Complete regression of human B-cell lymphoma xenografts in mice treated with recombinant anti-CD22 immunotoxin RFB4(dsFv)-PE38 at doses tolerated by cynomolgus monkeys
✍ Scribed by Robert J. Kreitman,; Qing-Cheng Wang,; David J.P. FitzGerald; Ira Pastan
- Book ID
- 101234065
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- French
- Weight
- 161 KB
- Volume
- 81
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
RFB4(dsFv)-PE38 is a recombinant immunotoxin in which the variable light domain (V L ) is disulfide bonded via cysteine residues to the variable heavy domain (V H ), which in turn is fused to PE38, a mutant form of Pseudomonas exotoxin A. RFB4 binds to CD22, which is a differentiation antigen expressed on the majority of B-cell leukemias and lymphomas. To examine the potential efficacy of RFB4(dsFv)-PE38 when administered at a dose schedule appropriate for phase I testing, mice bearing CA46 human CD22 ؉ Burkitt's lymphoma xenografts were treated on alternate days i.v. for 3 doses (QOD ؋3). Complete regressions were observed in 80% and 100% of mice treated with 200 and 275 g/kg QOD ؋3, respectively. The higher dose was 27% of the LD 50 and 34% of the LD 10 in mice. Because RFB4(dsFv)-PE38 is stable at 37°C, it could also be given by continuous infusion using pumps placed in the peritoneal cavity; complete regressions also resulted from this mode of administration. To study toxicology, a pilot toxicology study of RFB4(dsFv)-PE38 was undertaken in cynomolgus monkeys, which like humans but unlike mice have CD22, which binds RFB4. Doses of 100 and 500 g/kg i.v. QOD ؋3 were well tolerated, indicating that a dose that cured tumors in mice was tolerated by primates. Based on these preclinical results, RFB4(dsFv)-PE38 is being developed for the treatment of patients with CD22-positive leukemias and lymphomas.