillary leak syndrome will await produc tion and testing of Hal)').. ICs or highly purified whole antibody 1C preparations which contain only monomers. Further investigations into the mechanisms by which 1C binding to FCT receptor-bearing cells may lead to disruption of endothelial cell integrity may provide important clues to the pathogenesis of the capillary leak syndrome seen with a variety of biological therapies.