Purpose:Recombinant immunotoxins (rITs) targeting CD22 are highly active in hairy cell leukemia, but less so in acute lymphoblastic leukemia (ALL). This study aims to understand the variable activity of a rIT against ALL towards improving responses in clinical application. Experimental Design:We determined in vitro activity of rITs by WST-8 assays and the time needed to kill ALL cell lines and patient-derived ALL blasts by flow cytometry. The findings were translated into two systemic ALL xenograft models. Differences in time needed to kill KOPN-8 cells for distinct rITs were addressed biochemically. Results:In vitro activity (IC50) of anti-CD22 rIT varied 210-fold from 0.02 to 4.6 ng/ml. Activity also varied greatly depending on the time ALL cells were exposed to immunotoxin from <30 min to >4 days. For KOPN-8, the difference in exposure time was related to intracellular rIT-processing. We showed in newly developed ALL xenograft models, where immunotoxins have a short half-life, that the needed exposure time in vitro predicted the responses in vivo. By replacing bolus dose with small doses at frequent intervals or with continuous infusion, responses were substantially improved. We confirmed exposure time variability on patient-derived ALL samples and showed a correlation between exposure time needed to reach maximal cytotoxicity in vitro and their clinical response. Conclusions:The exposure time needed for rITs targeting CD22 to kill ALL cells varies widely. Our results suggest that ALL patients would have a better response rate to anti-CD22 immunotoxins if treated by continuous infusion rather than by bolus injections.
- Received October 14, 2015.
- Revision received March 23, 2016.
- Accepted April 16, 2016.
- Copyright ©2016, American Association for Cancer Research.