Four women with metastatic breast cancer were treated with monoclonal antibody 260F9-recombinant ricin A chain, a ricin A chain immunoconjugate (IC) which targets a Mr 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 μg/kg daily and the two others were treated with 50 μg/kg daily. The trial was suspended after four patients had been treated because patients treated with a continuous infusion schedule with this IC had developed significant neurological toxicity at doses similar to those used in this study. The half-life of the IC showed a t1/2α of approximately 1.8 h, a t1/2β of approximately 8.3 h, and a peak concentration of about 200 ng/ml, at the lower dose level, and showed a t1/2α of approximately 2.5 h, t1/2β 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, manifested by a syndrome consisting of weight gain, edema, hypoalbuminemia, and dyspnea. Similar symptoms were observed in patients treated by continuous infusions of the IC. This clinical syndrome, seen at doses of IC which were insufficient to saturate antigen-expressing malignant tumor deposits in this trial, has been seen in other IC therapy trials and in clinical trials using the cytokine interleukin 2. To investigate a possible mechanism responsible for this toxicity, human monocytes were incubated with varying concentrations of IC. There was detectable binding of IC to human monocytes at IC concentrations which were achieved clinically 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 Fcγ 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 IC 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 IC 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 mechanism of IC binding to human cells expressing Fcγ receptors with the clinical manifestations of the capillary leak syndrome will await production and testing of F(ab#x2019;)2 ICs or highly purified whole antibody IC preparations which contain only monomers. Further investigations into the mechanisms by which IC binding to Fcγ 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.
|Original language||English (US)|
|Number of pages||6|
|State||Published - Jul 15 1989|
ASJC Scopus subject areas
- Cancer Research